EP1228044A2 - Pyrrolo imidazole derivatives and their use as medicaments - Google Patents

Pyrrolo imidazole derivatives and their use as medicaments

Info

Publication number
EP1228044A2
EP1228044A2 EP00981195A EP00981195A EP1228044A2 EP 1228044 A2 EP1228044 A2 EP 1228044A2 EP 00981195 A EP00981195 A EP 00981195A EP 00981195 A EP00981195 A EP 00981195A EP 1228044 A2 EP1228044 A2 EP 1228044A2
Authority
EP
European Patent Office
Prior art keywords
pyrrolo
imidazol
benzyloxy
tetrahydro
naphthalene
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00981195A
Other languages
German (de)
French (fr)
Inventor
Alexander Doemling
Barbara Beck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Morphochem AG
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
Publication of EP1228044A2 publication Critical patent/EP1228044A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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-pyrroloimidazole derivatives, pharmaceutical compositions containing them, their preparation and use, in particular as tumor and cancer-dissolving and very particularly as antibiotic, in particular antibacterial, pharmaceuticals.
  • 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, patient survival over a long period of time is very uncertain. Furthermore, the chemotherapeutic and operative 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. In view of the generally increasing development of resistance in microorganisms or bacteria, there may also be a need for new and equally or even more potent antibiotics.
  • the imidazole radical is an optionally substituted imidazole cycle which can also be present as a salt
  • X, Y, A and B are independently carbon or nitrogen atoms, preferably X, Y, A and B being carbon atoms,
  • the radicals 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 - Can represent cycloaralkynyl, aryl, alkoxy and / or an optionally substituted ring to which one or two further, optionally substituted rings can be fused, and / or at least two of the Z radicals can be part of an optionally substituted ring , to which one or two further, optionally substituted rings can be fused.
  • the Z radicals are preferably, independently of one another, a hydrogen atom, a halogen atom, a pseudohalogen, more preferably adds a hydrogen atom, fluorine, chlorine, bromine or iodine, most preferably a hydrogen atom.
  • R i is a substituent, preferably a group of formula C ⁇ C j -G- substituted alkyl, such as -GC ⁇ C, - alkyl aryl, in particular G-benzyl; -G-aryl; -G-Ci-C j alkyl; -G- cycloalkyl; -G-heterocycloalkyl; -GC j - ⁇ - alkyl heteroaryl where G is CH 2 , 0, N or S, preferably 0, or R x is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and wherein the radicals Z bound to N and Y are independent from each other are C 1 -C 6 alkyl radicals, such as methyl radicals, cycloalkyl radicals or H atoms, preferably H atoms.
  • alkyl may e.g. represent a C ⁇ _50 alkyl group, preferably a C ⁇ _ 12 alkyl group, preferably a C ⁇ _6 alkyl group; an alkyl group e.g. 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, for example substituted or unsubstituted phenyl, Benzyl, naphthyl, biphenyl or anthracene groups or aromatic heterocycles with 5 or 6 ring atoms;
  • Ar is e.g. in the terms “aralkyl”, “arkenyl”, “aralkynyl” etc. and “cycloaralkyl”, cycloaralkenyl “, cycloaralkynyl” etc. as defined by “aryl”;
  • alkenyl for example, a C2-io A l ken YLG ru e PP / preferably represent a C2-6 ⁇ alkenyl having the double bond (s) at any position, and be unsubstituted or may be substituted; for example one, ethenyl, propenyl, isopropenyl or butenyl group;
  • alkynyl for example, a C2-io lkinyloli A, preferably a C 2-6 alkynyl group, which the triple bond (s) at any desired location and may be un- substituted or substituted; for example one, ethynyl, propynyl, isopropynyl or butynyl group;
  • cycloalkyl can e.g. represent an optionally substituted 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 no multiple bond in the carbocycle;
  • cycloalkenyl can represent, for example, an optionally substituted carbocycle having 3 to 20 carbon atoms, preferably having 5 to 15 carbon atoms and more preferably having 5 or 6 carbon atoms, which has at least one double bond in the carbocycle;
  • cycloalkynyl can represent an optionally substituted carbocycle having 3 to 20 carbon atoms, preferably having 5 to 15 carbon atoms, and more preferably having 9 or 10 carbon atoms, which has at least one triple bond in the carbocycle;
  • alkoxy can e.g. be a group of the formula -O-alkyl, -O-alkenyl, -O-alkynyl, -0-cycloalkyl, -O-cycloalkenyl, -O-cycloalkynyl, -O-aryl,
  • heteroaroyl can be, for example, 5-6-membered heterocyclic aromatic heterocycles having 1, 2 or 3 heteroatoms, such as substituted (as defined below) pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole , Thiazole, 1, 2, 4-triazole, 1, 2, 4-oxadiazole, 1,2,4-thiadiazole, 1, 2, 5-oxadiazole, 1, 2, 5-thiadiazole, tetrazole, pyridine, pyrylium , Thiapyrylium, pyridazine, pyrimidine, pyrazine, 1, 2, 3-triazine, 1, 2, 4-triazine, 1, 3, 5-triazine, 1,2,3,4-tetrazine, 1, 2, 3, 5 -Tetrazine, 1, 2, 4, 5-tetrazine, indole, coumarone, thionaphth
  • substituted or substituent can be defined as follows: -H, -OH, -R a , -O-alkyl, -O-aryl,
  • R a , R b , Rc and d Rd independently of one another, as defined above, can be alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhalogenoalkyl and or a link in a chain accordingly Alkylene, alkenylene, alkynylene, aroylene, heteroaroylene, heterocycle, aralkylene, aralkenylene or perhaloalkylene; R a , Rb, Rc and Rd may themselves be substituted, for example with alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhalogenoalkyl, the substituents of R a , R b , Rc and R d, however, are preferably unsubstituted; in the above formulas it is clear from the following
  • ring can represent an aromatic ring, a cycloalkyl, cycloalkenyl, cycloalkynyl or heterocyclic ring.
  • heterocyclic ring can e.g. B. represent a cycloalkyl, cycloalkenyl, cycloalkynyl or aromatic ring which, in addition to carbon atoms, contains 1, 2, 3 or 4 N, S or O atoms, 5- or 6-membered rings being preferred, the 1st or contain 2 N atoms.
  • the imidazole cycle can be, for example, unsubstituted or have, for example, 1, 2, 3 or 4, preferably 1, 2 or 3, substituents which are selected from halogen atoms, pseudohalogenes, substituted or unsubstituted alkyl, alkenyl, Alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl, alkoxy radicals and non-aromatic or aromatic or partially aromatic heterocyclic radicals which may be unsubstituted or substituted by one or more substituents which are selected from -OH, -R a , -O-alkyl, -O-aryl, -0- heteroaroyl, a -0-heterocycle , -NH 2 , -N0 2 ,
  • R a , Rb, Rc and Rd are independently defined as substituents alkyl, alkenyl, alkynyl, aroyl, Heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhaloalkyl or can be a link in the chain corresponding to alkylene, alkenylene, alkynylene, aroylene, heteroaroylene, heterocycles, aralkylene, aralkenylene or perhaloalkylene; R a , Rb, Rc and Rd themselves can be substituted, for example with alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocy- clus, aralkyl, aralkenyl or perhalo
  • the imidazole ring is preferably bound via its ring atom 5 to the atom X in formula I.
  • the imidazole ring particularly preferably has additional substituents in positions 1 and / or 4.
  • substituents on the imidazole cycle are cyclohexyl, indanyl, tetrahydronaphthyl, benzylpiperidinyl, benzyl, phenethyl, indolyl, methylindolyl, ethylindolyl, 5- (benzyloxy) -IH-pyrrolo [2, 3-cpyridinyl, fluorophenyl.
  • the imidazole ring at position 1 is particularly preferably substituted by cycloalkyls having preferably 5, 6 or 7 ring atoms to which aryls or heteroaryls having preferably 5 or 6 ring atoms are fused.
  • Particularly preferred heteroaryls are furan and thiophene.
  • the cycloalkyls, aryls and heteroaryls can have 1, 2, 3, 4 or 5 substituents such as, for example, halogen, -CF 3 , -OMe, -OH, -Me, preference being given to compounds which are unsubstituted or have a substituent.
  • the imidazole ring has, in addition or as an alternative to the substitution in position 1, a substituent in position 4.
  • This substituent is preferably substituted or unsubstituted alkyls, heteroaryls or aryls, with heteroaryls or aryls having 5 or 6 ring atoms being preferred.
  • the 3-pyrroloimidazole derivatives can also have the following general formula:
  • 3-pyrroloimidazole derivatives can have the following general formula:
  • the 3-pyrroloimidazole derivatives can particularly preferably have the following general formula:
  • the Z radicals are as defined above and the R radicals independently of one another are a hydrogen atom, a halogen atom, a pseudohalogen or an optionally substituted one
  • the radicals R are preferably independently of one another a hydrogen atom, a halogen atom, a pseudohalogen, more preferably a hydrogen atom, fluorine, chlorine, bromine or iodine, most preferably a hydrogen atom.
  • compositions according to the invention which contain at least one of the above compounds, if appropriate in combination with conventional carriers and / or adjuvants and / or auxiliaries.
  • the compounds according to the invention are highly effective, in particular in cancer and tumor prophylaxis and therapy. This effect allows the use of the active substances and pharmaceutical compositions according to the invention as chemotherapeutic agents in human and veterinary medicine.
  • chemotherapy drugs is a collective term for
  • antibiotic activity of the compounds or active substances according to the invention and the pharmaceutical compositions containing them is particularly pronounced. It is clear that the term "antibiotic” is to be understood in the broadest sense and e.g. antibacterial and antifungal or antifungicidal activity (also against yeast).
  • Systemic application means, for example, intravenous, intrapleural, intraperitoneal, rectal, oral application or the irrigation of body cavities and the bladder.
  • Local application means, for example, subcutaneous, intracutaneous, intratumoral, peritumoral application, for example in the form of injection solutions, injection suspensions, 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 and a particularly pronounced antibiotic effect in the case of systemic and local application.
  • the dose of the active compounds according to the invention is in the order of 0.1 to 100 mg / kg body weight per day, preferably 2 to 40 mg / kg body weight. In individual cases, the dosage can be higher or lower than indicated 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, gels, creams, soluble powders, lotions, emulsions, sprays, powders, suspensions, suppositories and injection solutions.
  • a formulation such as plasters, ointments, pastes, gels, creams, soluble powders, lotions, emulsions, sprays, powders, suspensions, suppositories and injection solutions.
  • the active compounds according to the invention can be formulated, for example, into injection solutions by dissolving them in dilute, physiologically compatible bases, given with the aid of solubilizers, and converting them into an injectable form of pH 6 to 8, in particular 6.9 to 7.5, by adding physiologically compatible acids.
  • physiologically compatible bases can be hydroxides, hydrogen carbonates, carbonates of the alkali and alkaline earth metals, in particular of potassium, sodium and calcium.
  • physiologically acceptable acids can be 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.
  • auxiliaries can be added to the formulation of the active compounds according to the invention - which can be used individually or in groups.
  • Such non-toxic and pharmaceutically suitable auxiliaries can be, for example, solid, semi-solid or liquid carriers, emulsifiers or dispersants, preservatives, antioxidants, UV absorbers.
  • the concentration of the active compounds according to the invention is between 1 and 90% by weight, preferably 5 to 50 Ge. %.
  • the dosage units of the active compounds according to the invention can consist, for example, of 1, 2, 3 or 4 individual 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.
  • creams, pastes, ointments and gels can contain customary excipients known to the person skilled in the art, for example waxes, paraffins, starches, vegetable and animal fats, cellulose derivatives, tragacanth, silica, talc ku, zinc oxide, bentonites, silicones, polyethylene glycols.
  • sprays and powders can contain customary excipients known to those skilled in the art, such as milk sugar, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder or mixtures thereof.
  • Sprays can also contain propellants, such as chlorofluorocarbons.
  • suppositories can contain customary excipients known to those skilled in the art, such as polyethylene glycols, fats or mixtures thereof.
  • the present invention also relates to antibody 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 the interior of the tumor.
  • These antibody conjugates can be packaged in liposomes.
  • Local application of the active substances according to the invention can be carried out by micromachines.
  • 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 tolerance.
  • combinations with other active ingredients serving the patient can be administered simultaneously or with a time delay.
  • the present invention also encompasses the use of the active ingredients described 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:
  • the compounds according to the invention are prepared in a conventional manner, e.g. according to van Leussen et al., J. Org. Chem., 42, 1977, 1153-1159.
  • Strep. pneumoniae c 100 ⁇ M 100% inhibition
  • Candida albicans c 100 ⁇ M 0% inhibition
  • Cytotoxicity L50 A549> 100 ⁇ M HepG2> 100 ⁇ M
  • Assay 1 Measurement of cell growth by determining the activity of the intracellular enzyme acid phosphatase. The added substrate p-nitrophenyl phosphate is converted by acid phosphatase into p-nitrophenol, which absorbs light at 405 nm. The intensity of the yellowing is proportional to the number of cells.
  • the HEPG-2 and A549 cell lines were incubated with the substance (0.1-100 ⁇ M)
  • Assay 2 Measurement of the cytotoxicity by quantitative determination of the enzyme lactate dehydrogenase (LDH), a stable cytosolic enzyme that is released into the medium during cell lysis. Released LDH is measured by a coupled enzyme assay, in which a tetrazolium salt is converted into a red formazan product, which can be detected at 490 nm. The amount of color generated is proportional to the number of lysed cells.
  • LDH lactate dehydrogenase
  • the HEPG2 and A549 cell lines were incubated with the substance (0.1-100 ⁇ M) for 24 h at 37 ° C. and 5% CO 2 . Inhibition test:
  • Test method microdilution assay
  • the test germs are grown overnight in Müller-Honton broth at 35 ° C +/- 2 ° C.
  • the germ suspension is centrifuged off (5000 rpm, 4 ° C.), the pellet is resuspended in fresh medium and incubated for a further 2 hours.
  • the pellet is then resuspended in 0.9% NaCl solution and the cell number is adjusted to approximately 10 8 CFU / ml using the standard curves.
  • a bacterial count is determined from the inoculum by spiraling (2 x 0.1 ml) a suitable dilution step on CASO agar plates.
  • Test execution The potential inhibitors are dispensed in a concentration in a microtiter assay plate with 96 wells, the wells Al-HI remaining empty.
  • the wells of the microtiter assay plates are inoculated with the set germ suspension.
  • the Al-Hl wells serve as growth controls.
  • the plates are measured in a plate reader (Biotek EL 311) at 550 nm.
  • the inhibition of bacterial or fungal growth in percent is calculated from the raw data.
  • Strep. pneumoniae c 100 ⁇ M 80% inhibition
  • Candida albicans c 100 ⁇ M 60% inhibition
  • Strep. pneumoniae c 100 ⁇ M 90% inhibition
  • Candida albicans c 100 ⁇ M 70% inhibition
  • Strep. pneumoniae c 100 ⁇ M 90% inhibition
  • Candida albicans c 100 ⁇ M 0% inhibition
  • Strep. pneumoniae c 100 ⁇ M 0% inhibition
  • Candida albicans c 100 ⁇ M 0% inhibition
  • Strep. pneumoniae c 100 ⁇ M 0% inhibition
  • Candida albicans c 100 ⁇ M 0% inhibition
  • Cytotoxicity L50 A549> 100 ⁇ M HepG2> 100 ⁇ M
  • Strep. pneumoniae c 100 ⁇ M 85% inhibition
  • Candida albicans c 100 ⁇ M 0% inhibition
  • Bac. subtilis c 50 ⁇ M 80% inhibition
  • Candida albicans c 200 ⁇ M 90% inhibition

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to 3-pyrrolo imidazole derivatives of general formula (I), wherein: the imidazole radical is an optionally substituted imidazole cycle; X, Y, A and B, independent of one another, represent carbon atoms or nitrogen atoms; radicals Z, independent of one another, represent a hydrogen atom, a halogen atom, a pseudohalogen, an optionally substituted alkyl radical, alkenyl radical, alkynyl radical, aralkyl radical, aralkenyl radical, aralkynyl radical, cycloalkyl radical, cycloalkenyl radical, cycloalkynyl radical, cycloaralkyl radical, cycloaralkenyl radical, cycloaralkynyl radical, aryl radical, alkoxy radical or an optionally substituted ring, on which one or two additional optionally substituted rings can be anellated, and/or at least two of the radicals Z can be part of an optionally substituted ring, on which one or two additional optionally substituted rings can be anellated. The invention also relates to pharmaceutical compositions which contain at least one of the aforementioned compounds, optionally in conjunction with conventional supports and/or adjuvants and/or auxiliary agents.

Description

Pyrroloimidazol-Derivate und ihre Verwendung als Arzneimittel Pyrroloimidazole derivatives and their use as medicines
Die vorliegende Erfindung betrifft neue 3-Pyrroloimidazol- Derivate, sie enthaltende pharmazeutische Zusammensetzungen, ihre Herstellung und Verwendung, insbesondere als tumor- und krebsauflösende und ganz besonders als antibiotische, insbesondere antibakterielle, Arzneimittel.The present invention relates to new 3-pyrroloimidazole derivatives, pharmaceutical compositions containing them, their preparation and use, in particular as tumor and cancer-dissolving and very particularly as antibiotic, in particular antibacterial, pharmaceuticals.
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 ungewiß. Weiterhin ist die che- motherapeutische 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 großem Interesse. Auch das Bestehen eines Bedürf- nisses nach neuen und gleich oder sogar stärker wirksamen Antibiotika kann in Anbetracht der allgemein zunehmenden Resistenzbildung bei Mikroorganismen bzw. Bakterien vorausgesetzt werden.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, patient survival over a long period of time is very uncertain. Furthermore, the chemotherapeutic and operative 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. In view of the generally increasing development of resistance in microorganisms or bacteria, there may also be a need for new and equally or even more potent antibiotics.
Es war daher die Aufgabe der vorliegenden Erfindung, neueIt was therefore the object of the present invention to create new ones
Wirkstoffe bereitzustellen, die eine verbesserte bzw. komplementäre Wirkung bei der Prophylaxe bzw. Therapie von Krebs und Tumoren bzw. eine besonders starke antibiotische, inbesondere antibakterielle, Wirksamkeit bei der Prophylaxe bzw. Bekämpfung/Therapie von Infektionen durch Mikroorganismen aufweisen. Diese Aufgaben werden durch die Bereitstellung von 3-Pyrrolo- imidazol-Derivaten der allgemeinen Formel (I): z zTo provide active substances which have an improved or complementary effect in the prophylaxis or therapy of cancer and tumors or a particularly strong antibiotic, in particular antibacterial, activity in the prophylaxis or control / therapy of infections by microorganisms. These tasks are accomplished by the provision of 3-pyrrolo-imidazole derivatives of the general formula (I): zz
N -Y' N -Y '
Z "A B /X Imidazol (I) i Z gelöst, worinZ "A B / X imidazole (I) i Z dissolved, wherein
der Imidazolrest ein gegebenenfalls substituierter Imida- zolcyclus ist, der auch als Salz vorliegen kann,the imidazole radical is an optionally substituted imidazole cycle which can also be present as a salt,
X, Y, A und B unabhängig voneinander Kohlenstoff- oder Stickstoffatome sind, wobei vorzugsweise X, Y, A und B Kohlenstoffatome sind,X, Y, A and B are independently carbon or nitrogen atoms, preferably X, Y, A and B being carbon atoms,
die Reste Z unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, einen gegebenenfalls substituierten Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl-, Cy- cloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl-, Aryl-, Al- koxyrest und/oder einen gegebenenfalls substituierten Ring darstellen können, an den ein oder zwei weitere, gegebenenfalls substituierte Ringe anelliert sein können, und/oder mindestens zwei der Reste Z Teil eines gegebenenfalls substituierten Rings sein können, an den ein oder zwei weitere, gegebenenfalls substituierte Ringe anelliert sein können. Be- vorzugt sind die Reste Z unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, stärker bevor- zugt ein Wasserstoffatom, Fluor, Chlor, Brom oder Jod, am stärksten bevorzugt ein Wasserstoffatom.the radicals 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 - Can represent cycloaralkynyl, aryl, alkoxy and / or an optionally substituted ring to which one or two further, optionally substituted rings can be fused, and / or at least two of the Z radicals can be part of an optionally substituted ring , to which one or two further, optionally substituted rings can be fused. The Z radicals are preferably, independently of one another, a hydrogen atom, a halogen atom, a pseudohalogen, more preferably adds a hydrogen atom, fluorine, chlorine, bromine or iodine, most preferably a hydrogen atom.
Vorzugsweise weisen die Reste Z - A =B - Z zusammen die For- melThe radicals Z - A = B - Z preferably have the formula together
auf, wobei Ri ein Substituent ist, vorzugsweise eine Gruppe der Formel -G- substituiertes C^Cj-Alkyl, wie -G-C^C,- Alkyl- Aryl, insbesondere -G-Benzyl; -G-Aryl; -G-Ci-Cj-Alkyl; -G- Cycloalkyl; -G-Heterocycloalkyl; -G-Cj-^-Alkyl-Heteroaryl wobei G CH2, 0, N oder S, vorzugsweise 0 ist, oder Rx ist ein Aryl, Heteroaryl, Cycloalkyl, Heterocycloalkyl, Cycloalkenyl, und wobei die an N und Y gebundenen Reste Z unabhängig voneinander C1-C6 Alkylreste, wie Methylreste, Cycloalkylreste oder H-Atome, vorzugsweise H-Atome sind. , where R i is a substituent, preferably a group of formula C ^ C j -G- substituted alkyl, such as -GC ^ C, - alkyl aryl, in particular G-benzyl; -G-aryl; -G-Ci-C j alkyl; -G- cycloalkyl; -G-heterocycloalkyl; -GC j - ^ - alkyl heteroaryl where G is CH 2 , 0, N or S, preferably 0, or R x is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and wherein the radicals Z bound to N and Y are independent from each other are C 1 -C 6 alkyl radicals, such as methyl radicals, cycloalkyl radicals or H atoms, preferably H atoms.
In der gesamten Beschreibung und den Ansprüchen kann der Ausdruck "Alkyl" z.B. eine Cι_50-Alkylgruppe, bevorzugt eine Cι_ 12-Alkylgruppe, vorzugsweise eine Cι_6-Alkylgruppe darstellen; so kann eine Alkylgruppe z.B. eine Methyl-, Ethyl-, Pro- pyl-, Isopropyl- oder Butylgruppe sein;Throughout the description and claims, the term "alkyl" may e.g. represent a Cι_50 alkyl group, preferably a Cι_ 12 alkyl group, preferably a Cι_6 alkyl group; an alkyl group e.g. 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";
sind "Aromaten" oder "Aryle" bzw. entsprechende Reste z.B. substituierte oder gegebenenfalls unsubstituierte Phenyl-, Benzyl-, Naphthyl-, Biphenyl- oder Anthracengruppen oder aromatische Heterocyclen mit 5 oder 6 Ringatomen;are "aromatics" or "aryls" or corresponding radicals, for example substituted or unsubstituted phenyl, Benzyl, naphthyl, biphenyl or anthracene groups or aromatic heterocycles with 5 or 6 ring atoms;
ist der Ausdruck "Ar" z.B. in den Ausdrücken "Aralkyl", "Ara- kenyl", "Aralkinyl" etc. und "Cycloaralkyl" , Cycloaralkenyl", Cycloaralkinyl" etc. , wie "Aryl" definiert;the expression "Ar" is e.g. in the terms "aralkyl", "arkenyl", "aralkynyl" etc. and "cycloaralkyl", cycloaralkenyl ", cycloaralkynyl" etc. as defined by "aryl";
kann der Ausdruck "Alkenyl" z.B. eine C2-io-AlkenylgruPPe/ vorzugsweise eine C2-6~Alkenylgruppe darstellen, die die Dop- pelbindung(en) an beliebiger Stelle aufweist und unsubsti- tuiert oder substituiert sein kann; beispielsweise eine, Ethenyl-, Propenyl-, Isopropenyl- oder Butenylgruppe;the term "alkenyl", for example, a C2-io A l ken YLG ru e PP / preferably represent a C2-6 ~ alkenyl having the double bond (s) at any position, and be unsubstituted or may be substituted; for example one, ethenyl, propenyl, isopropenyl or butenyl group;
kann der Ausdruck "Alkinyl" z.B. eine C2-io-Alkinylgruppe, vorzugsweise eine C2-6-Alkinylgruppe darstellen, die die Dreifachbindung(en) an beliebiger Stelle aufweist und un- substituiert oder substituiert sein kann; beispielsweise eine, Ethinyl-, Propinyl-, Isopropinyl- oder Butinylgruppe;the expression "alkynyl", for example, a C2-io lkinylgruppe A, preferably a C 2-6 alkynyl group, which the triple bond (s) at any desired location and may be un- substituted or substituted; for example one, ethynyl, propynyl, isopropynyl or butynyl group;
kann der Ausdruck "Cycloalkyl" z.B. einen gegebenenfalls sustituierten 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 im Carbocyclus keine Mehrfachbindung aufweist;the term "cycloalkyl" can e.g. represent an optionally substituted 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 no multiple bond in the carbocycle;
kann der Ausdruck "Cycloalkenyl" z.B. einen gegebenenfalls sustituierten 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 im Carbocyclus mindestens eine Doppel- bindung aufweist; kann der Ausdruck "Cycloalkinyl" z.B. einen gegebenenfalls sustituierten Carbocyclus mit 3 bis 20 C-Atomen, vorzugsweise mit 5 bis 15 C-Atomen und stärker bevorzugt mit 9 oder 10 C- Atomen darstellen, der im Carbocyclus mindestens eine Dreifachbindung aufweist;The term "cycloalkenyl" can represent, for example, an optionally substituted carbocycle having 3 to 20 carbon atoms, preferably having 5 to 15 carbon atoms and more preferably having 5 or 6 carbon atoms, which has at least one double bond in the carbocycle; For example, the term "cycloalkynyl" can represent an optionally substituted carbocycle having 3 to 20 carbon atoms, preferably having 5 to 15 carbon atoms, and more preferably having 9 or 10 carbon atoms, which has at least one triple bond in the carbocycle;
kann der Ausdruck "Alkoxy" z.B. eine Gruppe der Formel -O-Al- kyl, -O-Alkenyl, -O-Alkinyl, -0-Cycloalkyl , -O-Cycloalkenyl , -O-Cycloalkinyl, -O-Aryl sein,the term "alkoxy" can e.g. be a group of the formula -O-alkyl, -O-alkenyl, -O-alkynyl, -0-cycloalkyl, -O-cycloalkenyl, -O-cycloalkynyl, -O-aryl,
kann der Ausdruck "Heteroaroyl" z.B. 5-6 gliedrige hetero- cyclische aromatische Heterocyclen mit 1, 2 oder 3 Hetero- atomen wie z.B. substituiertes (wie nachstehend definiert) Pyrrol, Furan, Thiophen, Pyrazol, Isoxazol, Isothiazol, Imi- dazol, Oxazol, Thiazol, 1 , 2 , 4-Triazol, 1 , 2 , 4-Oxadiazol, 1,2,4-Thiadiazol, 1 , 2 , 5-Oxadiazol, 1 , 2 , 5-Thiadiazol, Tetra- zol, Pyridin, Pyrylium, Thiapyrylium, Pyridazin, Pyrimidin, Pyrazin, 1 ,2 , 3-Triazin, 1 , 2 , 4-Triazin, 1 , 3 , 5-Triazin, 1,2,3,4-Tetrazin, 1 , 2 , 3, 5-Tetrazin, 1 , 2 , 4 , 5-Tetrazin, Indol, Cumaron, Thionaphthen, Carbazol, Bibenzofuran, Dibenzothio- phen, ltf-lndazol, Indoxazol, Benzo[d]isothiazol, Anthranil, Benzimidazol, Benzoxazol, Benzothiazol, Benzotriazol, Chi- nolin, Isochinolin, Benzopyrylium, Thiabenzopyrylium, Acri- din, Benzo[g]chinolin, Benzo[ g]isochinolin, Benzo[c jchinolin, Cinnolin, Phthalazin, Chinazolin, Chinoxalin, Phenazin, Ben- zo[g]cinnolin, Benzo[g]chinazolin, Benzo[g]chinoxalin, 1,5- Naphthyridin, 1 , 6-Naphthyridin, 1 , 7-Naphthyridin, 1,8-Naph- thyridin, 2 , 6-Naphthyridin, 2 , 7-Naphthyridin, 1 , 7-Phenanthro- lin, 1, 8-Phenanthrolin, 1 , 9-Phenanthrolin, 1 , 10-Phenanthrolin, Indolizin, 4H-Chinolizin, Carbolin, Ergolin, Purin, Pteridin, Alloxazin, Flavin, bedeuten;The term "heteroaroyl" can be, for example, 5-6-membered heterocyclic aromatic heterocycles having 1, 2 or 3 heteroatoms, such as substituted (as defined below) pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole , Thiazole, 1, 2, 4-triazole, 1, 2, 4-oxadiazole, 1,2,4-thiadiazole, 1, 2, 5-oxadiazole, 1, 2, 5-thiadiazole, tetrazole, pyridine, pyrylium , Thiapyrylium, pyridazine, pyrimidine, pyrazine, 1, 2, 3-triazine, 1, 2, 4-triazine, 1, 3, 5-triazine, 1,2,3,4-tetrazine, 1, 2, 3, 5 -Tetrazine, 1, 2, 4, 5-tetrazine, indole, coumarone, thionaphthene, carbazole, bibenzofuran, dibenzothiophene, ltf-indazole, indoxazole, benzo [d] isothiazole, anthranil, benzimidazole, benzoxazole, benzothiazole, benzotriazole, chi - noline, isoquinoline, benzopyrylium, thiabenzopyrylium, acridine, benzo [g] quinoline, benzo [g] isoquinoline, benzo [cquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, phenazine, benzo [g] cinnoline, benzo [ g] quinazoline, benzo [g] quinoxaline, 1,5-naphthyridine , 1, 6-naphthyridine, 1, 7-naphthyridine, 1,8-naphthyridine, 2, 6-naphthyridine, 2, 7-naphthyridine, 1, 7-phenantholine, 1, 8-phenanthroline, 1, 9 -Phenanthroline, 1, 10-phenanthroline, Indolizine, 4H-quinolizine, carboline, ergoline, purine, pteridine, alloxazine, flavin;
kann der Ausdruck "substituiert" oder Substituent wie folgt definiert sein: -H, -OH, -Ra, -O-Alkyl, -O- Aryl,the term "substituted" or substituent can be defined as follows: -H, -OH, -R a , -O-alkyl, -O-aryl,
-O-Heteroaroyl, -O-Heterocyclus , -NH2, -N02, -CN, -N3, -CNRaNRbRc, -NRaRb, NRaRbRc *, Fluor, Chlor, Brom, a-, b-, bis w- Aminosäureester, -NRaCORb, -NRaC0XRb (X = -0, -NR, -PO0,2,3,4R, ~SOθ,l,2,4,R, -NRaNRbRC ) , -CORa, -C00Ra, -OCOORa, -CONRaRb, -OCONRaRb, -NRcCONRaRb, -Ra-0-Rb,-O-heteroaroyl, -O-heterocycle, -NH 2 , -N0 2 , -CN, -N 3 , -CNR a NR b R c , -NR a R b , NR a R b R c * , fluorine, chlorine , Bromine, a-, b-, to w- amino acid esters, -NR a COR b , -NR a C0XRb (X = -0, -NR, -PO 0 , 2,3,4R, ~ SOθ, l, 2, 4, R, -NR a NRbR C ), -COR a , -C00R a , -OCOOR a , -CONR a Rb, -OCONR a Rb, -NR c CONR a Rb, -R a -0-Rb,
-Rc-NRaRb, -Ra-S-Rb, -Ra-SO-Rb, -Ra-S (0 ) 2~Rb, -ORa-0-Rb, -NRaRb-0-Rc, -S02Ra, -SOι,2,3,4Ra-0-Rb, -CORa-ORb, -COORa-0-Rb, -OCORa-0-Rb, -OCOORa-0-Rb, -NRbCORa-0-Rb, -C0NRaRb-0-Rc, -0C0NRaRb-0-Rc , -NRcCONRaRb~0-Rd, -NRaC0Rb-0-Rc, -ORa-S-Rb, -NRaRb-S-Rc, -SOi , 2 , 3 , 4Ra~S-Rb, -C0Ra-S-Rb, -OCORa-S-Rb, -OCORa-S-Rb, -NRaC0Rb-S-Rc , -C0NRaRb-S-Rc, -NRaCONRbR -S-Rd. -0Ra-NRbRc , -NRaRb-NRcRd, -SOι,2,3,4Rb-NRbRc, -C0Ra-NRbRC , -C00Ra-NRbRC , -0C0Ra-NRbRC , -0C00Ra-NRbRc ι -NRaCONRbRc~NRdRe, -NRaC00Rb-NRcRd -0C0NRaRb-NRcRd, -NRaCONRbRc~NHRd, -NRaC00Rb-NRcRdr-R c -NR a Rb, -R a -S-Rb, -R a -SO-Rb, -R a -S (0) 2 ~ Rb, -OR a -0-Rb, -NR a R b - 0-R c , -S02R a , -SOι, 2,3,4Ra-0-Rb, -COR a -ORb, -COOR a -0-Rb, -OCOR a -0-Rb, -OCOOR a -0- Rb, -NRbCOR a -0-Rb, -C0NR a Rb-0-R c , -0C0NR a Rb-0-R c , -NR c CONR a Rb ~ 0-Rd, -NR a C0Rb-0-R c , -OR a -S-Rb, -NR a Rb-SR c , -SOi, 2, 3, 4Ra ~ S-Rb, -C0R a -S-Rb, -OCOR a -S-Rb, -OCOR a - S-Rb, -NR a C0Rb-SR c , -C0NR a Rb-SR c , -NR a CONRbR -S-Rd. -0R a -NRbRc, -NR a Rb-NR c Rd, -SOι, 2 , 3,4Rb-NRbRc, -C0R a -NRbR C , -C00R a -NRbR C , -0C0R a -NRbR C , -0C00R a -NRbRc ι -NR a CONRbRc ~ NRdRe, -NR a C00Rb-NR c Rd -0C0NR a Rb-NR c Rd, -NR a CONRbRc ~ NHRd, -NR a C00Rb-NR c Rdr
-P00Ra0Rb, -NRcP00Ra0Rb, -S02NRaRb, -S0NRaNRbRc, -SNRaRbNRcRd, -NRaS02Rb, -NRaS0NRbRc, -NRaSNRbNRcRd, -NRaS02NRbRe , -NRaSONRbNRcRd , -NRaSNRbNRcNRdRe , wobei die Substituenten z.B. über eine Doppelbindung gebunden oder anelliert sein können,-P00R a 0Rb, -NR c P00R a 0Rb, -S0 2 NR a R b , -S0NR a NR b R c , -SNR a R b NR c R d , -NR a S0 2 R b , -NR a S0NR b R c , -NR a SNR b NR c R d , -NR a S0 2 NR b Re, -NR a SONR b NR c Rd, -NR a SNR b NR c NR d Re, with the substituents, for example, via a double bond bound or fused,
wobei Ra, Rb, Rc und Rd unabhängig voneinander wie oben definiert als Substituenten Alkyl, Alkenyl, Alkinyl, Aroyl, He- teroaroyl, ein Heterocyclus, Aralkyl, Aralkenyl oder Perhalo- genalkyl sein können und oder Glied einer Kette entsprechend Alkylen, Alkenylen, Alkinylen, Aroylen, Heteroaroylen, He- terocyclen, Aralkylen, Aralkenylen oder Perhalogenalkylen sein können; Ra, Rb, Rc und Rd selbst substituiert sein können, beispielsweise mit Alkyl, Alkenyl, Alkinyl, Aroyl, He- teroaroyl, einem Heterocyclus, Aralkyl, Aralkenyl oder Perha- logenalkyl, wobei die Substituenten von Ra, Rb, Rc und Rd jedoch vorzugsweise unsubstituiert sind; wobei sich in den obigen Formeln durch die Bindigkeit der Atome, an die Ra, Rb, Rc und R gebunden sind, eindeutig ergibt, wann Ra, Rb, Rc und Rd Substituenten oder Kettenglieder ist (z.B.: ist in -CORa- RbRc a Kettenglied, da Kohlenstoff maximal vierbindig ist);where R a , R b , Rc and d Rd, independently of one another, as defined above, can be alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhalogenoalkyl and or a link in a chain accordingly Alkylene, alkenylene, alkynylene, aroylene, heteroaroylene, heterocycle, aralkylene, aralkenylene or perhaloalkylene; R a , Rb, Rc and Rd may themselves be substituted, for example with alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhalogenoalkyl, the substituents of R a , R b , Rc and R d, however, are preferably unsubstituted; in the above formulas it is clear from the bond of the atoms to which R a , Rb, Rc and R are bound when R a , R b , Rc and d R d are substituents or chain links (e.g.: is in - COR a - RbRc a chain link, since carbon is a maximum of four bonds);
kann der Ausdruck "Ring" einen Aromaten, einen Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl oder heterocyclischen Ring dar- stellen.the term "ring" can represent an aromatic ring, a cycloalkyl, cycloalkenyl, cycloalkynyl or heterocyclic ring.
Der Ausdruck "heterocyclischer Ring" kann z. B. einen Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl- oder aromatischen Ring darstellen, der neben C-Atomen 1, 2, 3 oder 4 N, S oder O-Atome enthält, wobei 5- oder 6-gliedrige Ringe bevorzugt werden, die 1 oder 2 N-Atome enthalten.The term "heterocyclic ring" can e.g. B. represent a cycloalkyl, cycloalkenyl, cycloalkynyl or aromatic ring which, in addition to carbon atoms, contains 1, 2, 3 or 4 N, S or O atoms, 5- or 6-membered rings being preferred, the 1st or contain 2 N atoms.
Der Imidazolcyclus kann z.B. unsubstituiert sein oder z.B. 1, 2, 3 oder 4, vorzugsweise 1, 2, oder 3, Substituenten aufwei- sen, der/die ausgewählt sind unter Halogenatomen, Pseudoha- logenen, substituierten oder unsubstituierten Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aralkinyl-, Cycloalkyl- , Cycloalkenyl-, Cycloalkinyl-, Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl-, Aryl-, Alkoxyresten und nicht-aromatischen oder aromatischen oder teilaromatischen heterocyclischen Resten, die unsubstituiert oder mit einem oder mehreren Substituenten substituiert sein können, der/die ausgewählt ist/sind unter -OH, -Ra, -O-Alkyl, -O-Aryl, -0- Heteroaroyl, einem -0-Heterocyclus, -NH2, -N02, -CN, -N3, - CNRaNRbRc, -NRaRb, NRaRbRc +, Fluor, Chlor, Brom, a- , b-, bis w- Aminosäureester, -NRaC0Rb,The imidazole cycle can be, for example, unsubstituted or have, for example, 1, 2, 3 or 4, preferably 1, 2 or 3, substituents which are selected from halogen atoms, pseudohalogenes, substituted or unsubstituted alkyl, alkenyl, Alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl, alkoxy radicals and non-aromatic or aromatic or partially aromatic heterocyclic radicals which may be unsubstituted or substituted by one or more substituents which are selected from -OH, -R a , -O-alkyl, -O-aryl, -0- heteroaroyl, a -0-heterocycle , -NH 2 , -N0 2 , -CN, -N 3 , - CNR a NR b R c , -NR a R b , NR a R b R c + , fluorine, chlorine, bromine, a-, b-, to w- amino acid esters, -NR a C0R b ,
-NRaC0XRb (X = -0, -NR, -PO0,2,3,4R, -SO0 , 1 , 2 , 4 ,R, -NRaNRbR ) -C0Ra, -C00Ra, -0C00Ra, -C0NRaRb, -0C0NRaRb, -NRcC0NRaRb, -Ra-0-Rb, -Rc-NRaRb, -Ra-S-Rb, -Ra-S0-Rb, -Ra-S(0)2-Rb, -ORa-0-Rb, -NRaRb-0-Rc, -Sθ2Ra, -S0ι , 2 , 3 , 4 a~0- Rb, -C0Ra-0Rb, -C00Ra-0-Rb, -OCORa-0-Rb, -0C00Ra-0-Rb, -NRbCORa-0-Rb, -C0NRaRb-0-Rc, -0C0NRaRb~0-Rc , -NRcCONRaRb-0-Rd, -NRaC0Rb-0-Rc , -ORa-S-Rb, -NRaRb-S-Rc, -SOι,2,3,4Ra-S-Rb, -C0Ra-S-Rb, -OCORa-S-Rb, -0C0Ra-S-Rb, -NRaC0Rb-S-Rc, -C0NRaRb-S-Rc, -NRaCONRbRC-S-Rd, -0Ra-NRbRC , -NRaRb-NRcRd, -SOl,2,3/4R -NRbRc, -C0Ra-NRbRC/ -C00Ra-NRbRC , -0C0Ra-NRbR , -0C00Ra-NRbRc > -NRaCONRbRc-NRd , -NRaC00Rb-NRcRdΛ -0C0NRaRb-NRcRd, -NRaC0NRbR -NHRd, -NRaCOORb-NRcRd, -P00Ra0Rb, -NRcP00Ra0Rb, -S02NRaRb, -S0NRaNRbRc, -SNRaRbNRcRd, -NRaS02Rb, -NRaS0NRbRc, -NRaSNRbNRcRd,-NR a C0XRb (X = -0, -NR, -PO 0 , 2,3,4R, -SO 0 , 1, 2, 4, R, -NR a NRbR) -C0R a , -C00R a , -0C00R a , -C0NR a Rb, -0C0NR a Rb, -NR c C0NR a Rb, -R a -0-Rb, -R c -NR a Rb, -R a -S-Rb, -R a -S0-Rb , -R a -S (0) 2-Rb, -OR a -0-Rb, -NR a Rb-0-R c , -Sθ2R a , -S0ι, 2, 3, 4 a ~ 0- Rb, - C0R a -0Rb, -C00R a -0-Rb, -OCOR a -0-Rb, -0C00R a -0-Rb, -NRbCOR a -0-Rb, -C0NR a Rb-0-R c , -0C0NR a Rb ~ 0-R c , -NR c CONR a Rb-0-Rd, -NR a C0Rb-0-R c , -OR a -S-Rb, -NR a Rb-SR c , -SOι, 2,3 , 4Ra-S-Rb, -C0R a -S-Rb, -OCOR a -S-Rb, -0C0R a -S-Rb, -NR a C0Rb-SR c , -C0NR a Rb-SR c , -NR a CONRbR C -S-Rd, -0R a -NRbR C , -NR a Rb-NR c Rd, -SOl, 2,3 / 4R -NRbRc, -C0R a -NRbR C / -C00R a -NRbR C , -0C0R a -NRbR, -0C00R a -NRbRc> -NR a CONRbR c -NRd, -NR a C00Rb-NR c RdΛ -0C0NR a Rb-NR c Rd, -NR a C0NRbR -NHRd, -NR a COORb-NR c Rd , -P00R a 0Rb, -NR c P00R a 0Rb, -S0 2 NR a R b , -S0NR a NR b R c , -SNR a R b NR c R d , -NR a S0 2 R b , -NR a S0NR b R c , -NR a SNR b NR c R d ,
-NRaS02NRb, -NRaS0NRbNRc, -NRaSNRbNRcNRd, wobei Ra, Rb, Rc und Rd unabhängig voneinander wie oben definiert als Substituenten Alkyl, Alkenyl, Alkinyl, Aroyl, Heteroaroyl, ein Heterocyclus, Aralkyl, Aralkenyl oder Perhalogenalkyl sein können oder als Glied einer Kette entsprechend Alkylen, Alkenylen, Alkinylen, Aroylen, Heteroaroylen, Heterocyclen, Aralkylen, Aralkenylen oder Perhalogenalkylen sein können; Ra, Rb, Rc und Rd selbst substituiert sein können, beispielsweise mit Alkyl, Alkenyl, Alkinyl, Aroyl, Heteroaroyl, einem Heterocy- clus, Aralkyl, Aralkenyl oder Perhalogenalkyl, wobei die Substituenten von Ra, Rb, Rc und Rd jedoch vorzugsweise unsubstituiert sind, wobei die Substituenten z.B. über eine Doppelbindung gebunden oder anelliert sein können.-NR a S0 2 NR b , -NR a S0NR b NR c , -NR a SNR b NR c NR d , where R a , Rb, Rc and Rd are independently defined as substituents alkyl, alkenyl, alkynyl, aroyl, Heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhaloalkyl or can be a link in the chain corresponding to alkylene, alkenylene, alkynylene, aroylene, heteroaroylene, heterocycles, aralkylene, aralkenylene or perhaloalkylene; R a , Rb, Rc and Rd themselves can be substituted, for example with alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocy- clus, aralkyl, aralkenyl or perhaloalkyl, but the substituents of R a , Rb, R c and Rd are preferably unsubstituted, it being possible for the substituents to be bonded or fused, for example, via a double bond.
Vorzugsweise ist der Imidazolring über sein Ringatom 5 an das Atom X in Formel I gebunden. Besonders bevorzugt weist der Imidazolring zusätzliche Substituenten in den Positionen 1 und/oder 4 auf.The imidazole ring is preferably bound via its ring atom 5 to the atom X in formula I. The imidazole ring particularly preferably has additional substituents in positions 1 and / or 4.
Konkrete Beispiele für Substituenten am Imidazolcyclus sind Cyclohexyl, Indanyl, Tetrahydronaphthyl, Benzylpiperidinyl, Benzyl, Phenethyl, Indolyl, Methylindolyl, Ethylindolyl, 5- (Benzyloxy ) -lH-pyrrolo[ 2 , 3-c Jpyridinyl, Fluorophenyl.Specific examples of substituents on the imidazole cycle are cyclohexyl, indanyl, tetrahydronaphthyl, benzylpiperidinyl, benzyl, phenethyl, indolyl, methylindolyl, ethylindolyl, 5- (benzyloxy) -IH-pyrrolo [2, 3-cpyridinyl, fluorophenyl.
Weitere bevorzugte Substituenten können den Beispielen entnommen werden .Further preferred substituents can be found in the examples.
Besonders bevorzugt ist der Imidazolring an Position 1 durch Cycloalkyle mit vorzugsweise 5, 6 oder 7 Ringatomen substituiert, an die Aryle oder Heteroaryle mit vorzugsweise 5 oder 6 Ringatomen anelliert sind. Besonders bevorzugte Heteroaryle sind Furan und Thiophen. Die Cycloalkyle, Aryle und Heteroaryle können 1, 2, 3, 4 oder 5 Substituenten wie z.B. Haloge- ne, -CF3, -OMe, -OH, -Me aufweisen, wobei Verbindungen bevorzugt werden, die unsubstituiert sind oder einen Substituenten aufweisen.The imidazole ring at position 1 is particularly preferably substituted by cycloalkyls having preferably 5, 6 or 7 ring atoms to which aryls or heteroaryls having preferably 5 or 6 ring atoms are fused. Particularly preferred heteroaryls are furan and thiophene. The cycloalkyls, aryls and heteroaryls can have 1, 2, 3, 4 or 5 substituents such as, for example, halogen, -CF 3 , -OMe, -OH, -Me, preference being given to compounds which are unsubstituted or have a substituent.
Gemäß einer weiteren bevorzugten Ausführungsform weist der Imidazolring zusätzlich oder alternativ zur Substitution in Position 1 einen Substituenten in Postition 4 auf. Bei diesem Substituenten handelt es sich vorzugsweise um substituierte oder unsubstituierte Alkyle, Heteroaryle oder Aryle, wobei Heteroaryle oder Aryle mit 5 oder 6 Ringatomen be- vorzugt werden.According to a further preferred embodiment, the imidazole ring has, in addition or as an alternative to the substitution in position 1, a substituent in position 4. This substituent is preferably substituted or unsubstituted alkyls, heteroaryls or aryls, with heteroaryls or aryls having 5 or 6 ring atoms being preferred.
Ferner können die 3-Pyrroloimidazol-Derivate folgende allgemeine Formel aufweisen: The 3-pyrroloimidazole derivatives can also have the following general formula:
Imidazol imidazole
stärker bevorzugt können die 3-Pyrroloimidazol-Derivate folgende allgemeine Formel aufweisen: more preferably the 3-pyrroloimidazole derivatives can have the following general formula:
besonders bevorzugt können die 3-Pyrroloimidazol-Derivate folgende allgemeine Formel aufweisen: The 3-pyrroloimidazole derivatives can particularly preferably have the following general formula:
wobei die Reste Z wie vorstehend definiert sind und die Reste R unabhängig voneinander ein Wasserstoffatom, ein Halogen- atom, ein Pseudohalogen, ein gegebenenfalls substituierterwherein the Z radicals are as defined above and the R radicals independently of one another are a hydrogen atom, a halogen atom, a pseudohalogen or an optionally substituted one
Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl-, Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl-, Aryl-, Aryloxy-, Aralkyloxy-, Alkoxyrest , ein Substituent oder ein heterocyclischer Ring sind und/oder zwei oder mehr der Reste R z. B. einen weiteren Ring bilden können. Bevorzugt sind die Reste R unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, stärker bevorzugt ein Wasserstoffatom, Fluor, Chlor, Brom oder Jod, am stärksten bevorzugt ein Wasser- stoffatom.Alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl, aryloxy, aralkyloxy, alkoxy radical, a substituent or are a heterocyclic ring and / or two or more of the radicals R z. B. can form another ring. The radicals R are preferably independently of one another a hydrogen atom, a halogen atom, a pseudohalogen, more preferably a hydrogen atom, fluorine, chlorine, bromine or iodine, most preferably a hydrogen atom.
Gemäß einer bevorzugten Ausführungsform werden Verbindungen der Formel I ausgeschlossen, in denen X=Y=A=B=N sind. Z.B. können 2 oder 3 der Atome X, Y, A und B N-Atome sein; auch können z.B. 2 oder 3 der Atome X, Y, A und B C-Atome sein.According to a preferred embodiment, compounds of the formula I in which X = Y = A = B = N are excluded. For example, can be 2 or 3 of the atoms X, Y, A and B N atoms; also 2 or 3 of the atoms X, Y, A and B can be carbon atoms, for example.
Ferner werden erfindungsgemäß pharmazeutische Zusammenset- zungen offenbart, die mindestens eine der vorstehenden Verbindungen gegebenenfalls in Kombination mit an sich üblichen Trägern und/oder Adjuvantien und/oder Hilfsstoffen enthalten.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 and / or auxiliaries.
Die erfindungsgemäßen Verbindungen weisen eine hohe Wirksam- keit, insbesondere bei der Krebs- und Tumorprophylaxe und -therapie auf. Diese Wirkung erlaubt die Verwendung der erfindungsgemäßen Wirkstoffe und pharmazeutischen Zusammensetzungen als Chemotherapeutika in der Human- und Tiermedizin.The compounds according to the invention are highly effective, in particular in cancer and tumor prophylaxis and therapy. This effect allows the use of the active substances and pharmaceutical compositions according to the invention as chemotherapeutic agents in human and veterinary medicine.
Der Begriff "Chemotherapeutika" ist ein Sammelbegriff fürThe term "chemotherapy drugs" is a collective term for
Substanzen mit (weitgehend) selektiv schädigender Wirkung auf Tumorzellen und Krankheitserreger. Man spricht auch allgemein von Cytostatika bzw. Antibiotika.Substances with (largely) selectively damaging effects on tumor cells and pathogens. One also speaks generally of cytostatics or antibiotics.
Besonders ausgeprägt ist die antibiotische Wirksamkeit der erfindungsgemäßen Verbindungen bzw. Wirkstoffe und der diese enthaltenden pharmazeutischen Zusammensetzungen. Es ist klar, das der Begriff "antibiotisch" im breitesten Sinn zu verstehen ist und z.B. antibakterielle und antimykotische bzw. an- tifungizide Wirkung (auch gegen Hefen) umfaßt.The antibiotic activity of the compounds or active substances according to the invention and the pharmaceutical compositions containing them is particularly pronounced. It is clear that the term "antibiotic" is to be understood in the broadest sense and e.g. antibacterial and antifungal or antifungicidal activity (also against yeast).
Dabei können die erfindungsgemäßen Verbindungen oder pharmazeutischen Zusammensetzungen lokal oder systemisch eingesetzt werden. 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, peritumorale Applikation, z.B. in Form von Injektionslösungen, Injektionssuspensionen, Cremes, Lotionen, Gelen und Salben.The compounds or pharmaceutical compositions according to the invention can be used locally or systemically. Systemic application means, for example, intravenous, intrapleural, intraperitoneal, rectal, oral application or the irrigation of body cavities and the bladder. Local application means, for example, subcutaneous, intracutaneous, intratumoral, peritumoral application, for example in the form of injection solutions, injection suspensions, creams, lotions, gels and ointments.
Die Lebenszeit von Tumorzellen in vitro wird durch die erfindungsgemäßen Wirkstoffe gegenüber Kontrollen signifikant 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 Applikation eine dosisabhängige tumorauflösende und eine besonders ausgeprägte antibiotische Wirkung. Die Dosis der erfindungsgemäßen Wirkstoffe liegt bei therapeutischem Einsatz pro Tag 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 höher oder niedriger sein als oben angegeben.The active substances according to the invention have a dose-dependent tumor-dissolving and a particularly pronounced antibiotic effect in the case of systemic and local application. When used therapeutically, the dose of the active compounds according to the invention is in the order of 0.1 to 100 mg / kg body weight per day, preferably 2 to 40 mg / kg body weight. In individual cases, the dosage can be higher or lower than indicated above.
Die erfindungsgemäßen Wirkstoffe können in bekannter Weise - dem individuellen Krankheitsbild entsprechend - in einer Formulierung angewendet werden, wie Pflaster, Salben, Pasten, Gele, Cremes, lösliche Pulver, Lotionen, Emulsionen, Sprays, Puder, Suspensionen, Suppositorien 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, gels, creams, soluble powders, lotions, emulsions, sprays, powders, suspensions, suppositories and injection solutions.
Die erfindungsgemäßen Wirkstoffe können z.B. zu Injektionslösungen formuliert werden, indem sie, gegebenen alls unter Zuhilfenahme von Lösungsvermittlern, in verdünnten physiologisch verträglichen 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. Beispielhafte physiologisch verträgliche Basen können Hydroxide, Hydrogencarbonate, Carbonate der Alkali- und Erdalkalimetalle, insbesondere von Kalium, Natrium und Calcium, sein.The active compounds according to the invention can be formulated, for example, into injection solutions by dissolving them in dilute, physiologically compatible bases, given with the aid of solubilizers, and converting them into an injectable form of pH 6 to 8, in particular 6.9 to 7.5, by adding physiologically compatible acids. Exemplary physiologically compatible bases can be hydroxides, hydrogen carbonates, carbonates of the alkali and alkaline earth metals, in particular of potassium, sodium and calcium.
Beispielhafte physiologisch verträgliche Säuren können Milchsäure, Citronensäure, Weinsäure, Oxalsäure, Äpfelsäure, Essigsäure, Ameisensäure, Benzoesäure, Salicylsäure, Salzsäure, Schwefelsäure oder Phosphorsäure sein.Exemplary physiologically acceptable acids can be 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.
Der Formulierung der erfindungsgemäßen Wirkstoffe - die einzeln oder zu mehreren eingesetzt werden können - können Hilfsstoffe beigemischt werden. Solche nichttoxischen und pharmazeutisch geeigneten Hilfsstoffe können zum Beispiel feste, halbfeste oder flüssige Trägerstoffe, Emulgier- oder Dispergiermittel, Konservierungsmittel, Antioxidationsmittel, UV-Absorber sein. Die Konzentration der erfindungsgemäßen Wirkstoffe liegt zwischen 1 und 90 Gew.%, vorzugsweise 5 bis 50 Ge . % .Auxiliaries can be added to the formulation of the active compounds according to the invention - which can be used individually or in groups. Such non-toxic and pharmaceutically suitable auxiliaries can be, for example, solid, semi-solid or liquid carriers, emulsifiers or dispersants, preservatives, antioxidants, UV absorbers. The concentration of the active compounds according to the invention is between 1 and 90% by weight, preferably 5 to 50 Ge. %.
Die Dosierungseinheiten der erfindungsgemäßen Wirkstoffe können beispielsweise bestehen aus 1, 2, 3 oder 4 Einzeldosen 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.The dosage units of the active compounds according to the invention can consist, for example, of 1, 2, 3 or 4 individual 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.
Cremes, Pasten, Salben und Gele können neben dem oder den Wirkstoffen übliche, dem Fachmann bekannte Trägerstoffe, bei- spielsweise Wachse, Paraffine, Stärken, pflanzliche und tierische Fette, Cellulosederivate, Traganth, Kieselsäure, Tal- ku , Zinkoxid, Bentonite, Silicone, Polyäthylenglycole, enthalten.In addition to the active ingredient (s), creams, pastes, ointments and gels can contain customary excipients known to the person skilled in the art, for example waxes, paraffins, starches, vegetable and animal fats, cellulose derivatives, tragacanth, silica, talc ku, zinc oxide, bentonites, silicones, polyethylene glycols.
Sprays und Puder können neben dem oder den Wirkstoffen übliche, dem Fachmann bekannte Trägerstoffe, wie Milchzucker, Talkum, Kieselsäure, Aluminiumhydroxid, Calciumsilikat 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 those skilled in the art, such as milk sugar, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder or mixtures thereof. Sprays can also contain propellants, such as chlorofluorocarbons.
Suppositorien können neben dem oder den Wirkstoffen übliche, dem Fachmann bekannte Trägerstoffe, wie Polyäthylenglycole, Fette oder Gemische davon, enthalten.In addition to the active ingredient (s), suppositories can contain customary excipients known to those skilled in the art, such as polyethylene glycols, fats or mixtures thereof.
Ebenso Gegenstand der vorliegenden Erfindung sind Antikörper- konjugate 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 Liposomen verpackt sein.The present invention also relates to antibody 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 the interior of the tumor. These antibody conjugates can be packaged in liposomes.
Die lokale Applikation der erfindungsgemässen Wirkstoffe kann durch Mikromaschinen erfolgen.Local application of the active substances 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 Liposomen 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 tolerance.
Soweit für die Behandlung der Tumorerkrankung oder der Infektion 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.So far for the treatment of the tumor disease or infection or for the general well-being of the patient or his Relatives of benefit, combinations with other active ingredients 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 hindern oder stören.The present invention also encompasses the use of the active ingredients described 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, Ade- nome, Cyst-Adenome, Papillome, Adenokarzinome auch vom cirrhoesen Typ, Basalzell-Karzinome, Sarkome beispielsweise Fibrosarkom, Liposarkom, Lymphosarkom, Rhabdomyosarkom, Myxo- sarkom, Chondrosarkom, Retikulumzellsarkom, Morbus Hodgkin, embryonale Tumore beispielsweise Neuroblastom, Nephroblastom, Teratom, Adamintom, Retroblastom, Haemangiom, Chordom, Odon- tom, Craniopharyngom, Hamartome beispielsweise Lymphoangiom, Exostosen, Neurofibrantose, Melanome, Lymphome, Hepatoblasto- me, Mammakarzinome, Cervixkarzinom, Choriokarzinom, Adeno- acantom, Androblastom, Leiomyom, Arrhenoblastom, Sertoli- zelltumor, Theca- und Granulosazelltumor , Germinom und Semi- nom, Ovarial- und Vulvakarzinom, Harnblasen- und Prostatakarzinom, durch Schistosomiasis hervorgerufene Tumoren, Astrocytom, Ependymogliome, Glioblastome , Medulloblastom, Oligodendrogliom, Spongioblastom, Meningeom sowie Tumoren der Schwan 'sehen Scheidenzellen, Pinealom, Haemangioblastom, Osteoclastom, Ewings Tumor, multiples Myelom, Mxcosis fungoi- des, Burkitt-Tumor, Leukaemien, beispielsweise akute und chronische lymphatische Leukaemie, akute und chronische Gra- nulocytenleukaemie, akute und chronische Monocytenleukaemie sowie Stammzellenleukaemie, Basaliom, Fibrom, Myom sowie die bei einem chirurgischen Eingriff einer lokalen Injektion zu- gänglichen Metastasen sämtlicher Tumorformen.Benign and malignant tumors of a solid or cystic nature, adenomas, cyst adenomas, papillomas, adenocarcinomas, also of the cirrhosis type, basal cell carcinomas, sarcomas, for example fibrosarcoma, liposarcoma, lymphosarcoma, rhabdomyosarcoma, myxosarcoma, chondrosorbarcoma, chondrosorbarcoma , embryonic tumors, for example neuroblastoma, nephroblastoma, teratoma, adamintoma, retroblastoma, hemangioma, chordoma, odontoma, craniopharyngoma, hamartomas, for example lymphoangioma, exostoses, neurofibrantosis, melanoma, lymphoma, hepatoblastoma, breast cancer, cancer of the carcinoma, breast cancer, cancer 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, glendioboblomomomomei, opendymogomomiomas Swan's tumors see vaginal cells, Pinealom, H aemangioblastoma, osteoclastoma, Ewings tumor, multiple myeloma, mxcosis fungoids, Burkitt tumor, leukemia, for example acute and Chronic lymphocytic leukemia, acute and chronic granulocyte leukemia, acute and chronic monocyte leukemia as well as stem cell leukemia, basalioma, fibroma, fibroid as well as the metastases of all types of tumors that are accessible during a surgical intervention from a local injection.
Als konkrete Beispiele für erfindungsgemäße Pyrroloimidazol- Derivate seien erwähnt:The following may be mentioned as concrete examples of pyrroloimidazole derivatives according to the invention:
3- ( l-Cyclohexyl- lH-imidazol-5-yl ) - l-methyl- lH-indol3- (l-cyclohexyl-lH-imidazol-5-yl) - l-methyl-lH-indole
Molecular Weight =279.39 Molecular Formula =C18H21 N3Molecular Weight = 279.39 Molecular Formula = C18H21 N3
[M+H]+. Found ISP-TOF-MS: 279.3882 [M+H]+; 302.3782 [M+Na]+.[M + H] +. Found ISP-TOF-MS: 279.3882 [M + H] +; 302.3782 [M + Na] +.
5- (Benzyloxy) -3- ( l-cyclohexyl-lH-imidazol-5-yl ) -lH-pyr- rolo[2 , 3-c]pyridin5- (Benzyloxy) -3- (l-cyclohexyl-lH-imidazol-5-yl) -lH-pyrrolo [2, 3-c] pyridine
Molecular Weight =372.47 Molecular Formula =C23H24N4OMolecular Weight = 372.47 Molecular Formula = C23H24N4O
[M+H]+. Found ISP-TOF-MS: 373.4739 [M+H]+; 395.4639 [M+Na]+, - ( l-Cyc lohexyl- lH-imidazol-5-yl ) - lH-indol[M + H] +. Found ISP-TOF-MS: 373.4739 [M + H] +; 395.4639 [M + Na] +, - (l-Cyclohexyl-lH-imidazol-5-yl) - lH-indole
- N- N
NN
NN
Molecular Weight =265.36 Molecular Formula =C17H19N3Molecular Weight = 265.36 Molecular Formula = C17H19N3
[M+H]+. Found ISP-TOF-MS: 266.3610 [M+H]+; 288.3511 [M+Na]+.[M + H] +. Found ISP-TOF-MS: 266.3610 [M + H] +; 288.3511 [M + Na] +.
1 7 5-Benzyloxy-3-[5-methyl-3-(5,6-dichloro-1 ,2,3,4-tetrahydro-naphthalen-1 - yl)-3H-imidazol-4-yl]-1 /-/-pyrrolo[2,3-c]pyridine 1 7 5-Benzyloxy-3- [5-methyl-3- (5,6-dichloro-1, 2,3,4-tetrahydro-naphthalen-1 - yl) -3H-imidazol-4-yl] -1 / - / - pyrrolo [2,3-c] pyridines
5-Benzyloxy-3-[5-methyl-3-(6,8-dichloro-1 ,2,3,4-tetrahydro-naphthalen-1 - yl)-3/-/-imidazol-4-yl]-1H-pyrrolo[2,3-c]pyridine5-Benzyloxy-3- [5-methyl-3- (6,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3 / - / - imidazol-4-yl] -1H -pyrrolo [2,3-c] pyridines
19 5-Benzyloxy-3-[5-methyl-3-(7,8-dichloro-1 ,2,3,4-tetrahydro-naphthalen-1 - yl)-3/-/-imidazol-4-yl]-1/-/-pyrrolo[2,3-c]pyridine19 5-Benzyloxy-3- [5-methyl-3- (7,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -3 / - / - imidazol-4-yl] - 1 / - / - pyrrolo [2,3-c] pyridines
20 5-Benzyloxy-3-[5-isopropyl-3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H- imidazol-4-yl]-1H-pyrrolo[2,3-c]pyridine20 5-Benzyloxy-3- [5-isopropyl-3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1H-pyrrolo [2,3-c ] pyridine
5-Benzyloxy-3-[5-isopropyl-3-(5-chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 3H-imidazol-4-yl]-1 r7-pyrrolo[2,3-c]pyridine5-Benzyloxy-3- [5-isopropyl-3- (5-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1 r7-pyrrolo [2 , 3-c] pyridine
">-> 5-Benzyloxy-3-[5-isopropyl-3-(6-chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 3r7-imidazol-4-yl]-1 H-pyrrolo[2,3-c]pyridine"> -> 5-benzyloxy-3- [5-isopropyl-3- (6-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3r7-imidazol-4-yl] -1 H -pyrrolo [2,3-c] pyridines
23 5-Benzyloxy-3-[5-isopropyl-3-(7-chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 3/-/-imidazol-4-yl]-1 r7-pyrrolo[2,3-c]pyridine23 5-Benzyloxy-3- [5-isopropyl-3- (7-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3 / - / - imidazol-4-yl] -1 r7 -pyrrolo [2,3-c] pyridines
24 5-Benzyloxy-3-[5-isopropyl-3-(8-chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 3/-/-imidazol-4-yl]-1 H-pyrrolo[2,3-c]pyridine .-) 5-Benzyloxy-3-[5-isopropyl-3-(5,8-dichloro-1 ,2,3,4-tetrahydro-naphthalen-1 - yl)-3/-/-imidazol-4-yl]-1 /-/-pyrrolo[2,3-c]pyridine24 5-Benzyloxy-3- [5-isopropyl-3- (8-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3 / - / - imidazol-4-yl] -1 H -pyrrolo [2,3-c] pyridine .-) 5-benzyloxy-3- [5-isopropyl-3- (5,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) - 3 / - / - imidazol-4-yl] -1 / - / - pyrrolo [2,3-c] pyridines
5-Benzyloxy-3-[5-isopropyl-3-(5,7-dichloro-1 ,2,3,4-tetrahydro-naphthalen-1 - yl)-3ry-imidazol-4-yl]-1 H-pyrrolo[2,3-c3pyridine5-Benzyloxy-3- [5-isopropyl-3- (5,7-dichloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3ry-imidazol-4-yl] -1 H-pyrrolo [2,3-c3pyridine
27 5-Benzyloxy-3-[5-isopropyl-3-(6,8-dichloro-1 ,2,3,4-tetrahydro-naphthalen-1 - yl)-3H-imidazol-4-yl]-1 /-/-pyrrolo[2,3-c]pyridine27 5-Benzyloxy-3- [5-isopropyl-3- (6,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -3H-imidazol-4-yl] -1 / - / H -pyrrolo [2,3-c] pyridine
28 5-Benzyloxy-3-[5-isopropyl-3-(7,8-dichloro-1 ,2,3,4-tetrahydro-naphthalen-1 - yl)-3/- -imidazol-4-yl3-1 /-/-pyrrolo[2,3-c]pyridine28 5-benzyloxy-3- [5-isopropyl-3- (7,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -3 / - -imidazol-4-yl3-1 / - / - pyrrolo [2,3-c] pyridines
29 1 -[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridiπ-3-yl)-1 -(1 ,2,3, 4-tetrahydro- naphthaleπ-1 -yl)-1 H-imidazol-4-yl]-ethanol29 1 - [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridiπ-3-yl) -1 - (1, 2,3, 4-tetrahydronaphthalenπ-1-yl) -1 H-imidazol-4-yl] -ethanol
30 1 -[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(6-chloro-1 , 2,3,4- tetrahydro-naphthalen-1 -yl)-1 H-imidazol-4-yl]-ethanol30 1 - [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (6-chloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -1 H-imidazol-4-yl] ethanol
1 -[5-(5-Benzyloxy-1 r -pyrrolo[2,3-c]pyridin-3-yl)-1 -(7-chloro-1 ,2,3,4- tetrahydro-πaphthalen-1 -yl)-1 H-imidazol-4-yl]-ethanol1 - [5- (5-Benzyloxy-1 r -pyrrolo [2,3-c] pyridin-3-yl) -1 - (7-chloro-1, 2,3,4-tetrahydro-πaphthalene-1-yl ) -1 H-imidazol-4-yl] ethanol
1 -[5-(5-Benzyloxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(8-chloro-1 , 2,3,4- tetrahydro-naphthalen-1 -yl)-1 ry-imidazol-4-yl]-ethanol1 - [5- (5-Benzyloxy-1H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (8-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -1 ry-imidazol-4-yl] ethanol
33 1 -[5-(5-Benzyloxy-1 /7-pyrrolo[2,3-c]pyridin-3-yl)-1 -(5,8-dichloro-1 , 2,3,4- tetrahydro-naphthalen-1 -yl)-1 H-imidazol-4-yl]-ethanol33 1 - [5- (5-Benzyloxy-1/7-pyrrolo [2,3-c] pyridin-3-yl) -1 - (5,8-dichloro-1, 2,3,4-tetrahydro-naphthalene -1 -yl) -1 H-imidazol-4-yl] ethanol
34 1 -[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(5,7-dichloro-1 ,2,3,4- tetrahydro-naphthalen-1 -yl)-1 H-imidazol-4-yl]-ethanol34 1 - [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (5,7-dichloro-1, 2,3,4-tetrahydro-naphthalene- 1 -yl) -1 H-imidazol-4-yl] ethanol
35 1 -[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(7,8-dichloro-1 , 2,3,4- tetrahydro-πaphthalen-1 -yl)-1 H-imidazol-4-yl]-ethanol35 1 - [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (7,8-dichloro-1, 2,3,4-tetrahydro-naphthalene- 1 -yl) -1 H-imidazol-4-yl] ethanol
36 1 -[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(6,8-dichloro-1 ,2,3,4- tetrahydro-naphthalen-1 -yl)-1 /-/-imidazol-4-yl]-ethanol 7 1 -[5-(5-Benzyloxy-1 -/-pyrrolo[2,3-c]pyridin-3-yl)-1 -(5-chloro-1 , 2,3,4- tetrahydro-naphthalen-1 -yl)-1 -/-imidazol-4-yl]-ethanol36 1 - [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (6,8-dichloro-1, 2,3,4-tetrahydro-naphthalene- 1 -yl) -1 / - / - imidazol-4-yl] ethanol 7 1 - [5- (5-benzyloxy-1 - / - pyrrolo [2,3-c] pyridin-3-yl) -1 - (5-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -1 - / - imidazol-4-yl] ethanol
38 2-[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(1 ,2,3,4-tetrahydro- naphthalen-1 -yl)-1 /-/-imidazol-4-yl]-ethanol38 2- [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (1, 2,3,4-tetrahydronaphthalen-1-yl) -1 / - / - imidazol-4-yl] -ethanol
39 2-[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(5-chloro-1 , 2,3,4- tetrahydro-naphthalen-1 -yl)-1 ry-imidazol-4-yl]-ethanol39 2- [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (5-chloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -1 ry-imidazol-4-yl] ethanol
40 2-[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(6-chloro-1 , 2,3,4- tetrahydro-naphthalen-1 -yl)-1 H-imidazol-4-yl]-etharιol 2-[5-(5-Benzyloxy-1r -pyrrolo[2,3-c]pyridin-3-yl)-1 -(7-chloro-1 ,2,3,4- tetrahydro-naphthalen-1 -yl)-1H-imidazol-4-yl]-ethanol40 2- [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (6-chloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -1 H-imidazol-4-yl] etharol 2- [5- (5-Benzyloxy-1r-pyrrolo [2,3-c] pyridin-3-yl) -1 - (7-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -1H-imidazol-4-yl] -ethanol
2-[5-(5-Benzyloxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(8-chloro-1 , 2,3,4- tetrahydro-naphthalen-1 -yl)-1H-imidazol-4-yl]-ethanol2- [5- (5-Benzyloxy-1H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (8-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -1H-imidazol-4-yl] -ethanol
2-[5-(5-Benzyloxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(5I8-dichloro-1 ,2,3,4- tetrahydro-naphthalen-1 -yl)-1 - -imidazol-4-yl]-ethanol2- [5- (5-Benzyloxy-1H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (5 I 8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -1 - -imidazol-4-yl] ethanol
2-[5-(5-Benzyloxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(6,8-dichloro-1 ,2,3,4- tetrahydro-naphthalen-1 -yl)-1 H-imidazol-4-yl]-ethanol2- [5- (5-Benzyloxy-1H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (6,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 - yl) -1 H-imidazol-4-yl] ethanol
2-[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(7,8-dichloro-1 ,2,3,4- tetrahydro-naphthalen-1 -yl)-1H-imidazol-4-yl]-ethanol2- [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (7,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 -yl) -1H-imidazol-4-yl] -ethanol
2-[5-(5-Benzyloxy-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 -(5,7-dichloro-1 ,2,3,4- tetrahydro-naphthalen-1 -yl)-1 H-imidazol-4-yl]-ethanol2- [5- (5-Benzyloxy-1 H-pyrrolo [2,3-c] pyridin-3-yl) -1 - (5,7-dichloro-1, 2,3,4-tetrahydro-naphthalene-1 -yl) -1 H-imidazol-4-yl] ethanol
5-Benzyloxy-3-[3-(4,5,6,7-tetrahydro-benzo[ό]thiophen-4-yl)-3/-/-imidazol-4- yl]-1 /-/-pyrrolo[2,3-c]pyridine5-benzyloxy-3- [3- (4,5,6,7-tetrahydro-benzo [ό] thiophene-4-yl) -3 / - / - imidazol-4-yl] -1 / - / - pyrrolo [ 2,3-c] pyridines
5-Benzyloxy-3-[3-(4,5,6,7-tetrahydro-benzofuran-4-yl)-3/-/-imidazol-4-yl]-1H- pyrrolo[2,3-c]pyridine5-benzyloxy-3- [3- (4,5,6,7-tetrahydro-benzofuran-4-yl) -3 / - / - imidazol-4-yl] -1H-pyrrolo [2,3-c] pyridines
5-Benzyloxy-3-[3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-3H- imidazol-4-yl]-1/-/-pyrrolo[2,3-c]pyridine5-Benzyloxy-3- [3- (6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl) -3H-imidazol-4-yl] -1 / - / - pyrrolo [2,3-c ] pyridine
5-Benzyloxy-3-[3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-3H- imidazol-4-yl]-1ry-pyrrolo[2,3-c]pyridine5-Benzyloxy-3- [3- (6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) -3H-imidazol-4-yl] -1ry pyrrolo [2,3-c] pyridines
5-(4-Chloro-benzyloxy)-3-[3-(1 ,2,3,4-tetrahydro-naph imidazol-4-yl3-1 r -pyrrolo[2,3-c]pyridine5- (4-Chloro-benzyloxy) -3- [3- (1, 2,3,4-tetrahydro-naph imidazol-4-yl3-1 r -pyrrolo [2,3-c] pyridine
5-(2,4-Dichloro-benzyloxy)-3-[3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H- imidazol-4-yl]-1H-pyrrolo[2,3-c]pyridine5- (2,4-dichloro-benzyloxy) -3- [3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1H-pyrrolo [2, 3-c] pyridines
5-(3-Chloro-benzyloxy)-3-[3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H- imidazol-4-yl]-1/-7'-pyrrolo[2,3-c]pyridine5- (3-Chloro-benzyloxy) -3- [3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1 / -7'-pyrrolo [ 2,3-c] pyridines
5-(2-Chloro-benzyloxy)-3-[3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H- imidazol-4-yl]-1 H-pyrrolo[2,3-c]pyridine5- (2-Chloro-benzyloxy) -3- [3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1 H-pyrrolo [2,3 c] pyridine
5-(2,3-Chloro-benzyloxy)-3-[3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H- imidazol-4-yl3-1 /-y-pyrrolo[2,3-c]pyridine5- (2,3-chloro-benzyloxy) -3- [3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl3-1 / -y-pyrrolo [ 2,3-c] pyridines
5-(2,5-Chloro-benzyloxy)-3-[3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H- imidazol-4-yl]-1 /- -pyrrolo[2,3-c]pyridine5- (2,5-chlorobenzyloxy) -3- [3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1 / - -pyrrolo [ 2,3-c] pyridines
5-(2,6-Chloro-benzyloxy)-3-[3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3/- - imidazol-4-yl]-1 H-pyrrolo[2,3-c]pyridine5- (2,6-Chloro-benzyloxy) -3- [3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3 / - - imidazol-4-yl] -1 H-pyrrolo [2,3-c] pyridines
5-(4-Chloro-benzyloxy)-3-[3-(5-chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 3H-imidazol-4-yl]-1/-/-pyrrolo[2,3-c]pyridine5- (4-chloro-benzyloxy) -3- [3- (5-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1 / - / -pyrrolo [2,3-c] pyridines
3-[3-(5-Chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H-imidazol-4-yl]-5-(2,4- dichloro-benzyloxy)-1r -pyrrolo[2,3-c]pyridine3- [3- (5-chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -5- (2,4-dichloro-benzyloxy) -1r - pyrrolo [2,3-c] pyridines
5-(2,4-Dichloro-benzyloxy)-3-[3-(5,8-dichloro-1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)-3/-/-imidazol-4-yl]-1/-/-pyrrolo[2,3-c]py dine5- (2,4-dichloro-benzyloxy) -3- [3- (5,8-dichloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3 / - / - imidazole-4- yl] -1 / - / - pyrrolo [2,3-c] py dine
3-[3-(8-Chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H-imidazol-4-yl]-5-(2,4- dichloro-benzyloxy)-1/-/-pyrrolo[2,3-c]pyridine3- [3- (8-Chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -5- (2,4-dichloro-benzyloxy) -1 / - / - pyrrolo [2,3-c] pyridines
5-Benzyloxy-3-[3-(8-chloro-5-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 3rτ'-imidazol-4-yl]-1 r -pyrrolo[2,3-c]pyridine5-benzyloxy-3- [3- (8-chloro-5-methoxy-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3rτ'-imidazol-4-yl] -1 r -pyrrolo [ 2,3-c] pyridines
5-Benzyloxy-3-[3-(5-chloro-8-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 3/-/-imidazol-4-yl3-1H-pyrrolo[2,3-c]pyridine5-benzyloxy-3- [3- (5-chloro-8-methoxy-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3 / - / - imidazol-4-yl3-1H-pyrrolo [ 2,3-c] pyridines
8-[5-(5-Benzyloxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-imidazol-1 -yl]-4-chloro- 5,6,7,8-tetrahydro-naphthalen-1-ol 65 3-[3-(5-Chloro-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H-imidazol-4-yl]-1H- pyrrolo[2,3-c]pyridin-5-ol8- [5- (5-Benzyloxy-1H-pyrrolo [2,3-c] pyridin-3-yl) imidazol-1-yl] -4-chloro-5,6,7,8-tetrahydro-naphthalene- 1-ol 65 3- [3- (5-Chloro-1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1H-pyrrolo [2,3-c] pyridine-5 -oil
66 5-Benzyloxy-3-[5-cyclopropyl-3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3H- imidazol-4-yl]-1H-pyrrolo[2,3-c]pyridine66 5-Benzyloxy-3- [5-cyclopropyl-3- (1, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -1H-pyrrolo [2,3-c ] pyridine
67 5-Benzyloxy-3-[5-cyclopropyl-3-(5-morpholin-4-yl-1 ,2,3,4-tetrahydro- naphthalen-1 -yl)-3/- -imidazol-4-yl]-1 /-/-pyrrolo[2,3-c]pyridine67 5-benzyloxy-3- [5-cyclopropyl-3- (5-morpholin-4-yl-1, 2,3,4-tetrahydronaphthalen-1-yl) -3 / - -imidazol-4-yl] -1 / - / - pyrrolo [2,3-c] pyridines
68 3-[5-Cyclopropyl-3-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-3/-/-imidazol-4-yl]-5- methoxy-1 H-pyrrolo[2,3-c]pyridine68 3- [5-Cyclopropyl-3- (1, 2,3,4-tetrahydro-naphthalen-1-yl) -3 / - / - imidazol-4-yl] -5-methoxy-1 H-pyrrolo [2 , 3-c] pyridine
Die Herstellung der erfindungsgemäßen Verbindungen erfolgt in an sich üblicher Weise, z.B. gemäß van Leussen et al., J. Org. Chem., 42, 1977, 1153-1159.The compounds according to the invention are prepared in a conventional manner, e.g. according to van Leussen et al., J. Org. Chem., 42, 1977, 1153-1159.
Nachstehend wird beispielhaft eine allgemeine Arbeitsvorschrift zur Darstellung von 1 , 5-disubstituierten Imidazolde- rivaten (Beispiele 1-2) beschrieben:A general working procedure for the preparation of 1,5-disubstituted imidazole derivatives (Examples 1-2) is described below by way of example:
6 mmol Amin und 6 mmol Aldehyd werden in 3 ml Dichlormethan zur Schiffbase über Nacht vorkondensiert, das Dichlormethan wird abgezogen und der Rückstand mit 3 ml Methanol versetzt. Zu dieser Suspension gibt man 6 mmol festes TOSMIC und 1 Äquivalent Base hinzu und kocht unter Rückfluß bei 80 °C vier Stunden. Das Lösungsmittel wird abgezogen und das Rohprodukt mittels präparativer HPLC gereinigt. 6 mmol of amine and 6 mmol of aldehyde are precondensed in 3 ml of dichloromethane to give the ship base overnight, the dichloromethane is stripped off and 3 ml of methanol are added to the residue. 6 mmol of solid TOSMIC and 1 equivalent of base are added to this suspension and the mixture is boiled under reflux at 80 ° C. for four hours. The solvent is removed and the crude product is purified by preparative HPLC.
Beispiel 1 :Example 1 :
5- ( Benzyloxy ) -3- ( l-tetrahydronaphtalin-lH-imidazol-5-yl ) -1H- pyrrol [ 2 , 3-c ]pyridin5- (Benzyloxy) -3- (l-tetrahydronaphthalene-1H-imidazol-5-yl) -1H-pyrrole [2, 3-c] pyridine
Molecular Weight =420.52Molecular Weight = 420.52
Exact Mass =420Exact Mass = 420
Molecular Formula =C27H24N40Molecular Formula = C27H24N40
Analytische Daten:Analytical data:
2H-NMR (CDC13, 400 MHz): δ = 1,26 (m, IH, ), 1,70 (m, IH, ); 1,86-2,08 (m, 4H, 2 CH2 ) ; 2,72-2,88 (m, IH, CH); 5,35 (s, 2H, 0-CH2); 6,91-7,46 (m, 13H, Imidazol, IH, Phenyl, 5H, Tetrahy- dronaphtyl, 4H, Pyrrolpyridin 2H); 8,43 (s, IH, Imidazol IH); 10,26 (d, IH, Pyrrolpyridin NH) 2 H NMR (CDC13, 400 MHz): δ = 1.26 (m, IH,), 1.70 (m, IH,); 1.86-2.08 (m, 4H, 2 CH2); 2.72-2.88 (m, IH, CH); 5.35 (s, 2H, 0-CH2); 6.91-7.46 (m, 13H, imidazole, IH, phenyl, 5H, tetrahydronaphtyl, 4H, pyrrole pyridine 2H); 8.43 (s, IH, imidazole IH); 10.26 (d, IH, pyrrole pyridine NH)
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser ; API-ES): 2,81 min. 421,1 C27H2lN40 = 420,52HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 2.81 min. 421.1 C 27 H 2l N 4 0 = 420.52
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums:Inhibition of bacterial growth:
Staph. aureus c=100μM 100% InhibitionStaph. aureus c = 100μM 100% inhibition
Bac. subtilis c=100μM 100% InhibitionBac. subtilis c = 100μM 100% inhibition
Strept. pneumoniae c=100μM 100% InhibitionStrep. pneumoniae c = 100μM 100% inhibition
Candida albicans c=100μM 0% InhibitionCandida albicans c = 100μM 0% inhibition
Cytotoxizität L50: A549 >100μM HepG2 >100μMCytotoxicity L50: A549> 100μM HepG2> 100μM
Zeilproliferation GI50: A549 >100μM 22% InhibitionLine proliferation GI50: A549> 100μM 22% inhibition
Beispiel 2:Example 2:
3-( 4-Benzylpiperidin-IH-imidazol-5-yl) -2-methyl-lH-indol3- (4-Benzylpiperidin-IH-imidazol-5-yl) -2-methyl-1H-indole
Molecular Formula =C24H26N4Molecular Formula = C24H26N4
Analytische Daten:Analytical data:
'H-NMR (CD30D, 400 MHz): δ = 1,97 (s, 3H, CH3); 2,31 (m, 8H, CH2); 3,72 (s, 2H, CH2); 6,99 - 7,54 (m, 11H, Indol, Imidazol, Phenyl)'H NMR (CD30D, 400 MHz): δ = 1.97 (s, 3H, CH 3 ); 2.31 (m, 8H, CH 2); 3.72 (s, 2H, CH 2); 6.99 - 7.54 (m, 11H, indole, imidazole, phenyl)
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 0,59 min. 371.2 C2,H26N4 = 370,50HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 0.59 min. 371.2 C 2 , H 26 N 4 = 370.50
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums:Inhibition of bacterial growth:
Staph. aureus c=100μM 100% Inhibition Bac. subtilis c=100μM 100% InhibitionStaph. aureus c = 100μM 100% inhibition Bac. subtilis c = 100μM 100% inhibition
Strept. pneumoniae c=100μM 90% Inhibition Candida albicans c=100μM 60% InhibitionStrep. pneumoniae c = 100μM 90% inhibition Candida albicans c = 100μM 60% inhibition
Cytotoxizität L50: A549 >100μMCytotoxicity L50: A549> 100μM
HepG2 >100μMHepG2> 100μM
Zellproliferation GI50: A549 >100μM 12% InhibitionCell proliferation GI50: A549> 100μM 12% inhibition
HepG2 >100μM 1% InhibitionHepG2> 100μM 1% inhibition
Wachstumshemmende, zytotoxische und antibiotische Eigenschaf- ten:Growth-inhibiting, cytotoxic and antibiotic properties:
Assay 1: Messung des Zellwachstums durch Bestimmung der Akti- vitität des intrazellulären Enzyms saure Phosphatase. Das zugegebene Substrat p-Nitrophenylphosphat wird durch saure Phosphatase in p-Nitrophenol umgewandelt, welches Licht bei 405 nm absorbiert. Die Intensität der Gelbfärbung ist hierbei proportional zur Anzahl der Zellen. Die Inkubation der Zelli- nien HEPG-2 und A549 mit der Substanz (0,1-100 μM) erfolgteAssay 1: Measurement of cell growth by determining the activity of the intracellular enzyme acid phosphatase. The added substrate p-nitrophenyl phosphate is converted by acid phosphatase into p-nitrophenol, which absorbs light at 405 nm. The intensity of the yellowing is proportional to the number of cells. The HEPG-2 and A549 cell lines were incubated with the substance (0.1-100 μM)
48 h und 96 h bei 37°C und 5 % C02.48 h and 96 h at 37 ° C and 5% C0 2 .
Assay 2: Messung der Zytotoxizität durch quantitative Bestimmung des Enzyms Lactatdehydrogenase (LDH), einem stabilen zytosolischen Enzym, welches bei der Zellyse ins Medium freigesetzt wird. Freigesetztes LDH wird durch einen gekoppelten Enzymassay gemessen, bei dem ein Tetrazoliumsalz in ein rotes Formazanprodukt umgewandelt wird, welches bei 490 nm detek- tiert werden kann. Die Menge an generierter Farbe ist hierbei proportional zur Anzahl an lysierten Zellen. Die Inkubation der Zellinie HEPG2 und A549 mit der Substanz (0,1-100 μM) er- folgte 24 h bei 37°C und 5 % C02. Inhibitionstest :Assay 2: Measurement of the cytotoxicity by quantitative determination of the enzyme lactate dehydrogenase (LDH), a stable cytosolic enzyme that is released into the medium during cell lysis. Released LDH is measured by a coupled enzyme assay, in which a tetrazolium salt is converted into a red formazan product, which can be detected at 490 nm. The amount of color generated is proportional to the number of lysed cells. The HEPG2 and A549 cell lines were incubated with the substance (0.1-100 μM) for 24 h at 37 ° C. and 5% CO 2 . Inhibition test:
Verwendete Nährmedien: Müller-Hinton-BouillonCulture media used: Müller-Hinton broth
Caso-AgarplattenCaso agar plates
Testmethode: MikrodilutionsassayTest method: microdilution assay
Die Testkeime werden über Nacht in Müller-Honton-Bouillon bei 35°C +/- 2°C angezogen. Die Keimsuspension wird abzentrifu- giert (5000 U/min, 4°C), das Pellet in frischem Medium resuspendiert und weitere 2h inkubiert. Anschließend wird das Pellet in 0.9%iger NaCl-Lösung resuspendiert und die Zellzahl anhand der Standard-Kurven auf etwa 108 KBE/ml eingestellt. Die so erhaltene Suspension wird anschließend in Müller- Hinton-Bouillon auf etwa 10" KBE/ml verdünnt (= Inokulum) .The test germs are grown overnight in Müller-Honton broth at 35 ° C +/- 2 ° C. The germ suspension is centrifuged off (5000 rpm, 4 ° C.), the pellet is resuspended in fresh medium and incubated for a further 2 hours. The pellet is then resuspended in 0.9% NaCl solution and the cell number is adjusted to approximately 10 8 CFU / ml using the standard curves. The suspension thus obtained is then diluted in Müller-Hinton broth to about 10 "CFU / ml (= inoculum).
Von dem Inokulum wird eine Keimzahlbestimmung durch Ausspira- lisieren (2 x 0.1 ml) einer geigneten Verdünnungsstufe auf CASO-Agarplatten durchgeführt.A bacterial count is determined from the inoculum by spiraling (2 x 0.1 ml) a suitable dilution step on CASO agar plates.
Testdurchführung: Auf eine Mikrotiter-Assay-Platte mit 96 Vertiefungen ("wells") werden in bestimmten Konzentrationen die potentiellen Inhibitoren dispensiert, wobei die Vertiefungen Al-Hl leer bleiben. Die Vertiefungen der Mikrotiter- Assay-Platten werden mit der eingestellten Keimsuspension beimpft. Als Wachstumskontrollen dienen die Vertiefungen Al- Hl. Sofort nach Inokulation sowie nach 24 und 48h Inkubation der Platten werden diese in einem Platten-Reader (Biotek EL 311) bei 550nm vermessen. Aus den Rohdaten wird die Inhibiti- on des Bakterien- bzw. Pilzwachstum in Prozent berechnet. Allgemeine Synthese der Verbindungen im 96er Format (Beispiele 3-9) :Test execution: The potential inhibitors are dispensed in a concentration in a microtiter assay plate with 96 wells, the wells Al-HI remaining empty. The wells of the microtiter assay plates are inoculated with the set germ suspension. The Al-Hl wells serve as growth controls. Immediately after inoculation and after 24 and 48 hours of incubation, the plates are measured in a plate reader (Biotek EL 311) at 550 nm. The inhibition of bacterial or fungal growth in percent is calculated from the raw data. General synthesis of the compounds in 96 format (Examples 3-9):
Pro Vertiefung werden 200 μl einer IM Aminlösung in Dichlor- methan, 200 μl einer 1 M Aldehydlosung in Dichlormethan und 1 äquiv. Et3N direkt zugeben. Die Reaktionsmischung läßt man über Nacht offen schütteln. Der gebildete Rückstand wird in 200 μl MeOH aufgenommen; 200 μl 2M TOSMIC-Lösung in Methanol. Die Platte wird mit einer Santopren-Noppenmatte (Firma Zins- ser Analytic GmbH, Frankfurt) und einer zusätzlichen Teflonmatte verschlossen und fest zugeschraubt. Der Alublock wird 4 h auf 80°C erhitzt. Nach dieser Zeit läßt man den Block abkühlen und öffnet die Reaktionsgefäße vorsichtig.200 μl of an IM amine solution in dichloromethane, 200 μl of a 1 M aldehyde solution in dichloromethane and 1 equivalent Et3N are added directly to each well. The reaction mixture is left to shake open overnight. The residue formed is taken up in 200 μl MeOH; 200 ul 2M TOSMIC solution in methanol. The plate is closed with a Santoprene knob mat (company Zsersser Analytic GmbH, Frankfurt) and an additional Teflon mat and screwed tight. The aluminum block is heated to 80 ° C for 4 h. After this time, the block is allowed to cool and the reaction vessels are carefully opened.
Das Lösungsmittel wird über Nacht abgedampft. Der Rückstand wird in 600 μl Essigester (EE) aufgenommen und mit 300 μl Wassser versetzt. Mit Hilfe einer PP-Plastikmatte wird die EE-Phase dreimal mit 300 μl Wasser ausgeschüttelt. Die Wasserphase wird jeweils abgezogen und in einer weiteren "Deep- Well"-Platte aufgefangen. Zur Entfernung der restlichen Wasserrückstände wird die EE-Phase mit einer Spatelspitze Natriumsulfat versetzt und geschüttelt. Die EE-Phase wird abzogen und das Salz mit 100 μl nachwaschen. Nun werden 2 x je 100 μl 2 N Salzsäure zugegeben und ausgeschüttelt. Die wäßrige Phase wird in einer weiteren Platte aufgefangen. In dieser befindet sich nun das gereingte Imidazolderivat , und zwar in Form seines Hydrochlorids . Beispiel 3The solvent is evaporated off overnight. The residue is taken up in 600 μl of ethyl acetate (EA) and 300 μl of water are added. Using a PP plastic mat, the RE phase is shaken out three times with 300 μl water. The water phase is drawn off in each case and collected in a further "deep-well" plate. To remove the remaining water residues, a spatula tip of sodium sulfate is added to the EE phase and shaken. The EE phase is drawn off and the salt is washed with 100 μl. Now 2 x 100 μl of 2N hydrochloric acid are added and shaken out. The aqueous phase is collected in a further plate. This contains the purified imidazole derivative, in the form of its hydrochloride. Example 3
3- ( 4 -Benzylpiperidin-IH- imidazol- 5-yl )-lH-indol3- (4-Benzylpiperidin-IH-imidazol-5-yl) -lH-indole
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 0, min. 357.2 C231H2N4 = 356.47HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 0.min. 357.2 C 231 H 2 N 4 = 356.47
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums: Staph. aureus c=100μM 100% InhibitionInhibition of bacterial growth: Staph. aureus c = 100μM 100% inhibition
Bac. subtilis c=100μM 100% InhibitionBac. subtilis c = 100μM 100% inhibition
Strept. pneumoniae c=100μM 80% InhibitionStrep. pneumoniae c = 100μM 80% inhibition
Candida albicans c=100μM 60% InhibitionCandida albicans c = 100μM 60% inhibition
Cytotoxizität L50 A549 >100μM HepG2 >100μMCytotoxicity L50 A549> 100μM HepG2> 100μM
Zeilproliferation GI50: A549 >100μM 26% Inhibition epG2 >100μM 48% Inhibition Beispiel 4 :Line proliferation GI50: A549> 100μM 26% inhibition epG2> 100μM 48% inhibition Example 4:
5- (Benzyloxy) -3-( 4-benzylpiperidin-lH-imidazol-5-yl )-lH- pyrrol [ 2 , 3-c jpyridin5- (Benzyloxy) -3- (4-benzylpiperidine-lH-imidazol-5-yl) -lH-pyrrole [2,3-cpyridine
Molecular Weighl =463 59Molecular Weighl = 463 59
Exact Mass =463Exact Mass = 463
Molecular Formula »C29H29N50Molecular Formula »C29H29N50
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 0,85 min. 464.2 C29H29N50 = 463,59HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 0.85 min. 464.2 C 29 H 29 N 5 0 = 463.59
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums:Inhibition of bacterial growth:
Staph. aureus c=100μM 100% InhibitionStaph. aureus c = 100μM 100% inhibition
Bac. subtilis c=100μM 100% InhibitionBac. subtilis c = 100μM 100% inhibition
Strept. pneumoniae c=100μM 90% InhibitionStrep. pneumoniae c = 100μM 90% inhibition
Candida albicans c=100μM 70% InhibitionCandida albicans c = 100μM 70% inhibition
Cytotoxizität L50: A549 >100μMCytotoxicity L50: A549> 100μM
HepG2 >100μMHepG2> 100μM
Zellproliferation GI50: A549 >100μM 41% Inhibition HepG2 >100μM 65% Inhibition Beispiel 5:Cell proliferation GI50: A549> 100μM 41% inhibition HepG2> 100μM 65% inhibition Example 5:
5- (Benzyloxy) -3-( 1- ( 3-methyl-butyl ) -lH-imidazol-5-yl )-lH- pyrrol[ 2 , 3-c ]pyridin5- (Benzyloxy) -3- (1- (3-methylbutyl) -IH-imidazol-5-yl) -IH-pyrrole [2,3-c] pyridine
Molecular Weight =360.46Molecular Weight = 360.46
Exact Mass =360Exact Mass = 360
Molecular Formula =C22H24N40Molecular Formula = C22H24N40
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES) 2,65 min. 361.2 C22H2,N40 = 360,46HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES) 2.65 min. 361.2 C 22 H 2 , N 4 0 = 360.46
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums Staph. aureus c=100μM 100% InhibitionInhibition of Staph Bacterial Growth. aureus c = 100μM 100% inhibition
Bac . subtilis c=100μM 100% InhibitionBac. subtilis c = 100μM 100% inhibition
Strept. pneumoniae c=100μM 90% InhibitionStrep. pneumoniae c = 100μM 90% inhibition
Candida albicans c=100μM 0% InhibitionCandida albicans c = 100μM 0% inhibition
Cytotoxizität L50: A549 >100μMCytotoxicity L50: A549> 100μM
HepG2 >100μMHepG2> 100μM
Zeilproliferation GI50: A549 >100μM 33% InhibitionLine proliferation GI50: A549> 100μM 33% inhibition
HepG2 >100μM 38% Inhibition Beispiel 6 :HepG2> 100μM 38% inhibition Example 6:
5- (Benzyloxy ) -3- ( 1- ( 3-ethylindol )- lH-imidazol-5-yl ) -1H- pyrrol [ 2 , 3-c ]pyridin5- (Benzyloxy) -3- (1- (3-ethylindol) - 1H-imidazol-5-yl) -1H-pyrrole [2, 3-c] pyridine
Molecular Weight =433.52Molecular Weight = 433.52
Exact Mass =433Exact Mass = 433
Molecular Formula =C27H23N50Molecular Formula = C27H23N50
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES) 2,46 min. 434.2 C27H23N50 = 433,52HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES) 2.46 min. 434.2 C 27 H 23 N 5 0 = 433.52
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums Staph. aureus c=100μM 85% Inhibition Bac . subtilis c=100μM 10% Inhibition Strept. pneumoniae c=100μM 10% Inhibition Candida albicans c=100μM 0% InhibitionInhibition of Staph Bacterial Growth. aureus c = 100μM 85% inhibition Bac. subtilis c = 100μM 10% inhibition strept. pneumoniae c = 100μM 10% inhibition Candida albicans c = 100μM 0% inhibition
Cytotoxizität L50: A549 >100μMCytotoxicity L50: A549> 100μM
HepG2 >100μMHepG2> 100μM
Zellproliferation GI50: A549 >100μM 19% Inhibition HepG2 >100μM 17% Inhibition Beispiel 7 :Cell proliferation GI50: A549> 100μM 19% inhibition HepG2> 100μM 17% inhibition Example 7:
3- ( 1- ( 1 , 2 , 3 , 4-Tetrahydronaphtyl ) -lH-imidazol-5-yl ) -2-methyl- lH-indol3- (1- (1, 2, 3, 4-tetrahydronaphthyl) -IH-imidazol-5-yl) -2-methyl-IH-indole
Molecular Weight =327.43Molecular Weight = 327.43
Exact Mass =327Exact Mass = 327
Molecular Formula =C22H21N3Molecular Formula = C22H21N3
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ , Acetonitril/Wasser; API-ES): 2,75 min. 328.2 C.2H21N3 = 327,43HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 2.75 min. 328.2 C. 2 H 21 N 3 = 327.43
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums: Staph. aureus c=100μM 40% InhibitionInhibition of bacterial growth: Staph. aureus c = 100μM 40% inhibition
Bac. subtilis c=100μM 76% InhibitionBac. subtilis c = 100μM 76% inhibition
Strept. pneumoniae c=100μM 0% InhibitionStrep. pneumoniae c = 100μM 0% inhibition
Candida albicans c=100μM 0% InhibitionCandida albicans c = 100μM 0% inhibition
Cytotoxicität L50: A549 >100μMCytotoxicity L50: A549> 100μM
HepG2 >100μMHepG2> 100μM
Zeilproliferation GI50: A549 >100μM 0% InhibitionLine proliferation GI50: A549> 100μM 0% inhibition
HepG2 >100μM 0% Inhibition Beispiel 8HepG2> 100μM 0% inhibition Example 8
3- ( l-N-Isopropylethylamin-lH-imidazol-5-yl )-2-methyl-lH-indol3- (1-N-isopropylethylamine-1H-imidazol-5-yl) -2-methyl-1H-indole
Molecular Weight =28239Molecular Weight = 28239
Exact Mass =282Exact Mass = 282
Molecular Formula =C17H22N4 Analytische Daten:Molecular Formula = C17H22N4 Analytical Data:
HPLC-MS (YMC ODS-A, 5cm, 2μ , Acetonitril/Wasser; API-ES) 0,82 min. 283.2 C17H22N4 = 282,39HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES) 0.82 min. 283.2 C 17 H 22 N 4 = 282.39
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums:Inhibition of bacterial growth:
Staph. aureus c=100μM 82% Inhibition Bac. subtilis c=100μM 39% InhibitionStaph. aureus c = 100μM 82% inhibition Bac. subtilis c = 100μM 39% inhibition
Strept. pneumoniae c=100μM 0% InhibitionStrep. pneumoniae c = 100μM 0% inhibition
Candida albicans c=100μM 0% InhibitionCandida albicans c = 100μM 0% inhibition
Cytotoxicität L50: A549 >100μM HepG2 >100μMCytotoxicity L50: A549> 100μM HepG2> 100μM
Zellproliferation GI50: A549 >100μM 10% InhibitionCell proliferation GI50: A549> 100μM 10% inhibition
HepG2 >100μM 0% Inhibition Beispiel 9 :HepG2> 100μM 0% inhibition Example 9:
5-(Methoxy)-3-( 1- ( 4-Hydroxyphenyl )ethyl-lH-imidazol-5-yl ) -1H- indoi5- (Methoxy) -3- (1- (4-hydroxyphenyl) ethyl-1H-imidazol-5-yl) -1H-indoi
Molecular Weight =33339Molecular Weight = 33339
Exact Mass =333Exact Mass = 333
Molecular Formula =C20H19N3O2Molecular Formula = C20H19N3O2
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 2,26 min. 334.2 C20H15N,O2 = 333,39HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 2.26 min. 334.2 C 20 H 15 N, O 2 = 333.39
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums: Staph. aureus c=100μM 25% InhibitionInhibition of bacterial growth: Staph. aureus c = 100μM 25% inhibition
Bac . subtilis c=100μM 38% InhibitionBac. subtilis c = 100μM 38% inhibition
Strept. pneumoniae c=100μM 85% InhibitionStrep. pneumoniae c = 100μM 85% inhibition
Candida albicans c=100μM 0% InhibitionCandida albicans c = 100μM 0% inhibition
Cytotoxicität L50: A549 >100μMCytotoxicity L50: A549> 100μM
HepG2 >100μMHepG2> 100μM
Zeilproliferation GI50: A549 >100μM 31% InhibitionLine proliferation GI50: A549> 100μM 31% inhibition
HepG2 >100μM 14% Inhibition Beispiel 10:HepG2> 100μM 14% inhibition Example 10:
3-[5-( 4-Fluoro-phenyl)-3-( 1,2,3, 4-tetrahydro-naphthalen-l- yl )-3H-imidazol-4-yl]-lH-indol3- [5- (4-Fluoro-phenyl) -3- (1,2,3, 4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -IH-indole
Molecular Weight =407.49Molecular Weight = 407.49
Exact Mass =407Exact Mass = 407
Molecular Formula =C27H22FN3Molecular Formula = C27H22FN3
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 3,425 min". [M+H] + : 408,2HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 3.425 min " . [M + H] + : 408.2
'H-NMR (DMSO, 400 MHz): δ = 1,531-1,666 (m, IH); 1,838 (m, IH); 2,009 (m, 2H); 2,691 (m, IH); 2,810 (m, IH); 5,011 (s, IH); 6,811-7,703 (m, 14H); 11,574 (s, IH, NH ) . "F-NMR (DMSO, 376.81 MHz): δ = -117,401 ppm 'H NMR (DMSO, 400 MHz): δ = 1.531-1.666 (m, IH); 1.838 (m, IH); 2.009 (m, 2H); 2.691 (m, IH); 2.810 (m, IH); 5.011 (s, IH); 6.811-7.703 (m, 14H); 11.574 (s, IH, NH). "F-NMR (DMSO, 376.81 MHz): δ = -117.40 ppm
Beispiel 11:Example 11:
5-Benzyloxy-3- [ 5- ( 4-f luoro-phenyl )-3- (1,2,3 , 4-tetrahydro- naphthalen-l-yl)-3H-imidazol-4-yl]-lH-pyrrolo[2 , 3-c]pyridin5-Benzyloxy-3- [5- (4-f luoro-phenyl) -3- (1,2,3, 4-tetrahydronaphthalen-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridine
Molecular Weight =514.61 Exact Mass =514 Molecular Formula =C33H27FN4OMolecular Weight = 514.61 Exact Mass = 514 Molecular Formula = C33H27FN4O
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 3,388 min. [M+H]*: 515,2HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 3.388 min. [M + H] * : 515.2
'H-NMR (DMSO, 400 MHz): δ = 1 , 563-1671 (m, IH), 1,880 (m, 2H),'H-NMR (DMSO, 400 MHz): δ = 1, 563-1671 (m, IH), 1.880 (m, 2H),
1,934 (m, IH); 2,665 (m, IH), 2,775 (m, IH); 4,996 (m, IH);1.934 (m, IH); 2.665 (m, IH), 2.775 (m, IH); 4.996 (m, IH);
5,352 (s, 2H); 6,486 (s, IH); 6,834-7,547 (m, 15H); 8,435 (s,5.352 (s, 2H); 6.486 (s, IH); 6.834-7.547 (m, 15H); 8.435 (s,
IH); 9.896 (s, IH); 11,790 (s, IH, NH) 19F-NMR: (DMSO, 376,77 MHz): δ = -117,106 ppmIH); 9,896 (s, IH); 11.790 (s, IH, NH) 19 F-NMR: (DMSO, 376.77 MHz): δ = -117.106 ppm
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums: Staph. aureus c=50μM 60% InhibitionInhibition of bacterial growth: Staph. aureus c = 50μM 60% inhibition
Bac . subtilis c=50μM 80% InhibitionBac. subtilis c = 50μM 80% inhibition
Candida albicans c=50μM 100% Inhibition Beispiel 12 :Candida albicans c = 50μM 100% inhibition Example 12:
5-Benzyloxy-3- ( 3-indan-1-y1-3H-imidazol-4-yl ) -lH-pyrrolo[ 2 , 3- c Jpyridin5-benzyloxy-3- (3-indan-1-y1-3H-imidazol-4-yl) -IH-pyrrolo [2,3-cpyridine
Molecular Weight =406.49Molecular Weight = 406.49
Exact Mass =406Exact Mass = 406
Molecular Formula =C26H22N4OMolecular Formula = C26H22N4O
Analytische DatenAnalytical data
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 2,987 min. [M+H] + : 407,2HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 2.987 min. [M + H] + : 407.2
'H-NMR (DMSO, 400 MHz): δ = 1,880 (s, IH); 2,178 ( , IH); 2,827 (m, IH); 2,971 (m, IH); 5,315 (s, 2H); 5,647 (m, IH); 6,826 (s, IH); 6,967-7,435 (m,HH ); 7,681 (s, IH); 8,410 (s, IH); 11,692 (s, IH, NH)'H NMR (DMSO, 400 MHz): δ = 1.880 (s, IH); 2,178 (, IH); 2.827 (m, IH); 2,971 (m, IH); 5.315 (s, 2H); 5,647 (m, IH); 6.826 (s, IH); 6.967-7.435 (m, HH); 7,681 (s, IH); 8.410 (s, IH); 11.692 (s, IH, NH)
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums:Inhibition of bacterial growth:
Staph. aureus c= 12,5μM 80% Inhibition Bac . subtilis c= 25 μM 100% InhibitionStaph. aureus c = 12.5μM 80% inhibition Bac. subtilis c = 25 μM 100% inhibition
Candida albicans c= 100 μM 60% Inhibition Beispiel 13 :Candida albicans c = 100 μM 60% inhibition Example 13:
l-[ 5-( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c ]pyridin-3-yl ) -imidazol-1- yl ] -indan-2-ol1- [5- (5-Benzyloxy-lH-pyrrolo [2,3-c] pyridin-3-yl) imidazol-1-yl] indan-2-ol
Molecular Weight =422.49Molecular Weight = 422.49
Exact Mass =422Exact Mass = 422
Molecular Formula =C26H22N402Molecular Formula = C26H22N402
Analytische Daten:Analytical data:
HPLC-MS (YMC ODS-A, 5cm, 2μ, Acetonitril/Wasser; API-ES): 2,885 min. [M+H] + : 423,2 lH-NMR (DMSO, 400 MHz): δ = 2 , 854-3 , 151 (m, 3H); 4,121(m, IH); 4,442(m, IH); 5,303(s, 2H); 6,885(s, IH); 7 , 013-7 , 400 (m, 11H); 7,757(s, IH); 8,415 (s, IH); 11,688 (s, IH, NH).HPLC-MS (YMC ODS-A, 5cm, 2μ, acetonitrile / water; API-ES): 2.885 min. [M + H] + : 423.2 l H-NMR (DMSO, 400 MHz): δ = 2.854-3, 151 (m, 3H); 4.121 (m, IH); 4,442 (m, IH); 5.303 (s, 2H); 6.885 (s, IH); 7, 013-7, 400 (m, 11H); 7,757 (s, IH); 8.415 (s, IH); 11.688 (s, IH, NH).
Biologische Daten:Biological data:
Inhibition des Bakterienwachstums:Inhibition of bacterial growth:
Staph. aureus c=100μM 90% Inhibition Bac. subtilis c=100μM 90% InhibitionStaph. aureus c = 100μM 90% inhibition Bac. subtilis c = 100μM 90% inhibition
Candida albicans c=200μM 90% Inhibition Candida albicans c = 200μM 90% inhibition

Claims

Patentansprüche claims
3-Pyrroloimidazol-Derivate der allgemeinen Formel (I)3-pyrroloimidazole derivatives of the general formula (I)
Imidazol (I) Imidazole (I)
worinwherein
der Imidazolrest ein gegebenenfalls substituierter Imida- zolcyclus ist,the imidazole radical is an optionally substituted imidazole cycle,
X, Y, A und B unabhängig voneinander Kohlenstoff- oder Stickstoffatome sind,X, Y, A and B are independently carbon or nitrogen atoms,
die Reste Z unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, einen gegebenenfalls substituierten Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl-, Cy- cloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl-, Aryl-, Al- koxyrest oder einen gegebenenfalls substituierten Ring darstellen, an den ein oder zwei weitere gegebenenfalls substituierte Ringe anelliert sein können, und/oder mindestens zwei der Reste Z Teil eines gegebenenfalls substituierten Rings sein können, an den ein oder zwei weitere, gegebenenfalls substituierte Ringe anelliert sein können. the radicals 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 an optionally substituted ring to which one or two further optionally substituted rings can be fused and / or at least two of the Z radicals can be part of an optionally substituted ring to which one or two further, optionally substituted rings can be fused.
2. 3-Pyrroloimidazol-Derivate nach Anspruch 1, die die folgende allgemeine Formel aufweisen:2. 3-pyrroloimidazole derivatives according to claim 1, which have the following general formula:
R -,R -,
,-z z, -z z
R -R -
Imidazolimidazole
Imidazol ImidazolImidazole imidazole
R \,R \,
Imidazol imidazole
„"
R azolR azole
Imidazol ImidazolImidazole imidazole
R RR R
N { N N r- -N 1 N N r ! — z flN {N N r - -N 1 NN r! - z fl
^Z N — ιι 1 z N -z^ Z N - ιι 1 z N -z
R ! 1 R N ( R ! 1 RN (
R Imidazol R Imidazol Imidazol R Imidazol R imidazole R im i dazol imidazole R imidazole
RR
R H R H H R R HR H HR
HH
N N \ fl NN N \ fl N
" ^ . . R- i| -2 N 4 !l -z N 1 ~Z"^.. R - i | - 2 N 4! L -z N 1 ~ Z
N N [ R Imidazol R |m|dazo| R R Imidazol R 1 ImidazolNN [R Imidazole R | m | dazo | RR imidazole R 1 imidazole
R HR H
H N-, „NH N-, "N
N N R_ ,1 ^ z n- I -Z N L ,NN R _, 1 ^ z n- I -ZN L ,
R ImidazolR imidazole
Imidazol wobei die Reste R unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, ein Pseudohalogen, ein gegebenenfalls substituierter Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl-, Cyclo- aralkyl-, Cycloaralkenyl-, Cycloaralkinyl-, Aryl-, Aryloxy-, Aralkyloxy-, Alkoxyrest , ein Substituent oder ein heterocy- clischer Ring sind und/oder zwei oder mehr der Reste R einen weiteren Ring bilden. imidazole where the radicals R 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, Are cycloaralkenyl, cycloaralkynyl, aryl, aryloxy, aralkyloxy, alkoxy, a substituent or a heterocyclic ring and / or two or more of the radicals R form a further ring.
3. 3-Pyrroloimidazol-Derivate nach Anspruch 2, die die folgende allgemeine Formel aufweisen:3. 3-pyrroloimidazole derivatives according to claim 2, which have the following general formula:
H R H NH R H N
R Imidazol ' ImidazolR imidazole ' imidazole
RR
Imidazolimidazole
dazol dazol
RR
R 1R 1
N ^ N ^
N 'N '
Imidazolimidazole
ol oil
RR
H H N N N NH H N N N N
R — R _ T -Z R - R _ T - Z
N N "" NN ""
\\
Imidazol Imidazol Imidazole imidazole
4. 3-Pyrroloimidazol-Derivate nach Anspruch 2, die die folgende allgemeine Formel aufweisen:4. 3-pyrroloimidazole derivatives according to claim 2, which have the following general formula:
R - R -
5. 3-Pyrroloimidazol-Derivate nach einem der vorstehenden Ansprüche, wobei Z im Falle von Halogen Brom, Chlor, Fluor oder Jod ist; im Falle von Alkyl, Alkenyl oder Alkinyl eine Cι_6- Alkyl-, C2-6-Alkenyl- oder C2-6-Alkinylgruppe ist, im Falle von Aralkyl eine Cι_6-Alkylphenyl-, Cι_6-Alkylbenzyl-, Cι_6~ Alkylnaphthyl-, Cι_6-Alkylbiphenyl- oder Cι_6-Alkylanthra- cenylgruppe ist, im Falle von Aralkenyl eine C2-6-Alkenyl~ phenyl-, C2-6-Alkenylbenzyl-, C2-6-Alkenylnaphthyl-, C2-6_A1- kenylbiphenyl- oder C2-6-Alkenylanthracenylgruppe ist, im Falle von Aralkinyl eine C2-6_AlkinylPhenyl- C2-6_Alkinyl- benzyl-, C2-6_Alkinylnaphthyl-, C2-6-Alkinylt,iphenyl- oder C2-6-Alkinylanthracenylgruppe ist, im Falle von Cycloalkyl eine Cyclopentyl- oder Cyclohexylgruppe ist, im Falle von Cycloalkenyl eine Cyclopentenyl- oder Cyclohexenylgruppe ist, im Falle von Cycloalkinyl eine Cyclopentinyl- oder Cyclohe- xinylgruppe ist, im Falle von Aryl eine Phenyl-, Benzyl-, Naphthyl-, Biphenyl- oder Anthracenylgruppe ist, im Falle von Alkoxy eine -O-C^-Alkyl-, -0-C2.6-Alkenyl- , -0-C2.6-Alkinyl- gruppe, eine -O-cyclopentyl- oder -O-cyclohexylgruppe, eine -O-cyclopentenyl- oder -O-cyclohexenylgruppe, eine -O-cyclo- pentinyl- oder -O-cyclohexinylgruppe oder eine -O-phenyl-, -O-benzyl-, -O-naphthyl- , -O-biphenyl- oder -O- anthracenylgruppe ist, wobei sämtliche der vorstehenden Gruppen gegebenenfalls substituiert sein können.5. 3-pyrroloimidazole derivatives according to any one of the preceding claims, wherein Z is bromine, chlorine, fluorine or iodine in the case of halogen; in the case of alkyl, alkenyl or alkynyl is a Cι_6- alkyl, C2-6 -A lkenyl or C2-6 -A alkynyl group, in the case of aralkyl a Cι_6-alkylphenyl, Cι_6-alkylbenzyl, Cι_6 ~ alkylnaphthyl, Cι_6-alkylbiphenyl or Cι_6-alkylanthracenyl group, in the case of aralkenyl is a C2-6 -A lk en yl ~ phenyl-, C2-6 -A lkenylbenzyl-, C2-6 -A lkenylnaphthyl-, C2-6 _A 1 - kenylbiphenyl or C2-6-alkenylanthracenyl group, in the case of aralkynyl a C2-6 _A lki n ylP hen yl- C2-6 _A lkinyl- benzyl-, C2-6 _A lkinylnaphthyl-, C2-6-Alki n ylt , is iphenyl or C2-6-alkynylanthracenyl group, in the case of cycloalkyl is a cyclopentyl or cyclohexyl group, in the case of cycloalkenyl is a cyclopentenyl or cyclohexenyl group, in the case of cycloalkynyl is a cyclopentinyl or cyclohexyl group, in the case of aryl one Is phenyl, benzyl, naphthyl, biphenyl or anthracenyl group in the case of Alkoxy is a -OC ^ alkyl, -0-C 2.6 alkenyl, -0-C 2.6 alkynyl group, an -O-cyclopentyl or -O-cyclohexyl group, an -O-cyclopentenyl or -O- cyclohexenyl group, an -O-cyclopentinyl or -O-cyclohexinyl group or an -O-phenyl, -O-benzyl, -O-naphthyl, -O-biphenyl or -O-anthracenyl group, all of which above groups may optionally be substituted.
6. 3-Pyrroloimidazol-Derivate nach einem der vorstehenden An- Sprüche, wobei der Imidazolcyclus 1, 2, 3 oder 4 Substituenten aufweist, der/die ausgewählt sind unter Halogenatomen, Pseudohalogenen, Alkyl-, Alkenyl-, Alkinyl-, Aralkyl-, Aralkenyl-, Aralkinyl-, Cycloalkyl-, Cycloalkenyl-, Cycloalkinyl- , Cycloaralkyl-, Cycloaralkenyl-, Cycloaralkinyl-, Aryl-, Alkoxyresten und nicht-aromatischen oder aromatischen oder teilaromatischen heterocyclischen Resten, die unsubstituiert sein können oder mit einem oder mehreren Substituenten substituiert sein können, die ausgewählt sind unter -OH, -Ra, -O-Alkyl, -O-Aryl, -O-Heteroaroyl , einem -O-Heterocyclus, -NH2, -N02, -CN, -N3, -CNRaNRbRc, -NRaRb, NRaRbRc +, Fluor, Chlor, Brom, a-, b- , bis w-Aminosäureester , -NRaCORb, -NRaCOXRb (X = -0, -NR, -PO0,2,3,4R, -SOo , 1 , 2 , 4 ,R, -NRaNRbRC ) , "CORa, -COORa, -OCOORa, -C0NRaRb, -OCONRaRb/ -NRcCONRaRb, -Ra-0-Rb, -Rc-NRaRb, -Ra-S-Rb, -Ra-SO-Rb, -Ra-S (0 ) 2~Rb, -ORa-0-Rb, -NRaRb-0-Rc, -S02Ra, -SOi , 2 , 3 , 4Ra~0-Rb, -C0Ra-0Rb,6. 3-pyrroloimidazole derivatives according to one of the preceding claims, wherein the imidazole cycle has 1, 2, 3 or 4 substituents which are selected from halogen atoms, pseudohalogens, alkyl, alkenyl, alkynyl, aralkyl, Aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaralkyl, cycloaralkenyl, cycloaralkynyl, aryl, alkoxy radicals and non-aromatic or aromatic or partly aromatic heterocyclic radicals, which may be unsubstituted or substituted by one or more substituents can be selected from -OH, -R a , -O-alkyl, -O-aryl, -O-heteroaroyl, an -O-heterocycle, -NH 2 , -N0 2 , -CN, -N 3 , -CNR a NR b R c , -NR a R b , NR a R b R c + , fluorine, chlorine, bromine, a-, b- to w-amino acid ester, -NR a COR b , -NR a COXRb ( X = -0, -NR, -PO 0 , 2,3,4R, -SOo, 1, 2, 4, R, -NR a NRbR C ), "COR a , -COOR a , -OCOORa, -C0NR a Rb, -OCONR a Rb / -NR c CONR a Rb, -R a -0-Rb, -R c -NR a Rb, -R a -S-Rb, -Ra-SO- Rb, -R a -S (0) 2 ~ Rb, -OR a -0-Rb, -NR a Rb-0-R c , -S02R a , -SOi, 2, 3, 4Ra ~ 0-Rb, - C0R a -0Rb,
-C00Ra-0-Rb, -0C0Ra-0-Rb, -OCOORa-0-Rb, -NRbCORa-0-Rb, -CONRaRb-0-Rc, -OCONRaRb-0-Rc, -NRcCONRaRb-0-Rd, -NRaCORb-0-Rc, -ORa-S-Rb, -NRaRb-S-Rc, -SOi f 2 , 3 , 4 a"S-Rb, -C0Ra-S-Rb, -OCORa-S-Rb, -OCORa-S-Rb, -NRaCORb-S-Rc , -CONRaRb-S-Rc, -NRaCONRbRc-S-Rd, -ORa-NRbRc , - RaRb-NRc df -SOι,2 3r 4 b~NRb c. -CORa-NRbRc , -COORa-NRbRc r -OCORa-NRbRc , -OCOORa-NRbRc - RaCONRb c-NRd, -NRaCOORb-NRcRd, -OCONRaRb-NRcRd, -NRaCONRbRc-NHRd, -NRaCOORb-NRcRd, -POORaORb, -NRcPOORaORb, -S02NRaRb, -SONRaNRbRc, -SNRaRbNRcRd, -NRaS02Rb, -NRaSONRbRc, -NRaSNRbNRcRd, -NRaS02NRb, -NRaSONRbNRc,-C00R a -0-Rb, -0C0R a -0-Rb, -OCOOR a -0-Rb, -NRbCOR a -0-Rb, -CONR a Rb-0-R c , -OCONR a Rb-0-R c , -NR c CONR a Rb-0-Rd, -NR a CORb-0-R c , -OR a -S-Rb, -NR a Rb-SR c , -SOi f 2, 3, 4 a "S -Rb, -C0R a -S-Rb, -OCORa-S-Rb, -OCOR a -S-Rb, -NR a CORb-SR c , -CONR a Rb-SR c , -NR a CONRbRc-S-Rd , -OR a -NRbR c , - R a Rb-NR c df -SOι, 2 3r 4 b ~ NRb c. -COR a -NRbR c , -COOR a -NRbRc r -OCOR a -NRbRc, -OCOORa-NRbRc - R a CONRb c-NRd, -NR a COORb-NR c Rd, -OCONR a Rb-NR c Rd, - NR a CONRbRc-NHRd, -NR a COORb-NR c Rd, -POOR a ORb, -NR c POOR a ORb, -S0 2 NR a R b , -SONR a NR b R c , -SNR a R b NR c R d , -NR a S0 2 R b , -NR a SONR b R c , -NR a SNR b NR c R d , -NR a S0 2 NR b , -NR a SONR b NR c ,
-NRaSNRbNRcNRd, wobei Ra, Rb? Rc und R unabhängig voneinander als Substituenten Alkyl, Alkenyl, Alkinyl, Aroyl, Heteroaroyl, ein Heterocyclus, Aralkyl, Aralkenyl oder Perhalogenal- kyl sein können oder als Glied einer Kette entsprechend Alky- len, Alkenylen, Alkinylen, Aroylen, Heteroaroylen, Heterocy- clen, Aralkylen, Aralkenylen oder Perhalogenalkylen sein können; und wobei Ra, Rb, Rc und Rd selbst mit Alkyl, Alkenyl, Alkinyl, Aroyl, Heteroaroyl, einem Heterocyclus, Aralkyl, Aralkenyl oder Perhalogenalkyl substituiert sein können.-NR a SNR b NR c NR d , where R a , Rb ? Rc and R can be independently of one another as substituents alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhaloalkyl or as a link in a chain corresponding to alkylene, alkenylene, alkynylene, aroylene, heteroaroylene, heterocycles , Aralkylene, aralkenylene or perhaloalkylene; and wherein R a , Rb, Rc and Rd themselves can be substituted with alkyl, alkenyl, alkynyl, aroyl, heteroaroyl, a heterocycle, aralkyl, aralkenyl or perhaloalkyl.
7. 3-Pyrrploimidazol Derivate nach einem der vorstehenden Ansprüche, nämlich7. 3-pyrrploimidazole derivatives according to any one of the preceding claims, namely
3-( l-Cyclohexyl-lH-imidazol-5-yl)-l-methyl-lH-indol 5- (Benzyloxy) -3- ( l-cyclohexyl-lH-imidazol-5-yl ) -lH-pyr- rolo[2,3-c]pyridin3- (l-Cyclohexyl-lH-imidazol-5-yl) -l-methyl-lH-indole 5- (benzyloxy) -3- (l-cyclohexyl-lH-imidazol-5-yl) -lH-pyrrolo [2,3-c] pyridine
3-(l-Cyclohexyl-lH-imidazol-5-yl)-lH-indol3- (l-cyclohexyl-lH-imidazol-5-yl) -lH-indole
5-Benzyloxy-3- [ 3- ( 5-chloro-l , 2,3, 4-tetrahydro-naphthalen-l- yl)-3E-imidazol-4-yl]-lE-pyrrolo[2,3-c]pyridine5-benzyloxy-3- [3- (5-chloro-l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3E-imidazol-4-yl] -lE-pyrrolo [2,3-c] pyridine
5-Benzyloxy-3- [ 3- ( 6-chloro-l , 2,3, 4-tetrahydro-naphthalen-l- yl)-3H-imidazol-4-yl]-lH-pyrrolo[2,3-c]pyridine5-benzyloxy-3- [3- (6-chloro-l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2,3-c] pyridine
5-Benzyloxy-3- [ 3- ( 7-chloro-l , 2,3, 4-tetrahydro-naphthalen-l- yl ) -3 H-imidazol-4-yl ] -lff-pyrrolo[ 2 , 3-c]pyridine5-benzyloxy-3- [3- (7-chloro-l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3 H-imidazol-4-yl] -lff-pyrrolo [2, 3-c ] pyridine
5-Benzyloxy-3- [ 3- ( 8-chloro-l , 2,3, 4-tetrahydro-naphthalen-l- yl)-3H-imidazol-4-yl]-lH-pyrrolo[2,3-c]pyridine5-benzyloxy-3- [3- (8-chloro-l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2,3-c] pyridine
5-Benzyloxy-3- [ 3- ( 5 , 8-dichloro-l , 2 , 3 , 4-tetrahydro-naphthalen- l-yl)-3f/-imidazol-4-yl]-lH-pyrrolo[2, 3-c]pyridine 5-Benzyloxy-3- [ 3- ( 5 , 7-dichloro-l , 2,3, 4-tetrahydro-naphthalen- l-yl)-3H-imidazol-4-yl]-lH-pyrrolo[ 2, 3-c]pyridine 5-Benzyloxy-3- [ 3- ( 5 , 6-dichloro-l , 2 , 3 , 4-tetrahydro-naphthalen- 1-yl ) -3 H-imidazol-4-yl]-lH-pyrrolo[ 2, 3-c]pyridine 5-Benzyloxy-3- [ 3- ( 6 , 8-dichloro-l , 2,3, 4-tetrahydro-naphthalen- l-yl)-3H-imidazol-4-yl]-lH-pyrrolo[ 2, 3-c]pyridine 5-Benzyloxy-3- [ 3- ( 7 , 8-dichloro-l , 2,3, 4-tetrahydro-naphthalen- l-yl)-3E-imidazol-4-yl]-lH-pyrrolo[2, 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 5-chloro-l , 2,3, 4-tetrahydro- naphthalen-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[ 2 , 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 5-chloro-l , 2,3, 4-tetrahydro- naphthalen-1-yl) -3H-imidazol-4-yl]-l2ϊ-pyrrolo[ 2, 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 6-chloro-l ,2,3, 4-tetrahydro- naphthalen-1-yl ) -3 H-imidazol-4-yl ] -lE-pyrrolo[ 2 , 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 7-chloro-l ,2,3, 4-tetrahydro- naphthaleh-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[ 2 , 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 8-chloro-l ,2,3, 4-tetrahydro- naphthalen-1-yl)-3tf-imidazol-4-yl]-l#-pyrrolo[ 2 , 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 5 , 8-dichloro-l , 2,3, 4-tetrahydro- naphthalen-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[ 2 , 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 5 , 7-dichloro-l ,2,3, 4-tetrahydro- naphthalen-1-yl )-3H-imidazol-4-yl ]-l -pyrrolo[2 , 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 5 , 6-dichloro-l , 2 , 3 , 4-tetrahydro- naphthalen-l-yl)-3H-imidazol-4-yl]-lH-pyrrolo[2, 3-c]pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 6 , 8-dichloro-l ,2,3 , 4-tetrahydro- naphthalen-l-yl)-3H-imidazol-4-yl]-lH-pyrrolo[2, 3-c] pyridine 5-Benzyloxy-3- [ 5-methyl-3- ( 7 , 8-dichloro-l , 2 , 3 , 4-tetrahydro- naphthalen-1-yl ) -3 H-imidazol-4-yl ] -liϊ-pyrrolo[ 2 , 3-c]pyridine 5-Benzyloxy-3- [ 5-isopropyl-3- (1,2,3, 4-tetrahydro-naphthalen- 1-yl ) -3tf-imidazol-4-yl ] -lH-pyrrolo [ 2 , 3-c]pyridine5-benzyloxy-3- [3- (5, 8-dichloro-l, 2, 3, 4-tetrahydro-naphthalene- l-yl) -3f / -imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [3- (5, 7-dichloro-l, 2,3, 4- tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [3- (5, 6-dichloro-l, 2, 3 , 4-tetrahydro-naphthalene-1-yl) -3 H -imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [3- (6, 8-dichloro-l , 2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [3- (7, 8- dichloro-l, 2,3,4-tetrahydro-naphthalene-l-yl) -3E-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-methyl- 3- (5-chloro-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-methyl-3- (5-chloro-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -l2ϊ-pyrrolo [2, 3-c] pyridine 5 -Benzyloxy-3- [5-methyl-3- (6-chloro-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3 H-imidazol-4-yl] -lE-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-methyl-3- (7-chloro-l, 2,3, 4-tetrahydro - naphthaleh-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-methyl-3- (8-chloro-l, 2, 3, 4-tetrahydronaphthalen-1-yl) -3tf-imidazol-4-yl] -l # -pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-methyl-3- (5, 8-dichloro-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5- methyl-3- (5, 7-dichloro-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -l-pyrrolo [2, 3-c] pyridines 5- Benzyloxy-3- [5-methyl-3- (5, 6-dichloro-l, 2,3,4-tetrahydronaphthalen-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-methyl-3- (6, 8-dichloro-l, 2,3, 4-tetrahydronaphthalen-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-methyl-3- (7, 8-dichloro-l, 2, 3, 4-tetrahydronaphthalen-1-yl) -3 H-imidazol-4-yl] -liϊ-pyrrolo [2, 3-c] pyridine 5-benzyloxy-3- [5-isopropyl-3- (1,2,3, 4-tetrahydro-naphthalene- 1-yl) -3tf-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3-[ 5-isopropyl-3- ( 5-chloro-l ,2,3, 4-tetrahydro- naphthalen-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[ 2 , 3-c]pyridine5-benzyloxy-3- [5-isopropyl-3- (5-chloro-l, 2,3,4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3- [ 5-isopropyl-3- ( 6-chloro-l ,2,3, 4-tetrahydro- naphthalen-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[ 2 , 3-c]pyridine5-Benzyloxy-3- [5-isopropyl-3- (6-chloro-l, 2,3,4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3-[ 5-isopropyl-3- ( 7-chloro-l , 2,3, 4-tetrahydro- naphthalen-1-yl) -3 H-imidazol-4-yl ]-lH-pyrrolo[ 2 , 3-c]pyridine5-Benzyloxy-3- [5-isopropyl-3- (7-chloro-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3 H-imidazol-4-yl] -lH-pyrrolo [2 , 3-c] pyridines
5-Benzyloxy-3-[ 5-isopropyl-3- ( 8-chloro-l ,2,3, 4-tetrahydro- naphthalen-l-yl)-3H-imidazol-4-yl]-lH-pyrrolo[ 2 , 3-c]pyridine5-benzyloxy-3- [5-isopropyl-3- (8-chloro-l, 2,3,4-tetrahydronaphthalen-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3-[5-isopropyl-3-(5, 8-dichloro-l , 2 ,3,4- tetrahydro-naphthalen-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[2,3- c]pyridine5-benzyloxy-3- [5-isopropyl-3- (5, 8-dichloro-l, 2, 3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [ 2,3-c] pyridines
5-Benzyloxy-3- [ 5-isopropyl-3- ( 5 , 7-dichloro-l , 2,3,4- tetrahydro-naphthalen-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[2 , 3- c]pyridine5-benzyloxy-3- [5-isopropyl-3- (5, 7-dichloro-l, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [ 2,3-c] pyridines
5-Benzyloxy-3-[ 5-isopropyl-3- ( 6 , 8-dichloro-l ,2,3,4- tetrahydrb-naphthalen-1-yl ) -3iϊ-imidazol-4-yl ] -lH-pyrrolo[ 2 , 3- c]pyridine5-benzyloxy-3- [5-isopropyl-3- (6, 8-dichloro-l, 2,3,4-tetrahydrb-naphthalen-1-yl) -3iϊ-imidazol-4-yl] -lH-pyrrolo [ 2,3-c] pyridines
5-Benzyloxy-3- [ 5-isopropyl-3- ( 7 , 8-dichloro-l , 2,3,4- tetrahydro-naphthalen-1-yl ) -3H-imidazol-4-yl ] -lH-pyrrolo[ 2 , 3- c]pyridine5-benzyloxy-3- [5-isopropyl-3- (7, 8-dichloro-l, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] -lH-pyrrolo [ 2,3-c] pyridines
1-[ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 1 , 2 , 3 , 4- tetrahydro-naphthalen-1-yl ) -lH-imidazol-4-yl ] -ethanol1- [5- (5-Benzyloxy-1H-pyrrolo [2, 3-c] pyridin-3-yl) -1- (1, 2, 3, 4-tetrahydro-naphthalene-1-yl) -IH-imidazole -4-yl] ethanol
1- [ 5- ( 5-Benzyloxy-liϊ-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 6-chloro-1- [5- (5-Benzyloxy-liϊ-pyrrolo [2, 3-c] pyridin-3-yl) -1- (6-chloro-
1,2,3 , 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4-yl ] -ethanol1,2,3,4-tetrahydro-naphthalene-1-yl) -IH-imidazol-4-yl] ethanol
1-[ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 7-chloro-1- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (7-chloro-
1,2,3, 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4-yl ] -ethanol1,2,3,4-tetrahydro-naphthalene-1-yl) -IH-imidazol-4-yl] ethanol
1- [ 5- ( 5-Benzyloxy-lH-pyrrolo [ 2 , 3-c]pyridin-3-yl ) -1- ( 8-chloro-1- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (8-chloro-
1,2,3, 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4-yl ] -ethanol1,2,3,4-tetrahydro-naphthalene-1-yl) -IH-imidazol-4-yl] ethanol
1- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 5 , 8- dichloro-1 , 2 , 3,4-tetrahydro-naphthalen-l-yl)-lH-imidazol-4- yl] -ethanol1- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (5, 8- dichloro-1, 2, 3,4-tetrahydro-naphthalene-l-yl) -lH-imidazol-4-yl] ethanol
1- [ 5- ( 5-Benzyloxy-lE-pyrrolo[ 2 , 3-c]pyridin-3-yl )-l- (5,7- dichloro-1 ,2,3, 4-tetrahydro-naphthalen-l-yl )-lH-imidazol-4- yl ] -ethanol1- [5- (5-Benzyloxy-lE-pyrrolo [2, 3-c] pyridin-3-yl) -l- (5,7-dichloro-1, 2,3,4-tetrahydro-naphthalene-l- yl) -lH-imidazol-4-yl] ethanol
1- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 7 , 8- dichloro-1 ,2,3, 4-tetrahydro-naphthalen-l-yl ) -IH-imidazol-4- yl ] -ethanol1- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (7, 8-dichloro-1, 2,3, 4-tetrahydro-naphthalene-l- yl) -IH-imidazol-4-yl] ethanol
1- [ 5- ( 5-Benzyloxy-lE-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 6 , 8- dichloro-1 ,2,3, 4-tetrahydro-naphthalen-l-yl )-lH-imidazol-4- yl] -ethanol1- [5- (5-Benzyloxy-lE-pyrrolo [2, 3-c] pyridin-3-yl) -1- (6, 8-dichloro-1, 2,3, 4-tetrahydro-naphthalene-l- yl) -lH-imidazol-4-yl] ethanol
1- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 5-chloro- 1,2,3, 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4-yl ] -ethanol1- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (5-chloro-1,2,3, 4-tetrahydro-naphthalene-l-yl) -lH-imidazol-4-yl] ethanol
2- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl )-l-(l,2,3,4- tetrahydro-naphthalen-1-yl )-lH-imidazol-4-yl]-ethanol2- [5- (5-Benzyloxy-1H-pyrrolo [2, 3-c] pyridin-3-yl) -l- (1,3,4,4-tetrahydro-naphthalene-1-yl) -IH-imidazole -4-yl] ethanol
2- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl )-l- ( 5-chloro- 1,2,3, 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4-yl ] -ethanol 2- [ 5- ( 5-Benzyloxy-liϊ-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 6-chloro- 1,2,3, 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4-yl ] -ethanol 2- [ 5- ( 5-Benzyloxy-1 H-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 7-chloro- 1,2,3, 4-tetrahydro-naphthalen-l-yl )-lH-imidazol-4-yl ] -ethanol 2- [ 5- ( 5-Benzyloxy-IH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 8-chloro- 1,2,3, 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4-yl ] -ethanol 2- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl )-1- ( 5 , 8- dichloro-1 , 2 , 3 , 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4- yl] -ethanol2- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -l- (5-chloro-1,2,3, 4-tetrahydro-naphthalene-l-yl) -lH-imidazol-4-yl] ethanol 2- [5- (5-benzyloxy-liϊ-pyrrolo [2,3-c] pyridin-3-yl) -1- (6-chloro-1,2,3 , 4-tetrahydro-naphthalene-l-yl) -lH-imidazol-4-yl] ethanol 2- [5- (5-benzyloxy-1H-pyrrolo [2, 3-c] pyridin-3-yl) - 1- (7-chloro-1,2,3,4-tetrahydro-naphthalene-l-yl) -lH-imidazol-4-yl] ethanol 2- [5- (5-benzyloxy-IH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (8-chloro-1,2,3, 4-tetrahydro-naphthalene-l-yl) -lH-imidazol-4-yl] ethanol 2- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (5, 8-dichloro-1, 2, 3, 4-tetrahydro-naphthalene-l-yl) -lH- imidazol-4-yl] ethanol
2- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 6 , 8- dichloro-1 , 2,3, 4-tetrahydro-naphthalen-l-yl ) -lH-imidazol-4- yl] -ethanol 2- [ 5- ( 5-Benzyloxy-lH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 7 , 8- dichloro-1 ,2,3 , 4-tetrahydro-naphthalen-l-yl )-lH-imidazol-4- yl]-ethanol2- [5- (5-Benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (6, 8-dichloro-1, 2,3, 4-tetrahydro-naphthalene-l- yl) -lH-imidazol-4-yl] ethanol 2- [5- (5-benzyloxy-lH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (7, 8- dichloro-1, 2,3, 4-tetrahydro-naphthalene-l-yl) -lH-imidazol-4-yl] ethanol
2- [ 5- ( 5-Benzyloxy-IH-pyrrolo[ 2 , 3-c]pyridin-3-yl ) -1- ( 5 , 7- dichloro-1 , 2,3, 4-tetrahydro-naphthalen-l-yl )-lH-imidazol-4- yl]-ethanol2- [5- (5-Benzyloxy-IH-pyrrolo [2, 3-c] pyridin-3-yl) -1- (5, 7-dichloro-1, 2,3, 4-tetrahydro-naphthalene-l- yl) -lH-imidazol-4-yl] ethanol
5-Benzyloxy-3-[ 3- ( 4 , 5 , 6 , 7-tetrahydro-benzo[J]thiophen-4-yl ) -5-benzyloxy-3- [3- (4, 5, 6, 7-tetrahydro-benzo [J] thiophene-4-yl) -
3H-imidazol-4-yl] -IH-pyrrolo[2 , 3-c]pyridine3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3- [ 3- ( 4 , 5 , 6 , 7-tetrahydro-benzofuran-4-yl ) -3H- imidazol-4-yl] -IH-pyrrolo[2 , 3-c]pyridine5-Benzyloxy-3- [3- (4, 5, 6, 7-tetrahydro-benzofuran-4-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3- [ 3- ( 6 , 7 , 8 , 9-tetrahydro-5H-benzocyclohepten-5- yl)-3H-imidazol-4-yl]-IH-pyrrolo[2 , 3-c]pyridine5-Benzyloxy-3- [3- (6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3- [ 3- ( 6 , 7 , 8 , 9-tetrahydro-5H-benzocyclohepten-6- yl)-3H-imidazol-4-yl]-IH-pyrrolo[2 , 3-c]pyridine5-Benzyloxy-3- [3- (6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-6-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5- ( 4-Chloro-benzyloxy)-3-[3-(l,2,3, 4-tetrahydro-naphthalen-l- yl)-3H-imidazol-4-yl]-IH-pyrrolo[2 , 3-c]pyridine5- (4-Chloro-benzyloxy) -3- [3- (l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3- c] pyridines
5- (2 ,4-Dichloro-benzyloxy)-3-[3-( 1 ,2 , 3 , 4-tetrahydro- naphthaleh-1-yl ) -3H-imidazol-4-yl ] -IH-pyrrolo [ 2 , 3-c]pyridine5- (2, 4-dichloro-benzyloxy) -3- [3- (1, 2, 3, 4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5- ( 3-Chloro-benzyloxy) -3- [ 3- ( 1 , 2 , 3 , 4-tetrahydro-naphthalen-l- yl)-3H-imidazol-4-yl]-IH-pyrrolo[2, 3-c]pyridine5- (3-Chloro-benzyloxy) -3- [3- (1, 2, 3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3- c] pyridines
5- ( 2-Chloro-benzyloxy)-3-[3-(l,2,3, 4-tetrahydro-naphthalen-l- yl)-3H-imidazol-4-yl]-IH-pyrrolo[2 , 3-c]pyridine5- (2-chloro-benzyloxy) -3- [3- (l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3- c] pyridines
5- ( 2 , 3-Chloro-benzyloxy ) -3- [ 3- ( 1 , 2 , 3 , 4-tetrahydro-naphthalen- l-yl)-3H-imidazol-4-yl]-IH-pyrrolo[2 , 3-c]pyridine5- (2, 3-Chloro-benzyloxy) -3- [3- (1, 2, 3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5- ( 2 , 5-Chloro-benzyloxy)-3-[3-(l,2,3, 4-tetrahydro-naphthalen- l-yl)-3H-imidazol-4-yl] -IH-pyrrolo[2 , 3-c]pyridine5- (2, 5-Chloro-benzyloxy) -3- [3- (l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5- ( 2 , 6-Chloro-benzyloxy)-3-[3-(l,2,3 , 4-tetrahydro-naphthalen-5- (2,6-chloro-benzyloxy) -3- [3- (1,2,3,4-tetrahydro-naphthalene-
1-yl ) -3H-imidazol-4-yl ] -IH-pyrrolo[ 2 , 3-c]pyridine1-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridines
5- ( 4-Chloro-benzyloxy) -3- [ 3- ( 5-chloro-l , 2,3, 4-tetrahydro- naphthalen-1-yl ) -3H-imidazol-4-yl ] -IH-pyrrolo [ 2 , 3-c]pyridine5- (4-Chloro-benzyloxy) -3- [3- (5-chloro-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3H-imidazol-4-yl] -IH-pyrrolo [ 2, 3-c] pyridines
3- [ 3- ( 5-Chloro-l , 2 , 3 , 4-tetrahydro-naphthalen-l-yl ) -3H- imidazol-4-yl]-5-(2 , 4-dichloro-benzyloxy )- IH-pyrrolo [ 2 , 3- c]pyridine3- [3- (5-Chloro-l, 2, 3, 4-tetrahydro-naphthalene-l-yl) -3H- imidazol-4-yl] -5- (2,4-dichloro-benzyloxy) - IH-pyrrolo [2,3-c] pyridines
5- ( 2 , 4-Dichloro-benzyloxy ) -3- [ 3- ( 5 , 8-dichloro-l , 2,3,4- tetrahydro-naphthalen- 1-yl) -3H- imidazol- 4 -yl] -IH-pyrrolo [2,3- c]pyridine5- (2, 4-dichloro-benzyloxy) -3- [3- (5, 8-dichloro-l, 2,3,4-tetrahydro-naphthalene-1-yl) -3H- imidazole- 4 -yl] - IH pyrrolo [2,3-c] pyridines
3- [ 3- ( 8-Chloro-l , 2 , 3 , 4-tetrahydro-naphthalen-l-yl ) -3H- imidazol-4-yl ] -5- ( 2 , 4-dichloro-benzyloxy ) -IH-pyrrolo [ 2 , 3- cjpyridine3- [3- (8-chloro-l, 2,3,4-tetrahydro-naphthalene-l-yl) -3H- imidazol-4-yl] -5- (2,4-dichloro-benzyloxy) -IH- pyrrolo [2, 3-cpyridines
5-Benzyloxy-3- [ 3- ( 8-chloro-5-methoxy-l , 2,3, 4-tetrahydro- naphthalen-l-yl)-3H-imidazol-4-yl]-lH-pyrrolo[2, 3-c] pyridine5-benzyloxy-3- [3- (8-chloro-5-methoxy-l, 2,3,4-tetrahydronaphthalen-l-yl) -3H-imidazol-4-yl] -lH-pyrrolo [2, 3-c] pyridines
5-Benzyloxy-3- [ 3- ( 5-chloro-8-methoxy-l , 2,3, 4-tetrahydro- naphthalen-1-yl ) -3H- imidazol- 4 -yl ] -IH-pyrrolo [ 2 , 3-c] pyridine5-benzyloxy-3- [3- (5-chloro-8-methoxy-l, 2,3, 4-tetrahydronaphthalen-1-yl) -3H-imidazole-4 -yl] -IH-pyrrolo [2, 3-c] pyridines
8- [ 5- ( 5 -Benzyloxy- IH-pyrrolo [ 2 , 3-c]pyridin-3-yl ) -imidazol- 1- yl ] -4-chloro-5 ,6,7, 8-tetrahydro-naphthalen-l-ol8- [5- (5-Benzyloxy-IH-pyrrolo [2, 3-c] pyridin-3-yl) imidazole-1-yl] -4-chloro-5, 6,7, 8-tetrahydro-naphthalene- l-ol
3- [ 3- ( 5-Chloro-l , 2,3, 4-tetrahydro-naphthalen-l-yl ) -3H- imidazol-4-yl] -IH-pyrrolo [2 , 3-c]pyridin-5-ol3- [3- (5-chloro-l, 2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridin-5- oil
5-Benzyloxy-3- [ 5-cyclopropyl-3- (1,2,3, 4-tetrahydro- naphthalen-l-yl)-3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridine5-benzyloxy-3- [5-cyclopropyl-3- (1,2,3, 4-tetrahydronaphthalen-l-yl) -3H-imidazol-4-yl] -IH-pyrrolo [2, 3-c] pyridine
5-Benzyloxy-3- [ 5-cyclopropyl-3- ( 5-morpholin-4-yl-l ,2,3,4- tetrahydro-naphthalen- 1-yl) -3H-imidazol-4-yl]- IH-pyrrolo [2,3- c] pyridine5-benzyloxy-3- [5-cyclopropyl-3- (5-morpholin-4-yl-l, 2,3,4-tetrahydro-naphthalene-1-yl) -3H-imidazol-4-yl] - IH- pyrrolo [2,3-c] pyridines
3- [ 5-Cyclopropyl-3- (1,2,3, 4-tetrahydro-naphthalen-l-yl ) -3H- imidazol-4-yl ] -5-methoxy-IH-pyrrolo[ 2 , 3-c] pyridine3- [5-Cyclopropyl-3- (1,2,3, 4-tetrahydro-naphthalene-l-yl) -3H-imidazol-4-yl] -5-methoxy-IH-pyrrolo [2, 3-c] pyridine
8. Pharmazeutische Zusammensetzung, die mindestens ein 3-Pyr- roloimidazol-Derivat nach einem der vorstehenden Ansprüche gegebenenfalls in Kombination mit an sich üblichen Trägern und/oder Adjuvantien und/oder Hilfsstoffen enthält. 8. Pharmaceutical composition containing at least one 3-pyrroloimidazole derivative according to one of the preceding claims, optionally in combination with conventional carriers and / or adjuvants and / or auxiliaries.
9. Pharmazeutische Zusammensetzung nach Anspruch 8, die als Pflaster, Salbe, Paste, Gel, Creme, lösliches Pulver, Lotion, Emulsion, Spray, Puder, Suspension, Suppositorium oder Injektionslösung formuliert ist.9. Pharmaceutical composition according to claim 8, which is formulated as a plaster, ointment, paste, gel, cream, soluble powder, lotion, emulsion, spray, powder, suspension, suppository or solution for injection.
10. Pharmazeutische Zusammensetzung nach Anspruch 8 oder 9, die mindestens ein Konjugat aus einem tumorspezifischen Antikörper und einer oder mehreren Verbindungen nach einem der vorstehenden Ansprüche enthält.10. A pharmaceutical composition according to claim 8 or 9, which contains at least one conjugate of a tumor-specific antibody and one or more compounds according to any one of the preceding claims.
11. Pharmazeutische Zusammensetzung nach einem der Ansprüche 8 bis 10, wobei die Wirkstoffe und gegebenenfalls die Konju- gate mit tumorspezifischen Antikörpern in Liposomen verpackt sind.11. Pharmaceutical composition according to one of claims 8 to 10, wherein the active substances and optionally the conjugates with tumor-specific antibodies are packaged in liposomes.
12. Verwendung der 3-Pyrroloimidazol-Derivate oder pharmazeutischen Zusammensetzungen nach einem der vorstehenden Ansprüche zur Therapie oder Prophylaxe von Tumor- oder Krebserkrankungen.12. Use of the 3-pyrroloimidazole derivatives or pharmaceutical compositions according to one of the preceding claims for the therapy or prophylaxis of tumor or cancer diseases.
13. Verwendung nach Anspruch 12, dadurch gekennzeichnet, daß die Tumor- oder Krebserkrankungen gut- und bösartige Tumoren solider oder cystischer Natur, Adenome, Cyst-Adenome, Papil- lome, Adenokarzinome, Adenokarzinome vom cirrhoesen Typ, Ba- salzellkarzinome, Sarkome, Fibrosarkome, Liposarkome, Lympho- sarkome, Rhabdomyosarkome, Myxosarkome, Chondrosarkome, Reti- kulumzellsarkome, Morbus Hodgkin, embryonale Tumore, Neuro- blastome, Nephroblastome, Teratome, Adamintome, Retroblasto- me, Haemangiome, Chordome, Odontome, Craniopharyngome, Hamar- tome, Lymphoangiome, Exostosen, Neurofibrantose, Melanome, Lymphome, Hepatoblastome, Mammakarzinome, Cervixkarzinome, Choriokarzinome, Adenoacantome, Androblastome, Leiomyome, Ar- rhenoblastome, Sertolizelltumore, Theca- und Granulosazell- Tumore, Germinome und Seminome, Ovarial- und Vulvakarzinome, Harnblasen- und Prostatakarzinome, durch Schistosomiasis her- vorgerufene Tumore, Astrocytome, Ependymogliome, Glioblasto- me, Medulloblastome, Oligodendrogliome, Spongioblastome, Me- ningeome, Tumore der Schwan 'sehen Scheidenzellen, Pinealome, Haemangioblastome, Osteoclastome, Ewings Tumore, multiple Myelome, Mxcosis fungoides, Burkitt-Tumore, Leukaemien, akute und chronische lymphatische Leukaemien, akute und chronische Granulocytenleukaemien, akute und chronische Monocytenleukae- mien, Stammzellenleukaemien, Basaliome, Fibrome, Myome und die bei einem chirurgischen Eingriff einer lokalen Injektion zugänglichen Metastasen sämtlicher Tumorformen sind.13. Use according to claim 12, characterized in that the tumor or cancer diseases benign and malignant 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, reticulum cell sarcomas, Hodgkin's disease, embryonic tumors, neuroblastomas, nephroblastomas, teratomas, adamintomas, retroblastomas, haemangiomas, chordomas, arterial tumors, odontomas , Exostoses, neurofibrantosis, melanoma, lymphoma, hepatoblastoma, breast cancer, cervical cancer, Choriocarcinomas, adenoacantomas, androblastomas, leiomyomas, arrhenoblastomas, sertoli cell tumors, theca and granulosa cell tumors, germinomas and seminomas, ovarian and vulvar carcinomas, bladder and prostate carcinomas, by schistrocytoma tumors, pre-, osteogymoma tumors, pre-existing, ectopic tumors Medulloblastomas, oligodendrogliomas, spongioblastomas, meningiomas, tumors of the swan see vaginal cells, pinealomas, haemangioblastomas, osteoclastomas, Ewings tumors, multiple myelomas, mxcosis fungoides, Burkitt tumors, leukaemias, acute and chronic lymphocytic leukemia, acute and chronic lymphocytic leukemia and chronic monocyte leukemias, stem cell leukemias, basaliomas, fibromas, fibroids and which are metastases of all types of tumors which are accessible to a local injection during surgery.
14. Verwendung der 3-Pyrroloimidazol-Derivate oder pharmazeutischen Zusammensetzungen nach einem der vorstehenden Ansprüche als Antibiotikum zur Therapie oder Prophylaxe von Infektionen durch Mikroorganismen.14. Use of the 3-pyrroloimidazole derivatives or pharmaceutical compositions according to one of the preceding claims as an antibiotic for the therapy or prophylaxis of infections by microorganisms.
15. Verwendung nach einem der Ansprüche 12 oder 14, dadurch gekennzeichnet, daß die 3-Pyrroloimidazol-Derivate oder pharmazeutischen Zusammensetzungen lokal oder systemisch eingesetzt werden. 15. Use according to one of claims 12 or 14, characterized in that the 3-pyrroloimidazole derivatives or pharmaceutical compositions are used locally or systemically.
EP00981195A 1999-10-07 2000-10-09 Pyrrolo imidazole derivatives and their use as medicaments Withdrawn EP1228044A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19948417 1999-10-07
DE19948417A DE19948417A1 (en) 1999-10-07 1999-10-07 Imidazole derivatives and their use as medicines
PCT/EP2000/009904 WO2001025213A2 (en) 1999-10-07 2000-10-09 Pyrrolo imidazole derivatives and their use as medicaments

Publications (1)

Publication Number Publication Date
EP1228044A2 true EP1228044A2 (en) 2002-08-07

Family

ID=7924877

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00981195A Withdrawn EP1228044A2 (en) 1999-10-07 2000-10-09 Pyrrolo imidazole derivatives and their use as medicaments

Country Status (7)

Country Link
US (1) US6699883B1 (en)
EP (1) EP1228044A2 (en)
JP (1) JP2003511373A (en)
AU (1) AU1853101A (en)
CA (1) CA2386795A1 (en)
DE (1) DE19948417A1 (en)
WO (1) WO2001025213A2 (en)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7641701B2 (en) * 2003-09-30 2010-01-05 X-Spine Systems, Inc. Spinal fusion system and method for fusing spinal bones
US7626021B2 (en) * 2004-07-27 2009-12-01 Sgx Pharmaceuticals, Inc. Fused ring heterocycle kinase modulators
AU2005269387A1 (en) 2004-07-27 2006-02-09 Sgx Pharmaceuticals, Inc. Fused ring heterocycle kinase modulators
BRPI0513916A (en) 2004-07-27 2008-05-20 Sgx Pharmaceuticals Inc pyrrol pyridine kinase modulators
US7361764B2 (en) 2004-07-27 2008-04-22 Sgx Pharmaceuticals, Inc. Pyrrolo-pyridine kinase modulators
US7405302B2 (en) * 2005-10-11 2008-07-29 Amira Pharmaceuticals, Inc. 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
GB2431927B (en) * 2005-11-04 2010-03-17 Amira Pharmaceuticals Inc 5-Lipoxygenase-activating protein (FLAP) inhibitors
US8399666B2 (en) * 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
AR065860A1 (en) * 2007-03-29 2009-07-08 Novartis Ag 3-IMIDAZOLIL-INDOLES FOR THE TREATMENT OF PROLIFERATIVE DISEASES
TW200920369A (en) * 2007-10-26 2009-05-16 Amira Pharmaceuticals Inc 5-lipoxygenase activating protein (flap) inhibitor
JP5791500B2 (en) * 2008-05-23 2015-10-07 パンミラ ファーマシューティカルズ，エルエルシー． 5-lipoxygenase activating protein inhibitor
US8546431B2 (en) 2008-10-01 2013-10-01 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
PE20120508A1 (en) 2009-06-17 2012-05-09 Vertex Pharma INHIBITORS OF THE REPLICATION OF FLU VIRUSES
CN103492381A (en) 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
UA118010C2 (en) 2011-08-01 2018-11-12 Вертекс Фармасьютікалз Інкорпорейтед INFLUENCES OF INFLUENZA VIRUS REPLICATION
TWI627173B (en) * 2013-09-26 2018-06-21 比利時商健生藥品公司 New 3-(1h-pyrazol-4-yl)-1h-pyrrolo[2,3-c]pyridine derivatives as nik inhibitors
SG10201804021TA (en) 2013-11-13 2018-07-30 Vertex Pharma Methods of preparing inhibitors of influenza viruses replication
EP3068776B1 (en) 2013-11-13 2019-05-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
JP6857617B2 (en) 2015-05-13 2021-04-14 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Influenza virus replication inhibitor
WO2016183116A1 (en) 2015-05-13 2016-11-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
HUE045355T2 (en) * 2016-07-21 2019-12-30 Inst Farmakologii Polskiej Akademii Nauk Imidazolyl-substituted indole derivatives binding 5-ht7 serotonin receptor and pharmaceutical compositions thereof
AU2022328217A1 (en) * 2021-08-12 2024-03-14 Kuleon Llc Hallucinogenic and non-hallucinogenic serotonin receptor agonists and methods of making and using the same

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL264338A (en) * 1960-05-04
DE3141063A1 (en) * 1981-10-13 1983-04-28 Schering Ag, 1000 Berlin Und 4619 Bergkamen NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
US4866084A (en) * 1987-07-17 1989-09-12 Harbor Branch Oceanographic Institution, Inc. Topsentin compounds effective against viruses and certain tumors
JP2722586B2 (en) * 1989-01-13 1998-03-04 大正製薬株式会社 Indolyl imidazole derivatives
US4970226A (en) * 1989-10-03 1990-11-13 Harbor Branch Oceanographic Institution, Inc. Bis-indole imidazole compounds which are useful antitumor and antimicrobial agents
EP0711768B1 (en) * 1994-05-31 2002-02-13 Mitsui Chemicals, Inc. Benzimidazole derivative
US6080772A (en) * 1995-06-07 2000-06-27 Sugen, Inc. Thiazole compounds and methods of modulating signal transduction
US5965558A (en) * 1995-06-19 1999-10-12 Ontogen Corporation Modulators of proteins with phosphotyrosine recognition units
WO1997016441A1 (en) * 1995-10-31 1997-05-09 Merck & Co., Inc. Substituted aryl pyrroles, compositions containing such compounds and methods of use
EP1021173A1 (en) * 1997-10-10 2000-07-26 Imperial College Innovations Limited Use of csaid?tm compounds for the management of uterine contractions
AR017200A1 (en) * 1997-12-23 2001-08-22 Astrazeneca Ab INHIBITING COMPOUNDS OF PROTEIN CINASE C, PHARMACEUTICALLY ACCEPTABLE SALTS OF THE SAME, PHARMACEUTICAL FORMULATIONS THAT UNDERSTAND THEM, USE THE SAME AND PROCESS FOR THE SYNTHESIS OF SUCH COMPOUNDS
PA8474101A1 (en) * 1998-06-19 2000-09-29 Pfizer Prod Inc PYROLEUM [2,3-D] PIRIMIDINE COMPOUNDS
FR2789392B1 (en) * 1999-02-04 2001-10-05 Hoechst Marion Roussel Inc NOVEL ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Gazz.Chim.Ital., 87, 1957, 11,18 *
J.Org.Chem. 65, 5, 2000, 1516 - 1524 *
Pharm.Chem.J.(Engl.Transl.), 2, 1970, 68 *
See also references of WO0125213A3 *

Also Published As

Publication number Publication date
DE19948417A1 (en) 2001-04-19
US6699883B1 (en) 2004-03-02
WO2001025213A2 (en) 2001-04-12
JP2003511373A (en) 2003-03-25
CA2386795A1 (en) 2001-04-12
WO2001025213A3 (en) 2001-06-07
AU1853101A (en) 2001-05-10
WO2001025213B1 (en) 2001-10-18

Similar Documents

Publication Publication Date Title
EP1228044A2 (en) Pyrrolo imidazole derivatives and their use as medicaments
DE60319364T2 (en) SUBSTITUTED PYRROLINS AS KINASE INHIBITORS
DE69907964T2 (en) 1,2-FELLENED CHINOLINE DERIVATIVES
DE69836332T2 (en) BENZYLIDEN-1,3-DIHYDRO-INDOL-2-ON DERIVATIVES AS INHIBITORS OF RECEPTOR TYROSINE KINASEN, ESPECIALLY BY RAF KINASEN
DE60002714T2 (en) SUBSTITUTED AZAOXINDOL DERIVATIVES
AU685821B2 (en) Substituted heterocyclylisoquinolinium salts and compositions and method of use thereof
CA2913223A1 (en) Pyrazolopyrrolidine derivatives and their use in the treatment of disease
DE69914357T2 (en) PYRIDIN-4-YL OR PYRIMIDIN-4-YL SUBSTITUTED PYRAZINE
EP3412675A1 (en) Imidazopyrrolidinone derivatives and their use in the treatment of disease
JP2000506537A (en) Novel N-7-heterocyclyl-pyrrolo [2,3-d] pyrimidines and uses thereof
EP1222191A2 (en) Benzodiazepin derivatives, the production and use thereof
DE3141063A1 (en) NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
DE60117835T2 (en) Amino-substituted tetracyclic compounds useful as anti-inflammatory agents and drugs containing them
WO2001034601A2 (en) Imidazopyridine derivatives as phosphodiesterase vii inhibitors
WO2019084496A1 (en) 6-(5-membered heteroaryl)isoquinolin-3-yl-(5-membered heteroaryl) carboxamides and preparation and use thereof
CN112236416A (en) Pyrimidine cyclohexenyl glucocorticoid receptor modulators
EP3558980B1 (en) Compounds for use in the treatment of kinetoplastid infection
EP0251194B1 (en) Use of carbocyclic and heterocyclic condensed dihydropyridines for the preparation of cardioprotective remedies and heterocyclic and carbocyclic condensed dihydropyridines and methods and intermediates for their preparation
WO2017165139A1 (en) 1,4,5-substituted 1,2,3-triazole analogues as antagonists of the pregnane x receptor
HU229095B1 (en) Farnesyl transferase inhibiting 1,2-annelated quinoline enantiomer pharmaceutical compositions containing
DE60106947T2 (en) oxindole derivatives
EP1519934B1 (en) Pyrazoloisoquinoline derivatives for inhibiting nf$g(k)b-inducing kinase (nik)
DE2409262A1 (en) IMIDAZO SQUARE BRACKET ON 1.2 ANGLE BRACKET FOR AZACYCLOALKANE
DE19947297A1 (en) Cyclic biphenyls, processes for their preparation and their use as medicines
WO2001019791A2 (en) 3-vinylpyrrole derivatives, method for the production thereof and their use as medicaments

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020311

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20040302

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20040802