WO2008015265A1 - Anthracen derivatives and their use for the treatment of benign and malignant tumorous diseases - Google Patents

Anthracen derivatives and their use for the treatment of benign and malignant tumorous diseases Download PDF

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WO2008015265A1
WO2008015265A1 PCT/EP2007/058046 EP2007058046W WO2008015265A1 WO 2008015265 A1 WO2008015265 A1 WO 2008015265A1 EP 2007058046 W EP2007058046 W EP 2007058046W WO 2008015265 A1 WO2008015265 A1 WO 2008015265A1
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unsubstituted
alkyl
compound
substituted
phenyl
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PCT/EP2007/058046
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German (de)
French (fr)
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Matthias Gerlach
Eckhard Günther
Peter Schmidt
Helge Prinz
Konrad BÖHM
Eberhard Unger
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Æterna Zentaris Gmbh
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Priority claimed from EP06016401A external-priority patent/EP1897864A1/en
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Publication of WO2008015265A1 publication Critical patent/WO2008015265A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
    • C07C49/798—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring containing rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/20—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups being part of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Definitions

  • the invention relates to novel anthracene derivatives for the treatment of benign and malignant tumor diseases.
  • These compounds act as inhibitors of tubulin polymerization and / or as inhibitors of microtubule-based motor proteins, in particular kinesins and dyneins, and are suitable for the treatment or prophylaxis of inhibition of tubulin polymerization and / or of inhibition by micro - Tubuli-based motor proteins treatable physiological and / or pathophysiological states and various tumor diseases.
  • tumors are a fundamental disease of higher organisms in the plant and animal kingdoms as well as in humans.
  • the widely accepted multi-step model of carcinogenesis assumes that by accumulating mutations in a single cell, their proliferation and differentiation behavior is altered to ultimately achieve a malignant state with metastasis through benign intermediates.
  • the term cancer or tumor conceals a clinical picture of more than 200 different individual diseases. Tumor diseases can be benign or malignant.
  • Important tumors are those of the lung, the breast, the stomach, the cervix, the prostate, the head and neck, the colon and rectum, the liver and the blood system.
  • the prognosis and the therapy behavior there are great differences. More than 90% of detected cases involve solid tumors that are currently difficult or impossible to treat, especially in advanced stages or metastases.
  • chemotherapy is an important pillar of cancer control. Despite great progress, it is so far failed to develop drugs that cause in the widespread solid tumors a significant prolongation of survival or even complete healing.
  • the problem of resistance development in established tumor therapeutics is becoming increasingly common in the clinic. It therefore makes sense to invent new medicines to fight cancer.
  • mitosis One possible approach to combating cancer is the inhibition of cell division (mitosis).
  • a large number of anti-mitotic drugs have been shown to be effective in clinical oncology. Examples include the alkaloids vincristine and vinblastine in the treatment of leukemia and Hodgkin's lymphoma, and paclitaxel and docetaxel for the treatment of metastatic breast, lung and ovarian cancers.
  • WO 2004/007470 describes novel antacanner derivatives and their use as medicaments.
  • the compounds described could act by inhibiting tubulin polymerization.
  • EP 1 645 556 describes arylpiperazine-benzoylamide derivatives which are useful as pharmaceutical agents and inhibitors of tubulin polymerization.
  • WO 02/060872 describes synthetic methods for compounds which can be characterized in a screening as potential inhibitors of tubulin polymerization.
  • Bryce-Smith and co-workers describe the photoaddition of diphenylacetylene, cycloocta-1,3-diene, and cyclooctene to anthraquinone.
  • a commercial application, especially as a pharmaceutical, is neither described nor suggested (Bryce-Smith D et al., Tetrahedron Letters 1968, 9 (24): 2863-2866).
  • the present invention therefore has the object of providing new substances which are suitable for the treatment of cancerous diseases.
  • the inventive task has in one aspect surprisingly been solved by adding novel anthracene derivatives according to the general formula (I) - A -
  • Substituent X is independently selected from the group consisting of: "O, S, NR11, N-OR12, geminally linked hydrogen and hydroxy";
  • Substituent Y is independently selected from the group consisting of: "O, S, NR 13, N-OR 14";
  • Substituents R1, R2, R3, R4, R5, R6, R7, R8 are independently selected independently from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted Heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, amino, mono-alkylamino, di-alkylamino, halogen, -F, -Cl, -Br, -I, alkyl substituted with one or more fluorine atoms, trifluoromethyl, cyano, straight-chain or branched
  • Substituent R9 is independently selected from the group consisting of: unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, -0R15, -NR16R17 ";
  • Substituent R10 is independently selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl";
  • Substituents R11, R12, R13, R14, R15, R16, R17 independently of one another are selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclic IyI, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl "with the proviso that the following are included in the general formula (I) Exclusions are: (i) Compound with Chemical Abstract Service (CAS) Registry No. 262378-52-9
  • Substituent X is independently selected from the group consisting of: "O, S, NH, geminally linked hydrogen and hydroxy";
  • Substituent Y is independently "O or S"
  • Substituents R1, R2, R3, R4, R5, R6, R7, R8 are independently "hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, trifluoromethyl";
  • Substituent R9 is independently selected from the group consisting of: "unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -OR15, -NR16R17";
  • Substituent R10 is independently “hydrogen, alkyl”.
  • new anthracene derivatives are selected from the group consisting of: 10- [2- (3,4-Dihydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 1):
  • alkyl in the context of this invention comprises acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chained and unsubstituted or monosubstituted or polysubstituted, having 1 to 20 carbon atoms, ie Cr 20 - alkanyl, C 2 - 2 o-alkenyls and C 2 - 2 o-alkynyl, preferably having from 1 to 8 carbon atoms, ie C r8 - alkanyls, C 2 - 8 alkenyls, and C 2 -.
  • alkynyls alkenyls have at least one C-C At least one double bond and alkynyls on at least one C-C triple bond, wherein alkynyls may additionally also have at least one carbon-carbon double bond.
  • cycloalkyl for the purposes of this invention means cyclic, non-aromatic hydrocarbons having 1 to 3 rings of 3 to 20, preferably 3 to 12 carbons, which may be saturated or unsaturated, more preferably (C 3 -C 8 ) -
  • the cycloalkyl radical may also be part of a bicyclic or polycyclic system, where, for example, the cycloalkyl radical having an aryl, heteroaryl or heterocyclyl radical as defined herein by any (s) possible and desired ring member ( The bonding to the compounds of the general formulas (I) and (II) can be effected via any and possible ring member of the cycloalkyl radical
  • Preferred cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and Cyclooctyl, cyclodecyl, cyclohexenyl, cyclopenten
  • heterocyclyl represents a 3- to 14-membered, preferably 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical containing at least 1, optionally 2, 3, 4 or Contains heteroatoms, in particular nitrogen, oxygen and / or sulfur, wherein the heteroatoms are the same or different and the cyclic radical is saturated or unsaturated, but not aromatic and may be unsubstituted or mono- or polysubstituted
  • the heterocyclyl radical may also be part a bi- or polycyclic system where, for example, the heterocyclyl radical is fused with an aryl, heteroaryl or cycloalkyl radical as defined herein by any possible and desired ring member (s)
  • the compounds of the general formulas (I) and (II) can be made via any and possible ring member of the heterocyclyl radical
  • Preferred heteroatoms are nitrogen, oxygen and sulfur
  • Preferred heterocyclyl radicals are tetrahydrofuryl, pyrrolidine nyl
  • aryl in the context of this invention means aromatic hydrocarbons having 3 to 14 C atoms, preferably 5 to 14 C atoms, more preferably having 6 to 14 C atoms, including phenyls, naphthyls and anthracenyls also be part of a bi- or polycyclic system, where, for example, the aryl radical is fused with a heterocyclyl, heteroaryl or cycloalkyl radical as defined herein by any possible and desired ring member (s), eg.
  • aryl radical can be unsubstituted or monosubstituted or polysubstituted, wherein the aryl substituents are identical or different and in any desired and possible position of the aryl radical Aryls can be.
  • Preferred aryl radicals are phenyl, biphenyl, naphthyl and anthracenyl, but also indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl.
  • heteroaryl represents a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, in particular nitrogen, oxygen and / or sulfur, where the heteroatoms are the same or different and the heterocycle is unsubstituted or monosubstituted or polysubstituted can be.
  • the heteroaryl substituents may be the same or different and may be in any desired and possible position of the heteroaryl.
  • the number of nitrogen atoms is preferably 0, 1, 2 or 3, and the oxygen and sulfur atoms are preferably 0 or 1.
  • the heteroaryl radical may also be part of a bi- or polycyclic system where, for example, the heteroaryl radical is substituted by a heterocyclyl radical.
  • the binding to the compounds of the general formulas (I) and (II) can be effected via any and possible ring member of the heteroaryl radical.
  • the heterocycle may also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • Preferred heteroaryl radicals are pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazole, tetrazole, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, phthalazinyl, indolyl, indazolyl, indolizine - nyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.
  • alkylcycloalkyl mean for the purposes of the present invention in that alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above and the cycloalkyl, heterocyclyl, aryl and heteroaryl radical has an alkyl radical, preferably C 1 -C 8 -alkyl radical, particularly preferably C 4 alkyl radical to which compounds of the general formulas (I) and (II) are bonded.
  • alkyl In connection with “alkyl”, “alkenyl” and “alkynyl”, the term “substituted” in the context of this invention means the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-arylalkyl, NH-heteroaryl-alkyl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , N (aryl-alkyl) 2 , N (Heteroaryl-alkyl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-aryl-alkyl, S-heteroaryl-alkyl, S-
  • aryl With respect to "aryl”, “aryl-alkyl”, “alkyl-aryl”, “heteroaryl”, heteroaryl-alkyl “,” alkyl Heteroaryl “,” heterocyclyl “,” heterocyclyl-alkyl “,” alkyl heterocyclyl “,” cycloalkyl “,” alkyl-cycloalkyl “and” cycloalkyl-alkyl "is understood by the term” substituted “in the context of this invention, the one - or multiple substitution, for example two-, three- or four-fold, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-aryl -alkyl, NH-heteroaryl-alkyl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , NC (O) al
  • cyanoalkyl means that an alkyl radical as defined above is bonded to a cyano group
  • the compounds of the general formulas (I) and (II) are bonded via the cyano group and n-propyl cyano.
  • carbonyl in the context of this invention means that an alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cyloalkyl, aryl, heteroaryl, aryl-alkyl, alkyl-aryl, heteroaryl-alkyl, alkyl-heteroaryl, heterocyclyl, alkyl-heterocyclyl and / or heterocyclyl-alkyl radical as defined above to a -C (O) - group is bound.
  • carboxyl in the context of this invention means that an alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cyloalkyl, aryl, heteroaryl, aryl-alkyl, alkyl-aryl, heteroaryl-alkyl, alkyl-heteroaryl, heterocyclyl, alkyl-heterocyclyl and / or heterocyclylalkyl radical is bound to a -C (O) O- group as defined above.
  • the binding to the compounds of the general formulas (I) and (II) takes place via the C (O) O- group. Examples are -C (O) O-CH 3 and -C (O) O-phenyl.
  • carboxyalkyl in the context of this invention means that a carboxy group as defined above is bonded to an alkyl radical as defined above. The binding to the compounds of the general formulas (I) and (II) takes place via the alkyl radical.
  • alkoxy in the context of this invention means that an alkyl radical as defined above is bonded to an oxygen atom.
  • the binding to the compounds of the general formulas (I) and (II) takes place via the oxygen atom. Examples are methoxy, ethoxy and n-propyloxy.
  • alkoxy in the terms “alkoxycarbonyl”, “arylalkoxy”, “heteroarylalkoxy”, “alkoxycarbonylamino”, “alkoxycarbonylaminoalkyl” has the meaning defined above.
  • the binding to the compounds of the general formulas (I) and (II) takes place in the case of "arylalkoxy” and “heteroarylalkoxy” via the oxygen atom. Examples are benzyloxy and indolyloxy.
  • alkoxycarbonyl-alkyl the bond to the compounds of the general formulas (I) and (II) takes place via the alkyl radical as defined above:
  • alkoxycarbonylamino the bond to the compounds of the general formulas (I) and (II) via the amino group, in the case of "alkoxycarbonylamino-alkyl” via the alkyl radical as defined above.
  • metal within the meaning of this invention includes metal ions such as sodium, potassium, lithium, magnesium, calcium, zinc and manganese ions.
  • halogen for the purposes of this invention, the halogen atoms fluorine, chlorine, bromine and iodine.
  • the compounds according to the invention may be present in the form of their racemates, in the form of pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers, both in substance and as pharmaceutically acceptable salts of these compounds.
  • the mixtures can be present in any mixing ratio of the stereoisomers.
  • the compounds according to the invention which have one or more centers of chirality and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se.
  • the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by using an optically active acid or base or by derivatization with an optically active reagent, such as an optically active alcohol, followed by cleavage of the residue.
  • the compounds according to the invention can be present in the form of their double bond isomers as "pure” E or Z isomers or in the form of mixtures of these double bond isomers.
  • the compounds of the invention may be in the form of tautomers.
  • the compounds according to the invention can be converted into their physiologically acceptable salts with inorganic and organic acids.
  • the pharmaceutically acceptable salts of the compounds of the invention are hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, trifluoroacetic, sulfoacetic, oxalic, malonic, maleic, succinic, tartaric, racemic, malic, embonic, Mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid formed.
  • the salts formed are, inter alia, hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, phosphates, methanesulfonates, tosylates, carbonates, hydrogencarbonates, formates, acetates, triflates, sulfoacetates, oxalates, malonates, maleates, succinates. te, tartrates, malates, embonates, almonds, fumarates, lactates, citrates, glutaminates and aspartates.
  • the stoichiometry of the formed salts of the compounds according to the invention can be integer or non-integer multiples of one.
  • Group such as the carboxy group or the phosphoric acid group, are converted with inorganic and organic bases in their physiologically acceptable salts.
  • Suitable inorganic bases are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, as organic bases ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine and lysine.
  • the stoichiometry of the formed salts of the compounds according to the invention can be integer or non-integer multiples of one.
  • the compounds of the general formulas (I) and (II) according to the invention if they contain groups capable of forming coordination compounds, can be converted with transition metals into coordination compounds / complex compounds.
  • the pharmaceutically acceptable coordination compounds / complex compounds of the compounds of the invention according to the general formulas (I) and (II) are formed with platinum salts.
  • the stoichiometry of the formed coordination compounds / complex compounds of the compounds according to the invention can thereby assume integer or non-integer ratios of the compounds according to the invention as ligands to the transition metal.
  • solvates and in particular hydrates of the compounds of the invention can be obtained by crystallization from a solvent or aqueous solution.
  • One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to give solvates and hydrates.
  • polymorphic forms It is known that chemical substances form solids, which in different There are states of order called polymorphic forms or modifications.
  • the various modifications of a polymorphic substance may differ greatly in their physical properties.
  • the compounds of the invention may exist in various polymorphic forms, while certain modifications may be metastable.
  • the compounds according to the invention may be present in the form of any prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which the actually biologically active form is released only by metabolism.
  • prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which the actually biologically active form is released only by metabolism.
  • the compounds according to the invention are potent inhibitors of tubulin polymerization and / or inhibitors of microtubule-based motor proteins, for example kinesins and dynins, in particular mitotic kinesins. Kinesins are described in detail in Miki H et al.
  • KIF kinesin superfamily
  • N-1 kinesins KIF5A, KIF5B, KIF5C, N-2 kinesins
  • Eg5 KIF1 1, KSP
  • BimC KIF8
  • N-3 kinesins KIF1A, KIF1B, KIF1C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 kinesins, KIF3A, KIF3B, KIF3C, KIF17 , N-5 kinesins, KIF4, KIF4A, KIF4B, KIF21A, KIF21B, N-6 kinesins, KIF23 (MKLP1, CHO1), KIF20A (Rab6-KIF), KIF20B (KIpMPPI), MKLP2, N-7 kinesins, KIF23 (MKLP1, CHO1), KIF20A (Rab6-KIF), KIF20B (KIpMPPI
  • the surprising dual mechanism of action makes the compounds according to the invention particularly suitable as medicaments for the treatment of benign and malignant tumor diseases in humans and animals.
  • Both the tubulin framework and engine proteins play an important role in mitosis, a specific phase of the cell cycle.
  • the advantageous inhibition of one or both targets prevents the correct formation of the mitotic spindle and thus the distribution of the genetic material to the daughter cells.
  • the uncontrollably dividing tumor cell is arrested in the cell cycle. This leads to a death of the tumor cell due to programmed cell death (apoptosis).
  • apoptosis programmed cell death
  • the compounds according to the invention advantageously show no serious side effects, such as, for example, neurotoxicity.
  • the inventive task has surprisingly been achieved in a further aspect by providing a process for the preparation of the compounds according to the invention.
  • the compounds according to the invention can be administered to all known mammals, in particular humans, for the treatment and / or prophylaxis.
  • the compounds of the invention are provided for the uses set forth above, wherein the mammal is selected from the group consisting of: "human, farm animal, livestock, pet, cattle, cow, sheep, pig, goat, horse, pony, Donkey, mule, mule, rabbit, rabbit, cat, dog, guinea pig, hamster, rat, mouse "and prefers a human being.
  • Substituent V is independently selected from the group consisting of: "O, S, NR28, N-OR29, geminally linked hydrogen and hydroxy;
  • Substituent Z is independently selected from the group consisting of: "O, S, NR30, N-OR31";
  • Substituents R18, R19, R20, R21, R22, R23, R24, R25 independently of one another are selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, amino, mono-alkylamino, di-alkylamino, halogen, -F, -Cl, -Br, -
  • substituent R26 is independently selected from the group consisting of:" unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted Heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl
  • compositions comprising at least one anthracene derivative according to the general formula (II).
  • substitution "geminally linked hydrogen and hydroxy" in connection with the substituent V is understood in the context of the present invention to mean that both “H” and “OH” are bonded to one and the same carbon atom.
  • anthracene derivatives according to the general formula (II) are provided as just described, wherein:
  • Substituent V is independently selected from the group consisting of: "O, S, NH, geminally linked hydrogen and hydroxy";
  • Substituent Z is independently “O or S"
  • Substituents R18, R19, R20, R21, R22, R23, R24, R25 are independently "hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, trifluoromethyl";
  • Substituent R26 is independently selected from the group consisting of: "unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -OR32, - NR33R34"; Substituent R27 is independently “hydrogen, alkyl” which may be used to make a drug.
  • compositions comprising at least one anthracene derivative according to the general formula (II) and this preferred embodiment.
  • anthracene derivatives according to the general formula (II) are provided as just described, wherein:
  • Substituent R27 is independently selected from the group consisting of: "3,4-
  • compositions comprising at least one anthracene derivative according to the general formula (II) and this preferred embodiment.
  • anthracene derivative compounds 1 to 43 are provided for the manufacture of a medicament.
  • compositions comprising at least one anthracene derivative compound 1 to 43.
  • the compounds according to the invention can be used for the treatment or prophylaxis of physiological and / or pathophysiological conditions which can be treated by the inhibition of tubulin polymerization and / or by the inhibition of microtubule-based motor proteins.
  • the microtubule-based motor proteins are selected from the group consisting of: "kinesins, dyneins, kinesin superfamily (KIF) protein, N-1 kinesins, KIF5A, KIF5B, KIF5C, N-2 kinesins, Eg5 (KIF1 1 , KSP), BimC (KIF8), N-3 kinesins, KIF1A, KIF1B, KIF1C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 kinesins, KIF3A, KIF3B, KIF3C, KIF17, N-5 kinesins, KIF4, KIF4A, KIF4B, KIF21A, KIF21B, N-6 kinesins, KIF23 (MKLP1, CHO1), KIF20A (Rab6-KIF), KIF20B (KIpMPPI), MKLP2, N-7
  • KIF6, KIF7, KIF9 and are preferably selected from the group consisting of:” Eg5 (KIF1 1, KSP), KIF4, KIF4A, KIF4B, KIF10 (CENP-E), KIF23 (MKLP1, CHO1) ".
  • the compounds according to the invention can be used for the treatment or prophylaxis of malignant tumors, benign tumors, solid / solid tumors, sarcomas, carcinomas, hyperproliferative disorders, carcinoids, Ewing sarcomas, Kaposi's sarcomas, brain tumors, tumors originating from the brain and / or nervous system and / or meninges (WO 99/01764), glioma, neuroblastoma, gastric cancer, kidney cancer, renal cell carcinoma, prostate cancer, prostate carcinoma, connective tissue tumors, soft tissue sarcoma, pancreatic tumors, liver tumors, head tumors, cervical tumors, esophageal cancer, thyroid cancer,
  • Osteosarcoma retinoblastoma, thymoma, testicular cancer, lung cancer, bronchial carcinoma, breast cancer, breast cancer, colorectal cancer, colorectal cancer, colon cancer, rectal cancer, gynocological tumors, ovarian tumors / ovarian tumors, uterine cancer, cervix cancer, cervical carcinoma, uterine cancer, carcinoma of the body, endometrial carcinoma, bladder cancer, bladder cancer, skin cancer, basalioma , Spinal, melanoma, intraocular melanoma, leukemia, chronic leukemia, acute leukemia and / or lymphoma. These indications also represent physiological and / or pathophysiological conditions that can be treated by the inhibition of tubulin polymerization and / or by the inhibition of microtubule-based motor proteins.
  • the inventive task was surprisingly achieved in that the compounds according to the invention in accordance with the aspects presented above, preferred embodiments and Uses for the preparation of a medicament, wherein the medicament additionally contains at least one further pharmacologically active substance.
  • the inventive task has surprisingly been achieved by providing the compounds according to the invention in accordance with the aspects, preferred embodiments and uses described above, for use in the manufacture of a medicament, wherein the medicament before and / or during and / or or after treatment with at least one other pharmacologically active substance.
  • the inventive task has surprisingly been achieved by providing the compounds according to the invention in accordance with the aspects, preferred embodiments and uses described above, for use in the manufacture of a medicament, wherein the medicament before and / or during and / or or after treatment with radiotherapy and / or surgery.
  • the compounds according to the invention can be administered in the context of this invention as individual substances or in combination with all known pharmacologically active substances in a combination therapy as shown.
  • the compounds according to the invention are provided for the uses described above, wherein the further pharmacologically active substance is selected from the group consisting of: "DNA topoisomerase I and / or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers, Hormone and / or Growth Factor Receptor Agonists and / or Antagonists, Signal Transduction Inhibitors, Antibodies to Growth Factors and Their Receptors, Kinase Inhibitors, Antimetabolites.
  • the further pharmacologically active substance is selected from the group consisting of: "DNA topoisomerase I and / or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers, Hormone and / or Growth Factor Receptor Agonists and / or Antagonists, Signal Transduction Inhibitors, Antibodies to Growth Factors and Their Receptors, Kinase Inhibitors, Antimetabolites.
  • the compounds of the present invention are provided for use as indicated above further pharmacologically active substance is selected from the group consisting of: mycin D, aminoglutethimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, cisplatin, celaspase, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, doxorubicin (adriamycin), DTIC (dacarbacin), epirubicin, Erbitux, erythrohydroxynonymloadin, ethinylestradiol, etoposide, fludarabine phosphates, fluoxymesterone, flutamide, gemcitabine, Gleevec / Glivec, Herceptin, hexamethylmelamine
  • the medicaments according to the invention can be administered as liquid, semisolid and solid dosage forms. This takes place in the respectively suitable manner in the form of aerosols, powders, powders and scattering powders, tablets, dragees, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, pastilles, capsules or suppositories.
  • the medicaments according to the invention may be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or patch; via the mouth and tongue mucosa, buccally, lingually or sublingually as a tablet, troche, dragee, linctus or gargle; via the gastric and intestinal mucosa, enterally as a tablet, dragees, capsule, solution, suspension or emulsion; via the rectal mucosa, rectal as suppository, rectal capsule or ointment; via the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonary or by inhalation as aerosol or inhalant; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellas or eye water; via the mucous membranes of the genital organs, intra va
  • the oral administration can be carried out, for example, in solid form as a tablet, capsule, gel capsule, dragee, granules or powder, but also in the form of a drinkable solution.
  • the novel compounds of the present invention as defined above, may be combined with known and commonly used physiologically acceptable excipients and carriers, e.g. Gum arabic, talc, starch, sugars, e.g.
  • the compounds of the invention may also be administered in a microparticulate, e.g. be dispersed nanoparticulate composition.
  • Non-oral administration can be accomplished, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants or by ointments, creams or suppositories.
  • Implants may contain inert materials, e.g. biodegradable polymers or synthetic silicones such as e.g. Silicone rubber.
  • Intravaginal administration may e.g. done by vaginal rings.
  • Intrauterine administration may e.g. by means of diaphragms or other suitable intrauterine devices.
  • transdermal administration in particular by means of a formulation suitable therefor and / or suitable means, e.g. Plaster, provided.
  • novel compounds according to the invention can also be combined with other pharmaceutically active substances.
  • the individual active ingredients may be administered simultaneously or separately, either by the same route (eg orally) or by separate routes (eg orally and by injection). They may be administered in equal or different amounts in a unit dose. It is also possible to use a specific dosage regimen, if appropriate. In this way, several of the novel compounds of the invention can be combined.
  • the dosage may vary widely depending on the nature of the indication, the severity of the disease, the mode of administration, the age, sex, body weight and the sensitivity of the subject to be treated. It is within the ability of one skilled in the art to determine a "pharmacologically effective amount" of the combined pharmaceutical composition, and may be administered in a single dose or multiple separate dosages.
  • a suitable unit dose is e.g. From 0.001 mg to 100 mg of the active ingredient, i. at least one compound according to the invention and optionally one further pharmaceutically active substance per kg of body weight of a patient.
  • compositions comprising a pharmacologically active amount of at least one compound according to the invention, preferably compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 and / or compound 43, as well as any pharmaceutically acceptable carriers and / or adjuvants, are covered by the present invention.
  • Preferred and particularly preferred pharmaceutical compositions are those comprising at least one of the aforementioned preferred compounds of the invention.
  • pharmaceutical compositions according to the present invention in addition to at least one compound according to the invention, as defined above, there may also be at least one further pharmaceutically active substance, as already mentioned in more detail above.
  • At least one of the novel compounds according to the invention, as defined above, is present in a pharmacologically active amount, preferably in a unit dose, eg above unit dose, before, preferably in a dosage form that allows oral administration.
  • the pharmaceutical compositions comprising the compounds according to the invention and the possibilities of use and administration thereof are referred to what has already been said in connection with the use of the novel compounds according to the invention.
  • kits comprising a pharmacologically active amount of at least one preferred compound according to the invention, as described above, and a pharmacologically active amount of at least one further pharmacologically active substance as defined above.
  • the compounds of the general formulas (I) and (II) are obtainable, for example, according to the following scheme 1.
  • the radicals R18 to R34 which differ in formula (II) from formula (I) are analogous to the radicals R1 to R17 of the formula (I).
  • the starting compounds 1 and 2 are either commercially available or can be prepared by methods known per se.
  • Compound 3 represents a valuable intermediate compound for the preparation of the compounds of the formulas (I) and (II) according to the invention.
  • the solvents and auxiliaries to be used if appropriate and the reaction parameters to be used, such as reaction temperature and duration, are known to the person skilled in the art on the basis of his specialist knowledge.
  • Step 1 Preparation of the 10-oxo-9 (10 / - /) - anthracenylidene-acetic acid
  • Step 2 Preparation of 10-oxo-9 (10 / - /) - anthracenylidene-acetic acid chloride
  • Step 3a Synthesis of 10- [2- (3,4-Dimethoxyphenyl) -2-oxo-ethylidene 1-9 (10 / - /) - anthracenone (Compound 6)
  • Step 3b 10- [2- (3,4-Dihydroxy-phenyl) -2-oxo-ethylidene-1-OH-anthracene-9-one (Compound 1)
  • Table 1 shows the% inhibition values and Table 2 shows the EC 50 values of the polymerization inhibition of tubulin with 30% associated proteins (MAPs).
  • Table 3 gives the EC 50 value of the polymerization inhibition.
  • Tables 4 and 5 give the EC 50 values of Eg5 inhibition for inventive compound 1.
  • KIF5A ATPase activity was tested in an in vitro assay for inhibition of KIF5A ATPase activity.
  • Recombinant full length KIF5A Niclas J, Navone F, Hom Booster N, VaIe RD Neuron 1994, 12: 1059-1072 was used.
  • microtubule-activatable ATPase The activity of the microtubule-activatable ATPase was determined by end-point assay. For tubulin isolation and preparation of microtubules s. Citations in Example II) b).
  • the compounds 1, 2, 4, 6, 7, 9, 10, 11, 12 and 13 according to the invention were tested for their anti-proliferative activity in a proliferation test on established tumor cell lines (DA Scuderio et al., Cancer Res. 48: 4827-4833).
  • the test used determines the cellular dehydrogenase activity and allows determination of cell vitality and, indirectly, cell number.
  • the cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line NCI-H460 ( NCI 503473). Furthermore, an RKOp27 cell system was used to study the cell cycle-specific action of the substance (Schmidt, M. et al., Oncogene 2000, 19 (20): 2423-9).
  • RKO is a human colon carcinoma line in which the cell cycle inhibitor p27 k ⁇ p1 can be induced to express by means of the ecdysone expression system and can be led to a cell cycle arrest specifically in G2.
  • a nonspecific substance inhibits proliferation regardless of whether the RKO cell is locked in G1 or G2 or not.
  • Cell cycle-specific substances such as tubulin inhibitors, however, are only cytotoxic if cells are not arrested and the cell cycle is traversed.
  • Table 7 shows the cytotoxic or growth-inhibiting activity of the compounds described with / without expression of p27 kp1 .
  • the compounds tested showed no cytotoxic activity in the induced state of p27 kp1 .
  • the results show a very potent inhibition of the proliferation of selected tumor cell lines by the compounds according to the invention.
  • the investigated cell lines are the murine L1210 (ATCC CCL219), the acute myeloid leukemia cell line LT12 (De Vries et al., University of Rotterdam) and the resistant lines L1210 / VCR (Asta Medica Laboratory) and LT12 / mdr ( De Vries et al., University of Rotterdam).
  • murine P388 cell line methyl-cholanthrene-induced lymphoid neoplasm
  • Io Studio e las cura the Tuomori; Milano doxorubicin-resistant P388
  • Table 8 shows the corresponding XTT data.
  • the cell cycle involves the development of the cell from one generation of cells to the next.
  • the cell During the resting phase (GO) and presynthetic phase (G1), the cell has a diploid chromosome set (2c).
  • S the amount of DNA is increased by replication.
  • G2M premitotic phase
  • M short-term mitotic phase
  • the reduplicated chromosomes are distributed evenly over two daughter cells, which then each again show a diploid DNA content and are in the G01 phase, so that the cell cycle can start anew.

Abstract

The present invention provides anthracen derivatives according to the general formulas (I) and (II), as well as selected anthracen derivative compounds. Further, the present invention provides a method for the production of such anthracen derivatives. Further, pharmaceutical formulations containing these anthracen derivatives are provided. The anthracen derivatives provided are particularly suited to be used for the treatment or prophylaxis of physiological and/or pathophysiological conditions that can be treated by means of the inhibition of the tubulin polymerization, and/or by means of the inhibition of microtubuli-based motor proteins, particularly of diverse tumorous diseases.

Description

Anthracen-Derivate und deren Verwendung zur Behandlung gutartiger und bösartiger Tumorerkrankungen Anthracene derivatives and their use for the treatment of benign and malignant tumors
Beschreibungdescription
Technisches GebietTechnical area
Die Erfindung betrifft neue Anthracen-Derivate zur Behandlung gutartiger und bösartiger Tumorerkrankungen. Diese Verbindungen wirken als Inhibitoren der Tubulin- Polymerisation und/oder als Inhibitoren Microtubuli-basierter Motorproteine, insbeson- dere Kinesine und Dyneine, und sind geeignet für die Behandlung oder Prophylaxe von durch die Inhibition der Tubulin-Polymerisation und/oder von durch die Inhibition Micro- tubuli-basierten Motorproteinen behandelbaren physiologischen und/oder pathophysio- logischen Zuständen sowie diverser Tumorerkrankungen.The invention relates to novel anthracene derivatives for the treatment of benign and malignant tumor diseases. These compounds act as inhibitors of tubulin polymerization and / or as inhibitors of microtubule-based motor proteins, in particular kinesins and dyneins, and are suitable for the treatment or prophylaxis of inhibition of tubulin polymerization and / or of inhibition by micro - Tubuli-based motor proteins treatable physiological and / or pathophysiological states and various tumor diseases.
Stand der TechnikState of the art
Für die nächsten Jahre wird ein dramatischer Anstieg der Tumorerkrankungen und der Tumor bedingten Todesfälle weltweit erwartet. Im Jahre 2001 waren weltweit etwa 10 Mio. Menschen an Krebs erkrankt und über 6 Mio. Menschen sind an dieser Erkrankung gestorben. Die Entwicklung von Tumoren ist eine fundamentale Erkrankung höherer Organismen im Pflanzen- und im Tierreich sowie beim Menschen. Das allgemein anerkannte Mehrschrittmodell der Krebsentstehung geht davon aus, dass durch Anhäufung von Mutationen in einer einzelnen Zelle deren Proliferations- und Differenzierungsverhalten so geändert wird, dass letztendlich über benigne Zwischenstufen ein maligner Zustand mit Metastasierung erreicht wird. Hinter dem Begriff Krebs oder Tu- mor verbirgt sich ein Krankheitsbild mit mehr als 200 verschiedenen Einzelerkrankungen. Tumorerkrankungen können gutartig oder bösartig verlaufen. Wichtige Tumoren sind die der Lunge, der Brust, des Magens, des Gebärmutterhalses, der Prostata, des Kopfes und Halses, des Dick- und Enddarmes, der Leber und des Blutsystems. Hinsichtlich des Verlaufs, der Prognose und des Therapieverhaltens gibt es große Unter- schiede. Mehr als 90% der erkannten Fälle betreffen solide Tumoren, die insbesondere in fortgeschrittenen Stadien bzw. bei Metastasierung gegenwärtig schwer oder nicht therapierbar sind. Neben der operative Entfernung oder der Bestrahlung ist die Chemotherapie eine wichtige Säule der Krebsbekämpfung. Trotz großer Fortschritte ist es bisher nicht gelungen, Medikamente zu entwickeln, die bei den weitverbreiteten soliden Tumoren eine deutliche Verlängerung der Überlebenszeit oder gar komplette Heilung bewirken. Zusätzlich tritt das Problem der Resistenzentwicklung bei etablierten Tu- mortherapeutika in der Klinik zunehmend häufiger auf. Es ist deshalb sinnvoll, neue Arzneimittel zur Bekämpfung der Krebserkrankung zu erfinden.For the next few years, a dramatic increase in tumors and tumor-related deaths worldwide is expected. In 2001, about 10 million people worldwide had cancer and more than 6 million people died from this disease. The development of tumors is a fundamental disease of higher organisms in the plant and animal kingdoms as well as in humans. The widely accepted multi-step model of carcinogenesis assumes that by accumulating mutations in a single cell, their proliferation and differentiation behavior is altered to ultimately achieve a malignant state with metastasis through benign intermediates. The term cancer or tumor conceals a clinical picture of more than 200 different individual diseases. Tumor diseases can be benign or malignant. Important tumors are those of the lung, the breast, the stomach, the cervix, the prostate, the head and neck, the colon and rectum, the liver and the blood system. With regard to the course, the prognosis and the therapy behavior, there are great differences. More than 90% of detected cases involve solid tumors that are currently difficult or impossible to treat, especially in advanced stages or metastases. In addition to surgical removal or radiation, chemotherapy is an important pillar of cancer control. Despite great progress, it is so far failed to develop drugs that cause in the widespread solid tumors a significant prolongation of survival or even complete healing. In addition, the problem of resistance development in established tumor therapeutics is becoming increasingly common in the clinic. It therefore makes sense to invent new medicines to fight cancer.
Ein möglicher Ansatz, Krebserkrankungen zu bekämpfen, ist die Hemmung der Zellteilung (Mitose). Eine große Anzahl von anti-mitotisch wirkenden Arzneimitteln hat sich bisher als wirksam in der klinischen Onkologie bewiesen. Beispiele hierfür sind die Alkaloide Vincristine und Vinblastine im Rahmen der Behandlung von Leukämie und Hodgkin's Lymphom sowie Paclitaxel und Docetaxel für die Behandlung von metasta- sierenden Brustkrebs, Lungen- und Eierstockkarzinomen.One possible approach to combating cancer is the inhibition of cell division (mitosis). A large number of anti-mitotic drugs have been shown to be effective in clinical oncology. Examples include the alkaloids vincristine and vinblastine in the treatment of leukemia and Hodgkin's lymphoma, and paclitaxel and docetaxel for the treatment of metastatic breast, lung and ovarian cancers.
Diese Substanzen zeigen jedoch einige schwere Nebenwirkungen, wie bspw. Neu- rotoxizität (Quasthoff S et al., J. Neural. 2002, 249: 9-17), und bewirken auch das Auf- treten von tw. multiplen Resistenzen (Gottesman MM et al., Nat. Rev. Cancer 2002, 2: 48-58; Dumontet C et al., J. Clin. Oncol. 1999, 17: 1061 -1070; Sangrajrang S et al., Chemotherapy 2000, 46: 327-334).However, these substances show some serious side effects, such as neurotoxicity (Quasthoff S et al., J. Neural., 2002, 249: 9-17), and also cause tw. MM, et al., Nat. Rev. Cancer 2002, 2: 48-58; Dumontet C et al., J. Clin. Oncol., 1999, 17: 1061-1070; Sangrajrang S et al., Chemotherapy 2000 , 46: 327-334).
Ein relativ junger Forschungsbereich beschäftigt sich mit der Untersuchung von Microtubuli-basierten Motorproteinen. Zu diesen zählen vor allem die Kinesine, die in den Organellentransport und in der Mitose involviert sind (Yildiz A et al., Trends Cell Biol. 2005, 15: 1 12-120). Die Kinesin-Superfamilie ist ausführlich in Miki H et al. (Proc. Natl. Acad. Sei. USA 2001 , 98: 7004-701 1 ) charakterisiert worden. Weitere relevante Arbeiten, die sich mit Kinesinen, ihren vielfältigen Funktionen und ersten Kinesin- Inhibitoren beschäftigen, sind: Hirokawa N et al., Exp. Cell Res. 2004, 301 : 50-59; Zhu C et al., Mol. Biol. Cell 2005, 16: 3187-3199; Sarli V et al., ChemMedChem 2006, 1 : 293-298.A relatively recent area of research is concerned with the study of microtubule-based motor proteins. These include, in particular, the kinesins involved in organelle transport and mitosis (Yildiz A et al., Trends Cell Biol. 2005, 15: 12-120). The kinesin superfamily is described in detail in Miki H et al. (Proc Natl Acad., USA 2001, 98: 7004-701). Other relevant papers dealing with kinesins, their diverse functions, and initial kinesin inhibitors are: Hirokawa N et al., Exp. Cell Res. 2004, 301: 50-59; Zhu C et al., Mol. Biol. Cell 2005, 16: 3187-3199; Sarli V et al. Chem. Chem. 2006, 1: 293-298.
Fand und Mitarbeiter beschreiben die kompetitive Photoaddition von Acetylenen an die C=C und C=O Bindungen von p-Chinonen. Eine gewerbliche Anwendung, insbesondere als Arzneimittel, ist weder beschrieben noch nahe gelegt (Farid S et al., Tetra- hedron Letters 1968, 9(39): 4147-4150).Fand and co-workers describe the competitive photoaddition of acetylenes to the C = C and C = O bonds of p-quinones. A commercial application, in particular as a pharmaceutical, is neither described nor suggested (Farid S et al., Tetrahedron Letters 1968, 9 (39): 4147-4150).
DE 102 01 228 beschreibt 10-Benzyliden-9(10H)anthracenone als neue Inhibitoren der Tubulinpolymerisation.DE 102 01 228 describes 10-benzylidene-9 (10H) anthracenones as novel inhibitors of tubulin polymerization.
DE 102 53 720 beschreibt 10-Phenylimino-9(10H)anthracenone als neue Inhibito- ren der Tubulinpolymerisation.DE 102 53 720 describes 10-phenylimino-9 (10H) anthracenones as new inhibitors. ren the Tubulinpolymerisation.
DE 102 53 746 beschreibt 10-Benzyliden-1 ,8-dichlor-9(10H)anthracenone als neue Inhibitoren der Tubulinpolymerisation.DE 102 53 746 describes 10-benzylidene-1, 8-dichloro-9 (10H) anthracenones as novel inhibitors of tubulin polymerization.
WO 2004/007470 beschreibt neue Antracenderivate und deren Verwendung als Arzneimittel. Die beschriebenen Verbindungen könnten durch Inhibition der Tubulinpolymerisation wirken.WO 2004/007470 describes novel antacanner derivatives and their use as medicaments. The compounds described could act by inhibiting tubulin polymerization.
EP 1 645 556 beschreibt Arylpiperazin-Benzoylamid-Derivate, die als pharmazeutische Mittel geeignet sind und Inhibitoren der Tubulinpolymerisation sind.EP 1 645 556 describes arylpiperazine-benzoylamide derivatives which are useful as pharmaceutical agents and inhibitors of tubulin polymerization.
WO 02/060872 beschreibt Synthesemethoden für Verbindungen, die in einem Screening als potentielle Inhibitoren der Tubulinpolymerisation charakterisiert werden können.WO 02/060872 describes synthetic methods for compounds which can be characterized in a screening as potential inhibitors of tubulin polymerization.
Bryce-Smith und Mitarbeiter beschreiben die Photoaddition von Diphenylacetylen, Cycloocta-1 ,3-dien und Cycloocten an Anthrachinon. Eine gewerbliche Anwendung, insbesondere als Arzneimittel, ist weder beschrieben noch nahe gelegt (Bryce-Smith D et al., Tetrahedron Letters 1968, 9(24): 2863-2866).Bryce-Smith and co-workers describe the photoaddition of diphenylacetylene, cycloocta-1,3-diene, and cyclooctene to anthraquinone. A commercial application, especially as a pharmaceutical, is neither described nor suggested (Bryce-Smith D et al., Tetrahedron Letters 1968, 9 (24): 2863-2866).
Polman und Mitarbeiter beschreiben photochemische Reaktionen von Acetylenen. Aromatische Ketone werden an Arylacetylene photoaddiert. Eine gewerbliche Anwendung, insbesondere als Arzneimittel, ist weder beschrieben noch nahe gelegt (Polman H et al., Recueil des Travaux Chimiques des Pays-Bas 1973, 92(7): 845-854).Polman and co-workers describe photochemical reactions of acetylenes. Aromatic ketones are photoadded to arylacetylenes. A commercial application, especially as a pharmaceutical, is neither described nor suggested (Polman H et al., Recueil des Travaux Chimiques des Pays-Bas 1973, 92 (7): 845-854).
Darstellung der ErfindungPresentation of the invention
Die vorliegende Erfindung hat daher die Aufgabe, neue Substanzen bereitzustellen, die zur Behandlung von Krebserkrankungen geeignet sind.The present invention therefore has the object of providing new substances which are suitable for the treatment of cancerous diseases.
Die erfinderische Aufgabe wurde in einem Aspekt überraschender Weise dadurch gelöst, dass neue Anthracen-Derivate gemäß der allgemeinen Formel (I) - A -The inventive task has in one aspect surprisingly been solved by adding novel anthracene derivatives according to the general formula (I) - A -
Figure imgf000005_0001
Figure imgf000005_0001
(I)(I)
bereitgestellt werden, worin: Substituent X unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NR1 1 , N-OR12, geminal geknüpfter Wasserstoff und Hydroxy";wherein Substituent X is independently selected from the group consisting of: "O, S, NR11, N-OR12, geminally linked hydrogen and hydroxy";
Substituent Y unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NR13, N-OR14";Substituent Y is independently selected from the group consisting of: "O, S, NR 13, N-OR 14";
Substituenten R1 , R2, R3, R4, R5, R6, R7, R8 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substitu- iertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl, Amino, Mono- Alkylamino, Di-Alkylamino, Halogen, -F, -Cl, -Br, -I, mit ein oder mehreren Fluoratomen substituiertes Alkyl, Trifluormethyl, Cyano, geradkettiges oder verzweigtes Cyano- alkyl, Carbonyl, Carboxyl, -COOH, Alkoxycarbonyl, Carboxy-alkyl, Alkoxycarbonyl- alkyl, Hydroxy, Alkoxy, Aryl-alkoxy, Benzyloxy, Heteroaryl-alkoxy, Alkoxycarbonylami- no, Alkoxycarbonylamino-alkyl";Substituents R1, R2, R3, R4, R5, R6, R7, R8 are independently selected independently from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted Heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, amino, mono-alkylamino, di-alkylamino, halogen, -F, -Cl, -Br, -I, alkyl substituted with one or more fluorine atoms, trifluoromethyl, cyano, straight-chain or branched cyanoalkyl, carbonyl, carboxyl, -COOH, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxy, alkoxy, aryl -alkoxy, benzyloxy, heteroaryl-alkoxy, alkoxycarbonylamino, alkoxycarbonylamino-alkyl ";
Substituent R9 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl, -0R15, -NR16R17";Substituent R9 is independently selected from the group consisting of: unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, -0R15, -NR16R17 ";
Substituent R10 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Hete- roaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl";Substituent R10 is independently selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl";
Substituenten R11 , R12, R13, R14, R15, R16, R17 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyc- IyI, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl"; mit der Maßgabe, dass die folgenden, unter die allgemeine Formel (I) fallenden Verbindungen ausgeschlossen sind: (i) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 262378-52-9Substituents R11, R12, R13, R14, R15, R16, R17 independently of one another are selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclic IyI, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl "with the proviso that the following are included in the general formula (I) Exclusions are: (i) Compound with Chemical Abstract Service (CAS) Registry No. 262378-52-9
Figure imgf000006_0001
Figure imgf000006_0001
(ii) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 121747-08-8
Figure imgf000007_0001
(ii) Connection to the Chemical Abstract Service (CAS) Registry No. 121747-08-8
Figure imgf000007_0001
(iii) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 63370-49-0
Figure imgf000007_0002
(iii) Connection to Chemical Abstract Service (CAS) Registry No. 63370-49-0
Figure imgf000007_0002
(iv) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 19661 -62-2
Figure imgf000008_0001
(iv) Connection to the Chemical Abstract Service (CAS) Registry No. 19661 -62-2
Figure imgf000008_0001
(v) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 17665-75-7
Figure imgf000008_0002
(v) Connection to the Chemical Abstract Service (CAS) Registry No. 17665-75-7
Figure imgf000008_0002
(vi) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 83498-19-5
Figure imgf000008_0003
(vii) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 42866-43-3(vi) Connection to the Chemical Abstract Service (CAS) Registry No. 83498-19-5
Figure imgf000008_0003
(vii) Connection to Chemical Abstract Service (CAS) Registry No. 42866-43-3
Figure imgf000009_0001
Figure imgf000009_0001
(viii) Verbindung mit der Beilstein Registry Nr. 3095926(viii) Connection to the Beilstein Registry No. 3095926
Figure imgf000009_0002
Figure imgf000009_0002
(ix) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 42866-49-9(ix) Connection to Chemical Abstract Service (CAS) Registry No. 42866-49-9
Figure imgf000009_0003
Figure imgf000009_0003
Unter der Substitution „geminal geknüpfter Wasserstoff und Hydroxy" im Zusammenhang mit dem Substituenten X wird im Rahmen der vorliegenden Erfindung verstanden, das sowohl „H" als auch „OH" an einem und dem gleichen Kohlenstoffatom gebunden sind. In einer bevorzugten Ausführungsform werden neue Anthracen-Derivat gemäß der allgemeinen Formel (I) und gemäß vorangehender obiger Substituenten-Definition bereitgestellt, worin:The substitution "geminally linked hydrogen and hydroxy" in connection with the substituent X is understood in the context of the present invention to mean that both "H" and "OH" are bonded to one and the same carbon atom. In a preferred embodiment there are provided novel anthracene derivatives according to general formula (I) and according to the above substituent definition above, wherein:
Substituent X unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NH, geminal geknüpfter Wasserstoff und Hydroxy";Substituent X is independently selected from the group consisting of: "O, S, NH, geminally linked hydrogen and hydroxy";
Substituent Y unabhängig „O oder S" ist;Substituent Y is independently "O or S";
Substituenten R1 , R2, R3, R4, R5, R6, R7, R8 unabhängig „Wasserstoff, Fluor, Chlor, Brom, lod, Hydroxy, Amino, Nitro, Cyano, Methyl, Trifluormethyl" sind;Substituents R1, R2, R3, R4, R5, R6, R7, R8 are independently "hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, trifluoromethyl";
Substituent R9 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Heteroaryl, -OR15, -NR16R17";Substituent R9 is independently selected from the group consisting of: "unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -OR15, -NR16R17";
Substituent R10 unabhängig „Wasserstoff, Alkyl" ist.Substituent R10 is independently "hydrogen, alkyl".
In einer weiteren bevorzugten Ausführungsform werden neue Anthracen-Derivate gemäß der allgemeinen Formel (I) und gemäß der beiden vorangehenden obigen Sub- stituenten-Definitionen bereitgestellt, worin: Substituent R9 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „3,4-In another preferred embodiment, there are provided novel anthracene derivatives according to the general formula (I) and according to the two preceding sub-substituent definitions above, wherein: substituent R9 is independently selected from the group consisting of: "3,4-
Dimethoxy-phenyl; 3,4-Dihydroxy-phenyl; 4-Methoxy-thiophen-2-yl, Thiomorpholin-4-yl; 4-Methoxy-phenyl; 4-(4-Methoxy-phenyl)-piperazin-1 -yl, 2-Hydroxy-3,4-dimethoxy- phenyl, 4-Methylphenyl; 4-Hydroxyphenyl; Thiophen-2-yl; 3-Hydroxyphenyl; 3-Methoxy- phenyl; 2,6-Dimethoxy-phenyl; 3,4,5-Trimethoxy-phenyl; Hydroxy; Methoxy; Phenyl; A- Chlorphenyl; 4-Bromphenyl; 4-Fluorphenyl; 3-Chlorphenyl; 3-Bromphenyl; 3- Fluorphenyl; 4-Fluor, 3-hydroxy-phenyl".Dimethoxy-phenyl; 3,4-dihydroxy-phenyl; 4-methoxy-thiophen-2-yl, thiomorpholin-4-yl; 4-methoxy-phenyl; 4- (4-methoxy-phenyl) -piperazine-1-yl, 2-hydroxy-3,4-dimethoxyphenyl, 4-methylphenyl; 4-hydroxyphenyl; Thiophen-2-yl; 3-hydroxyphenyl; 3-methoxyphenyl; 2,6-dimethoxy-phenyl; 3,4,5-trimethoxy-phenyl; hydroxy; methoxy; phenyl; A-chlorophenyl; 4-bromophenyl; 4-fluorophenyl; 3-chlorophenyl; 3-bromophenyl; 3-fluorophenyl; 4-fluoro, 3-hydroxy-phenyl ".
In einer weiteren bevorzugten Ausführungsform werden neue Anthracen-Derivate ausgewählt aus der Gruppe bestehend aus: 10-[2-(3,4-Dihydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 1):In a further preferred embodiment, new anthracene derivatives are selected from the group consisting of: 10- [2- (3,4-Dihydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 1):
Figure imgf000011_0001
Figure imgf000011_0001
10-[2-(4-Methoxy-thiophen-2-yl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 2):10- [2- (4-methoxy-thiophen-2-yl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 2):
Figure imgf000011_0002
Figure imgf000011_0002
10-(2-Oxo-2-thiomorpholin-4-ylethylidene)-1 OH-anthracen-9-one (Verbindung 3):10- (2-Oxo-2-thiomorpholin-4-yl-ethylidene) -1 OH-anthracen-9-one (Compound 3):
Figure imgf000011_0003
2-(10-Hydroxy-10H-anthracen-9-ylidene)-1 -(4-methoxy-phenyl)-ethanone (Verbindung 4):
Figure imgf000011_0003
2- (10-Hydroxy-10H-anthracen-9-ylidenes) -1- (4-methoxyphenyl) -ethanones (Compound 4):
Figure imgf000012_0001
Figure imgf000012_0001
10-{2-[4-(4-Methoxy-phenyl)-piperazin-1 -yl]-2-oxo-ethylidene}-1 OH-anthracen-9- one (Verbindung 5):10- {2- [4- (4-Methoxy-phenyl) -piperazin-1-yl] -2-oxo-ethylidene} -1 OH-anthracen-9-one (Compound 5):
Figure imgf000012_0002
Figure imgf000012_0002
10-[2-(3,4-Dimethoxy-phenyl)-2-oxo-ethyliden]-9(1 OH)-anthracenon (Verbindung 6):10- [2- (3,4-Dimethoxyphenyl) -2-oxo-ethylidene] -9 (1 OH) -anthracenone (Compound 6):
Figure imgf000012_0003
10-[2-(4-Methoxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 7):
Figure imgf000012_0003
10- [2- (4-Methoxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 7):
Figure imgf000013_0001
Figure imgf000013_0001
10-[2-(2-Hydroxy-3,4-dimethoxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 8)10- [2- (2-Hydroxy-3,4-dimethoxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 8)
Figure imgf000013_0002
Figure imgf000013_0002
10-(2-Oxo-2-p-tolyl-ethylidene)-1 OH-anthracen-9-one (Verbindung 9)10- (2-oxo-2-p-tolyl-ethylidene) -1 OH-anthracene-9-ones (compound 9)
Figure imgf000014_0001
Figure imgf000014_0001
10-[2-(4-Hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 10)10- [2- (4-Hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 10)
Figure imgf000014_0002
Figure imgf000014_0002
10-(2-Oxo-2-thiophen-2-yl-ethylidene)-1 OH-anthracen-9-one (Verbindung 11)10- (2-oxo-2-thiophen-2-yl-ethylidene) -1 OH-anthracen-9-one (Compound 11)
Figure imgf000014_0003
10-[2-(3-Hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 12)
Figure imgf000014_0003
10- [2- (3-Hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 12)
Figure imgf000015_0001
Figure imgf000015_0001
10-[2-(3-Methoxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 13)10- [2- (3-Methoxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 13)
Figure imgf000015_0002
Figure imgf000015_0002
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid 2,6-dimethoxy-phenyl ester (Verbindung 14)(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid 2,6-dimethoxy-phenyl ester (Compound 14)
Figure imgf000015_0003
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid methyl ester (Verbindung 15)
Figure imgf000015_0003
(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid methyl ester (Compound 15)
Figure imgf000016_0001
Figure imgf000016_0001
10-[2-Oxo-2-(3,4,5-trimethoxy-phenyl)-ethylidene]-1 OH-anthracen-9-one (Verbindung 16)10- [2-Oxo-2- (3,4,5-trimethoxyphenyl) ethylidene] -1 OH-anthracene-9-one (Compound 16)
Figure imgf000016_0002
Figure imgf000016_0002
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid (Verbindung 17)(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid (Compound 17)
Figure imgf000016_0003
-(2-Oxo-2-phenyl-ethylidene)-10H-anthracen-9-one (Verbindung 18)
Figure imgf000017_0001
-[2-(4-Chlor-phenyl)-2-oxo-ethyliden]-10/-/-anthracen-9-one (Verbindung 19)
Figure imgf000017_0002
-[2-(4-Brom-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 20)
Figure imgf000017_0003
-[2-(3-Chlor-phenyl)-2-oxo-ethyliden]-10/-/-anthracen-9-on (Verbindung 21)
Figure imgf000018_0001
-[2-(3-Brom-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 22)
Figure imgf000018_0002
-[2-(4-Fluor-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 23)
Figure imgf000018_0003
10-[2-(3-Fluor-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 24)
Figure imgf000016_0003
- (2-oxo-2-phenyl-ethylidenes) -10H-anthracen-9-ones (compound 18)
Figure imgf000017_0001
- [2- (4-chloro-phenyl) -2-oxo-ethylidene] -10 / - / - anthracene-9-one (Compound 19)
Figure imgf000017_0002
- [2- (4-Bromo-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 20)
Figure imgf000017_0003
- [2- (3-chloro-phenyl) -2-oxo-ethylidene] -10 / - / - anthracen-9-one (Compound 21)
Figure imgf000018_0001
- [2- (3-Bromo-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 22)
Figure imgf000018_0002
- [2- (4-fluoro-phenyl) -2-oxo-ethylidene] -1-OH-anthracen-9-one (compound 23)
Figure imgf000018_0003
10- [2- (3-fluoro-phenyl) -2-oxo-ethylidene] -1-OH-anthracen-9-one (Compound 24)
Figure imgf000019_0001
Figure imgf000019_0001
10-[2-(4-Fluor, 3-Hydroxy-phenyl)-2-oxo-ethyliden]-10H-anthracen-9-on (Verbindung 25)10- [2- (4-fluoro, 3-hydroxy-phenyl) -2-oxo-ethylidene] -10H-anthracen-9-one (Compound 25)
Figure imgf000019_0002
Figure imgf000019_0002
1 -(3,4-Dihydroxy-phenyl)-2-(10-thioxo-10H-anthracen-9-ylidene)-ethanone (Verbindung 26):1- (3,4-Dihydroxyphenyl) -2- (10-thioxo-10H-anthracen-9-ylidenes) -ethanones (Compound 26):
Figure imgf000019_0003
1 -(3,4-Dihydroxy-phenyl)-2-(10-imino-10H-anthracen-9-ylidene)-ethanone (Verbindung 27):
Figure imgf000019_0003
1 - (3,4-Dihydroxyphenyl) -2- (10-imino-10H-anthracen-9-ylidenes) -ethanones (Compound 27):
Figure imgf000020_0001
Figure imgf000020_0001
1 -(3-Hydroxy-phenyl)-2-(10-thioxo-10H-anthracen-9-ylidene)-ethanone (Verbindung 28):1- (3-Hydroxy-phenyl) -2- (10-thioxo-10H-anthracen-9-ylidenes) -ethanones (Compound 28):
Figure imgf000020_0002
Figure imgf000020_0002
1 -(3-Hydroxy-phenyl)-2-(10-imino-10H-anthracen-9-ylidene)-ethanon (Verbindung 29):1- (3-Hydroxy-phenyl) -2- (10-imino-10H-anthracen-9-ylidenes) -ethanone (Compound 29):
Figure imgf000020_0003
Figure imgf000020_0003
1 -(4-Fluor, 3-hydroxy-phenyl)-2-(10-thioxo-10H-anthracen-9-ylidene)-ethanon (Verbindung 30):1- (4-fluoro, 3-hydroxy-phenyl) -2- (10-thioxo-10H-anthracen-9-ylidenes) -ethanone (Compound 30):
Figure imgf000020_0004
1 -(4-Fluor, 3-hydroxy-phenyl)-2-(10-imino-10H-anthracen-9-ylidene)-ethanon (Verbindung 31):
Figure imgf000020_0004
1- (4-fluoro, 3-hydroxy-phenyl) -2- (10-imino-10H-anthracen-9-ylidenes) -ethanone (Compound 31):
Figure imgf000021_0001
Figure imgf000021_0001
1 ,4-Dichlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 32)1,4-dichloro-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 32)
Figure imgf000021_0002
Figure imgf000021_0002
1 ,2-Dichlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Ver- bindung 33)1,2-dichloro-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (compound 33)
Figure imgf000021_0003
3,4-Dichlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 34)
Figure imgf000021_0003
3,4-Dichloro-10- [2- (3-hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 34)
Figure imgf000022_0001
Figure imgf000022_0001
1 ,2-Methyl-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 35)1, 2-Methyl-10- [2- (3-hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 35)
Figure imgf000022_0002
Figure imgf000022_0002
3-Chlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 36)3-chloro-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-ones (Compound 36)
Figure imgf000023_0001
Figure imgf000023_0001
3-Brom-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 37)3-Bromo-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-ones (Compound 37)
Figure imgf000023_0002
Figure imgf000023_0002
10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-3-methyl-1 OH-anthracen-9-one (Verbindung 38)10- [2- (3-hydroxy-phenyl) -2-oxo-ethylidene] -3-methyl-1-OH-anthracen-9-one (Compound 38)
Figure imgf000024_0001
Figure imgf000024_0001
1 ,4-Dichlor-10-[2-(3,4-dihydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 39)1, 4-dichloro-10- [2- (3,4-dihydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 39)
Figure imgf000024_0002
Figure imgf000024_0002
3,4-Dimethyl-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 40)3,4-Dimethyl-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -10H-anthracene-9-one (Compound 40)
Figure imgf000025_0001
Figure imgf000025_0001
2-[2-Chlor-10-thioxo-10H-anthracen-9-ylidene]-1 -(3-hydroxy-phenyl)-ethanone (Verbindung 41)2- [2-Chloro-10-thioxo-10H-anthracen-9-ylidenes] -1- (3-hydroxy-phenyl) -ethanones (Compound 41)
Figure imgf000025_0002
Figure imgf000025_0002
3-Chlor-10-[2-(3,4-dihydroxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 42)3-Chloro-10- [2- (3,4-dihydroxyphenyl) -2-oxo-ethylidene] -10H-anthracene-9-one (Compound 42)
Figure imgf000026_0001
Figure imgf000026_0001
2-[2-Chlor-10-imino-10H-anthracen-9-ylidene]-1 -(3-hydroxy-phenyl)-ethanone (Verbindung 43)2- [2-Chloro-10-imino-10H-anthracen-9-ylidenes] -1- (3-hydroxy-phenyl) -ethanones (Compound 43)
Figure imgf000026_0002
Figure imgf000026_0002
bereitgestellt. Sollten chemischer Name und chemische Struktur der oben dargestellten Verbindungen aus Fehlergründen nicht korrespondieren, wird - um Unklarheiten vorzubeugen - die chemische Struktur jeder einzelnen Verbindung als maßgeblich für die eindeutige Beschreibung der Verbindung erachtet.provided. If the chemical name and chemical structure of the compounds shown above do not correspond for reasons of error, the chemical structure of each individual compound is considered to be decisive for the unambiguous description of the compound in order to prevent ambiguity.
Oben aufgeführte neue Anthracen- Derivate der allgemeinen generischen Formel (I), ihrer beiden bevorzugten generischen Ausführungsformen, die explizit aufge- führten Anthracen-Derivat- Verbindungen 1 bis 43 sowie die Anthracen-Derivate der allgemeinen generischen Formel (II) und ihrer beiden bevorzugten generischen Ausführungsformen werden im folgenden gemeinsam als „erfindungsgemäße Verbindungen" bezeichnet.The above listed new anthracene derivatives of general generic formula (I), their two preferred generic embodiments, which are explicitly listed. Anthracene derivative compounds 1 to 43 and the anthracene derivatives of the general generic formula (II) and their two preferred generic embodiments are hereinafter collectively referred to as "compounds according to the invention".
Die zur Erläuterung der erfindungsgemäßen Verbindungen angegebenen Ausdrücke und Begriffe haben grundsätzlich, sofern in der Beschreibung oder in den Ansprüchen nichts anderes angegeben ist, folgende Bedeutungen:The expressions and terms given for the explanation of the compounds according to the invention basically have the following meanings, unless stated otherwise in the description or in the claims:
Der Ausdruck „Alkyl" umfasst im Sinne dieser Erfindung acyclische gesättigte oder ungesättigte Kohlenwasserstoff reste, die verzweigt oder geradkettig sowie unsubstitu- iert oder ein- oder mehrfach substituiert sein können, mit 1 bis 20 C-Atomen, d.h. Cr20- Alkanyle, C2-2o-Alkenyle und C2-2o-Alkinyle, bevorzugt mit 1 bis 8 C-Atomen, d.h. Cr8- Alkanyle, C2-8-Alkenyle und C2-8-Alkinyle. Dabei weisen Alkenyle mindestens eine C-C- Doppelbindung und Alkinyle mindestens eine C-C-Dreifachbindung auf, wobei Alkinyle zusätzlich auch mindestens eine C-C-Doppelbindung aufweisen können. Bevorzugte Alkyl-Reste sind Methyl, Ethyl, n-Propyl, 2-Propyl, n-Butyl, sec.-Butyl, te/t-Butyl, n- Pentyl, /so-Pentyl, neo-Pentyl, n-Hexyl, 2-Hexyl, n-Heptyl, n-Octyl, , n-Nonyl, n-Decyl, n-Undecyl, n-Dodecyl, Ethylenyl (Vinyl), Ethinyl, Propenyl (-CH2CH=CH2; -CH=CH- CH3, -C(=CH2)-CH3), Propinyl (-CH2-C≡CH, -C≡C-CH3), Butenyl, Butinyl, Pentenyl, Pentinyl, Hexenyl, Hexinyl, Heptenyl, Heptinyl, Octenyl, Octadienyl und Octinyl.The term "alkyl" in the context of this invention comprises acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chained and unsubstituted or monosubstituted or polysubstituted, having 1 to 20 carbon atoms, ie Cr 20 - alkanyl, C 2 - 2 o-alkenyls and C 2 - 2 o-alkynyl, preferably having from 1 to 8 carbon atoms, ie C r8 - alkanyls, C 2 - 8 alkenyls, and C 2 -. 8 alkynyls alkenyls have at least one C-C At least one double bond and alkynyls on at least one C-C triple bond, wherein alkynyls may additionally also have at least one carbon-carbon double bond.Preferred alkyl radicals are methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, te / t-butyl, n-pentyl, / so-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl,, n-nonyl, n-decyl, n-undecyl, n-dodecyl, Ethyleneyl (vinyl), ethynyl, propenyl (-CH 2 CH = CH 2 ; -CH = CH-CH 3 , -C (= CH 2 ) -CH 3 ), propynyl (-CH 2 -C≡CH, -C≡ C-CH 3), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, hept enyl, heptynyl, octenyl, octadienyl and octynyl.
Der Ausdruck „Cycloalkyl" bedeutet für die Zwecke dieser Erfindung cyclische, nicht-aromatische Kohlenwasserstoffe mit 1 bis 3 Ringen mit 3 bis 20, bevorzugt 3 bis 12 Kohlenstoffen, die gesättigt oder ungesättigt sein können, besonders bevorzugt (C3- C8)-cycloalkyl. Der Cycloalkyl-Rest kann auch Teil eines bi- oder polycyclischen Systems sein, wo bspw. der Cycloalkyl-Rest mit einem Aryl-, Heteroaryl- oder Heterocyc- lyl-Rest wie hierin definiert durch jede(s) mögliche und gewünschte Ringmitglied(er) kondensiert ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) kann über jedes beliebige und mögliche Ringglied des Cycloalkyl-Restes erfolgen. Bevorzugte Cycloalkyl-Reste sind Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cyc- loheptyl und Cyclooctyl, Cyclodecyl, Cyclohexenyl, Cyclopentenyl und Cyclooctadienyl. Der Ausdruck „Heterocyclyl" steht für einen 3- bis 14-gliedrigen, bevorzugt 3-, 4-, 5- , 6-, 7- oder 8-gliedrigen cyclischen organischen Rest, der mindestens 1 , ggf. 2, 3, 4 oder 5 Heteroatome enthält, insbesondere Stickstoff, Sauerstoff und/oder Schwefel, wobei die Heteroatome gleich oder verschieden sind und der cyclische Rest gesättigt oder ungesättigt, aber nicht aromatisch ist und unsubstituiert oder ein- oder mehrfach substituiert sein kann. Der Heterocyclyl-Rest kann auch Teil eines bi- oder polycycli- schen Systems sein, wo bspw. der Heterocyclyl-Rest mit einem Aryl-, Heteroaryl- oder Cycloalkyl-Rest wie hierin definiert durch jede(s) mögliche und gewünschte Ringmit- glied(er) kondensiert ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) kann über jedes beliebige und mögliche Ringglied des Heterocyclyl-Restes erfolgen. Bevorzugte Heteroatome sind Stickstoff, Sauerstoff und Schwefel. Bevorzugte Heterocyclyl-Reste sind Tetrahydrofuryl, Pyrrolidinyl, Imidazolidinyl, Thiazolidinyl, Tetrahydropyranyl, Piperidinyl, Piperazinyl, Morpholinyl, Thiomorpholinyl, Thiapyrrolidi- nyl, Oxapiperazinyl, Oxapiperidinyl und Oxadiazolyl.The term "cycloalkyl" for the purposes of this invention means cyclic, non-aromatic hydrocarbons having 1 to 3 rings of 3 to 20, preferably 3 to 12 carbons, which may be saturated or unsaturated, more preferably (C 3 -C 8 ) - The cycloalkyl radical may also be part of a bicyclic or polycyclic system, where, for example, the cycloalkyl radical having an aryl, heteroaryl or heterocyclyl radical as defined herein by any (s) possible and desired ring member ( The bonding to the compounds of the general formulas (I) and (II) can be effected via any and possible ring member of the cycloalkyl radical Preferred cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and Cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl. The term "heterocyclyl" represents a 3- to 14-membered, preferably 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical containing at least 1, optionally 2, 3, 4 or Contains heteroatoms, in particular nitrogen, oxygen and / or sulfur, wherein the heteroatoms are the same or different and the cyclic radical is saturated or unsaturated, but not aromatic and may be unsubstituted or mono- or polysubstituted The heterocyclyl radical may also be part a bi- or polycyclic system where, for example, the heterocyclyl radical is fused with an aryl, heteroaryl or cycloalkyl radical as defined herein by any possible and desired ring member (s) The compounds of the general formulas (I) and (II) can be made via any and possible ring member of the heterocyclyl radical Preferred heteroatoms are nitrogen, oxygen and sulfur Preferred heterocyclyl radicals are tetrahydrofuryl, pyrrolidine nyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiapyrrolidinyl, oxapiperazinyl, oxapiperidinyl and oxadiazolyl.
Der Ausdruck „Aryl" bedeutet im Sinne dieser Erfindung aromatische Kohlenwasserstoffe mit 3 bis 14 C-Atomen, bevorzugt 5 bis 14 C-Atomen, besonders bevorzugt mit 6 bis 14 C-Atomen, u.a. Phenyle, Naphthyle und Anthracenyle. Der Aryl-Rest kann auch Teil eines bi- oder polycyclischen Systems sein, wo bspw. der Aryl-Rest mit ei- nem Heterocyclyl-, Heteroaryl- oder Cycloalkyl-Rest wie hierin definiert durch jede(s) mögliche und gewünschte Ringmitglied(er) kondensiert ist, bspw. mit Tetrahydrofuran, Tetrahydrothiophen, Pyrrolidin, Imidazolidin, Thiazolidin, Tetrahydropyran, Dihydropy- ran, Piperidin, Furan, Thiophen, Imidazol, Thiazol, Oxazol und Isoxazol. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) kann über jedes beliebige und mögliche Ringglied des Aryl-Restes erfolgen. Jeder Aryl-Rest kann unsubstituiert oder einfach oder mehrfach substituiert vorliegen, wobei die Aryl-Substituenten gleich oder verschieden und in jeder beliebigen und möglichen Position des Aryls sein können. Bevorzugte Aryl-Reste sind Phenyl, Biphenyl, Naphthyl und Anthracenyl, aber ebenso Indanyl, Indenyl oder 1 ,2,3,4-Tetrahydronaphthyl.The term "aryl" in the context of this invention means aromatic hydrocarbons having 3 to 14 C atoms, preferably 5 to 14 C atoms, more preferably having 6 to 14 C atoms, including phenyls, naphthyls and anthracenyls also be part of a bi- or polycyclic system, where, for example, the aryl radical is fused with a heterocyclyl, heteroaryl or cycloalkyl radical as defined herein by any possible and desired ring member (s), eg. with tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, thiazolidine, tetrahydropyran, dihydropyran, piperidine, furan, thiophene, imidazole, thiazole, oxazole and isoxazole The bonding to the compounds of the general formulas (I) and (II) can be effected via any desired compound Each aryl radical can be unsubstituted or monosubstituted or polysubstituted, wherein the aryl substituents are identical or different and in any desired and possible position of the aryl radical Aryls can be. Preferred aryl radicals are phenyl, biphenyl, naphthyl and anthracenyl, but also indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl.
Der Ausdruck „Heteroaryl" steht für einen 5-, 6- oder 7-gliedrigen cyclischen aromatischen Rest, der mindestens 1 , ggf. auch 2, 3, 4 oder 5 Heteroatome enthält, insbesondere Stickstoff, Sauerstoff und/oder Schwefel, wobei die Heteroatome gleich oder verschieden sind und der Heterocyclus unsubstituiert oder ein- oder mehrfach substitu- iert sein kann. Im Falle der Substitution am Heterocyclus können die Heteroarylsubsti- tuenten gleich oder verschieden sein und in jeder beliebigen und möglichen Position des Heteroaryls sein. Die Anzahl der Stickstoffatome ist bevorzugt 0, 1 , 2 oder 3, die der Sauerstoff und Schwefelatome bevorzugt 0 oder 1. Der Heteroaryl-Rest kann auch Teil eines bi- oder polycyclischen Systems sein, wo bspw. der Heteroaryl-Rest mit einem Heterocyclyl-, Aryl- oder Cycloalkyl-Rest wie hierin definiert durch jede(s) mögliche und gewünschte Ringmitglied(er) kondensiert ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) kann über jedes beliebige und mögliche Ringglied des Heteroaryl-Restes erfolgen. Der Heterocyclus kann auch Teil eines bi- oder polycyclischen Systems sein. Bevorzugte Heteroatome sind Stickstoff, Sauerstoff und Schwefel. Bevorzugte Heteroaryl- Reste sind Pyrrolyl, Furyl, Thienyl, Thiazolyl, Isothia- zolyl, Oxazolyl, Oxadiazolyl, Isoxazolyl, Pyrazolyl, Imidazolyl, Triazol, Tetrazol, Pyridi- nyl, Pyrimidinyl, Pyridazinyl, Pyrazinyl, Triazin, Phthalazinyl, Indolyl, Indazolyl, Indolizi- nyl, Chinolinyl, Isochinolinyl, Chinoxalinyl, Chinazolinyl, Pteridinyl, Carbazolyl, Phena- zinyl, Phenoxazinyl, Phenothiazinyl und Acridinyl.The term "heteroaryl" represents a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, in particular nitrogen, oxygen and / or sulfur, where the heteroatoms are the same or different and the heterocycle is unsubstituted or monosubstituted or polysubstituted can be. In the case of substitution on the heterocycle, the heteroaryl substituents may be the same or different and may be in any desired and possible position of the heteroaryl. The number of nitrogen atoms is preferably 0, 1, 2 or 3, and the oxygen and sulfur atoms are preferably 0 or 1. The heteroaryl radical may also be part of a bi- or polycyclic system where, for example, the heteroaryl radical is substituted by a heterocyclyl radical. , Aryl or cycloalkyl radical as defined herein by any possible and desired ring member (s). The binding to the compounds of the general formulas (I) and (II) can be effected via any and possible ring member of the heteroaryl radical. The heterocycle may also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur. Preferred heteroaryl radicals are pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazole, tetrazole, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, phthalazinyl, indolyl, indazolyl, indolizine - nyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.
Die Ausdrücke „Alkyl-Cycloalkyl", „Cycloalkylalkyl", „Alkyl-Heterocyclyl", „Heterocyc- lylalkyl", „Alkyl-Aryl", „Arylalkyl", „Alkyl-Heteroaryl" und „Heteroarylalkyl" bedeuten für die Zwecke der vorliegenden Erfindung, daß Alkyl, Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl die oben definierten Bedeutungen haben und der Cycloalkyl-, Heterocyclyl-, Aryl- und Heteroaryl-Rest über einen Alkyl-Rest, bevorzugt Ci-C8-Alkyl-Rest, besonders bevorzugt Ci-C4-Alkyl-Rest, an die Verbindungen der allgemeinen Formeln (I) und (II) gebunden ist.The terms "alkylcycloalkyl", "cycloalkylalkyl", "alkylheterocyclyl", "heterocyclylalkyl", "alkylaryl", "arylalkyl", "alkylheteroaryl" and "heteroarylalkyl" mean for the purposes of the present invention in that alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above and the cycloalkyl, heterocyclyl, aryl and heteroaryl radical has an alkyl radical, preferably C 1 -C 8 -alkyl radical, particularly preferably C 4 alkyl radical to which compounds of the general formulas (I) and (II) are bonded.
Im Zusammenhang mit „Alkyl", „Alkenyl" und „Alkinyl" versteht man unter dem Beg- riff „substituiert" im Sinne dieser Erfindung die Substitution eines Wasserstoffrestes durch F, Cl, Br, I, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Aryl, NH-Heteroaryl, NH-Aryl- alkyl, NH-Heteroaryl-alkyl, N H- Heterocyclyl, NH-Alkyl-OH, N(Alkyl)2, N(Aryl-alkyl)2, N(Heteroaryl-alkyl)2, N(Heterocyclyl)2, N(Alkyl-OH)2, NO, NO2, SH, S-Alkyl, S- Cycloalkyl, S-Aryl, S-Heteroaryl, S-Aryl-alkyl, S-Heteroaryl-alkyl, S-Heterocyclyl, S- Alkyl-OH, S-Alkyl-SH, S-Alkyl, S-S-Cycloalkyl, S-S-Aryl, S-S-Heteroaryl, S-S-Aryl-Alkyl, S-S-Heteroaryl-alkyl, S-S-Heterocyclyl, SS-Alkyl-OH, S-S-Alkyl-SH, S-S-Alkyl-C(O)- NH-Heterocyclyl, OH, O-Alkyl, O-Cycloalkyl, O-Cycloalkyl-alkyl, O-Aryl, O-Heteroaryl, O-Aryl-alkyl, O- Heteroaryl -alkyl, O-Heterocyclyl, O-Heterocyclyl-alkyl, O-Alkyl-OH, O- Alkyl-O-Alkyl, O-SO2-N(Alkyl)2, 0-SO2-OH, O-SO2-O-Alkyl, O-SO2-O-Cycloalkyl, O- SO2-O-Heterocyclylalkyl, O-SO2-O-Cycloalkyl-alkyl, O-SO2-O-AlkylHeterocyclylalkyl, O- SO2-O-Aryl, O-SO2-O-Heteroaryl, O-SO2-O-Arylalkyl, O-SO2-O-Heteroaryl-alkyl, O- SO2-Alkyl, O-SO2-Cycloalkyl, O-SO2-Heterocyclylalkyl, O-SO2-Cycloalkyl-alkyl, 0-SO2- AlkylHeterocyclylalkyl, O-SO2-Aryl, O-SO2-Heteroaryl, O-SO2-Aryl-alkyl, 0-SO2- Heteroaryl-alkyl, O-C(O)-Alkyl, O-C(O)-Cycloalkyl, O-C(O)-Heterocyclylalkyl, 0-C(O)- Cycloalkyl-alkyl, O-C(O)-AlkylHeterocyclylalkyl, O-C(O)-Aryl, O-C(O)-Heteroaryl, O- C(O)-Aryl-alkyl, O-C(O)-Heteroaryl-alkyl, O-C(O)O-Alkyl, O-C(O)O-Cycloalkyl, O- C(O)O-Heterocyclylalkyl, O-C(O)O-Cycloalkyl-alkyl, O-C(O)O-AlkylHeterocyclylalkyl, O-C(O)O-Aryl, O-C(O)O-Heteroaryl, O-C(O)O-Aryl-alkyl, O-C(O)O-Heteroaryl-alkyl, O- C(O)NH-Alkyl, O-C(O)NH-Cycloalkyl, O-C(O)NH-Heterocyclylalkyl, 0-C(O)NH- Cycloalkyl-alkyl, O-C(O)NH-AlkylHeterocyclylalkyl, O-C(O)NH-Aryl, 0-C(O)NH- Heteroaryl, O-C(O)NH-Aryl-alkyl, O-C(O)NH-Heteroaryl-alkyl, O-C(O)N(Alkyl)2, O- C(O)N(Cycloalkyl)2, O-C(O)N(Heterocyclylalkyl)2, O-C(O)N(Cycloalkyl-alkyl)2, O- C(O)N(AlkylHeterocyclylalkyl)2, O-C(O)N(Aryl)2, O-C(O)N(Heteroaryl)2, O-C(O)N(Aryl- alkyl)2, O-C(O)N(Heteroaryl-alkyl)2, 0-P(O)(OH)2, O-P(O)(O-Metall)2, O-P(O)(O-Alkyl)2l O-P(O)(O-Cycloalkyl)2, O-P(O)(O-Aryl)2l O-P(O)(O-Heteroaryl)2, O-P(O)(O-Aryl-alkyl)2l O-P(O)(O-Heteroaryl-alkyl)2,O-P(O)(N-Alkyl)2(N-Alkyl)2,O-P(O)(N-Cycloalkyl)2(N- Cycloalkyl)2!0-P(0)(N-Heterocyclylalkyl)2(N-Heterocyclyl-alkyl)2, 0-P(0)(N-Aryl)2(N- Aryl)2, O-P(O)(N-Heteroaryl)2(N-Heteroaryl)2, O-P(O)(N-Aryl-alkyl)2(N-Aryl-alkyl)2, O- P(O)(N-Heteroaryl-alkyl)2(N-Heteroaryl-alkyl)2, CHO, C(O)-Alkyl, C(S)-Alkyl, C(O)-Aryl, C(S)-Aryl, C(O)-Aryl-alkyl, C(S)-Aryl-alkyl, C(O)-Heterocyclyl, C(O)-Heteroaryl, C(O)- Heteroaryl-alkyl, C(S)-Heterocyclyl, CO2H, CO2-Alkyl, CO2-Cyclyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Aryl-alkyl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Aryl, C(O)NH-Heterocyclyl, C(O)NH-Alkyl-Heterocyclyl, C(O)N(Alkyl)2, C(O)N(Aryl-alkyl)2, C(O)N(Heteroaryl-alkyl)2, C(O)N(Heterocyclyl)2, SO-Alkyl, SO2-Alkyl, SO2-Aryl, SO2- Aryl-alkyl, SO2-Heteroaryl, SO2-Heteroaryl-alkyl, SO2NH2, SO3H, CF3, CHO, CHS, Al- kyl, Cycloalkyl, Cycloalkyl-alkyl, Aryl, Aryl-alkyl, Heteroaryl, Heteroaryl-alkyl, Heterocyc- IyI und/oder Heterocyclyl-alkyl, wobei unter mehrfach substituierten Resten solche zu verstehen sind, die entweder an verschiedenen oder an gleichen Atomen mehrfach, z.B. zwei- oder dreifach substituiert sind, beispielsweise dreifach am gleichen C-Atom wie im Falle von CF3, -CH2CF3 oder an verschiedenen Stellen wie im Falle von - CH(OH)-CH=CH-CHCI2. Die Mehrfachsubstitution kann mit dem gleichen oder verschiedenen Substituenten erfolgen.In connection with "alkyl", "alkenyl" and "alkynyl", the term "substituted" in the context of this invention means the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-arylalkyl, NH-heteroaryl-alkyl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , N (aryl-alkyl) 2 , N (Heteroaryl-alkyl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-aryl-alkyl, S-heteroaryl-alkyl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, S-alkyl, SS-cycloalkyl, SS-aryl, SS-heteroaryl, SS-aryl-alkyl, SS-heteroaryl-alkyl, SS heterocyclyl, SS-alkyl-OH, SS-alkyl-SH, SS-alkyl-C (O) -NH-heterocyclyl, OH, O-alkyl, O-cycloalkyl, O-cycloalkyl-alkyl, O-aryl, O -heteroaryl, O-aryl-alkyl, O-alkyl heteroaryl, O-heterocyclyl, O-heterocyclyl-alkyl, O-alkyl-OH, O-alkyl-O-alkyl, O-SO 2 -N (alkyl) 2, 0-SO 2 -OH, O-SO 2 -O-alkyl, O-SO 2 -O-cycloalkyl, O- SO 2 -O-heterocyclylalkyl, O-SO 2 -O-cycloalkyl-alkyl, O-SO 2 -O-AlkylHeterocyclylalkyl, SO 2 O-, -O-aryl, O-SO 2 -O-heteroaryl, O-SO 2 - O-arylalkyl, O-SO 2 -O-heteroaryl-alkyl, O-SO 2 -alkyl, O-SO 2 -cycloalkyl, O-SO 2 -heterocyclylalkyl, O-SO 2 -cycloalkyl-alkyl, O-SO 2 - AlkylHeterocyclylalkyl, O-SO 2 -aryl, O-SO 2 -heteroaryl, SO 2 O-aryl-alkyl, 0-SO 2 - heteroaryl-alkyl, OC (O) -alkyl, OC (O) -cycloalkyl, OC ( O) -heterocyclylalkyl, O-C (O) -cycloalkyl-alkyl, OC (O) -alkyl-heterocyclylalkyl, OC (O) -aryl, OC (O) -Heteroaryl, O-C (O) -aryl-alkyl, OC ( O) -Heteroaryl-alkyl, OC (O) O-alkyl, OC (O) O-cycloalkyl, O-C (O) O-heterocyclylalkyl, OC (O) O-cycloalkyl-alkyl, OC (O) O-alkyl-heterocyclylalkyl , OC (O) O-aryl, OC (O) O-heteroaryl, OC (O) O-aryl-alkyl, OC (O) O-heteroaryl-alkyl, O-C (O) -NH-alkyl, OC (O ) NH-cycloalkyl, OC (O) NH-heterocyclylalkyl, O-C (O) NH-cycloalkyl-alkyl, OC (O) NH-alkyl-heterocyclylalkyl, OC (O) NH-aryl, O-C (O) NH-heteroaryl , OC (O) NH-aryl-alkyl, OC (O) NH-heteroaryl-alkyl, OC (O) N (alkyl) 2 , O-C (O) N (cycloalk yl) 2 , OC (O) N (heterocyclylalkyl) 2 , OC (O) N (cycloalkyl-alkyl) 2 , O-C (O) N (alkyl-heterocyclylalkyl) 2 , OC (O) N (aryl) 2 , OC ( O) N (heteroaryl) 2 , OC (O) N (arylalkyl) 2 , OC (O) N (heteroarylalkyl) 2 , 0-P (O) (OH) 2 , OP (O) (O-) Metal) 2 , OP (O) (O-alkyl) 2l OP (O) (O -cycloalkyl ) 2 , OP (O) (O -aryl ) 2l OP (O) (O-heteroaryl) 2 , OP (O) (O-aryl-alkyl) 2l OP (O) (O-heteroaryl-alkyl) 2 , OP (O) (N-alkyl) 2 (N-alkyl) 2 , OP (O) (N-cycloalkyl) 2 (N - cycloalkyl) 2! 0-P (0) (N-heterocyclylalkyl) 2 (N-heterocyclyl-alkyl) 2 , 0-P (0) (N-aryl) 2 (N-aryl) 2 , OP (O) (N-heteroaryl) 2 (N-heteroaryl) 2 , OP (O) (N -aryl-alkyl) 2 (N-aryl-alkyl) 2 , O-P (O) (N-heteroaryl-alkyl) 2 (N-heteroaryl-alkyl) 2 , CHO, C (O) -alkyl, C (S) -alkyl, C (O) -aryl, C (S) -aryl, C (O) -aryl-alkyl, C (S) -aryl-alkyl, C (O) -heterocyclyl, C (O) -heteroaryl, C (O) -heteroaryl-alkyl, C (S) -heterocyclyl, CO 2 H, CO 2 -alkyl, CO 2 -cyclyl, CO 2 -heterocyclyl, CO 2 -Aryl, CO 2 heteroaryl, CO 2 aryl-alkyl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-aryl, C (O) NH-heterocyclyl, C (O ) NH-alkyl heterocyclyl, C (O) N (alkyl) 2 , C (O) N (arylalkyl) 2 , C (O) N (heteroarylalkyl) 2 , C (O) N (heterocyclyl) 2 , SO-alkyl, SO 2 -alkyl, SO 2 -aryl, SO 2 - aryl-alkyl, SO 2 -heteroaryl, SO 2 -heteroaryl-alkyl, SO 2 NH 2, SO 3 H, CF 3, CHO, CHS, Alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyc IyI and / or heterocyclyl-alkyl, where among multiply substituted radicals are to be understood such d, which are substituted on different or on the same atoms several times, for example two or three times, for example, three times on the same carbon atom as in the case of CF 3 , -CH 2 CF 3 or at different positions as in the case of - CH ( OH) -CH = CH-CHCl 2 . The multiple substitution can be with the same or different substituent.
In Bezug auf „Aryl", „Aryl-alkyl", „Alkyl-Aryl", „Heteroaryl", Heteroaryl-alkyl", „Alkyl- Heteroaryl", „Heterocyclyl", „Heterocyclyl-alkyl", „Alkyl-Heterocyclyl", „Cycloalkyl", „Al- kyl-Cycloalkyl" sowie „Cycloalkyl-alkyl" versteht man unter dem Begriff „substituiert" im Sinne dieser Erfindung die ein- oder mehrfache Substitution, z.B. zwei-, drei- oder vierfache Substitution, eines oder mehrerer Wasserstoffatome des Ringsystemes durch F, Cl, Br, I, CN, NH2, NH-Alkyl, NH-Aryl, NH-Heteroaryl, NH-Aryl-alkyl, NH-Heteroaryl- alkyl, NH-Heterocyclyl, NH-Alkyl-OH, N(Alkyl)2, NC(O)Alkyl, N(Aryl-alkyl)2, N(Heteroaryl-alkyl)2, N(Heterocyclyl)2, N(Alkyl-OH)2, NO, NO2, SH, S-Alkyl, S-Aryl, S- Heteroaryl, S-Aryl-alkyl, S-Heteroaryl-alkyl, S-Heterocyclyl, S-Alkyl-OH, S-Alkyl-SH, OH, O-Alkyl, O-Cycloalkyl, O-Cycloalkyl-alkyl, O-Aryl, O-Heteroaryl, O-Aryl-alkyl, O- Heteroaryl-alkyl, O-Heterocyclyl, O-Heterocyclyl-alkyl, O-Alkyl-OH, O-Alkyl-0-Alkyl, O- SO2-N(Alkyl)2, 0-SO2-OH, O-SO2-O-Alkyl, O-SO2-O-Cycloalkyl, 0-SO2-O- Heterocyclylalkyl, O-SO2-O-Cycloalkyl-alkyl, O-SO2-O-AlkylHeterocyclylalkyl, 0-SO2-O- Aryl, O-SO2-O-Heteroaryl, O-SO2-O-Aryl-alkyl, O-SO2-O-Heteroaryl-alkyl, O-SO2-Alkyl, O-SO2-Cycloalkyl, O-SO2-Heterocyclylalkyl, O-SO2-Cycloalkyl-alkyl, 0-SO2- AlkylHeterocyclylalkyl, O-SO2-Aryl, O-SO2-Heteroaryl, O-SO2-Aryl-alkyl, 0-SO2-With respect to "aryl", "aryl-alkyl", "alkyl-aryl", "heteroaryl", heteroaryl-alkyl "," alkyl Heteroaryl "," heterocyclyl "," heterocyclyl-alkyl "," alkyl heterocyclyl "," cycloalkyl "," alkyl-cycloalkyl "and" cycloalkyl-alkyl "is understood by the term" substituted "in the context of this invention, the one - or multiple substitution, for example two-, three- or four-fold, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-aryl -alkyl, NH-heteroaryl-alkyl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , NC (O) alkyl, N (aryl-alkyl) 2 , N (heteroaryl-alkyl) 2 , N (heterocyclyl ) 2 , N (alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-aryl-alkyl, S-heteroaryl-alkyl, S-heterocyclyl, S-alkyl- OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-cycloalkyl-alkyl, O-aryl, O-heteroaryl, O-aryl-alkyl, O-heteroaryl-alkyl, O-heterocyclyl, O- heterocyclyl-alkyl, O-alkyl-OH, O-alkyl-0-alkyl, O-SO 2 -N (alkyl) 2, 0-SO 2 -OH, O-SO 2 -O-alkyl, O-SO 2 - O-cycloalkyl, 0-SO 2 -O- heterocyclylalkyl, O-SO 2 -O-Cycl Oalkyl-alkyl, O-SO 2 -O-AlkylHeterocyclylalkyl, 0-SO 2 -O- aryl, O-SO 2 -O-heteroaryl, O-SO 2 -O-alkyl-aryl, O-SO 2 -O-heteroaryl alkyl, O-SO 2 -alkyl, SO 2 O-cycloalkyl, O-SO 2 -Heterocyclylalkyl, O-SO 2 cycloalkyl-alkyl, 0-SO 2 - AlkylHeterocyclylalkyl, O-SO 2 -aryl, O-SO 2- heteroaryl, O-SO 2 -aryl-alkyl, O-SO 2 -
Heteroaryl-alkyl, O-C(O)-Alkyl, O-C(O)-Cycloalkyl, O-C(O)-Heterocyclylalkyl, 0-C(O)- Cycloalkyl-alkyl, O-C(O)-AlkylHeterocyclylalkyl, O-C(O)-Aryl, O-C(O)-Heteroaryl, O- C(O)-Aryl-alkyl, O-C(O)-Heteroaryl-alkyl, O-C(O)O-Alkyl, O-C(O)O-Cycloalkyl, O- C(O)O-Heterocyclylalkyl, O-C(O)O-Cycloalkyl-alkyl, O-C(O)O-AlkylHeterocyclylalkyl, O-C(O)O-Aryl, O-C(O)O-Heteroaryl, O-C(O)O-Aryl-alkyl, O-C(O)O-Heteroaryl-alkyl, O- C(O)NH-Alkyl, O-C(O)NH-Cycloalkyl, O-C(O)NH-Heterocyclylalkyl, 0-C(O)NH- Cycloalkyl-alkyl, O-C(O)NH-AlkylHeterocyclylalkyl, O-C(O)NH-Aryl, 0-C(O)NH- Heteroaryl, O-C(O)NH-Aryl-alkyl, O-C(O)NH-Heteroaryl-alkyl, O-C(O)N(Alkyl)2, O- C(O)N(Cycloalkyl)2, O-C(O)N(Heterocyclylalkyl)2, O-C(O)N(Cycloalkyl-alkyl)2, O- C(O)N(AlkylHeterocyclylalkyl)2, O-C(O)N(Aryl)2, O-C(O)N(Heteroaryl)2, O-C(O)N(Aryl- alkyl)2, O-C(O)N(Heteroaryl-alkyl)2, 0-P(O)(OH)2, O-P(O)(O-Metall)2, O-P(O)(O-Alkyl)2, O-P(O)(O-Cycloalkyl)2, O-P(O)(O-Aryl)2, O-P(O)(O-Heteroaryl)2, O-P(O)(O-Aryl-alkyl)2, O-P(O)(O-Heteroaryl-alkyl)2,O-P(O)(N-Alkyl)2(N-Alkyl)2,O-P(O)(N-Cycloalkyl)2(N- Cycloalkyl)2,0-P(0)(N-Heterocyclylalkyl)2(N-Hetero-cycloalkyl)2, 0-P(0)(N-Aryl)2(N- Aryl)2, O-P(O)(N-Heteroaryl)2(N-Heteroaryl)2, O-P(O)(N-Aryl-alkyl)2(N-Aryl-alkyl)2, O- P(O)(N-Heteroaryl-alkyl)2(N-Heteroaryl-alkyl)2, CHO, C(O)-Alkyl, C(S)-Alkyl, C(O)-Aryl, C(S)-Aryl, C(O)-Aryl-alkyl, C(S)-Aryl-alkyl, C(O)-Heterocyclyl, C(S)-Heterocyclyl, CO2H, CO2-Alkyl, CO2-Aryl-alkyl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Aryl, C(O)NH- Heterocyclyl, C(O)N(Alkyl)2, C(O)N(Aryl-alkyl)2, C(O)N(Heteroaryl-alkyl)2, C(O)N(Heterocyclyl)2, SO-Alkyl, SO2-Alkyl, SO2-Aryl, SO2-Aryl-alkyl, SO2-Heteroaryl, SO2-Heteroaryl-alkyl, SO2NH2, SO3H, CF3, CHO, CHS, Alkyl, Cycloalkyl, Cycloalkyl- alkyl, Aryl, Aryl-alkyl, Heteroaryl, Heteroaryl-alkyl, Heterocyclyl und/oder Heterocyclyl- alkyl, wobei unter mehrfach substituierten Resten solche zu verstehen sind, die entweder an verschiedenen oder an gleichen Atomen mehrfach, z.B. zwei- oder dreifach substituiert sind, beispielsweise dreifach am gleichen C-Atom wie im Falle von CF3, - CH2CF3 oder an verschiedenen Stellen wie im Falle von -CH(OH)-CH=CH-CHCI2. Die Mehrfachsubstitution kann mit dem gleichen oder verschiedenen Substituenten erfolgen.Heteroaryl-alkyl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclylalkyl, O-C (O) -cycloalkyl-alkyl, OC (O) -alkyl-heterocyclylalkyl, OC (O) -aryl, OC (O) heteroaryl, O-C (O) -aryl-alkyl, OC (O) -heteroaryl-alkyl, OC (O) O-alkyl, OC (O) O-cycloalkyl, O-C (O) O Heterocyclylalkyl, OC (O) O -cycloalkyl-alkyl, OC (O) O-alkyl-heterocyclylalkyl, OC (O) O-aryl, OC (O) O-heteroaryl, OC (O) O-aryl-alkyl, OC (O ) O-Heteroaryl-alkyl, O-C (O) NH-alkyl, OC (O) NH-cycloalkyl, OC (O) NH-heterocyclylalkyl, O-C (O) NH-cycloalkyl-alkyl, OC (O) NH Alkyl heterocyclylalkyl, OC (O) NH-aryl, O-C (O) NH-heteroaryl, OC (O) NH-aryl-alkyl, OC (O) NH-heteroaryl-alkyl, OC (O) N (alkyl) 2 , O-C (O) N (cycloalkyl) 2 , OC (O) N (heterocyclylalkyl) 2 , OC (O) N (cycloalkyl-alkyl) 2 , O-C (O) N (alkyl-heterocyclylalkyl) 2 , OC (O ) N (aryl) 2 , OC (O) N (heteroaryl) 2 , OC (O) N (arylalkyl) 2 , OC (O) N (heteroarylalkyl) 2 , 0-P (O) (OH) 2 , OP (O) (O-metal) 2 , OP (O) (O-alkyl) 2 , OP (O) (O-cycloalkyl) 2 , OP (O) (O-aryl) 2 , OP (O) (O-heteroaryl) 2 , OP (O) (O-aryl-alkyl) 2 , OP (O) (O-heteroaryl-al kyl) 2 , OP (O) (N-alkyl) 2 (N-alkyl) 2 , OP (O) (N-cycloalkyl) 2 (N-cycloalkyl) 2 , 0-P (0) (N-heterocyclylalkyl) 2 (N-heterocycloalkyl) 2 , 0-P (O) (N-aryl) 2 (N-aryl) 2 , OP (O) (N-heteroaryl) 2 (N-heteroaryl) 2 , OP (O) ( N-aryl-alkyl) 2 (N-aryl-alkyl) 2 , O-P (O) (N-heteroaryl-alkyl) 2 (N-heteroaryl-alkyl) 2 , CHO, C (O) -alkyl, C ( S) -alkyl, C (O) -aryl, C (S) -aryl, C (O) -aryl-alkyl, C (S) -aryl-alkyl, C (O) -heterocyclyl, C (S) -heterocyclyl , CO 2 H, CO 2 alkyl, CO 2 -aryl-alkyl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-aryl, C (O) NH-heterocyclyl, C (O) N (alkyl) 2 , C (O) N (arylalkyl) 2 , C (O) N (heteroarylalkyl) 2 , C (O) N (heterocyclyl) 2 , SO-alkyl, SO 2 - Alkyl, SO 2 -aryl, SO 2 -aryl-alkyl, SO 2 -heteroaryl, SO 2 heteroarylalkyl, SO 2 NH 2 , SO 3 H, CF 3 , CHO, CHS, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl where multiply substituted radicals are understood as meaning those which are monosubstituted, for example monosubstituted or trisubstituted, either on different or on the same atoms, for example three times on the same C atom as in the case of CF 3 , -CH 2 CF 3 or on different positions as in the case of -CH (OH) -CH = CH-CHCl 2 . The multiple substitution can be with the same or different substituent.
Die Ausdrücke „Mono-Alkylamino" und „Di-Alkylamino" bedeuten im Rahmen dieserThe terms "monoalkylamino" and "di-alkylamino" mean in this context
Erfindung, dass ein bzw. zwei Alkylreste gemäß obiger Definition an ein Stickstoffatom gebunden sind. Die Bindung an die Verbindungen der allgemeinen Formel (I) erfolgt über das Stickstoff atom. Beispiele sind Ethylamino, Dimethylamino und Isopropylethy- lamino.Invention, that one or two alkyl radicals are bonded as defined above to a nitrogen atom. The binding to the compounds of the general formula (I) takes place via the nitrogen atom. Examples are ethylamino, dimethylamino and isopropylethylamine.
Der Ausdruck „Cyano-alkyl" bedeutet im Rahmen dieser Erfindung, dass ein Alkyl- rest gemäß obiger Definition an eine Cyanogruppe gebunden ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) erfolgt über die Cyanogruppe. Beispiele sind Methylcyano und n-Propylcyano.In the context of this invention, the term "cyanoalkyl" means that an alkyl radical as defined above is bonded to a cyano group The compounds of the general formulas (I) and (II) are bonded via the cyano group and n-propyl cyano.
Der Ausdruck "Carbonyl" bedeutet im Rahmen dieser Erfindung, dass ein Alkyl, Cycloalkyl, Cyloalkyl-alkyl, Alkyl-cyloalkyl, Aryl, Heteroaryl, Aryl-alkyl, Alkyl-aryl, Heteroaryl-alkyl, Alkyl-heteroaryl, Heterocyclyl, Alkyl-heterocyclyl und/oder Heterocyclyl- alkyl Rest gemäß obiger Definition an eine -C(O)- Gruppe gebunden ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) erfolgt über die -C(O)- Gruppe. Beispiele sind -C(O)-CH3, -C(O)-CH2CH3, -C(O)-isopropyl und -C(O)-tBu (tBu = tert. Butyl).The term "carbonyl" in the context of this invention means that an alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cyloalkyl, aryl, heteroaryl, aryl-alkyl, alkyl-aryl, heteroaryl-alkyl, alkyl-heteroaryl, heterocyclyl, alkyl-heterocyclyl and / or heterocyclyl-alkyl radical as defined above to a -C (O) - group is bound. The binding to the compounds of general formulas (I) and (II) via the -C (O) - group. Examples are -C (O) -CH 3 , -C (O) -CH 2 CH 3 , -C (O) -isopropyl and -C (O) -tBu (tBu = tert-butyl).
Der Ausdruck "Carboxyl" bedeutet im Rahmen dieser Erfindung, dass ein Alkyl, Cycloalkyl, Cyloalkyl-alkyl, Alkyl-cyloalkyl, Aryl, Heteroaryl, Aryl-alkyl, Alkyl-aryl, Heteroaryl-alkyl, Alkyl-heteroaryl, Heterocyclyl, Alkyl-heterocyclyl und/oder Heterocyclyl- alkyl Rest gemäß obiger Definitionen an eine -C(O)O- Gruppe gebunden ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) erfolgt über die - C(O)O- Gruppe. Beispiele sind -C(O)O-CH3 und -C(O)O-phenyl.The term "carboxyl" in the context of this invention means that an alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cyloalkyl, aryl, heteroaryl, aryl-alkyl, alkyl-aryl, heteroaryl-alkyl, alkyl-heteroaryl, heterocyclyl, alkyl-heterocyclyl and / or heterocyclylalkyl radical is bound to a -C (O) O- group as defined above. The binding to the compounds of the general formulas (I) and (II) takes place via the C (O) O- group. Examples are -C (O) O-CH 3 and -C (O) O-phenyl.
Der Ausdruck "Carboxy-alkyl" bedeutet im Rahmen dieser Erfindung, dass eine Carboxy Gruppe gemäß obiger Definition an einen Alkylrest gemäß obiger Definition gebunden ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) erfolgt über den Alkylrest.The term "carboxyalkyl" in the context of this invention means that a carboxy group as defined above is bonded to an alkyl radical as defined above. The binding to the compounds of the general formulas (I) and (II) takes place via the alkyl radical.
Der Ausdruck "Alkoxy" bedeutet im Rahmen dieser Erfindung, dass ein Alkylrest gemäß obiger Definition an ein Sauerstoffatom gebunden ist. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) erfolgt über das Sauerstoffatom. Bei- spiele sind Methoxy, Ethoxy und n-Propyloxy.The term "alkoxy" in the context of this invention means that an alkyl radical as defined above is bonded to an oxygen atom. The binding to the compounds of the general formulas (I) and (II) takes place via the oxygen atom. Examples are methoxy, ethoxy and n-propyloxy.
Der Ausdruck "Alkoxy" in den Begriffen "Alkoxycarbonyl", "Aryl-alkoxy", "Heteroaryl- alkoxy", "Alkoxycarbonylamino", "Alkoxycarbonylamino-alkyl" hat oben definierte Bedeutung. Die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) erfolgt bei "Aryl-alkoxy" und "Heteroaryl-alkoxy" über das Sauerstoffatom. Beispiele sind Ben- zyloxy und Indolyloxy.The term "alkoxy" in the terms "alkoxycarbonyl", "arylalkoxy", "heteroarylalkoxy", "alkoxycarbonylamino", "alkoxycarbonylaminoalkyl" has the meaning defined above. The binding to the compounds of the general formulas (I) and (II) takes place in the case of "arylalkoxy" and "heteroarylalkoxy" via the oxygen atom. Examples are benzyloxy and indolyloxy.
Bei "Alkoxycarbonyl" erfolgt die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) über die -C(O)- Gruppe.In the case of "alkoxycarbonyl", the bond to the compounds of the general formulas (I) and (II) takes place via the -C (O) group.
Bei „Alkoxycarbonyl-alkyl" erfolgt die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) über den Alkylrest gemäß oben definierter Bedeutung. Bei "Alkoxycarbonylamino" erfolgt die Bindung an die Verbindungen der allgemeinen Formeln (I) und (II) über die Aminogruppe; bei "Alkoxycarbonylamino-alkyl" über den Alkylrest gemäß oben definierter Bedeutung.In the case of "alkoxycarbonyl-alkyl", the bond to the compounds of the general formulas (I) and (II) takes place via the alkyl radical as defined above: In the case of "alkoxycarbonylamino", the bond to the compounds of the general formulas (I) and (II) via the amino group, in the case of "alkoxycarbonylamino-alkyl" via the alkyl radical as defined above.
Der Ausdruck „Metall" umfasst in diesem Sinne dieser Erfindung Metallionen wie Natrium-, Kalium-, Lithium-, Magnesium-, Calcium-, Zink- und Mangan-Ionen.The term "metal" within the meaning of this invention includes metal ions such as sodium, potassium, lithium, magnesium, calcium, zinc and manganese ions.
Der Ausdruck „Halogen" umfasst im Sinne dieser Erfindung die Halogenatome Fluor, Chlor, Brom und lod.The term "halogen" for the purposes of this invention, the halogen atoms fluorine, chlorine, bromine and iodine.
Sofern die erfindungsgemäßen Verbindungen mindestens ein Asymmetriezentrum aufweisen, können sie in Form ihrer Racemate, in Form der reinen Enantiomeren und/oder Diastereomeren oder in Form von Mischungen dieser Enantiomeren und/oder Diastereomeren vorliegen und zwar sowohl in Substanz als auch als pharmazeutisch annehmbare Salze dieser Verbindungen. Die Mischungen können in jedem beliebigen Mischungsverhältnis der Stereoisomeren vorliegen.If the compounds according to the invention have at least one asymmetric center they may be present in the form of their racemates, in the form of pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers, both in substance and as pharmaceutically acceptable salts of these compounds. The mixtures can be present in any mixing ratio of the stereoisomers.
So lassen sich beispielsweise die erfindungsgemäßen Verbindungen, welche ein oder mehrere Chiralitätszentren aufweisen und die als Racemate auftreten, nach an sich bekannten Methoden in ihre optischen Isomeren, also Enantiomere oder Diastere- omere auftrennen. Die Trennung kann durch Säulentrennung an chiralen Phasen oder durch Umkristallisation aus einem optisch aktiven Lösungsmittel oder unter Verwendung einer optisch aktiven Säure oder Base oder durch Derivatisierung mit einem optisch aktiven Reagenz, wie beispielsweise einem optisch aktiven Alkohol, und anschließender Abspaltung des Restes erfolgen.Thus, for example, the compounds according to the invention which have one or more centers of chirality and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se. The separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by using an optically active acid or base or by derivatization with an optically active reagent, such as an optically active alcohol, followed by cleavage of the residue.
Die erfindungsgemäßen Verbindungen können in Form ihrer Doppelbindungsisomere als „reine" E- oder Z-Isomere oder in Form von Mischungen dieser Doppelbindungsisomere vorliegen.The compounds according to the invention can be present in the form of their double bond isomers as "pure" E or Z isomers or in the form of mixtures of these double bond isomers.
Sofern möglich, können die erfindungsgemäßen Verbindungen in Form der Tauto- meren vorliegen.If possible, the compounds of the invention may be in the form of tautomers.
Die erfindungsgemäßen Verbindungen können, falls sie eine ausreichend basische Gruppe, wie zum Beispiel ein primäres, sekundäres oder tertiäres Amin besitzen, mit anorganischen und organischen Säuren in ihre physiologisch verträglichen Salze über- führt werden. Vorzugsweise werden die pharmazeutisch annehmbaren Salze der erfindungsgemäßen Verbindungen mit Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, p-Toluolsulfonsäure, Kohlensäure, Ameisensäure, Essigsäure, Trifluoressigsäure, Sulfoessigsäure, Oxalsäure, Malonsäure, Maleinsäure, Bernsteinsäure, Weinsäure, Traubensäure, Äpfelsäure, Embonsäure, Mandelsäure, Fumarsäure, Milchsäure, Citronensäure, Glutaminsäure oder Asparaginsäure gebildet. Bei den gebildeten Salzen handelt es sich u.a. um Hydrochloride, Hydrobromide, Sulfate, Hydrogensulfate, Phosphate, Methansulfonate, Tosylate, Carbonate, Hydrogencar- bonate, Formiate, Acetate, Triflate, Sulfoacetate, Oxalate, Malonate, Maleate, Succina- te, Tartrate, Malate, Embonate, Mandelate, Fumarate, Lactate, Citrate, Glutaminate und Aspartate. Die Stöchiometrie der gebildeten Salze der erfindungsgemäßen Verbindungen kann dabei ganzzahlige oder nicht ganzzahlige Vielfache von eins betragen.If they have a sufficiently basic group, such as, for example, a primary, secondary or tertiary amine, the compounds according to the invention can be converted into their physiologically acceptable salts with inorganic and organic acids. Preferably, the pharmaceutically acceptable salts of the compounds of the invention are hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, trifluoroacetic, sulfoacetic, oxalic, malonic, maleic, succinic, tartaric, racemic, malic, embonic, Mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid formed. The salts formed are, inter alia, hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, phosphates, methanesulfonates, tosylates, carbonates, hydrogencarbonates, formates, acetates, triflates, sulfoacetates, oxalates, malonates, maleates, succinates. te, tartrates, malates, embonates, almonds, fumarates, lactates, citrates, glutaminates and aspartates. The stoichiometry of the formed salts of the compounds according to the invention can be integer or non-integer multiples of one.
Die erfindungsgemäßen Verbindungen können, falls sie eine ausreichend saureThe compounds of the invention, if they are sufficiently acidic
Gruppe, wie zum Beispiel die Carboxygruppe oder die Phosphorsäuregruppe enthalten, mit anorganischen und organischen Basen in ihre physiologisch verträglichen Salze überführt werden. Als anorganische Basen kommen beispielsweise Natriumhydroxid, Kaliumhydroxid, Calciumhydroxid, als organische Basen Ethanolamin, Diethano- lamin, Triethanolamin, Cyclohexylamin, Dibenzylethylendiamin und Lysin in Betracht. Die Stöchiometrie der gebildeten Salze der erfindungsgemäßen Verbindungen kann dabei ganzzahlige oder nicht ganzzahlige Vielfache von eins betragen.Group, such as the carboxy group or the phosphoric acid group, are converted with inorganic and organic bases in their physiologically acceptable salts. Suitable inorganic bases are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, as organic bases ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine and lysine. The stoichiometry of the formed salts of the compounds according to the invention can be integer or non-integer multiples of one.
Die erfindungsgemäßen Verbindungen der allgemeinen Formeln (I) und (II) können, falls sie zur Bildung von Koordinationsverbindungen befähigte Gruppen enthalten, mit Übergangsmetallen in Koordinationsverbindungen / Komplexverbindungen überführt werden. Vorzugsweise werden die pharmazeutisch annehmbaren Koordinationsverbindungen / Komplexverbindungen der erfindungsgemäßen Verbindungen gemäß der allgemeinen Formeln (I) und (II) mit Platinsalzen gebildet. Die Stöchiometrie der gebildeten Koordinationsverbindungen / Komplexverbindungen der erfindungsgemäßen Verbindungen kann dabei ganzzahlige oder nicht ganzzahlige Verhältnisse der erfindungsgemäßen Verbindungen als Liganden zum Übergangsmetall annehmen.The compounds of the general formulas (I) and (II) according to the invention, if they contain groups capable of forming coordination compounds, can be converted with transition metals into coordination compounds / complex compounds. Preferably, the pharmaceutically acceptable coordination compounds / complex compounds of the compounds of the invention according to the general formulas (I) and (II) are formed with platinum salts. The stoichiometry of the formed coordination compounds / complex compounds of the compounds according to the invention can thereby assume integer or non-integer ratios of the compounds according to the invention as ligands to the transition metal.
Ebenfalls bevorzugt sind Solvate und insbesondere Hydrate der erfindungsgemäßen Verbindungen, die z. B. durch Kristallisation aus einem Lösungsmittel oder aus wässriger Lösung erhalten werden können. Es können sich dabei ein, zwei, drei oder beliebig viele Solvat- oder Wasser-Moleküle mit den erfindungsgemäßen Verbindungen zu Solvaten und Hydraten verbinden.Also preferred are solvates and in particular hydrates of the compounds of the invention, the z. B. can be obtained by crystallization from a solvent or aqueous solution. One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to give solvates and hydrates.
Es ist bekannt, dass chemische Substanzen Festkörper ausbilden, die in verschie- denen Ordnungszuständen vorliegen, die man als polymorphe Formen oder Modifikationen bezeichnet. Die verschiedenen Modifikationen einer polymorphen Substanz können sich in ihren physikalischen Eigenschaften stark unterscheiden. Die erfindungsgemäßen Verbindungen können in verschiedenen polymorphen Formen vorliegen, dabei können bestimmte Modifikationen metastabil sein.It is known that chemical substances form solids, which in different There are states of order called polymorphic forms or modifications. The various modifications of a polymorphic substance may differ greatly in their physical properties. The compounds of the invention may exist in various polymorphic forms, while certain modifications may be metastable.
Ebenfalls können die erfindungsgemäßen Verbindungen in Form beliebiger Prodrugs wie beispielsweise Ester, Carbonate, Carbamate, Harnstoffe, Amide oder Phosphate vorkommen, bei denen die tatsächlich biologisch aktive Form erst durch Verstoffwechselung freigesetzt wird.Likewise, the compounds according to the invention may be present in the form of any prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which the actually biologically active form is released only by metabolism.
Es ist bekannt, dass chemische Substanzen im Körper zu Metaboliten umgewandelt werden die gegebenenfalls ebenfalls die erwünschte biologische Wirkung - unter Umständen sogar in stärker ausgeprägter Form - hervorrufen können.It is known that chemical substances in the body are converted to metabolites which may also produce the desired biological effect - possibly even in a more pronounced form.
Entsprechende Prodrugs und Metabolite der erfindungsgemäßen Verbindungen sind als zur Erfindung gehörig anzusehen.Corresponding prodrugs and metabolites of the compounds according to the invention are to be regarded as belonging to the invention.
Mit den erfindungsgemäßen Verbindungen konnte jetzt überraschenderweise eine antiproliferative Aktivität in unterschiedlichen zellulären Tumor-Modellen aufgezeigt werden. Des weiteren konnte gezeigt werden, dass die erfindungsgemäßen Verbindungen potente Inhibitoren der Tubulin-Polymerisation und/oder Inhibitoren von die Microtubuli- basierten Motorproteinen, bspw. Kinesinen und Dyneinen, insbesondere von mitotischen Kinesinen, darstellen. Kinesine sind ausführlich in Miki H et al. (Proc. Natl. Acad. Sei. USA 2001 , 98: 7004-701 1 ) charakterisiert und klassifiziert worden und umfassen bspw. Kinesin-Superfamilie (KIF) Protein, N-1 Kinesine, KIF5A, KIF5B, KIF5C, N-2 Kinesine, Eg5 (KIF1 1 , KSP), BimC (KIF8), N-3 Kinesine, KIF1 A, KIF1 B, KIF1 C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 Kinesine, KIF3A, KIF3B, KIF3C, KIF17, N-5 Kinesine, KIF4, KIF4A, KIF4B, KIF21 A, KIF21 B, N-6 Kinesine, KIF23 (MKLP1 , CHO1 ), KIF20A (Rab6-KIF), KIF20B (KIpMPPI ), MKLP2, N-7 Kinesine, KIF10 (CENP- E), N-8 Kinesine, KIF18A, KIF18B, KIF22 (Kid), KIF19A, KIF19B, N-9 Kinesine, KIF12, N-10 Kinesine, KIF15 (Hklp2), N-1 1 Kinesine, KIF24, KIF25 (KNSL3), KIF26A, KIF26B, M-Kinesine, KIF2A (KIF2), KIF2B, KIF2C (MCAK), C-1 Kinesine, KIFC1 , C-2 Kinesine, KIFC2, KIFC3, KIF6, KIF7 und KIF9. Der überraschende duale Wirkmechanismus macht die erfindungsgemäßen Verbindungen besonders geeignet als Arzneimittel zur Behandlung von gut- und bösartigen Tumorerkrankungen am Menschen und Tieren. Sowohl das Tubulin-Gerüst als auch die Motorproteine spielen eine wichtige Rolle bei der Mitose, einer spezifischen Phase des Zellzyklus. Durch die vorteilhafte Hemmung eines oder beider Targets wird die korrekte Ausbildung der mitotischen Spindel und damit die Aufteilung des genetischen Materials auf die Tochterzellen verhindert. Die unkontrolliert sich teilende Tumorzelle wird im Zellzyklus arretiert. Dies führt in Folge zu einem Absterben der Tumorzelle durch den programmierten Zelltod (Apoptose). Dadurch ist eine effektive Bekämpfung des Tumors möglich und mittels der erfindungsgemäßen Verbindungen können (multiple) Resistenzen gegenüber bekannten Tumortherapeutika überwunden werden.Surprisingly, an antiproliferative activity in different cellular tumor models could now be demonstrated with the compounds according to the invention. Furthermore, it has been shown that the compounds according to the invention are potent inhibitors of tubulin polymerization and / or inhibitors of microtubule-based motor proteins, for example kinesins and dynins, in particular mitotic kinesins. Kinesins are described in detail in Miki H et al. (Proc Natl Acad., USA 2001, 98: 7004-701 1) have been characterized and classified and include, for example, kinesin superfamily (KIF) protein, N-1 kinesins, KIF5A, KIF5B, KIF5C, N-2 kinesins , Eg5 (KIF1 1, KSP), BimC (KIF8), N-3 kinesins, KIF1A, KIF1B, KIF1C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 kinesins, KIF3A, KIF3B, KIF3C, KIF17 , N-5 kinesins, KIF4, KIF4A, KIF4B, KIF21A, KIF21B, N-6 kinesins, KIF23 (MKLP1, CHO1), KIF20A (Rab6-KIF), KIF20B (KIpMPPI), MKLP2, N-7 kinesins, KIF10 (CENP-E), N-8 kinesins, KIF18A, KIF18B, KIF22 (Kid), KIF19A, KIF19B, N-9 kinesins, KIF12, N-10 kinesins, KIF15 (Hklp2), N-1 1 kinesins, KIF24, KIF25 (KNSL3), KIF26A, KIF26B, M-kinesins, KIF2A (KIF2), KIF2B, KIF2C (MCAK), C-1 kinesins, KIFC1, C-2 kinesins, KIFC2, KIFC3, KIF6, KIF7 and KIF9. The surprising dual mechanism of action makes the compounds according to the invention particularly suitable as medicaments for the treatment of benign and malignant tumor diseases in humans and animals. Both the tubulin framework and engine proteins play an important role in mitosis, a specific phase of the cell cycle. The advantageous inhibition of one or both targets prevents the correct formation of the mitotic spindle and thus the distribution of the genetic material to the daughter cells. The uncontrollably dividing tumor cell is arrested in the cell cycle. This leads to a death of the tumor cell due to programmed cell death (apoptosis). As a result, an effective control of the tumor is possible and by means of the compounds according to the invention, (multiple) resistances to known tumor therapeutics can be overcome.
Des Weiteren zeigen die erfindungsgemäßen Verbindungen aufgrund ihrer Spezifität und/oder des dualen Wirkmechanismus vorteilhafterweise keine schweren Neben- Wirkungen, wie bspw. Neurotoxizität.Furthermore, because of their specificity and / or the dual mechanism of action, the compounds according to the invention advantageously show no serious side effects, such as, for example, neurotoxicity.
Die erfinderische Aufgabe wurde in einem weiteren Aspekt überraschender Weise dadurch gelöst, dass ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen bereitgestellt wird.The inventive task has surprisingly been achieved in a further aspect by providing a process for the preparation of the compounds according to the invention.
Die erfindungsgemäßen Verbindungen können im Rahmen dieser Erfindung allen bekannten Säugetieren, insbesondere dem Menschen, zur Behandlung und/oder Prophylaxe verabreicht werden.In the context of this invention, the compounds according to the invention can be administered to all known mammals, in particular humans, for the treatment and / or prophylaxis.
In einer anderen bevorzugten Ausführungsform werden die erfindungsgemäßen Verbindungen bereitgestellt zu den oben dargestellten Verwendungen, wobei das Säugetier ausgewählt ist aus der Gruppe bestehend aus: „Mensch, Nutztier, Vieh, Haustier, Rind, Kuh, Schaf, Schwein, Ziege, Pferd, Pony, Esel, Maulesel, Maultier, Hase, Kaninchen, Katze, Hund, Meerschweinchen, Hamster, Ratte, Maus" und bevorzugt ein Mensch ist.In another preferred embodiment, the compounds of the invention are provided for the uses set forth above, wherein the mammal is selected from the group consisting of: "human, farm animal, livestock, pet, cattle, cow, sheep, pig, goat, horse, pony, Donkey, mule, mule, rabbit, rabbit, cat, dog, guinea pig, hamster, rat, mouse "and prefers a human being.
Die erfinderische Aufgabe wurde in einem weiteren Aspekt überraschender Weise dadurch gelöst, dass Anthracen-Derivate gemäß der allgemeinen Formel (II)
Figure imgf000038_0001
(H) bereitgestellt werden, worin:The inventive task has surprisingly been achieved in a further aspect by using anthracene derivatives according to the general formula (II)
Figure imgf000038_0001
(H), wherein:
Substituent V unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NR28, N-OR29, geminal geknüpfter Wasserstoff und Hydroxy;Substituent V is independently selected from the group consisting of: "O, S, NR28, N-OR29, geminally linked hydrogen and hydroxy;
Substituent Z unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NR30, N-OR31 ";Substituent Z is independently selected from the group consisting of: "O, S, NR30, N-OR31";
Substituenten R18, R19, R20, R21 , R22, R23, R24, R25 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsub- stituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl, Amino, Mono-Alkylamino, Di-Alkylamino, Halogen, -F, -Cl, -Br, -Substituents R18, R19, R20, R21, R22, R23, R24, R25 independently of one another are selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, amino, mono-alkylamino, di-alkylamino, halogen, -F, -Cl, -Br, -
I, mit ein oder mehreren Fluoratomen substituiertes Alkyl, Trifluormethyl, Cyano, geradkettiges oder verzweigtes Cyano-alkyl, Carbonyl, Carboxyl, -COOH, Alkoxy- carbonyl, Carboxy-alkyl, Alkoxycarbonyl-alkyl, Hydroxy, Alkoxy, Aryl-alkoxy, Benzy- loxy, Heteroaryl-alkoxy, Alkoxycarbonylamino, Alkoxycarbonylamino-alkyl"; Substituent R26 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl- alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl, -OR32, -NR33R34"; Substituent R27 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl"; Substituenten R28, R29, R30, R31 , R32, R33, R34 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsub- stituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl"; die zur Herstellung eines Arzneimittels verwendet werden können.I, alkyl substituted by one or more fluorine atoms, trifluoromethyl, cyano, straight-chain or branched cyanoalkyl, carbonyl, carboxyl, -COOH, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxy, alkoxy, arylalkoxy, benzyl- loxy, heteroarylalkoxy, alkoxycarbonylamino, alkoxycarbonylaminoalkyl ", substituent R26 is independently selected from the group consisting of:" unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted Heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, -OR32, -NR33R34 "; Substituent R27 is independently selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl; substituents R28, R29, R30 R31, R32, R33, R34 are independently selected independently from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl "; which can be used for the manufacture of a medicament.
Ebenso umfasst im Rahmen der vorliegenden Erfindung sind Arzneimittel umfas- send mindestens ein Anthracen-Derivat gemäß der allgemeinen Formel (II).Also included in the context of the present invention are pharmaceuticals comprising at least one anthracene derivative according to the general formula (II).
Unter der Substitution „geminal geknüpfter Wasserstoff und Hydroxy" im Zusammenhang mit dem Substituenten V wird im Rahmen der vorliegenden Erfindung verstanden, das sowohl „H" als auch „OH" an einem und dem gleichen Kohlenstoffatom gebunden sind.The substitution "geminally linked hydrogen and hydroxy" in connection with the substituent V is understood in the context of the present invention to mean that both "H" and "OH" are bonded to one and the same carbon atom.
In einer bevorzugten Ausführungsform werden Anthracen-Derivate gemäß der allgemeinen Formel (II) wie eben dargestellt bereitgestellt, worin:In a preferred embodiment, anthracene derivatives according to the general formula (II) are provided as just described, wherein:
Substituent V unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NH, geminal geknüpfter Wasserstoff und Hydroxy";Substituent V is independently selected from the group consisting of: "O, S, NH, geminally linked hydrogen and hydroxy";
Substituent Z unabhängig „O oder S"ist;Substituent Z is independently "O or S";
Substituenten R18, R19, R20, R21 , R22, R23, R24, R25 unabhängig „Wasserstoff, Fluor, Chlor, Brom, lod, Hydroxy, Amino, Nitro, Cyano, Methyl, Trifluormethyl" sind;Substituents R18, R19, R20, R21, R22, R23, R24, R25 are independently "hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, trifluoromethyl";
Substituent R26 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Heteroaryl, -OR32, - NR33R34"; Substituent R27 unabhängig „Wasserstoff, Alkyl" ist; die zur Herstellung eines Arzneimittels verwendet werden können.Substituent R26 is independently selected from the group consisting of: "unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -OR32, - NR33R34"; Substituent R27 is independently "hydrogen, alkyl" which may be used to make a drug.
Ebenso umfasst im Rahmen der vorliegenden Erfindung sind Arzneimittel umfassend mindestens ein Anthracen-Derivat gemäß der allgemeinen Formel (II) und dieser bevorzugten Ausführungsform.Also included within the scope of the present invention are pharmaceutical compositions comprising at least one anthracene derivative according to the general formula (II) and this preferred embodiment.
In einer bevorzugten Ausführungsform werden Anthracen-Derivate gemäß der allgemeinen Formel (II) wie eben dargestellt bereitgestellt, worin:In a preferred embodiment, anthracene derivatives according to the general formula (II) are provided as just described, wherein:
Substituent R27 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „3,4-Substituent R27 is independently selected from the group consisting of: "3,4-
Dimethoxy-phenyl; 3,4-Dihydroxy-phenyl; 4-Methoxy-thiophen-2-yl, Thiomorpholin- 4-yl; 4-Methoxy-phenyl; 4-(4-Methoxy-phenyl)-piperazin-1 -yl, 2-Hydroxy-3,4- dimethoxy-phenyl, 4-Methylphenyl; 4-Hydroxyphenyl; Thiophen-2-yl; 3- Hydroxyphenyl; 3-Methoxy-phenyl; 2,6-Dimethoxy-phenyl; 3,4,5-Trimethoxy- phenyl; Hydroxy; Methoxy; Phenyl; 4-Chlorphenyl; 4-Bromphenyl; 4-Fluorphenyl; 3-Dimethoxy-phenyl; 3,4-dihydroxy-phenyl; 4-methoxy-thiophen-2-yl, thiomorpholine-4-yl; 4-methoxy-phenyl; 4- (4-methoxy-phenyl) -piperazine-1-yl, 2-hydroxy-3,4-dimethoxyphenyl, 4-methylphenyl; 4-hydroxyphenyl; Thiophen-2-yl; 3-hydroxyphenyl; 3-methoxy-phenyl; 2,6-dimethoxy-phenyl; 3,4,5-trimethoxyphenyl; hydroxy; methoxy; phenyl; 4-chlorophenyl; 4-bromophenyl; 4-fluorophenyl; 3
Chlorphenyl; 3-Bromphenyl; 3-Fluorphenyl; 4-Fluor, 3-hydroxy-phenyl" die zur Herstellung eines Arzneimittels verwendet werden können.chlorophenyl; 3-bromophenyl; 3-fluorophenyl; 4-fluoro, 3-hydroxy-phenyl "which can be used for the manufacture of a medicament.
Ebenso umfasst im Rahmen der vorliegenden Erfindung sind Arzneimittel umfassend mindestens ein Anthracen-Derivat gemäß der allgemeinen Formel (II) und dieser bevorzugten Ausführungsform.Also included within the scope of the present invention are pharmaceutical compositions comprising at least one anthracene derivative according to the general formula (II) and this preferred embodiment.
In einer bevorzugten Ausführungsform werden Anthracen-Derivat- Verbindungen 1 bis 43 zur Herstellung eines Arzneimittels bereitgestellt.In a preferred embodiment, anthracene derivative compounds 1 to 43 are provided for the manufacture of a medicament.
Ebenso umfasst im Rahmen der vorliegenden Erfindung sind Arzneimittel umfas- send mindestens eine Anthracen-Derivat- Verbindung 1 bis 43.Also included in the context of the present invention are pharmaceuticals comprising at least one anthracene derivative compound 1 to 43.
Die erfindungsgemäßen Verbindungen können im Rahmen dieser Erfindung zur Behandlung oder Prophylaxe von durch die Inhibition der Tubulin-Polymerisation und/oder von durch die Inhibition Microtubuli-basierten Motorproteinen behandelbaren physiologischen und/oder pathophysiologischen Zuständen verwendet werden. In einer bevorzugten Ausführungsform sind die Microtubuli-basierten Motorproteine ausgewählt aus der Gruppe bestehend aus: „Kinesine, Dyneine, Kinesin-Superfamilie (KIF) Protein, N-1 Kinesine, KIF5A, KIF5B, KIF5C, N-2 Kinesine, Eg5 (KIF1 1 , KSP), BimC (KIF8), N-3 Kinesine, KIF1A, KIF1 B, KIF1 C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 Kinesine, KIF3A, KIF3B, KIF3C, KIF17, N-5 Kinesine, KIF4, KIF4A, KIF4B, KIF21 A, KIF21 B, N-6 Kinesine, KIF23 (MKLP1 , CHO1 ), KIF20A (Rab6-KIF), KIF20B (KIpMPPI ), MKLP2, N-7 Kinesine, KIF10 (CENP-E), N-8 Kinesine, KIF18A, KIF18B, KIF22 (Kid), KIF19A, KIF19B, N-9 Kinesine, KIF12, N-10 Kinesine, KIF15 (Hklp2), N-1 1 Kinesine, KIF24, KIF25 (KNSL3), KIF26A, KIF26B, M-Kinesine, KIF2A (KIF2), KIF2B, KIF2C (MCAK), C-1 Kinesine, KIFC1 , C-2 Kinesine, KIFC2, KIFC3,In the context of this invention, the compounds according to the invention can be used for the treatment or prophylaxis of physiological and / or pathophysiological conditions which can be treated by the inhibition of tubulin polymerization and / or by the inhibition of microtubule-based motor proteins. In a preferred embodiment, the microtubule-based motor proteins are selected from the group consisting of: "kinesins, dyneins, kinesin superfamily (KIF) protein, N-1 kinesins, KIF5A, KIF5B, KIF5C, N-2 kinesins, Eg5 (KIF1 1 , KSP), BimC (KIF8), N-3 kinesins, KIF1A, KIF1B, KIF1C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 kinesins, KIF3A, KIF3B, KIF3C, KIF17, N-5 kinesins, KIF4, KIF4A, KIF4B, KIF21A, KIF21B, N-6 kinesins, KIF23 (MKLP1, CHO1), KIF20A (Rab6-KIF), KIF20B (KIpMPPI), MKLP2, N-7 kinesins, KIF10 (CENP-E), N-8 Kinesins, KIF18A, KIF18B, KIF22 (Kid), KIF19A, KIF19B, N-9 Kinesins, KIF12, N-10 Kinesins, KIF15 (Hklp2), N-1 1 Kinesins, KIF24, KIF25 (KNSL3), KIF26A, KIF26B, M-kinesins, KIF2A (KIF2), KIF2B, KIF2C (MCAK), C-1 kinesins, KIFC1, C-2 kinesins, KIFC2, KIFC3,
KIF6, KIF7, KIF9" und sind bevorzugt ausgewählt aus der Gruppe bestehend aus: „Eg5 (KIF1 1 , KSP), KIF4, KIF4A, KIF4B, KIF10 (CENP-E), KIF23 (MKLP1 , CHO1 )".KIF6, KIF7, KIF9 "and are preferably selected from the group consisting of:" Eg5 (KIF1 1, KSP), KIF4, KIF4A, KIF4B, KIF10 (CENP-E), KIF23 (MKLP1, CHO1) ".
In einer weiteren bevorzugten Ausführungsform können die erfindungsgemäßen Verbindungen zur Behandlung oder Prophylaxe von malignen Tumoren, benignen Tu- moren, soliden/festen Tumoren, Sarkomen, Karzinomen, hyperproliferativen Erkrankungen, Carcinoiden, Ewing-Sarcomen, Kaposi-Sarkomen, Hirntumoren, Tumoren ausgehend vom Hirn und/oder Nervensystem und/oder Hirnhäuten (WO 99/01764), Gliomen, Neuroblastomen, Magenkrebs, Nierenkrebs, Nierenzellkarzinomen, Prostatakrebs, Prostatakarzinomen, Bindegewebstumoren, Weichteilsarkomen, Pankreastumoren, Lebertumoren, Kopftumoren, Halstumoren, Speiseröhrenkrebs, Schilddrüsenkrebs,In a further preferred embodiment, the compounds according to the invention can be used for the treatment or prophylaxis of malignant tumors, benign tumors, solid / solid tumors, sarcomas, carcinomas, hyperproliferative disorders, carcinoids, Ewing sarcomas, Kaposi's sarcomas, brain tumors, tumors originating from the brain and / or nervous system and / or meninges (WO 99/01764), glioma, neuroblastoma, gastric cancer, kidney cancer, renal cell carcinoma, prostate cancer, prostate carcinoma, connective tissue tumors, soft tissue sarcoma, pancreatic tumors, liver tumors, head tumors, cervical tumors, esophageal cancer, thyroid cancer,
Osteosarcomen, Retinoblastomen, Thymom, Hodenkrebs, Lungenkrebs, Bronchialkarzinomen, Brustkrebs, Mammakarzinomen, Darmkrebs, Kolorectaltumoren, Kolonkarzinomen, Rektumkarzinomen, gynokologische Tumoren, Ovartumoren/Ovarialtumoren, Gebärmutterkrebs, Gebärmutterhalskrebs, Zervixkarzinomen, Gebärmutterkörperkrebs, Korpuskarzinomen, Endometriumkarzinomen, Harnblasenkrebs, Blasenkrebs, Hautkrebs, Basaliomen, Spinaliomen, Melanomen, intraoculären Melanomen, Leukämien, chronischen Leukämien, akuten Leukämien und/oder Lymphomen verwendet werden. Diese Indikationen stellen auch durch die Inhibition der Tubulin-Polymerisation und/oder von durch die Inhibition Microtubuli-basierten Motorproteinen behandelbare physiologi- sehe und/oder pathophysiologische Zustände dar.Osteosarcoma, retinoblastoma, thymoma, testicular cancer, lung cancer, bronchial carcinoma, breast cancer, breast cancer, colorectal cancer, colorectal cancer, colon cancer, rectal cancer, gynocological tumors, ovarian tumors / ovarian tumors, uterine cancer, cervix cancer, cervical carcinoma, uterine cancer, carcinoma of the body, endometrial carcinoma, bladder cancer, bladder cancer, skin cancer, basalioma , Spinal, melanoma, intraocular melanoma, leukemia, chronic leukemia, acute leukemia and / or lymphoma. These indications also represent physiological and / or pathophysiological conditions that can be treated by the inhibition of tubulin polymerization and / or by the inhibition of microtubule-based motor proteins.
In einem weiteren Aspekt der vorliegenden Erfindung wurde die erfinderische Aufgabe überraschender weise dadurch gelöst, dass die erfindungsgemäßen Verbindungen gemäß der oben dargestellten Aspekte, bevorzugten Ausführungsformen und Verwendungen bereitgestellt werden, zur Verwendung zur Herstellung eines Arzneimittels, wobei das Arzneimittel zusätzlich mindestens eine weitere pharmakologisch aktive Substanz enthält.In a further aspect of the present invention, the inventive task was surprisingly achieved in that the compounds according to the invention in accordance with the aspects presented above, preferred embodiments and Uses for the preparation of a medicament, wherein the medicament additionally contains at least one further pharmacologically active substance.
In einem weiteren Aspekt der vorliegenden Erfindung wurde die erfinderische Aufgabe überraschender weise dadurch gelöst, dass die erfindungsgemäßen Verbindungen gemäß der oben dargestellten Aspekte, bevorzugten Ausführungsformen und Verwendungen bereitgestellt werden, zur Verwendung zur Herstellung eines Arzneimittels, wobei das Arzneimittel vor und/oder während und/oder nach der Behandlung mit mindestens einer weiteren pharmakologisch aktiven Substanz verabreicht wird.In a further aspect of the present invention, the inventive task has surprisingly been achieved by providing the compounds according to the invention in accordance with the aspects, preferred embodiments and uses described above, for use in the manufacture of a medicament, wherein the medicament before and / or during and / or or after treatment with at least one other pharmacologically active substance.
In einem weiteren Aspekt der vorliegenden Erfindung wurde die erfinderische Aufgabe überraschender weise dadurch gelöst, dass die erfindungsgemäßen Verbindungen gemäß der oben dargestellten Aspekte, bevorzugten Ausführungsformen und Verwendungen bereitgestellt werden, zur Verwendung zur Herstellung eines Arzneimittels, wobei das Arzneimittel vor und/oder während und/oder nach der Behandlung mit Strahlentherapie und/oder Chirurgie verabreicht wird.In a further aspect of the present invention, the inventive task has surprisingly been achieved by providing the compounds according to the invention in accordance with the aspects, preferred embodiments and uses described above, for use in the manufacture of a medicament, wherein the medicament before and / or during and / or or after treatment with radiotherapy and / or surgery.
Die erfindungsgemäßen Verbindungen können dabei im Rahmen dieser Erfindung als Einzelsubstanzen oder in Kombination mit allen bekannten pharmakologisch aktiven Substanzen in einer Kombinationstherapie wie dargestellt verabreicht werden.The compounds according to the invention can be administered in the context of this invention as individual substances or in combination with all known pharmacologically active substances in a combination therapy as shown.
In einer bevorzugten Ausführungsform werden die erfindungsgemäßen Verbindungen bereitgestellt zu den oben dargestellten Verwendungen, wobei die weitere phar- makologisch aktive Substanz ausgewählt ist aus der Gruppe bestehend aus: „DNA Topoisomerase I und/oder Il Inhibitoren, DNA Interkalatoren, alkylierende Agentien, Microtubuli Destabilisatoren, Hormon- und/oder Wachstumsfaktor-Rezeptor-Agonisten und/oder -Antagonisten, Hemmstoffen der Signaltransduktion, Antikörper gegen Wachstumsfaktoren und deren Rezeptoren, Kinase Inhibitoren, Antimetabolite". In einer bevorzugten Ausführungsform werden die erfindungsgemäßen Verbindungen bereitgestellt zu den oben dargestellten Verwendungen, wobei die weitere pharmakologisch aktive Substanz ausgewählt ist aus der Gruppe bestehend aus: "Actino- mycin D, Aminoglutethimid, Asparaginase, Avastin, Azathioprin, BCNU (Carmustine), Bleomycin, Busulfan, Carboplatin, CCNU (Lomustine), Chlorambucil, Cisplatin, Co- laspase, Cyclophosphamid, Cytarabin, Dactinomycin, Daunorubicin, Diethylstilbestrol, Doxorubicin (Adriamycin), DTIC (Dacarbacin), Epirubicin, Erbitux, Erythrohydroxynony- ladenin, Ethinylestradiol, Etoposide, Fludarabin Phosphate, Fluoxymesteron, Flutamid, Gemcitabin, Gleevec/Glivec, Herceptin, Hexamethylmelamin, Hydroxharnstoff, Hydro- xyprogesteron Caproat, Idarubicin, Ifosfamid, Interferon, Iressa, Irinotecan, L- Asparaginase, Leucovorin, Mechlorethamin, Medroxyprogesteron Acetat, Megestrol Acetat, Melphalan, Mesna, Methotrexat, Mitomycin C, Mitotan, Mitoxantrone, N- Phosphonoacetyl-L-aspartat (PALA), Oxaliplatin, Pentostatin, Plicamycin, Prednisolon, Prednison, Procarbazin, Raloxifen, Rapamycin, Semustin, Sorafenib, Streptozocin, Tamoxifen, Tarceva, Taxotere, Teniposide, Testosteron Propionat, Thioguanin, Thiote- pa, Topotecan, Trimethylmelamin, Uridine, Vinblastin, Vincristin, Vindesin, Vinorelbin, 2', 2'-Difluorodeoxycytidin, 5- Fluorodeoxyuridin Monophosphat, 5-Azacytidin Cladribin, 5-Fluorodeoxyuridin, 5-Fluorouarcil (5-FU), 6-Mercaptopurin".In a preferred embodiment, the compounds according to the invention are provided for the uses described above, wherein the further pharmacologically active substance is selected from the group consisting of: "DNA topoisomerase I and / or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers, Hormone and / or Growth Factor Receptor Agonists and / or Antagonists, Signal Transduction Inhibitors, Antibodies to Growth Factors and Their Receptors, Kinase Inhibitors, Antimetabolites. "In a preferred embodiment, the compounds of the present invention are provided for use as indicated above further pharmacologically active substance is selected from the group consisting of: mycin D, aminoglutethimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, cisplatin, celaspase, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, doxorubicin (adriamycin), DTIC (dacarbacin), epirubicin, Erbitux, erythrohydroxynonymloadin, ethinylestradiol, etoposide, fludarabine phosphates, fluoxymesterone, flutamide, gemcitabine, Gleevec / Glivec, Herceptin, hexamethylmelamine, hydroxurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, interferon, Iressa, irinotecan , L-asparaginase, leucovorin, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, N-phosphonoacetyl-L-aspartate (PALA), oxaliplatin, pentostatin, plicamycin, prednisolone, prednisone, procarbazine , Raloxifene, rapamycin, semustin, sorafenib, streptozocin, tamoxifen, tarceva, taxotere, teniposide, testosterone propionate, thioguanine, thiotope, topo tecan, trimethylmelamine, uridines, vinblastine, vincristine, vindesine, vinorelbine, 2 ', 2'-difluorodeoxycytidine, 5-fluorodeoxyuridine monophosphate, 5-azacytidine cladribine, 5-fluorodeoxyuridine, 5-fluorouracil (5-FU), 6-mercaptopurine ".
Die erfindungsgemäßen Arzneimittel können als flüssige, halbfeste und feste Arzneiformen verabreicht werden. Dies erfolgt in der jeweils geeigneten Weise in Form von Aerosolen, Pulver, Puder und Streupuder, Tabletten, Dragees, Emulsionen, Schäume, Lösungen, Suspensionen, Gele, Salben, Pasten, Pillen, Pastillen, Kapseln oder Suppositorien.The medicaments according to the invention can be administered as liquid, semisolid and solid dosage forms. This takes place in the respectively suitable manner in the form of aerosols, powders, powders and scattering powders, tablets, dragees, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, pastilles, capsules or suppositories.
Die erfindungsgemäßen Arzneimittel können in einer geeigneten Darreichungsform auf die Haut, epicutan als Lösung, Suspension, Emulsion, Schaum, Salbe, Paste oder Pflaster; über die Mund- und Zungenschleimhaut, buccal, lingual oder sublingual als Tablette, Pastille, Dragees, Linctus oder Gurgelwasser; über die Magen- und Darmschleimhaut, enteral als Tablette, Dragees, Kapsel, Lösung, Suspension oder Emulsion; über die Rectumschleimhaut, rectal als Suppositorium, Rectalkapsel oder Salbe; über die Nasenschleimhaut, nasal als Tropfen, Salben oder Spray; über das Bronchial- und Alveolarepithel, pulmonal oder per inhalationem als Aerosol oder Inhalat; über die Conjunctiva, conjunctival als Augentropfen, Augensalbe, Augentabletten, Lamellae oder Augenwasser; über die Schleimhäute der Genitalorgane, intravaginal als Vaginalkugeln, Salben und Spülung, intrauterin als Uterus-Pessare; über die ableitenden Harnwege, intraurethral als Spülung, Salbe oder Arzneistäbchen; in eine Arterie, intraarteriell als Injektion; in eine Vene, intravenös als Injektion oder Infusion; in die Haut, intracutan als Injektion oder Implantat; unter die Haut, subcutan als Injektion oder Implantat; in den Muskel, intramusculär als Injektion oder Implantat; in die Bauchhöhle, intraperitoneal als Injektion oder Infusion verabreicht werden.The medicaments according to the invention may be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or patch; via the mouth and tongue mucosa, buccally, lingually or sublingually as a tablet, troche, dragee, linctus or gargle; via the gastric and intestinal mucosa, enterally as a tablet, dragees, capsule, solution, suspension or emulsion; via the rectal mucosa, rectal as suppository, rectal capsule or ointment; via the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonary or by inhalation as aerosol or inhalant; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellas or eye water; via the mucous membranes of the genital organs, intra vaginally as vaginal balls, ointments and rinses, intrauterine as uterine pessaries; via the draining urinary tract, intraurethrally as a conditioner, ointment or medicament sticks; into an artery, intraarterially as injection; into a vein, intravenously as an injection or infusion; into the skin, intracutaneously as an injection or implant; under the skin, subcutaneously as an injection or implant; in the muscle, intramuscularly as an injection or implant; into the abdominal cavity, administered intraperitoneally as an injection or infusion.
Die orale Verabreichung kann beispielsweise in fester Form als Tablette, Kapsel, Gelkapsel, Dragee, Granulat oder Pulver, jedoch auch in Form einer trinkbaren Lösung erfolgen. Zur oralen Verabreichung können die neuen, erfindungsgemäßen Verbindungen, wie vorstehend definiert, mit bekannten und gewöhnlich verwendeten, physiologisch ver- träglichen Hilfs- und Trägerstoffen kombiniert werden, wie z.B. Gummiarabikum, Talkum, Stärke, Zucker wie z.B. Mannit, Methylcellulose, Lactose, Gelatine, oberflächenaktive Mittel, Magnesiumstearat, Cyclodextrine, wässrige oder nicht-wässrige Trägerstoffe, Verdünnungsmittel, Dispergiermittel, Emulgatoren, Schmiermittel, Konservierungsstoffe und Geschmacksstoffe (z.B. etherische Öle). Die erfindungsgemäßen Verbindungen können auch in einer mikropartikulären, z.B. nanopartikulären Zusammensetzung dispergiert sein.The oral administration can be carried out, for example, in solid form as a tablet, capsule, gel capsule, dragee, granules or powder, but also in the form of a drinkable solution. For oral administration, the novel compounds of the present invention, as defined above, may be combined with known and commonly used physiologically acceptable excipients and carriers, e.g. Gum arabic, talc, starch, sugars, e.g. Mannitol, methylcellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous vehicles, diluents, dispersants, emulsifiers, lubricants, preservatives and flavoring agents (e.g., essential oils). The compounds of the invention may also be administered in a microparticulate, e.g. be dispersed nanoparticulate composition.
Die nicht orale Verabreichung kann beispielsweise durch intravenöse, subkutane oder intramuskuläre Injektion steriler wässriger oder öliger Lösungen, Suspensionen oder Emulsionen, mittels Implantaten oder durch Salben, Cremes oder Suppositorien erfolgen. Gegebenenfalls kann auch eine Verabreichung als Retardform erfolgen. Implantate können inerte Materialen enthalten, z.B. biologisch abbaubare Polymere oder synthetische Silicone wie z.B. Silicongummi. Eine intravaginale Verabreichung kann z.B. mittels Vaginalringen erfolgen. Eine intrauterine Verabreichung kann z.B. mittels Diaphragmen oder anderer geeigneter intrauteriner Vorrichtungen erfolgen. Darüber hinaus ist auch eine transdermale Verabreichung, insbesondere mittels einer dazu geeigneten Formulierung und/oder geeigneter Mittel wie z.B. Pflaster, vorgesehen.Non-oral administration can be accomplished, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants or by ointments, creams or suppositories. Optionally, it can also be administered as a sustained-release form. Implants may contain inert materials, e.g. biodegradable polymers or synthetic silicones such as e.g. Silicone rubber. Intravaginal administration may e.g. done by vaginal rings. Intrauterine administration may e.g. by means of diaphragms or other suitable intrauterine devices. In addition, transdermal administration, in particular by means of a formulation suitable therefor and / or suitable means, e.g. Plaster, provided.
Wie bereits vorstehend erläutert, können die neuen, erfindungsgemäßen Verbindungen auch mit weiteren pharmazeutisch aktiven Wirkstoffen kombiniert werden. Im Rahmen einer Kombinationstherapie können die einzelnen wirksamen Bestandteile gleichzeitig oder getrennt verabreicht werden, und zwar entweder auf demselben Wege (z.B. oral) oder auf getrennten Wegen (z.B. oral und als Injektion). Sie können in gleichen oder unterschiedlichen Mengen in einer Einheitsdosis vorliegen bzw. verabreicht werden. Es kann auch ein bestimmtes Dosierungsregime angewendet werden, sofern dies zweckmäßig erscheint. Auf diese Weise können auch mehrere der neuen, erfindungsgemäßen Verbindungen miteinander kombiniert werden.As already explained above, the novel compounds according to the invention can also be combined with other pharmaceutically active substances. In combination therapy, the individual active ingredients may be administered simultaneously or separately, either by the same route (eg orally) or by separate routes (eg orally and by injection). They may be administered in equal or different amounts in a unit dose. It is also possible to use a specific dosage regimen, if appropriate. In this way, several of the novel compounds of the invention can be combined.
Die Dosierung kann je nach Art der Indikation, der Schwere der Erkrankung, der Art der Verabreichung, dem Alter, Geschlecht, Körpergewicht und der Sensitivität des zu behandelnden Subjekts in einem breiten Rahmen variieren. Es entspricht den Fähigkeiten eines Fachmanns, eine „pharmakologisch wirksame Menge" der kombinierten pharmazeutischen Zusammensetzung zu bestimmen. Die Verabreichung kann in einer einzigen Dosis oder mehreren getrennten Dosierungen erfolgen.The dosage may vary widely depending on the nature of the indication, the severity of the disease, the mode of administration, the age, sex, body weight and the sensitivity of the subject to be treated. It is within the ability of one skilled in the art to determine a "pharmacologically effective amount" of the combined pharmaceutical composition, and may be administered in a single dose or multiple separate dosages.
Eine geeignete Einheitsdosis ist z.B. 0,001 mg bis 100 mg des Wirkstoffs, d.h. mindestens einer erfindungsgemäßen Verbindung und gegebenenfalls einer weiteren pharmazeutisch aktiven Substanz, pro kg Körpergewicht eines Patienten.A suitable unit dose is e.g. From 0.001 mg to 100 mg of the active ingredient, i. at least one compound according to the invention and optionally one further pharmaceutically active substance per kg of body weight of a patient.
In einem weiteren Aspekt der vorliegenden Erfindung sind demnach auch pharmazeutische Zusammensetzungen umfassend eine pharmakologisch aktive Menge mindestens einer erfindungsgemäßen Verbindung, bevorzugt Verbindung 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42 und/oder Verbindung 43, sowie gegebe- nenfalls pharmazeutisch verträgliche Träger- und/oder Hilfsstoffe, von der vorliegenden Erfindung erfasst.Accordingly, in a further aspect of the present invention, pharmaceutical compositions comprising a pharmacologically active amount of at least one compound according to the invention, preferably compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 and / or compound 43, as well as any pharmaceutically acceptable carriers and / or adjuvants, are covered by the present invention.
Bevorzugte und besonders bevorzugte pharmazeutische Zusammensetzungen sind jene, die mindestens eine der vorstehend genannten bevorzugten erfindungsge- mäßen Verbindungen umfassen. In pharmazeutischen Zusammensetzungen gemäß der vorliegenden Erfindung können neben mindestens einer erfindungsgemäßen Verbindung, wie vorstehend definiert, auch noch mindestens eine weitere pharmazeutisch aktive Substanz vorliegen, wie vorstehend bereits näher aufgeführt.Preferred and particularly preferred pharmaceutical compositions are those comprising at least one of the aforementioned preferred compounds of the invention. In pharmaceutical compositions according to the present invention, in addition to at least one compound according to the invention, as defined above, there may also be at least one further pharmaceutically active substance, as already mentioned in more detail above.
In den erfindungsgemäßen pharmazeutischen Zusammensetzungen liegt mindestens eine der neuen, erfindungsgemäßen Verbindungen, wie vorstehend definiert, in einer pharmakologischen aktiven Menge, vorzugsweise in einer Einheitsdosis, z.B. der vorstehend genannten Einheitsdosis, vor, und zwar vorzugsweise in einer Verabreichungsform, die eine orale Verabreichung ermöglicht.In the pharmaceutical compositions according to the invention, at least one of the novel compounds according to the invention, as defined above, is present in a pharmacologically active amount, preferably in a unit dose, eg above unit dose, before, preferably in a dosage form that allows oral administration.
Bezüglich der erfindungsgemäßen Verbindungen umfassende pharmazeutische Zusammensetzungen sowie bezüglich der Verwendung der erfindungsgemäßen Verbindungen als Arzneimittel sei hinsichtlich Verwendungs- und Verabreichungsmöglichkeiten auf das bereits im Zusammenhang mit der Verwendung der neuen, erfindungsgemäßen Verbindungen selbst, Gesagte verwiesen.As regards the use of the compounds according to the invention as medicaments, the pharmaceutical compositions comprising the compounds according to the invention and the possibilities of use and administration thereof are referred to what has already been said in connection with the use of the novel compounds according to the invention.
In einem weiteren Aspekt der vorliegenden Erfindung wurde die erfinderischeIn a further aspect of the present invention, the inventive
Aufgabe überraschender Weise gelöst durch die Bereitstellung eines Kits umfassend eine pharmakologisch aktive Menge mindestens einer bevorzugten erfindungsgemäßen Verbindung, wie oben dargestellt, und eine pharmakologisch aktive Menge mindestens einer weiteren pharmakologisch aktiven Substanz wie vorstehend definiert. Problem solved surprisingly by the provision of a kit comprising a pharmacologically active amount of at least one preferred compound according to the invention, as described above, and a pharmacologically active amount of at least one further pharmacologically active substance as defined above.
Chemische Synthese:Chemical synthesis:
Die Verbindungen der allgemeinen Formeln (I) und (II) sind beispielsweise gemäß dem folgenden Schema 1 erhältlich. Die sich in Formel (II) von Formel (I) unterschei- denden Reste R18 bis R34 sind analog zu den Resten R1 bis R17 der Formel (I) zu betrachten.The compounds of the general formulas (I) and (II) are obtainable, for example, according to the following scheme 1. The radicals R18 to R34 which differ in formula (II) from formula (I) are analogous to the radicals R1 to R17 of the formula (I).
Schema 1Scheme 1
X: O, S, N-R11 oder N-0R12
Figure imgf000047_0001
X: O, S, N-R11 or N-0R12
Figure imgf000047_0001
22
Figure imgf000047_0002
Figure imgf000047_0002
Die Ausgangsverbindungen 1 und 2 sind entweder im Handel erhältlich oder können nach an sich bekannten Verfahrensweisen hergestellt werden. Die Verbindung 3 stellt eine wertvolle Zwischenverbindung für die Herstellung der erfindungsgemäßen Verbindungen der Formeln (I) und (II) dar. Die gegebenenfalls zu verwendenden Lösungs- und Hilfsmittel und anzuwendenden Reaktionsparameter wie Reaktionstemperatur und -dauer sind dem Fachmann aufgrund seines Fachwissens bekannt.The starting compounds 1 and 2 are either commercially available or can be prepared by methods known per se. Compound 3 represents a valuable intermediate compound for the preparation of the compounds of the formulas (I) and (II) according to the invention. The solvents and auxiliaries to be used if appropriate and the reaction parameters to be used, such as reaction temperature and duration, are known to the person skilled in the art on the basis of his specialist knowledge.
Die Benennung der erfindungsgemäßen Verbindungen, insbesondere der Verbindungen 1 bis 43, erfolgte mit der AutoNom 2000 - Software (ISIS ™/ Draw 2.5; MDL).The naming of the compounds according to the invention, in particular of the compounds 1 to 43, was carried out using the AutoNom 2000 software (ISIS ™ / Draw 2.5, MDL).
Die Inhalte aller zitierten Patentschriften und Referenzen werden hiermit durch Be- zugnahme aufgenommen.The contents of all cited patents and references are hereby incorporated by reference.
Die Erfindung wird anhand der nachfolgenden Beispiele näher erläutert, ohne jedoch auf diese Beispiele beschränkt zu sein. The invention will be explained in more detail with reference to the following examples, but without being limited to these examples.
BeispieleExamples
I) Herstellung von erfindungsgemäßen VerbindungenI) Preparation of compounds of the invention
Beispiel 1 :Example 1 :
10-[2-(3,4-Dihydroxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 1)10- [2- (3,4-Dihydroxyphenyl) -2-oxo-ethylidene] -10H-anthracene-9-one (Compound 1)
Figure imgf000049_0001
Figure imgf000049_0001
Stufe 1 : Darstellung der 10-Oxo-9(10/-/)-anthracenyliden-essiqsäureStep 1: Preparation of the 10-oxo-9 (10 / - /) - anthracenylidene-acetic acid
Man suspendierte 10.0 g 9(10H)Anthracenon (51.5 mmol) und 9.2 g Glyoxylsäure- Monohydrat (10.0 mmol) in 150 ml_ Ethanol. Das Gemisch wurde unter Stickstoff zum Sieden erhitzt. Während des Aufheizens gab man 6 Tropfen Piperidin zu, wobei sich das 9(10H)Anthracenon auflöste. Nach 4h war die Umsetzung abgeschlossen. Nach Abkühlung auf Raumtemperatur wurde anschließend der Ansatz auf 400 ml_ H2O und 10 ml_ 6N HCl gegossen und mit Dichlormethan (5x 50 ml_) extrahiert. Die vereinigten organischen Phasen wurden mehrfach mit Wasser gewaschen, über Na2SO4 getrocknet und im Wasserstrahlvakuum (Rotationsverdampfer) auf ein geringes Volumen eingeengt (30-40 ml_). Die farblose bis leicht gelblich gefärbte 10-Oxo-9(1 OH)-anthracenyliden-essigsäure fiel beim Stehenlassen im Eisbad (1 h) aus. Man saugte ab, presste den Filterkuchen und wusch mit 100 ml_ kaltem Dichlormethan. Dabei wurde nicht umgesetztes 9(10H)Anthracenon herausgelöst. Das Filtrat wurde zur Gewinnung weiterer Säure nochmals eingeengt und wie vorstehend behandelt. Das blass-gelbe Pulver wurde getrocknet (Trockenpistole) und ohne weitere Reinigung für die nächste Stufe 2 verwendet.10.0 g of 9 (10H) anthracenone (51.5 mmol) and 9.2 g of glyoxylic acid monohydrate (10.0 mmol) were suspended in 150 ml of ethanol. The mixture was heated to boiling under nitrogen. During heating, 6 drops of piperidine were added to dissolve 9 (10H) anthracenone. After 4 hours, the conversion was completed. After cooling to room temperature, the mixture was then poured onto 400 ml of H 2 O and 10 ml of 6N HCl and extracted with dichloromethane (5 × 50 ml). The combined organic phases were washed several times with water, dried over Na 2 SO 4 and concentrated in a water jet vacuum (rotary evaporator) to a small volume (30-40 ml_). The colorless to slightly yellowish-colored 10-oxo-9 (1 OH) -anthracenyliden-acetic acid precipitated on standing in an ice bath (1 h). It was sucked off, pressed the filter cake and washed with 100 ml of cold dichloromethane. Unreacted 9 (10H) anthracenone was dissolved out. The filtrate was concentrated again to obtain additional acid and treated as above. The pale yellow powder was dried (dry gun) and used without further purification for the next stage 2.
Ausbeute 7.60 g (59%) blass-gelber Feststoff Schmelzpunkt Fp.: 180-182 <€ FTIR: 1684, 1663 cm 1 Yield 7.60 g (59%) of pale yellow solid Melting point mp: 180-182 < € FTIR: 1684, 1663 cm 1
1H-NMR (DMS0-d6) δ = 8.15-8.07 (m, 2H), 7.93-7.91 (m, 1 H), 7.77-7.60 (m, 3H), 7.52- 7.43 (m, 2H), 7.08 (s, 1 H). 1 H-NMR (DMSO-d6) δ = 8.15-8.07 (m, 2H), 7.93-7.91 (m, 1H), 7.77-7.60 (m, 3H), 7.52-7.43 (m, 2H), 7.08 ( s, 1 H).
Stufe 2: Darstellung von 10-Oxo-9(10/-/)-anthracenyliden-essiqsäurechloridStep 2: Preparation of 10-oxo-9 (10 / - /) - anthracenylidene-acetic acid chloride
2.0 g 10-0x0-9(1 OH)-anthracenyliden-essigsäure (7.99 mmol) wurden in 30 ml Thio- nylchlorid suspendiert. Hierzu gab man 2 Tropfen N,N-Dimethylformamid und erhitzte unter Rückfluss für die Dauer von 2h zum Sieden. Anschließend ließ man auf Raum- temperatur abkühlen und entfernte das Thionylchlorid im Wasserstrahlvakuum. Der Rückstand wurde noch 2x mit jeweils 30 ml n-Hexan versetzt und dieses jeweils im Wasserstrahlvakuum bis zur Trockene entfernt. Das so erhaltene 10-Oxo-9(10H)- anthracenyliden-essigsäurechlorid konnte ohne weitere Aufreinigung in Stufe 3 weiterumgesetzt werden. Ausbeute 2.0 g (93%) gelber Feststoff Schmelzpunkt Fp.: 1 15 0C (Zers.) FTIR: 1757, 1658 cm 1 2.0 g of 10-0x0-9 (1 OH) -anthracenylidene-acetic acid (7.99 mmol) were suspended in 30 ml of thionyl chloride. To this was added 2 drops of N, N-dimethylformamide and heated to reflux under reflux for 2h. The mixture was then allowed to cool to room temperature and removed the thionyl chloride in a water jet vacuum. The residue was further added 2x with 30 ml of n-hexane and this each removed in a water-jet vacuum to dryness. The resulting 10-oxo-9 (10H) - anthracenylidene-acetic acid chloride could be further reacted without further purification in step 3. Yield 2.0 g (93%) yellow solid Melting point mp: 1 15 0 C (dec.) FTIR: 1757, 1658 cm 1
1H-NMR (DMSO-d6) δ = 8.15-8.07 (m, 3H), 7.93-7.91 (m, 1 H), 7.77-7.60 (m, 4H), 7.08 (s, 1 H). 1 H-NMR (DMSO-d6) δ = 8.15-8.07 (m, 3H), 7.93-7.91 (m, 1H), 7.77-7.60 (m, 4H), 7.08 (s, 1H).
Stufe 3a: Synthese von 10-[2-(3,4-Dimethoxy-phenyl)-2-oxo-ethyliden1-9(10/-/)- anthracenon (Verbindung 6)Step 3a: Synthesis of 10- [2- (3,4-Dimethoxyphenyl) -2-oxo-ethylidene 1-9 (10 / - /) - anthracenone (Compound 6)
Figure imgf000050_0001
2.15 g (8.0 mmol) 10-Oxo-9(10H)-anthracenyliden-essigsäurechlorid wurden unter Kühlung (Eis-Kochsalz-Bad) in 30 ml_ 1 ,2-Dichlorethan suspendiert. Anschließend gab man 1.07 g wasserfreies AICI3 (8 mmol) in einer Portion zu. Man rührte 10 min im Eis- bad und tropfte dann 1.1 1 g (8.00 mmol) 1 -,2- Dimethoxybenzol, gelöst in 5 ml_ 1 ,2- Dichlorethan, zu. Das Gemisch färbte sich dunkel und das 10-[2-(3,4-Dimethoxy- phenyl)-2-oxo-ethyliden]-9(10H)-anthracenon löste sich. Es wurde unter Eiskühlung gerührt (DC-Kontrolle, SiO2/DCM). Nach beendeter Umsetzung (1 -2 h) goss man auf 300 mL Wasser und 50 ml_ 6N HCl, rührte 10 min und extrahiert dann mit Dichlor- methan (4x 50 mL). Die vereinigten organischen Phasen wurden mehrfach mit Wasser gewaschen und über Natriumsulfat getrocknet. Man entfernte das Lösungsmittel im Wasserstrahlvakuum und reinigte den Rückstand mittels Säulenchromathographie an Kieselgel (EE/PE 7:3), wobei 0.97 g an 10-[2-(3,4-Dimethoxy-phenyl)-2-oxo-ethyliden]- 9(10H)-anthracenon (Verbindung 6) als gelber Feststoff resultierten.
Figure imgf000050_0001
2.15 g (8.0 mmol) of 10-oxo-9 (10H) -anthracenylidene-acetic acid chloride were suspended with cooling (ice-salt bath) in 30 ml of 1,2-dichloroethane. Subsequently, 1.07 g of anhydrous AICI 3 (8 mmol) were added in one portion. The mixture was stirred for 10 minutes in an ice bath and then added dropwise 1.1 1 g (8.00 mmol) of 1-, 2-dimethoxybenzene dissolved in 5 ml_ 1, 2-dichloroethane. The mixture turned dark and the 10- [2- (3,4-dimethoxyphenyl) -2-oxo-ethylidene] -9 (10H) -anthracenone dissolved. It was stirred with ice cooling (TLC control, SiO 2 / DCM). After completion of the reaction (1 -2 h) was poured onto 300 mL of water and 50 ml_ 6N HCl, stirred for 10 min and then extracted with dichloromethane (4x 50 mL). The combined organic phases were washed several times with water and dried over sodium sulfate. The solvent was removed in a water-jet vacuum and the residue was purified by column chromatography on silica gel (EA / PE 7: 3), giving 0.97 g of 10- [2- (3,4-dimethoxyphenyl) -2-oxo-ethylidene] - 9 (10H) -anthracenone (Compound 6) resulted as a yellow solid.
Ausbeute: 0.97 g (33% d. Th.) gelber Feststoff Schmelzpunkt Fp.: 160 0C FTIR: 1655, 1639 cm 1 Yield: (. 33% of theory.) 0.97 g of yellow solid melting point Mp .: 160 0 C FTIR: 1655, 1639 cm 1
1H-NMR (DMSO-d6) δ= 8.32 (d, 1 H); 8.20 (d, 1 H); 8.14 (d, 1 H); 7.81 (t, 1 H); 7.70 (s, 1 H); 7.69 (t, 1 H); 7.60 (d, 1 H); 7.55 (t, 1 H); 7.46 - 752 (m, 3H); 7.02 (d, 1 H); 3.82 (s, 3H); 3.79 (s, 3H)ppm. 1 H-NMR (DMSO-d6) δ = 8.32 (d, 1H); 8.20 (d, 1H); 8.14 (d, 1H); 7.81 (t, 1H); 7.70 (s, 1H); 7.69 (t, 1H); 7.60 (d, 1H); 7.55 (t, 1H); 7.46-752 (m, 3H); 7.02 (d, 1H); 3.82 (s, 3H); 3.79 (s, 3H) ppm.
Stufe 3b: 10-[2-(3,4-Dihvdroxy-phenyl)-2-oxo-ethylidene1-1 OH-anthracen-9-one (Verbindung 1) Eine Lösung von 342mg (1.0 mmol) 10-[2-(3,4-Dimethoxy-phenyl)-2-oxo-ethyliden]- 9(10H)-anthracenon (Verbindung 6) in 10 mL getrockneten Dichlormethan wurde bei - 70 0C (Aceton/Trockeneis) zu einer Lösung der 5-7fachen molaren Menge BBr3 in 20 mL DCM getropft (N2-Atmosphere). Man rührte das Gemisch 24 h, wobei man den Ansatz langsam auf Raumtemperatur erwärmen ließ. Anschließend goss man auf einen Überschuss Wasser und schüttelte kräftig durch. Man extrahierte mit Ethylacetat, trocknete über Na2SO4 und engte im Wasserstrahlvakuum ein. Der Rückstand wurde mittels Säulenchromathographie an Kieselgel gereinigt (EE/PE 7:3). Nach dem Einen- gen der Reinfraktionen kristallisierten 102mg von 10-[2-(3,4-Dihydroxy-phenyl)-2-oxo- ethylidene]-10H-anthracen-9-one (Verbindung 1) durch Zugabe von Hexan aus.Step 3b: 10- [2- (3,4-Dihydroxy-phenyl) -2-oxo-ethylidene-1-OH-anthracene-9-one (Compound 1) A solution of 342 mg (1.0 mmol) of 10- [2- (1.0 mmol) 3,4-Dimethoxy-phenyl) -2-oxo-ethylidene] - 9 (10H) -anthracenone (Compound 6) in 10 mL of dried dichloromethane at -70 0 C (acetone / dry ice) to a solution of 5-7fachen molar Amount BBr 3 in 20 mL DCM added dropwise (N 2 atmosphere). The mixture was stirred for 24 h, allowing the reaction to warm slowly to room temperature. Then you poured on a surplus of water and shook vigorously. The mixture was extracted with ethyl acetate, dried over Na 2 SO 4 and concentrated in a water jet vacuum. The residue was purified by column chromatography on silica gel (EE / PE 7: 3). After the of the pure fractions, 102 mg of 10- [2- (3,4-dihydroxyphenyl) -2-oxo-ethylidene] -10H-anthracen-9-one (compound 1) crystallized out by addition of hexane.
Ausbeute: 102 mg (30% d. Th. ) gelbes, amorphes Pulver Schmelzpunkt Fp.: 217<€ FTIR: 3255 (br), 1634 cm 1 Yield: 102 mg (30% of theory) yellow, amorphous powder melting point mp: 217 < € FTIR: 3255 (br), 1634 cm 1
1H-NMR (d6- DMSO) δ = 8.27 (d, 1 H, J= 8.21 Hz), 8.19-8.17 (m, 1 H), 8.14-8.1 1 (m, 1 H), 7.82-7.78 (m, 1 H), 7.68-7.64 (m, 2H), 7.54-7.47 (m, 3H), 7.36-7.33 (m, 2H), 6.78- 6.76 (d, 1 H); 1 H-NMR (d6-DMSO) δ = 8.27 (d, 1H, J = 8.21 Hz), 8.19-8.17 (m, 1H), 8.14-8.1 1 (m, 1H), 7.82-7.78 (m , 1H), 7.68-7.64 (m, 2H), 7.54-7.47 (m, 3H), 7.36-7.33 (m, 2H), 6.78-6.76 (d, 1H);
Folgende Verbindungen der allgemeinen Formeln (I) und (II) wurden analog zum Syntheseweg in Schema 1 synthetisiert:The following compounds of the general formulas (I) and (II) were synthesized analogously to the synthesis route in Scheme 1:
Beispiel 2: 10-[2-(4-Methoxy-thiophen-2-yl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 2)Example 2: 10- [2- (4-Methoxy-thiophen-2-yl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 2)
Figure imgf000052_0001
Figure imgf000052_0001
Schmelzpunkt Fp.: 200-201 0C FTIR: 1648, 1621 crrf1 Mp mp .: 200-201 0 C FTIR: 1648, 1621 crrf 1
1H-NMR (DMSO-d6) δ= 8.18 (d, 1 H); 8.12 - 8.15 (m, 2H); 8.04 (d, 1 H); 7.83 (t, 1 H); 7.65-7.70 (m, 2H); 7.52 - 7.59 (m, 2H); 7.52 (s, 1 H); 7.1 1 (d, 1 H); 3.81 (s, 3H) ppm. Beispiel 3: 1 H-NMR (DMSO-d6) δ = 8.18 (d, 1H); 8.12 - 8.15 (m, 2H); 8.04 (d, 1H); 7.83 (t, 1H); 7.65-7.70 (m, 2H); 7.52 - 7.59 (m, 2H); 7.52 (s, 1H); 7.1 1 (d, 1H); 3.81 (s, 3H) ppm. Example 3:
10-(2-Oxo-2-thiomorpholin-4-ylethylidene)-1 OH-anthracen-9-one (Verbindung 3)10- (2-oxo-2-thiomorpholin-4-yl-ethylidene) -1 OH-anthracen-9-one (compound 3)
Figure imgf000053_0001
Figure imgf000053_0001
Schmelzpunkt Fp.: 177-178<€ FTIR: 1659, 1628 cm1 Melting point mp: 177-178 < € FTIR: 1659, 1628 cm 1
1H-NMR (DMS0-d6)δ= 8.21 (d, 1H); 8.17 (d, 1H); 8.14 (d, 1H); 7.87 (d, 1H); 7.79 (t, 1 H); 7.78 (t, 1 H); 7.67 (t, 1 H); 7.64 (t, 1 H); 7.22 (s, 1 H); 3.85 (t, 1 H); 3.51 (t, 1 H); 2.62 (t, 1H);2.13(t, 1H)ppm. 1 H-NMR (DMSO-d6) δ = 8.21 (d, 1H); 8.17 (d, 1H); 8.14 (d, 1H); 7.87 (d, 1H); 7.79 (t, 1H); 7.78 (t, 1H); 7.67 (t, 1H); 7.64 (t, 1H); 7.22 (s, 1H); 3.85 (t, 1H); 3.51 (t, 1H); 2.62 (t, 1H); 2.13 (t, 1H) ppm.
Beispiel 4:Example 4:
2-(10-Hydroxy-10H-anthracen-9-ylidene)-1 -(4-methoxy-phenyl)-ethanone (Verbindung 4)2- (10-Hydroxy-10H-anthracen-9-ylidenes) -1- (4-methoxy-phenyl) -ethanones (Compound 4)
Figure imgf000053_0002
Figure imgf000053_0002
Schmelzpunkt Fp.: 169-1720C FTIR: 3421, 1638 cm1 Melting point M.p .: 169-172 0 C FTIR: 3421, 1638 cm 1
1H-NMR (DMS0-d6) δ= 7.98(d, 2H); 7.91 (d, 1 H); 7.46 (t, 1 H); 7.41 (t, 1 H); 7.31 (t, 1 H); 7.25 (d, 1H); 7.12 (s, 1H); 7.08 (t, 1H); 6.98 (d, 2H) 6.30 (d, 1H); 5.54 (d, 1H); 3.82 (s, 3H) ppm. 1 H-NMR (DMSO-d6) δ = 7.98 (d, 2H); 7.91 (d, 1H); 7.46 (t, 1H); 7.41 (t, 1H); 7.31 (t, 1H); 7.25 (d, 1H); 7.12 (s, 1H); 7.08 (t, 1H); 6.98 (d, 2H) 6.30 (d, 1H); 5.54 (d, 1H); 3.82 (s, 3H) ppm.
Beispiel 5:Example 5:
10-{2-[4-(4-Methoxy-phenyl)-piperazin-1 -yl]-2-oxo-ethylidene}-1 OH-anthracen-9-one (Verbindung 5)10- {2- [4- (4-Methoxy-phenyl) -piperazin-1-yl] -2-oxo-ethylidene} -1 OH-anthracen-9-one (Compound 5)
Figure imgf000054_0001
Figure imgf000054_0001
Schmelzpunkt Fp.: 189-190 <€Melting point mp .: 189-190 < €
1H-NMR (DMS0-d6) δ= 8.16 -8.22 (m, 3H); 7.87 (d, 1 H); 7.80 (t, 1 H); 7.73 (t, 1 H); 7.65 (t, 1 H); 7.63 (t, 1 H); 7.25 (s, 1 H); 6.80 (m, 4H); 3.72 (m, 2H); 3.67 (s, 3H); 3.01 (m, 2H); 2.58 (m, 2H) ppm. 1 H-NMR (DMSO-d6) δ = 8.16 -8.22 (m, 3H); 7.87 (d, 1H); 7.80 (t, 1H); 7.73 (t, 1H); 7.65 (t, 1H); 7.63 (t, 1H); 7.25 (s, 1H); 6.80 (m, 4H); 3.72 (m, 2H); 3.67 (s, 3H); 3.01 (m, 2H); 2.58 (m, 2H) ppm.
Beispiel 6:Example 6:
10-[2-(3,4-Dimethoxy-phenyl)-2-oxo-ethyliden]-9(1 OH)-anthracenon (Verbindung 6)10- [2- (3,4-Dimethoxyphenyl) -2-oxo-ethylidene] -9 (1 OH) -anthracenone (Compound 6)
Figure imgf000054_0002
Figure imgf000054_0002
Schmelzpunkt Fp.: 160 0C FTIR: 1655, 1639 cm 1 1H-NMR (DMS0-d6) δ= 8.32 (d, 1 H); 8.20 (d, 1 H); 8.14 (d, 1 H); 7.81 (t, 1 H); 7.70 (s, 1 H); 7.69 (t, 1 H); 7.60 (d, 1 H); 7.55 (t, 1 H); 7.46 - 752 (m, 3H); 7.02 (d, 1 H); 3.82 (s, 3H); 3.79 (s, 3H)ppm.Melting point mp: 160 ° C. FTIR: 1655, 1639 cm 1 1 H-NMR (DMSO-d6) δ = 8.32 (d, 1H); 8.20 (d, 1H); 8.14 (d, 1H); 7.81 (t, 1H); 7.70 (s, 1H); 7.69 (t, 1H); 7.60 (d, 1H); 7.55 (t, 1H); 7.46-752 (m, 3H); 7.02 (d, 1H); 3.82 (s, 3H); 3.79 (s, 3H) ppm.
Beispiel 7:Example 7:
10-[2-(4-Methoxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 7)10- [2- (4-methoxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 7)
Figure imgf000055_0001
Figure imgf000055_0001
Schmelzpunkt Fp.: 120-122 0C FTIR 1647, 1591 crrf1 Melting point M.p .: 120-122 0 C FTIR 1647, 1591 crrf 1
1H-NMR (DMSO-d6) δ= 8.32 (d, 1 H); 8.20 (d, 1 H); 8.14 (d, 1 H); 7.96 (d, 2H); 7.83 (t, 1 H); 7.72 (s, 1 H); 7.69 (t, 1 H); 7.46- 7.56 (m, 3H); 7.03 (d, 2H); 3.81 (s, 3H) ppm. 1 H-NMR (DMSO-d6) δ = 8.32 (d, 1H); 8.20 (d, 1H); 8.14 (d, 1H); 7.96 (d, 2H); 7.83 (t, 1H); 7.72 (s, 1H); 7.69 (t, 1H); 7.46-7.56 (m, 3H); 7.03 (d, 2H); 3.81 (s, 3H) ppm.
Beispiel 8:Example 8:
10-[2-(2-Hydroxy-3,4-dimethoxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 8)10- [2- (2-Hydroxy-3,4-dimethoxyphenyl) -2-oxo-ethylidene] -10H-anthracene-9-one (Compound 8)
Figure imgf000056_0001
Figure imgf000056_0001
Schmelzpunkt Fp.: 176-178 0C FTIR 3030, 1655, 1615 cm 1 Melting point M.p .: 176-178 0 C FTIR 3030, 1655, 1615 cm-1
1H-NMR (DMS0-d6) δ= 8.12 (d, 1 H); 8.00 (d, 1 H); 7.83 (d, 1 H); 7.71 (t, 1 H); 7.55 (t, 1 H); 7.48 (t, 1 H); 7.38 - 7.44 (m, 2H); 7.16 (d, 1 H); 6.70 (d, 1 H); 5.22 (s, 1 H); 5.17 (s, 1 H); 3.80 (s, 3H); 3.53 (s, 3H)ppm. 1 H-NMR (DMSO-d6) δ = 8.12 (d, 1H); 8.00 (d, 1H); 7.83 (d, 1H); 7.71 (t, 1H); 7.55 (t, 1H); 7.48 (t, 1H); 7.38 - 7.44 (m, 2H); 7.16 (d, 1H); 6.70 (d, 1H); 5.22 (s, 1H); 5.17 (s, 1H); 3.80 (s, 3H); 3.53 (s, 3H) ppm.
Beispiel 9:Example 9:
10-(2-Oxo-2-p-tolyl-ethylidene)-1 OH-anthracen-9-one (Verbindung 9)10- (2-oxo-2-p-tolyl-ethylidene) -1 OH-anthracene-9-ones (compound 9)
Figure imgf000057_0001
Figure imgf000057_0001
Smp.129 <€; FTIR 1645 cm1;Smp.129 < €; FTIR 1645 cm 1 ;
1H-NMR (CDCI3) δ=8.32 (dd, 1H), 8.23 (dd, 1H), 7.99 (d, 1H), 7.78, 7.15 (d, 2H), 7.72- 7.66 (m, 1H), 7.62-7.55 (m, 2H), 7.44-7.38 (m, 1H), 7.30-7.14 (m, 1H), 7.20 (s, 1H), 3.11 (s, 3H); 1 H-NMR (CDCI 3) δ = 8:32 (dd, 1H), 8.23 (dd, 1H), 7.99 (d, 1H), 7.78, 7.15 (d, 2H), 7.72- 7.66 (m, 1H), 7.62 7.55- (m, 1H), 7.30-7.14 (m, 1H), 7.20 (s, 1H), 3.11 (s, 3H);
Beispiel 10:Example 10:
10-[2-(4-Hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 10)10- [2- (4-Hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 10)
Figure imgf000057_0002
Figure imgf000057_0002
Smp.211-2120C; FTIR 3321, 1665, 1638 cm1; 1 H-NMR (CDCI3) δ= 8.32 (dd, 1 H), 8.23 (dd, 1 H), 7.99 (d, 1 H), 7.80, 6.77 (d, 2H), 7.72 - 7.67 (m, 1H), 7.62-7.56 (m, 2H), 7.44-7.39 (m, 1H), 7.32-7.29 (m, 1H), 7.17 (s, 1H), 6.14(s, 1H). Beispiel 11:Mp.211-212 0 C; FTIR 3321, 1665, 1638 cm 1 ; 1 H-NMR (CDCI 3) δ = 8:32 (dd, 1 H), 8.23 (dd, 1 H), 7.99 (d, 1 H), 7.80, 6.77 (d, 2H), 7.72 - 7.67 (m, 1H ), 7.62-7.56 (m, 2H), 7.44-7.39 (m, 1H), 7.32-7.29 (m, 1H), 7.17 (s, 1H), 6.14 (s, 1H). Example 11:
10-(2-Oxo-2-thiophen-2-yl-ethylidene)-10H-anthracen-9-one (Verbindung 11)10- (2-oxo-2-thiophen-2-yl-ethylidene) -10H-anthracene-9-ones (Compound 11)
Figure imgf000058_0001
Figure imgf000058_0001
Smp.1260C; FTIR 1658, 1623 cm1;Mp.126 0 C; FTIR 1658, 1623 cm 1 ;
1H-NMR (CDCI3) δ= 8.32 (dd, 1 H), 8.24 (dd, 1 H), 7.97 (d, 1 H), 7.74-7.68 (m, 2H), 7.63- 7.58 (m, 2H), 7.48-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.19 (s, 1H), 6.98-6.96 (m, 1H); 1 H-NMR (CDCl 3 ) δ = 8.32 (dd, 1H), 8.24 (dd, 1H), 7.97 (d, 1H), 7.74-7.68 (m, 2H), 7.63-7.58 (m, 2H , 7.48-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.19 (s, 1H), 6.98-6.96 (m, 1H);
Beispiel 12: 10-[2-(3-Hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 12)Example 12: 10- [2- (3-Hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 12)
Figure imgf000058_0002
Figure imgf000058_0002
Smp.1850C;Mp.185 0 C;
FTIR 1661, 1634 cm1;FTIR 1661, 1634 cm 1 ;
1H-NMR (CDCI3) δ= 8.25 (dd, 1H), 8.17 (dd, 1H), 7.92 (d, 1H), 7.65-7.61 (m, 1H), 7.55- 7.52 (m, 1H), 7.48 (d, 1H), 7.39-7.31 (m, 3H), 7.26-7.22 (m, 1 H), 7.18-7.14 (m, 1H), 7.12(s, 1H), 6.94-6.92 (m, 1H), 4.98 (s, 1H); Beispiel 13: 1 H-NMR (CDCI 3) δ = 8.25 (dd, 1H), 8.17 (dd, 1H), 7.92 (d, 1H), 7.65-7.61 (m, 1H), 7.55- 7:52 (m, 1H), 7:48 (d, 1H), 7.39-7.31 (m, 3H), 7.26-7.22 (m, 1H), 7.18-7.14 (m, 1H), 7.12 (s, 1H), 6.94-6.92 (m, 1H), 4.98 (s, 1H); Example 13:
10-[2-(3-Methoxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 13)10- [2- (3-methoxyphenyl) -2-oxo-ethylidene] -10H-anthracen-9-one (Compound 13)
Figure imgf000059_0001
Figure imgf000059_0001
Smp. 129-130 0CMp. 129-130 0 C
FTIR 1665 cm 1 ;FTIR 1665 cm 1 ;
1H-NMR (CDCI3) δ= 8.32 (dd, 1 H), 8.23 (dd, 1 H), 7.99 (d, 1 H), 7.72-7.68 (m, 1 H), 7.62- 7.58 (m, 1 H), 7.54 (dd, 1 H), 7.46-7.40 (m, 3H), 7.31 -7.28 (m, 1 H), 7.26-7.24 (m, 1 H), 7.20 (s, 1 H), 7.07-7.04 (m, 1 H), 3.78 (s, 3H); 1 H-NMR (CDCl 3 ) δ = 8.32 (dd, 1H), 8.23 (dd, 1H), 7.99 (d, 1H), 7.72-7.68 (m, 1H), 7.62- 7.58 (m, 1H), 7.54 (dd, 1H), 7.46-7.40 (m, 3H), 7.31-7.28 (m, 1H), 7.26-7.24 (m, 1H), 7.20 (s, 1H), 7.07 -7.04 (m, 1H), 3.78 (s, 3H);
Beispiel 14:Example 14:
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid 2,6-dimethoxy-phenyl ester (Verbindung 14)(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid 2,6-dimethoxy-phenyl ester (Compound 14)
Figure imgf000059_0002
Smp. 172 <€;
Figure imgf000059_0002
Mp. 172 < €;
FTIR 1722, 1662 cm 1 ;FTIR 1722, 1662 cm 1 ;
1H-NMR (CDCI3) δ 8.28-8.23 (m, 2H), 7.95 (d, 1 H), 7.68-7.64 (m, 1 H), 7.60-7.54 (m, 3H), 7.17 (t, 1 H), 6.96 (s, 1 H), 6.65 (d, 2H), 3.87 (s, 6H); Beispiel 15: 1 H-NMR (CDCl 3 ) δ 8.28-8.23 (m, 2H), 7.95 (d, 1H), 7.68-7.64 (m, 1H), 7.60-7.54 (m, 3H), 7.17 (t, 1 H), 6.96 (s, 1H), 6.65 (d, 2H), 3.87 (s, 6H); Example 15:
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid methyl ester (Verbindung 15)(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid methyl ester (Compound 15)
Figure imgf000060_0001
Figure imgf000060_0001
Smp. 1 13 0C FTIR 1721 , 1661 crrf1 ;Mp 1 13 0 C FTIR 1721, 1661 cm -1 ;
1H-NMR (CDCI3) δ 8.27-8.24 (m, 2H), 7.85-7.80 (m, 2H), 7.66-7.62 (m, 1 H), 7.60-7.54 (m, 3H), 6.66 (s, 1 H), 3.79 (s, 3H); 1 H-NMR (CDCl 3 ) δ 8.27-8.24 (m, 2H), 7.85-7.80 (m, 2H), 7.66-7.62 (m, 1H), 7.60-7.54 (m, 3H), 6.66 (s, 1H), 3.79 (s, 3H);
Beispiel 16: 10-[2-Oxo-2-(3,4,5-trimethoxy-phenyl)-ethylidene]-1 OH-anthracen-9-one (Verbindung 16)Example 16: 10- [2-Oxo-2- (3,4,5-trimethoxyphenyl) ethylidene] -1 OH-anthracene-9-one (Compound 16)
Figure imgf000060_0002
Figure imgf000060_0002
Smp. 151 -152 0CMp. 151 -152 0 C
FTIR 1658 crrf1 ;FTIR 1658 crrf 1 ;
1H-NMR (CDCI3) δ 8.30 (dd, 1 H), 8.22 (dd, 1 H), 7.98 (d, 1 H), 7.72-7.60 (m, 1 H), 7.49 (d, 1 H), 7.44-7.40 (m, 1 H), 7.12 (s, 1 H), 7.08 (s, 2H), 3.85 (s, 3H), 3.72 (s, 6H); Beispiel 17: 1 H-NMR (CDCl 3 ) δ 8.30 (dd, 1H), 8.22 (dd, 1H), 7.98 (d, 1H), 7.72-7.60 (m, 1H), 7.49 (d, 1H) , 7.44-7.40 (m, 1H), 7.12 (s, 1H), 7.08 (s, 2H), 3.85 (s, 3H), 3.72 (s, 6H); Example 17:
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid (Verbindung 17)(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid (Compound 17)
Figure imgf000061_0001
Figure imgf000061_0001
Smp. 180-182 0CMp. 180-182 0 C
FTIR: 1684, 1663 cm 1 ;FTIR: 1684, 1663 cm 1 ;
1H-NMR (DMS0-d6) δ 8.05-8.03 (m, 2H), 7.71 -7.69 (m, 1 H), 7.65-7.63 (m, 2H), 7.59- 7.57 (dd, 1 H), 7.50-7.44 (m, 2H), 7.07 (s, 1 H). 1 H-NMR (DMSO-d6) δ 8.05-8.03 (m, 2H), 7.71-7.69 (m, 1H), 7.65-7.63 (m, 2H), 7.59-7.57 (dd, 1H), 7.50- 7.44 (m, 2H), 7.07 (s, 1H).
Beispiel 18:Example 18:
10-(2-Oxo-2-phenyl-ethylidene)-10H-anthracen-9-one (Verbindung 18)10- (2-Oxo-2-phenyl-ethylidene) -10H-anthracen-9-ones (Compound 18)
Figure imgf000061_0002
Figure imgf000061_0002
Schmelzpunkt: 128 0C 1 H-NMR 1 H-NMR (DMS0-d6) δ = 8.33 (d, 1 H), 8.20 (d, 1 H), 8.13 (d, 1 H), 7.99 (d, 2H), 7.83 (t, 1 H), 7.74 (s, 1 H), 7.70 (t, 1 H), 7.67 (t, 1 H), 7.47 - 7.56 (m, 5H),Melting point: 128 0 C. 1 H-NMR 1 H-NMR (DMS0-d6) δ = 8:33 (d, 1 H), 8.20 (d, 1 H), 8.13 (d, 1 H), 7.99 (d, 2H) , 7.83 (t, 1H), 7.74 (s, 1H), 7.70 (t, 1H), 7.67 (t, 1H), 7.47 - 7.56 (m, 5H),
Die Verbindungen 19-43 lassen sich gemäß dem allgemeinen Schema 1 herstellen. II) Inhibierung der Polymerisation von TubulinCompounds 19-43 can be prepared according to general scheme 1. II) Inhibition of the polymerization of tubulin
a) Die erfindungsgemäßen Verbindungen 1 , 6, 7, 9, 10, 12, 13, 16 und 18 wurden in einem in-vitro Test auf Hemmung der Polymerisation von Rindertubulin getestet (D.M. Bollag et al. Cancer Res. 1995, 55: 2325-2333). In diesem Test wird durch Zyklen von Polymerisation und Depolymerisation aufgereinigtes Tubulin eingesetzt, welches durch Zugabe von GTP und Erwärmung zur Polymerisation gebracht wird.a) The compounds 1, 6, 7, 9, 10, 12, 13, 16 and 18 according to the invention were tested in an in vitro test for inhibition of the polymerization of bovine tubulin (DM Bollag et al., Cancer Res. 1995, 55: 2325 -2333). In this test, purified tubulin is used through cycles of polymerization and depolymerization, which is brought to polymerization by addition of GTP and heating.
In Tabelle 1 sind die %-lnhibitionswerte bzw. in Tabelle 2 die EC50-Werte der Polymerisationshemmung von Tubulin mit 30% assoziierten Proteinen (MAPs) angegeben.Table 1 shows the% inhibition values and Table 2 shows the EC 50 values of the polymerization inhibition of tubulin with 30% associated proteins (MAPs).
Tabelle 1Table 1
Figure imgf000062_0001
Figure imgf000062_0001
Tabelle 2Table 2
Figure imgf000062_0002
b) Die Verbindungen 1 , 2, 4 und 7 wurden in einem in-vitro Test auf Hemmung der Polymerisation von Schweinehirntubulin getestet. In diesem Test wird durch Zyklen von Polymerisation und Depolymerisation aufgereinigtes Tubulin eingesetzt (Shelanski et al. Proc. Natl. Acad. Sei. U. S.A. 1973, 70, 765-768 modifiziert nach Vater et al. Acta Histochem. Suppl. 1986, 33, 123-129), welches durch Zugabe von GTP und Erwärmung auf 37°C zur Polymerisation gebracht wird. Das eingesetzte Protein enthält neben dem Tubulin ca. 15% assoziierter Proteine (MAPs). Die Messwerte wurden turbi- dimetrisch nach Gaskin et al. J. Mol. Biol. 89 (1974) 737-755 erhoben.
Figure imgf000062_0002
b) Compounds 1, 2, 4 and 7 were tested in an in vitro assay for inhibition of porcine brain tubulin polymerization. Purified tubulin purified by cycles of polymerization and depolymerization is used in this assay (Shelanski et al., Proc. Natl. Acad., U.S.A. 1973, 70, 765-768, modified by Vater et al., Acta Histochem. Suppl., 1986, 33, 123 -129) which is brought to polymerization by addition of GTP and heating to 37 ° C. In addition to the tubulin, the protein used contains about 15% of associated proteins (MAPs). The measured values were turbidimetric according to Gaskin et al. J. Mol. Biol. 89 (1974) 737-755.
In Tabelle 3 ist der EC50 Wert der Polymerisationshemmung angegeben.Table 3 gives the EC 50 value of the polymerization inhibition.
Tabelle 3Table 3
Figure imgf000063_0001
Figure imgf000063_0001
III) Inhibition von Kinesin Eg5III) Inhibition of Kinesin Eg5
Die Verbindung 1 wurde in einem in-vitro Test auf Hemmung der Eg5-Aktivität untersucht [Kodama, T. et al. J. Biochem. 99: 1465-1472 (1986)]. Dabei kamen die rekombinanten Kinesine EgSi3-437 (Tabelle 3) und EgO1^06 (Tabelle 4) zum Einsatz.Compound 1 was tested in an in vitro assay for inhibition of Eg5 activity [Kodama, T. et al. J. Biochem. 99: 1465-1472 (1986)]. The recombinant kinesins EgSi 3-437 (Table 3) and EgO 1 ^ 06 (Table 4) were used.
In den Tabellen 4 und 5 sind die EC50 Werte der Eg5-Hemmung für die erfinderische Verbindung 1 angegeben.Tables 4 and 5 give the EC 50 values of Eg5 inhibition for inventive compound 1.
Tabelle 4Table 4
Figure imgf000064_0001
Figure imgf000064_0001
Tabelle 5Table 5
Figure imgf000064_0002
Figure imgf000064_0002
IV) Inhibition von Kinesin KIF5AIV) Inhibition of Kinesin KIF5A
Die Verbindung 1 wurde in einem in-vitro Test auf Hemmung der KIF5A ATPase- Aktivität untersucht. Dabei kam rekombinantes Volllängen KIF5A (Niclas J, Navone F, Hom-Booher N, VaIe RD Neuron 1994, 12:1059-1072) zum Einsatz.Compound 1 was tested in an in vitro assay for inhibition of KIF5A ATPase activity. Recombinant full length KIF5A (Niclas J, Navone F, Hom Booster N, VaIe RD Neuron 1994, 12: 1059-1072) was used.
Die Aktivität der Mikrotubulus-aktivierbaren ATPase wurden mittels end-point As- say bestimmt. Zur Tubulin-Isolierung und Herstellung der Mikrotubuli s. Zitate im Beispiel II) b).The activity of the microtubule-activatable ATPase was determined by end-point assay. For tubulin isolation and preparation of microtubules s. Citations in Example II) b).
In Tabelle 6 ist der EC50 Wert der ATPase- Hemmung von KIF5A durch die erfinderische Verbindung 1 angegeben.In Table 6, the EC 50 value given is the inhibition of ATPase KIF5A by the inventive compound. 1
Tabelle 6Table 6
Figure imgf000065_0001
Figure imgf000065_0001
V) Antiproliferative Wirkung an verschiedenen TumorzellinienV) Antiproliferative activity on various tumor cell lines
Die erfindungsgemäßen Verbindungen 1 , 2, 4, 6, 7, 9, 10, 11 , 12 und 13 wurden in einem Proliferationstest an etablierten Tumorzelllinien auf ihre anti-proliferative Akti- vität hin untersucht (D.A. Scuderio et al. Cancer Res. 1988, 48: 4827-4833).The compounds 1, 2, 4, 6, 7, 9, 10, 11, 12 and 13 according to the invention were tested for their anti-proliferative activity in a proliferation test on established tumor cell lines (DA Scuderio et al., Cancer Res. 48: 4827-4833).
Der verwendete Test bestimmt die zelluläre Dehydrogenase-Aktivität und ermöglicht eine Bestimmung der Zellvitalität und indirekt der Zellzahl.The test used determines the cellular dehydrogenase activity and allows determination of cell vitality and, indirectly, cell number.
Bei den verwendeten Zelllinien handelt es sich um die humane Cervixkarzinom Zelllinie KB/HeLa (ATCC CCL17), die ovariale Adenokarzinomzelllinie SKOV-3 (ATCC HTB77), die humane Glioblastom Zelllinie SF-268 (NCI 503138) und die Lungenkarzinom Zelllinie NCI-H460 (NCI 503473). Des Weiteren wurde zur Untersuchung der ZeII- zyklus-spezifischen Wirkung der Substanz ein RKOp27 Zellsystem verwendet (M. Schmidt et al. Oncogene 2000, 19(20): 2423-9).The cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line NCI-H460 ( NCI 503473). Furthermore, an RKOp27 cell system was used to study the cell cycle-specific action of the substance (Schmidt, M. et al., Oncogene 2000, 19 (20): 2423-9).
Bei RKO handelt es sich um eine humane Kolonkarzinomlinie, in der der Zellzyklu- sinhibitor p27kιp1 mittels des Ecdyson Expressionssystems induziert zur Expression gebracht und zu einem Zellzyklusarrest spezifisch in G2 geführt werden kann.RKO is a human colon carcinoma line in which the cell cycle inhibitor p27 kιp1 can be induced to express by means of the ecdysone expression system and can be led to a cell cycle arrest specifically in G2.
Eine unspezifisch wirkende Substanz hemmt die Proliferation unabhängig davon, ob die RKO Zelle in G1 oder G2 arretiert ist oder nicht. Zellzyklus-spezifische Substanzen wie beispielsweise Tubulininhibitoren sind hingegen nur dann zytotoxisch, wenn Zellen nicht arretiert sind und der Zellzyklus durchlaufen wird.A nonspecific substance inhibits proliferation regardless of whether the RKO cell is locked in G1 or G2 or not. Cell cycle-specific substances such as tubulin inhibitors, however, are only cytotoxic if cells are not arrested and the cell cycle is traversed.
In Tabelle 7 ist die zytotoxische bzw. wachstumshemmende Aktivität der beschriebenen Verbindungen mit / ohne Expression von p27kιp1 gezeigt. Die getesteten Verbindungen zeigten im induzierten Zustand von p27kιp1 keine zytotoxische Aktivität. Die Ergebnisse zeigen eine sehr potente Hemmung der Proliferation ausgewählter Tumor- zelllinien durch die erfindungsgemäßen Verbindungen. Tabelle 7Table 7 shows the cytotoxic or growth-inhibiting activity of the compounds described with / without expression of p27 kp1 . The compounds tested showed no cytotoxic activity in the induced state of p27 kp1 . The results show a very potent inhibition of the proliferation of selected tumor cell lines by the compounds according to the invention. Table 7
Figure imgf000067_0001
Figure imgf000067_0001
Vl) Antiproliferative Wirkung an verschiedenen multi-drug resistenten (MDR) TumorzelllinienVl) Antiproliferative activity on various multi-drug resistant (MDR) tumor cell lines
Zur weiteren Charakterisierung wurden die erfindungsgemäßen Verbindungen 6 und 7 gegenüber multi-drug resistenten (MDR) Zelllinien im Vergleich zu den nichtresistenten Wildtypzeillinien untersucht.For further characterization, compounds 6 and 7 according to the invention were tested against multi-drug-resistant (MDR) cell lines in comparison to the non-resistant wild-type cell lines.
Bei den untersuchten Zelllinien handelt es sich um die murine L1210 (ATCC CCL219), die akute myeloische Leukaemie Zelllinie LT12 (De Vries et al.; University Rotterdam) und um die resistenten Linien L1210/VCR (Asta Medica Laboratory) und LT12/mdr (De Vries et al.; University Rotterdam).The investigated cell lines are the murine L1210 (ATCC CCL219), the acute myeloid leukemia cell line LT12 (De Vries et al., University of Rotterdam) and the resistant lines L1210 / VCR (Asta Medica Laboratory) and LT12 / mdr ( De Vries et al., University of Rotterdam).
Außerdem wurden die murine P388 Zelllinie (methyl-cholanthrene-induced lymphoid neoplasm) [R. Supino et al.; Inst. Nazionale per Io Studio e las cura die Tu- mori; Milano)] sowie die Doxorubicin-resistente P388 (NSC-123127) als Testsysteme herangezogen.In addition, the murine P388 cell line (methyl-cholanthrene-induced lymphoid neoplasm) [R. Supino et al .; Inst. Nazionale by Io Studio e las cura the Tuomori; Milano)] and doxorubicin-resistant P388 (NSC-123127) were used as test systems.
In der Tabelle 8 sind die entsprechenden XTT-Daten dargestellt.Table 8 shows the corresponding XTT data.
Tabelle 8Table 8
Figure imgf000068_0001
Figure imgf000068_0001
VII) ZeI Izykl US- AnalyseVII) ZeI Izykl US analysis
Der Zellzyklus umfasst die Entwicklung der Zelle von einer Zellgeneration zur nächsten. Während der Ruhephase (GO) und präsynthetischen Phase (G1 ) besitzt die Zelle einen diploiden Chromosomensatz (2c). In der Synthesephase (S) wird die DNA Menge durch Replikation vermehrt. Die S-Phase endet mit Erreichen der prämitotischen Phase (G2M), in der die Zelle einen reduplizierten Chromosomenbestand (4c) und verdoppelten DNA-Gehalt aufweist. In der nachfolgenden, kurzdauernden Mitosephase (M) kommt es zur gleichmäßigen Aufteilung der reduplizierten Chromosomen auf zwei Tochterzellen, die dann jeweils wieder einen diploiden DNA Gehalt zeigen und sich in der G01 -Phase befinden, so daß der Zellzyklus neu beginnen kann.The cell cycle involves the development of the cell from one generation of cells to the next. During the resting phase (GO) and presynthetic phase (G1), the cell has a diploid chromosome set (2c). In the synthesis phase (S) the amount of DNA is increased by replication. The S phase ends when the premitotic phase (G2M) is reached, in which the cell has a reduplicated chromosome population (4c) and a doubled DNA content. In the subsequent, short-term mitotic phase (M), the reduplicated chromosomes are distributed evenly over two daughter cells, which then each again show a diploid DNA content and are in the G01 phase, so that the cell cycle can start anew.
Für die Zellzyklusanalyse wurden KB/HeLa Zellen (ATCC CCL17) mit den Testsubstanzen in unterschiedlichen Konzentrationen (0.1 -1000 nM) 24 Stunden bei 37<O behandelt.For the cell cycle analysis were KB / HeLa (ATCC CCL17) with the test substances in different concentrations (0.1 nM -1000) for 24 hours at 37 <O.
Der prozentuale Anteil der in der G2/M Phase des Zellzyklus arretierten Zellen nach Behandlung mit erfindungsgemäßen Verbindungen und ausgewählten Referenzsubstanzen ist in der nachfolgenden Tabelle 9 dargestellt. Die Ergebnisse wurden mit einer speziellen Analysesoftware (ModFit™) ausgewertet.The percentage of cells locked in the G2 / M phase of the cell cycle after treatment with compounds of the invention and selected reference substances is shown in Table 9 below. The results were evaluated with a special analysis software (ModFit ™).
Tabelle 9Table 9
Figure imgf000069_0001
Figure imgf000069_0001

Claims

Patentansprüche claims
1. Anthracen-Derivat gemäß der allgemeinen Formel (I)1. Anthracene derivative according to the general formula (I)
Figure imgf000070_0001
Figure imgf000070_0001
(I)(I)
worin:wherein:
Substituent X unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NR1 1 , N-OR12, geminal geknüpfter Wasserstoff und Hydroxy"; Substituent Y unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S,Substituent X is independently selected from the group consisting of: "O, S, NR11, N-OR12, geminally linked hydrogen and hydroxy"; substituent Y is independently selected from the group consisting of: "O, S,
NR13, N-OR14";NR13, N-OR14 ";
Substituenten R1 , R2, R3, R4, R5, R6, R7, R8 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstitu- iertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Hete- rocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroa- ryl-alkyl, Amino, Mono-Alkylamino, Di-Alkylamino, Halogen, -F, -Cl, -Br, -I, mit ein oder mehreren Fluoratomen substituiertes Alkyl, Trifluormethyl, Cyano, geradketti- ges oder verzweigtes Cyano-alkyl, Carbonyl, Carboxyl, -COOH, Alkoxycarbonyl, Carboxy-alkyl, Alkoxycarbonyl-alkyl, Hydroxy, Alkoxy, Aryl-alkoxy, Benzyloxy, He- teroaryl-alkoxy, Alkoxycarbonylamino, Alkoxycarbonylamino-alkyl";Substituents R1, R2, R3, R4, R5, R6, R7, R8 independently of one another are selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, amino, monoalkylamino, di-alkylamino, halogen , -F, -Cl, -Br, -I, alkyl substituted with one or more fluorine atoms, trifluoromethyl, cyano, straight-chain or branched cyano-alkyl, carbonyl, carboxyl, -COOH, alkoxycarbonyl, carboxyalkyl, alkoxycarbonyl-alkyl , Hydroxy, alkoxy, arylalkoxy, benzyloxy, heteroarylalkoxy, alkoxycarbonylamino, alkoxycarbonylaminoalkyl ";
Substituent R9 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „un- substituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, un- substituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl- alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl, -OR15, -NR16R17";Substituent R9 is independently selected from the group consisting of: "unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted substituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, -OR15, -NR16R17 ";
Substituent R10 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl";Substituent R10 is independently selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl";
Substituenten R11 , R12, R13, R14, R15, R16, R17 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl"; mit der Maßgabe, dass die folgenden, unter die allgemeine Formel (I) fallenden Verbindungen ausgeschlossen sind:Substituents R11, R12, R13, R14, R15, R16, R17 are independently selected independently from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl "with the proviso that the following compounds covered by the general formula (I) are excluded are:
(i) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 262378-52-9(i) Connection to Chemical Abstract Service (CAS) Registry No. 262378-52-9
Figure imgf000071_0001
(ii) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 121747-08-8
Figure imgf000072_0001
Figure imgf000071_0001
(ii) Connection to the Chemical Abstract Service (CAS) Registry No. 121747-08-8
Figure imgf000072_0001
Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 63370-49-0
Figure imgf000072_0002
Connection to Chemical Abstract Service (CAS) Registry No. 63370-49-0
Figure imgf000072_0002
(iv) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 19661 -62-2
Figure imgf000072_0003
(v) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 17665-75-7
Figure imgf000073_0001
(iv) Connection to the Chemical Abstract Service (CAS) Registry No. 19661 -62-2
Figure imgf000072_0003
(v) Connection to the Chemical Abstract Service (CAS) Registry No. 17665-75-7
Figure imgf000073_0001
(vi) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 83498-19-5
Figure imgf000073_0002
(vi) Connection to the Chemical Abstract Service (CAS) Registry No. 83498-19-5
Figure imgf000073_0002
(vii) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 42866-43-3
Figure imgf000073_0003
(viii) Verbindung mit der Beilstein Registry Nr. 3095926(vii) Connection to Chemical Abstract Service (CAS) Registry No. 42866-43-3
Figure imgf000073_0003
(viii) Connection to the Beilstein Registry No. 3095926
Figure imgf000074_0001
Figure imgf000074_0001
(ix) Verbindung mit der Chemical Abstract Service (CAS) Registry Nr. 42866-49-9(ix) Connection to Chemical Abstract Service (CAS) Registry No. 42866-49-9
Figure imgf000074_0002
Figure imgf000074_0002
2. Anthracen-Derivat gemäß der allgemeinen Formel (I) gemäß Anspruch 1 , worin:2. Anthracene derivative according to the general formula (I) according to claim 1, wherein:
Substituent X unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NH, geminal geknüpfter Wasserstoff und Hydroxy"; Substituent Y unabhängig „O oder S" ist;Substituent X is independently selected from the group consisting of: "O, S, NH, geminally linked hydrogen and hydroxy"; substituent Y is independently "O or S";
Substituenten R1 , R2, R3, R4, R5, R6, R7, R8 unabhängig „Wasserstoff, Fluor, Chlor, Brom, lod, Hydroxy, Amino, Nitro, Cyano, Methyl, Trifluormethyl" sind;Substituents R1, R2, R3, R4, R5, R6, R7, R8 are independently "hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, trifluoromethyl";
Substituent R9 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Heteroaryl, -OR15, -Substituent R9 is independently selected from the group consisting of: "unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -OR15, -
NR16R17";NR16R17 ";
Substituent R10 unabhängig „Wasserstoff, Alkyl" ist.Substituent R10 is independently "hydrogen, alkyl".
3. Anthracen-Derivat gemäß der allgemeinen Formel (I) gemäß einem der Ansprüche 1 bis 2, worin:3. Anthracene derivative according to the general formula (I) according to one of the claims 1 to 2, wherein:
Substituent R9 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „3,4- Dimethoxy-phenyl; 3,4-Dihydroxy-phenyl; 4-Methoxy-thiophen-2-yl, Thiomorpholin- 4-yl; 4-Methoxy-phenyl; 4-(4-Methoxy-phenyl)-piperazin-1 -yl, 2-Hydroxy-3,4- dimethoxy-phenyl; 4-Methylphenyl; 4-Hydroxyphenyl; Thiophen-2-yl; 3- Hydroxyphenyl; 3-Methoxy-phenyl; 2,6-Dimethoxy-phenyl; 3,4,5-Trimethoxy- phenyl; Hydroxy; Methoxy; Phenyl; 4-Chlorphenyl; 4-Bromphenyl; 4-Fluorphenyl; 3- Chlorphenyl; 3-Bromphenyl; 3-Fluorphenyl; 4-Fluor;3-hydroxy-phenyl"".Substituent R9 is independently selected from the group consisting of: "3,4-dimethoxy-phenyl; 3,4-dihydroxy-phenyl; 4-methoxy-thiophen-2-yl, thiomorpholine-4-yl; 4-methoxy-phenyl; 4- (4-methoxy-phenyl) -piperazine-1-yl, 2-hydroxy-3,4-dimethoxyphenyl; 4-methylphenyl; 4-hydroxyphenyl; Thiophen-2-yl; 3-hydroxyphenyl; 3-methoxy-phenyl; 2,6-dimethoxy-phenyl; 3,4,5-trimethoxyphenyl; hydroxy; methoxy; phenyl; 4-chlorophenyl; 4-bromophenyl; 4-fluorophenyl; 3-chlorophenyl; 3-bromophenyl; 3-fluorophenyl; 4-fluoro; 3-hydroxy-phenyl ''.
Anthracen-Derivat ausgewählt aus der Gruppe bestehend aus:Anthracene derivative selected from the group consisting of:
10-[2-(3,4-Dihydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 1):10- [2- (3,4-Dihydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 1):
Figure imgf000075_0001
Figure imgf000075_0001
10-[2-(4-Methoxy-thiophen-2-yl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 2):10- [2- (4-methoxy-thiophen-2-yl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 2):
Figure imgf000075_0002
10-(2-Oxo-2-thiomorpholin-4-ylethylidene)-1 OH-anthracen-9-one (Verbindung 3):
Figure imgf000075_0002
10- (2-Oxo-2-thiomorpholin-4-yl-ethylidene) -1 OH-anthracen-9-one (Compound 3):
Figure imgf000076_0001
Figure imgf000076_0001
2-(10-Hydroxy-10H-anthracen-9-ylidene)-1 -(4-methoxy-phenyl)-ethanone (Verbindung 4):2- (10-Hydroxy-10H-anthracen-9-ylidenes) -1- (4-methoxyphenyl) -ethanones (Compound 4):
Figure imgf000076_0002
Figure imgf000076_0002
10-{2-[4-(4-Methoxy-phenyl)-piperazin-1 -yl]-2-oxo-ethylidene}-1 OH-anthracen-9- one (Verbindung 5):10- {2- [4- (4-Methoxy-phenyl) -piperazin-1-yl] -2-oxo-ethylidene} -1 OH-anthracen-9-one (Compound 5):
Figure imgf000076_0003
10-[2-(3,4-Dimethoxy-phenyl)-2-oxo-ethyliden]-9(1 OH)-anthracenon (Verbindung 6):
Figure imgf000077_0001
Figure imgf000076_0003
10- [2- (3,4-Dimethoxyphenyl) -2-oxo-ethylidene] -9 (1 OH) -anthracenone (Compound 6):
Figure imgf000077_0001
10-[2-(4-Methoxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 7):
Figure imgf000077_0002
10- [2- (4-Methoxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 7):
Figure imgf000077_0002
10-[2-(2-Hydroxy-3,4-dimethoxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 8)
Figure imgf000078_0001
10- [2- (2-Hydroxy-3,4-dimethoxyphenyl) -2-oxo-ethylidene] -10H-anthracene-9-one (Compound 8)
Figure imgf000078_0001
10-(2-Oxo-2-p-tolyl-ethylidene)-1 OH-anthracen-9-one (Verbindung 9)
Figure imgf000078_0002
10- (2-oxo-2-p-tolyl-ethylidene) -1 OH-anthracen-9-ones (compound 9)
Figure imgf000078_0002
10-[2-(4-Hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 10)10- [2- (4-Hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 10)
Figure imgf000079_0001
Figure imgf000079_0001
10-(2-Oxo-2-thiophen-2-yl-ethylidene)-1 OH-anthracen-9-one (Verbindung 11)10- (2-oxo-2-thiophen-2-yl-ethylidene) -1 OH-anthracen-9-one (Compound 11)
Figure imgf000079_0002
Figure imgf000079_0002
10-[2-(3-Hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 12)10- [2- (3-Hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 12)
Figure imgf000079_0003
10-[2-(3-Methoxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 13)
Figure imgf000079_0003
10- [2- (3-Methoxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 13)
Figure imgf000080_0001
Figure imgf000080_0001
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid 2,6-dimethoxy-phenyl ester (Verbindung 14)(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid 2,6-dimethoxy-phenyl ester (Compound 14)
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid methyl ester (Verbindung 15)(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid methyl ester (Compound 15)
Figure imgf000080_0003
10-[2-Oxo-2-(3,4,5-trimethoxy-phenyl)-ethylidene]-1 OH-anthracen-9-one (Verbindung 16)
Figure imgf000081_0001
Figure imgf000080_0003
10- [2-Oxo-2- (3,4,5-trimethoxyphenyl) ethylidene] -1 OH-anthracene-9-one (Compound 16)
Figure imgf000081_0001
(I O-Oxo-10H-anthracen-9-ylidene)-acetic acid (Verbindung 17)
Figure imgf000081_0002
(I O-Oxo-10H-anthracene-9-ylidenes) -acetic acid (Compound 17)
Figure imgf000081_0002
10-(2-Oxo-2-phenyl-ethylidene)-1 OH-anthracen-9-one (Verbindung 18)
Figure imgf000081_0003
-[2-(4-Chlor-phenyl)-2-oxo-ethyliden]-10/-/-anthracen-9-one (Verbindung 19)
Figure imgf000082_0001
-[2-(4-Brom-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 20)
Figure imgf000082_0002
-[2-(3-Chlor-phenyl)-2-oxo-ethyliden]-10/-/-anthracen-9-on (Verbindung 21)
Figure imgf000082_0003
-[2-(3-Brom-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 22)
Figure imgf000083_0001
-[2-(4-Fluor-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 23)
Figure imgf000083_0002
-[2-(3-Fluor-phenyl)-2-oxo-ethyliden]-1 OH-anthracen-9-on (Verbindung 24)
Figure imgf000083_0003
10-[2-(4-Fluor, 3-Hydroxy-phenyl)-2-oxo-ethyliden]-10H-anthracen-9-on (Verbindung 25)10- (2-Oxo-2-phenyl-ethylidene) -1 OH-anthracene-9-ones (Compound 18)
Figure imgf000081_0003
- [2- (4-chloro-phenyl) -2-oxo-ethylidene] -10 / - / - anthracene-9-one (Compound 19)
Figure imgf000082_0001
- [2- (4-Bromo-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 20)
Figure imgf000082_0002
- [2- (3-chloro-phenyl) -2-oxo-ethylidene] -10 / - / - anthracen-9-one (Compound 21)
Figure imgf000082_0003
- [2- (3-Bromo-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 22)
Figure imgf000083_0001
- [2- (4-fluoro-phenyl) -2-oxo-ethylidene] -1-OH-anthracen-9-one (compound 23)
Figure imgf000083_0002
[2- (3-fluoro-phenyl) -2-oxo-ethylidene] -1-OH-anthracen-9-one (Compound 24)
Figure imgf000083_0003
10- [2- (4-fluoro, 3-hydroxy-phenyl) -2-oxo-ethylidene] -10H-anthracen-9-one (Compound 25)
Figure imgf000084_0001
Figure imgf000084_0001
1 -(3,4-Dihydroxy-phenyl)-2-(10-thioxo-10H-anthracen-9-ylidene)-ethanone (Verbindung 26):1- (3,4-Dihydroxyphenyl) -2- (10-thioxo-10H-anthracen-9-ylidenes) -ethanones (Compound 26):
Figure imgf000084_0002
Figure imgf000084_0002
1 -(3,4-Dihydroxy-phenyl)-2-(10-imino-10H-anthracen-9-ylidene)-ethanone (Verbindung 27):1 - (3,4-Dihydroxyphenyl) -2- (10-imino-10H-anthracen-9-ylidenes) -ethanones (Compound 27):
Figure imgf000084_0003
1 -(3-Hydroxy-phenyl)-2-(10-thioxo-10H-anthracen-9-ylidene)-ethanone (Verbindung 28):
Figure imgf000084_0003
1- (3-Hydroxy-phenyl) -2- (10-thioxo-10H-anthracen-9-ylidenes) -ethanones (Compound 28):
Figure imgf000085_0001
Figure imgf000085_0001
1 -(3-Hydroxy-phenyl)-2-(10-imino-10H-anthracen-9-ylidene)-ethanon (Verbindung 29):1- (3-Hydroxy-phenyl) -2- (10-imino-10H-anthracen-9-ylidenes) -ethanone (Compound 29):
Figure imgf000085_0002
Figure imgf000085_0002
1 -(4-Fluor, 3-hydroxy-phenyl)-2-(10-thioxo-10H-anthracen-9-ylidene)-ethanon (Verbindung 30):1- (4-fluoro, 3-hydroxy-phenyl) -2- (10-thioxo-10H-anthracen-9-ylidenes) -ethanone (Compound 30):
Figure imgf000085_0003
Figure imgf000085_0003
1 -(4-Fluor, 3-hydroxy-phenyl)-2-(10-imino-10H-anthracen-9-ylidene)-ethanon (Verbindung 31):1- (4-fluoro, 3-hydroxy-phenyl) -2- (10-imino-10H-anthracen-9-ylidenes) -ethanone (Compound 31):
Figure imgf000086_0001
Figure imgf000086_0001
1 ,4-Dichlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 32)1,4-dichloro-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (Compound 32)
Figure imgf000086_0002
Figure imgf000086_0002
1 ,2-Dichlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Ver- bindung 33)1,2-dichloro-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracene-9-one (compound 33)
Figure imgf000086_0003
3,4-Dichlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 34)
Figure imgf000086_0003
3,4-Dichloro-10- [2- (3-hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 34)
Figure imgf000087_0001
Figure imgf000087_0001
1 ,2-Methyl-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 35)1, 2-Methyl-10- [2- (3-hydroxy-phenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 35)
Figure imgf000087_0002
Figure imgf000087_0002
3-Chlor-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 36)3-chloro-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-ones (Compound 36)
Figure imgf000088_0001
Figure imgf000088_0001
3-Brom-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 37)3-Bromo-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-ones (Compound 37)
Figure imgf000088_0002
Figure imgf000088_0002
10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-3-methyl-1 OH-anthracen-9-one (Verbindung 38)10- [2- (3-hydroxy-phenyl) -2-oxo-ethylidene] -3-methyl-1-OH-anthracen-9-one (Compound 38)
Figure imgf000089_0001
Figure imgf000089_0001
1 ,4-Dichlor-10-[2-(3,4-dihydroxy-phenyl)-2-oxo-ethylidene]-1 OH-anthracen-9-one (Verbindung 39)1, 4-dichloro-10- [2- (3,4-dihydroxyphenyl) -2-oxo-ethylidene] -1 OH-anthracen-9-one (Compound 39)
Figure imgf000089_0002
Figure imgf000089_0002
3,4-Dimethyl-10-[2-(3-hydroxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 40)3,4-Dimethyl-10- [2- (3-hydroxyphenyl) -2-oxo-ethylidene] -10H-anthracene-9-one (Compound 40)
Figure imgf000090_0001
Figure imgf000090_0001
2-[2-Chlor-10-thioxo-10H-anthracen-9-ylidene]-1 -(3-hydroxy-phenyl)-ethanone (Verbindung 41)2- [2-Chloro-10-thioxo-10H-anthracen-9-ylidenes] -1- (3-hydroxy-phenyl) -ethanones (Compound 41)
Figure imgf000090_0002
Figure imgf000090_0002
3-Chlor-10-[2-(3,3-chloro-10- [2- (3,
4-dihydroxy-phenyl)-2-oxo-ethylidene]-10H-anthracen-9-one (Verbindung 42)4-dihydroxyphenyl) -2-oxo-ethylidene] -10H-anthracene-9-one (Compound 42)
Figure imgf000091_0001
Figure imgf000091_0001
2-[2-Chlor-10-imino-10H-anthracen-9-ylidene]-1 -(3-hydroxy-phenyl)-ethanone (Verbindung 43)2- [2-Chloro-10-imino-10H-anthracen-9-ylidenes] -1- (3-hydroxy-phenyl) -ethanones (Compound 43)
Figure imgf000091_0002
Figure imgf000091_0002
5. Verfahren zur Herstellung von Anthracen-Derivaten gemäß einem der Ansprüche 1 bis 4.5. A process for the preparation of anthracene derivatives according to any one of claims 1 to 4.
6. Pharmazeutische Zusammensetzung enthaltend eine pharmazeutisch aktive Menge mindestens einer Verbindung gemäß einem der Ansprüche 1 bis 4. 6. A pharmaceutical composition comprising a pharmaceutically active amount of at least one compound according to any one of claims 1 to 4.
7. Pharmazeutische Zusammensetzung gemäß Anspruch 6, wobei die mindestens eine Verbindung in einer Einheitsdosis von 0.001 mg bis 100 mg pro kg Körpergewicht des Patienten vorliegt.The pharmaceutical composition according to claim 6, wherein the at least one compound is present in a unit dose of 0.001 mg to 100 mg per kg body weight of the patient.
i 8. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 6 bis 7, wobei die Zusammensetzung zusätzlich pharmazeutisch akzeptable Träger- und/oder Hilfsstoffe enthält.8. Pharmaceutical composition according to one of claims 6 to 7, wherein the composition additionally contains pharmaceutically acceptable excipients and / or adjuvants.
9. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 6 bis 8, wobei die Zusammensetzung zusätzlich mindestens eine weitere pharmakologisch aktive9. A pharmaceutical composition according to any one of claims 6 to 8, wherein the composition additionally at least one further pharmacologically active
Substanz enthält.Contains substance.
10. Pharmazeutische Zusammensetzung gemäß Anspruch 9, wobei die weitere pharmakologisch aktive Substanz ausgewählt ist aus der Gruppe bestehend aus: „DNA Topoisomerase I und/oder Il Inhibitoren, DNA Interkalatoren, alkylierende Agen- tien, Microtubuli Destabilisatoren, Hormon- und/oder Wachstumsfaktor-Rezeptor- Agonisten und/oder -Antagonisten, Hemmstoffen der Signaltransduktion, Antikörper gegen Wachstumsfaktoren und deren Rezeptoren, Kinase Inhibitoren, Antime- tabolite".10. Pharmaceutical composition according to claim 9, wherein the further pharmacologically active substance is selected from the group consisting of: "DNA topoisomerase I and / or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers, hormone and / or growth factor Receptor agonists and / or antagonists, signal transduction inhibitors, antibodies to growth factors and their receptors, kinase inhibitors, antimitolites. "
1 1 . Pharmazeutische Zusammensetzung gemäß Anspruch 10, wobei die weitere pharmakologisch aktive Substanz ausgewählt ist aus der Gruppe bestehend aus: "Actinomycin D, Aminoglutethimid, Asparaginase, Avastin, Azathioprin, BCNU (Carmustine), Bleomycin, Busulfan, Carboplatin, CCNU (Lomustine), Chlorambucil, Cisplatin, Colaspase, Cyclophosphamid, Cytarabin, Dactinomycin, Daunorubicin,1 1. A pharmaceutical composition according to claim 10, wherein the further pharmacologically active substance is selected from the group consisting of: "actinomycin D, aminoglutethimide, asparaginase, Avastin, azathioprine, BCNU (carmustine), bleomycin, busulfan, carboplatin, CCNU (lomustine), chlorambucil, Cisplatin, colaspase, cyclophosphamide, cytarabine, dactinomycin, daunorubicin,
Diethylstilbestrol, Doxorubicin (Adriamycin), DTIC (Dacarbacin), Epirubicin, Erbitux, Erythrohydroxynonyladenin, Ethinylestradiol, Etoposide, Fludarabin Phosphate, Fluoxymesteron, Flutamid, Gemcitabin, Gleevec/Glivec, Herceptin, Hexamethylme- lamin, Hydroxharnstoff, Hydroxyprogesteron Caproat, Idarubicin, Ifosfamid, Interfe- ron, Iressa, Irinotecan, L-Asparaginase, Leucovorin, Mechlorethamin, Medroxypro- gesteron Acetat, Megestrol Acetat, Melphalan, Mesna, Methotrexat, Mitomycin C, Mitotan, Mitoxantrone, N-Phosphonoacetyl-L-aspartat (PALA), Oxaliplatin, Pen- tostatin, Plicamycin, Prednisolon, Prednison, Procarbazin, Raloxifen, Rapamycin, Semustin, Sorafenib, Streptozocin, Tamoxifen, Tarceva, Taxotere, Teniposide, Testosteron Propionat, Thioguanin, Thiotepa, Topotecan, Trimethylmelamin, Uridi- ne, Vinblastin, Vincristin, Vindesin, Vinorelbin, 2', 2'-Difluorodeoxycytidin, 5- Fluo- rodeoxyuridin Monophosphat, 5-Azacytidin Cladribin, 5-Fluorodeoxyuridin, 5- Fluorouarcil (5-FU), 6-Mercaptopurin".Diethylstilbestrol, doxorubicin (adriamycin), DTIC (dacarbacin), epirubicin, Erbitux, erythrohydroxynonyladenine, ethinylestradiol, etoposide, fludarabine phosphates, fluoxymesterone, flutamide, gemcitabine, Gleevec / Glivec, Herceptin, hexamethylmelamine, hydroxurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, Interferon, Iressa, irinotecan, L-asparaginase, leucovorin, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, N-phosphonoacetyl-L-aspartate (PALA), oxaliplatin, Pentostatin, plicamycin, prednisolone, prednisone, procarbazine, raloxifene, rapamycin, Semustin, sorafenib, streptozocin, tamoxifen, tarceva, taxotere, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, trimethylmelamine, uridines, vinblastine, vincristine, vindesine, vinorelbine, 2 ', 2'-difluorodeoxycytidine, 5-fluorodeoxyuridine Monophosphate, 5-azacytidine cladribine, 5-fluorodeoxyuridine, 5-fluorouracil (5-FU), 6-mercaptopurine ".
12. Verwendung eines Anthracen- Derivats gemäß der allgemeinen Formel (II)12. Use of an Anthracene Derivative According to the General Formula (II)
Figure imgf000093_0001
Figure imgf000093_0001
(H)(H)
worin:wherein:
Substituent V unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NR28, N-OR29, geminal geknüpfter Wasserstoff und Hydroxy;Substituent V is independently selected from the group consisting of: "O, S, NR28, N-OR29, geminally linked hydrogen and hydroxy;
Substituent Z unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S, NR30, N-OR31 ";Substituent Z is independently selected from the group consisting of: "O, S, NR30, N-OR31";
Substituenten R18, R19, R20, R21 , R22, R23, R24, R25 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsub- stituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substitu- iertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl, Amino, Mono-Alkylamino, Di-Alkylamino, Halogen, -F, -Cl, -Br, - I, mit ein oder mehreren Fluoratomen substituiertes Alkyl, Trifluormethyl, Cyano, geradkettiges oder verzweigtes Cyano-alkyl, Carbonyl, Carboxyl, -COOH, Alkoxy- carbonyl, Carboxy-alkyl, Alkoxycarbonyl-alkyl, Hydroxy, Alkoxy, Aryl-alkoxy, Benzy- loxy, Heteroaryl-alkoxy, Alkoxycarbonylamino, Alkoxycarbonylamino-alkyl";Substituents R18, R19, R20, R21, R22, R23, R24, R25 independently of one another are selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl-alkyl, amino, mono-alkylamino, di-alkylamino, halogen, F, -Cl, -Br, - I, alkyl substituted with one or more fluorine atoms, trifluoromethyl, cyano, straight-chain or branched cyanoalkyl, carbonyl, carboxyl, -COOH, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxy , Alkoxy, arylalkoxy, benzyl loxy, heteroaryl-alkoxy, alkoxycarbonylamino, alkoxycarbonylamino-alkyl ";
Substituent R26 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „un- substituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloal- kyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder sub- stituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl- alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl, -OR32, -NR33R34";Substituent R26 is independently selected from the group consisting of: "unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted Aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, -OR32, -NR33R34 ";
Substituent R27 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „Was- serstoff, unsubstituiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl";Substituent R27 is independently selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl";
Substituenten R28, R29, R30, R31 , R32, R33, R34 unabhängig voneinander unabhängig ausgewählt sind aus der Gruppe bestehend aus: „Wasserstoff, unsubsti- tuiertes oder substituiertes Alkyl, unsubstituiertes oder substituiertes Cycloalkyl, unsubstituiertes oder substituiertes Cycloalkyl-alkyl, unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Heterocyclyl-alkyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Aryl-alkyl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Heteroaryl-alkyl"; zur Herstellung eines Arzneimittels.Substituents R28, R29, R30, R31, R32, R33, R34 independently of one another are selected from the group consisting of: "hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl-alkyl, unsubstituted or substituted Heterocyclyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl; for the manufacture of a medicament.
13. Verwendung eines Anthracen- Derivats gemäß der allgemeinen Formel (II) gemäß Anspruch 12, worin: Substituent V unabhängig ausgewählt ist aus der Gruppe bestehend aus: „O, S,13. Use of an anthracene derivative according to the general formula (II) according to claim 12, wherein: substituent V is independently selected from the group consisting of: 'O, S,
NH, geminal geknüpfter Wasserstoff und Hydroxy";NH, geminally linked hydrogen and hydroxy ";
Substituent Z unabhängig „O oder S" ist;Substituent Z is independently "O or S";
Substituenten R18, R19, R20, R21 , R22, R23, R24, R25 unabhängig „Wasserstoff, Fluor, Chlor, Brom, lod, Hydroxy, Amino, Nitro, Cyano, Methyl, Trifluormethyl" sind; Substituent R26 unabhängig ausgewählt ist aus der Gruppe bestehend aus:Substituents R18, R19, R20, R21, R22, R23, R24, R25 are independently "hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, trifluoromethyl"; substituent R26 is independently selected from the group consisting of:
„unsubstituiertes oder substituiertes Heterocyclyl, unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Heteroaryl, -OR32, - NR33R34";Unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, -OR32, NR33R34 ";
Substituent R27 unabhängig „Wasserstoff, Alkyl" ist; zur Herstellung eines Arzneimittels.Substituent R27 is independently "hydrogen, alkyl" for the manufacture of a medicament.
14. Verwendung eines Anthracen- Derivats gemäß der allgemeinen Formel (II) gemäß einem der Ansprüche 12 bis 13, worin:14. Use of an anthracene derivative according to the general formula (II) according to one of claims 12 to 13, wherein:
Substituent R27 unabhängig ausgewählt ist aus der Gruppe bestehend aus: „3,4- Dimethoxy-phenyl; 3,4-Dihydroxy-phenyl; 4-Methoxy-thiophen-2-yl, Thiomorpholin- 4-yl; 4-Methoxy-phenyl; 4-(4-Methoxy-phenyl)-piperazin-1 -yl, 2-Hydroxy-3,4- dimethoxy-phenyl; 4-Methylphenyl; 4-Hydroxyphenyl; Thiophen-2-yl; 3-Substituent R27 is independently selected from the group consisting of: "3,4-dimethoxy-phenyl; 3,4-dihydroxy-phenyl; 4-methoxy-thiophen-2-yl, thiomorpholine-4-yl; 4-methoxy-phenyl; 4- (4-methoxy-phenyl) -piperazine-1-yl, 2-hydroxy-3,4-dimethoxyphenyl; 4-methylphenyl; 4-hydroxyphenyl; Thiophen-2-yl; 3
Hydroxyphenyl; 3-Methoxy-phenyl; 2,6-Dimethoxy-phenyl; 3,4,5-Trimethoxy- phenyl; Hydroxy; Methoxy; Phenyl; 4-Chlorphenyl; 4-Bromphenyl; 4-Fluorphenyl; 3- Chlorphenyl; 3-Bromphenyl; 3-Fluorphenyl; 4-Fluor;3-hydroxy-phenyl"; zur Herstellung eines Arzneimittels.hydroxyphenyl; 3-methoxy-phenyl; 2,6-dimethoxy-phenyl; 3,4,5-trimethoxyphenyl; hydroxy; methoxy; phenyl; 4-chlorophenyl; 4-bromophenyl; 4-fluorophenyl; 3-chlorophenyl; 3-bromophenyl; 3-fluorophenyl; 4-fluoro; 3-hydroxy-phenyl "for the manufacture of a medicament.
15. Verwendung eines Anthracen- Derivats gemäß Anspruch 4 zur Herstellung eines Arzneimittels.15. Use of an anthracene derivative according to claim 4 for the preparation of a medicament.
16. Arzneimittel umfassend mindestens ein Anthracen-Derivat gemäß einem der An- Sprüche 4, 12 bis 14.16. A pharmaceutical composition comprising at least one anthracene derivative according to any one of the- claims 4, 12 to 14.
17. Verwendung einer Verbindung gemäß einem der Ansprüche 4, 12 bis 14 zur Herstellung eines Arzneimittels zur Behandlung oder Prophylaxe von durch die Inhibition der Tubulin-Polymerisation und/oder von durch die Inhibition Microtubuli- basierten Motorproteinen behandelbaren physiologischen und/oder pathophysiolo- gischen Zuständen.17. Use of a compound according to any one of claims 4, 12 to 14 for the manufacture of a medicament for the treatment or prophylaxis of physiological and / or pathophysiological conditions treatable by the inhibition of tubulin polymerization and / or by the inhibition of microtubule-based motor proteins ,
18. Verwendung gemäß Anspruch 17, wobei die Microtubuli-basierten Motorproteine ausgewählt sind aus der Gruppe bestehend aus: „Kinesine, Dyneine, Kinesin- Superfamilie (KIF) Protein, N- 1 Kinesine, KIF5A, KIF5B, KIF5C, N-2 Kinesine, Eg518. Use according to claim 17, wherein the microtubule-based motor proteins are selected from the group consisting of: "kinesins, dyneins, kinesin superfamily (KIF) protein, N-1 kinesins, KIF5A, KIF5B, KIF5C, N-2 kinesins, Eg5
(KIF1 1 , KSP), BimC (KIF8), N-3 Kinesine, KIF1A, KIF1 B, KIF1 C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 Kinesine, KIF3A, KIF3B, KIF3C, KIF17, N-5 Kinesine, KIF4, KIF4A, KIF4B, KIF21A, KIF21 B, N-6 Kinesine, KIF23 (MKLP1 , CH01 ), KIF20A (Rab6-KIF), KIF20B (KIpMPPI ), MKLP2, N-7 Kinesine, KIF10 (CENP-E), N-8 Kinesine, KIF18A, KIF18B, KIF22 (Kid), KIF19A, KIF19B, N-9 Kinesine, KIF12, N-10 Kinesine, KIF15 (Hklp2), N-1 1 Kinesine, KIF24, KIF25 (KNSL3), KIF26A,(KIF1 1, KSP), BimC (KIF8), N-3 kinesins, KIF1A, KIF1B, KIF1C, KIF13A, KIF13B, KIF14, KIF16A, KIF16B, N-4 kinesins, KIF3A, KIF3B, KIF3C, KIF17, N-5 kinesins, KIF4, KIF4A, KIF4B, KIF21A, KIF21B, N-6 kinesins, KIF23 (MKLP1, CH01), KIF20A (Rab6 -KIF), KIF20B (KIpMPPI), MKLP2, N-7 kinesins, KIF10 (CENP-E), N-8 kinesins, KIF18A, KIF18B, KIF22 (Kid), KIF19A, KIF19B, N-9 kinesins, KIF12, N- 10 kinesins, KIF15 (Hklp2), N-1 1 kinesins, KIF24, KIF25 (KNSL3), KIF26A,
KIF26B, M-Kinesine, KIF2A (KIF2), KIF2B, KIF2C (MCAK), C- 1 Kinesine, KIFC1 , C-2 Kinesine, KIFC2, KIFC3, KIF6, KIF7, KIF9" und bevorzugt ausgewählt aus der Gruppe bestehend aus: „Eg5 (KIF1 1 , KSP), KIF4, KIF4A, KIF4B, KIF10 (CENP-E), KIF23 (MKLP1 , CHO1 )" sind.KIF26B, M-kinesins, KIF2A (KIF2), KIF2B, KIF2C (MCAK), C-1 kinesins, KIFC1, C-2 kinesins, KIFC2, KIFC3, KIF6, KIF7, KIF9 "and preferably selected from the group consisting of:" Eg5 (KIF1 1, KSP), KIF4, KIF4A, KIF4B, KIF10 (CENP-E), KIF23 (MKLP1, CHO1) ".
19. Verwendung gemäß einem der Ansprüche 12 bis 15 und 17 bis 18 zur Behandlung oder Prophylaxe von malignen Tumoren, benigne Tumoren, soliden/festen Tumoren, Sarkomen, Karzinomen, hyperproliferativen Erkrankungen, Carcinoiden, Ewing- Sarcomen, Kaposi-Sarkomen, Hirntumoren, Tumoren ausgehend vom Hirn und/oder Nervensystem und/oder Hirnhäuten, Gliomen, Neuroblastomen, Magenkrebs, Nierenkrebs, Nierenzellkarzinomen, Prostatakrebs, Prostatakarzinomen, Bindegewebstumoren, Weichteilsarkomen, Pankreastumoren, Lebertumoren, Kopftumoren, Halstumoren, Speiseröhrenkrebs, Schilddrüsenkrebs, Osteosarco- men, Retinoblastomen, Thymom, Hodenkrebs, Lungenkrebs, Bronchialkarzino- men, Brustkrebs, Mammakarzinomen, Darmkrebs, Kolorectaltumoren, Kolonkarzinomen, Rektumkarzinomen, gynokologische Tumoren, Ovartumo- ren/Ovarialtumoren, Gebärmutterkrebs, Gebärmutterhalskrebs, Zervixkarzinomen, Gebärmutterkörperkrebs, Korpuskarzinomen, Endometriumkarzinomen, Harnblasenkrebs, Blasenkrebs, Hautkrebs, Basaliomen, Spinaliomen, Melanomen, intrao- culären Melanomen, Leukämien, chronischen Leukämien, akuten Leukämien und/oder Lymphomen".19. Use according to any one of claims 12 to 15 and 17 to 18 for the treatment or prophylaxis of malignant tumors, benign tumors, solid / solid tumors, sarcomas, carcinomas, hyperproliferative diseases, carcinoids, Ewing sarcomas, Kaposi's sarcomas, brain tumors, tumors from the brain and / or nervous system and / or meninges, gliomas, neuroblastomas, stomach cancer, kidney cancer, renal cell carcinoma, prostate cancer, prostate cancer, connective tissue tumors, soft tissue sarcoma, pancreatic tumors, liver tumors, head tumors, cervical tumors, esophageal cancer, thyroid cancer, osteosarcomas, retinoblastomas, thymoma, Testicular cancer, lung cancer, bronchial carcinoma, breast cancer, breast cancer, colorectal cancer, colorectal cancer, colon carcinoma, rectal cancer, gyno-logical tumors, ovarian tumors / ovarian tumors, uterine cancer, cervix cancer, cervical carcinoma, uterine cancer, carcinoma of the body, endometrial carcinoma, bladder cancer, bladder cancer, skin cancer, Ba saliomas, spinaliomas, melanomas, intraocular melanomas, leukemias, chronic leukemias, acute leukemias and / or lymphomas ".
20. Verwendung gemäß einem der Ansprüche 12 bis 15 und 17 bis 19, wobei das Arzneimittel zusätzlich mindestens eine weitere pharmakologisch aktive Substanz enthält.20. Use according to any one of claims 12 to 15 and 17 to 19, wherein the medicament additionally contains at least one further pharmacologically active substance.
21. Verwendung gemäß einem der Ansprüche 12 bis 15 und 17 bis 20, wobei das Arzneimittel vor und/oder während und/oder nach der Behandlung mit mindestens ei- ner weiteren pharmakologisch aktiven Substanz verabreicht wird.21. Use according to any one of claims 12 to 15 and 17 to 20, wherein the medicament before and / or during and / or after the treatment with at least one ner further pharmacologically active substance is administered.
22. Verwendung gemäß einem der Ansprüche 20 bis 21 , wobei die weitere pharmakologisch aktive Substanz ausgewählt ist aus der Gruppe bestehend aus: „DNA To- poisomerase I und/oder Il Inhibitoren, DNA Interkalatoren, alkylierende Agentien,22. Use according to any one of claims 20 to 21, wherein the further pharmacologically active substance is selected from the group consisting of: "DNA to poisomerase I and / or II inhibitors, DNA intercalators, alkylating agents,
Microtubuli Destabilisatoren, Hormon- und/oder Wachstumsfaktor-Rezeptor- Agonisten und/oder -Antagonisten, Hemmstoffen der Signaltransduktion, Antikörper gegen Wachstumsfaktoren und deren Rezeptoren, Kinase Inhibitoren, Antime- tabolite".Microtubule destabilizers, hormone and / or growth factor receptor agonists and / or antagonists, signal transduction inhibitors, antibodies against growth factors and their receptors, kinase inhibitors, antimitolites. "
23. Verwendung gemäß Anspruch 22, wobei die weitere pharmakologisch aktive Substanz ausgewählt ist aus der Gruppe bestehend aus: "Actinomycin D, Aminoglu- tethimid, Asparaginase, Avastin, Azathioprin, BCNU (Carmustine), Bleomycin, Bu- sulfan, Carboplatin, CCNU (Lomustine), Chlorambucil, Cisplatin, Colaspase, Cyc- lophosphamid, Cytarabin, Dactinomycin, Daunorubicin, Diethylstilbestrol, Doxoru- bicin (Adriamycin), DTIC (Dacarbacin), Epirubicin, Erbitux, Erythrohydroxynonyla- denin, Ethinylestradiol, Etoposide, Fludarabin Phosphate, Fluoxymesteron, Fluta- mid, Gemcitabin, Gleevec/Glivec, Herceptin, Hexamethylmelamin, Hydrox- harnstoff, Hydroxyprogesteron Caproat, Idarubicin, Ifosfamid, Interferon, Iressa, I- rinotecan, L-Asparaginase, Leucovorin, Mechlorethamin, Medroxyprogesteron23. Use according to claim 22, wherein the further pharmacologically active substance is selected from the group consisting of: "actinomycin D, aminoglutethimide, asparaginase, avastin, azathioprine, BCNU (carmustine), bleomycin, bisulphane, carboplatin, CCNU ( Lomustine), chlorambucil, cisplatin, colaspase, cycophosphamide, cytarabine, dactinomycin, daunorubicin, diethylstilbestrol, doxorubicin (adriamycin), DTIC (dacarbacin), epirubicin, erbitux, erythrohydroxynonyladenine, ethinylestradiol, etoposide, fludarabine phosphates, fluoxymesterone, Flutamide, gemcitabine, Gleevec / Glivec, Herceptin, hexamethylmelamine, hydroxurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, interferon, Iressa, arginotecan, L-asparaginase, leucovorin, mechlorethamine, medroxyprogesterone
Acetat, Megestrol Acetat, Melphalan, Mesna, Methotrexat, Mitomycin C, Mitotan, Mitoxantrone, N-Phosphonoacetyl-L-aspartat (PALA), Oxaliplatin, Pentostatin, PIi- camycin, Prednisolon, Prednison, Procarbazin, Raloxifen, Rapamycin, Semustin, Sorafenib, Streptozocin, Tamoxifen, Tarceva, Taxotere, Teniposide, Testosteron Propionat, Thioguanin, Thiotepa, Topotecan, Trimethylmelamin, Uridine,Acetate, megestrol acetate, melphalan, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, N-phosphonoacetyl-L-aspartate (PALA), oxaliplatin, pentostatin, pi-camycin, prednisolone, prednisone, procarbazine, raloxifene, rapamycin, semustin, sorafenib , Streptozocin, tamoxifen, tarceva, taxotere, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, trimethylmelamine, uridine,
Vinblastin, Vincristin, Vindesin, Vinorelbin, 2', 2'-Difluorodeoxycytidin, 5- Fluorode- oxyuridin Monophosphat, 5-Azacytidin Cladribin, 5-Fluorodeoxyuridin, 5- Fluorouarcil (5-FU), 6-Mercaptopurin".Vinblastine, vincristine, vindesine, vinorelbine, 2 ', 2'-difluorodeoxycytidine, 5-fluorodeoxyuridine monophosphate, 5-azacytidine cladribine, 5-fluorodeoxyuridine, 5-fluorouarcil (5-FU), 6-mercaptopurine ".
24. Verwendung gemäß einem der Ansprüche 12 bis 15 und 17 bis 23, wobei das Arzneimittel vor und/oder während und/oder nach der Behandlung mit Strahlentherapie und/oder Chirurgie verabreicht wird. 24. Use according to any one of claims 12 to 15 and 17 to 23, wherein the medicament is administered before and / or during and / or after the treatment with radiotherapy and / or surgery.
25. Kit umfassend eine pharmakologisch aktive Menge mindestens einer Verbindung gemäß einem der Ansprüche 4, 12 bis 14 und eine pharmakologisch aktive Menge mindestens einer weiteren pharmakologisch aktiven Substanz gemäß einem der Ansprüche 9 bis 1 1. 25. Kit comprising a pharmacologically active amount of at least one compound according to any one of claims 4, 12 to 14 and a pharmacologically active amount of at least one further pharmacologically active substance according to any one of claims 9 to 1 1.
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