DE10015525A1 - Synthetic derivatives of lunular acid, medicaments containing this compound, process for the preparation of lunular acid derivatives and their use - Google Patents

Synthetic derivatives of lunular acid, medicaments containing this compound, process for the preparation of lunular acid derivatives and their use

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Publication number
DE10015525A1
DE10015525A1 DE10015525A DE10015525A DE10015525A1 DE 10015525 A1 DE10015525 A1 DE 10015525A1 DE 10015525 A DE10015525 A DE 10015525A DE 10015525 A DE10015525 A DE 10015525A DE 10015525 A1 DE10015525 A1 DE 10015525A1
Authority
DE
Germany
Prior art keywords
lunular
radical
carbon atoms
formula
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
DE10015525A
Other languages
German (de)
Inventor
Clarissa Gerhaeuser
Theophil Eicher
Rigobert Pick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Deutsches Krebsforschungszentrum DKFZ
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Deutsches Krebsforschungszentrum DKFZ filed Critical Deutsches Krebsforschungszentrum DKFZ
Priority to DE10015525A priority Critical patent/DE10015525A1/en
Priority to PCT/DE2001/001264 priority patent/WO2001074753A1/en
Priority to AU2001258200A priority patent/AU2001258200A1/en
Publication of DE10015525A1 publication Critical patent/DE10015525A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D333/28—Halogen atoms
    • 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
    • C07D333/34—Sulfur atoms

Abstract

The invention relates to lunularic acid derivatives which are suitable as chemopreventive agents.

Description

Die Erfindung betrifft synthetische Derivate von Lunularsäure, Arzneimittel enthaltend diese Verbindungen, Verfahren zur Herstellung der Lunularsäurederivate sowie deren Verwendung als chemopräventive Agentien gegen Krebserkrankungen.The invention relates to synthetic derivatives of lunular acid, Medicaments containing these compounds, processes for Production of the lunular acid derivatives and their use as chemopreventive agents against cancer.

Da Krebs eine Erkrankung ist, die heute aus verschiedensten Gründen (z. B. Älterwerden der Bevölkerung, negative Umwelteinflüsse usw.) schon ein Drittel der Bevölkerung von Industriestaaten betrifft und noch mit einer weiteren Zunahme der Erkrankungen zu rechnen ist, gibt es Bemühungen Stoffe herauszufinden, welche frühzeitig angewendet, einen Schutz vor dem Entstehen von Krebs geben (Krebsprophylaxe). Es gibt deshalb eine ausgedehnte Forschungsrichtung, die sich mit der Identifikation neuer chemopräventiver Agentien beschäftigt, um den dringenden Bedarf der Krebsverhütung zu decken.Because cancer is a disease that today comes from a wide variety Reasons (e.g. aging of the population, negative Environmental influences etc.) already a third of the population of Industrialized countries and with a further increase of illnesses, there are efforts to substance find out which applied early protection give before cancer develops (cancer prophylaxis). There are therefore an extensive research direction dealing with the Identifying new chemopreventive agents, to meet the urgent need for cancer prevention.

Die Aufgabe der vorliegenden Erfindung besteht in der Identifikation neuer chemopräventiver Agentien, die einfach und nebenwirkungsfrei anzuwenden sind.The object of the present invention is that Identification of new chemopreventive agents that are easy and are to be used without side effects.

Gelöst wird diese Aufgabe durch die Gegenstände der Patentansprüche.This task is solved by the objects of the Claims.

Von den Erfindern wurde bereits früher gefunden, daß Lunularsäure (2-Hydroxy-6-[2-(4-hydroxy­ phenyl)]ethylbenzoesäure) und Lunularin, die aus Leberblümchen, welche zur Kategorie der Moose gehören, isoliert werden können, eine chemopräventive Wirkung haben.The inventors have previously found that Lunular acid (2-hydroxy-6- [2- (4-hydroxy phenyl)] ethylbenzoic acid) and lunularin, which from Liverwort, which belongs to the moss category, can be isolated, have a chemopreventive effect.

Lunularsäure: R = COOH
Lunularin: R = HLunular acid: R = COOH
Lunularin: R = H

Jetzt wurde weiter herausgefunden, daß bestimmte Derivate der Lunularsäure eine noch weit über Lunularsäure und Lunularin hinausgehende positive Wirkung haben und selbst in geringen Dosen noch gegen Stoffwechselprozesse schützen, die für eine Krebsentstehung verantwortlich gemacht werden können. Gegenstand der Erfindung sind daher Verbindungen der allgemeinen Formel (I) oder (II)
Now it has also been found that certain derivatives of lunular acid have a positive effect which goes far beyond lunular acid and lunularin and even protect in small doses against metabolic processes which can be blamed for the development of cancer. The invention therefore relates to compounds of the general formula (I) or (II)

worin X ein beliebiger mono- oder polycyclischer (Hetero)Arylrest, der ggf. substituiert ist, ist. Beispiele hierfür sind ein carbocyclischer, monocyclischer Rest, beispielsweise die Phenylgruppe, ein heterocyclischer, monocyclischer Rest, beispielsweise die Gruppen Thienyl, Thiophenyl, Furyl, Furanyl, Pyranyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Pyridyl, Pyrazinyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, Thiazolyl, Oxazolyl, Indolyl, Furazannyl, Pyrrolinyl, Imidazolinyl, Pyrazolinyl, Thiazolinyl, Triazolyl, Tetrazolyl, sowie die Positionsisomeren des oder der Heteroatome, die diese Gruppen umfassen können, ein Rest bestehend aus carbocyclischen kondensierten Ringen, beispielsweise die Naphthylgruppe oder die Phe­ nanthrenylgruppe, ein Rest bestehend aus kondensierten heterocyclischen Ringen, beispielsweise Benzofuranyl, Benzothienyl, Benzimidazolyl, Benzothiazolyl, Naphtho[2,3- b]thienyl, Thianthrenyl, Isobenzofuranyl, Chromenyl, Xanthenyl, Phenoxathiinyl, Indolizinyl, Isoindolyl, 3H- Indolyl, Indolyl, Indazolyl, Purinyl, Chinolizinyl, Isochinolyl, Chinolyl, Phthalzinyl, Naphthyridinyl, Chinoxalinyl, Chinazolinyl, Chinolinyl, Pteridinyl, Carbazolyl, β-Carbolinyl, Cinnolinyl, Acridinyl, Phenazinyl, Phenothiazinyl, Phenoxazinyl, Indolinyl, Isoindolinyl, Imidazopyridyl, Imidazopyridmidinyl oder auch die kondensierten polycyclischen Systeme bestehend aus heterocyclischen Monozyklen, wie beispielsweise vorstehend definiert, wie beispielsweise Thionaphthenyl, Furo[2,3- b]pyrrol oder Thieno[2,3-b]furan, und insbesondere die Phenyl-, Furylgruppen, wie 2-Furyl, Imidazolyl, wie 2- Imidazolyl, Pyridyl, wie 2-Pyridyl, 3-Pyridyl, 4-Pyridyl, Pyrimidinyl, wie Pyridmid-2-yl, Thiazolyl, wie Thiazol-2-yl, Thiazolinyl, wie Thiazolin-2-yl, Triazolyl, wie Triazolyl-2- yl, Tetrazolyl, wie Tetrazol-2-yl, Benzimidazolyl, wie Benzimidazol-2-yl, Benzothiazolyl, Benzothiazol-2-yl, Purinyl, wie Purin-7-yl, oder Chinolyl, wie 4-Chinolyl.where X is any mono- or polycyclic (Hetero) aryl radical, which is optionally substituted. Examples this is a carbocyclic, monocyclic radical, for example the phenyl group, a heterocyclic group, monocyclic radical, for example the groups thienyl, Thiophenyl, furyl, furanyl, pyranyl, pyrrolyl, imidazolyl, Pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl, Pyridazinyl, thiazolyl, oxazolyl, indolyl, furazannyl, Pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, Triazolyl, tetrazolyl, and the positional isomers of or of the heteroatoms that these groups can include, a residue consisting of carbocyclic condensed rings, for example the naphthyl group or the Phe nanthrenyl group, a residue consisting of condensed heterocyclic rings, for example benzofuranyl, Benzothienyl, benzimidazolyl, benzothiazolyl, naphtho [2,3- b] thienyl, thianthrenyl, isobenzofuranyl, chromenyl, Xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H- Indolyl, indolyl, indazolyl, purinyl, quinolizinyl, Isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, Quinoxalinyl, quinazolinyl, quinolinyl, pteridinyl, Carbazolyl, β-carbolinyl, cinnolinyl, acridinyl, phenazinyl, Phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, Imidazopyridyl, Imidazopyridmidinyl or also the  condensed polycyclic systems consisting of heterocyclic monocycles, such as above defined, such as thionaphthenyl, furo [2,3- b] pyrrole or Thieno [2,3-b] furan, and especially those Phenyl, furyl groups, such as 2-furyl, imidazolyl, such as 2- Imidazolyl, pyridyl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, Pyrimidinyl, such as pyridmid-2-yl, thiazolyl, such as thiazol-2-yl, Thiazolinyl, such as thiazolin-2-yl, triazolyl, such as triazolyl-2- yl, tetrazolyl, such as tetrazol-2-yl, benzimidazolyl, such as Benzimidazol-2-yl, benzothiazolyl, benzothiazol-2-yl, Purinyl, such as Purin-7-yl, or quinolyl, such as 4-quinolyl.

In den obigen Formeln können R1 und R2 jeweils unabhängig voneinander Wasserstoff, einen geraden oder verzweigten Alkylrest mit 1 bis 30 Kohlenstoffatomen, einen geraden oder verzweigten Alkenylrest mit 2 bis 30 Kohlenstoffatomen, einen mono- oder polyzyklischen Alkylrest mit 3 bis 30 Kohlenstoff­ atomen, einen mono- oder polyzyklischen Alkenylrest mit 4 bis 30 Kohlenstoffatomen, oder einen mono- oder polyzyklischen aromatischen Rest bedeuten, wobei diese Reste gegebenenfalls durch einen oder mehrere Substituenten substituiert sein können. R1 und R2 können gleich oder verschieden sein.In the above formulas, R 1 and R 2 can each independently be hydrogen, a straight or branched alkyl radical having 1 to 30 carbon atoms, a straight or branched alkenyl radical having 2 to 30 carbon atoms, a mono- or polycyclic alkyl radical having 3 to 30 carbon atoms, is a mono- or polycyclic alkenyl radical having 4 to 30 carbon atoms, or a mono- or polycyclic aromatic radical, where these radicals can optionally be substituted by one or more substituents. R 1 and R 2 may be the same or different.

Es kann für R1 und/oder R2 jeder beliebige gerade oder verzweigte C1-30-Alkylrest verwendet werden. Beispiele hierfür sind Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, tert.-Butyl-, n-Butyl-, n-Hexyl-, 2-Methylpentyl-, 2,3- Dimethylbutyl-, n-Heptyl-, 2-Methylhexyl-, 2,2-Dimethylpentyl-, 3,3-Dimethylpentyl-, 3-Ethylpentyl-, n-Octyl-, 2,2- Dimethylhexyl-, 3,3-Dimethylhexyl-, 3-Methyl-3- ethylpentylgruppen. Bevorzugt sind wegen der besseren Löslichkeit kurze Alkylketten, wie Methyl-, Ethyl-, Propyl- und Isopropyl-. Bevorzugt sind R1 und R2 gerade C1-14-Alkylreste oder C3-14-Cycloalkylreste. Besonders bevorzugt stehen R1 und R2 für H, CH3 oder CH3CH2.Any straight or branched C 1-30 alkyl radical can be used for R 1 and / or R 2 . Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-butyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n -Heptyl-, 2-methylhexyl-, 2,2-dimethylpentyl-, 3,3-dimethylpentyl-, 3-ethylpentyl-, n-octyl-, 2,2-dimethylhexyl-, 3,3-dimethylhexyl-, 3-methyl -3-ethylpentyl groups. Short alkyl chains, such as methyl, ethyl, propyl and isopropyl, are preferred because of their better solubility. R 1 and R 2 are preferably straight C 1-14 alkyl radicals or C 3-14 cycloalkyl radicals. R 1 and R 2 are particularly preferably H, CH 3 or CH 3 CH 2 .

Es kann für R1 und/oder R2 jeder beliebige gerade oder verzweigte C2-30-Alkenylrest verwendet werden. Beispiele hierfür sind Vinyl-, Propenyl-, Isopropenyl-, Allyl-, 2-Methylallyl-, Butenyl- oder Isobutenyl-, Hexenyl- oder Isohexenyl-, heptenyl- oder Isoheptenyl-, Octenyl- oder Isooctenylgruppen. Bevorzugt sind Vinyl-, Propenyl- und Isopropenyl-.Any straight or branched C 2-30 alkenyl radical can be used for R 1 and / or R 2 . Examples of these are vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, hexenyl or isohexenyl, heptenyl or isoheptenyl, octenyl or isooctenyl groups. Vinyl, propenyl and isopropenyl are preferred.

So kann R1 und/oder R2 jeder beliebige Cycloalkylrest sein. Beispiele hierfür sind eine Cyclopropyl-, Cyclobutyl-, Cyclopentyl- oder Cyclohexyl-, Cycloheptyl-, Cxclooctyl-, Cyclononyl- oder Cyclodecylgruppen. Bevorzugt sind Cyclopropyl-, Cyclobutyl-, Cyclopentyl- und Cyclohexyl-.R 1 and / or R 2 can be any cycloalkyl radical. Examples include a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloheptyl, cycloctyl, cyclononyl or cyclodecyl group. Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferred.

Der für R1 und/oder R2 verwendbare Cycloalkenylrest mit 4 bis 30 Kohlenstoffatomen kann jeder beliebige Cycloalkenylrest sein. Beispiele hierfür sind eine Cyclobutenyl-, Cyclopentenyl- oder Cyclohexenyl-, Cycloheptenyl-, Cxclooctenyl-, Cyclononenyl- oder Cyclodecenylgruppen. Bevor­ zugt sind Cyclobutenyl-, Cyclopentenyl- oder Cyclohexenyl. Beispiele für polyzyklische Alkyl- bzw. Alkenylreste umfassen Norbornan, Adamantan oder Benzvalen.The cycloalkenyl radical having 4 to 30 carbon atoms which can be used for R 1 and / or R 2 can be any cycloalkenyl radical. Examples include a cyclobutenyl, cyclopentenyl or cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl groups. Before are given cyclobutenyl, cyclopentenyl or cyclohexenyl. Examples of polycyclic alkyl or alkenyl radicals include norbornane, adamantane or benzvalene.

Vorzugsweise vorhandene Substituenten der verschiedenen vorstehend angegebenen Reste X, R1 und/oder R2 sowie des Grundgerüsts als Substituent R3 können aus der folgenden Gruppe ausgewählt werden:
Preferred substituents of the various radicals X, R 1 and / or R 2 indicated above and of the basic structure as substituent R 3 can be selected from the following group:

  • - Halogen: Fluor, Chlor, Brom, Iod,- Halogen: fluorine, chlorine, bromine, iodine,
  • - Amino, Alkylamino, Dimethylamino oder Ethylamino, Dialkylamino, wie Dimethylamino, Diethylamino, Methylethylamino, wobei jeder dieser Dialkylaminoreste gegebenenfalls in Oxidform vorliegt,- amino, alkylamino, dimethylamino or ethylamino, Dialkylamino, such as dimethylamino, diethylamino, Methylethylamino, each of these dialkylamino residues optionally in oxide form,
  • - Aminoalkyl, wie Aminomethyl oder Aminoethyl,Aminoalkyl, such as aminomethyl or aminoethyl,
  • - Dialkylaminoalkyl, wie Dimethylaminomethyl oder - ethyl,Dialkylaminoalkyl, such as dimethylaminomethyl or ethyl,
  • - Dialkylaminoalkyloxy, wie Dimethylaminoethyloxy,Dialkylaminoalkyloxy, such as dimethylaminoethyloxy,
  • - Hydroxyl,- hydroxyl,
  • - freie, veresterte Carboxylgruppe, wie Alkoxycarbonyl, beispielsweise Methoxycarbonyl oder Ethoxycarbonyl, oder in ein Salz, beispielsweise durch ein Natrium- oder Kaliumatom überführt, Free, esterified carboxyl group, such as alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, or in a salt, for example with a sodium or transferred potassium atom,  
  • - Alkyl mit 1 bis 8 Kohlenstoffatomen, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.- Butyl, gegebenenfalls durch ein oder mehrere Halogen­ atom(e) substituiert, beispielsweise durch Fluor, wie Trifluormethyl,Alkyl having 1 to 8 carbon atoms, such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, tert.- Butyl, optionally by one or more halogen atom (s) substituted, for example by fluorine, such as Trifluoromethyl,
  • - Oxo, Cyano, Nitro, Formyl,- oxo, cyano, nitro, formyl,
  • - Acyl, wie Acetyl, Propionyl, Butyryl, Benzoyl,Acyl, such as acetyl, propionyl, butyryl, benzoyl,
  • - Acyloxy, wie Acetoxy oder ein Rest der Formel: -O-CO-(CH2)nCO2H, worin n = 1 bis 5,Acyloxy, such as acetoxy or a radical of the formula: -O-CO- (CH 2 ) n CO 2 H, where n = 1 to 5,
  • - Alkoxy, wie Methoxy, Ethoxy, Propyloxy, Isopropyloxy, Butyloxy,Alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, Butyloxy,
  • - Alkylthio, wie Methylthio, Ethylthio, Propylthio, Iso­ propylthio, Butylthio,Alkylthio, such as methylthio, ethylthio, propylthio, iso propylthio, butylthio,
  • - Carbamoyl,Carbamoyl,
  • - Alkenyl, wie Vinyl, Propenyl,Alkenyl, such as vinyl, propenyl,
  • - Alkinyl, wie Ethinyl, Propinyl und- alkynyl such as ethynyl, propynyl and
  • - Aryl, wie Phenyl, Furyl, Thienyl.Aryl, such as phenyl, furyl, thienyl.

Als Beispiele für derartige substituierte Reste können ein durch ein oder mehrere Halogenatom(e) substituierter Alkyl­ rest, wie die Trifluormethyl-, Trifluorbutyl-, Pentafluorpro­ pyl-, Pentafluorbutyl-, Pentafluorpentyl-, Heptafluorbutyl- oder Nonafluorbutylgruppe oder 2-Chlorethyl- genannt werden.Examples of such substituted radicals can be a alkyl substituted by one or more halogen atoms rest, such as the trifluoromethyl, trifluorobutyl, pentafluoroprop pyl, pentafluorobutyl, pentafluoropentyl, heptafluorobutyl or nonafluorobutyl group or 2-chloroethyl- may be mentioned.

Verbindungen der obigen Formeln (I) und (II) werden im weiteren mit dem Begriff "Lunularsäurederivate" beschrieben.Compounds of the formulas (I) and (II) above are described in further described with the term "lunular acid derivatives".

Bevorzugte Verbindungen sind:
Preferred connections are:

Erfindungsgemäß ganz bevorzugte Verbindungen sind:
Compounds which are very preferred according to the invention are:

Vorzugsweise werden die Verbindungen der obigen Formeln gemäß dem in Fig. 1 gezeigten Syntheseschema hergestellt.Preferably, the compounds of the above formulas are prepared according to the synthetic scheme shown in FIG. 1.

Die vorstehend genannten erfindungsgemäßen Verbindungen eignen sich zur Prävention von Krebserkrankungen aller Art, indem sie einerseits bestimmte Stoffwechselprozesse hemmen, bei denen Stoffe entstehen, die die Krebsentstehung fördern, und andererseits bestimmte Stoffwechselprozesse fördern, die beispielsweise karzinogene Substanzen abfangen. Die Modulation von Enzymen, die bei der metabolischen Aktivierung und Freisetzung von Carcinogenen beteiligt sind, ist einer der am besten untersuchten Mechanismen für chemoprotektive Agentien. Phase 1-Enzyme (Cytochrome P450) aktivieren Xenobiotika durch das Einfügen von funktionellen Gruppen, die diese Verbindungen besser wasserlöslich machen. Obwohl diese Funktionalisierung über Phase 1-Enzyme für die komplette Detoxifizierung von Substanzen notwendig ist, kann die Induktion von Phase 1- Enzymen das Risiko erhöhen, Carcinogene zu produzieren, die mit DNA reagieren können und Carcinogenese initiieren. Phase 2-Enzyme konjugieren die aktivierten Verbindungen an endogene Liganden, wie Glutathion oder Glucuron-, Essig- oder Schwefelsäure, wodurch die Freisetzung der Verbindungen in Form dieser Konjugate vermehrt wird. Allgemein stellt die Inhibierung von Phase 1-Enzymen gleichzeitig mit der Induktion von Phase 2 Enzymen eine logische Strategie bei der Chemoprävention dar, was besonders vorteilhaft in frühen Stadien der Carcinogenese ist. Um Modulatoren des Arzneimittel-Metabolismus zu identifizieren und damit eine Aussage über chemopräventive Agentien zu erhalten, werden beispielsweise die inhibitorischen Effekte auf die Phase 1 Cyp1A Aktivität und auf die Induktion der Phase 2 NAD(P)H:Chinonreduktase (QR) Aktivität bestimmt. Dazu werden beispielsweise β-Naphthoflavon-induzierte Rattenhepatomzellen als Quelle von Cyp1A verwendet. Die zeitabhängige Dealkylierung von 3-Cyano-7-ethoxycumarin (CEC) zu 3-Cyano-7- hydroxycumarin kann fluorometrisch in 96-Loch-Platten verfolgt werden (Crespi et al., Anal. Biochem. (1997), 248 (1): 188- 190). Die Induktion von QR-Aktivität als Modell-Phase 2-Enzym wird beispielsweise colorimetrisch in kultivierten Hepa 1c1c7- Zellen gemessen. Dazu wird die NADPH-abhängige Menadiol- vermittelte Reduktion von MTT (3-(4,5-dimethylthiazo-2-yl)- 2,5-diphenyltetrazoliumbromid) in blaues Formazan untersucht (Prochaska et al., Anal. Biochem. 1988, 169(2): 328-336).The above-mentioned compounds according to the invention are suitable to prevent cancer of all types by on the one hand inhibit certain metabolic processes in which Substances are created that promote the development of cancer, and on the other hand, promote certain metabolic processes that intercept carcinogenic substances, for example. The modulation of enzymes involved in metabolic activation and Carcinogens release is one of the most best studied mechanisms for chemoprotective agents. Phase 1 enzymes (cytochrome P450) activate xenobiotics the insertion of functional groups that link these  make it more water soluble. Although this functionalization about phase 1 enzymes for the complete detoxification of Substances is necessary, the induction of phase 1- Enzymes increase the risk of producing carcinogens can react with DNA and initiate carcinogenesis. phase 2-enzymes conjugate the activated compounds to endogenous Ligands such as glutathione or glucuron, vinegar or Sulfuric acid, causing the release of the compounds in Form of these conjugates is propagated. In general, the Inhibition of phase 1 enzymes simultaneously with induction of phase 2 enzymes a logical strategy in the Chemoprevention represents what is particularly beneficial in early Stages of carcinogenesis. To modulators of the Identify drug metabolism and therefore a To get information about chemopreventive agents for example the inhibitory effects on phase 1 Cyp1A activity and induction of phase 2 NAD (P) H: Quinone reductase (QR) activity determined. To do this for example, beta-naphthoflavone-induced rat hepatoma cells used as the source of Cyp1A. The time-dependent Dealkylation of 3-cyano-7-ethoxycoumarin (CEC) to 3-cyano-7- Hydroxycoumarin can be monitored fluorometrically in 96-hole plates (Crespi et al., Anal. Biochem. (1997), 248 (1): 188- 190). Induction of QR activity as a model phase 2 enzyme is used, for example, colorimetrically in cultivated Hepa 1c1c7 Cells measured. For this, the NADPH-dependent menadiol mediated reduction of MTT (3- (4,5-dimethylthiazo-2-yl) - 2,5-diphenyltetrazolium bromide) in blue formazan (Prochaska et al., Anal. Biochem. 1988, 169 (2): 328-336).

Die Verbindungen der obigen Formeln sind gut verträglich und können im Rahmen eines Arzneimittels zur Prävention von Krebserkrankungen verabreicht werden.The compounds of the above formulas are well tolerated and can be used as part of a drug for the prevention of Cancer can be administered.

Das erfindungsgemäße Arzneimittel kann auf verschiedenen Wegen verabreicht werden, z. B. oral, parenteral, kutan, subkutan, intravenös, intramuskulär oder rektal. Bevorzugt ist die nicht-invasive, d. h. orale, subkutane oder rektale, Verabreichung. Das Arzneimittel wird einem Patienten über einen vom Arzt zu bestimmenden Zeitraum oder wird stetig über lange Zeiträume verabreicht. Das Arzneimittel kann sowohl Menschen als auch Säugern verabreicht werden. Das Arzneimittel bietet sich auch an als Überstützungsmedikation vor, während oder nach einer Tumortherapie (Operation, Bestrahlung und/oder Chemotherapie) an.The medicament according to the invention can be used in various ways be administered, e.g. B. oral, parenteral, cutaneous, subcutaneous, intravenously, intramuscularly or rectally. The is preferred non-invasive, i.e. H. oral, subcutaneous or rectal,  Administration. The medicine is given to a patient a period to be determined by the doctor or is continuously over administered for long periods. The medicine can both Humans can be administered as well. The Medicine also offers itself as a support medication before, during or after tumor therapy (surgery, radiation and / or Chemotherapy).

Die Dosierung der erfindungsgemäßen Verbindung wird vom Arzt anhand der patientenspezifischen Parameter wie z. B. Alter, Gewicht, Geschlecht, Schwere der Erkrankung, etc. bestimmt.The dosage of the compound of the invention is the doctor based on the patient-specific parameters such. B. age, Weight, gender, severity of the disease, etc. determined.

Entsprechend der Art der Verabreichung wird das Arzneimittel in geeigneter Weise formuliert, z. B. in Form von einfachen oder dragierten Tabletten, Hart- oder Weichgelatinekapseln, Pulver zur Rekonstitution vor Gebrauch, Granulaten, Suppositorien, Ovula, Injektionspräparaten, Infusionslösungen, Pomaden, Cremes, Gels, Mikrosphären, Implantaten, die nach üblichen galenischen Verfahren hergestellt werden.According to the mode of administration, the drug formulated in a suitable manner, e.g. B. in the form of simple or coated tablets, hard or soft gelatin capsules, Powder for reconstitution before use, granules, Suppositories, ovula, injectables, infusion solutions, Pomades, creams, gels, microspheres, implants after usual galenical processes can be produced.

Die erfindungsgemäßen Verbindungen können gegebenenfalls zu­ sammen mit weiteren Wirkstoffen und mit in pharmazeutischen Zusammensetzungen üblichen Exzipientien formuliert werden, z. B. je nach herzustellendem Präparat Talk, Gummi arabicum, Lactose, Stärke, Magnesiumstearat, Kakaobutter, wäßrige und nichtwäßrige Träger, Fettkörper mit tierischem oder pflanzli­ chem Ursprung, Paraffinderivate, Glykole (insbesondere Polyethylenglykol), verschiedene Weichmacher, Dispergiermittel oder Emulgatoren, Konservierungsstoffe.The compounds of the invention can optionally be added together with other active ingredients and in pharmaceutical Compositions usual excipients are formulated e.g. B. Depending on the preparation to be made talc, gum arabic, Lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fat bodies with animal or vegetable chem origin, paraffin derivatives, glycols (especially Polyethylene glycol), various plasticizers, dispersants or emulsifiers, preservatives.

Zur Herstellung flüssiger Präparate können Additive wie Natri­ umchloridlösung, Ethanol, Sorbit, Glycerin, Olivenöl, Mande­ löl, Propylenglycol oder Ethylenglycol verwendet werden.Additives such as natri can be used to produce liquid preparations Chloride solution, ethanol, sorbitol, glycerin, olive oil, almond oil, propylene glycol or ethylene glycol can be used.

Es können auch Infusions- oder Injektionslösungen hergestellt werden. Diese sind bevorzugt wäßrige Lösungen oder Suspensio­ nen, wobei es möglich ist, diese vor Gebrauch herzustellen, beispielsweise aus lyophilisierten Präparaten, die den Wirkstoff alleine oder zusammen mit einem Träger, wie Mannit, Lactose, Glucose, Albumin und dergleichen, enthalten. Die gebrauchsfertigen Lösungen werden sterilisiert und gegebenen­ falls mit Hilfsmitteln vermischt, beispielsweise mit Konser­ vierungsstoffen, Stabilisatoren, Emulgatoren, Lösungsvermitt­ lern, Puffern und/oder Salzen zur Regulierung des osmotischen Drucks. Die Sterilisierung kann durch Sterilfiltration durch Filter mit einer kleinen Porengröße erzielt werden, wonach die Zusammensetzung gegebenenfalls lyophilisiert werden kann. Geringe Mengen an Antibiotika können auch zugesetzt werden, um die Beibehaltung der Sterilität zu unterstützen.Infusion or injection solutions can also be prepared become. These are preferably aqueous solutions or suspensions which it is possible to make before use, for example from lyophilized preparations containing the active ingredient  alone or with a carrier like mannitol, Lactose, glucose, albumin and the like. The Ready-to-use solutions are sterilized and given if mixed with aids, for example with canners crossing agents, stabilizers, emulsifiers, solubilizers Learn, buffer and / or salts to regulate the osmotic Pressure. Sterilization can be done by sterile filtration Filters with a small pore size can be obtained, after which the Composition can optionally be lyophilized. Small amounts of antibiotics can also be added to to support the maintenance of sterility.

Vorteilhaft ist die Bereitstellung des erfindungsgemäßen Arzneimittels in einer Dosis-Einheits-Form zur Verabreichung an einen Säuger.The provision of the invention is advantageous Medicament in a unit dose form for administration to a mammal.

Die Erfindung betrifft auch Arzneimittel bzw. pharmazeutische Zusammensetzungen, die eine therapeutisch wirksame Menge des aktiven Inhaltsstoffs (erfindungsgemäße Verbindung der obigen Formeln) zusammen mit organischen oder anorganischen inerten festen oder flüssigen pharmazeutisch verträglichen Trägern bzw. Verdünnungsmitteln, die für die beabsichtigte Verabreichung geeignet sind, und die mit den aktiven Inhaltsstoffen nicht nachteilig wechselwirken, enthalten.The invention also relates to pharmaceuticals or pharmaceuticals Compositions containing a therapeutically effective amount of the active ingredient (compound according to the invention of the above Formulas) together with organic or inorganic inert solid or liquid pharmaceutically acceptable carriers or diluents for the intended Administration are suitable, and those with the active Ingredients do not interact adversely.

Die Erfindung betrifft auch ein Verfahren zur Produktion einer pharmazeutischen Zusammensetzung, die dadurch gekennzeichnet ist, daß die erfindungsgemäße Verbindung mit einem pharmazeu­ tisch verträglichen Träger vermischt wird.The invention also relates to a method for producing a pharmaceutical composition characterized is that the compound of the invention with a pharmazeu table compatible carrier is mixed.

Unter den erfindungsgemäßen Medikamenten können insbesondere die im experimentellen Teil beschriebenen Verbindungen und ganz besonders die Verbindungen, bei denen in der obigen Formel (I) oder (II) R1 und/oder R2, die gleich oder verschieden sein können, eine Methyl-, Ethyl-, Propyl- oder Isoproylgruppe ist, genannt werden.In particular, among the medicaments according to the invention the compounds described in the experimental section and especially the connections in which in the above Formula (I) or (II) R1 and / or R2, the same as or can be different, a methyl, ethyl, propyl or Isoproylgruppe is called.

Die erfindungsgemäßen Arzneimittel bzw. pharmazeutischen Zusammensetzungen umfassen als Wirkstoff mindestens einen wie vorstehend definierten Wirkstoff. Gegebenenfalls können noch weitere pharmazeutische Wirkstoffe in die Zusammensetzung aufgenommen werden, wie z. B.The pharmaceuticals or pharmaceuticals according to the invention  Compositions comprise at least one as active ingredient Active ingredient defined above. If necessary, you can still other active pharmaceutical ingredients in the composition be included such. B.

  • - Antioxidantien [z. B. red. Gluthathion, N- Acetylcystein, natürliche Polyphenole wie Grüntee- (Epigallcate-chingallat und andere Catechine) oder Rotweinbestandteile (Resveratrol), Anthocyanidine, Flavonoide, Procyanidine],- Antioxidants [e.g. B. red. Gluthathione, N- Acetylcysteine, natural polyphenols such as green tea (Epigallcate-Chingallat and other catechins) or Red wine ingredients (resveratrol), anthocyanidins, Flavonoids, procyanidins],
  • - Vitamine [z. B. hochdosiertes Vitamin C, Vitamin E, Vitamin A, Vitamin D],- Vitamins [e.g. B. high-dose vitamin C, vitamin E, Vitamin A, vitamin D],
  • - Mineralstoffe [z. B. Magnesium, Zink, Calcium],- minerals [e.g. B. magnesium, zinc, calcium],
  • - Spurenelemente [z. B. Selen],- trace elements [e.g. B. Selenium],
  • - Entzündungshemmer [z. B. Cyclooxygenase 1 oder 2 Hemmer (Nichtsteroidale Entzündungshemmer NSAIDs, wie ASS etc.), Lipoxygenasehemmer oder Hemmstoffe der induzierbaren Stickstoffoxidsynthese],- anti-inflammatories [e.g. B. Cyclooxygenase 1 or 2 inhibitors (Nonsteroidal anti-inflammatory NSAIDs, such as ASA etc.), lipoxygenase inhibitors or inhibitors of inducible nitric oxide synthesis],
  • - Hormommodulatoren [z. B. Antiöstrogene (z. B. Tamoxifen, Genistein) oder Aromatasehemmer],- hormone modulators [e.g. B. anti-estrogens (e.g. tamoxifen, Genistein) or aromatase inhibitors],
  • - Angiogenesehemmer [z. B. Genistein],- angiogenesis inhibitors [e.g. B. Genistein],
  • - Modulatoren der Signalübertragung [z. B. Proteinkinase­ hemmer (z. B. Curcumin oder Ras-Farnesylierungshemmer, wie Perillylalkohol oder Limonen)],- Signal transmission modulators [e.g. B. Protein kinase inhibitors (e.g. curcumin or Ras farnesylation inhibitors, such as perillyl alcohol or limes)],
  • - Proliferationshemmer,- proliferation inhibitors,
  • - Ornithin-Decarboxylase-Hemmer [z. B. DFMO]- Ornithine decarboxylase inhibitors [e.g. B. DFMO]
  • - Apoptose-Induktoren- apoptosis inducers
  • - Ballaststoffe (auch als Vorstufen von kurzkettigen Fettsäuren)- Dietary fiber (also as precursors of short-chain Fatty acids)
  • - Induktoren von Zellproliferationsprozessen [z. B. Natriumbutyrat]- Inductors of cell proliferation processes [e.g. B. Sodium butyrate]

Die Erfindung wird weiter anhand der Figur erläutert:The invention is further illustrated by the figure:

Fig. 1: Syntheseschema Fig. 1: Synthesis scheme

Fig. 2: Dosis-abhängige Inhibierung der präneoplastischen Läsionsbildung in einem MMOC-Modell durch EC-252 Fig. 2: Dose-dependent inhibition of preneoplastic lesion formation in an MMOC model by EC-252

Die Erfindung wird anhand der nachstehenden Beispiele näher erläutert.The invention is illustrated by the examples below explained.

Beispiel 1example 1 Verfahren zur Herstellung von E-6-(ω- Styryl)salicylsäuremethylester (EC-9)Process for the production of E-6- (ω- Styryl) salicylic acid methyl ester (EC-9)

Zu einer Lösung von Natriummethanolat in Methanol (bereitet durch Auflösen von 9,20 g (400 mMol) Natrium in 300 ml wasserfreiem Methanol) gibt man 56,3 g (100 mMol) (3-Acetoxy- 2-methoxycarbonyl)benzyl-triphenyl-phosphoniumbromid (Eicher et al., Synthesis 1988, S. 525) und rührt 30 Min. bei +20°C. Danach fügt man 10,6 g (100 mMol) Benzaldehyd (käufliches Produkt frisch destilliert) zu und erhitzt das Reaktionsgemisch 4 Std. unter Rückfluß. Danach kühlt man auf Raumtemperatur ab, neutralsiert durch Zugabe von Eisessig und entfernt das Solvens im Vakuum. Man nimmt den Rückstand in 300 ml Chloroform auf, wäscht zweimal mit je 100 ml Wasser, trocknet die organische Phase über MgSO4, filtriert sie über 200 g Kieselgel (Nachelution mit wenig CHCl3) und entfernt das Solvens im Vakuum. Man erhält ein farbloses Öl, das in ca. 150 ml Petrolether (40-60°C) aufgenommen und bei -30°C (15 h) zur Kristallisation gebracht wird. Man erhält 23,6 g (93%) farblose Nadeln, E/Z-Gemisch, Smp. 51-52°C. Aus dem E/Z-Gemisch kann durch Erhitzen in Toluol (30 Std. unter Rückfluß) in Gegenwart von Iod (einige mg) das reine E-konfigurierte Produkt quantitativ erhalten werden (Smp.: 56-57°C).To a solution of sodium methoxide in methanol (prepared by dissolving 9.20 g (400 mmol) of sodium in 300 ml of anhydrous methanol) is added 56.3 g (100 mmol) of (3-acetoxy-2-methoxycarbonyl) benzyl triphenyl phosphonium bromide (Eicher et al., Synthesis 1988, p. 525) and stirred for 30 min at + 20 ° C. Then 10.6 g (100 mmol) of benzaldehyde (commercial product freshly distilled) are added and the reaction mixture is heated under reflux for 4 hours. The mixture is then cooled to room temperature, neutralized by adding glacial acetic acid and the solvent is removed in vacuo. The residue is taken up in 300 ml of chloroform, washed twice with 100 ml of water each time, the organic phase is dried over MgSO 4 , filtered through 200 g of silica gel (post-elution with a little CHCl 3 ) and the solvent is removed in vacuo. A colorless oil is obtained which is taken up in about 150 ml of petroleum ether (40-60 ° C.) and brought to crystallization at -30 ° C. (15 h). 23.6 g (93%) of colorless needles, E / Z mixture, mp. 51-52 ° C. The pure E-configured product can be obtained quantitatively from the E / Z mixture by heating in toluene (30 hours under reflux) in the presence of iodine (mp: 56-57 ° C.).

Beispiel 2Example 2 Verfahren zur Herstellung von 6-(2- Phenylethyl)salicylsäuremethylester (EC-1)Process for the preparation of 6- (2- Phenylethyl) salicylic acid methyl ester (EC-1)

22,0 g (86,3 mMol) des Produkts aus Beispiel 1 werden in 300 ml Essigester gelöst. Man fügt 2,0 g Palladium auf Aktivkohle (5%) als Katalysator zu und hydriert in einer konventionelle Hydrierapparatur (Fa. Parr) bei 5 bar Wasserstoff-Überdruck. Nach ca. 4 Std. ist die Wasserstoff-Aufnahme beendet. Man filtriert vom Katalysator ab, entfernt das Solvens im Vakuum, nimmt den Rückstand in Chloroform auf und filtriert die CHCl3 -Lösung über 300 g Kieselgel (Nachelution mit wenig CHCl3). Das Filtrat wird im Vakuum vom Solvens befreit und der Rückstand aus Petrolether (40-60°C) umkristallisiert. Man erhält 19,9 g (90%) des Produkts, farblose Prismen, Smp. 55-56°C.22.0 g (86.3 mmol) of the product from Example 1 are dissolved in 300 ml of ethyl acetate. 2.0 g of palladium on activated carbon (5%) are added as a catalyst and hydrogenation is carried out in a conventional hydrogenation apparatus (from Parr) at 5 bar hydrogen pressure. The hydrogen uptake ends after about 4 hours. The catalyst is filtered off, the solvent is removed in vacuo, the residue is taken up in chloroform and the CHCl 3 solution is filtered through 300 g of silica gel (post-elution with a little CHCl 3 ). The filtrate is freed from solvent in vacuo and the residue is recrystallized from petroleum ether (40-60 ° C). 19.9 g (90%) of the product, colorless prisms, mp. 55-56 ° C. are obtained.

Beispiel 3Example 3 Verfahren zur Herstellung von E-1-(5-Bromthienyl)-2-[(2- ethosycarbonyl-3-methoxy)phenyl]ethen (EC-252)Process for the preparation of E-1- (5-bromothienyl) -2 - [(2- ethosycarbonyl-3-methoxy) phenyl] ethene (EC-252)

Zu einer Lösung von Natriummethanolat in Methanol (bereitet durch Auflösen von 0,30 g (13,0 mMol) Natrium in 50 ml wasserfreiem Methanol) gibt man 5,63 g (10,0 mMol) (2- Ethoxycarbonyl-3-methoxy)benzyl-triphenyl-phosphoniumbromid (Eicher et al., Synthesis 1988, S. 525) und rührt 30 Min. bei +20°C. Danach fügt man 1,91 g (10,0 mMol) 5-Bromthiophen-2- carbaldehyd (Fa. Acros Organics, Geel, Belgien) zu und rührt das Reaktionsgemisch 24 Std. bei +20°C. Das auskristallisierte Produkt wird abgesaugt und in 50 ml Chloroform gelöst, Die Lösung wird über 50 g Kieselgel filtriert (Nachelution mit wenig CHCl3). Das Solvens wird im Vakuum abdestilliert und der Rückstand [2,90 g (79%) E/Z-Gemisch] zweimal aus Ethanol umkristallsiert. Man erhält 1,84 g (50%) des Produkts, gelbliche Nadeln, Smp. 93-94°C.To a solution of sodium methoxide in methanol (prepared by dissolving 0.30 g (13.0 mmol) of sodium in 50 ml of anhydrous methanol) is added 5.63 g (10.0 mmol) (2-ethoxycarbonyl-3-methoxy) benzyl-triphenyl-phosphonium bromide (Eicher et al., Synthesis 1988, p. 525) and stirred for 30 minutes at + 20 ° C. Then 1.91 g (10.0 mmol) of 5-bromothiophene-2-carbaldehyde (Acros Organics, Geel, Belgium) are added and the reaction mixture is stirred at + 20 ° C. for 24 hours. The product which has crystallized out is filtered off with suction and dissolved in 50 ml of chloroform. The solution is filtered through 50 g of silica gel (post-elution with a little CHCl 3 ). The solvent is distilled off in vacuo and the residue [2.90 g (79%) E / Z mixture] recrystallized twice from ethanol. 1.84 g (50%) of the product are obtained, yellowish needles, mp. 93-94 ° C.

Beispiel 4Example 4 Bestimmung der chemopräventiven Aktivität ausgewählter LunularsäurederivateDetermination of the chemopreventive activity of selected Lunular acid derivatives

Hepa1c1c7-Zellen (ATCC American Type Culture Collection, Rockville, Maryland, USA) sät man in einer 96-Lochplatte in einer Dichte von 2 × 104 Zellen/ml (200 µl pro Loch) in α-MEM enthaltend 100 Einheiten/ml Penicillin G-Na, 100 Einheiten/ml Streptomycinsulfat und 250 ng/ml Amphotericin B (Gibco BRL, Grand Island, NY) ergänzt mit 10% fötalem Rinderserum bei 37°C in einer 5%igen CO2-Atmosphäre aus. Nach einer Präinkubationszeit von 24 Stunden wurde das Medium erneuert, die Testverbindungen (Lunularin, Lunularsäure [beide Kontrolle], EC-1, EC-9 und EC-252) gelöst in 10% DMSO (10 µl, Endkonzentration 0,5%) zugegeben und die Platten für weitere 48 Stunden inkubiert. Die QR-Aktivität wurde durch Messen der NADPH-abhängigen Menadiol-vermittelten Reduktion von. MTT (3- (4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazoliumbromid) zu blauem Formazan gemessen (Prochaska et al., Anal. Biochem. 1988, 169(2): 328-336). Die Proteine wurden durch Kristallviolett-Färbung eines identischen Satzes von Platten bestimmt. Die Induktion der QR-Aktivität wurde aus dem Verhältnis der spezifischen Enzymaktiviäten der mit den Verbindungen behandelten Zellen zu einer Lösungsmittelkontrolle berechnet. Die CD-Werte (benötigte Konzentration in µM, um die spezifische Enzymaktivität zu verdoppeln) wurden erzeugt. Die CD-Werte wurden mit den IC50- Werten (halbmaximale inhibitorische Konzentration der Zell- Lebensfähigkeit in µM) ins Verhältnis gesetzt, um den chemopräventiven Index CI zu erhalten. Zusätzliche Tests wurden in einer von Hepa 1c1c7-Zellen abgeleiteten Mutanten- Zelllinie (BPrc1) unternommen, welche unfähig ist, den Ah Rezeptor-Ligandenkomplex in den Kern zu translocieren.Hepa1c1c7 cells (ATCC American Type Culture Collection, Rockville, Maryland, USA) are sown in a 96-well plate at a density of 2 × 10 4 cells / ml (200 μl per well) in α-MEM containing 100 units / ml penicillin G-Na, 100 units / ml streptomycin sulfate and 250 ng / ml amphotericin B (Gibco BRL, Grand Island, NY) supplemented with 10% fetal bovine serum at 37 ° C in a 5% CO 2 atmosphere. After a preincubation time of 24 hours, the medium was renewed and the test compounds (lunularin, lunular acid [both controls], EC-1, EC-9 and EC-252) dissolved in 10% DMSO (10 μl, final concentration 0.5%) were added and incubated the plates for an additional 48 hours. QR activity was determined by measuring the NADPH-dependent menadiol-mediated reduction in. MTT (3- (4,5-dimethylthiazo-2-yl) -2,5-diphenyltetrazolium bromide) measured to blue formazan (Prochaska et al., Anal. Biochem. 1988, 169 (2): 328-336). Proteins were determined by crystal violet staining on an identical set of plates. The induction of QR activity was calculated from the ratio of the specific enzyme activities of the cells treated with the compounds to a solvent control. The CD values (concentration in µM required to double the specific enzyme activity) were generated. The CD values were compared with the IC50 values (half-maximal inhibitory concentration of cell viability in µM) in order to obtain the chemopreventive index CI. Additional testing was done in a mutant cell line (BP r c1) derived from Hepa 1c1c7 cells, which is unable to translocate the Ah receptor-ligand complex into the nucleus.

Tabelle 1 Table 1

Induktion von NAD(P)H : Chinonoxidoreduktase (QR) durch ausgewählte Bibenzyle (alle Daten in µM) Induction of NAD (P) H: quinone oxidoreductase (QR) by selected bibenzyls (all data in µM)

Nachfolgend wurde die Dosis-abhängige Induktion von Cyp1A- Aktivität in kultivierten Hepa1c1c7 bestimmt. Die Heapa1c1c7- Zellen wurden analog wie oben beschrieben für 24 Stunden mit 0,5 µM β-Naphthoflavon, einem klassischen bifunktionellen Induktor von Arzneimittel-metabolisierenden Enzymen, behandelt. Zum Vergleich des induzierenden Potentials wurden die für die 10-fache Anhebung der Cyp1A-Aktivität erforderlichen Konzentrationen ermittelt. Da die Induktion von Cyp1A zu der Aktivierung von Procarcinogenen führen kann, wurde weiter das Potential, um Cyp1A-Aktivität zu inhibieren, getestet. Diese Untersuchungen wurden an Lysaten von β- Naphthoflavon-induzierten H4IIE Rattenhepatoma-Zellen und CEC als Substrat gemacht. H4IIE-Zellen (ATCC American Type Culture Collection, Rockville, Maryland, USA) werden dazu in 10 cm Zellkulturplatten mit einer Dichte von 1 × 106 Zellen in 10 ml MEME-Medium mit den gleichen Zusätzen, wie vorstehend für das α-MEM-Medium angegeben, ausgesät und für 24 Stunden bei 37°C, 5% CO2 Atmosphäre kultiviert. Danach wird das Medium erneuert und die Zellen für 38 Std. mit 10 µM β-Naphthoflavon zur Induktion von Cyp1A induziert. Anschließend werden die Zellen dreimal mit phosphatgepufferter Kochsalzlösung (PBS) gewaschen, durch Abschaben in 1 ml 200 mM Kaliumphosphatpuffer, pH 7,4 mit 10 mM MgCl2 (Puffer 1) geerntet und sofort in flüssigem Stickstoff eingefroren. Zur Aktivitätsbestimmung wird das Zellhomogenat bei Raumtemperatur aufgetaut, zur Lyse durch eine Kanüle Nr. 20 gedrückt und mit Puffer 1 auf 10 ml verdünnt. 90 µl dieser Lösung (ca. 5-25 µg Protein) werden in 96-Lochplatten zu einer Mischung aus 10 µl der Testsubstanz in DMSO und 100 µl Reaktionsgemisch (2-fach konzentriert) enthaltend 2,6 mM NADP, 6,6 mM Glucose-6- Phospaht, 10 µM 3-Cyano-7-Ethoxycumarin (CEC) und 0,5 Einheiten Glucose-6-phosphatdehydrogenase gegeben. Der Ansatz wird kurz gemischt. Die Kinetik der zeitabhängigen Dealkylierung von CEC wird 45 Min. lang bei 37°C im Mikrotiterplattenfluorimeter mit einer Anregungswellenlänge von 409 nm und einer Emissionswellenlänge von 460 nm aufgenommen (vgl. Crespi et al., Anal. Biochem. (1997), 248 (1), S. 188-190). The dose-dependent induction of Cyp1A activity in cultured Hepa1c1c7 was subsequently determined. The Heapa1c1c7 cells were treated analogously as described above for 24 hours with 0.5 μM β-naphthoflavone, a classic bifunctional inducer of drug-metabolizing enzymes. To compare the inducing potential, the concentrations required for the 10-fold increase in Cyp1A activity were determined. Since the induction of Cyp1A can lead to the activation of procarcinogens, the potential to inhibit Cyp1A activity was further tested. These studies were carried out on lysates of beta-naphthoflavone-induced H4IIE rat hepatoma cells and CEC as a substrate. H4IIE cells (ATCC American Type Culture Collection, Rockville, Maryland, USA) are in 10 cm cell culture plates with a density of 1 × 10 6 cells in 10 ml MEME medium with the same additives as for the α-MEM- Medium specified, sown and cultivated for 24 hours at 37 ° C, 5% CO 2 atmosphere. The medium is then renewed and the cells are induced for 38 hours with 10 μM β-naphthoflavone to induce Cyp1A. The cells are then washed three times with phosphate-buffered saline (PBS), harvested by scraping in 1 ml of 200 mM potassium phosphate buffer, pH 7.4 with 10 mM MgCl 2 (buffer 1) and immediately frozen in liquid nitrogen. To determine activity, the cell homogenate is thawed at room temperature, pressed through a No. 20 cannula for lysis and diluted to 10 ml with buffer 1. 90 µl of this solution (approx. 5-25 µg protein) are mixed in 96-well plates to a mixture of 10 µl of the test substance in DMSO and 100 µl reaction mixture (2-fold concentrated) containing 2.6 mM NADP, 6.6 mM glucose -6- Phosphaht, 10 uM 3-cyano-7-ethoxycoumarin (CEC) and 0.5 units of glucose-6-phosphate dehydrogenase. The approach is briefly mixed. The kinetics of the time-dependent dealkylation of CEC is recorded for 45 min at 37 ° C. in a microtiter plate fluorimeter with an excitation wavelength of 409 nm and an emission wavelength of 460 nm (cf. Crespi et al., Anal. Biochem. (1997), 248 (1 ), Pp. 188-190).

Tabelle 2 Table 2

Modulation von Cyp1A-Aktivität durch ausgewählte Bibenzyle (alle Daten in µM) Modulation of Cyp1A activity by selected bibenzyls (all data in µM)

Beispiel 5Example 5 Nachweis der chemopräventiven Aktivität erfindungsgemäßer Verbindungen im Maus-BrustdrüsenmodellDetection of the chemopreventive activity according to the invention Connections in the mouse mammary gland model

Ein Nachteil von in-vitro Untersuchungen ist, daß die glatte Übertragbarkeit auf die in-vivo Situation oft nicht gegeben ist. Es wurde jedoch jetzt ein Organkulturmodell entwickelt, das als Klammer zwischen Kurzzeit-in vitro-Versuchen und Langzeit-in vivo-Carcinogenesemodellen dienen kann. Dies ist das Maus-Brustdrüsenmodell (mouse mammary glands, MMOC; Mehta et al., Carcinogenesis 1995, 16(2), S. 399-404). Dieses System kombiniert die Vorteile eines in-vitro-Modells (Einfachheit, Handhabbarkeit, Dauer) mit den komplexen zellulären, metabolischen und Entwicklungsbedingungen in einem Organismus.A disadvantage of in vitro investigations is that the smooth Transferability to the in vivo situation is often not possible is. However, an organ culture model has now been developed that as a bracket between short-term in vitro experiments and Long-term in vivo carcinogenesis models can serve. This is the mouse mammary glands (MMOC; Mehta et al., Carcinogenesis 1995, 16 (2), pp. 399-404). This system combines the advantages of an in vitro model (simplicity, Manageability, duration) with the complex cellular, metabolic and developmental conditions in an organism.

3 bis 4 Wochen alte jungfräuliche weibliche BALB/c Mäuse wurden durch tägliche subkutane Injektionen mit 1 µg Östradiol 17ß und 1 mg Progesteron für 9 Tage vorbereitet. Am Tag 10 werden die Tiere durch zervikale Dislokation getötet und das thorikale Brustdrüsenpaar entnommen, das auf ein Seidengewebe gelegt wird. Diese Gewebepräparationen wurden 10 Tage in serumfreiem Waymouth MB752/I-Medium (5 Drüsen/5 ml Medium/Platte) inkubiert. Das Medium ist ergänzt mit 2 mM Glutamin, Antibiotika (Penicillin und Streptomycin, jeweils 100 Einheiten/ml Lösung) und wachstumsfördernden Hormonen, 5 µg Insulin, 5 µg Prolaktin, 1 µg Aldosteron und 1 µg Hydrocortison pro ml Medium. Das Carcinogen DMBA (2 µg/ml) wird dem Medium für 24 Stunden zwischen den Tagen 3 und 4 zugesetzt. Dieses Zeitinterval stellt den Zeitraum der DNA- Synthese dar. Kontrollplatten wurden mit DMSO (DMBA- Lösungsmittel) behandelt. Nach 10 Tagen Inkubation wurden die Drüsen für weitere 14 in einem Medium gehalten, das nur Insulin (5 µg/ml) enthielt. Während der gesamten Kulturdauer wurden die Drüsen bei 37°C in einer 5% CO2 Atmosphäre gehalten.3 to 4 week old virgin female BALB / c mice were prepared by daily subcutaneous injections with 1 µg estradiol 17ß and 1 mg progesterone for 9 days. On day 10, the animals are sacrificed by cervical dislocation and the thoracic pair of mammary glands is removed, which is placed on a silk tissue. These tissue preparations were incubated in serum-free Waymouth MB752 / I medium (5 glands / 5 ml medium / plate) for 10 days. The medium is supplemented with 2 mM glutamine, antibiotics (penicillin and streptomycin, each 100 units / ml solution) and growth-promoting hormones, 5 µg insulin, 5 µg prolactin, 1 µg aldosterone and 1 µg hydrocortisone per ml medium. The carcinogen DMBA (2 µg / ml) is added to the medium for 24 hours between days 3 and 4. This time interval represents the period of DNA synthesis. Control plates were treated with DMSO (DMBA solvent). After 10 days of incubation, the glands were kept in medium containing only insulin (5 µg / ml) for another 14. Throughout the culture period, the glands were kept at 37 ° C in a 5% CO 2 atmosphere.

Die erfindungsgemäße Verbindung EC-252 (Testagenz) wurde in verschiedenen Konzentration zu dem Medium für die Tage 0-10 gegeben (10-15 Drüsen pro Konzentration). Carcinogen­ behandelte Drüsen ohne Testagenz dienten als Positivkontrolle. Am Ende des Experiments nach 24 Tagen wurden die Drüsen in 10% Formalin fixiert, mit Alauncarmin gefärbt und morphokologisch das Vorhandensein von Drüsenläsionen untersucht. Das Auftreten (Inzidenz) von gebildeten Läsionen (Prozentsatz der Drüsen mit Läsionen bezüglich der Gesamtanzahl der Drüsen pro Gruppe) in der mit EC-252 behandelten Gruppe wird mit den Läsionen in der nur mit DMBA-behandelten Gruppe (unbehandelte Gruppe = DMBA- Kontrolle) verglichen und daraus der Prozentsatz der Inhibierung berechnet. Das Ergebnis ist in Fig. 2 gezeigt.The compound EC-252 (test agent) according to the invention was added in various concentrations to the medium for days 0-10 (10-15 glands per concentration). Carcinogen-treated glands without test agents served as a positive control. At the end of the experiment after 24 days, the glands were fixed in 10% formalin, stained with alauncarmine and the presence of gland lesions was examined morphocologically. The occurrence (incidence) of lesions formed (percentage of glands with lesions in relation to the total number of glands per group) in the group treated with EC-252 is compared with the lesions in the group treated only with DMBA (untreated group = DMBA control) compared and calculated the percentage of inhibition. The result is shown in Fig. 2.

Claims (9)

1. Lunularsäurederivat gekennzeichnet durch Formel (I) oder (II):
worin X einen mono- oder polycyclischen (Hetero)Arylrest bedeutet,
R1 und/oder R2 jeweils unabhängig voneinander einen geraden oder verzweigten Alkylrest mit 1 bis 30 Koh­ lenstoffatomen, einen geraden oder verzweigten Alkenylrest mit 2 bis 30 Kohlenstoffatomen, einen mono- oder polyzyklischen Alkylrest mit 3 bis 30 Koh­ lenstoffatomen, einen mono- oder polyzyklischen Alkenylrest mit 4 bis 30 Kohlenstoffatomen, oder einen mono- oder polyzyklischen aromatischen Rest mit 6 bis 30 Kohlenstoffatomen bedeuten,
wobei die Reste X, R1, R2 gegebenenfalls durch einen oder mehrere Substituenten substituiert sein können, wobei diese Substituenten und/oder R3 ausgewählt sind
aus:
  • - Halogen: Fluor, Chlor, Brom, Iod.
  • - Amino, Alkylamino, Dimethylamino oder Ethylamino, Dialkylamino, wie Dimethylamino, Diethylamino, Methylethylamino, wobei jeder dieser Dialkylaminoreste gegebenenfalls in Oxidform vorliegt,
  • - Aminoalkyl, wie Aminomethyl oder Aminoethyl,
  • - Dialkylaminoalkyl, wie Dimethylaminomethyl oder - ethyl,
  • - Dialkylaminoalkyloxy, wie Dimethylaminoethyloxy,
  • - Hydroxyl,
  • - freie, veresterte Carboxylgruppe, wie Alkoxycarbonyl, beispielsweise Methoxycarbonyl oder Ethoxycarbonyl, oder in ein Salz, beispielsweise durch ein Natrium- oder Kaliumatom überführt,
  • - Alkyl mit 1 bis 8 Kohlenstoffatomen, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.- Butyl, gegebenenfalls durch ein oder mehrere Halogenatom(e) substituiert, beispielsweise durch Fluor, wie Trifluormethyl,
  • - Oxo, Cyano, Nitro, Formyl,
  • - Acyl, wie Acetyl, Propionyl, Butyryl, Benzoyl,
  • - Acyloxy, wie Acetoxy oder ein Rest der Formel:
    O-CO-(CH2)nCO2H, worin n = 1 bis 5,
  • - Alkoxy, wie Methoxy, Ethoxy, Propyloxy, Isopropyloxy, Butyloxy,
  • - Alkylthio, wie Methylthio, Ethylthio, Propylthio, Isopropylthio, Butylthio,
  • - Carbamoyl,
  • - Alkenyl, wie Vinyl, Propenyl,
  • - Alkinyl, wie Ethinyl, Propinyl und
  • - Aryl, wie Phenyl, Furyl, Thienyl.
1. Lunular acid derivative characterized by formula (I) or (II):
in which X denotes a mono- or polycyclic (hetero) aryl radical,
R1 and / or R2 each independently of one another is a straight or branched alkyl radical having 1 to 30 carbon atoms, a straight or branched alkenyl radical having 2 to 30 carbon atoms, a mono- or polycyclic alkyl radical having 3 to 30 carbon atoms, a mono- or polycyclic alkenyl radical with 4 to 30 carbon atoms, or a mono- or polycyclic aromatic radical with 6 to 30 carbon atoms,
where the radicals X, R1, R2 can optionally be substituted by one or more substituents, these substituents and / or R 3 being selected
out:
  • - Halogen: fluorine, chlorine, bromine, iodine.
  • Amino, alkylamino, dimethylamino or ethylamino, dialkylamino, such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino residues optionally being in oxide form,
  • Aminoalkyl, such as aminomethyl or aminoethyl,
  • Dialkylaminoalkyl, such as dimethylaminomethyl or ethyl,
  • Dialkylaminoalkyloxy, such as dimethylaminoethyloxy,
  • - hydroxyl,
  • free, esterified carboxyl group, such as alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, or converted into a salt, for example by a sodium or potassium atom,
  • Alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, optionally substituted by one or more halogen atoms, for example by fluorine, such as trifluoromethyl,
  • - oxo, cyano, nitro, formyl,
  • Acyl, such as acetyl, propionyl, butyryl, benzoyl,
  • Acyloxy, such as acetoxy or a radical of the formula:
    O-CO- (CH 2 ) n CO 2 H, where n = 1 to 5,
  • Alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,
  • Alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,
  • Carbamoyl,
  • Alkenyl, such as vinyl, propenyl,
  • - alkynyl such as ethynyl, propynyl and
  • Aryl, such as phenyl, furyl, thienyl.
2. Lunularsäurederivat nach Anspruch 1 gekennzeichnet durch Formel (III) oder (IV):
2. Lunular acid derivative according to claim 1, characterized by formula (III) or (IV):
3. Lunularsäurederivat nach Anspruch 1 oder 2 mit der Formel (V), (VI) oder (VII):
3. Lunular acid derivative according to claim 1 or 2 with the formula (V), (VI) or (VII):
4. Arzneimittel gekennzeichnet durch einen Gehalt an - mindestens einer Verbindung der allgemeinen Formel (I), (II), (III), (IV), (V), (VI) oder (VII).4. Medicinal products characterized by - at least one compound of the general formula (I), (II), (III), (IV), (V), (VI) or (VII). 5. Arzneimittel nach einem der Ansprüche 1-4, umfassend zusätzlich Vitamine, Mineralstoffe, Antioxidantien, Spurenelemente, Entzündungshemmer, Hormonmodulatoren, Angiogenesehemmer, Modulatoren der Signalübertragung, Proliferationshemmer, Ornithindecarboxylasehemmer, Apoptose-Induktoren, Ballaststoffe und/oder Induktoren von Zellproliferationsprozessen.5. Medicament according to one of claims 1-4, comprising additionally vitamins, minerals, antioxidants, Trace elements, anti-inflammatories, hormone modulators, Angiogenesis inhibitors, modulators of signal transmission, Proliferation inhibitors, ornithine decarboxylase inhibitors, Apoptosis inducers, fiber and / or Inducers of cell proliferation processes. 6. Arzneimittel nach einem der Ansprüche 1-5 bereitgestellt in einer Dosis-Einheits-Form zur Verabreichung an einen Säuger.6. Medicament according to one of claims 1-5  provided in a unit dose form for Administration to a mammal. 7. Arzneimittel nach einem der Ansprüche 1-6 umfassend weiter einen pharmazeutisch verträglichen inerten Träger oder ein Verdünnungsmittel.7. Medicament according to one of claims 1-6 comprising a pharmaceutically acceptable inert Carrier or a diluent. 8. Verwendung eines Arzneimittels gemäß einem der Ansprüche 1-8 zur Prävention einer Krebserkrankung.8. Use of a drug according to one of the Claims 1-8 for the prevention of cancer. 9. Verfahren zur Herstellung eines Arzneimittels nach einem der Ansprüche 1-7, dadurch gekennzeichnet, daß die Verbindung gemäß Formel (I) oder (II) mit einem pharmazeutisch verträglichen Träger oder Verdünnungsmittel vermischt wird.9. Process for the manufacture of a drug by one of claims 1-7, characterized in that the compound of formula (I) or (II) with a pharmaceutically acceptable carrier or Diluent is mixed.
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US20020058708A1 (en) * 2000-08-16 2002-05-16 Inman Wayne D. Compositions containing hypotriglyceridemically active stilbenoids
WO2003079986A2 (en) * 2002-03-18 2003-10-02 Bristol-Myers Squibb Company Uracil derivatives as inhibitors of tnf-alpha converting enzyme (tace) and matrix metalloproteinases
EP1845087A1 (en) 2006-04-14 2007-10-17 Mutabilis SA Hydroxyphenyl derivatives and biological applications thereof
KR20120128594A (en) 2009-09-01 2012-11-27 에프에이비 파마 에스에이에스 Novel antibacterial hydroxyphenyl compound
EP2801347B1 (en) * 2013-05-10 2019-08-07 Rahn Ag Carboxylated stilbenes for activating AMPK and sirtuins
AU2017383102B2 (en) * 2016-12-23 2023-05-11 The University Of Queensland Inhibitors of SOX18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases

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