EP1521750A1 - Novel macrocycles for the treatment of cancer diseases - Google Patents

Novel macrocycles for the treatment of cancer diseases

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Publication number
EP1521750A1
EP1521750A1 EP03763869A EP03763869A EP1521750A1 EP 1521750 A1 EP1521750 A1 EP 1521750A1 EP 03763869 A EP03763869 A EP 03763869A EP 03763869 A EP03763869 A EP 03763869A EP 1521750 A1 EP1521750 A1 EP 1521750A1
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Prior art keywords
group
groups
formula
compounds
alkyl
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EP03763869A
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German (de)
French (fr)
Inventor
Gerhard Hoefle
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D315/00—Heterocyclic compounds containing rings having one oxygen atom as the only ring hetero atom according to more than one of groups C07D303/00 - C07D313/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

Definitions

  • Epothilones (DE 4138042) are natural substances with an extraordinary biological effect, for example as mitosis inhibitors, microtubule-modifying agents, cytotoxics or fungicides. In particular, they have paclitaxel-like properties and outperform paclitaxel (Taxol ® ) in some tests. Some derivatives are currently in clinical trials for the treatment of cancer (Nicolaou et al. In Ange. Chem. Int. Ed. 1998, 37, 2014-2045; Flörsheimer et al. In Expert Opin. Ther. Patents 2001, 11, 951 - 968).
  • the aim of the present invention was to provide new epothilone-like derivatives which have a higher activity or better pharmacological properties than the natural products and the derivatives known hitherto.
  • the present invention relates to compounds of the general formula (I):
  • R 1 is a C 6 alkyl, a C 2 6 alkynyl or a C 2 - 6 alkenyl radical
  • R 2 is a hydrogen atom or a C 6 alkyl radical
  • X-Y is selected from the following groups:
  • R 3 is a halogen atom, a C 6 alkyl, a C 2 6 alkenyl or a C 6 heteroalkyl radical,
  • R 5 is a hydrogen atom or a methyl group
  • R 6 is an optionally substituted aryl or heteroaryl group
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, isobutyl , tert-butyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • Alkenyl groups preferably have one or two (particularly preferably one) double bonds or alkynyl groups have one or two (particularly preferably one) triple bonds.
  • alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms are replaced by a halogen atom (preferably F or Cl), such as, for. B. the 2, 2, 2-trichloroethyl, or the trifluoromethyl group.
  • halogen atom preferably F or Cl
  • heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms are each represented by an oxygen, nitrogen, phosphorus, boron, selenium , Silicon or sulfur atom are replaced (preferably oxygen, sulfur or nitrogen).
  • heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
  • heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, iso-propyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, iso-propylethylamino, methyl-aminomethyl, iso-methylaminomethyl - Propylaminoethyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl.
  • heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkyl nitrile groups.
  • cycloalkyl refers to a saturated or partially unsaturated (e.g. cycloalkenyl) cyclic group which has one or more rings (preferably 1 or 2) which form a skeleton which has 3 to 14 carbon atoms, preferably 3 to 10 ( contains in particular 3, 4, 5, 6 or 7) carbon atoms.
  • B. cyclic ketones such. B. cyclohexanone, 2-cyclohexenone or cyclopentanone.
  • cycloalkyl groups are the cyclopropyl, cyclobutyl, cyclopentyl, spiro [4, 5] decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, cubanyl, bicyclo [4.3.0] nonyl -, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or the cyclohex-2-enyl group.
  • heterocycloalkyl refers to a cycloalkyl group as defined above, in which one or more (preferably 1, 2 or 3) ring carbon atoms are each represented by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen , Sulfur or nitrogen) are replaced.
  • a heterocycloalkyl group preferably has 1 or 2 rings with 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms.
  • alkylcycloalkyl refers to groups which, in accordance with the above definitions, contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups, e.g. B. alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups.
  • An alkylcycloalkyl group preferably contains a cycloalkyl group which has one or two ring systems which form a skeleton which contains 3 to 10 (in particular 3, 4, 5, 6 or 7) carbon atoms and one or two alkyl, alkenyl or alkynyl groups with 1 or 2 to 6 carbon atoms.
  • heteroalkylcycloalkyl refers to alkylcycloalkyl groups, as defined above, in which one or more (preferably 1, 2 or 3) carbon atoms each have an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced.
  • one or more carbon atoms each have an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced.
  • oxygen, sulfur or nitrogen preferably oxygen, sulfur or nitrogen
  • Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocylcloalkenyl, the cyclic groups being saturated or single, double or triple unsaturated.
  • aryl or Ar refers to an aromatic group that has one or more rings, such as Bicycloaryl, and is formed by a structure which contains 6 to 14 carbon atoms, preferably 6 to 10 (in particular 6) carbon atoms.
  • aryl (or Ar) also refers to groups in which one or more hydrogen atoms are each replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 or NO 2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aromatic group that has one or more rings, such as bicycloheteroaryl, and is formed by a skeleton that contains 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6) ring atoms and one or more (preferably 1, 2, 3 or 4) contains oxygen, nitrogen, phosphorus and / or sulfur ring atoms (preferably 0, S and / or N).
  • heteroaryl also refers to groups in which one or more hydrogen atoms are each replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 or NO 2 groups.
  • Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, Carbazolyl, acridinyl, pyrimidyl, 2, 3 'bifuryl, 3-pyrazolyl and isoquinolinyl groups.
  • aralkyl refers to groups which, according to the above definitions, contain both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups, such as, for. B. aryl-alkyl, arylalkenyl, aryl-alkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl-cycloalkyl and alkylarylcycloalkenyl groups.
  • aralkyle examples include toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalenes, indanone, phenylcyclopentyl, cumene, cyclo-hexylphenyl, fluorene and indane.
  • An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) with 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group with 5 or 6 ring carbon atoms.
  • heteroaralkyl refers to an aralkyl group as defined above, in which one or more (preferably 1, 2, 3 or 4) carbon atoms are each represented by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced, d. H. to groups which, according to the above definitions, contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups.
  • a heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) with 5 or 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group 5 or 6 ring carbon atoms, where 1, 2, 3 or 4 of these carbon atoms are each replaced by oxygen, sulfur or nitrogen atoms.
  • Examples are aryl heteroalkyl, aryl heterocycloalkyl, aryl heterocycloalkenyl, arylalkyl heterocycloalkyl, arylalkenyl heterocycloalkyl, arylalkynyl heterocycloalkyl, arylalkyl heterocycloalkenyl, heteroarylalkyl,
  • This expression also relates to groups which are substituted with unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C -C 6 heteroalkyl, C 3 -C ⁇ 0 cycloalkyl, C 2 -C 9 heterocycloalkyl, C ⁇ -Cio aryl, C 1 -C 9 heteroaryl, C 7 -C ⁇ 2 aralkyl or C 2 -Cu heteroaralkyl groups are substituted.
  • Compounds of formula (I) can contain one or more centers of chirality due to their substitution.
  • the present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
  • the present invention also includes all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof.
  • the present invention further encompasses all tautomeric forms of the compounds of the formula (I).
  • Preferred compounds of the formula (I) are those in which R 1 is a methyl group.
  • R 2 is a hydrogen atom or a methyl group.
  • R 3 is a methyl group, a trifluoromethyl group or a group of the formula COOH (in particular a trifluoromethyl group).
  • R 6 is an optionally substituted 5- or 6-membered heteroaryl radical having 1, 2 or 3 heteroatoms, selected from S, N and 0.
  • R 6 is particularly preferably an optionally substituted thiazole ring or pyridine ring.
  • R 4 is furthermore preferably a group with the following formula:
  • Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts (or mixed salts) of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, Citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • Compounds of formula (I) can be solvated, in particular hydrated. Hydration can occur, for example, during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I).
  • the compounds of the formula (I) contain asymmetric C atoms, they can be present either as achiral compounds, diastereomer mixtures, mixtures of enantiomers or as optically pure compounds. Furthermore, the present invention also encompasses all cis / trans isomers of the present compounds of the general formula (I) and mixtures thereof.
  • the pharmaceutical compositions according to the present invention contain at least one compound of the formula (I) as active ingredient and optionally one or more carriers and / or one or more adjuvants.
  • the pro-drugs (see, for example, BRB Silverman, Medicinal Chemistry, VCH Weinheim, 1995, Chapter 8, p. 361ff), which are also the subject of the present invention, consist of a compound of the formula (I) and at least one pharmacologically acceptable protective group which is split off under physiological conditions, e.g. an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. an ethoxy, benzyloxy, acetyl or acetyloxy group.
  • pharmacologically acceptable protective group which is split off under physiological conditions, e.g. an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. an ethoxy, benzyloxy, acetyl or acetyloxy group.
  • the present invention also relates to the use of these active compounds for the production of medicaments for the treatment of cancer.
  • compounds of formula (I) are administered using known and acceptable modes, either individually or in combination with any other therapeutic agent.
  • Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, eg as an injectable solution; rectally as suppositories; by Inhalation, e.g. as a powder formulation or spray, transdermally or intranasally.
  • the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic drug carriers, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof , Talc, stearic acid or its salts, dry skimmed milk and the like.
  • drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and / or polyols can be used.
  • drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils, petroleum, animal and / or synthetic oils can be used.
  • drug carriers such as vegetable oils, petroleum, animal and / or synthetic oils, wax, fat and / or polyols can be used.
  • Compressed gases suitable for this purpose such as oxygen, nitrogen, noble gases and / or carbon dioxide, can be used for aerosol formulations.
  • the pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and / or antioxidants.
  • Combinations with other therapeutic agents may include other agents that are commonly used to treat cancer.
  • the dose of the biologically active compound according to the invention can vary within wide limits and can be adjusted to individual needs.
  • a dose of 1 ⁇ g to 100 mg / kg body weight per day is generally suitable, a preferred dose being 10 ⁇ g to 25 mg / kg per day. In suitable cases, the dose can also be below or above the values given above.
  • epothilone derivatives of the formula (I) can be prepared according to the following scheme, starting from known compounds (WO0232844) with standard reactions (Nicolaou et al. Angew. Chem. Int. Ed. 1998, 37, 2014-2045).
  • P is a standard protecting group for aldehydes such as. B. methyl or both groups P together are a CH 2 CH 2 group.

Abstract

The invention relates to novel macrocycles of general formula (1) and to the use thereof in the treatment of cancer diseases.

Description

Neue akrocyclen zur Behandlung von Krebserkrankungen New acrocycles for the treatment of cancer
Epothilone (DE 4138042) sind Naturstoffe mit außerordentlicher biologischer Wirkung, z.B. als Mitosehemmer, Mikrotubuli- modifizierende Agenzien, Cytotoxica oder Fungizide. Insbesondere verfügen sie über Paclitaxel-ähnliche Eigenschaften und übertreffen Paclitaxel (Taxol®) in einigen Tests noch an Aktivität. Einige Derivate befinden sich derzeit in klinischen Studien zur Behandlung von Krebserkrankungen (Nicolaou et al. in Ange . Chem. Int. Ed. 1998, 37, 2014-2045; Flörsheimer et al . in Expert Opin . Ther. Patents 2001, 11, 951- 968) .Epothilones (DE 4138042) are natural substances with an extraordinary biological effect, for example as mitosis inhibitors, microtubule-modifying agents, cytotoxics or fungicides. In particular, they have paclitaxel-like properties and outperform paclitaxel (Taxol ® ) in some tests. Some derivatives are currently in clinical trials for the treatment of cancer (Nicolaou et al. In Ange. Chem. Int. Ed. 1998, 37, 2014-2045; Flörsheimer et al. In Expert Opin. Ther. Patents 2001, 11, 951 - 968).
Ziel der vorliegenden Erfindung war es, neue Epothilonartige Derivate bereitzustellen, die eine höhere Wirksamkeit bzw. bessere pharmakologische Eigenschaften als die Naturstoffe und die bisher bekannten Derivate aufweisen.The aim of the present invention was to provide new epothilone-like derivatives which have a higher activity or better pharmacological properties than the natural products and the derivatives known hitherto.
Die vorliegende Erfindung betrifft Verbindungen der allgemeinen Formel (I) : The present invention relates to compounds of the general formula (I):
worin wherein
R1 ein Cι_6 Alkyl-, ein C2_6 Alkinyl- oder ein C2-6 Alkenylrest ist,R 1 is a C 6 alkyl, a C 2 6 alkynyl or a C 2 - 6 alkenyl radical,
R2 ein Wasserstoffatom oder ein Cι-6 Alkylrest ist,R 2 is a hydrogen atom or a C 6 alkyl radical,
X-Y aus folgenden Gruppen ausgewählt ist:X-Y is selected from the following groups:
R3 ein Halogenatom, ein Cι_6 Alkyl-, ein C2_6 Alkenyl- oder ein Cι-6 Heteroalkylrest ist,R 3 is a halogen atom, a C 6 alkyl, a C 2 6 alkenyl or a C 6 heteroalkyl radical,
R4 ein Bicycloaryl-, ein Bicycloheteroarylrest oder eine Gruppe der Formel -C(R5)=CHR6 ist,R 4 is a bicycloaryl, a bicycloheteroaryl radical or a group of the formula -C (R 5 ) = CHR 6 ,
R5 ein Wasserstoffatom oder eine Methylgruppe ist undR 5 is a hydrogen atom or a methyl group and
R6 eine gegebenenfalls substituierte Aryl- oder Heteroarylgruppe ist,R 6 is an optionally substituted aryl or heteroaryl group,
oder ein pharmakologisch akzeptables Salz, Solvat, Hydrat oder eine pharmakologisch akzeptable Formulierung derselben. Der Ausdruck Alkyl bezieht sich auf eine gesättigte, geradkettige oder verzweigte Kohlenwasserstoffgruppe, die 1 bis 20 Kohlenstoffatome, vorzugsweise 1 bis 12 Kohlenstoffatome, besonders bevorzugt 1 bis 6 Kohlenstoffatome aufweist, z.B. die Methyl-, Ethyl-, Propyl-, Isopropyl-, Isobutyl-, tert-Butyl, n-Hexyl-, 2 , 2-Dimethylbutyl- oder n-Octyl-Gruppe .or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof. The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, isobutyl , tert-butyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.
Die Ausdrücke Alkenyl und Alkinyl beziehen sich auf zumindest teilweise ungesättigte, geradkettige oder verzweigte Kohlenwasserstoffgruppen, die 2 bis 20 Kohlenstoffatome, vorzugsweise 2 bis 12 Kohlenstoffatome, besonders bevorzugt 2 bis 6 Kohlenstoffatome aufweisen, z. B. die Ethenyl-, Allyl-, Acetylenyl-, Propargyl-, Isoprenyl- oder Hex-2-enyl-Gruppe . Bevorzugt weisen Alkenylgruppen eine oder zwei (besonders bevorzugt eine) Doppelbindungen bzw. Alkinylgruppen eine oder zwei (besonders bevorzugt eine) Dreifachbindungen auf.The terms alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Alkenyl groups preferably have one or two (particularly preferably one) double bonds or alkynyl groups have one or two (particularly preferably one) triple bonds.
Des weiteren beziehen sich die Begriffe Alkyl, Alkenyl und Alkinyl auf Gruppen, bei der ein oder mehrere Wasserstoffatome durch ein Halogenatom (bevorzugt F oder Cl) ersetzt sind wie z. B. die 2 , 2 , 2-Trichlorethyl- , oder die Trifluormethylgruppe .Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms are replaced by a halogen atom (preferably F or Cl), such as, for. B. the 2, 2, 2-trichloroethyl, or the trifluoromethyl group.
Der Ausdruck Heteroalkyl bezieht sich auf eine Alkyl-, eine Alkenyl- oder eine Alkinyl-Gruppe, in der ein oder mehrere (bevorzugt 1, 2 oder 3) Kohlenstoffatome jeweils durch ein Sauerstoff-, Stickstoff-, Phosphor-, Bor-, Selen-, Siliziumoder Schwefelatom ersetzt sind (bevorzugt Sauerstoff, Schwefel oder Stickstoff) . Der Ausdruck Heteroalkyl bezieht sich des weiteren auf eine Carbonsäure oder eine von einer Carbonsäure abgeleitete Gruppe wie z. B. Acyl , Acylalkyl, Alkoxycarbonyl , Acyloxy, Acyloxyalkyl, Carboxyalkylamid oder Alkoxycarbonyloxy . Beispiele für Heteroalkylgruppen sind Gruppen der Formeln Ra-0-Ya-, Ra-S-Ya-, Ra-N(Rb)-Ya-, Ra-CO-Ya- , Ra-0-CO-Ya-, Ra-C0-0-Ya-, Ra-CO-N(Rb)-Ya-, R-N (Rb) -CO-Y- , Ra-0-CO-N (Rb) -Ya- , Ra-N(Rb)-C0-O-Ya-, Ra-N(R )-C0-N(Rc)-Ya-, Ra-0-CO-0-Ya- , Ra-N(Rb) -C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-0-CS-Ya-, Ra-CS-0-Ya-, Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-0-CS-N (Rb) -Ya- , R-N(Rb) -CS-0-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-0-CS-0-Ya- , Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-C0-N(Rb)-Ya-, Ra-N (Rb) -CO-S-Ya- , Ra-S-CO-0-Ya-, Ra-0-CO-S-Ya-, Ra-S-C0-S-Ya- , Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N (Rb) -CS-S-Y3- , Ra-S-CS-0-Ya- , Ra-0-CS-S-Ya-, wobei Ra ein Wasserstoffatom, eine d-C6-Alkyl-, eine C2-C6-Alkenyl- oder eine C2-C6-Alkinylgruppe; Rb ein Wasserstoffatom, eine Cι-C6-Alkyl- , eine C2-C6-Alkenyl- oder eine C-C6-Alkinylgruppe; Rc ein Wasserstoffatom, eine Cι-C6-Alkyl- , eine C2-C6-Alkenyl- oder eine C2-C6-Alkinylgruppe; Rd ein Wasserstoffatom, eine Cι-C6-Alkyl- , eine C2-C6-Alkenyl- oder eine C2-C6-Alkinylgruppe und Ya eine direkte Bindung, eine Cι-C6- Alkylen-, eine C -C6-Alkenylen- oder eine C-C6-Alkinylengruppe ist, wobei jede Heteroalkylgruppe mindestens ein Kohlenstoffatom enthält und ein oder mehrere Wasserstoffatome jeweils durch Fluor- oder Chloratome ersetzt sein können. Konkrete Beispiele für Heteroalkylgruppen sind Methoxy, Trifluormethoxy, Ethoxy, n-Propyloxy, iso-Propyloxy, tert- Butyloxy, Methoxymethyl , Ethoxymethyl , Methoxyethyl , Methylamino, Ethylamino, Dimethylamino, Diethylamino, iso- Propylethylamino, Methyl-aminomethyl , Ethylaminomethyl, Di-iso- Propylaminoethyl, Enolether, Dimethylaminomethyl, Dimethylaminoethyl, Acetyl, Propionyl, Butyryloxy, Acetyloxy, Methoxycarbonyl , Ethoxy-carbonyl , N-Ethyl-N-Methylcarbamoyl oder N-Methylcarbamoyl . Weitere Beispiele für Heteroalkylgruppen sind Nitril-, Isonitril, Cyanat-, Thiocyanat-, Isocyanat-, Isothiocyanat und Alkylnitril-gruppen. Der Ausdruck Cycloalkyl bezieht sich auf eine gesättigte oder teilweise ungesättigte (z. B. Cycloalkenyl) cyclische Gruppe, die einen oder mehrere Ringe (bevorzugt 1 oder 2) aufweist, die ein Gerüst bilden, welches 3 bis 14 Kohlenstoffatome, vorzugsweise 3 bis 10 (insbesondere 3, 4, 5, 6 oder 7) Kohlenstoffatome enthält. Der Ausdruck Cycloalkyl bezieht sich weiterhin auf Gruppen, bei denen ein oder mehrere Wasserstoffatome jeweils durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, =0, SH, =S, NH2, =NH oder N0-Gruppen ersetzt sind also z. B. cyclische Ketone wie z. B. Cyclohexanon, 2-Cyclohexenon oder Cyclopentanon. Weitere konkrete Beispiele für Cycloalkylgruppen sind die Cyclopropyl- , Cyclobutyl-, Cyclopentyl- , Spiro [4, 5] decanyl- , Norbornyl-, Cyclohexyl-, Cyclopentenyl-, Cyclohexadienyl- , Decalinyl-, Cubanyl-, Bicyclo [4.3.0]nonyl-, Tetralin-, Cyclopentylcyclohexyl- , Fluorcyclohexyl- oder die Cyclohex-2-enyl-Gruppe .The term heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms are each represented by an oxygen, nitrogen, phosphorus, boron, selenium , Silicon or sulfur atom are replaced (preferably oxygen, sulfur or nitrogen). The term heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy. Examples of heteroalkyl groups are groups of the formulas R a -0-Y a -, R a -SY a -, R a -N (R b ) -Y a -, R a -CO-Y a -, R a -0- CO-Y a -, R a -C0-0-Y a -, R a -CO-N (R b ) -Y a -, RN (R b ) -CO-Y-, R a -0-CO- N (R b ) -Y a -, R a -N (R b ) -C0-OY a -, R a -N (R) -C0-N (R c ) -Y a -, R a -0- CO-0-Y a -, R a -N (R b ) -C (= NR d ) -N (R c ) -Y a -, R a -CS-Y a -, R a -0-CS- Y a -, R a -CS-0-Y a -, R a -CS-N (R b ) -Y a -, R a -N (R b ) -CS-Y a -, R a -0- CS-N (R b ) -Y a -, RN (R b ) -CS-0-Y a -, R a -N (R b ) -CS-N (R c ) -Y a -, R a - 0-CS-0-Y a -, R a -S-CO-Y a -, R a -CO-SY a -, R a -S-C0-N (R b ) -Y a -, R a - N (R b ) -CO-SY a -, R a -S-CO-0-Y a -, R a -0-CO-SY a -, R a -S-C0-SY a -, R a - S-CS-Y a -, R a -CS-SY a -, R a -S-CS-N (R b ) -Y a -, R a -N (R b ) -CS-SY 3 -, R a -S-CS-0-Y a -, R a -0-CS-SY a -, where R a is a hydrogen atom, a dC 6 alkyl, a C 2 -C 6 alkenyl or a C 2 - C 6 alkynyl group; R b is a hydrogen atom, a C 6 -C 6 alkyl, a C 2 -C 6 alkenyl or a CC 6 alkynyl group; R c is a hydrogen atom, a -C 6 alkyl, a C 2 -C 6 alkenyl or a C 2 -C 6 alkynyl group; R d is a hydrogen atom, a Cι-C 6 alkyl, a C 2 -C 6 alkenyl or a C 2 -C 6 alkynyl group and Y a is a direct bond, a Cι-C 6 - alkylene, a C Is -C 6 -alkenylene or a CC 6 -alkinylene group, each heteroalkyl group containing at least one carbon atom and one or more hydrogen atoms can each be replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, iso-propyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, iso-propylethylamino, methyl-aminomethyl, iso-methylaminomethyl - Propylaminoethyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkyl nitrile groups. The term cycloalkyl refers to a saturated or partially unsaturated (e.g. cycloalkenyl) cyclic group which has one or more rings (preferably 1 or 2) which form a skeleton which has 3 to 14 carbon atoms, preferably 3 to 10 ( contains in particular 3, 4, 5, 6 or 7) carbon atoms. The term cycloalkyl also refers to groups in which one or more hydrogen atoms are in each case replaced by fluorine, chlorine, bromine or iodine atoms or OH, = 0, SH, = S, NH 2 , = NH or NO groups z. B. cyclic ketones such. B. cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are the cyclopropyl, cyclobutyl, cyclopentyl, spiro [4, 5] decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, cubanyl, bicyclo [4.3.0] nonyl -, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or the cyclohex-2-enyl group.
Der Ausdruck Heterocycloalkyl bezieht sich auf eine Cycloalkylgruppe wie oben definiert, in der ein oder mehrere (bevorzugt 1, 2 oder 3) Ring-Kohlenstoffatome jeweils durch ein Sauerstoff-, Stickstoff-, Silizium-, Selen-, Phosphor- oder Schwefelatom (bevorzugt Sauerstoff, Schwefel oder Stickstoff) ersetzt sind. Bevorzugt besitzt eine Heterocycloalkylgruppe 1 oder 2 Ringe mit 3 bis 10 (insbesondere 3, 4, 5, 6 oder 7) Ringatomen. Der Ausdruck Heterocycloalkyl bezieht sich weiterhin auf Gruppen, bei denen ein oder mehrere Wasserstoffatome jeweils durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, =0, SH, =S, NH2, =NH oder N02-Gruppen ersetzt sind. Beispiele sind die Piperidyl-, Morpholinyl- , Urotropinyl- , Pyrrolidinyl-, Tetrahydrothiophenyl-, Tetrahydropyranyl- , Tetrahydro-furyl- , Oxacyclopropyl- , Azacyclopropyl- oder 2- Pyrazolinyl-Gruppe sowie Lactarne, Lactone, cyclische Imide und cyclische Anhydride.The term heterocycloalkyl refers to a cycloalkyl group as defined above, in which one or more (preferably 1, 2 or 3) ring carbon atoms are each represented by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen , Sulfur or nitrogen) are replaced. A heterocycloalkyl group preferably has 1 or 2 rings with 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms. The term heterocycloalkyl also refers to groups in which one or more hydrogen atoms are each replaced by fluorine, chlorine, bromine or iodine atoms or OH, = 0, SH, = S, NH 2 , = NH or NO 2 groups , Examples are the piperidyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, oxacyclopropyl, azacyclopropyl or 2- Pyrazolinyl group and lactarne, lactones, cyclic imides and cyclic anhydrides.
Der Ausdruck Alkylcycloalkyl bezieht sich auf Gruppen, die entsprechend den obigen Definitionen sowohl Cycloalkyl- wie auch Alkyl-, Alkenyl- oder Alkinylgruppen enthalten, z. B. Alkylcycloalkyl-, Alkylcycloalkenyl- , Alkenylcycloalkyl- und Alkinylcycloalkylgruppen. Bevor-zugt enthält eine Alkylcycloalkylgruppe eine Cycloalkyl-gruppe, die einen oder zwei Ringsysteme aufweist, die ein Gerüst bilden, welches 3 bis 10 (insbesondere 3, 4, 5, 6 oder 7) Kohlenstoffatome enthält und eine oder zwei Alkyl-, Alkenyl- oder Alkinylgruppen mit 1 oder 2 bis 6 Kohlenstoffatomen.The term alkylcycloalkyl refers to groups which, in accordance with the above definitions, contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups, e.g. B. alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group which has one or two ring systems which form a skeleton which contains 3 to 10 (in particular 3, 4, 5, 6 or 7) carbon atoms and one or two alkyl, alkenyl or alkynyl groups with 1 or 2 to 6 carbon atoms.
Der Ausdruck Heteroalkylcycloalkyl bezieht sich auf Alkylcycloalkylgruppen, wie oben definiert, in der ein oder mehrere (bevorzugt 1, 2 oder 3) Kohlenstoffatome jeweils durch ein Sauerstoff-, Stickstoff-, Silizium-, Selen-, Phosphor- oder Schwefelatom (bevorzugt Sauerstoff, Schwefel oder Stickstoff) ersetzt sind. Bevorzugt besitzt eineThe term heteroalkylcycloalkyl refers to alkylcycloalkyl groups, as defined above, in which one or more (preferably 1, 2 or 3) carbon atoms each have an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced. Preferably has one
Heteroalkylcycloalkylgruppe 1 oder 2 Ringsysteme mit 3 bis 10 (insbesondere 3, 4, 5, 6 oder 7) Ringatomen und eine oder zwei Alkyl, Alkenyl, Alkinyl oder Heteroalkylgruppen mit 1 oder 2 bis 6 Kohlenstoffatomen. Beispiele derartiger Gruppen sind Al- kylheterocycloalkyl , Alkylheterocycloalkenyl, Alkenyl- heterocycloalkyl, Alkinylheterocycloalkyl , Heteroalkyl-cyclo- alkyl, Heteroalkylheterocycloalkyl und Heteroalkyl- heterocylcloalkenyl, wobei die cyclischen Gruppen gesättigt oder einfach, zweifach oder dreifach ungesättigt sind.Heteroalkylcycloalkyl group 1 or 2 ring systems with 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups with 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocylcloalkenyl, the cyclic groups being saturated or single, double or triple unsaturated.
Der Ausdruck Aryl bzw. Ar bezieht sich auf eine aromatische Gruppe, die einen oder mehrere Ringe hat, wie beispielsweise Bicycloaryl, und durch ein Gerüst gebildet wird, das 6 bis 14 Kohlenstoffatome, vorzugsweise 6 bis 10 (insbesondere 6) Kohlenstoffatome enthält. Der Ausdruck Aryl (bzw. Ar) bezieht sich weiterhin auf Gruppen, bei denen ein oder mehrere Wasserstoffatome jeweils durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, SH, NH2, oder N02-Gruppen ersetzt sind. Beispiele sind die Phenyl-, Naphthyl-, Biphenyl-, 2-Fluorphenyl , Anilinyl-, 3- Nitrophenyl oder 4-Hydroxy-phenyl-Gruppe .The term aryl or Ar refers to an aromatic group that has one or more rings, such as Bicycloaryl, and is formed by a structure which contains 6 to 14 carbon atoms, preferably 6 to 10 (in particular 6) carbon atoms. The term aryl (or Ar) also refers to groups in which one or more hydrogen atoms are each replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 or NO 2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
Der Ausdruck Heteroaryl bezieht sich auf eine aromatische Gruppe, die einen oder mehrere Ringe hat, wie beispielsweise Bicycloheteroaryl, und durch ein Gerüst gebildet wird, das 5 bis 14 Ringatome, vorzugsweise 5 bis 10 (insbesondere 5 oder 6) Ringatome enthält und ein oder mehrere (bevorzugt 1, 2, 3 oder 4) Sauerstoff-, Stickstoff-, Phosphor- und/oder Schwefel- Ringatome (bevorzugt 0, S und/oder N) enthält. Der Ausdruck Heteroaryl bezieht sich weiterhin auf Gruppen, bei denen ein oder mehrere Wasserstoffatome jeweils durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, SH, NH2, oder N02-Gruppen ersetzt sind. Beispiele sind 4-Pyridyl-, 2-Imidazolyl- , 3- Phenylpyrrolyl- , Thiazolyl-, Oxazolyl-, Triazolyl-, Tetrazolyl-, Isoxazolyl-, Indazolyl-, Indolyl-, Benzimidazolyl- , Pyridazinyl-, Chinolinyl-, Purinyl-, Carbazolyl-, Acridinyl-, Pyrimidyl-, 2 , 3 '-Bifuryl- , 3-Pyrazolyl- und Isochinolinyl-Gruppen.The term heteroaryl refers to an aromatic group that has one or more rings, such as bicycloheteroaryl, and is formed by a skeleton that contains 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6) ring atoms and one or more (preferably 1, 2, 3 or 4) contains oxygen, nitrogen, phosphorus and / or sulfur ring atoms (preferably 0, S and / or N). The term heteroaryl also refers to groups in which one or more hydrogen atoms are each replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 or NO 2 groups. Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, Carbazolyl, acridinyl, pyrimidyl, 2, 3 'bifuryl, 3-pyrazolyl and isoquinolinyl groups.
Der Ausdruck Aralkyl bezieht sich auf Gruppen, die entsprechend den obigen Definitionen sowohl Aryl- wie auch Alkyl-, Alkenyl-, Alkinyl- und/oder Cycloalkylgruppen enthalten, wie z. B. Aryl- alkyl-, Arylalkenyl- , Aryl-alkinyl-, Arylcycloalkyl- , Arylcycloalkenyl- , Alkylaryl-cycloalkyl- und Alkylarylcycloalkenylgruppen. Konkrete Beispiele für Aralkyle sind Toluol, Xylol, Mesitylen, Styrol, Benzylchlorid, o- Fluortoluol, lH-Inden, Tetralin, Dihydronaphthaline, Indanon, Phenylcyclopentyl, Cumol, Cyclo-hexylphenyl , Fluoren und Indan. Bevorzugt enthält eine Aralkylgruppe ein oder zwei aromatische Ringsysteme (1 oder 2 Ringe) mit 6 bis 10 Kohlenstoffatomen und ein oder zwei Alkyl-, Alkenyl- und/oder Alkinylgruppen mit 1 oder 2 bis 6 Kohlenstoffatomen und/oder eine Cyclo-alkylgruppe mit 5 oder 6 Ringkohlenstoffatomen .The term aralkyl refers to groups which, according to the above definitions, contain both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups, such as, for. B. aryl-alkyl, arylalkenyl, aryl-alkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl-cycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyle are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalenes, indanone, phenylcyclopentyl, cumene, cyclo-hexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) with 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group with 5 or 6 ring carbon atoms.
Der Ausdruck Heteroaralkyl bezieht sich auf eine Aralkyl-gruppe wie oben definiert, in der ein oder mehrere (bevorzugt 1, 2, 3 oder 4) Kohlenstoffatome jeweils durch ein Sauerstoff-, Stickstoff-, Silizium-, Selen-, Phosphor-, Bor- oder Schwefelatom (bevorzugt Sauerstoff, Schwefel oder Stickstoff) ersetzt sind, d. h. auf Gruppen, die entsprechend den obigen Definitionen sowohl Aryl- bzw. Heteroaryl- wie auch Alkyl-, Alkenyl-, Alkinyl- und/oder Heteroalkyl- und/oder Cycloalkyl- und/oder Heterocyclo-alkylgruppen enthalten. Bevorzugt enthält eine Heteroaralkylgruppe ein oder zwei aromatische Ringsysteme (1 oder 2 Ringe) mit 5 oder 6 bis 10 Kohlenstoffatomen und ein oder zwei Alkyl-, Alkenyl- und/oder Alkinyl-gruppen mit 1 oder 2 bis 6 Kohlenstoffatomen und/oder eine Cycloalkylgruppe mit 5 oder 6 Ringkohlenstoffatomen, wobei 1, 2, 3 oder 4 dieser Kohlenstoffatome jeweils durch Sauerstoff-, Schwefel- oder Stickstoffatome ersetzt sind.The term heteroaralkyl refers to an aralkyl group as defined above, in which one or more (preferably 1, 2, 3 or 4) carbon atoms are each represented by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced, d. H. to groups which, according to the above definitions, contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. A heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) with 5 or 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group 5 or 6 ring carbon atoms, where 1, 2, 3 or 4 of these carbon atoms are each replaced by oxygen, sulfur or nitrogen atoms.
Beispiele sind Arylheteroalkyl- , Arylheterocycloalkyl- , Aryl- heterocycloalkenyl- , Arylalkylheterocycloalkyl- , Arylalkenylheterocycloalkyl- , Arylalkinylheterocyclo-alkyl- , Arylalkylheterocycloalkenyl- , Heteroarylalkyl- ,Examples are aryl heteroalkyl, aryl heterocycloalkyl, aryl heterocycloalkenyl, arylalkyl heterocycloalkyl, arylalkenyl heterocycloalkyl, arylalkynyl heterocycloalkyl, arylalkyl heterocycloalkenyl, heteroarylalkyl,
Heteroarylalkenyl- , Heteroarylalkinyl- , Heteroarylheteroalkyl- , Heteroarylcycloalkyl- , Heteroarylcycloalkenyl- , Heteroarylheterocycloalkyl- , Heteroarylheterocycloalken-yl- , Heteroarylalkylcycloalkyl- , Heteroarylalkylhetero-cycloalkenyl- , Heteroarylheteroalkylcycloalkyl- , Hetero- arylheteroalkylcycloalkenyl- und Heteroarylheteroalkyl- heterocycloalkyl-Gruppen, wobei die cyclischen Gruppen gesättigt oder einfach, zweifach oder dreifach ungesättigt sind. Konkrete Beispiele sind die Tetrahydroisochinolinyl- , Benzoyl-, 2- oder 3-Ethyl-indolyl- , 4-Methylpyridino- , 2-, 3- oder 4-Methoxyphenyl- , 4-Ethoxyphenyl- , 2-, 3- oder 4-Carboxyphenylalkylgruppe .Heteroarylalkenyl, heteroarylalkynyl, heteroaryl heteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, Heteroarylheterocycloalkyl-, Heteroarylheterocycloalken-yl, Heteroarylalkylcycloalkyl-, Heteroarylalkylhetero-cycloalkenyl, Heteroarylheteroalkylcycloalkyl-, hetero- arylheteroalkylcycloalkenyl- Heteroarylheteroalkyl- and heterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri are polyunsaturated. Specific examples are the tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group ,
Die Ausdrücke Cycloalkyl, Heterocycloalkyl, Alkylcyclo-alkyl, Heteroalkylcycloalkyl, Aryl, Heteroaryl, Aralkyl und Heteroaralkyl beziehen sich auch auf Gruppen, in denen ein oder mehrere Wasserstoffatome solcher Gruppen jeweils durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, =0, SH, =S, NH2, =NH oder N02-Gruppen ersetzt sind.The terms cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups are each represented by fluorine, chlorine, bromine or iodine atoms or OH, = 0 , SH, = S, NH 2 , = NH or N0 2 groups are replaced.
Der Ausdruck "gegebenenfalls substituiert" bezieht sich auf Gruppen, in denen ein oder mehrere Wasserstoffatome jeweils durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, =0, SH, =S, NH2, =NH oder N02-Gruppen ersetzt sind. Dieser Ausdruck bezieht sich weiterhin auf Gruppen, die mit unsubstituierten Ci-C6 Alkyl-, C2-C6 Alkenyl-, C2-C6 Alkinyl-, Cι-C6 Heteroalkyl-, C3-Cι0 Cycloalkyl-, C2-C9 Heterocycloalkyl-, Cβ-Cio Aryl-, C1-C9 Heteroaryl-, C7-Cι2 Aralkyl- oder C2-Cu Heteroaralkyl-Gruppen substituiert sind.The term "optionally substituted" refers to groups in which one or more hydrogen atoms are each represented by fluorine, chlorine, bromine or iodine atoms or OH, = 0, SH, = S, NH 2 , = NH or NO 2 groups are replaced. This expression also relates to groups which are substituted with unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C -C 6 heteroalkyl, C 3 -Cι 0 cycloalkyl, C 2 -C 9 heterocycloalkyl, Cβ-Cio aryl, C 1 -C 9 heteroaryl, C 7 -Cι 2 aralkyl or C 2 -Cu heteroaralkyl groups are substituted.
Schutzgruppen sind dem Fachmann bekannt und z. B. in P . J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994 sowie in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1999 beschrieben. Gängige Aminoschutzgruppen sind z. B. t-Butyloxycarbonyl- (Boc) , Benzyloxycarbonyl- (Cbz, Z) , Benzyl- (Bn) , Benzoyl- (Bz) , Fluorenylmethyloxycarbonyl- (Fmoc) , Allyloxycarbonyl- (Alloc) , Trichlorethyloxycarbonyl- (Troc) , Acetyl- oder Trifluoracetylgruppen.Protecting groups are known to the expert and z. B. in P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994 and in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1999 described. Common amino protecting groups are e.g. B. t-Butyloxycarbonyl- (Boc), Benzyloxycarbonyl- (Cbz, Z), Benzyl- (Bn), Benzoyl- (Bz), Fluorenylmethyloxycarbonyl- (Fmoc), Allyloxycarbonyl- (Alloc), Trichlorethyloxycarbonyl- (Troc), Acetyl- or trifluoroacetyl groups.
Verbindungen der Formel (I) , können aufgrund ihrer Substitution ein oder mehrere Chiralitätszentren enthalten. Die vorliegende Erfindung umfasst daher sowohl alle reinen Enantiomere und alle reinen Diastereomere, als auch deren Gemische in jedem Mischungsverhältnis. Des weiteren sind von der vorliegenden Erfindung auch alle cis/trans-Isomeren der Verbindungen der allgemeinen Formel (I) sowie Gemische davon umfasst. Des weiteren sind von der vorliegenden Erfindung alle tautomeren Formen der Verbindungen der Formel (I) umfasst.Compounds of formula (I) can contain one or more centers of chirality due to their substitution. The present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio. Furthermore, the present invention also includes all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof. The present invention further encompasses all tautomeric forms of the compounds of the formula (I).
Bevorzugt sind Verbindungen der Formel (I) wobei R1 eine Methylgruppe ist.Preferred compounds of the formula (I) are those in which R 1 is a methyl group.
Des weiteren bevorzugt sind Verbindungen der Formel (I), wobei R2 ein Wasserstoffatom oder eine Methylgruppe ist.Also preferred are compounds of formula (I), wherein R 2 is a hydrogen atom or a methyl group.
Wiederum bevorzugt sind Verbindungen der Formel (I), wobei R3 eine Methylgruppe, eine Trifluormethylgruppe oder eine Gruppe der Formel COOH ist (insbesondere eine Trifluormethylgruppe) .Again preferred are compounds of formula (I), wherein R 3 is a methyl group, a trifluoromethyl group or a group of the formula COOH (in particular a trifluoromethyl group).
Weiter bevorzugt sind Verbindungen der Formel (I) , wobei R6 ein gegebenenfalls substituierter 5- oder 6-gliedriger Heteroarylrest mit 1, 2 oder 3 Heteroatomen, ausgewählt aus S, N und 0 ist. Besonders bevorzugt ist R6 ein gegebenenfalls substituierter Thiazolring oder Pyridinring.Further preferred are compounds of formula (I), wherein R 6 is an optionally substituted 5- or 6-membered heteroaryl radical having 1, 2 or 3 heteroatoms, selected from S, N and 0. R 6 is particularly preferably an optionally substituted thiazole ring or pyridine ring.
Für die Reste bzw. Ausdrücke Bicycloaryl- undFor the radicals or expressions bicycloaryl and
Bicycloheteroarylrest kann auch auf folgenden Stand der Technik verwiesen werden:Bicycloheteroaryl radical can also be referred to the following prior art:
1. K. C. Nicolaou et al . Chemistry & Biology 7, 593 (2000) 2. K.-H. Altmann et al . Bioorg. Med. Chem. Lett. 10, 2765 (2000) 3. K. C. Nicolaou et al . Chem. Eur. J. 6, 2783 (2000)1. K.C. Nicolaou et al. Chemistry & Biology 7, 593 (2000) 2. K.-H. Altmann et al. Bioorg. Med. Chem. Lett. 10, 2765 (2000) 3. K.C. Nicolaou et al. Chem. Eur. J. 6, 2783 (2000)
Des weiteren bevorzugt ist R4 eine Gruppe mit folgender Formel:R 4 is furthermore preferably a group with the following formula:
Beispiele für pharmakologisch akzeptable Salze der Verbindungen der Formel (I) sind Salze (oder Mischsalze) von physiologisch akzeptablen Mineralsäuren wie Salzsäure, Schwefelsäure und Phosphorsäure oder Salze von organischen Säuren wie Methan- sulfonsäure, p-Toluolsulfonsäure, Milchsäure, Essigsäure, Tri- fluoressigsäure, Zitronensäure, Bernsteinsäure, Fumarsäure, Maleinsäure und Salicylsäure . Verbindungen der Formel (I) können solvatisiert , insbesondere hydratisiert sein. Die Hydratisierung kann z.B. während des Herstellungsverfahrens oder als Folge der hygroskopischen Natur der anfänglich wasserfreien Verbindungen der Formel (I) auftreten. Wenn die Verbindungen der Formel (I) asymmetrische C-Atome enthalten, können sie entweder als achirale Verbindungen, Diastereomeren-Gemische, Gemische von Enantiomeren oder als optisch reine Verbindungen vorliegen. Des weiteren sind von der vorliegenden Erfindung auch alle cis/trans-Isomeren der vorliegenden Verbindungen der allgemeinen Formel (I) sowie Gemische davon umfasst. Die pharmazeutischen Zusammensetzungen gemäß der vorliegenden Erfindung enthalten mindestens eine Verbindung der Formel (I) als Wirkstoff und fakultativ einen oder mehrere Trägerstoffe und/oder ein oder mehrere Adjuvantien.Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts (or mixed salts) of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, Citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Compounds of formula (I) can be solvated, in particular hydrated. Hydration can occur, for example, during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I). If the compounds of the formula (I) contain asymmetric C atoms, they can be present either as achiral compounds, diastereomer mixtures, mixtures of enantiomers or as optically pure compounds. Furthermore, the present invention also encompasses all cis / trans isomers of the present compounds of the general formula (I) and mixtures thereof. The pharmaceutical compositions according to the present invention contain at least one compound of the formula (I) as active ingredient and optionally one or more carriers and / or one or more adjuvants.
Die Pro-Drugs (siehe z. B. R. B. Silverman, Medizinische Chemie, VCH Weinheim, 1995, Kapitel 8, S. 361ff) , die ebenfalls Gegenstand der vorliegenden Erfindung sind, bestehen aus einer Verbindung der Formel (I) und mindestens einer pharmakologisch akzeptablen Schutzgruppe, die unter physiologischen Bedingungen abgespalten wird, z.B. einer Alkoxy- , Aralkyloxy-, Acyl- oder Acyloxy-Gruppe, wie z.B. einer Ethoxy-, Benzyloxy- , Acetyl- oder Acetyloxy-Gruppe .The pro-drugs (see, for example, BRB Silverman, Medicinal Chemistry, VCH Weinheim, 1995, Chapter 8, p. 361ff), which are also the subject of the present invention, consist of a compound of the formula (I) and at least one pharmacologically acceptable protective group which is split off under physiological conditions, e.g. an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. an ethoxy, benzyloxy, acetyl or acetyloxy group.
Die therapeutische Verwendung der Verbindungen der Formel (I), ihrer pharmakologisch akzeptablen Salze bzw. Solvate und Hydrate sowie Formulierungen und pharmazeutischen Zusammensetzungen liegt ebenfalls im Rahmen der vorliegenden Erfindung.The therapeutic use of the compounds of formula (I), their pharmacologically acceptable salts or solvates and hydrates as well as formulations and pharmaceutical compositions is also within the scope of the present invention.
Auch die Verwendung dieser Wirkstoffe zur Herstellung von Arzneimitteln zur Behandlung von Krebserkrankungen ist Gegenstand der vorliegenden Erfindung. Im allgemeinen werden Verbindungen der Formel (I) unter Anwendung der bekannten und akzeptablen Modi, entweder einzeln oder in Kombination mit einem beliebigen anderen therapeutischen Mittel verabreicht. Solche therapeutisch nützlichen Mittel können auf einem der folgenden Wege verabreicht werden: oral, z.B. als Dragees, überzogene Tabletten, Pillen, Halbfeststoffe, weiche oder harte Kapseln, Lösungen, Emulsionen oder Suspensionen; parenteral, z.B. als injizierbare Lösung; rektal als Suppositorien; durch Inhalation, z.B. als Pulverformulierung oder Spray, transdermal oder intranasal. Zur Herstellung solcher Tabletten, Pillen, Halbfeststoffe, überzogenen Tabletten, Dragees und harten Gelatinekapseln kann das therapeutisch verwendbare Produkt mit pharmakologisch inerten, anorganischen oder organischen Arzneimittelträgersubstanzen vermischt werden, z.B. mit Lactose, Sucrose, Glucose, Gelatine, Malz, Silicagel, Stärke oder Derivaten derselben, Talkum, Stearinsäure oder ihren Salzen, Trockenmagermilch und dgl . Zur Herstellung von weichen Kapseln kann man Arzneimittelträgerstoffe wie z.B. pflanzliche Öle, Petroleum, tierische oder synthetische Öle, Wachs, Fett und/oder Polyole einsetzen. Zur Herstellung von flüssigen Lösungen und Sirups kann man Arzneimittelträgerstoffe wie z.B. Wasser, Alkohole, wäßrige Salzlösung, wäßrige Dextrose, Polyole, Glycerin, pflanzliche Öle, Petroleum, tierische und/oder synthetische Öle verwenden. Für Suppositorien kann man Arzneimittelträgerstoffe wie z.B. pflanzliche Öle, Petroleum, tierische und/oder synthetische Öle, Wachs, Fett und/oder Polyole verwenden. Für Aerosol-Formulierungen kann man komprimierte Gase, die für diesen Zweck geeignet sind, wie z.B. Sauerstoff, Stickstoff, Edelgase und/oder Kohlendioxid einsetzen. Die pharmazeutisch verwendbaren Mittel können auch Zusatzstoffe zur Konservierung, Stabilisierung, Emulgatoren, Süßstoffe, Aromastoffe, Salze zur Veränderung des osmotischen Drucks, Puffer, Umhüllungszusatzstoffe und/oder Antioxidantien enthalten.The present invention also relates to the use of these active compounds for the production of medicaments for the treatment of cancer. In general, compounds of formula (I) are administered using known and acceptable modes, either individually or in combination with any other therapeutic agent. Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, eg as an injectable solution; rectally as suppositories; by Inhalation, e.g. as a powder formulation or spray, transdermally or intranasally. To produce such tablets, pills, semi-solids, coated tablets, dragees and hard gelatin capsules, the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic drug carriers, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof , Talc, stearic acid or its salts, dry skimmed milk and the like. For the production of soft capsules, drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and / or polyols can be used. For the preparation of liquid solutions and syrups, drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils, petroleum, animal and / or synthetic oils can be used. For suppositories, drug carriers such as vegetable oils, petroleum, animal and / or synthetic oils, wax, fat and / or polyols can be used. Compressed gases suitable for this purpose, such as oxygen, nitrogen, noble gases and / or carbon dioxide, can be used for aerosol formulations. The pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and / or antioxidants.
Kombinationen mit anderen therapeutischen Mitteln können weitere Wirkstoffe beinhalten, die gewöhnlich zur Behandlung von Krebserkrankungen eingesetzt werden. Zur Behandlung von Krebserkrankungen kann die Dosis der erfindungsgemäßen biologisch aktiven Verbindung innerhalb breiter Grenzen variieren und kann auf den individuellen Bedarf eingestellt werden. Im allgemeinen ist eine Dosis von 1 μg bis 100 mg/kg Körpergewicht pro Tag geeignet, wobei eine bevorzugte Dosis 10 μg bis 25 mg/kg pro Tag ist. In geeigneten Fällen kann die Dosis auch unter oder über den oben angegebenen Werten liegen .Combinations with other therapeutic agents may include other agents that are commonly used to treat cancer. For the treatment of cancer, the dose of the biologically active compound according to the invention can vary within wide limits and can be adjusted to individual needs. A dose of 1 μg to 100 mg / kg body weight per day is generally suitable, a preferred dose being 10 μg to 25 mg / kg per day. In suitable cases, the dose can also be below or above the values given above.
Die Epothilonderivate der Formel (I) können nach folgendem Schema ausgehend von bekannten Verbindungen (WO0232844) mit Standardumsetzungen (Nicolaou et al . Angew. Chem. Int. Ed. 1998, 37, 2014-2045) hergestellt werden. The epothilone derivatives of the formula (I) can be prepared according to the following scheme, starting from known compounds (WO0232844) with standard reactions (Nicolaou et al. Angew. Chem. Int. Ed. 1998, 37, 2014-2045).
In diesem Schema ist P eine Standard-Schutzgruppe für Aldehyde wie z. B. Methyl bzw. beide Gruppen P sind zusammen eine CH2CH2 Gruppe .In this scheme, P is a standard protecting group for aldehydes such as. B. methyl or both groups P together are a CH 2 CH 2 group.
Verbindungen mit R gleich Bicycloheteroaryl können über folgende Zwischenstufen hergestellt werden: Compounds with R equal to bicycloheteroaryl can be prepared via the following intermediates:
Die weitere Synthese folgt den bekannten Epothilonsynthesen.The further synthesis follows the known epothilone syntheses.
BeispieleExamples

Claims

Patentansprüche claims
1 . Verbindungen der allgemeinen Formel ( I )1 . Compounds of the general formula (I)
ii
worin wherein
R1 ein Cι_6 Alkyl-, ein C2_6 Alkinyl- oder ein C.6 Alkenyl- rest ist,R 1 is a Cι_, a C 2 _ 6 alkynyl or C 6 alkenyl radical is 6 alkyl,
R2 ein Wasserstoffatom oder ein Cι-6 Alkylrest ist,R 2 is a hydrogen atom or a C 6 alkyl radical,
X-Y aus folgenden Gruppen ausgewählt istX-Y is selected from the following groups
' ~~ oder ^/ Λ'' ~~ or ^ / Λ'
R3 ein Halogenatom, ein Cι_6 Alkyl-, ein C2-6 Alkenyl- oder ein Cι_6 Heteroalkylrest ist,R 3 is a halogen atom, a C 6 alkyl, a C 2 - 6 alkenyl or a C 6 heteroalkyl radical,
R4 ein Bicycloaryl- , ein Bicycloheteroarylrest oder eine Gruppe der Formel -C(R5)=CHR6 ist,R 4 is a bicycloaryl, a bicycloheteroaryl radical or a group of the formula -C (R 5 ) = CHR 6 ,
R5 ein Wasserstoffatom oder eine Methylgruppe ist und R6 eine gegebenenfalls substituierte Aryl- oder Heteroarylgruppe ist,R 5 is a hydrogen atom or a methyl group and R 6 is an optionally substituted aryl or heteroaryl group,
oder ein pharmakologisch akzeptables Salz, Solvat, Hydrat oder eine pharmakologisch akzeptable Formulierung derselben.or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.
2. Verbindungen der Formel (I), wobei R1 eine Methylgruppe ist .2. Compounds of formula (I), wherein R 1 is a methyl group.
3. Verbindungen nach Anspruch 1 oder 2, wobei R2 ein Wasserstoffatom oder eine Methylgruppe ist.3. Compounds according to claim 1 or 2, wherein R 2 is a hydrogen atom or a methyl group.
4. Verbindungen nach einem der Ansprüche 1 bis 3, wobei R3 eine Methylgruppe, eine Trifluormethylgruppe oder eine Gruppe der Formel COOH ist.4. Compounds according to any one of claims 1 to 3, wherein R 3 is a methyl group, a trifluoromethyl group or a group of the formula COOH.
5. Verbindungen nach einem der Ansprüche 1 bis 4, wobei R3 eine Trifluormethylgruppe ist.5. Compounds according to any one of claims 1 to 4, wherein R 3 is a trifluoromethyl group.
6. Verbindungen nach einem der Ansprüche 1 bis 5, wobei R6 ein gegebenenfalls substituierter 5- oder 6-gliedriger Heteroarylrest mit 1, 2 oder 3 Heteroatomen, ausgewählt aus S, N und 0 ist.6. Compounds according to any one of claims 1 to 5, wherein R 6 is an optionally substituted 5- or 6-membered heteroaryl radical having 1, 2 or 3 heteroatoms, selected from S, N and 0.
7. Verbindungen nach einem der Ansprüche 1 bis 5, wobei R6 ein gegebenenfalls substituierter Thiazolring oder Pyridinring ist .7. Compounds according to any one of claims 1 to 5, wherein R 6 is an optionally substituted thiazole ring or pyridine ring.
8. Verbindungen nach einem der Ansprüche 1 bis 5, wobei R4 eine Gruppe mit folgender Formel ist: 8. Compounds according to any one of claims 1 to 5, wherein R 4 is a group having the following formula:
9. Pharmazeutische Zusammensetzung, die eine Verbindung nach einem der Ansprüche 1 bis 8 und fakultativ einen oder mehrere Trägerstoffe und/oder ein oder mehrere Adjuvanzien enthält .9. A pharmaceutical composition containing a compound according to any one of claims 1 to 8 and optionally one or more carriers and / or one or more adjuvants.
10. Verwendung einer Verbindung oder einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 9 zur Behandlung von Krebserkrankungen. 10. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 9 for the treatment of cancer.
EP03763869A 2002-07-15 2003-07-15 Novel macrocycles for the treatment of cancer diseases Withdrawn EP1521750A1 (en)

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AU2003260002B2 (en) 2002-08-23 2010-03-18 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
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US7645782B2 (en) * 2002-11-28 2010-01-12 Wolfgang Richter Thia-epothilone derivatives for the treatment of cancer
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