WO2006131340A2 - Pyrrolones that act as peptide deformylase (pdf) inhibitors - Google Patents

Pyrrolones that act as peptide deformylase (pdf) inhibitors Download PDF

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WO2006131340A2
WO2006131340A2 PCT/EP2006/005429 EP2006005429W WO2006131340A2 WO 2006131340 A2 WO2006131340 A2 WO 2006131340A2 EP 2006005429 W EP2006005429 W EP 2006005429W WO 2006131340 A2 WO2006131340 A2 WO 2006131340A2
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group
alkyl
cycloalkyl
heterocycloalkyl
heteroalkyl
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PCT/EP2006/005429
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German (de)
French (fr)
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WO2006131340A3 (en
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Michael Thormann
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Origenis Ag
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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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • C07D207/34—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 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—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

Definitions

  • the present invention relates to novel inhibitors of peptide deformylase (PDF). These compounds are of particular interest as antibiotics, anticancer drugs, antiparasitics and herbicides.
  • PDF peptide deformylase
  • Peptide deformylase is a metalloenzyme, depending on
  • Organism contains iron or zinc in the active center. Analyzes at the genome level have shown that in addition to bacteria, parasites, plants (Giglione et al., EMBO J. 19 (21): 5916-5929 (2000)) and mammals also contain peptide deformylase. The enzyme is detectable in prokaryotes and in organelles of eukaryotes and plays a vital role in protein metabolism (Lee et al., J. Clin. Invest. 114: 1107-1116 (2004)). Peptide deformylase catalyzes the removal of the formyl group from the N-terminus of N-formylated proteins in a post-translational modification. Without the enzyme peptide deformylase, fully functional proteins can not be produced. Peptide deformylase is the target of a new class of antibiotics, anticancer drugs, antiparasitics and herbicides called peptide deformylase inhibitors.
  • the aim of the present invention was to provide novel inhibitors of peptide deformylase which are synthetically accessible by a simple route.
  • the present invention relates to compounds of the formula (D, wherein
  • R 1 and R 2 independently of one another represent a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaryl radical; aralkyl group, or Ri and R 2 together are part of an optionally substituted cycloalkyl ring or heterocycloalkyl ring having preferably 3 to 8 ring atoms;
  • R 3 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • R 4 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical, or R 3 and R 4 together Part of an optionally substituted cycloalkyl or heterocycloalkyl ring having preferably 3 to 8 ring atoms;
  • R 5 is a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • R 6 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • R 7 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
  • X is a group of formula -CH 2 -NOH-CHS, -NOH-CHS, -NOH-CHO, -CH 2 -NOH-CHO, -CH 2 -CHOH-CHO or -CHOH-CHO- or is selected from the following formulas :
  • U is a bond, CH 2 , NH, O or S
  • V is 0, S, NH or CH 2
  • W is 0, S, NH or CH 2
  • Y is OH or NH 2
  • E is a bond , CH 2 , NH, O or S is and the groups D, G and M independently of one another are N or CH, it being possible for all the above radicals to be optionally substituted,
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group having in particular 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, e.g. the methyl, ethyl, propyl, isopropyl, n-butyl, 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 having in particular 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, e.g. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • Alkenyl groups preferably have one or two (particularly preferably one) double bonds or alkinyl groups one or two (particularly preferably one) triple bonds.
  • heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms are represented by an oxygen, nitrogen, phosphorus, boron, selenium, Silicon or sulfur atom are replaced (preferably oxygen, sulfur or nitrogen).
  • heteroalkyl further refers to a carboxylic acid or a carboxylic acid derived group such as acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
  • R d is a hydrogen atom, a Ci-C ⁇ - alkyl, C 2 -C 6 alkenyl or a C 2 -C 6 alkynyl group and Y a is a direct bond, a Ci-C ß -alkylene, C2 C 6 is alkenylene or a C 2 -C 6 alkynylene group, each of
  • Heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms.
  • Heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl,
  • Enol ethers 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 alkylnitrile groups.
  • cycloalkyl refers to a saturated or partially unsaturated (eg cycloalkenyl) cyclic group which has one or more rings (preferably 1 or 2) which in particular have 3 to 14 ring carbon atoms, preferably 3 to 10 (in particular 3, 4, 5, 6 or 7) contains ring carbon atoms.
  • 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 included 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.
  • Examples are the piperidyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, oxacyclopropyl, azacyclopropyl or 2-pyrazolinyl group and also lactams, lactones, cyclic imides and cyclic anhydrides.
  • alkylcycloalkyl refers to groups containing, in accordance with the above definitions, both cycloalkyl and alkyl, alkenyl or alkynyl groups, e.g. Alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups.
  • An alkylcycloalkyl group preferably contains a cycloalkyl group which has one or two rings with 3 to 10 (in particular 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms contains.
  • heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms and / or carbon atoms are replaced by an oxygen,
  • a heteroalkylcycloalkyl group has 1 or 2 rings of 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups of 1 or 2 to 6 carbon atoms.
  • Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl wherein the cyclic groups are saturated or mono-, di- or triunsaturated.
  • aryl or Ar refers to an aromatic group which has one or more rings having in particular 6 to 14 ring carbon atoms, preferably 6 to 10 (in particular 6) ring carbon atoms.
  • aryl (or Ar) furthermore refers to groups in which one or more hydrogen atoms are represented by fluorine, chlorine, bromine or iodine atoms or -COOH, -OH, -SH, -NH 2 , or -NÜ 2 - Groups are replaced. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxy-phenyl group.
  • heteroaryl refers to an aromatic group which contains one or more rings having in particular 5 to 14 ring atoms, preferably 5 to 10 (in particular 5 or 6) ring atoms, and one or more (preferably 1, 2, 3 or 4) oxygen atoms. , Nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N).
  • heteroaryl further refers to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or -COOH, -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 containing, in accordance with the above definitions, both aryl and alkyl, alkenyl, alkynyl and / or cycloalkyl groups, e.g. Arylalkyl, alkylaryl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups.
  • aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane.
  • An aralkyl group preferably contains one or two aromatic rings having 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms and / or a cycloalkyl group having 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) ring carbon atoms and / or carbon atoms are represented by an oxygen, nitrogen, silicon, selenium, phosphorus, boron - or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced, ie groups which according to the above definitions both aryl or heteroaryl as well as alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups.
  • a heteroaralkyl group contains one or two aromatic rings having 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms and / or a Cycloalkyl group having 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms are replaced by oxygen, sulfur or nitrogen atoms.
  • Examples are arylheteroalkyl, arylheterocycloalkyl,
  • Ci-C ⁇ alkyl C 2 -C O alkenyl, C 2 -C 6 alkynyl, Ci-C ⁇ heteroalkyl, C 3 -C 0 cycloalkyl, C 2 -Cg heterocycloalkyl, C ⁇ -Cio aryl, C1-C9 heteroaryl, C 7 -C 2 aralkyl or C 2 -Cn heteroaralkyl groups are substituted.
  • Compounds of formula (I) may contain one or more chiral centers due to their substitution.
  • the present invention therefore encompasses both all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
  • all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof are also encompassed by the present invention.
  • all tautomeric forms of the compounds of the formula (I) are encompassed by the present invention.
  • X is a group of the formula -CH 2 -CO-NHOH, -CO-NHOH, -CH 2 -NOH-CHS, -NOH-CHS, -CH 2 -NOH-CHO, -NOH-CHO, -CH 2 -CO-CH 2 OH, -CO-CH 2 OH, -CH 2 -CHOH-CHO, -CHOH-CHO or a group having one of the following formulas:
  • X is preferably a group of the formula -CO-NHOH.
  • Ri is a hydrogen atom.
  • R 2 is a C 3 _ 7 alkyl or C 3 _ 7 alkyl or hetero-C 3-7 alkylcycloalkyl, or heteroalkyl cycloalkyl group; in particular an n-butyl or an n-pentyl group.
  • R 3 is a hydrogen atom or a methyl group, or R 3 and R 4 together form part of an optionally substituted cycloalkyl ring or Heterocycloalkylrings having preferably 3 to 8 ring atoms, in particular 4-6 ring atoms
  • R 4 is a hydrogen atom or an optionally substituted heteroaryl radical; in particular a hydrogen atom, a pyridyl, benzofuranyl, furanyl, thiazolyl, imidazolyl or a p-Aminobenzamidinylrest.
  • R 5 is an optionally substituted C 20 alkyl group, an optionally substituted branched C 20 alkyl group, an optionally substituted aryl, heteroaryl or an optionally substituted cycloalkyl group.
  • R 5 is an optionally substituted C 2 - 6 alkyl group or an optionally substituted branched C 2 - 6 alkyl group, an o-, m- or p-substituted or o- and m-disubstituted phenyl group.
  • R 5 is a propyl, isopropyl, phenyl, o-nitrophenyl, p-hydroxyphenyl, m-hydroxyphenyl, m, p-dihydroxyphenyl, m-amidinophenyl, cyclohexyl, cyclopropyl or 3 ' -Indolyl distr.
  • radicals Re and R 7 are hydrogen atoms.
  • n is equal to 1.
  • Examples of pharmacologically acceptable salts of the compounds of the formula (I) are 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, formic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • Compounds of the formula (I) can be solvated, especially be hydrated. For example, hydration may occur during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I).
  • compositions according to the present invention contain at least one compound of formula (I) as active ingredient and optionally excipients and / or adjuvants.
  • the prodrugs (eg RB Silverman, Medicinal Chemistry, VCH Weinheim, 1995, Chapter 8, p. 361ff), which are also the subject of the present invention, consist of a compound of formula (I) and at least one pharmacologically acceptable protecting group is cleaved under physiological conditions, eg a hydroxy, alkoxy, aralkyloxy, acyl or acyloxy group, e.g. a methoxy, ethoxy, benzyloxy, acetyl or acetyloxy group.
  • physiological conditions eg a hydroxy, alkoxy, aralkyloxy, acyl or acyloxy group, e.g. a methoxy, ethoxy, benzyloxy, acetyl or acetyloxy group.
  • compounds of the formula (I) are of great interest, above all, as inhibitors of metalloproteinases (in particular of PDF).
  • the use of these active ingredients for the preparation of medicaments for the prevention and / or treatment of diseases, in particular those which are mediated by PDF, is the subject of the present invention.
  • compounds of formula (I) using the known and acceptable modes, either alone or in combination with any other therapeutic agent.
  • the administration can take place, for example, in one of the following ways: orally, eg as dragees, coated tablets,
  • the therapeutically useful product may be mixed with pharmacologically inert, inorganic or organic excipients, e.g.
  • excipients such as e.g. vegetable oils, petroleum, animal or synthetic oils, wax, grease, polyols. to
  • excipients such as water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerol, vegetable oils, petroleum, animal or synthetic oils.
  • excipients such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols.
  • aerosol formulations one can use compressed gases that are suitable for this purpose, such as oxygen, nitrogen and carbon dioxide.
  • the pharmaceutically acceptable agents may also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for Containing changes in osmotic pressure, buffers, coating additives and antioxidants.
  • the plate was shaken for 20 min at RT.

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Abstract

The invention relates to compounds of formula (I). Said compounds are novel inhibitors of peptide deformylase (PDF) and are therefore of great interest when used in particular as novel antibiotics, active agents against cancer, antiparasitic agents and herbicides.

Description

Peptid-Dθfoxmylasθ (PDF) Inhibitoren 3 Peptid-Dθfoxmylasθ (PDF) Inhibitors 3
Die vorliegende Erfindung betrifft neue Inhibitoren der Peptid-Deformylase (PDF). Diese Verbindungen sind insbesondere als Antibiotika, Wirkstoffe gegen Krebs, Antiparasitika und Herbizide von großem Interesse.The present invention relates to novel inhibitors of peptide deformylase (PDF). These compounds are of particular interest as antibiotics, anticancer drugs, antiparasitics and herbicides.
Peptiddeformylase ist ein Metalloenzym, das je nachPeptide deformylase is a metalloenzyme, depending on
Organismus Eisen oder Zink im aktiven Zentrum enthält. Analysen auf Genom-Ebene haben gezeigt, dass neben Bakterien auch Parasiten, Pflanzen (Giglione et al., EMBO J. 19 (21) : 5916-5929 (2000)) und Säugetiere Peptiddeformylase enthalten. Das Enzym ist bei Prokaryonten und in Organellen von Eukaryonten nachweisbar und spielt eine vitale Rolle im Proteinstoffwechsel (Lee et al., J. Clin. Invest. 114:1107- 1116 (2004)). Peptiddeformylase katalysiert die Entfernung der Formyl-Gruppe vom N-Terminus N-formylierter Proteine in einer posttranslationalen Modifikation. Ohne das Enyzm Peptiddeformylase können keine voll funktionsfähigen Proteine entstehen. Die Peptiddeformylase ist der Angriffspunkt einer neuen Klasse von Antibiotika, Wirkstoffen gegen Krebs, Antiparasitika und Herbiziden, die Peptiddeformylase-Inhibitoren genannt werden.Organism contains iron or zinc in the active center. Analyzes at the genome level have shown that in addition to bacteria, parasites, plants (Giglione et al., EMBO J. 19 (21): 5916-5929 (2000)) and mammals also contain peptide deformylase. The enzyme is detectable in prokaryotes and in organelles of eukaryotes and plays a vital role in protein metabolism (Lee et al., J. Clin. Invest. 114: 1107-1116 (2004)). Peptide deformylase catalyzes the removal of the formyl group from the N-terminus of N-formylated proteins in a post-translational modification. Without the enzyme peptide deformylase, fully functional proteins can not be produced. Peptide deformylase is the target of a new class of antibiotics, anticancer drugs, antiparasitics and herbicides called peptide deformylase inhibitors.
Ziel der vorliegenden Erfindung war es, neue Inhibitoren von Peptid-Deformylase bereitzustellen, die synthetisch auf einfachem Wege zugänglich sind.The aim of the present invention was to provide novel inhibitors of peptide deformylase which are synthetically accessible by a simple route.
Die vorliegende Erfindung betrifft Verbindungen der Formel (D,
Figure imgf000003_0001
worinThe present invention relates to compounds of the formula (D,
Figure imgf000003_0001
wherein
die Reste Ri und R2 unabhängig voneinander ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkyl- cycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Hetero- aralkylrest sind, oder Ri und R2 zusammen Teil eines gegebenenfalls substituierten Cycloalkylrings oder Heterocycloalkylrings mit vorzugsweise 3 bis 8 Ringatomen sind;R 1 and R 2 independently of one another represent a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaryl radical; aralkyl group, or Ri and R 2 together are part of an optionally substituted cycloalkyl ring or heterocycloalkyl ring having preferably 3 to 8 ring atoms;
R3 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist;R 3 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R4 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist, oder R3 und R4 zusammen Teil eines gegebenenfalls substituierten Cycloalkylrings oder Heterocycloalkylrings mit vorzugsweise 3 bis 8 Ringatomen sind;R 4 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical, or R 3 and R 4 together Part of an optionally substituted cycloalkyl or heterocycloalkyl ring having preferably 3 to 8 ring atoms;
n gleich 1 oder 2 ist; A-B zusammen eine Gruppe der Formel -CO-CR7- oder -C(OR6)=C- ist;n is 1 or 2; AB together is a group of the formula -CO-CR 7 - or -C (OR 6 ) = C-;
Q ein Schwefel oder ein Kohlenstoffatom oder eine S=O Gruppe, insbesondere ein Kohlenstoffatom, ist;Q is a sulfur or a carbon atom or an S = O group, in particular a carbon atom;
R5 ein Wasserstoffatom, ein Halogenatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cyclo- alkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Hetero- cycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist;R 5 is a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R6 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist;R 6 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R7 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist; undR 7 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical; and
X eine Gruppe der Formel -CH2-NOH-CHS, -NOH-CHS, -NOH-CHO, -CH2-NOH-CHO, -CH2-CHOH-CHO oder -CHOH-CHO ist oder aus folgenden Formeln ausgewählt ist:X is a group of formula -CH 2 -NOH-CHS, -NOH-CHS, -NOH-CHO, -CH 2 -NOH-CHO, -CH 2 -CHOH-CHO or -CHOH-CHO- or is selected from the following formulas :
Figure imgf000004_0001
wobei U eine Bindung, CH2, NH, 0 oder S ist, V gleich 0, S, NH oder CH2 ist, W gleich 0, S, NH oder CH2 ist und Y gleich OH oder NH2 ist, E eine Bindung, CH2, NH, 0 oder S ist und die Gruppen D, G und M unabhängig voneinander N oder CH sind, wobei alle vorstehenden Reste gegebenenfalls substituiert sein können,
Figure imgf000004_0001
wherein U is a bond, CH 2 , NH, O or S, V is 0, S, NH or CH 2 , W is 0, S, NH or CH 2 and Y is OH or NH 2 , E is a bond , CH 2 , NH, O or S is and the groups D, G and M independently of one another are N or CH, it being possible for all the above radicals to be optionally substituted,
oder ein pharmazeutisch akzeptables Salz, Solvat, Hydrat oder eine pharmazeutisch akzeptable Formulierung derselben.or a pharmaceutically acceptable salt, solvate, hydrate or a pharmaceutically acceptable formulation thereof.
Der Ausdruck Alkyl bezieht sich auf eine gesättigte, geradkettige oder verzweigte Kohlenwasserstoffgruppe, die insbesondere 1 bis 20 Kohlenstoffatome, vorzugsweise 1 bis 12 Kohlenstoffatome, besonders bevorzugt 1 bis 6 Kohlenstoffatome aufweist, z.B. die Methyl-, Ethyl-, Propyl-, Isopropyl-, n-Butyl-, Isobutyl-, tert-Butyl-, n-Hexyl-, 2, 2-Dimethylbutyl- oder n-Octyl-Gruppe .The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group having in particular 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, e.g. the methyl, ethyl, propyl, isopropyl, n-butyl, 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 insbesondere 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 having in particular 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, e.g. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Alkenyl groups preferably have one or two (particularly preferably one) double bonds or alkinyl groups one or two (particularly preferably one) triple bonds.
Des weiteren beziehen sich die Begriffe Alkyl, Alkenyl und Alkinyl auf Gruppen, bei denen z.B. ein oder mehrere Wasserstoffatome durch ein Halogenatom (bevorzugt F oder Cl), -COOH, -OH, -SH, -NH2, -NO2, =0, =S, =NH ersetzt sind wie z.B. die 2, 2, 2-Trichlorethyl-, oder die Trifluormethylgruppe . 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 durch ein Sauerstoff-, Stickstoff-, Phosphor-, Bor-, Selen-, Silizium- oder Schwefelatom ersetzt sind (bevorzugt Sauerstoff, Schwefel oder Stickstoff) . Der Ausdruck Heteroalkyl bezieht sich des weiteren auf eine Carbonsäure oder eine von einer Carbonsäure abgeleiteten Gruppe wie z.B. Acyl, Acylalkyl, Alkoxycarbonyl, Acyloxy, Acyloxyalkyl, Carboxyalkylamid oder Alkoxycarbonyloxy .Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which, for example, one or more hydrogen atoms by a halogen atom (preferably F or Cl), -COOH, -OH, -SH, -NH 2 , -NO 2 , = 0 , = S, = NH are replaced, such as the 2, 2, 2-trichloroethyl, or the trifluoromethyl group. 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 represented by an oxygen, nitrogen, phosphorus, boron, selenium, Silicon or sulfur atom are replaced (preferably oxygen, sulfur or nitrogen). The term heteroalkyl further refers to a carboxylic acid or a carboxylic acid derived group such as acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
Beispiele für Heteroalkylgruppen sind Gruppen der Formeln Ra-O-Ya-, Ra-S-Ya-, Ra-N(Rb)-Ya-, Ra-CO-Ya-, Ra-O-CO-Ya-, Ra-CO-O-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N (Rb) -CO-Ya-, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb) -CO-O-Y3-, Ra-N (Rb) -CO-N (Rc) -Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb) -C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N(Rb) -Ya-, Ra-N (Rb) -CS-Ya-, Ra-O-CS-N(Rb) -Ya-, Ra-N (Rb) -CS-O-Y3-, Ra-N (Rb) -CS-N (Rc) -Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N (Rb) -Y3-, Ra-N(Rb) -CO-S-Y3-, Ra-S-CO-O-Ya-, R3-0-C0-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb) -Ya-, Ra-N (Rb) -CS-S-Y3-, R3-S-CS-0-Ya-, Ra-O-CS-S-Ya-, wobei R3 ein Wasserstoffatom, eine Ci-Cε-Alkyl-, eine C2-C6~Alkenyl- oder eine C2-C6- Alkinylgruppe; Rb ein Wasserstoffatom, eine Ci-Cβ-Alkyl-, eine C2-C6-Alkenyl- oder eine C2~C6-Alkinylgruppe; Rc einExamples of heteroalkyl groups are groups of the formulas R a -OY a , R a -SY a , R a -N (R b ) -Y a , R a -CO-Y a , R a -O-CO- Y a -, R a -CO-OY a -, R a -CO-N (R b) -Y a -, R a -N (R b) -CO-Y a -, R a -O-CO- N (R b ) -Y a -, R a -N (R b ) -CO-OY 3 -, R a -N (R b ) -CO-N (R c ) -Y a -, R a -O -CO-OY a -, R a -N (R b ) -C (= NR d ) -N (R c ) -Y a -, R a -CS-Y a -, R a -O-CS-Y a -, R a -CS-OY a -, R a -CS-N (R b ) -Y a -, R a -N (R b ) -CS-Y a -, R a -O-CS-N (R b ) -Y a -, R a -N (R b ) -CS-OY 3 -, R a -N (R b ) -CS-N (R c ) -Y a -, R a -O- CS-OY a -, R a -S-CO-Y a -, R a -CO-SY a -, R a -S-CO-N (R b ) -Y 3 -, R a -N (R b ) -CO-SY 3 -, R a -S-CO-OY a -, R 3 -0-C0-SY a -, R a -S-CO-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 3 -S-CS- 0-Y a -, R a -O-CS-SY a -, where R 3 is a hydrogen atom, a Ci-Cε-alkyl, C2-C6 ~ alkenyl or a C2-C 6 - alkynyl; R b represents a hydrogen atom, a Ci-Cβ alkyl, a C 2 -C 6 alkenyl or a C 2 ~ C 6 alkynyl group; R c
Wasserstoffatom, eine Ci-Cβ-Alkyl-, eine C2-C6-Alkenyl- oder eine C2-Cg-Alkinylgruppe; Rd ein Wasserstoffatom, eine Ci-Cβ- Alkyl-, eine C2-C6-Alkenyl- oder eine C2-C6-Alkinylgruppe und Ya eine direkte Bindung, eine Ci-Cß-Alkylen-, eine C2-C6- Alkenylen- oder eine C2~C6-Alkinylengruppe ist, wobei jedeHydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -Cg alkynyl; R d is a hydrogen atom, a Ci-Cβ- alkyl, C 2 -C 6 alkenyl or a C 2 -C 6 alkynyl group and Y a is a direct bond, a Ci-C ß -alkylene, C2 C 6 is alkenylene or a C 2 -C 6 alkynylene group, each of
Heteroalkylgruppe mindestens ein Kohlenstoffatom enthält und ein oder mehrere Wasserstoffatome 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, Dirnethylamino, Diethylamino, iso-Propylethylamino, Methyl- aminomethyl, Ethylaminomethyl, Di-iso-Propylaminoethyl,Heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms. Concrete examples of Heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl,
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.Enol ethers, 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 alkylnitrile groups.
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 insbesondere 3 bis 14 Ringkohlenstoffatome, vorzugsweise 3 bis 10 (insbesondere 3, 4, 5, 6 oder 7) Ringkohlenstoffatome enthält. Der Ausdruck Cycloalkyl bezieht sich weiterhin auf Gruppen, bei denen ein oder mehrere Wasserstoffatome durch Fluor-, Chlor-, Brom- oder Jodatome oder -COOH, -OH, =0, -SH, =S, -NH2, =NH oder -NO2- 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 cycloalkyl refers to a saturated or partially unsaturated (eg cycloalkenyl) cyclic group which has one or more rings (preferably 1 or 2) which in particular have 3 to 14 ring carbon atoms, preferably 3 to 10 (in particular 3, 4, 5, 6 or 7) contains ring carbon atoms. The term cycloalkyl furthermore refers to groups in which one or more hydrogen atoms are represented by fluorine, chlorine, bromine or iodine atoms or -COOH, -OH, = O, -SH, SS, -NH 2 , NHNH or NO 2 - groups are replaced, so for example cyclic ketones such as 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) Ringkohlenstoffatome 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 durch Fluor-, Chlor-, Brom- oder Jodatome oder -COOH, -OH, =0, -SH, =S, - NH2, =NH oder -NO2-Gruppen ersetzt sind. Beispiele sind die Piperidyl-, Morpholinyl-, Urotropinyl-, Pyrrolidinyl-, Tetrahydrothiophenyl-, Tetrahydropyranyl-, Tetrahydro- furyl-, Oxacyclopropyl-, Azacyclopropyl- oder 2-Pyrazolinyl- Gruppe sowie Lactame, 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 included 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 furthermore refers to groups in which one or more hydrogen atoms are represented by fluorine, chlorine, bromine or iodine atoms or -COOH, -OH, = O, -SH, SS, -NH 2 , NHNH or NO 2 groups are replaced. Examples are the piperidyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, oxacyclopropyl, azacyclopropyl or 2-pyrazolinyl group and also lactams, lactones, cyclic imides and cyclic anhydrides.
Der Ausdruck Alkylcycloalkyl bezieht sich auf Gruppen, die entsprechend den obigen Definitionen sowohl Cycloalkyl- als auch Alkyl-, Alkenyl- oder Alkinylgruppen enthalten, z.B. Alkylcycloalkyl-, Alkylcycloalkenyl-, Alkenylcycloalkyl- und Alkinylcycloalkylgruppen. Bevorzugt enthält eine Alkylcyclo- alkylgruppe eine Cycloalkylgruppe, die einen oder zwei Ringe mit 3 bis 10 (insbesondere 3, 4, 5, 6 oder 7) Ringkohlenstoffatomen aufweist und eine oder zwei Alkyl-, Alkenyl- oder Alkinylgruppen mit 1 oder 2 bis 6 Kohlenstoffatomen enthält.The term alkylcycloalkyl refers to groups containing, in accordance with the above definitions, both cycloalkyl and alkyl, alkenyl or alkynyl groups, e.g. Alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group which has one or two rings with 3 to 10 (in particular 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms contains.
Der Ausdruck Heteroalkylcycloalkyl bezieht sich auf Alkylcycloalkylgruppen, wie oben definiert, in der ein oder mehrere (bevorzugt 1, 2 oder 3) Ringkohlenstoffatome und/oder Kohlenstoffatome durch ein Sauerstoff-,The term heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms and / or carbon atoms are replaced by an oxygen,
Stickstoff-, Silizium-, Selen-, Phosphor- oder Schwefelatom (bevorzugt Sauerstoff, Schwefel oder Stickstoff) ersetzt sind. Bevorzugt besitzt eine Heteroalkylcycloalkylgruppe 1 oder 2 Ringe 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 Alkylheterocycloalkyl, Alkylheterocycloalkenyl, Alkenylheterocycloalkyl, Alkinylheterocycloalkyl, Heteroalkylcycloalkyl, Heteroalkylheterocycloalkyl und Heteroalkyl- heterocycloalkenyl, wobei die cyclischen Gruppen gesättigt oder einfach, zweifach oder dreifach ungesättigt sind.Nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced. Preferably, a heteroalkylcycloalkyl group has 1 or 2 rings of 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups of 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl wherein the cyclic groups are saturated or mono-, di- or triunsaturated.
Der Ausdruck Aryl bzw. Ar bezieht sich auf eine aromatische Gruppe, die einen oder mehrere Ringe mit insbesondere 6 bis 14 Ringkohlenstoffatomen, vorzugsweise 6 bis 10 (insbesondere 6) Ringkohlenstoffatomen aufweist. Der Ausdruck Aryl (bzw. Ar) bezieht sich weiterhin auf Gruppen, bei denen ein oder mehrere Wasserstoffatome durch Fluor-, Chlor-, Brom- oder Jodatome oder -COOH, -OH, -SH, -NH2, oder -NÜ2-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 which has one or more rings having in particular 6 to 14 ring carbon atoms, preferably 6 to 10 (in particular 6) ring carbon atoms. The term aryl (or Ar) furthermore refers to groups in which one or more hydrogen atoms are represented by fluorine, chlorine, bromine or iodine atoms or -COOH, -OH, -SH, -NH 2 , or -NÜ 2 - Groups are replaced. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxy-phenyl group.
Der Ausdruck Heteroaryl bezieht sich auf eine aromatische Gruppe, die einen oder mehrere Ringe mit insbesondere 5 bis 14 Ringatomen, vorzugsweise 5 bis 10 (insbesondere 5 oder 6) Ringatomen enthält und ein oder mehrere (bevorzugt 1, 2, 3 oder 4) Sauerstoff-, Stickstoff-, Phosphor- oder Schwefel- Ringatome (bevorzugt 0, S oder N) enthält. Der Ausdruck Heteroaryl bezieht sich weiterhin auf Gruppen, bei denen .ein oder mehrere Wasserstoffatome durch Fluor-, Chlor-, Brom- oder Jodatome oder -COOH, -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 which contains one or more rings having in particular 5 to 14 ring atoms, preferably 5 to 10 (in particular 5 or 6) ring atoms, and one or more (preferably 1, 2, 3 or 4) oxygen atoms. , Nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N). The term heteroaryl further refers to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or -COOH, -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- als auch Alkyl-, Alkenyl-, Alkinyl- und/oder Cycloalkylgruppen enthalten, wie z.B. Arylalkyl-, Alkylaryl-, Arylalkenyl-, Arylalkinyl-, Arylcycloalkyl-, Arylcycloalkenyl-, Alkylarylcycloalkyl- und Alkylarylcycloalkenylgruppen. Konkrete Beispiele für Ar- alkyle sind Toluol, Xylol, Mesitylen, Styrol, Benzylchlorid, o-Fluortoluol, 1H-Inden, Tetralin, Dihydronaphthalin, Indanon, Phenylcyclopentyl, Cumol, Cyclohexylphenyl, Fluoren und Indan. Bevorzugt enthält eine Aralkylgruppe ein oder zwei aromatische Ringe mit 6 bis 10 Ringkohlenstoffatomen 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 containing, in accordance with the above definitions, both aryl and alkyl, alkenyl, alkynyl and / or cycloalkyl groups, e.g. Arylalkyl, alkylaryl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Concrete examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic rings having 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms and / or a cycloalkyl group having 5 or 6 ring carbon atoms.
Der Ausdruck Heteroaralkyl bezieht sich auf eine Aralkylgruppe wie oben definiert, in der ein oder mehrere (bevorzugt 1, 2, 3 oder 4) Ringkohlenstoffatome und/oder Kohlenstoffatome 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 Heterocycloalkylgruppen enthalten. Bevorzugt enthält eine Heteroaralkylgruppe ein oder zwei aromatische Ringe mit 5 oder 6 bis 10 Ringkohlenstoffatomen und ein oder zwei Alkyl-, Alkenyl- und/oder Alkinylgruppen mit 1 oder 2 bis 6 Kohlenstoffatomen und/oder eine Cycloalkylgruppe mit 5 oder 6 Ringkohlenstoffatomen, wobei 1, 2, 3 oder 4 dieser Kohlenstoffatome 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) ring carbon atoms and / or carbon atoms are represented by an oxygen, nitrogen, silicon, selenium, phosphorus, boron - or sulfur atom (preferably oxygen, sulfur or nitrogen) are replaced, ie groups which according to the above definitions both aryl or heteroaryl as well as alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. Preferably, a heteroaralkyl group contains one or two aromatic rings having 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms and / or a Cycloalkyl group having 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms are replaced by oxygen, sulfur or nitrogen atoms.
Beispiele sind Arylheteroalkyl-, Arylheterocycloalkyl-,Examples are arylheteroalkyl, arylheterocycloalkyl,
Arylheterocycloalkenyl-, Arylalkylheterocycloalkyl-, Aryl- alkenylheterocycloalkyl-, Arylalkinylheterocycloalkyl-, Arylalkylheterocycloalkenyl-, Heteroarylalkyl-, Heteroaryl- alkenyl-, Heteroarylalkinyl-, Heteroarylheteroalkyl-, Heteroarylcycloalkyl-, Heteroarylcycloalkenyl-, Heteroaryl- heterocycloalkyl-, Heteroarylheterocycloalkenyl-, Hetero- arylalkylcycloalkyl-, Heteroarylalkylhetero-cycloalkenyl-, Heteroarylheteroalkylcycloalkyl-, Heteroarylheteroalkyl- cycloalkenyl- und Heteroarylheteroalkylheterocycloalkyl- 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-Carboxy- phenylalkylgruppe .Arylheterocycloalkenyl-, Arylalkylheterocycloalkyl-, aryl alkenylheterocycloalkyl-, alkenyl, heterocycloalkyl Arylalkinylheterocycloalkyl-, Arylalkylheterocycloalkenyl-, heteroarylalkyl, heteroaryl heteroarylalkynyl- Heteroarylheteroalkyl-, Heteroarylcycloalkyl-, Heteroarylcycloalkenyl-, heteroaryl, Heteroarylheterocycloalkenyl-, arylalkylcycloalkyl- hetero-, Heteroarylalkylhetero-cycloalkenyl, Heteroarylheteroalkylcycloalkyl-, Heteroarylheteroalkyl- cycloalkenyl and Heteroarylheteroalkylheterocycloalkyl- groups, wherein the cyclic groups are saturated or mono-, di- or triunsaturated. Specific examples are the tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxy - phenylalkyl 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 durch Fluor-, Chlor-, Brom- oder Jodatome oder OH, =0, SH, =S, NH2, =NH oder NÜ2-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 represented by fluorine, chlorine, bromine or iodine atoms or OH, = 0, SH, = S, NH 2 , = NH or NÜ 2 groups are replaced.
Der Ausdruck "gegebenenfalls substituiert" bezieht sich auf Gruppen, in denen ein oder mehrere Wasserstoffatome z.B. durch Fluor-, Chlor-, Brom- oder Jodatome oder -COOH, -OH, =0, -SH, =S, -NH2, =NH oder -NO2-Gruppen ersetzt sind. Dieser Ausdruck bezieht sich weiterhin auf Gruppen, die mit unsubstituierten Ci-Cβ Alkyl-, C2-CO Alkenyl-, C2-C6 Alkinyl-, Ci-Cβ Heteroalkyl-, C3-Ci0 Cycloalkyl-, C2-Cg Heterocycloalkyl-, Cβ-Cio Aryl-, C1-C9 Heteroaryl-, C7-Ci2 Aralkyl- oder C2-Cn Heteroaralkyl-Gruppen substituiert sind.The term "optionally substituted" refers to groups in which one or more hydrogen atoms are substituted by, for example, fluorine, chlorine, bromine or iodine atoms or -COOH, -OH, = O, -SH, = S, -NH 2 , = NH or -NO 2 groups are replaced. This term continues to refer to groups that use unsubstituted Ci-Cβ alkyl, C 2 -C O alkenyl, C 2 -C 6 alkynyl, Ci-Cβ heteroalkyl, C 3 -C 0 cycloalkyl, C 2 -Cg heterocycloalkyl, Cβ-Cio aryl, C1-C9 heteroaryl, C 7 -C 2 aralkyl or C 2 -Cn heteroaralkyl groups are substituted.
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) may contain one or more chiral centers due to their substitution. The present invention therefore encompasses both all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio. Furthermore, all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof are also encompassed by the present invention. Furthermore, all tautomeric forms of the compounds of the formula (I) are encompassed by the present invention.
Bevorzugt sind Verbindungen der Formel (I), wobei W gleich NH ist und V gleich O, S oder NH ist.Preference is given to compounds of the formula (I) where W is NH and V is O, S or NH.
Weiter bevorzugt sind Verbindungen der Formel (I), wobei eine, zwei oder drei der Gruppen D, G und M Stickstoffatome sind.Further preferred are compounds of the formula (I) wherein one, two or three of the groups D, G and M are nitrogen atoms.
Besonders bevorzugt sind Verbindungen der Formel (I), wobei X eine Gruppe der Formel -CH2-CO-NHOH, -CO-NHOH, -CH2-NOH-CHS, -NOH-CHS, -CH2-NOH-CHO, -NOH-CHO, -CH2-CO-CH2OH, -CO-CH2OH, -CH2-CHOH-CHO, -CHOH-CHO oder eine Gruppe mit einer der folgenden Formeln ist:
Figure imgf000013_0001
Particular preference is given to compounds of the formula (I) in which X is a group of the formula -CH 2 -CO-NHOH, -CO-NHOH, -CH 2 -NOH-CHS, -NOH-CHS, -CH 2 -NOH-CHO, -NOH-CHO, -CH 2 -CO-CH 2 OH, -CO-CH 2 OH, -CH 2 -CHOH-CHO, -CHOH-CHO or a group having one of the following formulas:
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000013_0003
Insbesondere bevorzugt ist X eine Gruppe der Formel -CO-NHOH.In particular, X is preferably a group of the formula -CO-NHOH.
Weiterhin bevorzugt ist Ri ein Wasserstoffatom.Further preferably, Ri is a hydrogen atom.
Weiter bevorzugt ist R2 eine C3_7 Alkyl- oder C3_7 Hetero- alkyl- oder C3-7 Alkylcycloalkyl- oder Heteroalkyl- cycloalkylgruppe; insbesondere eine n-Butyl- oder eine n- Pentylgruppe .More preferably, R 2 is a C 3 _ 7 alkyl or C 3 _ 7 alkyl or hetero-C 3-7 alkylcycloalkyl, or heteroalkyl cycloalkyl group; in particular an n-butyl or an n-pentyl group.
Weiter bevorzugt ist R3 ein Wasserstoffatom oder eine Methylgruppe oder R3 und R4 zusammen Teil eines gegebenenfalls substituierten Cycloalkylrings oder Heterocycloalkylrings mit vorzugsweise 3 bis 8 Ringatomen, insbesondere 4 - 6 Ringatomen sindMore preferably, R 3 is a hydrogen atom or a methyl group, or R 3 and R 4 together form part of an optionally substituted cycloalkyl ring or Heterocycloalkylrings having preferably 3 to 8 ring atoms, in particular 4-6 ring atoms
Wiederum bevorzugt ist R4 ein Wasserstoffatom oder ein gegebenenfalls substituierter Heteroarylrest ; insbesondere ein Wasserstoffatom, ein Pyridyl-, Benzofuranyl-, Furanyl-, Thiazolyl-, Imidazolyl- oder ein p-Aminobenzamidinylrest .Again, preferably R 4 is a hydrogen atom or an optionally substituted heteroaryl radical; in particular a hydrogen atom, a pyridyl, benzofuranyl, furanyl, thiazolyl, imidazolyl or a p-Aminobenzamidinylrest.
Weiter bevorzugt ist R5 eine gegebenenfalls substituierte Ci- 20 Alkylgruppe, eine gegebenenfalls substituierte verzweigte Ci-20 Alkylgruppe, eine gegebenenfalls substituierte Aryl-, Heteroaryl- oder eine gegebenenfalls substituierte Cyclo- alkylgruppe. Besonders bevorzugt ist R5 eine gegebenenfalls substituierte C2-6 Alkylgruppe oder eine gegebenenfalls substituierte verzweigte C2-6 Alkylgruppe, eine o-, m- oder p-substituierte oder o- und m-disubstituierte Phenylgruppe . Insbesondere bevorzugt ist R5 eine Propyl-, Isopropyl-, Phenyl-, o-Nitrophenyl-, p-Hydroxyphenyl-, m-Hydroxyphenyl-, m, p-Dihydroxyphenyl-, m-Amidinophenyl-, Cyclohexyl-, Cyclopropyl- oder 3 ' -Indolylgruppe.More preferably R 5 is an optionally substituted C 20 alkyl group, an optionally substituted branched C 20 alkyl group, an optionally substituted aryl, heteroaryl or an optionally substituted cycloalkyl group. Particularly preferably, R 5 is an optionally substituted C 2 - 6 alkyl group or an optionally substituted branched C 2 - 6 alkyl group, an o-, m- or p-substituted or o- and m-disubstituted phenyl group. Most preferably R 5 is a propyl, isopropyl, phenyl, o-nitrophenyl, p-hydroxyphenyl, m-hydroxyphenyl, m, p-dihydroxyphenyl, m-amidinophenyl, cyclohexyl, cyclopropyl or 3 ' -Indolylgruppe.
Weiter bevorzugt sind die Reste Re bzw. R7 Wasserstoffatome .More preferably, the radicals Re and R 7 are hydrogen atoms.
Weiter bevorzugt ist n gleich 1.More preferably, n is equal to 1.
Beispiele für pharmakologisch akzeptable Salze der Verbindungen der Formel (I) sind Salze von physiologisch akzeptablen Mineralsäuren wie Salzsäure, Schwefelsäure und Phosphorsäure; oder Salze von organischen Säuren wie Methan- sulfonsäure, p-Toluolsulfonsäure, Milchsäure, Ameisensäure, Essigsäure, Trifluoressigsäure, 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.Examples of pharmacologically acceptable salts of the compounds of the formula (I) are 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, formic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Compounds of the formula (I) can be solvated, especially be hydrated. For example, hydration may occur during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I).
Die pharmazeutischen Zusammensetzungen gemäß der vorliegenden Erfindung enthalten mindestens eine Verbindung der Formel (I) als Wirkstoff und fakultativ Trägerstoffe und/oder Adjuvantien.The pharmaceutical compositions according to the present invention contain at least one compound of formula (I) as active ingredient and optionally excipients and / or adjuvants.
Die Pro-Drugs (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 Hydroxy-, Alkoxy-, Aralkyloxy-, Acyl- oder Acyloxy-Gruppe, wie z.B. einer Methoxy-, Ethoxy-, Benzyloxy-, Acetyl- oder Acetyloxy-Gruppe .The prodrugs (eg RB Silverman, Medicinal Chemistry, VCH Weinheim, 1995, Chapter 8, p. 361ff), which are also the subject of the present invention, consist of a compound of formula (I) and at least one pharmacologically acceptable protecting group is cleaved under physiological conditions, eg a hydroxy, alkoxy, aralkyloxy, acyl or acyloxy group, e.g. a methoxy, 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 ist ebenfalls Gegenstand der vorliegenden Erfindung.The therapeutic use of the compounds of the formula (I), their pharmacologically acceptable salts or solvates and hydrates, as well as formulations and pharmaceutical compositions is likewise provided by the present invention.
Verbindungen der Formel (I) sind erfindungsgemäß vor allem als Inhibitoren von Metalloproteinasen (insbesondere von PDF) von grossem Interesse. Auch die Verwendung dieser Wirkstoffe zur Herstellung von Arzneimitteln zur Vorbeugung und/oder Behandlung von Erkrankungen, insbesondere solche, die durch PDF vermittelt werden, 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. Die Verabreichung kann z.B. auf einem der folgenden Wege erfolgen: oral, z.B. als Dragees, überzogene Tabletten,According to the invention, compounds of the formula (I) are of great interest, above all, as inhibitors of metalloproteinases (in particular of PDF). The use of these active ingredients for the preparation of medicaments for the prevention and / or treatment of diseases, in particular those which are mediated by PDF, is the subject of the present invention. In general, compounds of formula (I) using the known and acceptable modes, either alone or in combination with any other therapeutic agent. The administration can take place, for example, in one of the following ways: orally, eg as dragees, coated tablets,
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 z.B. als Pflaster 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, SiIi- cagel, 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, Polyole einsetzen. ZurPills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenteral, e.g. as an injectable solution; rectally as suppositories; by inhalation, e.g. as a powder formulation or spray, transdermally e.g. as a patch or intranasally. For the preparation of such tablets, pills, semi-solids, coated tablets, dragées and hard gelatin capsules, the therapeutically useful product may be mixed with pharmacologically inert, inorganic or organic excipients, e.g. 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 preparation of soft capsules, excipients such as e.g. vegetable oils, petroleum, animal or synthetic oils, wax, grease, polyols. to
Herstellung von flüssigen Lösungen und Sirups kann man Arzneimittelträgerstoffe wie z.B. Wasser, Alkohole, wäßrige Salzlösung, wäßrige Dextrose, Polyole, Glycerin, pflanzliche Öle, Petroleum, tierische oder synthetische Öle verwenden. Für Suppositorien kann man Arzneimittelträgerstoffe wie z.B. pflanzliche Öle, Petroleum, tierische oder synthetische Öle, Wachs, Fett und Polyole verwenden. Für Aerosol- Formulierungen kann man komprimierte Gase, die für diesen Zweck geeignet sind, wie z.B. Sauerstoff, Stickstoff und Kohlendioxid einsetzen. Die pharmazeutisch verwendbaren Mittel können auch Zusatzstoffe zur Konservierung, Stabilisierung, Emulgatoren, Süßstoffe, Aromastoffe, Salze zur Veränderung des osmotischen Drucks, Puffer, Umhüllungszusatzstoffe und Antioxidantien enthalten.To prepare liquid solutions and syrups, one may use excipients such as water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerol, vegetable oils, petroleum, animal or synthetic oils. For suppositories, one may use excipients such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations, one can use compressed gases that are suitable for this purpose, such as oxygen, nitrogen and carbon dioxide. The pharmaceutically acceptable agents may also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for Containing changes in osmotic pressure, buffers, coating additives and antioxidants.
Verbindungen der Formel (I) können durch Umsetzung von Verbindungen der Formeln X-[CR1R2Jn-NH2 (II), R3-CO-R4 (III) und R5-Q (=0) -CH2-CO-COOEt oder R5-Q (=0) -CH2-CO-COOMe oder R5-Q (=0) -CH2-CO-COOH (IV) hergestellt werden, wobei die Reste wie vorstehend definiert sind.Compounds of formula (I) may be prepared by reacting compounds of formulas X- [CR 1 R 2 J n -NH 2 (II), R 3 -CO-R 4 (III) and R 5 -Q (= O) -CH 2 -CO-COOEt or R 5 -Q (= O) -CH 2 -CO-COOMe or R 5 -Q (= O) -CH 2 -CO-COOH (IV), the radicals being as defined above ,
BeispieleExamples
Allgemeine Arbeitsvorschrift:General procedure:
50 μl einer 0,2 M Lösung von Amin (II) in Ethanol : Dichlor- methan (1:1) wurden auf einer 96-Well Platte dispensiert.50 μl of a 0.2 M solution of amine (II) in ethanol: dichloromethane (1: 1) were dispensed on a 96-well plate.
Dazu wurden 50 μl einer 0,2 M Lösung des Aldehyds (R3 = H) bzw. Ketons (III) in Ethanol : Dichlormethan (1:1) gegeben.To this was added 50 μl of a 0.2 M solution of the aldehyde (R 3 = H) or ketone (III) in ethanol: dichloromethane (1: 1).
Die Platte wurde für 20 min bei RT geschüttelt.The plate was shaken for 20 min at RT.
Anschliessend wurden 50 μl einer 0,2 M Lösung der Ketosäure (IV) in Ethanol: Dichlormethan (1:1) dispensiert. Die Platte wurde über Nacht bei RT geschüttelt und das Lösungsmittel anschliessend evaporiert.Subsequently, 50 μl of a 0.2 M solution of the keto acid (IV) in ethanol: dichloromethane (1: 1) were dispensed. The plate was shaken overnight at RT and the solvent was subsequently evaporated.
Die folgenden Verbindungen wurden unter Verwendung der geeigneten Ausgangsmaterialien gemäß der allgemeinenThe following compounds were prepared using the appropriate starting materials according to the general
Arbeitsvorschrift hergestellt und massenspektrometrisch identifiziert. Alle Verbindungen wurden auf Ihre Aktivität als PDF-Inhibitoren untersucht (Für den Assay siehe: D. Chen et al . , Antimicrobial Agents and Chemotherapy, Jan. 2004, S. 250-261) und wiesen IC50 Werte im Bereich zwischen 1 nmol/1 und 50 μmol/1 auf.Working instructions prepared and identified by mass spectrometry. All compounds were tested for activity as PDF inhibitors (For the assay, see: D. Chen et al., Antimicrobial Agents and Chemotherapy, Jan. 2004, pp. 250-261) and had IC 50 values ranging between 1 nmol / 1 and 50 .mu.mol / 1 on.
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
2- [2-Benzofuran-2-yl-4-hydroxy-3- (4-imidazol-l-yl-benzoyl) -5-oxo- 2, 5-dihydro-pyrrol-l-yl] -hexansäure hydroxyamid 515 23 515 .24 537 .21 n.d.
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
2- [2-Benzofuran-2-yl-4-hydroxy-3- (4-imidazol-1-yl-benzoyl) -5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 515 23 515 .24 537 .21 nd
2- [3-Hydroxy-2-oxo-4- (pyridin-4- carbonyl) -5-thiophen-2-yl-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 416. 16 416 .16 438 14 n.d.2- [3-Hydroxy-2-oxo-4- (pyridine-4-carbonyl) -5-thiophen-2-yl-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 416. 16 416.16 438 14 nd
2- ( 3-Cyclohexancarbonyl-4-hydroxy- 5-oxo-2-thiazol-2-yl-2, 5-dihydro- pyrrol-l-yl) -hexansäure hydroxyamic 422. 22 422 .21 444 .2 444 .22- (3-Cyclohexanecarbonyl-4-hydroxy-5-oxo-2-thiazol-2-yl-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamic 422. 22 422 .21 444 .2 444 .2
2- [3-Cyclohexancarbonyl-2- (3- fluoro-phenyl) -4-hydroxy-5-oxo-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 433. 26 433 .27 455. 24 455. 252- [3-Cyclohexanecarbonyl-2- (3-fluoro-phenyl) -4-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 433. 26 433 .27 455. 24 455 25
2- [3- (2, 2-Dimethyl-propionyl) -4- hydroxy-5-oxo-2- (2-trifluoromethyl- phenyl) -2, 5-dihydro-pyrrol-l-yl] - hexansäure hydroxyamid 457. 24 n. ci. 479. 22 479. 242- [3- (2,2-Dimethyl-propionyl) -4-hydroxy-5-oxo-2- (2-trifluoromethylphenyl) -2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 457. 24 n. Ci. 479. 22 479. 24
2- (2-tert-Butyl-4-hydroxy-3- isobutyryl-5-oxo-2, 5-dihydro- pyrrol-l-yl) -hexansäure hydroxyamid 355. 28 n. ci. 377. 26 377. 182- (2-tert-Butyl-4-hydroxy-3-isobutyryl-5-oxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamide 355. 28 n.ci. 377. 26 377. 18
2-[2-Benzofuran-2-yl-3-(2,2- dimethyl-propionyl) -4-hydroxy-5- oxo-2, 5-dihydro-pyrrol-l-yl] - hexansäure hydroxyamid 429. 25 429 24 451. 23 451. 242- [2-Benzofuran-2-yl-3- (2,2-dimethyl-propionyl) -4-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 429. 25 429 24 451. 23 451. 24
2- (3-Cyclohexancarbonyl-2- cyclopropyl-4-hydroxy-5-oxo-2, 5- dihydro-pyrrol-1-yl) -hexansäure hydroxyamid 379. 27 379. 27 401. 26 401. 272- (3-Cyclohexanecarbonyl-2-cyclopropyl-4-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamide 379. 27 379. 27 401. 26 401. 27
2- [3- (2, 2-Dimethyl-propionyl) -4- hydroxy-2-isopropyl-5-oxo-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 355. 28 355. 35 377. 26 377. 242- [3- (2,2-Dimethyl-propionyl) -4-hydroxy-2-isopropyl-5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 355. 28 355. 35 377. 26 377. 24
2- [2- ( 3-Fluoro-phenyl) -4-hydroxy-5- oxo-3- (pyridin-4-carbonyl) -2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 428. 19 428. 22 450. 18 n. d2- [2- (3-fluoro-phenyl) -4-hydroxy-5-oxo-3- (pyridine-4-carbonyl) -2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 428. 19 428 22 450. 18 n. D
2- [3-Hydroxy-2-oxo-4- (pyridin-4- carbonyl) -5-m-tolyl-2, 5-dihydro- 424. 23 424. 23 446. 21 n.d •
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
2- [3-Benzoyl-2- (2, 3-dihydroxy- phenyl) -4-hydroxy-5-oxo-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 441 .2 n. d. 463 .18 463.192- [3-hydroxy-2-oxo-4- (pyridine-4-carbonyl) -5-m-tolyl-2,5-dihydro-424,23,424,234,446,211
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
2- [3-Benzoyl-2- (2,3-dihydroxyphenyl) -4-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 441 .2 nd 463 .18 463.19
2- (3-Benzoyl-4-hydroxy-5-oxo-2-o- tolyl-2, 5-dihydro-pyrrol-l-yl) - hexansäure hydroxyamid 423. 23 423 .25 445 .21 445.222- (3-Benzoyl-4-hydroxy-5-oxo-2-o-tolyl-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamide 423. 23 423 .25 445 .21 445.22
2- ( 3-Cyclopropancarbonyl-4-hydroxy- 5-oxo-2-pyridin-4-yl-2, 5-dihydro- pyrrol-l-yl) -hexansäure hydroxyamid 374. 21 374 .25 396 .19 n.d.2- (3-Cyclopropanecarbonyl-4-hydroxy-5-oxo-2-pyridin-4-yl-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamide 374. 21 374 .25 396 .19 n.d.
2- (3-Cyclohexancarbonyl-4-hydroxy- 5-oxo-2-pyridin-2-yl-2, 5-dihydro- pyrrol-l-yl) -hexansäure hydroxyamid 416. 27 416 .27 438 .25 n.d.2- (3-Cyclohexanecarbonyl-4-hydroxy-5-oxo-2-pyridin-2-yl-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamide 416. 27 416.27 438 .25 n.d.
2- (3-Benzoyl-4-hydroxy-5-oxo-2- chinolin-2-yl-2, 5-dihydro-pyrrol-l- yl) -hexansäure hydroxyamid 460. 22 460 .24 482 .21 n.d.2- (3-Benzoyl-4-hydroxy-5-oxo-2-quinolin-2-yl-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamide 460. 22 460.24 482 .21 n.d.
2- [3-Cyclohexancarbonyl-4-hydroxy- 2- (5-methyl-furan-2-yl) -5-oxo-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 419. 27 n.d. 441 25 441.262- [3-Cyclohexanecarbonyl-4-hydroxy-2- (5-methyl-furan-2-yl) -5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 419. 27 n.d. 441 25 441.26
2- [3-Cyclohexancarbonyl-2- (2- fluoro-phenyl) -4-hydroxy-5-oxo-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 433. 26 433 27 455 24 455.262- [3-Cyclohexanecarbonyl-2- (2-fluoro-phenyl) -4-hydroxy-5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 433. 26 433 27 455 24 455.26
2- [3-Hydroxy-4- (4-methyl-benzoyl) - 5- (2-methylsulfanyl-ethyl) -2-oxo- 2, 5-dihydro-pyrrol-l-yl] -hexansäure hydroxyamid 421. 23 421. 22 443. 21 443.22- [3-Hydroxy-4- (4-methyl-benzoyl) -5- (2-methylsulfanyl-ethyl) -2-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 421. 23 421 22 443. 21 443.2
2- [2- (2, 3-Dimethoxy-phenyl) -A- hydroxy-5-oxo-3- (pyridin-4- carbonyl) -2, 5-dihydro-pyrrol-l-yl] - hexansäure hydroxyamid 470. 23 470. 25 492. 22 n.d.2- [2- (2,3-Dimethoxyphenyl) -A-hydroxy-5-oxo-3- (pyridine-4-carbonyl) -2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 470. 23 470. 25 492. 22 nd
2- (3-Benzoyl-4-hydroxy-2-isopropyl- 5-oxo-2, 5-dihydro-pyrrol-l-yl) - hexansäure hydroxyamid 375. 23 n. c I. 397. 22 397.222- (3-Benzoyl-4-hydroxy-2-isopropyl-5-oxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid hydroxyamide 375. 23 n. C I. 397. 22 397.22
2- [2-Benzyl-4-hydroxy-3- (4-methyl- benzoyl) -5-oxo-2, 5-dihydro-pyrrol- l-yl] -hexansäure hydroxyamid 437. 25 437. 24 459. 23 459.24 2- [3-Cyclopropancarbonyl-4-hydroxy- 2- (5-methyl-furan-2-yl) -5-oxo-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 377. 21 377 .2 399 19 399.192- [2-Benzyl-4-hydroxy-3- (4-methylbenzoyl) -5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 437. 25 437. 24 459. 23 459.24 2- [3-Cyclopropanecarbonyl-4-hydroxy-2- (5-methyl-furan-2-yl) -5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 377. 21 377 .2 399 19 399.19
2- [ 3-Hydroxy-2-oxo-4- (pyridin-4- carbonyl) -5- (3, 4, 5-trimethoxy- phenyl) -2, 5-dihydro-pyrrol-l-yl] - hexansäure hydroxyamid 500. 25 500. 25 522. 23 n. d.2- [3-Hydroxy-2-oxo-4- (pyridine-4-carbonyl) -5- (3, 4, 5-trimethoxyphenyl) -2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 500. 25 500. 25 522. 23 nd
2- [2- (2-Fluoro-phenyl) -4-hydroxy-3- (4-methyl-benzoyl) -5-oxo-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 441. 22 441. 23 463 .2 463.212- [2- (2-Fluorophenyl) -4-hydroxy-3- (4-methyl-benzoyl) -5-oxo-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 441. 22 441 23 463 .2 463.21
2- [3-Hydroxy-4- (4-methyl-benzoyl) - 2-oxo-5-pyridin-2-yl-2, 5-dihydro- pyrrol-l-yl] -hexansäure hydroxyamid 424. 23 424. 23 446. 21 n.d.2- [3-Hydroxy-4- (4-methylbenzoyl) -2-oxo-5-pyridin-2-yl-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 424. 23 424. 23 446. 21 nd
2- [3-Hydroxy-2-oxo-4- (pyridin-4- carbonyl) -5-chinolin-2-yl-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 461. 22 461. 23 483 .2 n.d.2- [3-Hydroxy-2-oxo-4- (pyridine-4-carbonyl) -5-quinolin-2-yl-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 461. 22 461. 23 483 .2 nd
2- [3-Hydroxy-2-oxo-4- (pyridin-4- carbonyl) -5-pyridin-2-yl-2, 5- dihydro-pyrrol-1-yl] -hexansäure hydroxyamid 411 2 411 .2 433. 18 n.d.2- [3-Hydroxy-2-oxo-4- (pyridine-4-carbonyl) -5-pyridin-2-yl-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 411 2 411 .2 433 18 nd
2- [3-Hydroxy-2-oxo-4- (pyridin-4- carbonyl) -5-o-tolyl-2, 5-dihydro- pyrrol-l-yl] -hexansäure hydroxyamid 424. 23 424. 23 446. 21 n.d. n.d. = nicht detektiert 2- [3-Hydroxy-2-oxo-4- (pyridine-4-carbonyl) -5-o-tolyl-2,5-dihydro-pyrrol-1-yl] -hexanoic acid hydroxyamide 424. 23 424. 23 446. 21 nd n.d. = not detected

Claims

Patentansprüche claims
Verbindungen der Formel (i;Compounds of the formula (i;
Figure imgf000028_0001
worin
Figure imgf000028_0001
wherein
die Reste Ri und R2 unabhängig voneinander ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Hetero- alkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcyclo- alkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest sind, oder R1 und R2 zusammen Teil eines gegebenenfalls substituierten Cycloalkylrings oder Heterocycloalkylrings sind;R 1 and R 2 independently of one another represent a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a group Heteroaralkyl radical, or R 1 and R 2 together are part of an optionally substituted cycloalkyl or heterocycloalkyl ring;
R3 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkyl- cycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist;R 3 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R4 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkyl- cycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist, oder R3 und R4 zusammen Teil eines gegebenenfalls substituierten Cycloalkylrings oder Heterocycloalkylrings sind;R 4 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical, or R 3 and R 4 together form part of an optionally substituted cycloalkyl or heterocycloalkyl ring;
n gleich 1 oder 2 ist;n is 1 or 2;
A-B zusammen eine Gruppe der Formel -CO-CR7- oder -C(OR6)=C- ist;AB together is a group of the formula -CO-CR 7 - or -C (OR 6 ) = C-;
Q ein Schwefelatom oder ein Kohlenstoffatom oder eine S=O Gruppe ist;Q is a sulfur atom or a carbon atom or an S = O group;
R5 ein Wasserstoffatom, ein Halogenatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist;R 5 is a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R6 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkyl- cycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist;R 6 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R7 ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkyl- cycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist; undR 7 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical; and
X eine Gruppe der Formel -CH2-NOH-CHS, -NOH-CHS, -NOH-CHO, -CH2-NOH-CHO, -CH2-CHOH-CHO oder -CHOH-CHO ist oder aus folgenden Formeln ausgewählt ist:
Figure imgf000030_0001
wobei U eine Bindung, CH2, NH, O oder S ist, V gleich O, S, NH oder CH2 ist, W gleich O, S, NH oder CH2 ist und Y gleich OH oder NH2 ist, E eine Bindung, CH2, NH, O oder S ist und die Gruppen D, G und M unabhängig voneinander N oder CH sind,X is a group of formula -CH 2 -NOH-CHS, -NOH-CHS, -NOH-CHO, -CH 2 -NOH-CHO, -CH 2 -CHOH-CHO or -CHOH-CHO- or is selected from the following formulas :
Figure imgf000030_0001
wherein U is a bond, CH 2 , NH, O or S, V is O, S, NH or CH 2 , W is O, S, NH or CH 2 and Y is OH or NH 2 , E is a bond , CH 2 , NH, O or S and the groups D, G and M are independently N or CH,
oder ein pharmazeutisch akzeptables Salz, Solvat, Hydrat oder eine pharmazeutisch akzeptable Formulierung derselben.or a pharmaceutically acceptable salt, solvate, hydrate or a pharmaceutically acceptable formulation thereof.
2. Verbindungen nach Anspruch 1, wobei X eine Gruppe der Formel -CO-NHOH ist.2. Compounds according to claim 1, wherein X is a group of the formula -CO-NHOH.
3. Verbindungen nach Anspruch 1 oder 2, wobei Ri ein Wasserstoffatom ist.3. Compounds according to claim 1 or 2, wherein Ri is a hydrogen atom.
4. Verbindungen nach Anspruch 1, 2 oder 3, wobei R2 eine C3-7 Alkyl- oder C3_7 Heteroalkylgruppe ist.4. Compounds according to claim 1, 2 or 3, wherein R 2 is a C 3 - 7 alkyl or C 3 _ 7 heteroalkyl group.
5. Verbindungen nach Anspruch 1, 2 oder 3, wobei R2 eine n-Butyl- oder eine n-Pentylgruppe ist.5. Compounds according to claim 1, 2 or 3, wherein R 2 is an n-butyl or an n-pentyl group.
6. Verbindungen nach Anspruch 1, 2, 3, 4 oder 5, wobei R3 ein Wasserstoffatom ist.6. Compounds according to claim 1, 2, 3, 4 or 5, wherein R 3 is a hydrogen atom.
7. Verbindungen nach Anspruch 1, 2 oder 3, wobei R5 eine Propyl-, Isopropyl-, Phenyl-, o-Nitrophenyl-, p-Hydroxyphenyl-, m-Hydroxyphenyl-, m, p-Dihydroxy- phenyl-, Furanyl-, Thiazolyl-, Imidazolyl-, m- Amidinophenyl-, Cyclohexyl-, Cyclopropyl- oder 3'- Indolylgruppe ist.7. Compounds according to claim 1, 2 or 3, wherein R 5 is a propyl, isopropyl, phenyl, o-nitrophenyl, p-hydroxyphenyl, m-hydroxyphenyl, m, p-dihydroxyphenyl, furanyl , Thiazolyl, imidazolyl, m Amidinophenyl, cyclohexyl, cyclopropyl or 3'-indolyl group.
8. Verbindungen nach Anspruch 1, 2, 3, 4, 5, 6 oder 7, wobei die Reste Rε bzw. R7 Wasserstoffatome sind.8. Compounds according to claim 1, 2, 3, 4, 5, 6 or 7, wherein the radicals Rε and R 7 are hydrogen atoms.
9. Verbindungen nach Anspruch 1, 2, 3, 4, 5, 6, 7 oder 8, wobei n gleich 1 ist.9. Compounds according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein n is 1.
10. Pharmazeutische Zusammensetzung, die eine Verbindung nach einem der Ansprüche 1 bis 9 und fakultativ Trägerstoffe und/oder Adjuvanzien enthält.10. A pharmaceutical composition containing a compound according to any one of claims 1 to 9 and optionally excipients and / or adjuvants.
11. Verwendung einer Verbindung oder einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 10 zur11. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 10 for
Inhibierung von Metalloproteinasen.Inhibition of metalloproteinases.
12. Verwendung einer Verbindung oder einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 10 zur Inhibierung von Peptid Deformylase (PDF) .12. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 10 for the inhibition of peptide deformylase (PDF).
13. Verwendung einer Verbindung oder einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 10 zur Behandlung und/oder Vorbeugung von Erkrankungen, die durch Metalloproteinase-Aktivität vermittelt werden.Use of a compound or a pharmaceutical composition according to any one of claims 1 to 10 for the treatment and / or prevention of diseases mediated by metalloproteinase activity.
14. Verwendung einer Verbindung oder einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 10 zur Behandlung und/oder Vorbeugung von Erkrankungen, die durch Peptid Deformylase (PDF) Aktivität vermittelt werden. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 10 for the treatment and / or prevention of diseases mediated by peptide deformylase (PDF) activity.
15. Verwendung einer Verbindung oder einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 10 als Antibiotikum, Wirkstoff gegen Krebs, Antiparasitikum oder Herbizid. 15. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 10 as an antibiotic, anti-cancer drug, antiparasitic or herbicide.
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