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Definitions

• the invention relates to thiazolidinones, to their production and to their use as inhibitors of polo-like kinases (PIk) for treating various diseases.
• PIk polo-like kinases
• Tumour cells are distinguished by an uninhibited cell-cycle process. On the one hand, this is based on the loss of control proteins, such as RB, p16, p21 , p53, etc., as well as the activation of so-called accelerators of the cell-cycle process, the cyclin-dependent kinases (Cdks).
• the Cdks are an anti-tumour target protein that is acknowledged in pharmaceutics.
• Plk-1 A high expression rate of Plk-1 was found in 'non-small cell lung' cancer (Wolf et al. Oncogene, 14, 543 et seq., 1997), in melanomas (Strebhardt et al. JAMA, 283, 479 et seq., 2000), in 'squamous cell carcinomas' (Knecht et al. Cancer Res, 59, 2794 et seq., 1999) and in 'esophageal carcinomas' (Tokumitsu et al. lnt J Oncol 15, 687 et seq., 1999).
• Plk-1 constitutive expression of Plk-1 in NIH-3T3 cells resulted in a malignant transformation (increased proliferation, growth in soft agar, colony formation and tumour development in hairless mice) (Smith et al. Biochem Biophys Res Comm, 234, 397 et seq., 1997).
• antisense-oligo-molecules did not inhibit the growth and the viability of primary human mesangial cells (Mundt et al., Biochem Biophys Res Comm, 269, 377 et seq., 2000).
• sequence identity within the PIk domains of the polo family is between 40 and 60%, so that partial interaction of inhibitors of a kinase occurs with one or more other kinases of this family. Depending on the structure of the inhibitor, however, the action can also take place selectively or preferably on only one kinase of the polo family.
• the object of this invention is now to make available additional substances that inhibit kinases of the polo family in the micro- and nanomolar range.
• a and B independently of one another, stand for hydrogen, halogen, hydroxy,
• heterocycloalkyl itself optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or optionally can be interrupted by one or more -C(O)- or -SO 2 - groups in the ring and/or optionally one or more double bonds can be contained in the ring and/or the ring itself optionally can be substituted in one or more places, in the same way or differently, with
• -SO 2 - groups in the ring and/or optionally one or more double bonds can be contained in the ring, and/or the ring itself optionally can be substituted in one or more places, in the same way or differently, with Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl, CrC 6 -hydroxyalkyl or with the group -NR 3 R 4 ,
• M stands for CrC ⁇ -alkyl that optionally is substituted in one or more places, in the same way or differently, with the group -NR 3 R 4 or C 3 -C 6 - heterocycloalkyl
• X stands for -NH- or -NR 5 -
• R 1 stands for Ci-C 4 -alkyl, C 3 -cycloalkyl, allyl or propargyl that optionally is substituted in one or more places, in the same way or differently, with halogen
• R 2 stands for hydrogen or for C r C 6 -alkyl, CrC ⁇ -alkoxy, CrC 6 -alkenyl,
• R 2 and R 5 together form a C 3 -C 6 -heterocycloalkyl ring, which is interrupted at least once by nitrogen and optionally can be interrupted in one or more places by oxygen or sulfur and /or optionally can be interrupted by one or more -C(O)- or -SO 2 - groups in the ring and/or optionally one or more double bonds can be contained in the ring, and /or the ring itself optionally can be substituted in one or more places, in the same way or differently, with cyano, halogen, hydroxy, CrC 6 -alkyl, C 3 -C 6 -cycloalkyl, C r C 6 -hydroxyalkyl, C r C 6 -alkoxyalkyl or with the group -NR 3 R 4 Or -COR 6 , and /or can be substituted with aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with halogen, d-C ⁇ -alk
• R 3 and R 4 independently of one another, stand for hydrogen or for Ci-C ⁇ -alkyi, CrC ⁇ -alkoxy, -CO-CrC ⁇ -alkyl or aryl that optionally is substituted in one or more places, in the same way or differently, with halogen, hydroxy, C 3 -C ⁇ -heterocycloalkyl, Ci-C ⁇ -hydroxyalkoxy or with the group -NR 3 R 4 , whereby the heterocycloalkyl itself optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or optionally can be interrupted by one or more -C(O)- or -SO 2 - groups in the ring and/or optionally one or more double bonds can be contained in the ring, and whereby the C 3 -C 6 -heterocycloalkyl ring itself optionally can be substituted in one or more places, in the same way or differently, with cyano, halogen, CrC ⁇ -alkyl
• R 3 and R 4 together form a C 3 -C 6 -heterocycloalkyl ring, which is interrupted at least once by nitrogen and optionally can be interrupted in one or more places by oxygen or sulfur and /or optionally can be interrupted by one or more -C(O)- or -SO 2 - groups in the ring and/or optionally one or more double bonds can be contained in the ring, and/or the heterocycloalkyl ring itself optionally can be substituted in one or more places, in the same way or differently, with d-C ⁇ -alkyl,
• R 5 stands for C r C 6 -alkyl, C r C 6 -alkenyl, or CrC 6 -alkynyl that optionally is substituted in one or more places, in the same way or differently, with halogen, hydroxy, cyano, C r C 6 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 - heterocycloalkyl, or with the group -NR 3 R 4 , whereby the heterocycloalkyl itself optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or optionally can be interrupted by one or more -C(O)- or -SO 2 groups in the ring and/or optionally one or more double bonds can be contained in the ring, and whereby the C 3 -C 6 -heterocycloalkyl ring itself in each case optionally can be substituted in one or more places, in the same way or differently, with cyano, halogen, d-
• R 7 stands for -(CH 2 ) n -aryl or -(CH 2 ) n -heteroaryl, and n stands for an integer of 1 , 2, 3, 4, 5 or 6, as well as the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof, are suitable inhibitors of the kinases of the polo family.
• the compounds of general formula I according to the invention essentially inhibit the polo-like kinases, upon which is based their action against, for example, cancer, such as solid tumours and leukemia; auto-immune diseases, such as psoriasis, alopecia, and multiple sclerosis, chemotherapy agent-induced alopecia and mucositis; cardiovascular diseases, such as stenoses, arterioscleroses and restenoses; infectious diseases, such as those, e.g., produced by unicellular parasites, such as trypanosoma, toxoplasma or Plasmodium, or produced by fungi; nephrological diseases, such as, e.g., glomerulonephritis; chronic neurodegenerative diseases, such as Huntington's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases, such as ischemias of the brain and neurotraumas; viral infections, such as, e.
• Stereoisomers are defined as E/Z- and R/S-isomers as well as mixtures that consist of E/Z- and R/S-isomers.
• alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert. -butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl, and the isomers thereof.
• alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec. -butyloxy, tert- butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy, and the isomers thereof.
• alkenyl is defined in each case as a straight-chain or branched alkenyl group, whereby, for example, the following radicals are meant: vinyl, propen-1 -yl, propen-2-yl, but-1 -en-1 -yl, but-1 -en-2-yl, but-2-en-1 -yl, but-2-en-2-yl, 2-methyl- prop-2-en-1 -yl, 2-methyl-prop-1 -en-1 -yl, but-1 -en-3-yl, but-3-en-1 -yl, and allyl.
• alkynyl is defined in each case as a straight-chain or branched alkynyl radical that contains 2 to 6, preferably 2 to 4, C atoms.
• the following radicals can be mentioned: acetylene, propyn-1-yl, propyn-3-yl, but-1 -yn-1 -yl, but- 1 -yn-4-yl, but-2-yn-1 -yl, but-1 -yn-3-yl, etc.
• heterocycloalkyl stands for an alkyl ring that comprises 3 to 6 carbon atoms, in which one or more carbon contains is (are) replaced by one or more heteroatoms that are the same or different, such as, e.g., oxygen, sulfur or nitrogen and/or optionally can be interrupted by one or more -C(O)- or -SO2- groups in the ring, and/or optionally one or more double bonds can be contained in the ring, and can contain another substituent on one or more carbon, nitrogen or sulfur atoms, optionally independently of one another.
• Substituents on the heterocycloalkyl ring can be: cyano, halogen, hydroxy, CrC ⁇ -alkyl, d-C ⁇ -alkoxy, Ci-C 6 -alkoxyalkyl, C r C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, aryl, or the group -NR 3 R 4 , -CO-NR 3 R 4 , -SO 2 R 3 or -SO 2 NR 3 R 4 .
• heterocycloalkyls there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thimorpholinyl, piperazinyl, trithianyl, quinuclidinyl, pyrolidonyl, N-methylpyrolidinyl, 2-hydroxymethylpyrolidinyl, 3- hydroxypyrolidinyl, N-methylpiperazinyl, N-acetylpiperazinyl, N- methylsulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2- hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, nor
• cycloalkyl is defined as a monocyclic alkyl ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings, such as, for example, adamantanyl.
• the cycloalkyl can optionally also be benzocondensed, such as, e.g., (tetralin)yl, etc.
• halogen is defined in each case as fluorine, chlorine, bromine or iodine.
• aryl is defined in each case as having 3 to 12 carbon atoms, preferably 6 to 12 carbon atoms, such as, for example, cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl etc, phenyl being preferred.
• heteroaryl is understood as meaning an aromatic ring system which comprises 3 to 16 ring atoms, preferably 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzocondensed.
• heteroaryl is selected from thienyl, furanyl, pyrrolidinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H- pyrazolyl etc., and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.
• Preferred heteroaryl radicals are, for example, 5-membered ring heterocycles, such as thiophene, furanyl, oxazolyl, thiazole, imidazolyl and benzo derivatives thereof, and 6-membered ring heterocycles, such as pyridinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl and benzo derivatives thereof.
• 5-membered ring heterocycles such as thiophene, furanyl, oxazolyl, thiazole, imidazolyl and benzo derivatives thereof
• 6-membered ring heterocycles such as pyridinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl and benzo derivatives thereof.
• C 1 -C 6 as used throughout this text, e.g.
• C r C 6 -alkyl in the context of the definition of "C r C 6 -alkyl", “C r C 6 -alkoxy”, “C r C 6 -hydroxyalkyl”, “C 1 -C 6 - hydroxyalkoxy”, or “d-C 6 -alkoxyalkoxy”, etc., is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “CrC 6 " is to be interpreted as any sub-range comprised therein, e.g.
• alkenyl or "alkynyl”, as used throughout this text, is to be understood as meaning an alkenyl or alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms.
• C 2 -C 6 is to be interpreted as any subrange comprised therein, e.g. C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , C 3 -C 5 , C 3 -C 4 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 ; preferably C 2 -C 3 .
• C 1 -C 4 As used herein, the term "C 1 -C 4 ", as used throughout this text, e.g. in the context of the definition of "CrC 4 -alkyl", etc., is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3, or 4 carbon atoms. It is to be understood further that said term “C 1 -C 4 " is to be interpreted as any preferable sub-range comprised therein, e.g. C 1 -C 4 , C 2 -C 3 , C 1 -C 2 , C 1 -C 3 , C 2 -C 4 .
• C 3 -C 6 As used herein, the term "C 3 -C 6 ", as used throughout this text, e.g. in the context of the definitions of "C 3 -C 6 -cycloalkyl” or “C 3 -C 6 -heterocycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms, or a heterocycloalkyl group having a finite number of ring atoms, of 3 to 6, i.e. 3, 4, 5, or 6 carbon atoms, preferably 5 or 6 carbon atoms. It is to be understood further that said term “C 3 -C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 6 , C 4 -C 5 , C 5 -C 6 ; preferably C 5 -C 6 .
• Isomers are defined as chemical compounds of the same summation formula but different chemical structure. In general, constitutional isomers and stereoisomers are distinguished. Constitutional isomers have the same summation formula but are distinguished by the way in which their atoms or atom groups are linked. These include functional isomers, position isomers, tautomers or valence isomers.
• Stereoisomers have basically the same structure (constitutional) - and thus also the same summation formula - but are distinguished by the spatial arrangement of the atoms.
• Configurational isomers are stereoisomers that can be converted into one another only by bond breaking. These include enantiomers, diastereomers and E/Z (cis/trans)isomers.
• Enantiomers are stereoisomers that behave like image and mirror image to one another and do not exhibit any plane of symmetry. All stereoisomers that are not enantiomers are referred to as diastereomers. E/Z (cis/trans)isomers on double bonds are a special case.
• Conformational isomers are stereoisomers that can be converted into one another by the rotation of single bonds.
• the compounds of general formula I according to the invention also contain the possible tautomeric forms and comprise the E- or Z-isomers or, if a chiral center is present, also the racemates and enantiomers. Among the latter, double-bond isomers are also defined.
• the compounds according to the invention can also be present in the form of solvates, especially hydrates, whereby the compounds according to the invention consequently contain polar solvents, especially water, as structural elements of the crystal lattice of the compounds according to the invention.
• polar solvent especially water
• the proportion of polar solvent, especially water can be present in a stoichiometric or else unstoichiometric ratio.
• stoichiometric solvates and hydrates hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates or hydrates are also mentioned.
• the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl- glucamine, lysine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropane diol, Sovak base, and 1 -amino- 2,3,4-butanetriol.
• the readily soluble alkali and alkaline-earth salts as well as N-methyl-glucamine, dimethyl-glucamine, ethyl- glucamine, lysine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane,
• physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, succinic acid, methylsulphonic acid, para-toluenesulphonic acid, etc:
• a and B independently of one another, stand for hydrogen, halogen, hydroxy, -NR 3 R 4 , cyano or nitro, or for Ci-C 4 -alkyl, CrC ⁇ -alkoxy or C 3 -C 6 -heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with halogen, hydroxy, C 3 -C 6 -heterocycloalkyl or with the group -NR 3 R 4 or -C0(NR 3 )-M, whereby the heterocycloalkyl itself optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms, and/or optionally can be interrupted by one or more -C(O)- or -SO 2 groups in the ring and/or optionally one or more double bonds can be contained in the ring and/or the ring itself optionally can be substituted in one or more places, in the same way or differently, with
• L stands for d-C ⁇ -alkyl or C 3 -C 6 -heterocydoalkyl that optionally is substituted in one or more places, in the same way or differently, with d-C ⁇ -hydroxyalkoxy, Ci-C 6 -alkoxyalkoxy, C 3 -C 6 -heterocycloalkyl or with the group -NR 3 R 4 , whereby the heterocycloalkyl itself optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or optionally can be interrupted by one or more -C(O)- or -SO 2 groups in the ring and/or optionally one or more double bonds can be contained in the ring and/or the ring itself optionally can be substituted in one or more places, in the same way or differently, with Ci-C 6 -alkyl, C 3 -Q- cycloalkyl, Ci-C 6 -hydroxyalkyl or with the group -NR 3 R 4 ,
• M stands for d-C ⁇ -alkyl that optionally is substituted in one or more places, in the same way or differently, with the group -NR 3 R 4 or C 3 -Q- heterocycloalkyl,
• X stands for -NH- or -NR 5 -
• R 1 stands for CrC 4 -alkyl, C 3 -cycloalkyl, allyl or propargyl that optionally is substituted in one or more places, in the same way or differently, with halogen,
• R 2 stands for hydrogen or for Ci-C 6 -alkyl, d-C ⁇ -alkoxy, Ci-C 6 -alkenyl, d-C6-alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with halogen, hydroxy, cyano, d-C 6 -alkyl, d-C 6 -alkoxy, d-C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 - heterocycloalkyl, d-C 6 -alkynyl, aryl, aryloxy, heteroaryl or with the group -S-d-C 6 -alkyl, -COR 6 , -NR 3 R 4 , -NR 3 C(O)-L or -NR
• CrC ⁇ -alkyl C 3 -C 6 -cycloalkyl, Ci-C 6 -hydroxyalkyl, d-C ⁇ -alkoxyalkyl or with the group -NR 3 R 4 or -COR 6 and/or can be substituted with aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with halogen, d-C ⁇ -alkoxy or with the group -COR 6 ,
• R 3 and R 4 independently of one another, stand for hydrogen or for d-C ⁇ -alkyl, Ci-C 6 -alkoxy, -CO-d-C 6 -alkyl or aryl that optionally is substituted in one or more places, in the same way or differently, with halogen, hydroxy, C 3 -C 6 -heterocycloalkyl, C r C 6 -hydroxyalkoxy or with the group -NR 3 R 4 , whereby the heterocycloalkyl itself optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms and/or optionally can be interrupted by one or more -C(O)- or -SO 2 - groups in the ring and/or optionally one or more double bonds can be contained in the ring and whereby the C 3 -C 6 -heterocycloalkyl ring itself in each case optionally can be substituted in one or more places, in the same way or differently, with cyano, halogen, d-
• R 6 stands for hydroxy, C r C 6 -alkyl, C r C 6 -alkoxy or the group -NR 3 R 4 ,
• R 7 stands for -(CH 2 ) n -aryl or -(CH ⁇ J n -heteroaryl, and n stands for an integer of 1 , 2, 3, 4, 5 or 6, as well as the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof, have been shown to be especially effective.
• a and B independently of one another, stand for hydrogen, halogen, or for Ci-C 4 -alkyl or pyrrolidinyl that optionally is substituted in one or more places, in the same way or differently, with halogen, hydroxy or with the group -NR 3 R 4 or -CO(NR 3 J-M, M stands for C r C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with the group -NR 3 R 4 or C 3 -C 6 - heterocycloalkyl, X stands for -NH-, R 1 stands for CrC 4 -alkyl that optionally is substituted in one or more places, in the same way or differently, with halogen,
• R 2 stands for hydrogen or for Ci-C ⁇ -alkyi or CrC 6 -alkynyl that optionally is substituted in one or more places, in the same way or differently, with halogen, cyano, or Ci-C 6 -alkoxy, R 3 and R 4 , independently of one another, stand for hydrogen or for C r C 6 -alkyl, CrC ⁇ -alkoxy, -CO-Ci -C ⁇ -alkyl or aryl that optionally is substituted in one or more places, in the same way or differently, with halogen, hydroxy, C 3 -C 6 -heterocycloalkyl, CrC ⁇ -hydroxyalkoxy or with the group -NR 3 R 4 , whereby the heterocycloalkyl itself optionally can be interrupted by one or more nitrogen, oxygen and/or sulfur atoms, and/or optionally can be interrupted by one or more -C(O)- or -SO 2 - groups in the ring and/or optionally one
• a and B independently of one another, stand for hydrogen, halogen, hydroxy, methoxy or pyrrolidinyl,
• X stands for -NH-
• R 1 stands for ethyl
• R 2 stands for ethyl or propynyl, as well as the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof, are extremely effective.
• a subject of this invention is also the use of the compounds of general formula I, which may be for the production of a pharmaceutical agent for treating cancer, auto-immune diseases, chemotherapy agent-induced alopecia and mucositis, cardiovascular diseases, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections.
• a subject of this invention is also the use of the compounds of general formula I for the production of a pharmaceutical agent for treating cancer, solid tumours and leukemia; auto-immune diseases: psoriasis, alopecia and multiple sclerosis; cardiovascular diseases: stenoses, arterioscleroses, and restenoses; infectious diseases: diseases that are caused by unicellular parasites; nephrological diseases: glomerulonephritis; chronic neurodegenerative diseases: Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases: ischemias of the brain and neurotraumas; and viral infections: cytomegalic infections, herpes, hepatitis B and C, and HIV.
• the compounds according to the invention can be used in the case of cancer, autoimmune diseases, cardiovascular diseases, infectious diseases, nephrological diseases, neurodegenerative diseases and viral infections.
• the invention also comprises pharmaceutical agents that contain at least one compound of general formula I.
• Such pharmaceutical agents are used in the treatment of cancer, autoimmune diseases, cardiovascular diseases, infectious diseases, nephrological diseases, neurodegenerative diseases and viral infections.
• the compounds according to the invention are mixed in the pharmaceutical agents with suitable formulation substances and vehicles.
• a subject of this invention is thus also a pharmaceutical preparation for enteral, parenteral and oral administration.
• a pharmaceutical preparation which, in addition to the active ingredient for the enteral or parenteral administration, contains suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, plant oils, polyalkylene glycols, etc.
• suitable pharmaceutical, organic or inorganic inert carrier materials such as, for example, water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, plant oils, polyalkylene glycols, etc.
• the pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories, or capsules, or in liquid form, for example as solutions, suspensions or emulsions.
• they optionally contain adjuvants such as preservatives, stabilizing agents, wetting agents or emulsifiers, salts for changing the osmotic pressure, or buffers.
• injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil
• carrier systems surface-active adjuvants such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof as well as liposomes or components thereof can also be used.
• tablets coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are suitable.
• talc and/or hydrocarbon vehicles or binders such as, for example, lactose, corn or potato starch.
• the administration can also be done in liquid form, such as, for example, as a juice, to which optionally a sweetener, or, if necessary, one or more flavoring substances, is added.
• the dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
• the daily dose is 0.5-1 ,000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses.
• the compounds according to the invention are used as inhibitors of polo-like kinases.
• Polo-like kinases are defined as in particular PIk 1 , PIk 2, PIk 3 and PIk 4.
• Reaction conditions a) Saponification in the presence of Pd-tetrakis- triphenylphosphine and barbituric acid; b) Condensation with aldehydes; c) Saponification in the presence of Pd-tetrakis-triphenylphosphine and barbituric acid; d) Amide formation from the free carboxylic acid; e) Condensation with aldehydes; f) Amide formation from the free carboxylic acid.
• the production of the compounds of general formula I can be carried out in principle via two alternative synthesis routes.
• the process variant I comprises the intermediate products 2 and 3 starting from the starting material 1 that is already described in the International Application WO 03/093249.
• the process variant Il comprises the intermediate products 4 and 5 starting from the same starting material 1. Both process variants are also suitable for use in parallel-synthetic production processes of compounds of general formula I. Based on the process, the radicals X-R2 or Q of the test compounds according to the invention can be widely varied in the last synthesis stage in each case.
• the corresponding compound can also be produced by condensation of the corresponding amides with aldehydes :
• Recombinant human Plk-1 (6xHis) was purified from baculovirus-infected insect cells (Hi5).
• NP40 1 mmol of DTT, protease inhibitors; 0.1 mmol of Na2VO3 in 50 mmol of HEPES, pH 7.5.
• stop solution 500 ⁇ mol of ATP; 500 mmol of EDTA; 1% Triton X100; 100 mg/ml of streptavidin-coated SPA beads in PBS.
• the beads are sedimented by centrifuging (10 minutes, 1500 rpm).
• the incorporation of 33P- ⁇ - ATP in casein is intended as a measurement of enzyme activity by ⁇ -counting.
• Test substances are used in various concentrations (0 ⁇ mol, as well as in the range of 0.01 - 30 ⁇ mol).
• the final concentration of the solvent dimethyl sulfoxide is 1.5% in all batches.
• Cultivated human MaTu breast tumour cells were flattened out at a density of 5000 cells/ measuring point in a 96-well multititer plate in 200 ⁇ l of the corresponding growth medium. After 24 hours, the cells of one plate (zero-point plate) were colored with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 ⁇ l), to which the test substances were added at various concentrations (0 ⁇ m, as well as in the range of 0.01 -30 ⁇ m; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test substances.

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