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Definitions

• the invention relates to thiazolidones, their preparation and use as inhibitors of the Polo Like Kinase (Pik) for the treatment of various diseases.
• Tumor cells are characterized by an unrestrained cell cycle process. This is based on the one hand on the loss of control proteins such as RB, p16, p21, p53, etc., and the activation of so-called accelerators of the cell-cycle process, the cyclin-dependent kinases (Cdk's).
• the Cdk's are a pharmacy recognized anti-tumor target protein.
• Plk-1 A high expression rate of Plk-1 has been reported in non-small cell lung cancer (Wolf et al Oncogene, 14, 543ff, 1997), in melanomas (Strebhardt et al., JAMA, 283, 479ff, 2000). squamous cell carcinomas' (Knecht et al., Cancer Res, 59, 2794ff, 1999) and in 'esophageal carcinomas' (Tokumitsu et al., Int J Oncol 15, 687ff, 1999).
• Plk-1 in NIH-3T3 cells resulted in malignant transformation (increased proliferation, growth in soft agar, colony formation and tumor development in nude mice (Smith et al., Biochem Biophys Res Comm, 234, 397ff. , 1997).
• Microinjection of Plk-1 antibodies into HeLa cells resulted in defective mitosis (Lane et al., Journal Cell Biol, 135, 1701 et seq., 1996).
• a '20 -mer 'antisense oligo inhibited the expression of Plk-1 in A549 cells and stopped their viability. Likewise, a clear anti-tumor effect could be shown in nude mice (Mundt et al., Biochem Biophys ResComm, 269, 377ff., 2000).
• antisense oligo molecules did not inhibit the growth and viability of primary human mesangial cells (Mundt et al., Biochem Biophys ResComm, 269, 377ff., 2000).
• sequence identity within the polypic spiking domains is between 40 and 60%, so that in part interaction of inhibitors of a kinase with one or more other kinases of this family occur.
• the effect of the inhibitors can also be selective or preferred on only one polo family kinase.
• the object of the present invention is to provide further substances which inhibit kinases of the polo family in the nanomolar range.
• Q is aryl or heteroaryl
• a and B independently of one another are hydrogen, halogen, hydroxyl, amino or nitro or optionally mono- or polysubstituted by identical or different substituents with halogen, hydroxy, C 3 -C 6 -heterocycloalkyl or with the group -NR 3 R 4 or - CO (NR 3 ) -M substituted dC 3 alkyl or CC 6 - alkoxy, where the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally by one or more - ( CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and / or the ring itself may be mono- or polysubstituted, identically or differently, with C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -hydroxyalkyl or with the group
• M represents optionally mono- or polysubstituted, identically or differently, with the group -NR 3 R 4 or C 3 -C 6 -heterocycloalkyl-substituted CC 6 -alkyl
• X stands for -NH- or -NR 5 -
• R 1 for optionally mono- or polysubstituted by identical or different halogens substituted C-
• R 2 is hydrogen or optionally mono- or polysubstituted, identical or different with halogen, hydroxy , cyano, C 6 - alkyl, C ⁇ -C 6 -alkoxy, -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 - heterocycloalkyl, C ⁇ -C 6 alkynyl, aryl, aryloxy, heteroaryl or Ci-C ⁇ -al
• R 3 and R 4 independently of one another are hydrogen or optionally mono- or polysubstituted by identical or different radicals Halogen, hydroxy, C 3 -C 6 heterocycloalkyl, C ⁇ -C6 hydroxyalkoxy or with the group -NR 3 R 4 is substituted C ⁇ -C 6 -alkyl, C 6 - alkoxy, -CO-C ⁇ -C 6 - Alkyl or aryl, wherein the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally interrupted by one or more - (CO) - or -SO 2 - groups in the ring and / or optionally one or more double bonds in the ring can be contained and wherein the C 3 -C itself in each case optionally mono- or polysubstituted 6 -heterocycloalkyl, identically or differently, with cyano, halogen, C ⁇ -C 6 -alkyl, C 6 -Hy
• R 5 is optionally substituted one or more times, identically or differently with halogen, hydroxy, cyano, CrC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 - C ⁇ -heterocycloalkyl, or substituted with the group -NR 3 R 4 C ⁇ -C 6 alkyl, C -C 6 alkenyl, -CC 6 -Alkinyi, wherein the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally by one or more - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds can be contained in the ring and wherein the C 3 -C itself in each case optionally mono- or polysubstituted 6 -heterocycloalkyl, identically or differently with cyano, halogen, C ⁇ -C6 alkyl, -C 6 hydroxyalky
• the compounds of the general formula I according to the invention essentially inhibit the polo like kinases, as well as their action for example against cancer, such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapeutic-induced alopecia and mucositis, cardiovascular diseases, such as stenoses, atherosclerosis and restenosis, infectious diseases such.
• cancer such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapeutic-induced alopecia and mucositis, cardiovascular diseases, such as stenoses, atherosclerosis and restenosis, infectious diseases such.
• cancer such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis, chemotherapeutic-induced alopecia and mucositis, cardiovascular diseases, such as stenoses, athe
• 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 brain ischaemia and neurotrauma, viral infections such as. As cytomegalovirus infections, herpes, hepatitis B and C, and HIV-based diseases.
• Stereoisomers are to be understood as meaning E / Z and R / S isomers and mixtures of E / Z and R / S isomers.
• Alkyl is in each case 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.
• alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.
• Alkoxy is in each case a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec. Butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.
• alkoxy radical such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec. Butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.
• alkenyl substituents are in each case straight-chain or branched, for example the following radicals being 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, allyl.
• Alkynyl is in each case to be understood as meaning a straight-chain or branched alkynyl radical which contains 2-6, preferably 2-4, C atoms.
• the following radicals called: acetylene, propyn-1-yl, propyn-3-yl, but-1-yn-1-yl, but-1-yn-4-yl, but-2-yn-1-yl, but-1 in-3-yl, etc.
• Heterocycloalkyl stands for an alkyl ring comprising 3 to 6 carbon atoms which, instead of the carbon, has one or more identical or different heteroatoms, such as, for example, B. oxygen, sulfur or nitrogen and / or optionally by one or more - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and at one or more Carbon, nitrogen or sulfur optionally independently of one another may contain a further substituent.
• Substituents on the heterocycloalkyl ring may be:
• heterocycloalkyl z examples are: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, pyrolidonyl, N-methylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, Hydroxypyrrolidinyl, N-methylpiperazinyl, N-acetylpiperazinyl, N-
• Methylsulfonylpiperazinyl 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, nortropinyl, 1, 1-dioxothiomorpholinyl, etc.
• Cycloalkyl is to be understood as meaning monocyclic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings such as, for example, adamantanyl.
• the cycloalkyl may optionally also be benzo-fused, e.g. (Tetralin) yl etc.
• Halogen is in each case fluorine, chlorine, bromine or iodine.
• the aryl radical has in each case 6 to 12 carbon atoms, for example naphthyl, biphenyl and in particular phenyl.
• the heteroaryl group comprises in each case 3 to 16 ring atoms and may contain one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur in the ring, instead of the carbon, and may be mono-, bi- or tricyclic, and may additionally be benzo-fused in each case.
• quinolinyl isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, tetralinyl etc.
• Preferred heteroaryl radicals are, for example, 5-ring heteroaromatics, such as thiophene, furanyl, oxazolyl, thiazole, imidazolyl and benzo derivatives thereof and 6-membered heteroaromatics, such as pyridinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl and benzo derivatives thereof.
• 5-ring heteroaromatics such as thiophene, furanyl, oxazolyl, thiazole, imidazolyl and benzo derivatives thereof
• 6-membered heteroaromatics such as pyridinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl and benzo derivatives thereof.
• the aryl radical comprises in each case 3 to 12 carbon atoms and may each be benzo-fused. Examples which may be mentioned are: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, tetralinyl, etc.
• Isomers are to be understood as meaning chemical compounds of the same empirical formula but of different chemical structure. In general, one distinguishes constitutional isomers and stereoisomers. Constitutional isomers have the same molecular formula, but differ in how their atoms or atomic groups are linked. These include functional isomers, positional isomers, tautomers or valence isomers.
• Stereoisomers basically have the same structure (constitution) - and therefore also the same molecular formula - but differ by the spatial arrangement of the atoms.
• Configuration isomers are stereoisomers that can only be converted into each other by bond breaking. These include enantiomers, diastereomers and E / Z (ice / trans) isomers.
• Enantiomers are stereoisomers that behave in the same way as image and mirror image and have no plane of symmetry. All stereoisomers that are not enantiomers are called diastereomers. A special case is E / Z (ice / trans) isomers of double bonds.
• Conformational isomers are stereoisomers that can be converted into each other by the rotation of single bonds.
• the compounds of general formula I according to the invention also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, also the racemates and enantiomers. These include double bond isomers.
• the compounds according to the invention can also be present in the form of solvates, in particular of hydrates, the compounds according to the invention accordingly containing polar solvents, in particular of water, as structural element of the crystal lattice of the compounds according to the invention.
• the proportion of polar solvent, in particular water can be present in a stoichiometric or even unstoichiometric ratio.
• stoichiometric solvates hydrates, we also speak of hemi, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates.
• suitable salts are the physiologically tolerated salts of organic and inorganic bases, such as, for example, the readily soluble alkali and alkaline earth salts and N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, A inopropandiol, Sovak base, 1-amino-2,3,4-butanetriol.
• organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth salts and N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane
• physiologically acceptable salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and the like.
• a and B independently of one another are hydrogen, halogen, hydroxyl, amino or nitro or optionally mono- or polysubstituted, identically or differently, with halogen, hydroxyl, C 3 -C 6 -heterocycloalkyl or with the group -NR 3 R 4 or -CO (NR 3 ) -M-substituted dC 3 -alkyl or C 1 -C 6 -alkyl Alkoxy, where the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or may be interrupted by one or more - (CO) - or -SO 2 - groups in the ring and / or or optional
• M is C 1 -C 6 -alkyl which is optionally mono- or polysubstituted identically or differently with the group -NR 3 R 4 or C 3 -C 6 -heterocycloalkyl
• X is -NH- or -NR 5 -
• R 1 is optionally is mono- or polysubstituted by identical or different halogen-substituted dC 4 alkyl, C 3 -cycloalkyl, allyl or propargyl
• R 2 is hydrogen or one is optionally substituted one or more times, identically or differently with halogen, hydroxy, cyano, CC 6 - alkyl, C ⁇ -C6 alkoxy, CRCE hydroxyalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 - heterocycloalkyl, C ⁇ -C 6 alkynyl, aryl, aryloxy, heteroaryl or with the group -S-C r is C 6
• R 3 and R 4 independently of one another represent hydrogen or optionally mono- or polysubstituted, identical or different, with halogen, hydroxyl, C 3 -C 6 -heterocycloalkyl, -CC 6 -hydroxyalkoxy or with the group -NR 3 R 4 C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, -CO-C 1 -C 6 -alkyl or aryl, where the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or or optionally by one or more - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and wherein the C 3 -C 6 -Heterocycloalkylring itself each optionally optionally one or more times, same or different with cyano, halogen, C ⁇ -C 6 -alkyl,
• a and B independently of one another are hydrogen, halogen, hydroxyl, amino or nitro or optionally mono- or polysubstituted by identical or different substituents with halogen, hydroxy, C 3 -C 6 -heterocycloalkyl or with the group -NR 3 R 4 or - CO (NR 3 ) -M substituted CC 3 alkyl or CC 6 - alkoxy, wherein the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally by one or more - ( CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and / or the ring itself optionally one or more times, same or different with -CC 6 alkyl, C 3 -C 6 cycloalkyl, C ⁇ -C 6 - may be substituted hydroxyalkyl or with the group -NR 3 R 4 or -
• R 1 is optionally mono- or polysubstituted by identical or different halogen-substituted C 1 -C 4 -alkyl, C 3 -cycloalkyl, AHyl or propargyl,
• R 2 represents hydrogen or represents optionally mono- or polysubstituted, identically or differently with halogen, hydroxy, cyano, CrC 6 - C ⁇ -C alkyl, 6 alkoxy, d-Ce-hydroxyalkyl, C 3 -C 6 cycloalkyl, C C 3 -C 6 -heterocycloalkyl, C 1 -C 6 -alkynyl, aryl, aryloxy, heteroaryl or with the group -SC C 6 -alkyl, -COR 6 , -NR 3 R 4 , -NR 3 (CO) -L or - NR 3 COOR 7 substituted -CC 6 alkyl, -CC 6 alkoxy, CC 6 - alkenyl, -CC 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl or heteroaryl where the heterocycloalkyl itself may optionally be interrupted
• R 2 and R 5 together form a C 3 -C 6 heterocycloalkyl ring which is interrupted at least once by nitrogen and may optionally be interrupted once or several times by oxygen or sulfur and / or optionally by one or more - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and / or the ring itself optionally one or more times, same or different with cyano, halogen, hydroxy, C 1 -C 6 -alkyl, C 3 -C 6 cycloalkyl, C ⁇ -C 6 hydroxyalkyl, -C 6 alkoxyalkyl or substituted with the group -NR 3 R 4 or -COR 6 can and / or singly with optionally one or more times, identically or differently with halogen , C 1 -C 6 -alkoxy or with the group - COR 6 -substituted aryl or heteroaryl may be substituted, R
• R 3 and R 4 together form a C 3 -C 6 -HeterocycloalkyIring which is interrupted at least once by nitrogen and may optionally be interrupted by one or more times by oxygen or sulfur and / or optionally by one or more - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and / or the heterocycloalkyl ring itself optionally one or more times, same or different with -CC 6 alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxyalkyl, cyano, hydroxy or may be substituted by the group -NR 3 R 4 ,
• R 5 is optionally substituted one or more times, identically or differently with halogen, hydroxy, cyano, CrC 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 - C 6 substituted heterocycloalkyl, or with the group -NR 3 R 4 C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl, where the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally by an or a plurality of - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and wherein the C 3 -C 6 -Heterocycloalkylring itself each optionally one or more times, the same or differently, with cyano, halogen, C ⁇ -C6 alkyl, CC 6 hydroxyal
• R 6 is hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or the group -NR 3 R 4 , R 7 is - (CH 2 ) n -aryl or - (CH) n -heteroaryl and n is 1 - 6, and their solvates, hydrates, stereoisomers, diastereomers,
• Q is phenyl, naphthyl or indolyl
• a and B independently of one another are hydrogen, halogen, hydroxyl, amino or nitro or optionally mono- or polysubstituted by identical or different substituents with pyrrolidinyl, piperidinyl, piperazinyl or C -C -substituted with the group --N (CC 6 -alkyl) 2 3 alkyl or C ⁇ -C are 6 alkoxy wherein pyrrolidinyl, piperidinyl or piperazinyl itself optionally substituted one or more times, identically or differently, with C ⁇ -C 6 alkyl or C ⁇ -C 6 hydroxyalkyl may be substituted, or -CO (NH) -M, -CO (NCH 3 ) -M, -NH (CO) -L, -NH (CO) -NH-L, -SO 2 (NH) -M or -SO 2 (NCH 3 ) - Stand,
• L is optionally mono- or polysubstituted, identically or differently, with C 1 -C 6 -hydroxyalkoxy, C -C 6 -alkoxyalkoxy, pyrrolidinyl, piperazinyl or C 1 -C 6 -alkyl or pyridyl which is substituted by -N (C 1 -C 6 -alkyl) 2, where Pyrrolidinyl or piperazinyl itself may optionally be monosubstituted or polysubstituted, identically or differently, by C 1 -C 6 -alkyl,
• M is optionally substituted one or more times, identically or differently, with the group -N (C ⁇ -C6 alkyl) 2 or pyrrolidinyl substituted C ⁇ ⁇ C 6 - is alkyl, X is -NH- or -NR 5 - group,
• R 1 represents optionally mono- or polysubstituted by identical or different halogen-substituted C 1 -C 4 -alkyl
• R 2 represents hydrogen or represents optionally Ci-C ⁇ - alkyl, C ⁇ -C 6 -alkoxy, C one or more times, identically or differently with halogen, hydroxy, cyano, 6 hydroxyalkyl, C 3 -C 6 cycloalkyl , Tetrahydrofuranyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, phenoxy, biphenyl, naphthyl, thienyl, furanyl, tetrazolyl, pyridyl or with the group -SC-C 1 -C 6 -alkyl, -CONH 2 , -COO-C 1 -C 6 - Alkyl, - N is CrCe-alkylh, -N (-CC 6 -alkyl) phenyl, -NH (CO) -L substituted CVC ⁇ -alkyl, C 1 -C 6 -alkenyl, C 1 -
• R 5 is optionally mono- or polysubstituted by identical or different C 1 -C 6 -alkoxy-substituted C 1 -C 6 -alkyl or C 1 -C 6 -alkenyl, and also their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.
• Q is phenyl, naphthyl or indolyl
• a and B are independently hydrogen, halogen, hydroxy, amino or nitro or optionally mono- or polysubstituted, identically or differently, with pyrrolidinyl, piperidinyl, piperazinyl or with the group --N (CH 3 ) 2 -substituted C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, pyrrolidinyl, piperidinyl or piperazinyl itself optionally being or polysubstituted, identically or differently, with C 1 -C 3 -alkyl or C 1 -C 3 -hydroxyalkyl, or for the group -CO-NH- (CH 2 ) 2 -N (CH 3 ) 2 , -CO-NH- ( CH 2 ) 2 - N (C 2 H 5 ) 2 , -CO-N (CH 3 ) - (CH 2 ) 2 -N (CH 3 ) 2 ,
• X is -NH- or - NR 6 - stands,
• R 1 represents optionally mono- or polysubstituted by identical or different halogen-substituted C 1 -C 3 -alkyl, represents hydrogen or optionally mono- or polysubstituted, identical or different, with halogen, hydroxyl, cyano, C 1 -C 6 -alkyl, C 6 -hydroxyalkyl, methoxy, C 3 -C 6 -cycloalkyl, tetrahydrofuranyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, phenoxy, biphenyl, naphthyl, thienyl, furanyl, tetrazolyl or pyridyl or with the group -S-CH 3) -COOCH 3 , -COOC 2 H 5 , -CO-NH 2 , -OCF 3 , - N (CH 3 ) -phenyl, -N (C 1 -C 12 -al
• R 5 represents optionally mono- or polysubstituted, identically or differently with dC 6 -alkoxy-substituted dC 3 -alkyl or dC 3 -alkenyl, and their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.
• Q represents phenyl, naphthyl, quinolinyl, benzimidazolyl, indolyl, indazolyl, thiazolyl, imidazolyl or pyridyl
• a and B independently of one another represent hydrogen, halogen, hydroxyl, amino or nitro or optionally mono- or polysubstituted, identically or differently, with hydroxyl , C 3 -C 6 -heterocycloalkyl or -NR 3 R 4 or -CO (NR 3 ) (CH 2 ) n NR 3 R 4 -substituted dC 3 -alkyl or dC 6 -alkoxy, the heterocycloalkyl itself being optionally may be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally interrupted by one or more - (CO) - or -SO 2 - groups in the ring and / or optionally one or more double bonds in the ring may be contained and
• X is oxygen, -NH- or -NR 5 -,
• R 1 represents optionally mono- or polysubstituted by identical or different halogen-substituted C 1 -C 3 -alkyl, C 3 -cycloalkyl, allyl or propargyl
• R 2 is hydrogen or mono- or optionally me rfach, identically or differently with halogen, hydroxy, cyano, dC 6 alkyl, d-C ⁇ -alkoxy, d-C ⁇ hydroxyalkyl, C -C 6 cycloalkyl, C 3 -C 6 - heterocycloalkyl, aryl, heteroaryl or with the group -S-C 1 -C 6 -alkyl, -COR 6 , -NR 3 R 4 , -NR 3 (CO) -C 1 -C 6 -alkyl, -NR 3 (CO) -aryl, -NR 3 (CO) -Heteroaryl, -NR 3 COOR 7 , -NR 3 (CS) NR
• R 5 is optionally substituted one or more times, identically or differently with halogen, hydroxy, cyano, dC 6 alkoxy, C 3 -C ⁇ cycloalkyl, C 3 -C 6 - heterocycloalkyl, or substituted with the group -NR 3 R 4 C -C ⁇ -alkyl, Ci-C ⁇ -alkenyl, Ci-C ⁇ -alkynyl, wherein the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally by one or more - (CO ) - or -SO 2 - Groups may be interrupted in the ring and / or optionally one or more double bonds in the ring may be contained and wherein the C 3 -C 6 -Heterocycloalkylring itself each optionally one or more times, same or different with cyano, halogen, C 1 -C 6 -alkyl , C 1 -C 6 -hydroxyal
• R 7 is - (CH 2 ) n -aryl or - (CH 2 ) n -heteroaryl and n is 1-6, and their stereoisomers, diastereomers, enantiomers and salts.
• Q is phenyl, naphthyl, quinolinyl, benzimidazolyl or indolyl
• a and B independently of one another are hydrogen, halogen, hydroxyl, amino or nitro or optionally mono- or polysubstituted, identically or differently, with hydroxyl, pyrrolidinyl, piperidinyl, piperazinyl or with the group --N (CH 3 ) 2 , --N ( C 2 H 5 ) 2 or -CO (NH) (CH 2 ) 2 N (C 2 H 5 ) 2 substituted C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, where pyrrolidinyl, piperidinyl or piperazinyl itself optionally - or more times, identically or differently, with C ⁇ -C 3 alkyl, C 3 -C 6 cycloalkyl, -C 3 - hydroxyalkyl or may be substituted with the group -N (C 2 H 5) 2, or for the group COOH, -COOCH 3 , -COOC 2 H 5 , -CONH 2 ,
• X is oxygen, -NH- or -NR 5 -,
• R 1 is optionally mono- or polysubstituted by identical or different fluorine, chlorine, bromine or iodine, C 1 -C 3 -alkyl or C 3 -cycloalkyl,
• R 2 is optionally substituted one or more times, identically or differently, by fluorine, chlorine, bromine, iodine, hydroxy, cyano, C 6 -alkyl, C 6 - hydroxyalkyl, methoxy, or with the group -S-CH 3, -COOCH 3 , COOC 2 H 5 , -NH (CH 3 ), -N (CH 3 ) 2 , -NHC (CH 3 ) 3 , -NH (CO) -CH 3 , -NH (CO) -phenyl, - NH (CO) -O- (CH 2 ) -phenyl, -N (CH 3 ) - (CS) -NH (CH 3 ), -N (CH 3 ) - (CS) -N (CH 3 ) 2 or with the following ring systems C 3 -C 8 -cycloalkyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, phen
• R 5 is optionally substituted one or more times, identically or differently with halogen, hydroxy, cyano, C 6 -alkoxy, C 3 -C 6 cycloalkyl, C 3 -C6- heterocycloalkyl, or with the group -N (CH 3 ) 2 substituted d-Cs-alkyl, Ci-Cs-alkenyl, -C-C 3 -alkynyl, and their stereoisomers, diastereomers, enantiomers and
• Another object of the present invention are compounds of general formula IA
• Q is aryl or heteroaryl
• a and B independently of one another are hydrogen, halogen, hydroxyl, amino or nitro or optionally mono- or polysubstituted by identical or different substituents with halogen, hydroxy, C 3 -C 6 -heterocycloalkyl or with the group -NR 3 R 4 or - CO (NR 3 ) -M substituted dC 3 alkyl or -C-C 6 alkoxy, wherein the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally by one or more - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and / or the ring itself optionally one or more times, same or different with Ci-C ⁇ -alkyl , C 3 -Ce -cycloalkyl, C may be C 6 -hydroxyalkyl or may be substituted by the group -NR 3 R
• R 3 and R 4 independently of one another are hydrogen or optionally mono- or polysubstituted, identically or differently, by halogen, hydroxyl, C 3 -Ce-heterocycloalkyl, C 1 -C -hydroxyalkoxy or C 1 -C 6 -substituted with the group -NR 3 R 4 Alkyl, C 1 -C 6 -alkoxy, -CO-C 1 -C 6 -alkyl or aryl, where the heterocycloalkyl itself may optionally be interrupted by one or more nitrogen, oxygen and / or sulfur atoms and / or optionally by an or a plurality of - (CO) - or -SO 2 - groups may be interrupted in the ring and / or optionally one or more double bonds may be contained in the ring and wherein the C 3 -C 6 -Heterocycloalkylring itself each optionally one or more times, the same or may be substituted by cyano, halogen, C
• R 6 is hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or the group -NR 3 R 4 , and also their solvates, hydrates, stereoisomers, diastereomers,
• Q is phenyl, quinolinyl, indolyl or naphthyl
• a and B independently of one another are hydrogen or halogen or optionally mono- or polysubstituted, identical or different, with halogen, hydroxyl or with the group -NC C ⁇ -alkyl) 2 or -CO (NH) -M-substituted C -C 3 - Alkyl or C 1 -C 6 -alkoxy or -NH (CO) -L, -NH (CO) -NH-L, -COR 6 , -CO (NH) -M, -CO (NCH 3 ) -M, -SO 2 (NH) -M or -SO 2 (NCH 3 ) -M,
• L is optionally mono- or polysubstituted by identical or different pyrrolidinyl-substituted -CC 6 alkyl
• M 6 alkyl optionally mono- or polysubstituted, identically or differently, with the group -N (dC 6 alkyl) 2 or pyrrolidinyl substituted CrC, R 1 is C 1 -C 3 -alkyl,
• R 2a is allyl or propargyl
• R 6 is hydroxy, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, and also their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.
• Another object of the invention are the preparation examples 1 to 75, and their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts. These compounds differ from those of general formula I by the presence of an ester residue, rather than an amide bond. These compounds are suitable for inhibiting kinases of the polo family. These compounds are also known as
• D is the group -NO 2 , -NH 2 or -NH (CO) OC (CH 3 ) 3 and E is -CC 6 - alkoxy or halogen and R 3 and R 4 are those described in the general formula I.
• R 3 and R 4 are those described in the general formula I. Have significance as intermediates for the preparation of the compounds of general formula I.
• D is the group -NO 2 , -NH 2 or -NH (CO) OC (CH 3 ) 3 and G is the group -NR 3 R 4 and R 3 , R 4 and n are those represented by the general formula I have described meaning as intermediates for the preparation of the substances of the general formula I.
• a pharmaceutical preparation which, in addition to the active substance for enteral or parenteral administration, is suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic , Lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
• the pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If appropriate, they also contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for changing the osmotic pressure or buffer.
• adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for changing the osmotic pressure or buffer.
• Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
• Surfactant auxiliaries such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof and liposomes or components thereof can also be used as carrier systems.
• tablets, dragees or capsules with talc and / or hydrocarbon carriers or binders such as lactose, corn or potato starch
• talc and / or hydrocarbon carriers or binders such as lactose, corn or potato starch
• the application can also take place in liquid form, for example as juice, which may be accompanied by a sweetener.
• enteral, parenteral and oral applications are also the subject of the present invention.
• the dosage of the active ingredients may vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease being treated, and similar factors.
• the daily dose is 0.5-1000 mg, preferably 50-200 mg, which dose may be given as a single dose to be administered once or divided into 2 or more daily doses.
• the present invention is the use of the compounds of general formula I for the preparation of a medicament for the treatment of cancer, autoimmune diseases, cardiovascular diseases, chemotherapeutic-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections , Cancerous tumors and leukemia, autoimmune psoriasis, alopecia and multiple sclerosis, cardiovascular diseases, stenosis, arteriosclerosis and restenosis, infectious diseases caused by unicellular parasites, nephrology glomerulonephritis, chronic neurodegenerative diseases Huntington's disease, amyotrophic lateral sclerosis , Parkinson's disease, AIDS dementia and Alzheimer's disease, brain ischemia in acute neurodegenerative diseases and neurotrauma, and viral infections are cytomegalovirus infections, herpes, hepatitis B or C, and HIV disorders.
• medicaments for the treatment of the abovementioned disorders which contain at
• the compounds of the general formula I according to the invention are, inter alia, excellent inhibitors of the polo-like kinases, such as Plk1, Plk2, Plk3 and Plk4.
• the isomer mixtures can be prepared by conventional methods such as crystallization, chromatography or salt formation in the isomers, such as. B. are separated into the enantiomers, diastereomers or E / Z isomers, provided that the isomers are not in equilibrium with each other.
• the preparation of the salts is carried out in a customary manner by adding a solution of the compound of formula I with the equivalent amount or an excess of a base or acid, optionally in solution, and separating the precipitate or working up the solution in a conventional manner.
• R ⁇ C 1 - C 6 alkyl or - (CH 2) n C i - C 6 - alkoxy, or - (CH 2) n d - C 6 - alkoxyalkoxy
• R ⁇ C 1 - C 6 alkyl or - (CH 2) n C i - C 6 - alkoxy, or - (CH 2) ⁇ Ci - C 6 - alkoxyalkoxy where A and Q have the meaning given in general formula I.
• R ⁇ C 1 - C 6 alkyl or - the meaning given in general formula I alkoxyalkoxy wherein A, Q and R 3 - (CH 2) n C i - C ⁇ - alkoxy, or - (CH 2) n d - C 6 to have.
• reaction mixture is treated with water and extracted with ethyl acetate.
• organic solution is washed successively with 4 normal hydrochloric acid, with half-saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulfate, concentrated and after recrystallization from ethanol / dichloromethane (1: 3) 1.45 g of
• Example INT15 N- (3-nitro-phenyl) -acrylamide Analogously to Example INT12) are from 20 g of 3-nitroaniline, 61 mL of triethylamine and
• Example INT13 Analogously to Example INT13), from 5.0 g of the compound prepared under Example INT15), 18.2 ml of triethylamine and 2.56 ml of pyrrolidine, after purification by chromatography on silica gel, 5.52 g of the title compound are obtained.
• 1 H-NMR (DMSO-d6): ⁇ 1, 60-1, 76 (m, 4H); 2.38-2.58 (m, 6H); 2.72 (t, 2H); 7.60 (t, 1H); 7.85-7.93 (m, 2H); 8.64 (s, 1H); 10.56 (s, 1H) ppm.
• Example INT17 N- (3-amino-phenyl) -3-pyrrolidin-1-yl-propionamide
• Example INT16 5.5 g of the compound described under Example INT16 are dissolved in 200 ml of ethanol and treated with 450 mg of palladium on carbon (10%). It is stirred for 4 hours under a hydrogen atmosphere at room temperature. After filtration through diatomaceous earth and condensing off the solvent on a rotary evaporator, 4.8 g of the title compound are obtained.
• Example INT19 3-amino-N- (3-pyrrolidin-1-yl-propyl) -benzamide 1 g of the compound described under Example INT18) are dissolved in 50 ml of THF and treated with 1 g of Raney nickel. It will be 3 hours under hydrogen atmosphere stirred at room temperature. After filtration through diatomaceous earth and condensing off the solvent on a rotary evaporator, 810 mg of the title compound are obtained.
• Example INT23 420 mg of the compound described under Example INT23 are dissolved in 20 ml of ethanol and mixed with 120 mg of palladium on carbon (10%). It is stirred for 4 hours under a hydrogen atmosphere at room temperature. After filtration through diatomaceous earth and condensing off the solvent on a rotary evaporator, 340 mg of the title compound are obtained.
• a suspension of 10 g of 4-nitrophenol, 11 g of (2-chloro-ethyl) -dimethyl-amine and 27.1 g of potassium carbonate in 200 ml of acetone is refluxed for 15 hours.
• the batch is freed from the solvent under reduced pressure and the residue is taken up in ethyl acetate. It is extracted three times with 200 ml of sodium hydroxide solution (1N) and the combined organic phases are dried over sodium carbonate, the solvent is distilled off on a rotary evaporator and the title compound is obtained in 50% yield.
• reaction mixture is poured onto saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo.
• the crude product is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 33.9 g of product are obtained.
• Example INT124 Analogously to Example INT124, the product of Example INT 29) can be obtained.
• 1 H NMR (DMSO-d6): ⁇ 0.90 (t, 3H); 1.20-1, 40 (m, 8H); 1, 61 (m, 2H); 4.15 (t, 2H); 4.23 (q, 2H); 4.39 (q, 2H) ppm.
• esters are cleaved into the free acids. It has been noticed that the compounds which have an allyl ester are more easily split into the free acid than ethyl esters.
• Example 141 [5- [1- [acetyl- (6-amino-pyridin-3-yl) -amino] -meth- (E / Z) -lyidene] -3-ethyl-4-oxo-thiazolidine (2) (E or Z)) - ylidenes] -cyano-acetic acid ethyl ester
• Example 166 Analogous to the synthesis of Example 166, the following compounds can also be prepared:
• Recombinant human Plk-1 (6xHis) was purified from baculovirus-infected insect cells (Hi5).
• 10 ng (recombinantly prepared, purified) PLK enzyme is incubated for 90 min at room temperature with biotinylated casein and 33P-D-ATP as substrate in a volume of 15 .mu.l in 384well Greiner Small Volume microtiter plates (final concentrations in the buffer: 660 ng / ml PLK 0.7 ⁇ M casein, 0.5 ⁇ M ATP including 400 nCi / ml 33P- ⁇ -ATP, 10 mM MgCl 2, 1 mM MnCI 2, 0.01% NP40, 1 mM DTT, protease inhibitors, 0.1 mM Na 2 VO 3 in 50 mM HEPES pH 7.5).
• stop solution 500 ⁇ M ATP, 500 mM EDTA, 1% Triton X100, 100 mg / ml streptavidin coated SPA beads in PBS.
• Test substances are used in various concentrations (0 ⁇ M and in the range 0.01-30 ⁇ M).
• the final concentration of the dimethylsulfoxide solvent is 1.5% in all batches. proliferation assay
• Cultured human MaTu breast tumor cells were plated at a density of 5000 cells / measuring point in a 96-well multititer plate in 200 ⁇ l of the appropriate growth medium. After 24 hours, the cells of one plate (zero point plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 ⁇ l) containing the test substances at various concentrations (0 ⁇ M and in the range 0.01 - 30 ⁇ M, the final concentration of the solvent dimethylsulfoxide was 0.5%) were added replaced. The cells were in for 4 days
• Tables 1 to 3 show that the compounds according to the invention inhibit PLK in the nanomolar range.
• Fig. 1 shows the function of Pik -1
• Pik-1 activates CDC25 C. This activates the CDK / cyclin B complex and transfers the cell from G2 to M-status.
• PIkl plays an important role during cytokinesis, especially in the formation of bipolar spindle apparatus and chromosome separation during the late mitosis phase. Plk-1 is also needed during centrosome maturation and binds to so-called 'kinesin engines'.

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