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Dihydropteridione intermediate compoundsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos, , At Least Three Rings In The Polycyclo Ring System,Dihydropteridione intermediate compounds description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080113992, Dihydropteridione intermediate compounds. Brief Patent Description - Full Patent Description - Patent Application Claims
APPLICATION DATA [0001] This application is a divisional application of U.S. Ser. No. 11/210,951 filed Aug. 24, 2005 which claims benefit to European Patent Application no. EP 04 020 125.3 filed Aug. 25, 2004. FIELD OF INVENTION [0002] The present invention relates to new dihydropteridinones of general formula (I) wherein the groups L, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meanings given in the claims and specification, the isomers thereof, processes for preparing these dihydropteridinones and their use as pharmaceutical compositions. BACKGROUND TO THE INVENTION [0003] Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity. WO 01/019825 and WO 03/020722 describe the use of pteridinone derivatives for the treatment of tumoral diseases. [0004] Tumour cells wholly or partly elude regulation and control by the body and are characterised by uncontrolled growth. This is based on the one hand on the loss of control proteins, such as e.g. Rb, p16, p21 and p53 and also on the activation of so-called accelerators of the cell cycle, the cyclin-dependent kinases (CDK's). [0005] In addition, the protein kinase Aurora B has been described as having an essential function during entry into mitosis. Aurora B phosphorylates histone H3 at Ser10 and thus initiates chromosome condensation (Hsu et al. 2000, Cell 102:279-91). A specific cell cycle arrest in the G2/M phase may however also be triggered e.g. by the inhibition of specific phosphatases such as e.g. Cdc25C (Russell and Nurse 1986, Cell 45:145-53). Yeasts with a defective Cdc25 gene arrest in the G2 phase, while overexpression of Cdc25 leads to premature entry into the mitosis phase (Russell and Nurse 1987, Cell 49:559-67). Moreover, an arrest in the G2/M phase may also be triggered by the inhibition of certain motor proteins, the so-called kinesins such as e.g. Eg5 (Mayer et al. 1999, Science 286:971-4), or by agents which stabilise or destabilise microtubules (e.g. colchicin, taxol, etoposide, vinblastin and vincristine) (Schiff and Horwitz 1980, Proc Natl Acad Sci USA 77:1561-5). [0006] In addition to the cyclin-dependent and Aurora kinases the so-called polo-like kinases, a small family of serine/threonine kinases, play an important part in the regulation of the eukaryotic cell cycle. Hitherto, the polo-like kinases PLK-1, PLK-2, PLK-3 and PLK-4 have been described in the literature. PLK-1 in particular has been shown to play a central part in the regulation of the mitosis phase. PLK-1 is responsible for the maturation of the centrosomes, for the activation of phosphatase Cdc25C, and for the activation of the Anaphase Promoting Complex (Glover et al. 1998, Genes Dev. 12:3777-87; Qian et al. 2001, Mol Biol Cell. 12:1791-9). The injection of PLK-1 antibodies leads to a G2 arrest in untransformed cells, whereas tumour cells arrest in the mitosis phase (Lane and Nigg 1996, J. Cell Biol. 135:1701-13). Overexpression of PLK-1 has been demonstrated for various types of tumour, such as non-small-cell lung cancer, plate epithelial carcinoma, breast and colorectal carcinoma (Wolf et al. 1997, Oncogene 14:543-549; Knecht et al. 1999, Cancer Res. 59:2794-2797; Wolf et al. 2000, Pathol. Res. Pract. 196:753-759; Takahashi et al. 2003, Cancer Sci. 94:148-52). Therefore, this category of proteins also constitutes an interesting approach to therapeutic intervention in proliferative diseases (Liu and Erikson 2003, Proc Natl Acad Sci USA 100:5789-5794). [0007] The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours. [0008] The aim of the present invention is to provide new compounds having an antiproliferative activity. DESCRIPTION OF THE INVENTION [0009] The problem according to the invention is solved by the following compounds of formula (I). [0010] Accordingly, the present invention relates to dihydropteridinones of general formula (I) wherein [0011] L denotes a single bond, or a bridging double-bonded group selected from among C.sub.1-C.sub.6-alkylene, C.sub.2-C.sub.6-alkenylene, C.sub.2-C.sub.6-alkynylene, C.sub.3-C.sub.7-cycloalkylene, C.sub.1-C.sub.4-alkylene-C.sub.6-C.sub.10-arylene-C.sub.1-C.sub.4-alkylen- e, C.sub.1-C.sub.4-alkylene-C.sub.6-C.sub.10-arylene, --O, --O--C.sub.1-C.sub.6-alkylene, --O--C.sub.3-C.sub.6-alkenylene, --O--C.sub.3-C.sub.6-alkynylene, --O---C.sub.3-C.sub.7-cycloalkylene, --O--C.sub.1-C.sub.4-alkylene-C.sub.6-C.sub.10-arylene-C.sub.1-C.sub.4-al- kylene, --O--C.sub.1-C.sub.4-alkylene-C.sub.6-C.sub.10-arylene, --NR.sup.7-- and --NR.sup.7--C.sub.1-C.sub.6-alkylene, --NR.sup.7--C.sub.3-C.sub.6-alkenylene, --NR.sup.7--C.sub.3-C.sub.6-alkynylene, --NR.sup.7--C.sub.3-C.sub.7-cycloalkylene, --NR.sup.7--C.sub.1-C.sub.4-alkylene-C.sub.6-C.sub.10-arylene-C.sub.1-C.s- ub.4-alkylene, --NR.sup.7--C.sub.1-C.sub.4-alkylene-C.sub.6-C.sub.10-arylene, which may optionally be substituted by one or more groups R.sup.9; [0012] R.sup.1 and R.sup.2, which may be identical or different, denote hydrogen, or a group selected from among C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl and C.sub.2-C.sub.6-alkynyl, which may optionally be mono- or polysubstituted by one or more groups R.sup.9, or [0013] R.sup.1 and R.sup.2 together denote C.sub.2-C.sub.6-alkylene, in which optionally one or two methylene groups may be replaced by one of the groups --O or --NR.sup.7, and which may optionally be mono- or polysubstituted by one or more groups R.sup.9; [0014] R.sup.3 denotes hydrogen or a group selected from C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.3-C.sub.8-cycloalkyl and C.sub.6-C.sub.14-aryl, which may optionally be mono- or polysubstituted by one or more groups R.sup.9; or [0015] R.sup.3 and R.sup.2 or R.sup.3 and R.sup.1 together denote C.sub.2-C.sub.6-alkylene which may optionally be mono- or polysubstituted by one or more groups R.sup.9; [0016] R.sup.4 denotes hydrogen, halogen, CN, OH, --NK.sup.7R.sup.8 or a group selected from among C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyloxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkenyloxy, C.sub.2-C.sub.6-alkynyl and C.sub.2-C.sub.6-alkynyloxy, which may optionally be mono- or polysubstituted by one or more groups R.sup.10; [0017] R.sup.5 denotes phenyl, which may optionally be mono- or polysubstituted by one or more groups R.sup.11 or [0018] R.sup.5 phenyl which is monosubstituted by a group R.sup.6, or [0019] R.sup.5 denotes C.sub.1-C.sub.4-alkyl which may optionally be mono- or polysubstituted by one or more groups R.sup.9, or [0020] R.sup.6 denotes --NR.sup.7R.sup.8 or a 5-10-membered heterocycloalkyl group which may contain one, two or three heteroatoms selected from among nitrogen, oxygen and sulphur, preferably nitrogen or oxygen, and which may optionally be mono- or polysubstituted by one or more of the groups R.sup.12; [0021] R.sup.7 and R.sup.8, which may be identical or different, denote hydrogen or C.sub.1-C.sub.6-alkyl, [0022] R.sup.9 denotes halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, CN, OH or CF.sub.3; [0023] R.sup.10 denotes halogen, OH, CN, .dbd.O, C.sub.1-C.sub.6-alkyloxy, COOK.sup.7, NR.sup.7R.sup.8, CONR.sup.7R.sup.8, SO.sub.2R.sup.7, CHF.sub.2 or CF.sub.3; [0024] R.sup.11 denotes halogen, OH, CN, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, COOR.sup.7, CONR.sup.7R.sup.8, SO.sub.2R.sup.7, CHF.sub.2, CF.sub.3, C.sub.6-C.sub.10-aryl or C.sub.1-C.sub.6-alkylene-C.sub.6-C.sub.10-aryl; [0025] R.sup.12 denotes halogen, CF.sub.3, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylene-C.sub.6-C.sub.10-aryl, C.sub.3-C.sub.8-cycloalkyl or C.sub.1-C.sub.6-alkylene-C.sub.3-C.sub.8-cycloalkyl; optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. [0026] Preferred are compounds of general formula (I), wherein [0027] L denotes a single bond, or a bridging double-bonded group selected from among C.sub.1-C.sub.6-alkylene, C.sub.2-C.sub.6-alkenylene, C.sub.2-C.sub.6-alkynylene, C.sub.3-C.sub.7-cycloalkylene, C.sub.1-C.sub.4-alkylene-C.sub.6-C.sub.10-arylene-C.sub.1-C.sub.4-alkylen- e, --O, --O--C.sub.1-C.sub.4-alkylene, --NR.sup.7-- and --NR.sup.7--C.sub.1-C.sub.4-alkylene, which may optionally be substituted by one or more groups R.sup.9; [0028] R.sup.1 and R.sup.2, which may be identical or different, denote hydrogen, or a group selected from among C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl and C.sub.2-C.sub.6-alkynyl, which may optionally be mono- or polysubstituted by one or more groups R.sup.9, or [0029] R.sup.1 and R.sup.2 together denote C.sub.2-C.sub.6-alkylene, in which optionally one or two methylene groups may be replaced by one of the groups --O or --NR.sup.7, and which may optionally be mono- or polysubstituted by one or more groups R.sup.9; [0030] R.sup.3 denotes hydrogen or a group selected from C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.3-C.sub.8-cycloalkyl and C.sub.6-C.sub.14-aryl, which may optionally be mono- or polysubstituted by one or more groups R.sup.9; or [0031] R.sup.3 and R.sup.2 or R.sup.3 and R.sup.1 together denote C.sub.2-C.sub.6-alkylene which may optionally be mono- or polysubstituted by one or more groups R.sup.9; [0032] R.sup.4 denotes hydrogen, halogen, CN, OH, --NR.sup.7R.sup.8 or a group selected from among C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyloxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkenyloxy, C.sub.2-C.sub.6-alkynyl and C.sub.2-C.sub.6-alkynyloxy, which may optionally be mono- or polysubstituted by one or more groups R.sup.10; [0033] R.sup.5 denotes phenyl, which may optionally be mono- or polysubstituted by one or more groups R.sup.11, or [0034] R.sup.5 denotes phenyl which is monosubstituted by a group R.sup.6, or [0035] R.sup.5 denotes C.sub.1-C.sub.4-alkyl which may optionally be mono- or polysubstituted by one or more groups R.sup.9, or [0036] R.sup.6 denotes a 5-10-membered heterocycloalkyl group which may contain one, two or three heteroatoms selected from among nitrogen, oxygen and sulphur, preferably nitrogen or oxygen, and which may optionally be mono- or polysubstituted by one or more of the groups R.sup.12; [0037] R.sup.7 and R.sup.8, which may be identical or different, denote hydrogen or C.sub.1-C.sub.6-alkyl, R.sup.9 denotes halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, CN, OH or CF.sub.3; [0038] R.sup.10 denotes halogen, OH, CN, .dbd.O, C.sub.1-C.sub.6-alkyloxy, COOR.sup.7, CONR.sup.7R.sup.8, SO.sub.2R.sup.7, CHF.sub.2 or CF.sub.3; [0039] R.sup.11 denotes halogen, OH, CN, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, COOR.sup.7, CONR.sup.7R.sup.8, SO.sub.2R.sup.7, CHF.sub.2, CF.sub.3, C.sub.6-C.sub.10-aryl or C.sub.1-C.sub.6-alkylene-C.sub.6-C.sub.10-aryl; [0040] R.sup.12 denotes halogen, CF.sub.3, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylene-C.sub.6-C.sub.10-aryl, C.sub.3-C.sub.8-cycloalkyl or C.sub.1-C.sub.6-alkylene-C.sub.3-C.sub.8-cycloalkyl; optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. [0041] Also preferred are compounds of general formula (I), wherein [0042] L denotes a single bond, --O, --O--C.sub.1-C.sub.3-alkylene, --NR.sup.7, --NR.sup.7--C.sub.1-C.sub.3-alkylene or C.sub.1-C.sub.4-alkylene, which may optionally be substituted by one or more groups R.sup.9; [0043] R.sup.1 and R.sup.2, which may be identical or different, denote hydrogen, or a group selected from among C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl and C.sub.2-C.sub.4-alkynyl, which may optionally be mono- or polysubstituted by one or more groups R.sup.9, or [0044] R.sup.1 and R.sup.2 together denote C.sub.2-C.sub.4-alkylene which may optionally be mono- or polysubstituted by one or more groups R.sup.9; [0045] R.sup.3 denotes hydrogen or a group selected from C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.7-cycloalkyl and C.sub.6-C.sub.10-aryl, which may optionally be mono- or polysubstituted by one or more groups R.sup.9; or [0046] R.sup.3 and R.sup.2 or R.sup.3 and R.sup.1 together denote C.sub.2-C.sub.4-alkylene which may optionally be mono- or polysubstituted by one or more groups R.sup.9; [0047] R.sup.4 denotes hydrogen, fluorine, chlorine, bromine, --NR.sup.7R.sup.3 or a group selected from among C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, C.sub.2-C.sub.4-alkenyloxy and C.sub.2-C.sub.4-alkynyloxy, which may optionally be mono- or polysubstituted by one or more groups R.sup.10; [0048] R.sup.5 denotes phenyl which may optionally be mono- or disubstituted by one or more groups R.sup.11, or [0049] R.sup.5 denotes phenyl which is monosubstituted by a group R.sup.6, or [0050] R.sup.5 denotes a group selected from among methyl, ethyl, propyl and butyl which may optionally be mono- or disubstituted by one or more groups R.sup.9; [0051] R.sup.6 denotes a heterocycloalkyl selected from among piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl and morpholinyl which may optionally be mono- or polysubstituted by one or more of the groups R.sup.12; [0052] R.sup.7 and R.sup.8, which may be identical or different, denote hydrogen or C.sub.1-C.sub.4-alkyl, R.sup.9 denotes halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, CN, OH or CF.sub.3; [0053] R.sup.10 denotes halogen, OH, .dbd.O, C.sub.1-C.sub.4-alkyloxy or CF.sub.3; [0054] R.sup.11 denotes halogen, OH, CN, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, COOR.sup.7, CF.sub.3, or C.sub.1-C.sub.4-alkylene-phenyl; [0055] R.sup.12 denotes C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkylene-phenyl, C.sub.3-C.sub.6-cycloalkyl or C.sub.1-C.sub.4-alkylene-C.sub.3-C.sub.6-cycloalkyl; optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. [0056] Also preferred are compounds of general formula (I), wherein [0057] L denotes a single bond, C.sub.1-C.sub.4-alkylene, --O, --O--C.sub.1-C.sub.3-alkylene, --NH or --NH--C.sub.1-C.sub.3-alkylene; [0058] R.sup.1 and R.sup.2, which may be identical or different, denote hydrogen, or a group selected from among C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl and C.sub.2-C.sub.4-alkynyl, which may optionally be mono- or disubstituted by a group selected from among fluorine, chlorine, OH and CF.sub.3; [0059] or [0060] R.sup.3 denotes hydrogen or a group selected from C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.7-cycloalkyl and C.sub.6-C.sub.10-aryl, which may optionally be mono- or disubstituted by a group selected from among fluorine, chlorine, methyl, ethyl, OH, methyloxy, ethyloxy and CF.sub.3; [0061] R.sup.4 denotes hydrogen, fluorine, chlorine, bromine, --NR.sup.7R.sup.8 or a group selected from among C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, C.sub.2-C.sub.4-alkenyloxy and C.sub.2-C.sub.4-alkynyloxy, which may optionally be mono- or disubstituted by a group selected from among fluorine, chlorine, OH, methoxy, ethoxy and CF.sub.3; [0062] R.sup.5 denotes phenyl, which may optionally be mono- or disubstituted by a group selected from among methyl, ethyl, OH, fluorine, chlorine, CF.sub.3, COOH, COOmethyl or COOethyl, or [0063] R.sup.5 denotes phenyl which is monosubstituted by a heterocycloalkyl selected from among piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl and morpholinyl, which may be mono- or disubstituted by methyl, ethyl, benzyl, phenethyl, cyclopropyl or cyclopropylmethyl, or [0064] R.sup.5 denotes a group selected from among methyl, ethyl, propyl and butyl which may optionally be mono- or disubstituted by one or more groups selected from among fluorine, chlorine, OH and CF.sub.3; [0065] R.sup.7 and R.sup.8, which may be identical or different, denote hydrogen, methyl or ethyl, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. [0066] Also preferred are compounds of general formula (I), wherein [0067] L denotes a single bond, --CH.sub.2, --CH.sub.2--CH.sub.2, --O, --O--CH.sub.2, --O--CH.sub.2--CH.sub.2, --NH, --NH--CH.sub.2 or --NH--CH.sub.2--CH.sub.2--; [0068] R.sup.1 and R.sup.2, which may be identical or different, denote hydrogen or a group selected from among methyl, ethyl, propyl, butyl, allyl and propargyl, which may optionally be mono- or disubstituted by a group selected from among fluorine, chlorine and CF.sub.3; [0069] R.sup.3 denotes hydrogen or a group selected from among methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopentyl, cyclohexyl and phenyl, which may optionally be mono- or disubstituted by a group selected from among fluorine, chlorine, methyl, ethyl, methyloxy, ethyloxy and CF.sub.3; [0070] R.sup.4 denotes hydrogen, methyl, ethyl, propyl, methyloxy, ethyloxy or propyloxy; [0071] R.sup.5 denotes phenyl, which may optionally be mono- or disubstituted by a group selected from among methyl, OH, fluorine, CF.sub.3, COOH, COOmethyl or COOethyl, or [0072] R.sup.5 denotes phenyl which is monosubstituted by a heterocycloalkyl selected from among piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl, which may be mono- or disubstituted by methyl, ethyl, benzyl, phenethyl, cyclopropyl or cyclopropylmethyl; [0073] R.sup.5 denotes a group selected from among methyl, ethyl, propyl and butyl which may optionally be mono- or disubstituted by one or more groups selected from the group fluorine, chlorine and CF.sub.3; [0074] optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. [0075] Of particular importance according to the invention are compounds of general formula (I), wherein [0076] L denotes a single bond, or a bridging double-bonded group selected from among --CH.sub.2, --CH.sub.2--CH.sub.2, --O, --O--CH.sub.2, --O--CH.sub.2--CH.sub.2, --NH, --NH--CH.sub.2 or --NH--CH.sub.2--CH.sub.2, preferably a single bond or a group selected from --CH.sub.2, --CH.sub.2--CH.sub.2, --O, --O--CH.sub.2, --NH or --NH--CH.sub.2, and the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 and R.sup.9 may have one of the meanings given above or hereinafter, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. Continue reading about Dihydropteridione intermediate compounds... 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