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Inhibitors of cdc25 phosphatasesRelated 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, Piperazines (i.e., Fully Hydrogenated 1,4-diazines), Additional Hetero Ring Attached Directly Or Indirectly To The Piperazine Ring By Nonionic BondingInhibitors of cdc25 phosphatases description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060154933, Inhibitors of cdc25 phosphatases. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] A subject of the present invention is new inhibitors of cdc25 phosphatases, and in particular of cdc25-C phosphatase. [0002] Control of the transition between the different phases of the cell cycle during mitosis or meiosis is provided by a group of proteins, the enzymatic activities of which are associated with different states of phosphorylation. These states are controlled by two large classes of enzymes: the kinases and the phosphatases. [0003] Synchronization of the different phases of the cell cycle thus allows reorganisation of the cell architecture at each cycle in all of the living world (microorganisms, yeasts, vertebrates, plants). Among the kinases, the cyclin-dependent kinases (CDKs) play a major role in this control of the cell cycle. Their activities are regulated by their molecular associations with other proteins called cyclins. In addition, endogenous inhibitors are capable of preventing these activities. Several inhibitors of this family of kinases are already identified and studied in several therapeutic fields such as oncology for preventing the division of tumour cells (McDonald and el-Deiry, Int. J. Oncol. (2000), 16, 871-886) or also neurobiology for preventing natural or chemically-induced apoptosis of normal cells (for example the neurones) (cf. Maas et al., J. Neurochem. (1998), 70, 1401-1410; Park et al., J. Neurosci. (1997) 17, 1256-1270). [0004] Moreover, the enzymatic activity of these different CDKs is controlled by two other families of enzymes which work in opposition (Jessus and Ozon, Prog. Cell cycle Res. (1995), 1, 215-228). The first groups together kinases such as Wee1 and Mik1 which deactivate the CDKs by phosphorylating certain amino acids (Den Haese et al., Mol. Biol. Cell (1995), 6, 371-385). The second groups together phosphatases such as Cdc25 which activate the CDKs by dephosphorylating tyrosine and threonine residues of CDKs (Gould et al., Science (1990), 250, 1573-1576). Dephosphorylation will be carried out in the first instance thanks to a protein/protein interaction between the cyclin and cdc25, and this complex will in the second instance target CDK (Morris and Divita, J. Mol. Biol. (1999), 286, 475-487). In addition, cyclin B is itself phosphorylated by the Cdc2 kinase (cdk1) to which it is associated (Borgne et al., J. Biol. Chem. (1999), 274, 11977-11986). [0005] If a single form of cdc25 is described in yeast, a family of 3 genes, cdc25-A, cdc25-B and cdc25-C, code for the human cdc25 proteins. In addition, variants originating from alternative splicing of the cdc25B gene have been identified: they are cdc25B 1, cdc25B2 and cdc25B3 (Baldin et al., Oncogene (1997), 14, 2485-2495). The proteins coded by these variants would be localized differently within the cell (Davezac et al., Oncogene (2000), 19, 2179-2185). cdc25 activity is regulated by the Cdc2 and Cdk2 kinases. But in the absence of cdc2 kinase, the activity of cdc25 can be activated by other kinases (Izumi and Maller, Mol. Biol. Cell (1995), 6, 215-226). Among these, the chk1 protein phosphorylates cdc25-C on a serine in position 216, which increases its affinity for a chaperone protein 14-3-3. This bond neutralises cdc25-C and consequently maintains the cdk1 enzyme in a phosphorylated state and therefore inactive, not allowing entry into mitosis. The chaperone protein allows the complex to pass into the cytoplasm thanks to a protein unit of nuclear export (Lopez-Girona et al., Nature (1999), 397, 172-175). [0006] A chemical inhibitor of chk1 (SB-218070) allows a cell to continue its cell cycle despite the induction of the DNA break. This aspect allows the effectiveness of certain cytotoxic compounds such as campthotecin to be increased (Jackson et al., Cancer Res. (2000), 60, 566-572). [0007] The role of cdc25 phosphatases in oncogenesis was described initially by the Beach group showing that cdc25A and cdc25B by co-operating with Ha-RASG12V form foci after transfection of normal cells (Galaktionov et al., Science (1995), 269, 1575-1577). The transforming activity of cdc25A and cdc25B is also observed when transfection is carried out in cells having a lack of the RB1 tumour suppressor gene. In addition, the expression of the cdc25-A and -B genes appears to be under the direct control of the protein coded by the c-Myc oncogene (Galaktionov et al., Nature (1996), 382, 511-517). On the other hand, cdc25-C phosphatase does not seem to be controlled by the latter. [0008] The overexpression of cdc25, and principally cdc25-A, appears to prevent the cell from stopping its cell cycle in the event of aggression on the genome and thus avoids a possible repair process (Mailand et al., Science (2000), 288, 1425-1429). [0009] Moreover, the overexpression of the different forms of cdc25 is now reported in many classifications of human tumors: [0010] Breast cancer: measurement by riboprobe shows that 32% of tumors over-express cdc25-B. The overexpression of cdc25-A is shown in nearly 50% of cancers of the breast and is associated with a poor prognosis (Cangi et al., Resume 2984, AACR meeting San Francisco, 2000). [0011] Lymphomas: in the circulating lymphocytes, the expressions of the RNAs of cdc25-B1 and -B3 are detected by RT-PCR while the expressions of cdc25-A, -B2 and -C are very weak or undetectable. On the other hand, analysis of these genes in non-hodgkin's lymphomas shows a strong expression of cdc25-A and -B2 in approximately 35% of the tumors. The cdc25-B1 and -B3 variants are themselves detected in all of the tumors analysed. On the other hand, the expression of cdc25-C remains very weak in the sample group (Hernandez et al., Int. J. Cancer (2000), 89, 148-152). It is important to note the correlation between the expression of proteins such as myc and cdc25. 26 of 35 (74%) non-hodgkin's lymphomas with a raised level of cdc25-B also show an over-expression of c-myc. On the other hand, 27 out of 28 (96%) tumors with a low level of cdc25-B expression do not show any detectable c-myc (P<0.0001). This suggests that the expression of cdc25 associated with that of myc could participate in the development of this type of lymphoma (Hemandez et al., Cancer Res. (1998), 58, 1762-1767). [0012] Neck and head cancers: of 20 tumors examined by quantitative RT-PCR, Gasparotto et al. note that CDC25-A and -8 are over-expressed whilst cdc25-C is expressed very little (Gasparotto et al., Cancer Res. (1997), 57, 2366-2368). [0013] Moreover, the E. Sausville group reports an inverse correlation between the level of expression of cdc25-B in a panel of 60 cell lines and their sensitivity to CDK inhibitors such as Olumucine or Flavopiridol, suggesting that the presence of cdc25 can provide resistance to certain anti-tumor agents and more particularly to CDK inhibitors (Hose et al., Proceedings of AACR, Abstract 3571, San Francisco, 2000). [0014] Vitamin K3, also called menadione, was the first selective inhibitor of cdc25 phosphatase described (Ham et al., Bioorg. Med. Chem. Lett. (1998) 8, 2507-2510). Other cdc25 inhibitors have since been identified and have an inhibitory activity of micromolar order on the recombinant enzymes. Among these products, the following can be noted: [0015] 1. Naphthoquinone analogues derived from menadione (Ham et al., Bioorg. Med. Chem. Lett. (1998) 8, 2507-2510). [0016] 2. Cpd5, a thioalkyl derivative of vitamin K (Tamura et al., Cancer Res. (2000), 60, 1317-1325). The inhibition constants (Kis) measured on cdc25-A, -B2 & -C are 15, 1.7 and 1.3 .mu.mol respectively. [0017] 3. 4-(benzyl-(2-[(2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-- 2-decanoylaminobutanoic acid also called SC-alpha alpha delta 9 (Tamura et al., Oncogene (1999) 18, 6989-6996). [0018] 4. Certain compounds originating from a Ugi library containing groups mimicking phosphates are non-competitive inhibitors of cdc25-A which do not act on the active site. The most active compound has an IC.sub.50 of 0.5 .mu.M and the interaction site is in the process of being identified (Bergnes et al., Bioorg Med. Chem. Lett. (1999), 9, 2849-2854). [0019] 5. Quinolin-4-one and 1,7-naphthyridin-4-one derivatives. Certain compounds are inhibitors both of cdc25 and cdc2 (el-Subbagh et al., Arch. Pharm. (Weinheim.) (1999), 332, 19-24). [0020] 6. Dysidiolide and derivatives containing a .gamma.-hydroxy butenolide group. The effectiveness of these products is discussed in Blanchard et al., Bioorg. Med. Chem. Lett. (1999), 9, 2537-2538. [0021] 7. Certain 5-substituted 2-bromoindolo[3,2-b]quinoxalines. Certain of these compounds are inhibitors of both cdc25 and cdc2 (Abadi et al., Arch. Pharm. (Weinheim) (1998), 331, 352-358). [0022] The PCT Application WO 00/17190 describes amidine derivatives which inhibit the NO synthases and trap the free radicals. Because of this, these compounds present numerous pharmacological properties and their use can be envisaged in the treatment of numerous pathologies, principally in the field of neurology. A simplified general formula of these compounds could be general formula (ET1): in which A represents a radical which traps free radicals, for example a substituted phenyl radical; X and Y are linking chains, for example alkylene, alkylenecarbonyl, carbonylalkylene radicals; R represents H or alkyl; and B represents a carbocyclic or heterocyclic aryl radical, and preferably the 2-thienyl radical. [0023] The invention offers new inhibitors of cdc25, and in particular of cdc25-C, which correspond to general formula (I) defined below. These compounds are capable of being used as medicaments, in particular in the treatment of the following diseases/disorders: [0024] inhibition of tumorous proliferation when used alone or in combination with other treatments; [0025] inhibition of the proliferation of normal cells when used alone or in combination with other treatments; [0026] the prevention of spontaneous alopecia; [0027] the prevention of alopecia induced by exogenous products; [0028] the prevention of radiation-induced alopecia; [0029] the prevention of spontaneous or induced apoptosis of normal cells; [0030] the prevention of meiosis and fertilization; [0031] the prevention of oocyte maturation; [0032] all of the diseases/disorders corresponding to the uses mentioned for CDK inhibitors, and in particular non-tumorous proliferative diseases (for example: angiogenesis, psoriasis or the recurrence of stenosis), tumorous proliferative diseases, parasitology (proliferation of protozoa), viral infections, neurodegenerative diseases, myopathies; [0033] all of the diseases/disorders corresponding to clinical uses of vitamin K and its derivatives; [0034] Moreover, the compounds of the present invention are also, because of their properties of inhibiting cdc25 phosphatases, capable of being used to inhibit the proliferation of microorganisms, in particular yeasts. One of the advantages of these compounds is their low toxicity on healthy cells. [0035] At present, the Applicant has discovered in a surprising manner that the compounds corresponding to general formula (I) in which: A represents an (A1) radical in which two of the R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 groups represent hydrogen atoms and the other three are chosen independently from a hydrogen atom, a halogen atom and an alkyl, hydroxy, alkoxy, alkylcarbonyloxy, alkylthio or NR.sup.6R.sup.7 radical, it being understood moreover that: [0036] either R.sup.1 and one of R.sup.2 and R.sup.4 are chosen independently from a hydroxy, alkylcarbonyloxy and NW.sup.6R.sup.7 radical, [0037] or R.sup.2 and one of R.sup.3 and R.sup.5 are chosen independently from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0038] or R.sup.4 and one of R.sup.3 and R.sup.5 are chosen independently from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0039] or also one of R.sup.1, R.sup.3 and R.sup.5 is chosen from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical, and the B--N(W)--X--Y remainder is attached to the A radical by a nitrogen atom, R.sup.6 and R.sup.7 representing, independently each time that they occur, a hydrogen atom or an alkyl radical or R.sup.6 and R.sup.7 forming together with the nitrogen atom a heterocycle with 4 to 7 members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being chosen independently from the --CR.sup.8R.sup.9--, --O--, --S-- and --NR.sup.10-radicals, R.sup.8 and R.sup.9 independently representing each time that they occur a hydrogen atom or an alkyl, alkoxy, benzyloxycarbonylamino or dialkylamino radical, and R.sup.10 independently representing each time that it occurs a hydrogen atom or an alkyl radical, or also A represents an (A2) radical in which: [0040] either R.sup.11 and one of R.sup.13, R.sup.14 and R.sup.15 represent hydroxy radicals whilst the other radicals among R.sup.13, R.sup.14 and R.sup.15 as well as R.sup.16 represent hydrogen atoms, [0041] or R.sup.12 and R.sup.16 represent hydroxy radicals whilst R.sup.11, R.sup.13, R.sup.14 and R.sup.15 represent hydrogen atoms; Continue reading about Inhibitors of cdc25 phosphatases... 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