WO2009078588A2 - Composition for prevention and treatment of cancer containing pyrimidine derivatives inhibiting activity of protein phosphatases or pharmaceutically acceptable salts thereof as an active ingredient - Google Patents
Composition for prevention and treatment of cancer containing pyrimidine derivatives inhibiting activity of protein phosphatases or pharmaceutically acceptable salts thereof as an active ingredient Download PDFInfo
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- WO2009078588A2 WO2009078588A2 PCT/KR2008/006718 KR2008006718W WO2009078588A2 WO 2009078588 A2 WO2009078588 A2 WO 2009078588A2 KR 2008006718 W KR2008006718 W KR 2008006718W WO 2009078588 A2 WO2009078588 A2 WO 2009078588A2
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- cancer
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to a composition for the prevention and treatment of various cancers, which inhibits protein phosphatases, containing a pyrimidine derivative as an active ingredient. The pyrimidine derivatives according to the present invention effectively inhibit the activities of protein phosphatases, such as Cdc25A and Cdc25B, and may be useful in the prevention and treatment of breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, bone marrow cancer, and the like.
Description
Description
COMPOSITION FOR PREVENTION AND TREATMENT OF CANCER CONTAINING PYRIMIDINE DERIVATIVES INHIBITING ACTIVITY OF PROTEIN PHOSPHATASES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS
AN ACTIVE INGREDIENT Technical Field
[1] The present invention relates to pyrrolidine derivatives which inhibit the activity of protein phosphatases (PPases) such as PTPlB (protein tyrosine phosphatase IB), LAR (leukocyte antigen-related), CD45 (cluster of differentiation 45), Yop (Yersinia entero- colytica tyrosine phosphatase), PPl (protein phosphatases 1), VHR (vaccinia human- related) as well as Cdc25 (cell division cycle 25), and more particularly, to a composition for the prevention and treatment of cancer, which contains the pyrimidine derivatives and pharmaceutically acceptable salts thereof as an active ingredient. Background Art
[2] Protein phosphorylation and dephosphorylation are widely known as important regulatory mechanisms which are used for cellular signal transduction in various stages of the cellular functions. On the whole, cellular signals are mediated through phosphorylation and dephosphorylation, catalyzed by kinases and protein phosphatases, respectively. Due to their characteristic activities, particularly, protein phosphatases (PPases), which are responsible for dephosphorylation, are known to play pivotal roles in the in vivo modulation and regulation of fundamental cellular signaling mechanisms for metabolism, growth, proliferation and differentiation. Among these protein phosphatases are Cdc25 (Cdc25A, Cdc25B, and Cdc25C), functioning to remove phosphate from tyrosine, PTPlB, Prl-3, LAR, CD45, Cdc25A, Yop, PPl, VHR and the like.
[3] Hereinafter, the results of the prior researches related to these PPases will be described.
[4] 1. Cdc25
[5] Cdc25 phosphatase is a kind of dual specific phosphatase for acting on both phosphor-tyrosine and phosphor-threonine. The Cdc25 phosphatase is responsible for the activation of cyclin dependent kinase (CDK) by removing inhibitory phosphate from tyrosine and threonine residues of CDK, which is implicated in the cell division cycle. A high level of CDK induces the activation of the MPF (M phase promoting factor) to increase the miotic activity in the M phase of cell cycle, resulting in cell proliferation. Accordingly, inhibiting the activity of the Cdc25 phosphatase interfere with
cell division to thus prevent cell proliferation. Cdc25 has been reported to have three homologues, Cdc25A, Cdc25B, and Cdc25C, in human cells. Among them, Cdc25A or Cdc25B is inferred to play an important role in carcinogenesis because it is the most highly expressed in cancer cells, for example, breast cancer, rectal cancer, non- Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and the like, and recent studies have revealed that Cdc25A is also included in the adhesion-dependent proliferation of sensitive myeloid leukaemia cells. By inducing M phase arrest, therefore, Cdc25 inhibitors can be targets for developing anticancer agents, extensive and intensive research has been studied on the inhibitors (Ontani, T. et al, J. of Antibiotics 2000, 53, 337; Lazo, J. S. et al., Bioorg. Mded. Chem. Lett. 2000, 8, 1451).
[6] 2. PTPlB
[7] PTPlB as the first identified intercellular protein phophastase, was isolated from the human placenta and found to have a molecular weight of -50 kDa, and then cloned.
[8] PTPlB is highly expressed in various human cells. Particularly, PTPlB acts to inhibit the phosphorylation not only of insulin receptor (IR) but also of insulin receptor substrate (IRS-I) in the signal transduction pathway of insulin. It was demonstrated through the biochemical experiment conducted by Kennedy and Ramachandran, in which PTPlB knock-out mice were observed to exhibit the increase of insulin sensitivity and, when injected with insulin, to increase the phosphorylation of insulin receptors in hepatic and muscular cells {Science 1999, 283, 1544). Diabetes mellitus type II, an insulin-indepedent diabetes, is a metabolic disorder that is primarily characterized by insulin resistance of the organs (muscles, liver, lipocytes) where insulin disfunctions, although the pancreas normally secretes insulin. The dephosphorylation of the insulin receptor (IR) was found to be directly responsible for insulin resistance and be implicated in diabetes mellitus type II. Having potential activity to overcome insulin resistance and normalize the level of glucose and insulin in the blood without causing hypoglycemia, accordingly, PTPlB inhibitors, acting against the dephosphorylation of IR, have been extensively studied with the aim of developing therapeutic agents for diabetes mellitus type II.
[9] For example, Wyeth-Ayerst and American Home Products disclosed 10 or more patents in which a broad spectrum of PTPlB inhibitors is described (US 6121271, US 6110963, US 6110962, US 6103708, US 6063815, US 6057316, US 6001867, WO 9961436, WO 9961410, WO 9958522, WO 9958521, WO 9958520, WO 9958519, WO 9958518, WO 9958514, WO 9958511), and published many relevant articles (M. S. et al., J. Med. Chem. 2000, 43, 995; Malamas, M. S. et al., J. Med. Chem. 2000, 43, 1293; Wrobel, J. et al., Bioorg. & Med. Chem. Lett. 2000, 10, 1535). Through the above studies of PTPlB inhibitors, new compounds, including benzofuran and ben-
zothiophene biophenyl, were reported to have IC50 values of tens of nM. A material which is also able to more effectively reduce the level of glucose in the blood than ciglitazone, which has been widely used as a therapeutic agent for diabetes mellitus, was found through in vivo experiments with mice. Recently, the development of the ertiprotafib, a kind of PTPlB inhibitor, represented by the following structural formulas, has been discontinued in phase II clinical testing.
[10] [H] Also, Abbott Company has continuously tried to develop PTPlB inhibitors on the basis of various chemical skeletons. (W 00264840, US 2002-077347, US 2002-072516, Diabetes 2002, 52(8), 2405). Prof. Zhang, Albert Einstein College of Medicine of Yeshiva University, suggested novel structures for PTPlB inhibitors by virtual screening, and also by molecular modeling using PTPlB crystalline structure (Zhang, Z. et al., J. Biol. chem. 2002, 277 (35), 31818. /. Med. Chem. 2000, 43, 146, Bioorg. & Med. Chem. Lett. 2000, 10, 457, Bioorg. & Med. Chem. Lett. 2000, 10, 923).
[12] Novo Nordisk/Ontogen Company introduced a low molecular weight oxaly- laminoaryl acid derivative, which is neither derived from phosphatic acid nor from peptides (W 0 9946237, 9946267, 0117516, Iversen, L. F. et. al., J. Med. Chem. 2002, 45 (20), 4443; J. Biol. Chem. 2000, 275, 10300; Moller, N. P. H. et al., J. Biol. Chem. 2000, 275, 7101). According to their research, they emphasized that the synthetic PTPlB inhibitor has high selectivity for other protein tyrosine phosphatases.
Novo Nordisk/Ontogen WO 9946237
[14] Continuing to study PTPlB inhibitors, Merck Frosst Canada suggested α,α-difluoromethylenephosphonates structures (WO 0146206, 0146205, 0146204, 0146203, 0069889, 001721 1 , 0006712).
[15] Although there are such a large quantity of results as mentioned above, no materials have passed the complete clinical testing thus far. So there is an urgent need to find
novel compounds which can be used in humans.
[16] 3. CD45
[17] For cells to grow normally, a balance between highly elaborate signals is required.
When the balance between them is broken and activation signals remain alone, cells grow uncontrollably, thus resulting in the occurrence of disorders. CD45 plays an essential role in terminating the signal transduction responsible for the uncontrollable growth of cells. CD45, a transmembrane PTPase (Protein Tyrosine Phosphatase), was known as an important role in signal transduction in T-cell or B-cells. In CD45 knockout mice, Janus kinase (JAK) and STAT (signal transducer and activators of transcription) are observed to be activated by cytokines and interferon, demonstrating that CD45 interrupts the signal transduction of cytokines by inhibiting JAK.
[18] In addition, CD45 negatively regulates interleukin-3-mediated cellular proliferation, erythropoietin-dependent hematopoieisis and antiviral responses. This indicates that CD45 suppresses the activity of the immune system of attacking foreign invaders, leading to the suppression of cancer cell proliferation and autoimmune diseases. Based on this finding, CD45 inhibitors can be available to prevent transplant rejection. In fact, extensive research into CD45 inhibitors has been conducted and the results thereof are disclosed in many patents and articles, issued to AstraZeneca Company (W 0 0146125, 0145681, 0145680, R. A. Urbanek et al, J. Med. Chem. 2001, 44, 1777 and to others (JP2001114678, JP2001114689, WO 0128991, 0119830, 0119831, 0116097, 0128991). However, in spite of the extensive research results, no materials have succeeded in passing clinical testing, and thus there is an urgent need for a novel material for CD45 inhibitors.
[19] 4. LAR
[20] It was hypothesized that LAR might be involved in the physiological modulation of insulin receptor signaling in intact cells. This conclusion was reached from data obtained by comparing the rate of dephosphorylation/inactivation of purified IR using PTPlB as well as the cytoplasmic domains of LAR. To examine whether the transmembrane PTPase LAR can modulate insulin receptor signaling in vivo, antisense inhibition was recently employed. In this test, LAR protein levels were specifically suppressed by approximately 60% in a rat hepatoma cell line. This suppression of the LAR protein level was paralleled by an approximately 150% increase in the insulin- dependent autophosphorylation of the insulin receptor.
[21] However, only a modest 35% increase in insulin receptor tyrosine kinase (IRTK) activity was observed, whereas reduced LAR levels resulted in a 350% increase in insulin-dependent phosphatidylinositol 3-kinase (PI 3-kinase) activity. The authors speculated that LAR could specifically dephosphorylate tyrosine residues, which are critical for PI 3-kinase activation, either on the insulin receptor itself or on a
downstream substrate. Therefore, LAR inhibitors are expected to be useful in the treatment of obesity, impaired glucose intolerance, diabetes mellitus, hypertension, and partially ischemic diseases. In spite of the results from extensive research and studies, there are no compounds that have passed clinical tests thus far. Thus, there is a need for a novel material applicable to human bodies for the treatment of such diseases. [22] 5. VHR
[23] VHR, a dual specific phosphatase, extracellularly regulates extracellular signal receptor kinase 1 (ERKl) and ERK2, both belonging to a subclass of mitogen- activated protein kinase (MAPK), to mediate mitogenic signaling. Since VHR is involved in controlling cell cycles, its inhibitors, like Cdc25 inhibitors, can be available as anticancer agents (Osada, H. et al, FEBS Letters 1995, 372, 54).
[24] 6. Pri-3
[25] Genetic level changes occurred in colon cancer thus far was the inactivation of tumor suppressors. However, these low-molecular weight materials are not suitable as targets for a novel anticancer drug. A recent report (Saha et al., Science 2001, 294, 1343) says that the novel phosphatase Prl-3 is commonly overexpressed in the metastasis of various colon cancer cells. The activity of Prl-3 is essential in the metastasis of colon cancer, therefore, effective Prl-3 inhibitors may be a drug target which can provide a new turning point for the therapy of colon cancer in the metastasis phase.
[26] As elucidated above, overexpression or activity alteration of various protein phosphatases are reported to cause various diseases. The Cdc25 phosphatase, particularly, is observed in breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and the like. Recent studies have revealed that Cdc25A is also involved in the adhesion-dependent proliferation of sensitive myeloid leukemia cells. Therefore, the development of compounds having inhibitory activity against the protein phosphatases could be useful in the prevention and treatment of specific diseases, such as diabetes, autoimmune diseases, and various cancers.
[27] Accordingly, the present inventors conducted intensive and thorough research on the development of compounds which can inhibit the activity of the protein phosphatases, found those compounds through a computer-aided drug design protocol including the homology modeling and the structure-based virtual screening, and identified the inhibitory activity against the protein phosphatases by those compounds, resulting in the completion of the present invention.
Disclosure of Invention
Technical Problem
[28] An object of the present invention is to provide a composition for the prevention and
treatment of various cancers, which contains pyrimidine derivatives inhibiting the activity of protein phosphatases (PPases) or pharmaceutically acceptable salts thereof as an active ingredient. Technical Solution
[29] To achieve the object, the present invention provides a composition for the prevention and treatment of various cancers, which contains pyrimidine derivatives inhibiting the activity of protein phosphatases (PPases) or pharmaceutically acceptable salts thereof as an active ingredient. Advantageous Effects
[30] The pyrimidine derivatives according to the present invention effectively inhibit the activity of protein phosphatases, such as Cdc25A and Cdc25B, and can be useful in the prevention and treatment of various cancers caused by the activity thereof, such as breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and the like. Brief Description of Drawings
[31] The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
[32] FIG. 1 illustrates the arrangement of catalytic domain sequences of Cdc25 A and Cdc25B according to an embodiment of the present invention;
[33] FIG. 2 illustrates 3-dimentsional (3D) structures of Cdc25A and Cdc25B according to an embodiment of the present invention; and
[34] FIG. 3 is a graph showing the 3D structure conformational energy of Cdc25 A formed by the homology modeling, and 3D structure conformational energies of X-ray crystal structures of Cdc25A and Cdc25B (red line: Cdc25A formed by the homology modeling, green line: X-ray crystal structure of Cdc25 A, black line: X-ray crystal structure of Cdc25B) according to an embodiment of the present invention. Best Mode for Carrying out the Invention
[35] The present invention provides a composition for the prevention and treatment of cancers, which contains a derivative which inhibits the activity of protein phosphatases, represented by the following Chemistry Figure 1 as an active ingredient.
[36] ChemistryFigure 1
[Chem.l]
[37] where,
[38] R1 and R3 are independently or selectively one selected from the group consisting of hydrogen; CrC4 linear or branched alkyl; and C5-C7 aryl group which is unsubstituted or substituted with Q-C4 linear or branched alkyl group, [39] R2 and R5 are independently or selectively one selected from the group consisting of
, where each R7, R8, and R9 is one selected from the group consisting of halogen, C) - C4 linear or branched alkyl group, Q-C4 alkenyl, and carboxyl group,
[40] R10 and Rπ are independently or selectively one selected from the group consisting of hydrogen, halogen, C1-C4 linear or branched alkyl group, and nitro group,
, and
[42] [43] Preferably, [44] R1 is phenyl, methylphenyl or dimethylphenyl, [45] R2 and R5 are independently or selectively one selected from the group consisting of
-c≡
[46] R3 is hydrogen,
-SH and
[48] [49] More specifically, the compounds represented by Chemistry Figure 1 include the following:
[50] (1)
2-(2-(5-(4-chlorophenyl)furan-2-yl)vinyl)-6-raercapto-4-oxo-l-phenyl-l,2,3,4-tetrahyd ropyrimidine-5-carbonitrile; [51] (2)
2-(5-(2,5-dichlorophenyl)f uran-2-yl)-6-mercapto-4-oxo- 1 -phenyl- 1 ,2,3 ,4-tetrahydropyr imidine-5-carbonitrile; [52] (3)
2-(5-(3-chlorophenyl)furan-2-yl)-6-mercapto-4-oxo-l-phenyl-l,2,3,4-tetrahydropyrimi dine-5-c arbonitrile ; [53] (4)
2-(5-(2-chloro-4-nitrophenyl)furan-2-yl)-6-mercapto-4-oxo-l-phenyl-l,2,3,4-tetrahydr opyrimidine-5-carbonitrile; [54] (5)
2-(5-(2-chlorophenyl)furan-2-yl)-6-mercapto-4-oxo- 1 -phenyll- 1 ,2,3 ,4-tetrahydiOpyrira idine-5-carbonitrile; [55] (6)
2-(5-(3,4-dichlorophenyl)furan-2-yl)-6-mercapto-4-oxo-l-phenyl-l,2,3,4-tetrahydropyr imidine-5-carbonitrile; [56] (7)
3-((4-((2,4,6-trioxo-3-metha-tolyl-tetrahydropyrimidin-5(6H)-ylidene)methyl)phenoxy
)methyl)benzoic acid; and [57] (8)
2-(5-((3-(3,5-diraethylphenyl)-2,4,6-trioxo-tetrahydropyriraidm-5(6H)-ylidene)methyl) furan-2-yl)benzoic acid.
[58] The chemical formulas of the compounds are summarized in the following Table 1.
[59] Table 1
[60] The derivatives of Chemistry Figure 1 according to the present invention may be also provided in the form of a pharmaceutically acceptable salt. An acid addition salt formed by a pharmaceutically acceptable free acid may be useful as a salt. The acid addition salt may be obtained from an inorganic acid, such as hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and a non-toxic acid, such as aliphatic mono- and di- carboxylate, phenyl- substituted alkanoate, hydroxy alkanoate and alkanedioate, aromatic acid, aliphatic and aromatic sulfonic acid. These pharmaceutically acceptable salts include sulfate, py- rosulfate, bisulfate, sulphite, bisulphite, nitrate, phosphate, monohydrogen phosphate,
dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexane-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methane sulfonate, propane sulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate or mandelate.
[61] The acid addition salt according to the present invention may be prepared by a conventional method, for example, by dissolving the derivative of Chemistry Figure 1 in excess of an acid solution and precipitating the resulting salt in an organic solvent, such as methanol, ethanol, acetone or acetonitrile.
[62] It may be prepared by heating an equal volume of the derivative of Chemistry Figure
1 and acid or alcohol in water, then evaporating the mixture, and drying or filtrating the precipitated salt under vacuum.
[63] In addition, a pharmaceutically acceptable metal salt may be prepared using bases.
An alkaline metal or alkaline earth metal salt may be obtained, for example by dissolving the compound in excess of an alkaline metal hydroxide or alkaline earth metal hydroxide solution, filtrating the insoluble compound salt, evaporating the filtrate and drying the salt. Then, preparation of sodium, potassium or calcium salt is appropriate as a metal salt in the manufacture of drugs. Furthermore, the corresponding silver salt may be obtained by reacting an alkaline metal or alkaline earth metal with a suitable silver salt (e.g., silver nitrate).
[64] The compounds of the present invention may be also provided in the form of a solvate, particularly a hydrate. Hydration may occur during separation of the compound or after a period of time due to the hydroscopic properties of the compound.
[65] The derivatives of Chemical Figure 1 in the present invention have an efficacy of inhibiting the activity of protein phosphatases, particularly Cdc25.
[66] Cdc25 phosphatase is a kind of dual specific phosphatase for acting on both phosphor-tyrosine and phosphor-threonine. The Cdc25 phosphatase is responsible for the activation of cyclin dependent kinase (CDK) by removing inhibitory phosphate from tyrosine and threonine residues of CDK, which is implicated in the cell division cycle. A high level of CDK induces the activation of the MPF (M phase promoting factor) to increase the miotic activity in the M phase of cell cycle, resulting in cell proliferation. Accordingly, inhibiting the activity of the Cdc25 phosphatase interferes with cell division to thus prevent cell proliferation. Cdc25 has been reported to have three homologues, Cdc25A, Cdc25B, and Cdc25C, in human cells. Among them, Cdc25A or
Cdc25B is inferred to play an important role in carcinogenesis because it is the most highly expressed in cancer cells, for example, breast cancer, rectal cancer, non- Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and the like, and recent studies have revealed that Cdc25A is also included in the adhesion-dependent proliferation of sensitive myeloid leukaemia cells. By inducing M phase arrest, therefore, Cdc25 inhibitors can be targets for developing anticancer agents (Ontani, T. et al., /. of Antibiotics 2000, 53, 337; Lazo, J. S. et al., Bioorg. Mded. Chem. Lett. 2000, 8, 1451).
[67] After the derivative of Chemistry Figure 1 according to the present invention was inserted into E. coli, in which the catalytic domains of Cdc25A and Cdc25B phosphatases (Cdc25A: 336~523rd residue, Cdc25B: 378~566th residue) were expressed, and the inhibitory activities of Cdc25A and Cdc25B were measured, they were recorded as 2.25-48.54 μM and 1.97-65.17 μM, respectively, indicating that those values are equivalent or about 20 times more, compared to the inhibitory activities of conventional Cdc25 phosphatase inhibitors (Cdc25A: 4.56-5.49 μM, Cdc25B: 19.17-23.63 μM).
[68] Thus, the derivatives of Chemistry Figure 1 according to the present invention inhibit the activities of Cdc25 A and Cdc25B and may be useful in the prevention and treatment of various cancers.
[69] Preferably, the cancers may be breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, bone marrow cancer and the like in the composition of the present invention.
[70] Further, the present invention provides a method for preventing and treating various cancers comprising administering a therapeutically effective amount of pyrimidine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, to a mammal or a patient in need. Preferably, the mammal is human.
[71] The composition may be formulated into oral or non-oral administration forms. For the oral administrations, for example, tablets and capsules are available. These formulations may contain a diluent (e.g.: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricant (e.g.: silica, talc, stearic acid, or magnesium or calcium salt thereof and/or polyethylene glycol), in addition to an active ingredient. The tablets may also contain a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone, in some cases, a disintegrant, such as starch, agar, alginic acid or sodium salt thereof or a boiling mixture and/or an absorbent, a colorant, a flavor and a sweetner. The formulations may be mixed, granulized, or coated according to a method well known in the art. Furthermore, a representative non-oral administration may be a formulation for injection, preferably an isotonic aqueous solution or suspension.
[72] The composition is sterilized or/and may contain an auxiliary agent, such as a preservative, a stabilizer, wettable agent, emulsifier, an osmotic pressure-controlling salt and/or a buffer, and other therapeutically effective materials, and may be prepared by a conventional method.
[73] The pharmaceutical composition of the present invention may be administered via a non-oral route, such as an intravenous or intramuscular, or orally administered for a specific purpose, and the derivative of Chemistry Figure 1 may be once or many times administered at a dose of 0.01 to 100 rag/kg (body weight) a day, preferably at a dose of 0.1 to 50 mg/kg (body weight) a day. The dosage level of administration to a certain patient depends on the weight of the patient, age, sex, health, diet, administration time, administration method and excretion, and combination of medicines and severity of the disease.
[74] Hereinafter, the present invention will be described in more detail with the following examples, which are set forth to illustrate, but are not construed to limit the present invention.
Mode for the Invention
[75] Screening of protein phosphatase inhibitory compounds
[76] Step 1: Homology modeling of Cdc25A
[77] An experiment was carried out selecting Cdc25A and Cdc25B as protein phosphatases. Then, a modeling of the 3D-structure of Cdc25A was performed using the X- ray crystallographic structure of Cdc25B as a template.
[78] Specifically, an alignment of sequences in catalytic domains of Cdc25A and Cdc25B is shown in FIG. 1. The Cdc25A was obtained from the SWISS-PROT protein sequence data bank (http://www.expasy.org/sprot/ ;accession number P30304). The ClustalW package program was utilized using the BLOSUM matrix in order to convert the sequence alignment in catalytic domains of Cdc25A and Cdc25B into a point, and parameters such as GAP OPEN, GAP EXTENTION, and GAP DISTENCE are set into 10, 0.05, and 8, respectively. As shown in FIG. 1, it was to be understood that the two domains almost corresponded with each other, and the identity and similarity between them were 66.7 % and 76.5 %, respectively. In general, a homology modeling can be performed when the identity is 30 % or more. The dotted line of the rectangle in the sequences represents an active site.
[79] Subsequently, the 3D structure of catalytic domains of Cdc25A using the
MODELLER 6v2 program based on the sequence alignment of the highest points. In order to minimize any hindrance by spatial limitations, an optimum method was used, including molecular dynamics. Furthermore, an enumeration algorithm was also used in the loop modeling to increase the accuracy of the calculated structure. The
3D-structure of the Cdc25 A, formed by these methods and that of the X-ray crys- tallinity of the CDd25B used as a template were shown in FIG. 2.
[80] FIG. 2 shows the 3D-structure of the Cdc25A (a), formed by the homology modeling and that of the X-ray crystal of the Cd25B (b). As shown in FIG. 2, the two enzymes have similar structures, but the amino acid arrangements and structures in active sites differ between them.
[81] A validation was evaluated through the calculation of the 3D-structure conformational energy of the Cdc25A, formed by the 3D-structures and modeling of X-ray ciystal of Cdc25A and Cdc25B using the ProSa 2003 program, and the results are shown in FIG. 3.
[82] As shown in FIG. 3, it was to be understood that the 3D-structure conformational energy of the Cdc25 A, formed by the homology modeling had a similar pattern as the conformational energy distributions of the other X-ray crystallographic structures. Thus, it was identified that the 3D-structure of the Cdc25A, formed by the homology modeling was an acceptable model.
[83] Step 2: Screening of compounds capable of recognizing the active sites of proteins
[84] Subsequently, the chemical structures of the compounds capable of recognizing the active sites of protein enzymes were screened using a virtual screening method. Specifically, the conversion of the binding affinity into the score and rank was performed by obtaining the Interbioscreen Database (http://www.ibscreen.com) which includes chemical structures of about 85,000 natural and synthetic compounds, docking them into 3D active sites of Cdc25 A, formed by the homology modeling through the AutoDock program, and measuring the bonding energies between amino acids on the active sites. Among them, the above described compounds (1 ) to (8), derivatives of Chemistry Figure 1, with the high points were obtained. These compounds were available from Interbioscreen, Inc.
[85] <EXAMPLE> Measurement of the inhibitory activities of protein phosphatases
[86] The catalytic domains of the two Cdc25 (Cdc25A: 336~523rd residue, Cdc25B:
378~566th residue) were expressed in the E. coli., using the pET28a (Novagen) along with 6 histidine tags in the N-terrninal. The expressed Cdc25 phosphatase was purified with a Ni-NTA affinity resin (Qiagen) and crystallized in a buffer (-75 0C) which contained 20 mM Tris-HCl, pH 8.0, 0.2 M NaCl, and 5 mM DTT until the next enzyme experiment. In the phosphatase experiment using a 96-well plate, the reaction mixture includes the compound of Chemistry Figure 1 dissolved in 180 m-C of a reaction buffer (20 mM Tris-HCl, pH 8.0, 0.01 % Triton X-100, 5 mM DTT) and 10 mM 6,8-difluoiO-4-methylum-belliferyl phosphate (DiFMUP, Molecular probe), 10 mi of enzyme (30 nM Cdc25A or 20 nM Cdc25B), and 10 w& of DMSO. The reaction was carried out at the room temperature for 20 minutes, and terminated by addition of 1
mM sodium orthovanadate (final concentration). The fluorescence was then measured on a plate reader, excited at 355 ran and emitted at 460 nm. The IC50 values were measured 3 times or more, using these methods and the mean values are shown in Table 2. The IC50 values of 2,3-bis-(2-hydroxy-ethylsulfanyl)-[l ^naphthoquinone (comparative example 1) and 2-(2-mercaptoethanol)3-methyl-l,4-naphthoquinone (comparative example 2), described in the reference as positive control groups were measured 3 times or more using the same method and the mean values are shown in Table 2. The compounds in the positive control groups have a micromolar inhibitory activity against the Cdc25 phosphatase and are known as the most effective growth inhibitor in various cancer cell lines.
[87] Table 2 [Table 2] [Table ] The IC50 values (μM) of compounds against the Cdc25 phosphatase
[88] As shown in Table 2, it is to be understood that the derivatives of Chemistry Figure 1 according to the present invention had 2.25-48.54 μM and 1.97-65.17 μM in inhibitory activity against Cdc25A and Cdc25B, respectively and the values were equivalent or about 20 times or more, compared to the inhibitory activities of conventional Cdc25 phosphatase inhibitors (comparative examples #1 & 2)(Cdc25A: 4.56-5.49 μM, Cdc25B: 19.17-23.63 μM). In particular, compounds #1, 2, 4, and 6 have high values in inhibitory activity against the protein phosphatases. Thus, the derivatives of Chemistry Figure 1 according to the present invention may be effectively used for the prevention and treatment of various cancers caused by Cdc25, because they exhibit effective inhibitory activities against protein phosphatases.
[89] Preparation examples for the composition of the present invention will be described in the following examples.
[90] <Preparation example #1> Tablets (Direct Compression)
[91] 5.0 mg of the derivative of Chemistry Figure 1 was sieved, followed by preparation of tablets by mixing and compressing 14.1 mg of lactose, 0.8 mg of CrossPovidone USNF, and 0.1 mg of magnesium stearate.
[92] Preparation example #2> Tablets (Wet Granulation)
[93] 5.0 mg of the derivative of Chemistry Figure 1 was sieved, followed by mixing 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of Polysolvate 80 was dissolved in purified water, and by microgranulation, by adding the appropriate amount of the solution. The microgranules were dried and sieved, followed by mixing 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. Tablets were prepared by compressing the compounds.
[94] <Preparation example #3> Powders and Capsules
[95] 5.0 mg of an active ingredient was sieved, followed by mixing 14.8 mg of lactose,
10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate with it. The compound was filled into a hard No. 5 gelatin capsule using an appropriate apparatus.
[96] <Preparation #4> Injections
[97] Injection was prepared by containing 100 mg of an active ingredient, as well as 180 mg of mannitol, 26 mg of Na2HPO4 • 12H2O, and 2947 mg of distilled water.
Claims
(1)
2-(2-(5-(4-chlorophenyl)furan-2-yl)vinyl)-6-mercapto-4-oxo- 1 -phenyl- 1 ,2,3 ,4-tet rahydropyrimidine-5-carbonitrile;
(2)
2-(5-(2,5-dichlorophenyl)furan-2-yl)-6-mercapto-4-oxo-l-phenyl-l,2,3,4-tetrahy dropyrimidine-5-carbonitrile;
(3)
2-(5-(3 -chlorophenyl)furan-2-yl)-6-mercap to-4-oxo~ 1 -phenyl- 1,2,3 ,4-tetrahydrop yrimidine-5-carbonitri.le;
(4)
2-(5-(2-chloro-4-nitrophenyl)furan-2-yl)-6-mercapto-4-oxo-l-phenyl-l,2,3,4-teti- ahydropyrimidine-5-carbonitrile;
(5)
2-(5-(2-chlorophenyl)furan-2-yl)-6-mercapto-4-oxo-l-phenyll-l,2,3,4-tetrahydro pyrimidine-5-carbonitrile;
(6)
2-(5-(3,4-dichlorophenyl)furan-2-yl)-6-mercapto-4-oxo-l-phenyl-l,2,3,4-tetraliy diOpyrimidine-5-carbonitrile;
(7)
3-((4-((2,4,6-trioxo-3-metha-tolyl-tetrahydropyrimidin-5(6H)-ylidene)methyl)ph enoxy)methyl)benzoic acid; and
(8)
2-(5-((3-(3,5-dimethylphenyl)-2,4,6-trioxo-tetrahydiOpyrimidin-5(6H)-ylidene)m ethyl)furan-2-yl)benzoic acid.
[4] The composition as set forth in claim 1, wherein the protein phosphatase is
Cdc25A, Cdc25B, Cdc25C, PTPlB, Prl-3, LAR, CD45, Yop, PPl, or VHR.
[5] The composition as set forth in claim 1, wherein the protein phosphatase is
Cdc25A, Cdc25B, or Cdc25C.
[6] The composition as set forth in claim 1, wherein the protein phosphatase is
Cdc25A or Cdc25B.
[7] The composition as set forth in claim 1, wherein the cancer is one selected from the group consisting of breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and bone marrow cancer.
[8] A use of pyrimidine derivative represented by Chemical Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof in manufacture of drugs for preventing and treating one or more cancers selected from the group consisting of breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and bone marrow cancer.
[9] A method for preventing and treating various cancers comprising administering a therapeutically effective amount of pyrimidine derivative represented by Chemical Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof, to a mammal or a patient in need.
[10] The method as set forth in claim 10, wherein the mammal is human.
[11] The method as set forth in claim 10, wherein the cancer is one selected from the group consisting of breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and bone marrow cancer.
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KR101800507B1 (en) | 2015-09-18 | 2018-01-18 | 주식회사 이엔이티아이 | How to take advantage of the purification plants equipment and self-cleaning screen to clean up pollution by continue flowing sewage and process wastewater into the river |
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US4873228A (en) * | 1986-09-02 | 1989-10-10 | The University Of Melbourne | 2-oxo-4-carboxy-pyrimidines and their use as anti-malaria and anti-cancer agents |
KR910009957B1 (en) * | 1989-12-29 | 1991-12-07 | 한국과학기술원 | Process for preparation of 2-furyl pyrimidine derivatives |
WO2005121106A1 (en) * | 2004-06-11 | 2005-12-22 | N.V. Organon | 4-phenyl-pyrimidine-2-carbonitrile derivatives |
WO2006079556A2 (en) * | 2005-01-31 | 2006-08-03 | Basf Aktiengesellschaft | Substituted 5-phenyl pyrimidines i in therapy |
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US4873228A (en) * | 1986-09-02 | 1989-10-10 | The University Of Melbourne | 2-oxo-4-carboxy-pyrimidines and their use as anti-malaria and anti-cancer agents |
KR910009957B1 (en) * | 1989-12-29 | 1991-12-07 | 한국과학기술원 | Process for preparation of 2-furyl pyrimidine derivatives |
WO2005121106A1 (en) * | 2004-06-11 | 2005-12-22 | N.V. Organon | 4-phenyl-pyrimidine-2-carbonitrile derivatives |
WO2006079556A2 (en) * | 2005-01-31 | 2006-08-03 | Basf Aktiengesellschaft | Substituted 5-phenyl pyrimidines i in therapy |
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LAZO, J.S. ET AL.: 'Discovery and Biological Evaluation of a New Family of Potent Inhibitors of the Dual Specificity Protein Phosphatase Cdc25' JOURNAL OF MEDICINAL CHEMISTRY vol. 44, no. 24, 2001, ISSN 0022-2623 pages 4042 - 4049 * |
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WO2019043706A1 (en) * | 2017-08-31 | 2019-03-07 | Bar-Ilan University | Novel barbituric acid derivatives, their preparation and use thereof as leukocyte transmigration inhibitors and for treating inflammatory diseases, autoimmune diseases and cancer |
US11492333B2 (en) | 2017-08-31 | 2022-11-08 | Bar-Ilan University | Barbituric acid derivatives, their preparation and use thereof as leukocyte transmigration inhibitors and for treating inflammatory diseases, autoimmune diseases and cancer |
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