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NOVEL FLUORINE-CONTAINING BISPHOSPHONIC ACID DERIVATIVE AND USE THEREOF

外国特許コード F160008854
整理番号 (S2015-0409-N0)
掲載日 2016年9月23日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2016JP052960
国際公開番号 WO 2016125757
国際出願日 平成28年2月1日(2016.2.1)
国際公開日 平成28年8月11日(2016.8.11)
優先権データ
  • 特願2015-018260 (2015.2.2) JP
発明の名称 (英語) NOVEL FLUORINE-CONTAINING BISPHOSPHONIC ACID DERIVATIVE AND USE THEREOF
発明の概要(英語) In the present invention, a series of fluorine-containing bisphosphonic acids where alkylamine side chains have been added to the carbon atoms of P-C(F)-P, a series of fluorine-containing bisphosphonic acids where heterocyclic groups containing amino groups or nitrogen groups substituted for heterocyclic groups have been added, and a series of fluorine-containing bisphosphonic acid derivatives where the acid moiety thereof has been esterified by alkoxymethyl groups such as POM groups, n-butanoyloxymethyl (BuOM) groups, and the like, that is, fluorine-containing bisphosphonic acids and fluorine-containing bisphosphonic acid derivatives represented by general formula (I) (where each symbol is as defined in the specification), are capable of efficiently inducing propagation of peripheral blood γδ-type T cells that express Vγ2Vδ2-type T cell receptors which have superior cytotoxicity against tumor cells and viral infection cells, and sensitizing tumor cells and viral infection cells to the cytotoxicity of γδ-type T cells.
従来技術、競合技術の概要(英語) BACKGROUND ART
Bisphosphonic acid P-C-P skeleton is a compound of the group comprising, a high affinity for bone tissue and bone migration.In addition, the first generation of acid or etidronic acid bisphosphonic acid is, by the action of the fluid phase endocytosis system cells such as osteoclasts mono site selectively captured, analogs and metabolic conversion to ATP, ATP receptors and seems to act, in cytotoxicity.In this way, the first generation of bisphosphonic acid, osteoclasts by inducing cell death, suppressing bone resorption.Using these properties, various bisphosphonic acid applied to the bone-related disorders.Specifically, osteoporosis, osteitis fibrosa cystica deformation, bone reconstruction, such as malignant tumor at the time of hypercalcemia, bone fragility or prevention of disorders involving calcium concentration fluctuation used as therapeutic agents.In addition, pamidronic acid, alendronic acid, ibandronic acid belonging to the second generation bisphosphonic acid and the like, and, risedronic acid, zoledronic acid belong to the third generation bisphosphonic acid and the like, and a side chain containing a nitrogen atom, a nitrogen-containing type referred to as bisphosphonic acid.These bisphosphonic acid, mono-site system cells such as osteoclasts selectively captured, diphosphate synthase specifically inhibited, indicating cytotoxicity.By utilizing the properties thereof, various nitrogen-containing type bisphosphonic acid osteoporosis and malignancy at the time of hypercalcemia-improving drugs used.Recently, pre-menopausal estrogen sensitive multiple myeloma or breast cancer cases with respect to initial chemotherapy or endocrine therapy, adjuvant therapy drug zoledronic acid is used as the dominant extended disease-free survival have been reported (non-patent document 1, 2).This is because, when the nitrogen-containing-bisphosphonic acid, directly to the tumor cells, and/or indirectly through the activation of immune cells and the cytotoxic effect of, for anti-tumor effects of thought.
For example, administered to the living body in some of the acid or etidronic acid, incorporated into cells by the action of fluid phase endocytosis, transferred to the nucleoside monophosphate, nucleoside triphosphate compound is converted to the acids edge.This metabolite is, nucleoside triphosphates using high energy phosphate bond an antagonistic biological enzyme reaction has been shown to inhibit.In the case of osteoclast cell capture, suppressed bone resorption, lowers the concentration of calcium in plasma.In the case of tumor cells, tumor cells are injured, a direct anti-tumor effect is expected.
In addition, the shift to the second generation within the cell and the third-generation bisphosphonic acid is a nitrogen-containing type, such as cholesterol metabolites in the biosynthetic pathway of isoprenoid system involved diphosphate synthase has been shown to inhibit.Such enzymes are, isopentenyl diphosphate and dimethylallyl diphosphate from geranyl diphosphate synthesis reaction, geranyl diphosphate and isopentenyl diphosphate from diphosphate synthesized which catalyzes the reaction.Therefore, due to inhibition of diphosphate synthase, geranyl diphosphate located downstream of the metabolic pathway is blocked and, isopentenyl diphosphate as a substrate of an enzyme is accumulated in the considered.Geranyl diphosphate located downstream of the biosynthetic pathway is interrupted, isoprenoid-based compounds, cholesterol, fat-soluble vitamins, bile acids, such as the biosynthesis of lipoprotein not, suppressed the growth of tumor cells is considered.
Typically, the green diphosphate synthase synthesized of the diphosphate and geranylgeranyl diphosphate, isoprenyl group, Ras, Rho, Rap, Rab, Rac is transferred to the so-called small g protein.In this way, a small g protein was transferred to the isoprenyl group, isoprenyl group functions as an anchor for the cell membrane, a true effect of small g protein moves to the plasma membrane site, cell proliferation, adhesion and the like, critical physiological functions.However, nitrogen-containing type bisphosphonic acid is zoledronic acid such as diphosphate synthase inhibition, due to the inhibition the isoprenyl group transfer, the membrane is prevented small g protein, as a result inhibit the growth of tumor cells.This is, indicated by the nitrogen-containing type direct anti-tumor effect bisphosphonic acid which is one of a mechanism to explain.
Further, diphosphate synthase is impeded, isopentenyl diphosphate as its substrate increases the intracellular concentration.This increase in the intracellular concentration of isopentenyl diphosphate, sensed transmembrane protein 3A1, and a change of the V γ 2V δ 2 type having T cell receptor recognition by γ δ type T (non-patent document 3, 4).As a result, γ δ-type T cells causes degranulation, release perforin and granzyme B, tumor cells and virus-infected cells induces apoptosis.In this way, nitrogen-containing type bisphosphonic acid is, via the activation of immune cells, tumor cells and virus-infected cells indirectly efficiently are shown to be a failure.
Nitrogen-containing type bisphosphonic acid as described above direct and indirect this cytotoxicity can be, how much the injury to the cells to be captured, then, the degree to which the diphosphate synthase which is capable of inhibiting depends on.However, the current clinical indications of a bisphosphonic acid are all adapted to the purposes of improving the bone has been synthesized as event for, at the site of action of osteoclasts to the affinity to the bone, osteoclasts are cytotoxic to cells as an index compound synthesis, and, screening is performed.However, in the development of agents on tumor and viral infection, the height of the bone-transfer properties, on the other hand, the arrival of the tumor cells and virus-infected cells caused a decrease in the factor.
Therefore, for improved direct cytotoxic if so desired, one target reduction bone-transfer properties is required.On the other hand, in γ δ-type immune effector T cell activation when the purpose of the improvement, the antigen presenting cell and the cellular uptake of a mono-site system, and, γ δ-type T cell activating ability as an index of the drug development needs to be performed.In this way, bone absorption as an index for screening the compound which does not, it is assumed that the bisphosphonic acid bisphosphonic acid having a basic skeleton different from systematic composition is required.
Current, alkylphenone-based on a low - molecular fluorine is about 3 among the agents that have a basic skeleton.Why agent containing a fluorine atom or is connected to the superiority of, has not been fully resolved.However, heretofore, in the development stage of bisphosphonic acid is risedronic acid of the fluorine-containing type bisphosphonic acid P-C-P C hydroxyl groups bonded to the skeleton is replaced with a fluorine only.This is because, in the bisphosphonic acid, the introduction of a fluorine atom in synthetic and is caused to be difficult.Therefore, a series of fluorine-containing type bisphosphonic acid derivatives of the synthetic route Argonide, system was synthesized, consider the physiological activity, important research in drug development bisphosphonic acid and deployment.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • NAGASAKI UNIVERSITY
  • 発明者(英語)
  • TANAKA YOSHIMASA
  • MIZUTA SATOSHI
  • UEDA HIROSHI
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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