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NOVEL FLUORINE-CONTAINING BISPHOSPHONIC ACID DERIVATIVE AND USE THEREOF

Foreign code F160008854
File No. (S2015-0409-N0)
Posted date Sep 23, 2016
Country WIPO
International application number 2016JP052960
International publication number WO 2016125757
Date of international filing Feb 1, 2016
Date of international publication Aug 11, 2016
Priority data
  • P2015-018260 (Feb 2, 2015) JP
Title NOVEL FLUORINE-CONTAINING BISPHOSPHONIC ACID DERIVATIVE AND USE THEREOF
Abstract 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.
Outline of related art and contending technology 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.
Scope of claims (In Japanese)[請求項1]
下記一般式(I):
[化1]
(式中、Cyはフェニル基又は複素環基であり、Yは水素原子、アルキル基、ハロゲン原子、ハロゲン化アルキル基、水酸基、ハロゲン原子若しくはアルコキシ基で置換されてもよいアリール基、又は、アラルキルオキシ基であり、Fはフッ素原子であり、Pはリン原子を表し、Rは水素原子又はアルキル基であり、R1及びR2は、同一又は互いに異なって、水素原子又はアルキルカルボニルオキシアルキル基であり、jは0又は1の数を表し、mは0又は1の数を表し、nは1~6の整数を表す。ただし、Cyが3-ピリジル基であり、mが1であり、nが1であり、Yが水素原子であり、R1及びR2が水素原子である場合を除く)で表される化合物又はその薬学的に許容される塩。
[請求項2]
一般式(I)において、Cyがフェニル基である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項3]
一般式(I)において、Cyが窒素原子、硫黄原子及び酸素原子から選ばれる1~3個の原子を含む5~10員環の複素環基である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項4]
一般式(I)において、Cyが窒素原子及び硫黄原子から選ばれる1又は2個の原子を含む5又は6員環の複素環基である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項5]
一般式(I)において、Cyがイミダゾリル基、チアゾリル基、ピリジル基、ピリミジル基、又は7-アザインドリル基である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項6]
一般式(I)において、Yが水素原子、C1-3アルキル基、ハロゲン原子、ハロゲン化アルキル基又はフェニル基であり、R1及びR2が同一又は互いに異なって、水素原子又はC2-7アルキルカルボニルオキシ-C1-3アルキル基である、請求項1~5のいずれか1項に記載の化合物又はその薬学的に許容される塩。
[請求項7]
一般式(I)において、jが1であり、Cyがイミダゾリル基であり、Yが水素原子又はハロゲン原子であり、R1及びR2が同一又は互いに異なって、水素原子又はC2-7アルキルカルボニルオキシ-C1-3アルキル基である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項8]
一般式(I)において、jが0であり、Yが水素原子又はC1-3アルキル基であり、R1及びR2が同一又は互いに異なって、水素原子又はC2-7アルキルカルボニルオキシ-C1-3アルキル基である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項9]
一般式(I)において、jが0であり、Yが水素原子であり、Rが水素原子であり、R1及びR2が水素原子である、請求項1に記載の化合物又はその薬学的に許容される塩。
[請求項10]
一般式(I)において、jが0であり、YがC1-3アルキル基であり、RがC1-6アルキル基であり、R1及びR2が水素原子である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項11]
一般式(I)において、jが1であり、Cyがイミダゾリル基であり、Yが水素原子であり、R1及びR2が同一又は互いに異なって、水素原子又はピバロイルオキシメチル(POM)基である、請求項1記載の化合物又はその薬学的に許容される塩。
[請求項12]
下記式で表される化合物のいずれか1つ又はその薬学的に許容される塩:
[化2]
[請求項13]
請求項1~12のいずれかに1項に記載の化合物又はその薬学的に許容される塩を有効成分として含む医薬組成物。
[請求項14]
抗腫瘍細胞剤である、請求項13に記載の医薬組成物。
[請求項15]
抗ウイルス感染細胞剤である、請求項13に記載の医薬組成物。
[請求項16]
リンパ球処理剤である、請求項13に記載の医薬組成物。
[請求項17]
請求項1~12のいずれか1項に記載の化合物又はその薬学的に許容される塩の有効量を生体に投与することを特徴とする体内におけるリンパ球の処理方法。
[請求項18]
請求項1~12のいずれか1項に記載の化合物又はその薬学的に許容される塩の有効量を生体に投与することを特徴とするγδ型T細胞の増殖及び/又は誘導方法。
[請求項19]
請求項1~12のいずれか1項に記載の化合物又はその薬学的に許容される塩の有効量を生体に投与することを特徴とする腫瘍細胞及びウイルス感染細胞の増殖抑制方法。
[請求項20]
請求項1~12のいずれか1項に記載の化合物又はその薬学的に許容される塩の有効量を生体に投与することを特徴とするがんおよびウイルス感染症の治療方法。
[請求項21]
請求項1~12のいずれか1項に記載の化合物又はその薬学的に許容される塩を、生体外においてγδ型T細胞を含む検体に作用させることを特徴とするγδ型T細胞の増殖及び/又は誘導方法。
[請求項22]
請求項1~12のいずれか1項に記載の化合物又はその薬学的に許容される塩を、生体から採取したγδ型T細胞を含む検体に作用させることにより、γδ型T細胞を増殖及び/又は誘導させる工程、及び、当該γδ型T細胞を生体に戻す工程を含む腫瘍細胞およびウイルス感染細胞の増殖抑制方法。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NAGASAKI UNIVERSITY
  • Inventor
  • TANAKA, Yoshimasa
  • MIZUTA, Satoshi
  • UEDA, Hiroshi
IPC(International Patent Classification)
Specified countries 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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