JP2017520588A - Ral GTPアーゼを標的とする抗癌化合物及びそれを使用する方法 - Google Patents
Ral GTPアーゼを標的とする抗癌化合物及びそれを使用する方法 Download PDFInfo
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- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
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- 238000004237 preparative chromatography Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
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- 229960003415 propylparaben Drugs 0.000 description 1
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- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
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- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
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- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
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- 238000012582 total correlation spectroscopy experiment Methods 0.000 description 1
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
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- 239000008215 water for injection Substances 0.000 description 1
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- 229940045860 white wax Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
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- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
本発明は、米国立衛生研究所により付与された認可番号CA091846、CA075115及びCA104106の下で政府による支援を受けている。米国政府は本発明に対して一定の権利を有する。
(ここで、
R1は水素、ハロゲン、−OH、−O−R8、C1〜C12アルキル、C3〜C12アルケニル、C4〜C12ジエニル、C6〜C12トリエニル、C8〜C12テトラエニル、C6〜C12アリール、置換C6〜C12アリール、C1〜C12アルコキシ、カルボキシ、シアノ、C1〜C12アルカノイルオキシ、C1〜C12アルキルチオ、C1〜C12アルキルスルホニル、C2〜C12アルコキシカルボニル、C2〜C12アルカノイルアミノ、S−R8、−SO2−R8、−NHSO2R8及び−NHCO2R8から選択され、
R2は水素、ハロゲン、−OH、−O−R8、C1〜C12アルキル、C3〜C12アルケニル、C4〜C12ジエニル、C6〜C12トリエニル、C8〜C12テトラエニル、C6〜C12アリール、置換C6〜C12アリール、C1〜C12アルコキシ、カルボキシ、シアノ、C1〜C12アルカノイルオキシ、C1〜C12アルキルチオ、C1〜C12アルキルスルホニル、C2〜C12アルコキシカルボニル、C2〜C12アルカノイルアミノ、S−R8、−SO2−R8、−NHSO2R8及び−NHCO2R8から選択され、
R3、R4、R5、R6及びR7は独立して水素;ハロゲン;−OH;−O−R8;C1〜C12アルキル;C3〜C12アルケニル;C4〜C12ジエニル;C6〜C12トリエニル;C8〜C12テトラエニル;イミダゾール;C6〜C12アリール;C1〜C12アルコキシ;カルボキシ;シアノ;C1〜C12アルカノイルオキシ;C1〜C12アルキルチオ;C1〜C12アルキルスルホニル;C2〜C12アルコキシカルボニル;C2〜C12アルカノイルアミノ;S−R8;−SO2−R8;−NHSO2−R8;−NHCO2−R8;ハロゲン、酸素、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC1〜C12アルキル;並びにハロゲン、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC6〜C12アリールから選択されるか、又は、
R3及びR4がともにシクロヘキサン、1,4−ジオキサン若しくはフェニルを形成し、
R8はハロゲン、酸素、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC1〜C12アルキル;又はハロゲン、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC6〜C12アリールである)、並びにその薬学的に許容可能なエナンチオマー、ジアステレオマー、ラセミ体及び塩、並びにその薬学的に許容可能なエナンチオマー、ジアステレオマー、ラセミ体及び塩を有する本発明の化合物である。
から選択される化学構造を有する。
分子モデリングを、かかる分子が不活性状態を安定化することを期待してRal−GTP(活性型)よりもRal−GDP(不活性型)に優先的に結合する化合物を発見するために用いた。活性型及び不活性型のRalAの三次元構造の検査により、ヌクレオチド結合部位から近いが、それとは異なるポケットの形状の違いが明らかになった(図1)。このポケット(アロステリック部位)は以前に記載のC3bot結合部位と同様であり、スイッチ−II領域(Ral70〜Ral77)、ヘリックスα2(Ral78〜Ral85)及びヘリックスα3の一面により構成される(図1A)。比較に使用される結晶構造は、exo84(PDBコード1ZC4、図1C)又はsec5(PDBコード1UAD、図1D)と複合したRalA−GDP(PDBコード2BOV、図1B)及びRalA−GNP(非加水分解性形態のGTP)を含んでいた。各結合部位について算出された体積はRalA−GDPでは175Å3(図1B)、RalA−GNP−exo84では155Å3(図1C)、RalA−GNP−sec5では116Å3(図1D)であった。RalB−GDP結晶構造は公表されていないが、RalB−GNP構造(PDBコード2KE5、図1)では、この結合ポケットは殆ど存在しない。
選択された88個の化合物を、培養物中の生細胞におけるRalA活性化を阻害するそれらの能力について評価した。
標的への化合物の直接結合を確認するために、TROSY 15N−HSQC(横緩和最適化異核種単一量子コヒーレンス)NMRを用いた。pET16b(Novagen)プラスミド中のRalB(Q72L突然変異体)は、Darerca Owen博士(ケンブリッジ大学)の好意により提供された。RalBを、GDP又は非加水分解性形態のGTP、GMPNPP(GNP、Sigma-Aldrich)をローディングする付加的な工程により精製した。均一13C15N二重標識タンパク質を、15N−NH4Cl及び13C−グルコースを添加したM9培地中で作製した。サンプルをNMRのために50mMリン酸ナトリウム(pH7.6)、100mM NaCl及び1mM MgCl2中で調製した。全てのNMR実験をAgilent 900MHzシステムにおいて25℃で記録した。RalB−GNP複合体についての共鳴帰属(Resonance assignments)は、生体分子磁気共鳴データバンク(BMRB、コード:15230)に寄託された以前に公表された研究から得られた。RalB−GDP複合体の化学シフト帰属は、HNCACB、CBCA(CO)NH及びCOCNH−TOCSY実験を用いて独立して得られた。全てのNMRデータをNMRPipeを用いて処理し、CCPNMR分析プログラムを用いて分析した。帰属はPINEに続く手動検証を用いる自動化帰属によって得られた。15N−HSQC実験を用いてRalBタンパク質(100μM)からのアミドシフトをモニタリングし、続いて重水素化DMSO中で再構成した化合物を添加した。最終サンプル中のDMSO濃度は0.5%又は1%であった。対照サンプルは0.5%又は1%重水素化DMSOから作製し、化合物を含有する全てのサンプルをそれらの対応するDMSO対照と比較した。
ヒト肺癌細胞成長に対するRBC8及びBQU57の効果を評価した。足場非依存性におけるRalの役割は既知であるため、軟寒天における成長阻害アッセイを行った。4つのヒト肺癌細胞H2122、H358、H460及びCalu6を薬物取込み、生物学的特異性及び効果を決定するために一連の実験で使用した。軟寒天における足場非依存性条件下のヒト肺癌細胞の成長阻害を測定するために、様々な濃度の薬物を含有する3mlの0.4%低融点アガロース中の細胞を6ウェルプレート(2mlの1%低融点アガロースで作られる基層でコーティングした)に1ウェル当たり15000細胞播種した。(細胞株に応じて)インキュベーションの2週間〜4週間後に、細胞を1mg/mlのMTTで染色し、コロニーを顕微鏡下で計数した。IC50値は、DMSO処理対照と比較してコロニー数の50%の低減をもたらす薬物の濃度として規定した。
Ral活性及び腫瘍成長の阻害をヒト肺癌マウスモデルにおいて評価した。RBC8及びBQU57の薬物動態(PK)をヌードマウスにおいて初めに分析し、バイオアベイラビリティを試験した。単回腹腔内注射(50mg/Kg)の後、血液サンプルを投与後0〜5時間の時間間隔(9つの時点)で採取した。曲線下面積(AUC)、Cmax及びt1/2を含む薬物動態パラメーターをLC−MS/MSによるノンコンパートメント法を用いて推定し、良好な薬物候補を規定する有利な特性が示された(上掲の表1を参照されたい)。
本発明の化合物を以下の合成スキーム及び材料に従って合成した。
2−(置換)−ベンジリデンマロノニトリル
6−アミノ−1,3−二置換−4−フェニル−1,4−ジヒドロピラノ[2,3−c]ピラゾール−5−カルボニトリル
アニスアルデヒド、ベンズアルデヒド、1,4−ベンゾジオキサン−6−カルボキサルデヒド、ベンジル−ヒドラジン、6−ブロモ−2−ピリジンカルボキサルデヒド、重水素化クロロホルム(CDCl3)、重水素化ジメチルスルホキシド(DMSO−d6)、3,5−ジフルオロベンズアルデヒド、アセト酢酸エチル、ベンゾイル酢酸エチル、3,4−ジメトキシベンゾイル酢酸エチル、エチル−ヒドロクプレイン塩酸塩、4−メトキシベンゾイル酢酸エチル、4−フルオロベンズアルデヒド、3−フルオロ−4−メトキシベンズアルデヒド、4−ホルミルベンゾニトリル、4−イソプロピルベンズアルデヒド、4−(1H−イミダゾール−1−イル)ベンズアルデヒド、マロノニトリル、メチル−ヒドラジン、フェニル−ヒドラジン、3−ピリジンカルボキサルデヒド、ナトリウムエトキシド、トリメチルアミン(TEA)、2,4,6−トリメトキシベンズアルデヒド及び4−(トリフルオロメトキシ)ベンズアルデヒドはSigma-Aldrich Chemical Company(St. Louis,MO)から購入した。酢酸エチル(EtOAc)、HPLCグレードメタノール(MeOH)、HPLCグレードアセトニトリル(ACN)、HPLCグレード水(H2O)、ギ酸、酢酸アンモニウム、ヘキサン及び塩化メチレン(DCM)はFisher Scientific(Pittsburgh,PA)から入手した。エタノールはDecon Laboratories, Inc.(King of Prussia,PA)から購入した。シリカゲル60Å 40μm〜63μmはSorbent Technologies(Norcross,GA)から購入した。
3−メチル−1−フェニル−1H−ピラゾール−5(4H)−オン(1): アセト酢酸エチル(9.02mL、71.2mmol)のEtOH溶液(130mL)を、0℃においてフェニル−ヒドラジン(7.00g、64.7mmol)で処理した。混合物を常温へとゆっくりと加温した後、60℃に加熱した(3時間)。溶媒を真空除去し、残渣をシリカゲルカラムクロマトグラフィ(EtOAc:ヘキサン;1:1)によって精製して、1(7.60g、43.6mmol、収率67%)を明黄色の粉末として得た。1H−NMR(400MHz)CDCl3:7.87〜7.85(d,2H)、7.41〜7.37(t,2H)、7.19〜7.16(t,1H)、3.42(s,2H)、2.19(s,3H)、13C−NMR(100MHz)CDCl3:170.5、156.2、138.0、128.8、125.0、118.8、43.0、17.0;LC/MS−MS:175.0→77.1m/z;30のGS1及びGS2、DP=56、CE=25、CXP=4、tR=3.52分。
分子量:351.22
6−アミノ−4−(5−ブロモチオフェン−2−イル)−1,3−ジメチル−1,4−ジヒドロピラノ[2,3−c]ピラゾール−5−カルボニトリル(54): エタノール(10mL)中の5−ブロモチオフェン−2−カルバルデヒド(0.548g、2.87mmol)、マロノニトリル(0.190g、2.87mmol)及びトリエチルアミン(0.40mL、2.87mmol)の混合物を10分間撹拌し、その後2(0.321g、2.87mmol)を添加した。反応混合物を22時間後に濾過し、析出物をエタノールで再結晶化して、54(221mg、0.628mmol、収率22%)を明橙色の固体として得た。1H−NMR(400MHz)DMSO:7.18(s,2H)、7.02〜7.02(d,1H)、6.86〜6.85(d,1H)、4.93(s,1H)、3.56(s,3H)、1.81(s,3H);13C−NMR(100MHz)DMSO:159.9、151.9、144.2、143.1、130.3、126.0、120.3、110.8、95.8、58.3、33.9、33.2、12.8。LC/MS−MS:352.9→287.0m/z;30のGS1及びGS2、DP=66、CE=29、CXP=18、tR=4.3分。
分子量:413.29
6−アミノ−4−(5−ブロモチオフェン−2−イル)−1−メチル−3−フェニル−1,4−ジヒドロピラノ[2,3−c]ピラゾール−5−カルボニトリル(55): エタノール(6mL)中の5−ブロモチオフェン−2−カルバルデヒド(0.328g、1.72mmol)、マロノニトリル(0.114g、1.72mmol)及びトリエチルアミン(0.240mL、1.72mmol)の混合物を10分間撹拌し、その後3(0.300g、1.72mmol)を添加した。反応混合物を22時間後に濃縮し、SiO2カラムクロマトグラフィ(DCM中、2%MeOH)によって精製して、55(80mg、0.194mmol、収率11%)を橙色の固体として得た。1H−NMR(400MHz)DMSO:7.61〜7.59(d,2H)、7.30〜7.23(m,5H)、6.92〜6.91(d,1H)、6.78〜6.77(d,1H)、5.41(s,1H)、3.74(s,3H);13C−NMR(100MHz)DMSO:159.3、151.9、145.4、144.8、133.0、130.3、128.8、128.2、126.6、125.8、120.2、110.4、95.2、59.1、34.5、33.9。LC/MS−MS:415.1→348.0m/z;30のGS1及びGS2、DP=81、CE=31、CXP=22、tR=4.5分。
Claims (18)
- 下記化学構造:
(ここで、
R1は水素、ハロゲン、−OH、−O−R8、C1〜C12アルキル、C3〜C12アルケニル、C4〜C12ジエニル、C6〜C12トリエニル、C8〜C12テトラエニル、C6〜C12アリール、置換されたC6〜C12アリール、C1〜C12アルコキシ、カルボキシ、シアノ、C1〜C12アルカノイルオキシ、C1〜C12アルキルチオ、C1〜C12アルキルスルホニル、C2〜C12アルコキシカルボニル、C2〜C12アルカノイルアミノ、S−R8、−SO2−R8、−NHSO2R8及び−NHCO2R8から選択され、
R2は水素、ハロゲン、−OH、−O−R8、C1〜C12アルキル、C3〜C12アルケニル、C4〜C12ジエニル、C6〜C12トリエニル、C8〜C12テトラエニル、C6〜C12アリール、置換されたC6〜C12アリール、C1〜C12アルコキシ、カルボキシ、シアノ、C1〜C12アルカノイルオキシ、C1〜C12アルキルチオ、C1〜C12アルキルスルホニル、C2〜C12アルコキシカルボニル、C2〜C12アルカノイルアミノ、S−R8、−SO2−R8、−NHSO2R8及び−NHCO2R8から選択され、
R3、R4、R5、R6及びR7は独立して水素;ハロゲン;−OH;−O−R8;C1〜C12アルキル;C3〜C12アルケニル;C4〜C12ジエニル;C6〜C12トリエニル;C8〜C12テトラエニル;イミダゾール;C6〜C12アリール;C1〜C12アルコキシ;カルボキシ;シアノ;C1〜C12アルカノイルオキシ;C1〜C12アルキルチオ;C1〜C12アルキルスルホニル;C2〜C12アルコキシカルボニル;C2〜C12アルカノイルアミノ;S−R8;−SO2−R8;−NHSO2−R8;−NHCO2−R8;ハロゲン、酸素、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC1〜C12アルキル;並びにハロゲン、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC6〜C12アリールから選択されるか、又は、
R3及びR4がともにシクロヘキサン、1,4−ジオキサン若しくはフェニルを形成し、
R8はハロゲン、酸素、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC1〜C12アルキル;又はハロゲン、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC6〜C12アリールである)、並びにその薬学的に許容可能なエナンチオマー、ジアステレオマー、ラセミ体及び塩を有する化合物。 - R1が水素;メチル;フェニル;メチル−フェニル;メトキシ;ハロゲン、C1〜C6アルキル及びC1〜C6アルコキシから選択される1つ〜3つの基で置換されたC6〜C12アリールから選択される、請求項1に記載の化合物。
- R2が水素;メチル;フェニル;メチル−フェニル;メトキシ;ハロゲン、C1〜C6アルキル及びC1〜C6アルコキシから選択される1つ〜3つの基で置換されたC6〜C12アリールから選択される、請求項1に記載の化合物。
- R3が水素;ハロゲン;メトキシ;ハロゲンで任意に置換されたC1〜C6アルキル;シアノ;イミダゾール;並びにハロゲン及びC1〜C6アルコキシから選択される1つ〜3つの基で置換されたC6〜C12アリールから選択される、請求項1に記載の化合物。
- 下記化学構造:
を有する、請求項1に記載の化合物。 - 少なくとも1つの請求項1に記載の化合物と少なくとも1つの医薬賦形剤とを含む医薬組成物。
- 請求項6に記載の医薬組成物を含む医薬パッケージ。
- 請求項6に記載の医薬組成物と、該組成物についての処方情報と、容器とを含む、医薬キット。
- 被験体において癌を防止、治療、改善する、又は癌の転移を防止する方法であって、該方法がRal GTPアーゼを阻害する化合物を治療に効果的な量、それを必要とする被験体に投与することを含み、該化合物が下記化学構造:
(ここで、
R1は水素、ハロゲン、−OH、−O−R8、C1〜C12アルキル、C3〜C12アルケニル、C4〜C12ジエニル、C6〜C12トリエニル、C8〜C12テトラエニル、C6〜C12アリール、置換C6〜C12アリール、C1〜C12アルコキシ、カルボキシ、シアノ、C1〜C12アルカノイルオキシ、C1〜C12アルキルチオ、C1〜C12アルキルスルホニル、C2〜C12アルコキシカルボニル、C2〜C12アルカノイルアミノ、S−R8、−SO2−R8、−NHSO2R8及び−NHCO2R8から選択され、
R2は水素、ハロゲン、−OH、−O−R8、C1〜C12アルキル、C3〜C12アルケニル、C4〜C12ジエニル、C6〜C12トリエニル、C8〜C12テトラエニル、C6〜C12アリール、置換C6〜C12アリール、C1〜C12アルコキシ、カルボキシ、シアノ、C1〜C12アルカノイルオキシ、C1〜C12アルキルチオ、C1〜C12アルキルスルホニル、C2〜C12アルコキシカルボニル、C2〜C12アルカノイルアミノ、S−R8、−SO2−R8、−NHSO2R8及び−NHCO2R8から選択され、
R3、R4、R5、R6及びR7は独立して水素;ハロゲン;−OH;−O−R8;C1〜C12アルキル;C3〜C12アルケニル;C4〜C12ジエニル;C6〜C12トリエニル;C8〜C12テトラエニル;イミダゾール;C6〜C12アリール;C1〜C12アルコキシ;カルボキシ;シアノ;C1〜C12アルカノイルオキシ;C1〜C12アルキルチオ;C1〜C12アルキルスルホニル;C2〜C12アルコキシカルボニル;C2〜C12アルカノイルアミノ;S−R8;−SO2−R8;−NHSO2−R8;−NHCO2−R8;ハロゲン、酸素、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC1〜C12アルキル;並びにハロゲン、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC6〜C12アリールから選択されるか、又は、
R3及びR4がともにシクロヘキサン、1,4−ジオキサン若しくはフェニルを形成し、
R8はハロゲン、酸素、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC1〜C12アルキル;又はハロゲン、C1〜C6アルキル、C6〜C10アリール及びC1〜C6アルコキシから選択される1つ〜3つの基で任意に置換されたC6〜C12アリールである)、並びにその薬学的に許容可能なエナンチオマー、ジアステレオマー、ラセミ体及び塩を有する、方法。 - R1が水素;メチル;フェニル;メチル−フェニル;メトキシ;ハロゲン、C1〜C6アルキル及びC1〜C6アルコキシから選択される1つ〜3つの基で置換されたC6〜C12アリールから選択される、請求項9に記載の方法。
- R2が水素;メチル;フェニル;メチル−フェニル;メトキシ;ハロゲン、C1〜C6アルキル及びC1〜C6アルコキシから選択される1つ〜3つの基で置換されたC6〜C12アリールから選択される、請求項9に記載の方法。
- R3が水素;ハロゲン;メトキシ;ハロゲンで任意に置換されたC1〜C6アルキル;シアノ;イミダゾール;並びにハロゲン及びC1〜C6アルコキシから選択される1つ〜3つの基で置換されたC6〜C12アリールから選択される、請求項9に記載の方法。
- 前記化合物が、下記化学構造:
を有する、請求項9に記載の方法。 - 前記化合物が医薬組成物内において前記被験体に投与される、請求項9に記載の方法。
- 前記医薬組成物が、治療に効果的な量の前記化合物と、薬学的に許容可能な担体とから本質的になる、非経口投与又は経口投与に適した単相医薬組成物である、請求項14に記載の方法。
- 前記医薬組成物が、1つ若しくは複数のI型ゲラニルゲラニルトランスフェラーゼ(GGTアーゼ−I)阻害剤、外科手術、化学療法、放射線療法、免疫療法、又はそれらの組合せと併せて投与される、請求項14に記載の方法。
-
から選択される化学構造を有する化合物。 - 被験体において癌を防止、治療、改善する、又は癌の転移を防止する方法であって、該方法がRal GTPアーゼを阻害する化合物を治療に効果的な量、それを必要とする被験体に投与することを含み、該化合物が、
から選択される化学構造を有する、方法。
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CN106604731A (zh) | 2017-04-26 |
AU2015287567A1 (en) | 2017-02-16 |
EP3166609B1 (en) | 2020-03-11 |
JP7102012B2 (ja) | 2022-07-19 |
US10202397B2 (en) | 2019-02-12 |
US11472812B2 (en) | 2022-10-18 |
US10676480B2 (en) | 2020-06-09 |
AU2020277293B2 (en) | 2021-10-21 |
US20190135824A1 (en) | 2019-05-09 |
US20200255442A1 (en) | 2020-08-13 |
USRE48557E1 (en) | 2021-05-18 |
JP6672255B2 (ja) | 2020-03-25 |
KR20200034824A (ko) | 2020-03-31 |
KR20190022929A (ko) | 2019-03-06 |
EP3686202A1 (en) | 2020-07-29 |
JP2020105195A (ja) | 2020-07-09 |
AU2020277293A1 (en) | 2021-01-07 |
KR20170018084A (ko) | 2017-02-15 |
US20170204112A1 (en) | 2017-07-20 |
CA2954560A1 (en) | 2016-01-14 |
KR102093848B1 (ko) | 2020-03-30 |
IL249959A0 (en) | 2017-03-30 |
EP3166609A1 (en) | 2017-05-17 |
CA2954560C (en) | 2021-12-28 |
EP3166609A4 (en) | 2017-12-27 |
CN106604731B (zh) | 2021-05-18 |
WO2016007905A1 (en) | 2016-01-14 |
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