JP2018536666A - γ−アマニチンの誘導体 - Google Patents
γ−アマニチンの誘導体 Download PDFInfo
- Publication number
- JP2018536666A JP2018536666A JP2018527167A JP2018527167A JP2018536666A JP 2018536666 A JP2018536666 A JP 2018536666A JP 2018527167 A JP2018527167 A JP 2018527167A JP 2018527167 A JP2018527167 A JP 2018527167A JP 2018536666 A JP2018536666 A JP 2018536666A
- Authority
- JP
- Japan
- Prior art keywords
- group
- amaninamide
- compound
- acid
- specifically
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
- C07K1/065—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for hydroxy functions, not being part of carboxy functions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
スキーム1(6*:構造6 R1=Me;R2=Fmoc;R3=ベンジル):
が、直交的保護戦略(orthogonal protection strategy)によって保護可能であり、γ−ヒドロキシイソロイシンをアミノ酸3として有するアマトキシンの合成に有用であるという意外な見解を論拠としている。
− 20%ピペリジンのDMF溶液(1:4)を3〜5分間;
− 1〜5%DBU/DMF;
− 20%ピペリジン及び1〜5%DBUを、DMF中に溶かした溶液;
− モルホリン/DMF(1:1);
− 45°Cのピペリジン/DMF(1:4);
− 0.1M HOBtを、ピペリジン/DMF(1:4)中に溶かした溶液;
− Bu4N+F-をDMF中に溶かした溶液、及び他のテトラアルキルアンモニウムフルオライド;並びに
− 2%HOBt、2%ヘキサメチレンイミン、25%N−メチルピロリジンをDMSO/NMP(1:1)中に溶かした溶液。
スキーム1(6*:構造4 R1=Me;R2=Fmoc;R3=ベンジル):
(i)樹脂、特に、メリフィールド樹脂;リンクアミド樹脂;及びTHP−樹脂からなる群から選択される樹脂;
(ii)保護ヒドロキシプロリン、特にフルオレニルメチルオキシカルボニル−(Fmoc−)−保護O−アリルヒドロキシプロリン(FmocHypOAll);
(iii)保護アスパラギン、特にFmoc−保護N−トリチルアスパラギン(Fmoc(N−Tri)AsnOH);
(iv)保護Cys−Trpジペプチド、特に−SH及び−OH保護基(FmocCys(S−2−((o−NO2Ph)SO2Trp−O−Allyl))]OH)を用いたFmoc−保護Cys−Trpジペプチド;
(v)保護グリシン、特にFmoc−保護グリシン(FmocGly);
(vi)保護イソロイシン、特にFmoc−保護イソロイシン(FmocIle);
(vii)ペプチド共役試薬、特に、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート(TBTU);ベンゾトリアゾール−1−イル−オキシトリピロリジノホスホニウムヘキサフルオロホスフェート(PyBOP);及びo−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスファート(HATU)からなる群から選択されるペプチド共役試薬;並びに
(viii)第三級アミン、特にN,N−ジイソプロピルエチルアミン(DiPEA)で処理した。
(b)反復FmocN−脱保護と;(a)化合物6を樹脂Lと反応させる工程で得られたGを、Fmoc−(N−Tri)Asn−OH;FmocCys(S−2−((o−NO2Ph)SO2Trp−O−Allyl))]OH、Fmoc−Gly−OH、Fmoc−Ile−OH、Fmoc−Gly−OHと共役する工程によって、化合物Hを生ずる。
(c)HのO−アリル−及びN−Fmoc脱保護、続いて、環化によって、化合物Iが生ずる(B環閉鎖):
(b)M(工程(a)において化合物6と化合物7又は化合物8とを反応させて得られたもの)を、Fmoc−(N−Tri)Asn−OH;Fmoc−(S−Tri)Cys−OH、Fmoc−Gly−OH、Fmoc−Ile−OH、Fmoc−Gly−OH及びN−Boc−HPIOH1[1 Zanotti, Giancarlo; Birr Christian; Wieland Theodor; International Journal of Peptide & Protein Research 18 (1981) 162-8]と反復FmocN−脱保護、共役して、化合物Nを生ずる。
(i)化合物1の事例では、アマトキシンアミノ酸1のγC原子(アミド結合)におけるアミド基の窒素原子;
(ii)化合物2の事例では、アマトキシンアミノ酸1のγC原子(エステル結合)における酸基の酸素原子;
(iii)化合物3の事例では、アマトキシンアミノ酸1のγC原子におけるヒドロキサム酸基の酸素原子;
(iv)アマトキシンアミノ酸3のδC原子におけるヒドロキシ基の酸素原子、特に、エステル結合、エーテル結合又はウレタン結合を介して;あるいは
(v)アマトキシンアミノ酸4の6’C原子;並びに
(vi)アミノ酸4の窒素環。
1.ベンジル(2S,3R,4S)−2−((((9H−フルオレン−イル)メトキシ)カルボニル)アミノ)−4−アセトキシ−3−メチルペンタノエートHDP30.1485の合成
MS(ESI+)実測値:268.09[MH]+;計算値:267.20(C14H26BNO3)
工程1.1.2:
MS(ESI+)実測値:310.07[MH]+;計算値:309.21(C16H28BNO4)
MS(ESI+)実測値:332.13[M+Na]+;計算値:332.21(C16H28BNNaO4)
1H NMR(500MHz,メタノール−d4)δ 5.08(dq,J=9.6,6.2Hz,1H)、3.85(d,J=2.8Hz,1H)、2.30(dqd,J=9.8,7.0,2.7Hz,1H)、2.02(s,3H)、1.95〜1.70(m,8H)、1.65(dt,J=19.0,7.4Hz,2H)、1.49〜1.40(m,2H)、1.27(d,J=6.2Hz,3H)、1.07(d,J=7.1Hz,3H)、0.53(s,2H)。
13C NMR(126MHz,メタノール−d4)δ 175.83,172.02,72.88,57.55,49.51,40.79,32.76,32.55,32.25,31.93,25.52,25.22,21.15,18.61,13.02。
1.2 (2S,3R,4S)−2−((((9H−フルオレン−イル)メトキシ)カルボニル)アミノ)−4−アセトキシ−3−メチルペンタノエートHDP30.1427の合成
MS(ESI+)実測値:412,23[MH]+;計算値:411.17(C23H25N6)
1H NMR(500MHz,クロロホルム−d)δ 7.77(d,J=7.6Hz,2H)、7.61(t,J=6.7Hz,2H)、7.44〜7.37(m,2H)、7.32(tdd,J=7.5,2.8,1.2Hz,2H)、5.54(d,J=9.3Hz,1H)、4.93〜4.84(m,1H)、4.50(dd,J=9.2,3.1Hz,1H)、4.44〜4.33(m,2H)、4.25(t,J=7.4Hz,1H)、2.51〜2.41(m,1H)、2.04(s,3H)、1.26(d,J=6.0,Hz 3H)、1.04(d,J=7.0Hz,3H)。
13C NMR(126MHz,CDCl3)δ 176.26,171.23,156.48,143.77,143.59,141.24,127.70,127.06,125.12,71.22,67.36,55.93,47.04,41.21,21.11,18.43,14.27。
1.3 化合物6(ベンジル(2S,3R,4S)−2−((((9H−フルオレン−イル)メトキシ)カルボニル)−アミノ)−4−アセトキシ−3−メチルペンタノエート(HDP30.1485)の合成
収量:2.41g(80%)
MS(ESI+)実測値:524.43[M+Na]+;計算値:524.22(C30H31NaNO6)
1H NMR(500MHz,クロロホルム−d)δ 7.76(d,J=7.5Hz,2H)、7.61(t,J=7.3Hz,2H)、7.44〜7.27(m,9H)、5.53(d,J=9.3Hz,1H)、5.18(s,2H)、4.92〜4.82(m,1H)、4.50(dd,J=9.3,3.4Hz,1H)、4.37(qd,J=10.6,7.4Hz,2H)、4.24(t,J=7.4Hz,1H)、2.44(ddt,J=13.5,10.0,5.0Hz,1H)、1.98(s,3H)、1.23(d,J=6.2Hz,3H)、0.99(d,J=7.0Hz,3H)。
13C NMR(126MHz,CDCl3)δ 171.56,170.84,156.49,143.88,143.66,141.22,135.18,128.64,128.24,127.65,127.05,125.16,119.91,76.71,70.99,67.30,67.14,56.18,47.08,41.19,21.05,18.28,14.22。
2.HDP30.0287の合成
MS(ESI+)実測値:445.43[MH]+;計算値:444.24(C28H32N2O3)
2.2 HDP30.0083(TrNH−Gly−Ile−OH)の合成
MS(ESI+)実測値:431,48[MH]+;計算値:430.23(C27H30N2O3)
2.3 HDP30.0084(TrNH−Gly−Ile−Gly−OMe)の合成
MS(ESI+)実測値:501.29[MH]+;計算値:501.26(C30H35N3O4)
MS(ESI+)実測値:524.33[M+Na]+;計算値:524.26(C30H35N3NaO4)
2.4 HDP30.0089(H2N−Gly−Ile−Gly−OMe)の合成
H2N−Gly−Ile−Gly−OMe × TFAの1.40g(71%)白色固体
MS(ESI+)実測値:260.23[MH]+;計算値:259.15(C11H21N3O4)
2.5 HDP30.0263(BocHpi−Gly−Ile−Gly−OMe)の合成
MS(ESI+)実測値:562.34[MH]+;計算値:561.28(C27H39N5O8)
MS(ESI+)実測値:584.41[M+Na]+;計算値:584.28(C27H39N5NaO8)
2.6 HDP30.0287(BocHpi−Gly−Ile−Gly−OH)の合成
S(ESI+)実測値:548.10[MH]+;計算値:547.26(C26H37N5O6)
MS(ESI+)実測値:570.30[M+Na]+;計算値:570.26(C26H37N5NaO6)
MS(ESI+)実測値:1095.10[2M+H]+
3.γ−アマニンアミドHDP30.1790の合成
3.1 HDP30.1788の合成
MS(ESI+)実測値:576.23[MH]+;計算値:575.17(C30H26F5NO5)
3.2 HDP30.1502の合成
経路B(Ueki et al., Chem. Lett. 1993, 721-724):
MS(ESI+)実測値:671.31[MH]+;計算値:670.33(C39H46N2O8)
MS(ESI+)実測値:693.50[M+Na]+;計算値:693.33(C39H46N2NaO8)
3.3 HDP30.1170(FmocNH−Cys(STr)−Asn(NHTr)−OH)の合成
MS(ESI+)[M+Na]+ 実測値:964.21;計算値:964.34(C60H51N3NaO6S)
MS(ESI+)[2M+H]+ 実測値:1882.43;計算値:1883.71(C120H103N6O12S2)
MS(ESI+)[2M+Na]+ 実測値:1904.79;計算値:1905.69(C120H102N6NaO12S2)
3.4 HDP30.1668
MS(ESI+)実測値:1372.15[MH]+;計算値:1371.60(C84H85N5O11S)
MS(ESI+)実測値:1394.73[M+Na]+;計算値:1394.60(C84H85N5NaO11S)
3.5 HDP30.1606の合成
MS(ESI+)実測値:1679.28[MH]+;計算値:1678.78(C95H110N10O16S)
MS(ESI+)実測値:1701.68[M+Na]+;計算値:1701.78(C95H110N10NaO16S)
3.6 HDP30.1607の合成
MS(ESI+)実測値:1021.53[MH]+;計算値:1020.44(C48H64N10O13S)
MS(ESI+)実測値:1043.63[M+Na]+;計算値:1043.44(C48H64N10NaO13S)
3.7 HDP30.1676の合成
MS(ESI+)実測値:931.48[MH]+;計算値:930.39(C41H58N10O13S)
MS(ESI+)実測値:953.59[M+Na]+;計算値:953.39(C41H58N10NaO13S)
3.8 HDP30.1679の合成
MS(ESI+)実測値:913.44[MH]+;計算値:912.38(C41H56N10O12S)
MS(ESI+)実測値:935.58[M+Na]+;計算値:935.38(C41H56N10NaO12S)
3.9 HDP30.1790の合成
MS(ESI+)実測値:871.51[MH]+;計算値:870.37(C39H54N10O11S)
MS(ESI+)実測値:893.69[M+Na]+;計算値:893.37(C39H54N10NaO11S)
Claims (8)
- 構造(2S,3R,4S)−CH3−CH(OR1)−CH(CH3)−CH(NHR2)−C(=O)OR3(構造6)を有する化合物であって、式中のR1〜R3が保護基であり、R2が開裂する可能性のある条件下でR1及びR3は安定であり、R3が開裂する可能性のある条件下で、特にR1がアルカノイル、具体的にはアセチル又はCH3COCH2CO−であり、R2がFmocであり、且つR3がベンジル又はt−ブチルである場合に、R1及びR2は安定である、化合物。
- 構造6*
- (a)構造5の化合物を、銅又はホウ素で、特に9−ボラビシクロ[3,3,1]ノナン(9−BBN)で錯化する工程と;(b)4−ヒドロキシ基を、化合物R1’−C(=O)−X(式中、Xは脱離基であり、具体的には式中のR1’がアルキル、具体的にはC1-6アルキル、具体的にはメチルである)でアシル化する工程と;(c)金属錯体を開裂する工程と;(d)α−アミノ基を、R2基で、具体的にはFmoc基で保護する工程と;(e)カルボキシル基を、R3基で、具体的にはベンジル基又はt−ブチル基で保護する工程と;を含む、構造6(2S,3R,4S)−CH3−CH(OR1)−CH(CH3)−CH(NHR2)−C(=O)OR3の化合物の合成方法。
- 請求項1又は2に記載の化合物と;アマトキシン又はその前駆体を合成するための少なくとも1つの追加的な試薬と;を含むキット。
- (a1)請求項1に記載の化合物から保護基R2を開裂させる工程と;(a2)工程(a1)に従って得られた遊離アミノ基を含む、6の脱保護変種を、ヒドロキシプロリンの活性化変種、その保護変種、又はそのシントン、あるいは特に、7、8及びLから選択される構造の化合物に、共役させる工程と;を含む、アマトキシン又はその前駆体分子の合成方法
- γ−アマニンアミド(1;x=0、1又は2)、γ−アマニンアミド酸(2;x=0、1又は2)、及びγ−アマニナミドヒドロキサム酸(3;x=0、1又は2)である、化合物
- γ−アマニンアミド(1;x=0、1若しくは2)、γ−アマニンアミド酸(2;x=0、1若しくは2)、又はγ−アマニナミドヒドロキサム酸(3;x=0、1若しくは2)と標的結合部分との複合体であって、前記複合体に任意で含まれるリンカー部分が、一方の側にて、前記γ−アマニンアミド(1;x=0、1若しくは2)、γ−アマニンアミド酸(2;x=0、1若しくは2)若しくはγ−アマニナミドヒドロキサム酸(3;x=0、1若しくは2)中に存在する位置又は官能性基に連結され、且つもう一方の側にて、前記標的結合部分中に存在する位置又は官能性基に連結される、複合体。
- γ−アマニンアミド(1;x=0、1若しくは2)、γ−アマニンアミド酸(2;x=0、1若しくは2)、又はγ−アマニナミドヒドロキサム酸(3;x=0、1若しくは2)と;結合部分と;の複合体であって、前記結合部分が、一方の側にて、前記γ−アマニンアミド(1;x=0、1若しくは2)、γ−アマニンアミド酸(2;x=0、1若しくは2)若しくはγ−アマニナミドヒドロキサム酸(3;x=0、1又lは2)中に存在する位置又は官能性基に連結され、且つ前記複合体が、標的結合部分中に存在する位置又は官能性基に直接的に若しくは間接的に連結しうる位置又は官能性基を更に含む、複合体。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2022173139A JP2023010733A (ja) | 2015-11-27 | 2022-10-28 | γ-アマニチンの誘導体 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15003389 | 2015-11-27 | ||
EP15003389.2 | 2015-11-27 | ||
PCT/EP2016/078984 WO2017089607A1 (en) | 2015-11-27 | 2016-11-28 | Derivatives of gamma-amanitin |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022173139A Division JP2023010733A (ja) | 2015-11-27 | 2022-10-28 | γ-アマニチンの誘導体 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2018536666A true JP2018536666A (ja) | 2018-12-13 |
Family
ID=54849077
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018527167A Pending JP2018536666A (ja) | 2015-11-27 | 2016-11-28 | γ−アマニチンの誘導体 |
JP2022173139A Pending JP2023010733A (ja) | 2015-11-27 | 2022-10-28 | γ-アマニチンの誘導体 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022173139A Pending JP2023010733A (ja) | 2015-11-27 | 2022-10-28 | γ-アマニチンの誘導体 |
Country Status (7)
Country | Link |
---|---|
US (1) | US10723766B2 (ja) |
EP (1) | EP3380451A1 (ja) |
JP (2) | JP2018536666A (ja) |
CN (1) | CN108495840A (ja) |
AU (1) | AU2016360828B2 (ja) |
CA (1) | CA3005683A1 (ja) |
WO (1) | WO2017089607A1 (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190328901A1 (en) | 2016-06-17 | 2019-10-31 | Magenta Therapeutics, Inc. | Compositions and methods for the depletion of cells |
KR20190107097A (ko) | 2017-01-20 | 2019-09-18 | 마젠타 테라퓨틱스 인코포레이티드 | Cd137+ 세포의 고갈을 위한 조성물 및 방법 |
CN110997676B (zh) | 2017-08-07 | 2022-12-20 | 海德堡医药研究有限责任公司 | 合成鹅膏蕈碱的新方法 |
KR20200037207A (ko) | 2017-08-07 | 2020-04-08 | 하이델베르크 파마 리서치 게엠베하 | 신규한 아마니틴 합성 방법 |
CN114191564A (zh) * | 2017-08-18 | 2022-03-18 | 四川百利药业有限责任公司 | 一种非天然鹅膏毒肽类抗体偶联物 |
WO2021122744A1 (en) * | 2019-12-16 | 2021-06-24 | Heidelberg Pharma Research Gmbh | Synthesis of amanin and its derivatives |
CN115715294A (zh) * | 2020-06-09 | 2023-02-24 | 海德堡医药研究有限责任公司 | 用于合成含硫醚肽的方法 |
CN112089710B (zh) * | 2020-08-07 | 2022-04-01 | 郑州大学 | 4-羟基异亮氨酸在制备抗肿瘤药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012523383A (ja) * | 2009-04-08 | 2012-10-04 | ファウルシュティヒ,ハインツ | がんの治療のためのアマトキシンと複合体形成した標的結合部分 |
JP2014508767A (ja) * | 2011-03-10 | 2014-04-10 | ハイデルベルク ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 改善されたリンケージを有するアマトキシン複合体 |
JP2015528799A (ja) * | 2012-07-13 | 2015-10-01 | ハイデルベルク ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング | アマトキシンビルディングブロック及びアマトキシンの合成方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG48759A1 (en) | 1990-01-12 | 2002-07-23 | Abgenix Inc | Generation of xenogenic antibodies |
EP1859811B1 (en) | 2006-05-27 | 2011-08-24 | Faulstich, Heinz, Dr. | Use of conjugates of amatoxins or phallotoxins with macromolecules for tumor and inflammation therapy |
US9233173B2 (en) | 2009-04-08 | 2016-01-12 | Deutsches Krebsforschungszentrum | Amatoxin-armed therapeutic cell surface binding components designed for tumour therapy |
SG176085A1 (en) * | 2009-05-15 | 2011-12-29 | Stichting Nl Kanker Inst | Lysine compounds and their use in site- and chemoselective modification of peptides and proteins |
EP2889624B1 (en) | 2009-08-10 | 2018-10-03 | UCL Business PLC | Reversible covalent linkage of functional molecules |
-
2016
- 2016-11-28 EP EP16802044.4A patent/EP3380451A1/en not_active Withdrawn
- 2016-11-28 AU AU2016360828A patent/AU2016360828B2/en active Active
- 2016-11-28 JP JP2018527167A patent/JP2018536666A/ja active Pending
- 2016-11-28 WO PCT/EP2016/078984 patent/WO2017089607A1/en active Application Filing
- 2016-11-28 CN CN201680080145.4A patent/CN108495840A/zh active Pending
- 2016-11-28 US US15/779,510 patent/US10723766B2/en active Active
- 2016-11-28 CA CA3005683A patent/CA3005683A1/en not_active Abandoned
-
2022
- 2022-10-28 JP JP2022173139A patent/JP2023010733A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012523383A (ja) * | 2009-04-08 | 2012-10-04 | ファウルシュティヒ,ハインツ | がんの治療のためのアマトキシンと複合体形成した標的結合部分 |
JP2014508767A (ja) * | 2011-03-10 | 2014-04-10 | ハイデルベルク ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 改善されたリンケージを有するアマトキシン複合体 |
JP2015528799A (ja) * | 2012-07-13 | 2015-10-01 | ハイデルベルク ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング | アマトキシンビルディングブロック及びアマトキシンの合成方法 |
Non-Patent Citations (4)
Title |
---|
CHEMBIOCHEM, vol. 16(10), JPN6020034531, 2015, pages 1420 - 1425, ISSN: 0004344259 * |
INTERNATIONAL JOURNAL OF PEPTIDE & PROTEIN RESEARCH, vol. 34(3), JPN6020034532, 1989, pages 222 - 228, ISSN: 0004344260 * |
INTERNATIONAL JOURNAL OF PEPTIDE & PROTEIN RESEARCH, vol. 40(6), JPN6020034534, 1992, pages 551 - 558, ISSN: 0004344262 * |
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 106(16), JPN6020034533, 1984, pages 4606 - 4615, ISSN: 0004344261 * |
Also Published As
Publication number | Publication date |
---|---|
WO2017089607A1 (en) | 2017-06-01 |
US10723766B2 (en) | 2020-07-28 |
CA3005683A1 (en) | 2017-06-01 |
CN108495840A (zh) | 2018-09-04 |
AU2016360828B2 (en) | 2021-06-24 |
JP2023010733A (ja) | 2023-01-20 |
EP3380451A1 (en) | 2018-10-03 |
AU2016360828A1 (en) | 2018-05-31 |
US20180346519A1 (en) | 2018-12-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7362714B2 (ja) | アマニチンコンジュゲート | |
JP2018536666A (ja) | γ−アマニチンの誘導体 | |
KR101988005B1 (ko) | 개선된 연결을 갖는 아마톡신-접합체 | |
EP2964264B1 (en) | Amatoxin derivatives | |
AU2011307195B2 (en) | Amatoxin-conjugates with improved linkers | |
JP7165720B2 (ja) | アマニチンの新規な合成方法 | |
JP7220199B2 (ja) | アマニチンの新規な合成方法 | |
RU2792210C2 (ru) | Новый способ синтеза аманитинов | |
RU2575854C2 (ru) | Конъюгаты аматоксина с улучшенными связями | |
NZ785704A (en) | Novel amanitin conjugates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190919 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200827 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200915 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20201214 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210315 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210824 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20211122 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220224 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20220628 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20221028 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20221101 |