CN1027267C - Ll-e33288抗肿瘤抗生素的n-酰基衍生物的制备方法 - Google Patents
Ll-e33288抗肿瘤抗生素的n-酰基衍生物的制备方法 Download PDFInfo
- Publication number
- CN1027267C CN1027267C CN90102100A CN90102100A CN1027267C CN 1027267 C CN1027267 C CN 1027267C CN 90102100 A CN90102100 A CN 90102100A CN 90102100 A CN90102100 A CN 90102100A CN 1027267 C CN1027267 C CN 1027267C
- Authority
- CN
- China
- Prior art keywords
- dihydro
- acetyl
- ethyl acetate
- formyl
- perhaps
- 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.)
- Expired - Lifetime
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/29—Micromonospora
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Communicable Diseases (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明涉及LL-E33288抗肿瘤抗生素的N-酰基衍生物的制备方法,即将抗生素与合适的取代酸酐,酰氯、乙酸和甲酸的混合酸酐或丁二烯酸的单甲酸的酸酐进行酰基反应;或者再进一步用硼氢化钠还原,得到相应的二氢化物。
Description
本申请是1987年1月30日申请的序号为004154的专利申请的部分续展申请。
本发明涉及通过将抗生素与相当的不饱和的或饱和的酸酐酰基阳离子或酰基氯反应而制备的LL-E33288抗生素配合物的αBr 2,βBr 1,γBr 1,αI 2,βI 1,γI 1和δI 1成分的N-酰基衍生物以及αBr 2,βBr 1,γBr 1,αI 2,βI 1,γI 1和δI 1成分的N-酰基-二氢衍生物。这些N-酰基衍生物是有效的抗菌剂和抗癌剂。
图Ⅰ:N-乙酰-LL-E33288δI 1的质(子磁共振)谱。
图Ⅱ:N-甲酰-LL-E33288δI 1的质(子磁共振)谱。
图Ⅲ:N-乙酰-LL-E33288γI 1的紫外线吸收谱线。
图Ⅳ:N-乙酰-LL-E33288γI 1的红外线吸收谱线。
图Ⅴ:N-乙酰-LL-E33288γI 1的质(子磁共振)谱。
图Ⅵ:N-乙酰-LL-E33288γI 1的碳-13磁共振谱。
图Ⅶ:N-乙酰-二氢-LL-E33288γI 1的紫外线吸收谱线。
图Ⅷ:N-乙酰-二氢-LL-E33288γI 1的质(子磁共振)谱。
在1987年1月30日申请的美国专利009321号中描述并要求保护了通称之为LL-E33288配合物的一族抗菌剂和抗癌剂,它们被用来制备本发明的N-酰基衍生物。上述专利申请描述的LL-E33288配合物,其成员有:LL-E33288αBr 1、LL-E33288αBr 2、LL-E33288αBr 3、LL-E33288αBr 4、LL-E33288βBr 1、LL-E33288βBr 2、LL-E33288γBr 1、LL-E33288αI 1、LL-E33288αI 2、LL-E33288αI 3、LL-E33288βI 1、LL-E33288βI 2、LL-E33288γI 1和LL-E33288δI 1、以及通过利用Micromonospora echinosporassp.calichensis的新菌株或者其天然的或衍生的突变种的好氧发酵的生产方法。上述命名的有些成分的已提出的化学结构将在009321号申请号中透露,并在下述表Ⅰ中再现。
表Ⅰ
LL-E33288成分的提出的结构
名称 R1R2X
E33288αI 2H C2H5I
E33288βI 1R3(CH3)2CH I
E33288γI 1R3C2H5I
E33288δI 1R3CH3I
E33288αBr 2H C2H5Br
E33288βBr 1R3(CH3)2CH Br
E33288γBr 1R3C2H5Br
从表Ⅰ中所透露的结构可以看到,LL-E33288抗生素配合物的αBr 2,βBr 1,γBr 1,αI 2,βI 1,γI 1和δI 1成分每种成分包含有一个二级氨基,它是取代的4-氨基戊糖单元的部分。现在已经发现,任何上述成分与不饱和的或饱和的,取代的或非取代的烷基或者芳基酸酐、酰基氯或相当的酰基阳离子进行反应导致在如下图1中所示的在二级氨基引引入酰基部分。
其中W是附着于表Ⅰ中氨基戊糖的R2NH的取代基,R为氢或支链的或无支链的烷基(C1-10)或链烯基(C1-10),芳基或杂芳基,或芳-烷基(C1-5)或杂芳-烷基(C1-5),它们都可选择地被一个或一个以上的羟基、氨基、羧基、卤素、硝基、低级(C1-3)烷氧基,或低级(C1-5)硫代烷氧基所取代。
N-酰基衍生物也可从LL-E33288抗生素的二氧衍生物制备的,即从专利申请004154号的二氢-LL-E33288αBr 2、二氢-LL-E33288βBr 1、二氢-LL-E33288γBr 1、二氢-LL-E33288αI 2、二氢-LL-E33288βI 1、二氢-LL-E33288γI 1和二氢-LL-E33288δI 1来制备。
作为一个例子,-LL-E33288γI 1,与甲醇中的乙酸酐反应产生N-乙酰基-LL-E33288γI 1,而LL-E33288δI 1,与乙酸和甲酸的混合酸酐反应产生N-甲酰-LL-E33288 δI 1,这两者都是有效的新的抗肿瘤抗生素。二氢-LL-E33288γI 1,甲醇中的乙酸酐反应产生N-乙酰基-二氢-LL-E33288γI 1;N-乙酰基-二氢-LL-E33288γI 1还可通过N-乙酰基-LL-E33288γI 1,与硼氢化钠在专利申请中004154号所述的条件下反应而制得,LL-E33288的N-酰基衍生物和二氢-LL-E33288抗癌抗生素的一些化学结构在下面的表Ⅱ中所示出:
表Ⅱ
LL-E33288的N-酰基衍生物和二氢
-LL-E33288抗生素的提出结构
名称 R1R2R4R5X
N-酰基-二氢
LL-E33288αI 2H C2H5OH H I
N-酰基
LL-E33288αI 2H C2H5=O I
N-酰基-二氢
LL-E33288βI 1R3(CH3)2CH OH H I
N-酰基
LL-E33288βI 1R3(CH3)2CH =O I
N-酰基-二氢
LL-E33288γI 1R3C2H5OH H I
N-酰基
LL-E33288γI 1R3C2H5=O I
N-酰基-二氢
LL-E33288δI 1R3CH3OH H I
N-酰基
LL-E33288δI 1R3CH3=O I
N-酰基-二氢
LL-E33288αBr 2H C2H5OH H B
N-酰基
LL-E33288αBr 2H C2H5=O B
N-酰基-二氢
LL-E33288βBr 1R3(CH3)2CH OH H B
N-酰基
LL-E33288βBr 1R3(CH3)2CH OH H B
N-酰基-二氢
LL-E33288γBr 1R3C2H5OH H B
N-酰基
LL-E33288γBr 1R3C2H5=O B
R为氢或支链的或无支链的烷基(C1-10)或者链烯基(C1-10),芳基或杂芳基,或芳-烷基(C1-5)或杂芳-烷基(C1-5)它们都可选择地被一个或一个以上的羟基、氨基、羧基、卤素、硝基、低级烷氧基(C1-3),或者低级硫代烷氧基(C1-5)所取代。
LL-E33288抗肿瘤抗生素的N-酰基衍生物中的四个,即N-乙酰基-LL-E33288δI 1,N-甲酰
基-LL-E33288δI 1,N-乙酰基-LL-E33288γI 1,和N-乙酰基-二氢-LL-E33288γI 1,的物理化学特性描述如下。
N-乙酰-LL-E33288δI 2:
a)分子量:1395,由FABMS法测定;
b)分子式:C56H74N3O22IS,通过高分辨率FABMS测定M+R的精确质量对于C56H74N3O22IS4K是1434.239;以及
c)质(子磁共振)谱:如图Ⅰ所示(300兆赫,CDCl3)。
N-甲酰-LL-E33288 δI 1:
a)分子量:1381,由FABMS法测定;
b)分子式:C55H72N3O22IS4,通过高分辩率FABMS测定M+H的精确质量对于C55H72N3O2IS4K是1420.212;以及
c)质(子磁共振)谱:如图Ⅱ所示(300兆赫,CDCl3)。
N-乙酰-LL-E33288γI 1:
a)分子量:1409,由FABMS法测定;
b)分子式:C57H76N3O22IS4,通过高分辨率FABMS测定M+H的精确质量对于C57H76N3O2IS4是1410.2954;以及
c)紫外线吸收光谱:如图Ⅲ所示(甲醇),
d)红外线吸收光谱:如图Ⅳ所示(KBr片),
e)质(子磁共振)谱:如图Ⅴ所示(300兆赫,CDCl3)
f)碳-13磁共振谱:如图Ⅵ所示(7543兆赫,CDCl3,TMS为ppm位移标线),显著峰如下所列:
14.0q 17.6q 17.11 19.0q 244.q 22.8q
25.4q 36.7t 36.9t 39.2t 47.6t 51.6
52.4q 53.1t 57.0q 57.2q 58.8t 60.9q
61.7q 64.4d 67.0d 68.1d 68.4d 69.0d
69.1q 70.5d 71.1d 71.7s 71.9d 72.4d
77.6q 80.8d 83.2s 87.0s 93.5s 97.9d
98.1s 99.7d 100.9s 101.3d 102.6d 123.2d
124.5d 127.1d 130.2s 133.4s 136.5s 142.9s
143,0s 150.6s 151.5s 155.0s 172.3s 191.9s
192.1s
N-乙酰基-二氢-LL-E33288γI 1:
a)紫外线吸收光谱:如图Ⅶ所示(甲醇);
b)质(子磁共振)如图Ⅷ所示(300兆赫,CDCl3)
LL-E33288抗肿瘤抗生素的N-酰基衍生物的最方便的表征鉴定是用高性能液相色谱法(HPLC)和薄层色谱法(TLC)。
用于某些LL-E33288抗肿瘤抗菌素的N-酰基衍生物的表征鉴定的分析用HPLC体系如下所示:
柱:分析化学用Sepralyte C18,5μ,4.6mm×25cm
流动相:0.2M乙酸铵水溶液,pH6.0:乙腈,50∶50
流速:1.5毫升/分钟
检测:UV254nm和UV280nm
表Ⅲ给出了一些LL-E33288抗肿瘤抗生素的N-酰衍生物的近似的保留时间:
表Ⅲ
N-酰基-LL-E-33288
抗肿瘤抗生素 保留时间(分钟)
N-乙酰-LL-E-33288γI 16.6
N-甲酰-LL-E-33288γI 16.2
N-乙酰-LL-E-33288δI 14.5
N-甲酰-LL-E-33288δI 14.2
LL-E-33288γI 18.0
LL-E-33288δI 16.0
用于LL-E-33288抗肿瘤抗生素的N-酰基衍生物的表征鉴定的较好的TLC体系如下所示:
吸收剂:Whatman高性能TLC(HPTLC)板,LHP-KF型;
检测:在短波紫外线灯(254nm)下通过骤冷效应显色
溶剂***:用0.1M pH7.0磷酸盐水溶液缓冲剂饱和的乙酸乙酯
表Ⅳ给出了上述TLC体系中的一些LL-E-33288抗肿瘤抗生素的N-酰基衍生物的近似Rf值
表Ⅳ
N-酰基-LL-E-33288抗肿瘤抗生素 Rf
N-甲酰-LL-E-33288γI 10.53
N-乙酰-LL-E-33288γI 10.53
N-乙酰-LL-E-33288δI 10.25
N-甲酰-LL-E-33288δI 10.31
N-乙酰-二氢-LL-E-33288δI 10.38
N-单甲基丁二酰LL-E-33288δI 10.42
LL-E-33288γI 10.25
LL-E-33288δI 10.14
LL-E-33288抗肿瘤抗生素的N-酰基衍生物是有用的杀菌剂,N-乙酰-LL-E-33288δI 1、N-甲酰-LL-E-33288δI 1和N-乙酰-LL-E-33288γI 1的体外抗菌污性是通过标准琼脂稀释方法针对***和革兰氏阴性细菌进行测定的。将含有浓度降低二倍的抗生素的Meeller-Hinton琼脂倒入陪替氏培养皿。琼脂的表面借助Steers复制装置接种1至5×104菌落形成单位的细菌,可抑制35℃温度下保温培养约18小时后细菌菌种的生长的N-酰基-LL-E33288抗肿瘤抗菌素的最低浓度被记录为该菌株的最小的抑制浓度(MIC),结构列于表Ⅴ。
表Ⅴ
N-酰基-LL-E33288
抗菌素的体外抗菌活性
最低抑制浓度
N-乙酰- N-甲酰- N-乙酰-
微生物 LL- LL- LL-
E33288δ E33288δ E33288γ
大肠杆菌 2 2 >2
CMC84-11
大肠杆菌 2 1 >2
No.311(MP)
大肠杆菌 1 1 >2
ATCC25922
肺炎克霉伯氏杆菌 8 4 >2
CMC84-5
肺炎克霉伯氏杆菌 1 1 2
AD(MP)
阴沟肠杆菌 4 4 >2
CMC84-4
粘质沙雷氏菌 8 4 >2
F-35(MP)
绿脓假单胞菌 4 2 >2
12-4-4(MP)
绿脓假单胞菌 4 2 >2
TACC27853
金黄色葡萄球菌 0.12 0.06 0.008
Smith(MP)
金黄色葡萄球菌 0.25 0.12 0.06
ATCC25923
表皮葡萄球菌 0.015 0.03 0.12
ATCC12228
粪链球菌 0.06 0.06 0.12
ATCC29212
粪链球菌 0.12 0.12 0.12
IO83-28
LL-E33288抗肿瘤抗生素的N-酰基衍生物也是有效的抗肿瘤剂,如同生物化学诱导测定法测定的那样,它是可专门测定一种化学剂直接地或间接地引起DNA损害的能力的细菌测定***。用于这个试验的微生物指示物是Ecolilamba细胞溶素原,遗传学方法构成一种DNA损伤事件,从而导致酶β-半乳糖甘酶(β-galactosidase)基因的表达。这种酶可以通过生化测定作为已发生已发生DNA损伤的表征来进行定性和定量测定。
由Elespuru,R.和Yarmolinsky,M.在《环境诱变》(Environmental Mutagenesis)1,65(1979)中所公开的定量的液体生物化学诱导测定法的改良方法,被用来评价这些化合物。
国立癌症研究所已经发展了某些体内试验***和记录书(protocls),用于验证化合物以确定它们作为抗肿瘤剂的适合性。Geran等已经在《癌症化疗报告》(Cancer Chemotherapy Reports)的第Ⅳ部分,第3卷,第2号(1972)中作了报道。这些记录书中已经确定一些标准的筛选试验,这些标准筛选试验一般是在抗肿瘤剂的试验领域中应用。在这些***中,淋巴性白血病P388,黑色素黑瘤B16和结肠26腺癌对本发明来说是特别适用的。这些肿瘤被用于作为在鼠内可移植的肿瘤进行试验。一般说来,明显有效的抗肿瘤活性,是以处理过的动物(T)对对照动物(C)的平均存活时间。增加百分数表示在这些记录书中,是表示对人体白血病和实体肿瘤具有同样的结果。
淋巴细胞血病P388试验
所用的动物是BDF小鼠,同一性别,最轻的重量为17克,而且所有小鼠重量相差在3克以内。每个试验组为5至6个小鼠。肿瘤转植物是通过腹膜内注射0.5毫升在含有106淋巴细胞血病P388的细胞的腹水液体。试验化合物是在0.5毫升正常盐水中0.2%Rlucel的体积中,在第1、5和9腹膜内施日天(相对于肿瘤接种),以所示的剂量。对小鼠称重,并对存活者有规律地记录30天,计算存活时间的中值和处理小鼠(T)/对照小鼠(C)的存活时间的比率。本发明抗肿瘤抗生素,LL-E33288 γI 1被用作为阳性对照(positivevontrol)。
N-乙酰-LL-E33288 δI 1-N-甲酰-LL-E33288δI 1和N-乙酰-LL-E33288γI 1的试验
结果列于表Ⅵ。如图T/C×100(%)为125或大于125,试验化合物就被认为具有有效的抗肿瘤活性。
表Ⅵ
淋巴白血病P388试验
存活时间 T/C
化合物 剂量(毫 中值 ×100
克/公斤) (天) (%)
盐 11.0
N-乙酰 0.1 13.0 118
-LL-E33288δI 10.05 29.5 268
0.025 26.0 236
0.0125 20.0 182
0.006 20.0 182
N-乙酰 0.1 11.5 105
-LL-E33288δI 10.05 30.0 273
0.025 25.0 227
0.0125 23.0 209
0.006 19.5 177
N-甲酰 0.1 12.5 114
-LL-E33288δI 10.05 27.0 245
0.025 22.5 205
0.0125 21.0 191
0.006 20.5 186
LL-E33288γI 10.01 13.0 118
0.005 25.0 227
0.0025 30.0 273
0.00125 26.5 241
LL-E3328γI 10.08 18 164
0.04 29.5 268
0.02 28.0 255
0.005 17.5 159
0.0025 14.0 127
0.00125 13.5 123
LL-E33288γI 10.01 22.5 205
0.005 26.0 236
0.0025 24.5 223
0.00125 21.0 191
0.0006 19.0 173
黑色素黑瘤B16试验
所用的动物为BDF小鼠,同一性别,最轻重量为17克,且重量相差不超过3克,一般每组6只小鼠。将1克黑色素瘤B16肿瘤在10毫升冷平衡的(balanched)盐溶液中匀化,再将0.5毫等分试样的均浆在腹膜下移植入每个试验小鼠。在第1至9天(相对于肿瘤的接种)以各种剂量腹膜施用试验化合物。对鼠进行称重,存活者有规律记录60天。计算存活时间中值和处理的小鼠(T)/对照的小鼠(C)的存活时间比率。本发明抗肿瘤抗菌生素LL-E-33288γI 1被用作为对照对照(posi-tive control)。
N-乙酰-LL-E-33288 δI 1和N-乙酰-LL-E-33288γI 1的试验结果列于表Ⅶ,如果T/C×100(%)为125或大于125试验化合物就被认为具有有效的抗肿瘤活性。
表Ⅶ
黑色素黑瘤B16试验
存活时间 T/C
化合物 剂量(毫 中值 ×100
克/公斤) (天) (%)
盐 21.0
N-乙酰 0.025 35.5 118
-LL-E33288δI 10.0125 27.5 131
0.006 26.0 124
0.003 25.0 119
0.0015 21.5 102
LL-E33288γI 10.0025 39.0 186
0.00125 39.0 186
0.0006 35.0 167
0.0003 29.5 140
0.00015 24.5 117
盐 21.0
N-乙酰 0.025 26.0 124
-LL-E33288γI 10.0125 38.0 181
0.006 39.0 186
0.003 33.5 160
0.0015 26.5 126
0.0007 26.0 124
0.00035 24.5 116
0.00017 23.5 112
LL-E33288γI 10.005 8.0 38
0.0025 27.0 129
0.00125 41.0 198
0.0006 45.0 214
0.0003 35.5 169
0.00015 35.0 167
0.00007 34.5 164
0.00003 31 148
结肠26尕癌试验
所用的动物是CD2F1雌性小鼠,最轻重量为17克,而且重量相差不超过3克,每试验组5至6只小鼠,每次试验有三组(每组5至6只小鼠)作为未处理的对照组。肿瘤移植物是通过腹膜内注
射0.5毫升含有抗菌剂的Eagle′sMEM培养基中的2%结肠26浆。在第1、5和9天(相对于肿瘤移植剂量)腹膜内施用试验化合物。对鼠进行称重,并有规律记录死亡数30天。计算处理过的小鼠(T)/比较对组小鼠(C)的存活中值,本发明的抗肿瘤抗生素LL-E33288γ被用作为阳性对照。
N-乙酰-LL-E-33288δI的试验结果列于表Ⅷ,如果T/C×100(%)为130或大于130,就认为试验化合物具有有效的抗肿瘤活性。
表Ⅷ
克隆26腺癌试验
存活时间 T/C
化合物 剂量(毫 中值 ×100
克/公斤) (天) (%)
盐 16.0
N-乙酰 0.5 22.5 141
-LL-E33288δI 10.025 40.0 250
0.0125 21.0 131
0.006 24.5 153
0.003 19.0 119
0.0015 19.0 119
0.0017 19.0 119
LL-E33288γI 10.01 14.0 88
0.005 35.0 219
0.0025 21.5 134
0.00125 24.0 150
0.0006 19.5 122
0.0003 18.0 113
0.00015 17.5 109
用下列非限制性的实施例进一步描述本发明。
实施例1
N-乙酰-LL-E33288δI 1的制备和纯化。
将乙酸酐2(毫升)滴加到在冰-水浴中冷却的经部分纯化的LL-E33288δI的搅拌的甲醇溶液中(608毫克,57%纯度,60毫升)。将反应混合物在0℃搅拌1小时,然后慢慢加热至室温,再让反应继续进行3个小时。然后将反应混合物真空浓缩,并将残余物溶解在二氯甲烷和水各60毫升的混合液中,用稀释的氢氧化钠水溶液中和水溶液相,以从有机相中去除过多的乙酸。对有机相进行分离,经无水硫酸钠干燥,浓缩至小体积,并通过加入乙烷沉淀给出604毫克粗制N-乙酰-LL-E-33288δI 1。
将上述粗制的N-乙酰-LL-E-33288δI 1溶解在8毫升乙腈:0.2M乙酸铵(35∶65)之中pH6.0,在Sepralyte C18柱(1.5×21厘米)上分四批进行层析,以10毫升/分钟洗脱柱,先用乙腈∶0.2M乙酸铵pH6.0(35∶65)洗脱30分钟,随后再用线性梯度乙腈:0.2M乙酸铵pH6.0(40∶60)洗脱用60分钟。在整过层析过程,柱洗脱液在UV254nm监视,并每2.5分钟收集馏份。峰位级分用HPLC分析,根据HPLC分析,将含有纯N-乙酰-LL-E-33288δI 1的级分集中起来并在真空中浓缩以去除乙腈。将存在于水溶液混合物中N-乙酰-LL-E-33288δI 1抽提到乙酸乙酯中,并将乙酸乙酯相在无水硫酸钠上干燥,浓缩至一个小体积,并通过加入乙烷沉淀给出161毫升半纯化的N-乙酰-LL-E-33288δI 1。
TLC分析(E.Merck二氧化硅胶60F254预涂铝片,0.2毫米,3%存用0.1M磷酸二氢钾饱和的乙酸乙酯中的异丙醇,通过使用琼脂生化诱导测定法的生物自显影法检测)表明上述的半纯化的N-乙酰-LL-E-33288δI 1样品含有微量未处理的LL-E33288δI 1。将所述半纯化的N-乙酰-LL-E-33288δI 1(160毫克)溶解在1毫升乙酸乙酯中,将在Bio-SilA(20-44μ,Bio-RodLaboratories)柱上层析,用乙酸乙酯填充和平衡。先用乙酸乙酯以流率为3.6毫升/分钟洗脱3.5小时,收集78毫升级分。将洗脱液改成用0.1M磷酸二氢钾饱和的乙酸乙酯中的3%异丙醇,洗脱继续进行3.5小时。如前所述用TLC分析级分,这些含有纯N-乙酰-LL-E-33288δI 1的级分(级分58-64)汇集起来在真空中浓缩至干燥,重新溶解在少量的乙酸乙酯之中,并通过加入己烷进行沉淀。给出118毫***纯的N-乙酰-LL-E-33288δI 1,不含有可检测出量的未酰化的抗冲瘤抗生素。质子磁共振谱如图1所示。
实施例2
N-甲酰-LL-E-33288δI 1的制备和纯化
通过将200微升甲酸滴加入在冰水浴中冷却的400微升乙酸酸酐之中来制备新鲜的乙酸和甲酸的混合酸酐。然后,将反应混合物在50℃加热5分钟以完成酸酐交换,接着保持在0℃,将如上制备的乙酸和甲酸的混合酸酐(100μl)滴加到在冰-水浴中冷却部分纯化的LL-E-33288δI 1的搅拌
甲醇溶液之中(92毫克,45%纯度,30毫升)。让反应混合物在0℃搅拌45分钟,然后将己烷(20毫升)加入反应混合物真空浓缩混合物使其干燥。再在乙酸乙酯中重新溶解残余物,并通过加己烷让其沉淀,给出厚的、稠粘的沉淀物,通过离心收集之。沉淀物重新溶解在少量乙酸乙酯中,并再次加入己烷使之再沉淀,给出粗的N-甲酰-LL-E-33288 δI 1将上述的粗的N-甲酰-LL-E-33288δI 1样品通过制备TLC在硅胶上部分纯化(二块Anatech二氧化硅胶GF预涂板,2000μ,20×20厘米),用以pH7的磷酸缓冲液饱和的乙酸乙酯洗脱剪下所需要带,通过用二氯甲烷∶甲醇(80∶20)洗涤二氧化硅胶回收N-甲酰-LL-E-33288δI 1经过加工给出100毫升部分纯化的N-甲酰-LL-E-33288δI 1。
将上述的部分纯化的N-甲酰-LL-E-33288δI 1溶解在1毫升乙腈∶乙酸铵(35∶65),pH6.0之中,并在Sepralyte C18柱(1.5×20厘米)上层析,用pH6.0乙腈∶0.2M乙酸铵(35∶65)以8毫升/分钟洗脱该柱1.75小时,在UV254nm监视,并收集20毫升级分。用HPLC分析峰级分,收集根据HPLC分析含有纯N-甲酰-LL-E-33288δI的级分,真空浓缩以除去乙腈。用乙酸乙酯抽提含有N-甲酰-LL-E-33288δI 1混浊的水混合物,再浓缩乙酸乙酯相使之浓缩干燥。将残余物再次溶解在二氯甲烷中,经无水硫酸钠干燥,浓缩,并加己烷使之沉淀,给出36.5毫克半纯化的N-甲酰-LL-E-33288δI 1。
TLC分析(E.Merck二氧化硅胶60F254预涂的铝片,0.2毫米,在用0.1M磷酸氢钾饱和的乙酸乙酯中的3%异丙醇,通过使用琼脂生化诱导测定法的生物自显影法检测)显示上述的半纯化的N-甲酰-LL-E-33288δI 1试验含有微量未处理的LL-E33288δI 1和γI 1。将所述半纯化的N-甲酰-LL-E-33288δ(36.5毫克)溶解在1毫升乙酸乙酯中,并在生物硅胶A(20-44μ,Bio-RodLabor-atories)柱(1.5厘米×23厘米)上层析,用乙酸乙酯填充和平衡。先用乙酸乙酯以流率1.2毫升/分钟将柱洗脱2小时,收集6毫升级分。将洗脱液改成乙酸乙酯∶甲醇(93∶3),再继续洗脱2小时。级分通过用TLC分析(E.Flerck二氧化硅胶60F254预涂的铝片,0.2毫米,用0.1M磷酸氢钾饱和的乙酸乙酯中的3%异丙醇,通过喷洒在8%磷酸水溶液中的3%乙酸铜溶液检测),将这些含有纯化的N-甲酰-LL-E-33288δI 1(级分35-38)汇集起来,真空浓缩至干燥。将残余物再溶解在少量的乙酸乙酯之中,通过加入己烷使之沉积。给出N-乙酰-LL-E-33288δI 1试样,它仍被微量未反应的LL-E-33288δI 1污染。试样再次在用乙酸乙酯充填和平衡的Bio-SilA柱(0.8×20厘米)上层析,用乙酸乙酯以流率为1.2毫升/分钟洗脱该柱4小时,收集6毫升馏组分。通过如前所述的TLC分析组分,将这些含有纯的N-甲酰-LL-E-33288δI 1(级分14-33)汇集起来并如前所述进行加工,给出12.2毫***纯的N-甲酰-LL-E-33288δI 1不含有可检测量的未酰化的母抗生素。质子磁共振谱显示在图Ⅱ中。
实施例3
N-甲酰-LL-E-33288δI 1的制备和纯化
将如实施例2中所述方法所制备的新鲜乙酸和甲酸的混合酸酐滴加到在冰-水浴中冷却的被搅拌的部分纯化的LL-E-33288δI 1的甲醇溶液(689毫克,70%纯度,在150毫升中)。让反应混合物在6℃搅拌1个小时,然后将过量的己烷加入,真空将该混合物真空浓缩至大约75毫升。将乙酸乙酯(约200毫升)加到溶液中,并将混合物浓缩到约50毫升,通过加入300毫升己烷沉淀粗的N-甲酰-LL-E-33288δI 1(676毫克)。
将所述的粗的N-甲酰-LL-E-33288δI 1溶解在3毫升乙酸乙酯中,并在用乙酸乙酯填充和平衡的Bio-SilA(40-80μ)柱(2.5×95cm)上层析,用乙酸乙酯以10毫升/分钟洗脱该柱,直至黄色带跑出柱(1.75小时)。然后用0.1M磷酸二氢钾饱和的乙酸乙酯以5毫升/分钟再洗脱5小时。整个层析过程,汇集20毫升级分。级分用TLC分析(E.Merck二氧化硅60F254预涂的铝片,0.2毫米,用0.1M磷酸二氢钾饱和的乙酸乙酯中的3%异丙醇,通过喷洒在8%磷酸水溶液中的3%乙酸乙酯溶液测定)再将含有级分(92-98)的主要N-甲酰-LL-E-33288汇集起来,并通过浓缩和沉积加工,给出294毫克部分纯化的N-甲酰-LL-E-33288δI 1、TLC分析(通过使用琼脂生化诱导测定法的生物自显影法检测)该样品显示出它没有任何未反应的LL-E-33288δI 1。
将部分纯化的N-甲酰-LL-E-33288δI 1溶解在4毫升乙腈∶0.2M乙酸铵(35∶65),pH6.0中,并将其在用pH6.0乙腈∶0.2M乙酸铵(35∶65)平衡的Sepralyte C18柱(1.5×45厘米)上分二批层析。柱同相同的溶剂以8毫升/分钟洗脱3小时,在UV254nm处监视,并收集20毫升级分。通过HPLC分析峰级分,将那些根据HPLC分析含有纯的N-甲酰-LL-E-33288δI 1的汇集起来,并真空浓缩以去除乙腈。将存在于水溶液混合物中的N-甲酰-LL-E-33288δI 1在乙酸乙酯中抽提,再通过浓缩和沉淀加工,给出160毫克纯的N-甲酰-LL-E-33288δI 1。
实施例4
N-乙酰-LL-E-33288γI 1的制备
将乙酸酐滴加至在冰-水浴中冷却的被搅拌的部分纯化的LL-E-33288γI 1的甲醇溶液(1.25克,85%纯度,在100毫升甲醇中)。让反应混合物在0℃搅拌1时,然后慢慢热至室温,并将反应继续进行2个小时。然后将反应混合物真空浓缩并将残余物溶解在二氯甲烷和水各100毫升的混合物之中。用稀释的氢氧化钠水溶液中和水溶液相,以从有机相中去除大部分乙酸。分离有机相,经无水硫酸钠干燥,浓缩至一定的小体积,再通过加入己烷将产品沉积,给出1.18克80%的纯的N-乙酰-LL-E-33288γI 1,它可以按照实例1中所述的下列方法纯化,给出纯的N-乙酰-LL-E-33288γI 1。紫外线光谱,红外光谱,质谱和碳-13谱显示在图Ⅲ-Ⅶ。
实施例5
N-甲酰-LL-E33288γI 1的制备
将如实施例2中所述的方法制备的新鲜乙酸和甲酸的混合酸酐滴加到在冰-水浴中冷却的被搅拌的分析纯的LL-E33288γI 1的甲醇溶液中(49.6毫克,在50毫升甲醇中)。将反应混合物在0℃搅拌1小时,接着在室温过夜。然后将其浓缩干燥,重新溶解在少量的乙酸乙酯中,通过加入己烷沉积该产品。把干的沉淀物重新溶解在10毫升甲醇中,再用乙酸和甲酸的混合酸酐(400μl)处理,反应混合物在室温搅拌2个小时,通过如前所述的浓缩和沉积加工,给出粗的N-甲酰-LL-E-33288δI 1呈米色。通过制备性TLC(二只20cm×20cmAnaltechq锥形的二氧化硅胶GF板,用被0.1M磷酸二氢钾饱和的在乙酸乙酯中的3%异丙醇洗脱)来纯化所述的粗的N-甲酰-LL-E33288γI 1,给出半纯化的N-甲酰-LL-E33288γI 1。
实施例6
N-乙酰-二氢-LL-E33288γI 1的制备
将2毫升甲基碘加入在8搅拌的无水乙醇中的25毫克N-乙酰-LL-E33288γI 1(如实施例4中所述方法制备的)的溶液中,把混合物在冰-水浴中冷却。分二次等量地往其中加入1毫升0.4M的氢硼化钠乙醇溶液。当反应完成时(在加完第二份氢硼化钠溶液以后10分钟),通过加入400μl的4M乙酸的乙醇溶液分解硼酸盐配合物。然膈将混合物浓缩为一种金黄色残余物再继续将金黄色残余物10毫升的乙酸乙酯中,用10毫升二氯甲烷稀释,并再浓缩至干燥。这种残余物重新溶解在乙酸乙酯中,滤掉不溶解的硼酸盐,该溶液浓缩至干燥,给出一种米色固体,将该固体悬浮在4毫升水中,并穿过Bord ElrtTM(国际分析化学(Analytrchem lnternational))C18柱体,随后用水、甲醇∶水(1∶1)以及甲醇各4毫升依次洗脱该柱体。将含有大多数N-乙酰-二氢-LL-E33288γI的甲醇洗脱液,浓缩,给出米色固体,并进一步通过制备性TLC纯化(Analtech二氧化硅胶GF,20×20cm,100μ层厚,乙酸乙酯∶甲醇(97∶3)洗脱液),给出分析纯的N-乙酰-二氢-LL-E33288γI 1。紫外光谱和共振谱显示在图Ⅷ中。
实施例7
N-单甲基丁二酰-LL-E33288γI 1的制备
将丁二酸的单甲基酯的酸酐(55毫克)以三份加到甲醇(2毫升)中的LL-E33288γI 1(12.3毫克)的溶液中,并在室温保持3天。浓缩反应混合物至干燥,将残余物再溶解在少量乙酸乙酯中,加入乙烷使之沉淀。用二***彻底地将浆状沉淀物研碎,然后再溶解在少量乙酸乙酯中,加入二***和己烷使之沉淀,同给出粗的N-单甲基丁二酰-LL-E33288γI 1。
Claims (1)
1、一种制备一般式如下的N-酰基衍生物的方法:
其中W为:
R为H或CH2,R1为氢或
R2为CH3、C2H5或者CH(CH3)2;R4为H且R5为OH,或者R4为OH且R5为H,或者R4和R5一起形成羰基;以及X为碘或溴原子,该N-酰基衍生物是从下式化合物:
即标记为抗生素LL-E33288,αBr 2,βBr 1,γBr 1,α1 2,β2 1,γⅠ 1,δⅠ 1以及它们的二氢对应物制备而得的,其特征在于,将抗生素H-N-W(其中,R4和R5一起形成羰基)与合适的取代的酸酐,酰氯、乙酸和甲酸的混合酸酐或丁二烯酸的单甲酯的酸酐反应,反应在甲醇中、于-5℃~5℃的温度下进行1个小时,再在室温下进行一至二十四小时;用已烷从乙酸乙酯中沉淀;
层析纯化;
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/338,928 US5079233A (en) | 1987-01-30 | 1989-04-14 | N-acyl derivatives of the LL-E33288 antitumor antibiotics, composition and methods for using the same |
US07/338928 | 1989-04-14 | ||
US07/338,928 | 1989-04-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1048390A CN1048390A (zh) | 1991-01-09 |
CN1027267C true CN1027267C (zh) | 1995-01-04 |
Family
ID=23326735
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN90102100A Expired - Lifetime CN1027267C (zh) | 1989-04-14 | 1990-04-14 | Ll-e33288抗肿瘤抗生素的n-酰基衍生物的制备方法 |
Country Status (23)
Country | Link |
---|---|
US (1) | US5079233A (zh) |
EP (2) | EP0392376B1 (zh) |
JP (1) | JP3083309B2 (zh) |
KR (1) | KR0149493B1 (zh) |
CN (1) | CN1027267C (zh) |
AT (2) | ATE207926T1 (zh) |
AU (1) | AU627863B2 (zh) |
CA (1) | CA2014472C (zh) |
CZ (2) | CZ284618B6 (zh) |
DE (2) | DE69034194T2 (zh) |
DK (2) | DK1097937T3 (zh) |
ES (2) | ES2240000T3 (zh) |
FI (1) | FI97889C (zh) |
HK (2) | HK1035540A1 (zh) |
IE (1) | IE20011013A1 (zh) |
IL (1) | IL93732A (zh) |
NO (1) | NO172938C (zh) |
NZ (1) | NZ233149A (zh) |
PH (1) | PH27361A (zh) |
PT (1) | PT93715B (zh) |
SG (1) | SG47857A1 (zh) |
SK (1) | SK281179B6 (zh) |
ZA (1) | ZA902839B (zh) |
Families Citing this family (125)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5712374A (en) * | 1995-06-07 | 1998-01-27 | American Cyanamid Company | Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates |
WO1997014421A1 (en) * | 1995-10-20 | 1997-04-24 | University Of Utah Research Foundation | Namenamicin, an enediyne antitumor antibiotic from the marine ascidian polysyncraton lithostrotum |
US20040009535A1 (en) | 1998-11-27 | 2004-01-15 | Celltech R&D, Inc. | Compositions and methods for increasing bone mineralization |
ES2350454T3 (es) | 1998-11-27 | 2011-01-24 | Ucb Pharma S.A. | Composiciones y métodos para incrementar la mineralización de la sustancia ósea. |
US20040001827A1 (en) * | 2002-06-28 | 2004-01-01 | Dennis Mark S. | Serum albumin binding peptides for tumor targeting |
US20060228364A1 (en) * | 1999-12-24 | 2006-10-12 | Genentech, Inc. | Serum albumin binding peptides for tumor targeting |
CA2390691C (en) * | 1999-12-24 | 2016-05-10 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US20050287153A1 (en) * | 2002-06-28 | 2005-12-29 | Genentech, Inc. | Serum albumin binding peptides for tumor targeting |
US20040023910A1 (en) * | 2001-09-28 | 2004-02-05 | Zhiming Zhang | Use of cyr61 in the treatment and diagnosis of human uterine leiomyomas |
US20110045005A1 (en) | 2001-10-19 | 2011-02-24 | Craig Crowley | Compositions and methods for the treatment of tumor of hematopoietic origin |
PL224001B1 (pl) | 2002-05-02 | 2016-11-30 | Wyeth Corp | Sposób wytwarzania stabilnej liofilizowanej kompozycji obejmującej monomeryczne koniugaty pochodna kalicheamycyny/przeciwciało anty-CD22, kompozycja otrzymana tym sposobem oraz jej zastosowanie |
ES2586401T3 (es) | 2003-06-16 | 2016-10-14 | Ucb Pharma S.A. | Anticuerpos específicos para la esclerostina y métodos para aumentar la mineralización ósea |
WO2005012531A2 (en) * | 2003-08-01 | 2005-02-10 | Genentech, Inc. | Antibody cdr polypeptide sequences with restricted diversity |
US20050282168A1 (en) * | 2003-09-29 | 2005-12-22 | Wyeth | Cell surface molecules as markers and therapeutic agents against kidney cancers |
CA3062320C (en) | 2003-11-06 | 2022-11-15 | Seattle Genetics, Inc. | Monomethylvaline compounds capable of conjugation to ligands |
BRPI0417107A (pt) | 2003-12-19 | 2007-02-06 | Genentech Inc | fragmento de anticorpo, métodos de preparação do fragmento de anticorpo, ácido nucléico isolado, composições, célula hospedeira e métodos de fabricação e de geração de fragmento de anticorpo |
TW200539855A (en) * | 2004-03-15 | 2005-12-16 | Wyeth Corp | Calicheamicin conjugates |
NZ579482A (en) | 2004-06-01 | 2011-02-25 | Genentech Inc | Antibody drug conjugates and methods |
US20060222850A1 (en) * | 2005-04-01 | 2006-10-05 | The University Of Chicago | Synthesis of a self assembled hybrid of ultrananocrystalline diamond and carbon nanotubes |
PT2990422T (pt) | 2004-09-03 | 2018-10-18 | Genentech Inc | Antagonistas humanizados anti-beta7 e suas utilizações |
BRPI0515113A (pt) * | 2004-09-10 | 2008-07-01 | Wyeth Corp | anticorpos anti-5t4 humanizados e conjugados de anticorpo anti-5t4/caliqueamicina |
PL1791565T3 (pl) | 2004-09-23 | 2016-10-31 | Modyfikowane cysteiną przeciwciała i koniugaty | |
JP2008515889A (ja) * | 2004-10-05 | 2008-05-15 | ジェネンテック・インコーポレーテッド | 毒性の低下した治療剤 |
EP1817059A2 (en) | 2004-12-01 | 2007-08-15 | Genentech, Inc. | Conjugates of 1,8-bis-naphthalimides with an antibody |
US20070003559A1 (en) * | 2005-07-01 | 2007-01-04 | Wyeth | Methods of determining pharmacokinetics of targeted therapies |
EP1957531B1 (en) | 2005-11-07 | 2016-04-13 | Genentech, Inc. | Binding polypeptides with diversified and consensus vh/vl hypervariable sequences |
WO2007064919A2 (en) * | 2005-12-02 | 2007-06-07 | Genentech, Inc. | Binding polypeptides with restricted diversity sequences |
AU2006338198B2 (en) * | 2005-12-02 | 2012-04-26 | Genentech, Inc. | Binding polypeptides and uses thereof |
AU2006321975A1 (en) * | 2005-12-06 | 2007-06-14 | Wyeth | Interleukin-11 compositions and methods of use |
BRPI0620697A2 (pt) | 2005-12-15 | 2011-11-22 | Genentech Inc | anticorpos isolados, molécula de ácido nucléico, vetor, célula hopedeira, linhagem celular, método para a produção de um anticorpo, composição, métodos para identificar a presença de poliubiquitina, para tratar uma doença, para determinar a presença de uma poliubiquitina, para separar as proteìnas poliubiquitinadas, para determinar a função e/ou atividade da poliubiquitina em uma célula e para determinar a função e/ou atividade da poliubiquitina em uma amostra e fragmento de ligação ao antìgeno |
CN103360496B (zh) | 2006-01-05 | 2015-11-18 | 健泰科生物技术公司 | 抗ephb4抗体及其使用方法 |
TW200806685A (en) * | 2006-02-21 | 2008-02-01 | Wyeth Corp | Processes for the convergent synthesis of calicheamicin derivatives |
AU2007226696C1 (en) | 2006-03-10 | 2016-02-04 | Wyeth Llc | Anti-5T4 antibodies and uses thereof |
AR059851A1 (es) | 2006-03-16 | 2008-04-30 | Genentech Inc | Anticuerpos de la egfl7 y metodos de uso |
MX2008015132A (es) | 2006-05-30 | 2008-12-10 | Genentech Inc | Anticuerpos e inmunoconjugados y sus usos. |
US8436147B2 (en) | 2006-10-27 | 2013-05-07 | Genentech, Inc. | Antibodies and immunoconjugates and uses therefor |
US7834154B2 (en) | 2007-02-09 | 2010-11-16 | Genentech, Inc. | Anti-ROBO4 antibodies and uses therefor |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
SI2155258T1 (sl) | 2007-05-22 | 2017-10-30 | Wyeth Llc | Izboljšani postopki za izdelavo hidrazidov |
PE20090309A1 (es) * | 2007-06-04 | 2009-04-18 | Wyeth Corp | Conjugado portador-caliqueamicina y un metodo de deteccion de caliqueamicina |
PE20090321A1 (es) | 2007-06-04 | 2009-04-20 | Genentech Inc | Anticuerpos anti-notch1 nrr, metodo de preparacion y composicion farmaceutica |
AR069501A1 (es) | 2007-11-30 | 2010-01-27 | Genentech Inc | Anticuerpos anti- vegf (factor de crecimiento endotelial vascular) |
CA2711736A1 (en) | 2008-01-18 | 2009-07-23 | Medimmune, Llc | Cysteine engineered antibodies for site-specific conjugation |
KR101924831B1 (ko) | 2008-04-09 | 2018-12-05 | 제넨테크, 인크. | 면역 관련 질병의 치료를 위한 신규한 조성물 및 방법 |
BRPI0908665A2 (pt) * | 2008-05-16 | 2020-08-18 | Genentech Inc | método para a determinação da eficácia de um antagonista de integrina beta7 para o tratamento de um distúrbio inflamatório gastrointestinal, método de predição da responsividade de um paciente, método para a determinaçao da dosagem de um antagonista de integrina beta7, método para determinaçao do regime terapêutico de um antagonista de integrina beta7, método para predição de prognóstico de uma doença inflamatória intestinal, método de elaboração de um tratamento e método de identificação de uma população de linfócitos |
EP2318832B1 (en) | 2008-07-15 | 2013-10-09 | Academia Sinica | Glycan arrays on ptfe-like aluminum coated glass slides and related methods |
SG10201402742YA (en) | 2009-03-20 | 2014-08-28 | Genentech Inc | Bispecific anti-her antibodies |
DK3702371T3 (da) | 2009-03-25 | 2022-11-28 | Genentech Inc | Anti-FGFR3-antistoffer og fremgangsmåder ved anvendelse af disse |
CN102802661B (zh) | 2009-06-22 | 2016-01-13 | 米迪缪尼有限公司 | 用于位点特异性偶联的工程改造的Fc区 |
EP2473522B1 (en) | 2009-09-02 | 2016-08-17 | Genentech, Inc. | Mutant smoothened and methods of using the same |
BR112012009245A2 (pt) | 2009-10-19 | 2019-09-24 | Genentech Inc | ''anticorpo,polinucleotídeo,celula hospedeira,método para fabricar um anticorpo,imunoconjugado,formulação farmacêutica e uso do anticorpo'' |
ES2534646T3 (es) | 2009-10-22 | 2015-04-27 | F. Hoffmann-La Roche Ag | Anticuerpos anti-hepsina y métodos de uso de los mismos |
EP2490718B1 (en) | 2009-10-22 | 2016-01-13 | F.Hoffmann-La Roche Ag | Methods and compositions for modulating hepsin activation of macrophage-stimulating protein |
WO2011056494A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor-like kinase-1 antagonist and vegfr3 antagonist combinations |
WO2011056497A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor type iib compositions and methods of use |
WO2011056502A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Bone morphogenetic protein receptor type ii compositions and methods of use |
RU2585488C2 (ru) | 2009-11-05 | 2016-05-27 | Дженентек, Инк. | Способы и композиция для секреции гетерологичных полипептидов |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
WO2011071577A1 (en) | 2009-12-11 | 2011-06-16 | Genentech, Inc. | Anti-vegf-c antibodies and methods using same |
MX2012007379A (es) | 2009-12-23 | 2012-08-31 | Genentech Inc | Anticuerpos anti-bv8 y usos de los mismos. |
KR101723615B1 (ko) | 2010-01-12 | 2017-04-06 | 한상선 | 천연 한약재를 이용한 샴푸 조성물 |
KR101510413B1 (ko) | 2010-02-08 | 2015-04-08 | 어젠시스 인코포레이티드 | 161p2f10b 단백질에 결합하는 항체 약물 컨쥬게이트 |
US10338069B2 (en) | 2010-04-12 | 2019-07-02 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
AU2011261362B2 (en) | 2010-06-03 | 2016-06-09 | Genentech, Inc. | Immuno-pet imaging of antibodies and immunoconjugates and uses therefor |
TW202344270A (zh) | 2010-09-29 | 2023-11-16 | 美商艾澤西公司 | 與191p4d12蛋白結合之抗體藥物共軛物(adc) |
US8481680B2 (en) | 2010-10-05 | 2013-07-09 | Genentech, Inc. | Mutant smoothened and methods of using the same |
WO2012092539A2 (en) | 2010-12-31 | 2012-07-05 | Takeda Pharmaceutical Company Limited | Antibodies to dll4 and uses thereof |
WO2012103165A2 (en) | 2011-01-26 | 2012-08-02 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
PE20142312A1 (es) | 2011-10-28 | 2015-01-25 | Genentech Inc | Combinaciones terapeuticas y metodos para tratar el melanoma |
EP2589609A1 (en) | 2011-11-03 | 2013-05-08 | Pierre Fabre Medicament | Antigen binding protein and its use as addressing product for the treatment of cancer |
CN102584915B (zh) * | 2011-12-31 | 2014-07-23 | 沈阳药科大学 | 一种芳香酸类化合物及其用途 |
CA2862979A1 (en) | 2012-01-09 | 2013-07-18 | The Scripps Research Institute | Humanized antibodies with ultralong cdr3s |
AU2013208003B2 (en) | 2012-01-09 | 2017-12-14 | The Scripps Research Institute | Ultralong complementarity determining regions and uses thereof |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
ES2723885T3 (es) | 2012-07-19 | 2019-09-03 | Daiichi Sankyo Co Ltd | Anticuerpos anti-Siglec-15 |
CA2880007C (en) | 2012-07-25 | 2021-12-28 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
JP6302909B2 (ja) | 2012-08-18 | 2018-03-28 | アカデミア シニカAcademia Sinica | シアリダーゼの同定および画像化のための細胞透過性プローブ |
BR112015003751B1 (pt) | 2012-08-23 | 2021-12-07 | Agensys, Inc. | Conjugados anticorpo-fármaco, uso dos mesmos, composição farmacêutica, vetor, anticorpos ou fragmentos de ligação ao antígeno, método para produzir os mesmos e anticorpo ou fragmento de ligação ao antígeno que se liga a 158p1d7 |
EP2914630B1 (en) | 2012-11-05 | 2021-03-03 | Pierre Fabre Medicament | Novel antigen binding proteins and their use as addressing product for the treatment of cancer |
WO2014210397A1 (en) | 2013-06-26 | 2014-12-31 | Academia Sinica | Rm2 antigens and use thereof |
WO2014210564A1 (en) | 2013-06-27 | 2014-12-31 | Academia Sinica | Glycan conjugates and use thereof |
US10640574B2 (en) | 2013-07-18 | 2020-05-05 | Taurus Biosciences, Llc | Humanized antibodies with ultralong complementary determining regions |
WO2015017146A2 (en) | 2013-07-18 | 2015-02-05 | Fabrus, Inc. | Antibodies with ultralong complementarity determining regions |
CN105722534B (zh) | 2013-08-01 | 2019-05-31 | 艾更斯司股份有限公司 | 结合cd37蛋白的抗体药物偶联物(adc) |
KR102298172B1 (ko) | 2013-09-06 | 2021-09-06 | 아카데미아 시니카 | 변화된 글리코실 그룹을 갖는 당지질을 사용한 인간 iNKT 세포 활성화 |
CN105828841A (zh) | 2013-11-04 | 2016-08-03 | 辉瑞大药厂 | 抗-efna4抗体-药物缀合物 |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2015109180A2 (en) | 2014-01-16 | 2015-07-23 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
KR20160111964A (ko) | 2014-01-29 | 2016-09-27 | 샹하이 헨그루이 파마수티컬 컴퍼니 리미티드 | 리간드-세포독성 약물 접합체, 이의 제조방법 및 이의 용도 |
ES2694857T3 (es) | 2014-02-04 | 2018-12-27 | Genentech, Inc. | Smoothened mutante y métodos de uso de la misma |
CN106415244B (zh) | 2014-03-27 | 2020-04-24 | 中央研究院 | 反应性标记化合物及其用途 |
KR20220018620A (ko) | 2014-04-25 | 2022-02-15 | 피에르 파브르 메디카먼트 | Igf-1r 항체 및 암 치료를 위한 운반체를 어드레싱하는 그의 용도 |
HUE053287T2 (hu) | 2014-04-30 | 2021-06-28 | Pfizer | PTK-7 elleni ellenanyag-drog konjugátumok |
EP3149045B1 (en) | 2014-05-27 | 2023-01-18 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
KR102512592B1 (ko) | 2014-05-27 | 2023-03-21 | 아카데미아 시니카 | 항-her2 글리코항체 및 이의 용도 |
EP3149036A4 (en) | 2014-05-27 | 2017-12-27 | Academia Sinica | Anti-cd20 glycoantibodies and uses thereof |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
CA2950433A1 (en) | 2014-05-28 | 2015-12-03 | Academia Sinica | Anti-tnf-alpha glycoantibodies and uses thereof |
WO2016034968A1 (en) | 2014-09-02 | 2016-03-10 | Pfizer Inc. | Therapeutic antibody |
US9879042B2 (en) | 2014-09-08 | 2018-01-30 | Academia Sinica | Human iNKT cell activation using glycolipids |
RU2017119185A (ru) | 2014-11-05 | 2018-12-05 | Дженентек, Инк. | Антитела против fgfr2/3 и способы их применения |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
US10342858B2 (en) | 2015-01-24 | 2019-07-09 | Academia Sinica | Glycan conjugates and methods of use thereof |
CN112430268A (zh) | 2015-01-24 | 2021-03-02 | 中央研究院 | 癌症标记及其使用方法 |
CA2975875A1 (en) | 2015-02-04 | 2016-08-11 | Genentech, Inc. | Mutant smoothened and methods of using the same |
MA45326A (fr) | 2015-10-20 | 2018-08-29 | Genentech Inc | Conjugués calichéamicine-anticorps-médicament et procédés d'utilisation |
WO2017095823A1 (en) | 2015-11-30 | 2017-06-08 | The Regents Of The University Of California | Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen |
AU2017213826A1 (en) | 2016-02-04 | 2018-08-23 | Curis, Inc. | Mutant smoothened and methods of using the same |
WO2017153432A1 (en) | 2016-03-07 | 2017-09-14 | Pierre Fabre Medicament | A new universal method to capture and analyze adcs for characterization of drug distribution and the drug-to-antibody ratio in biological samples |
CA3016170A1 (en) | 2016-03-08 | 2017-09-14 | Academia Sinica | Methods for modular synthesis of n-glycans and arrays thereof |
WO2018009811A1 (en) | 2016-07-08 | 2018-01-11 | Genentech, Inc. | Use of human epididymis protein 4 (he4) for assessing responsiveness of muc 16-positive cancer treatment |
CN109963868B (zh) | 2016-08-22 | 2023-11-14 | 醣基生医股份有限公司 | 抗体、结合片段及使用方法 |
US20190048073A1 (en) | 2017-07-20 | 2019-02-14 | Pfizer Inc. | Anti-gd3 antibodies and antibody-drug conjugates |
EP3720504A1 (en) | 2017-12-06 | 2020-10-14 | Synaffix B.V. | Enediyne conjugates |
CN112739340A (zh) | 2018-07-23 | 2021-04-30 | 美真达治疗公司 | 抗cd5抗体药物缀合物(adc)在同种异体细胞疗法中的用途 |
CA3114137A1 (en) | 2018-09-26 | 2020-04-02 | Jiangsu Hengrui Medicine Co., Ltd. | Ligand-drug conjugate of exatecan analogue, preparation method therefor and application thereof |
US20220267452A1 (en) | 2019-07-12 | 2022-08-25 | Chugai Seiyaku Kabushiki Kaisha | Anti-mutation type fgfr3 antibody and use therefor |
US20220306736A1 (en) | 2019-09-04 | 2022-09-29 | Y-Biologics Inc. | Anti-vsig4 antibody or antigen binding fragment and uses thereof |
JP2023511163A (ja) | 2020-01-22 | 2023-03-16 | 上海森輝医薬有限公司 | エリブリン誘導体の薬物複合体、その調製方法及びその医薬的応用 |
MX2022011770A (es) | 2020-03-25 | 2022-10-18 | Jiangsu Hengrui Pharmaceuticals Co Ltd | Composicion farmaceutica que contiene un conjugado de anticuerpo-farmaco y uso de la misma. |
TW202144014A (zh) | 2020-03-25 | 2021-12-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 一種抗體藥物偶聯物的製備方法 |
TW202302645A (zh) | 2021-03-03 | 2023-01-16 | 法商皮爾法伯製藥公司 | 抗vsig4抗體或抗原結合片段及其用途 |
CA3218086A1 (en) | 2021-04-30 | 2022-11-03 | Pierre Fabre Medicament | New stable anti-vista antibody |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5644076B2 (zh) * | 1973-07-12 | 1981-10-16 | ||
EP0276485B1 (en) * | 1987-01-30 | 2002-06-12 | American Cyanamid Company | Dihydro derivatives of LL-E33288 antibiotics |
US4837206A (en) * | 1987-04-29 | 1989-06-06 | Bristol-Myers Company | Esperamicin derivatives |
ES2061586T3 (es) * | 1987-10-30 | 1994-12-16 | American Cyanamid Co | Analogos disulfuricos de agentes antitumorales ll-e33288. |
IL115770A (en) * | 1989-04-14 | 1999-03-12 | American Cyanamid Co | Substituted disulfides of formula q-sp-ss-w their preparation and use for inhibiting the growth of tumours and for treating bacterial infections |
-
1989
- 1989-04-14 US US07/338,928 patent/US5079233A/en not_active Expired - Lifetime
-
1990
- 1990-03-13 IL IL9373290A patent/IL93732A/en not_active IP Right Cessation
- 1990-03-30 NZ NZ233149A patent/NZ233149A/en unknown
- 1990-04-06 AT AT90106601T patent/ATE207926T1/de not_active IP Right Cessation
- 1990-04-06 DE DE69034194T patent/DE69034194T2/de not_active Expired - Fee Related
- 1990-04-06 ES ES00128100T patent/ES2240000T3/es not_active Expired - Lifetime
- 1990-04-06 AT AT00128100T patent/ATE297405T1/de not_active IP Right Cessation
- 1990-04-06 ES ES90106601T patent/ES2162783T3/es not_active Expired - Lifetime
- 1990-04-06 DK DK00128100T patent/DK1097937T3/da active
- 1990-04-06 EP EP90106601A patent/EP0392376B1/en not_active Expired - Lifetime
- 1990-04-06 DE DE69033839T patent/DE69033839T2/de not_active Expired - Lifetime
- 1990-04-06 SG SG1996004747A patent/SG47857A1/en unknown
- 1990-04-06 DK DK90106601T patent/DK0392376T3/da active
- 1990-04-06 EP EP00128100A patent/EP1097937B1/en not_active Expired - Lifetime
- 1990-04-10 PT PT93715A patent/PT93715B/pt not_active IP Right Cessation
- 1990-04-11 PH PH40366A patent/PH27361A/en unknown
- 1990-04-11 NO NO901654A patent/NO172938C/no not_active IP Right Cessation
- 1990-04-12 CA CA002014472A patent/CA2014472C/en not_active Expired - Lifetime
- 1990-04-12 IE IE20011013A patent/IE20011013A1/en not_active IP Right Cessation
- 1990-04-12 ZA ZA902839A patent/ZA902839B/xx unknown
- 1990-04-12 JP JP02095244A patent/JP3083309B2/ja not_active Expired - Lifetime
- 1990-04-12 FI FI901865A patent/FI97889C/fi active IP Right Grant
- 1990-04-12 AU AU53248/90A patent/AU627863B2/en not_active Expired
- 1990-04-13 SK SK1883-90A patent/SK281179B6/sk not_active IP Right Cessation
- 1990-04-13 KR KR1019900005138A patent/KR0149493B1/ko not_active IP Right Cessation
- 1990-04-13 CZ CS901883A patent/CZ284618B6/cs not_active IP Right Cessation
- 1990-04-13 CZ CZ0053598A patent/CZ297668B6/cs not_active IP Right Cessation
- 1990-04-14 CN CN90102100A patent/CN1027267C/zh not_active Expired - Lifetime
-
1998
- 1998-11-24 HK HK01105824A patent/HK1035540A1/xx not_active IP Right Cessation
- 1998-11-24 HK HK98112287A patent/HK1011368A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1027267C (zh) | Ll-e33288抗肿瘤抗生素的n-酰基衍生物的制备方法 | |
CN1133642C (zh) | 核苷5’-硫代磷酰氨基酸酯化合物 | |
CN1101944A (zh) | 制备带羟基或酰氧基的紫杉烷的酶方法及其应用 | |
CN1044299A (zh) | 抗菌素bu-3608的丝氨酸类似物 | |
CN100344647C (zh) | 磷酸化肽的标记方法及选择吸附方法,使用于该方法的配位化合物、该配位化合物的制造方法及该配位化合物的原料化合物 | |
CN1108657A (zh) | 雪花胺衍生物、其制备方法及其作为药物的用途 | |
CN1176644A (zh) | 路易斯x衍生物及其制备方法 | |
CN1058294C (zh) | 路斯绰达克星化合物的制备方法 | |
CN1492859A (zh) | 嘧啶无环核苷衍生物、其制备方法及其用途 | |
CN1031532A (zh) | 杂环化合物 | |
CN1171992C (zh) | L-脯氨酸4位羟基化酶的制备方法 | |
CN1109041C (zh) | 制备取代的二硫化衍生物及其靶形式的方法 | |
CN1918143A (zh) | 连接子化合物、配体络合物和它们的制备方法 | |
CN1106401A (zh) | 新的大环内酯类化合物及其应用 | |
CN1069969A (zh) | 作为兴奋性氨基酸神经递质拮抗剂的合成芳基多胺 | |
CN1671723A (zh) | 新的偕二氟化化合物、其制备方法及其应用 | |
CN86106534A (zh) | 碳环嘌呤核苷,其制备及用途 | |
CN1028997C (zh) | 新蒽环型药物衍生物或其药学上允许的酸加成盐的制法 | |
CN1896065A (zh) | 1-(3′,4′,5′-三取代苯基)-异喹啉类化合物及其制备方法和用途 | |
CN100343234C (zh) | 用于检测氨肽酶的活性和/或从革兰氏阴性菌中区分革兰氏阳性菌的酶底物,含有该酶底物的培养基及其应用 | |
CN1213400A (zh) | N-保护d-脯氨酸衍生物的制备方法 | |
CN1018646B (zh) | 苷的制备方法 | |
CN1085254C (zh) | 顺式-3-羟基-l-脯氨酸的制造方法 | |
CN1105367A (zh) | 葡糖胺衍生物及该衍生物和其合成中间体的制备方法 | |
CN1192999C (zh) | 用作葡萄糖-6-磷酸移位酶抑制剂的芳族二酮基衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
OR01 | Other related matters | ||
C56 | Change in the name or address of the patentee |
Owner name: WYETH(AMERICAN HOME PRODUCTS) HOLDING CO., LTD. Free format text: FORMER NAME OR ADDRESS: AMERICAN CYANAMID COMPANY |
|
CP01 | Change in the name or title of a patent holder |
Patentee after: Wyeth Holding Corp. Patentee before: American Cyanamid Co. |
|
C17 | Cessation of patent right | ||
CX01 | Expiry of patent term |
Granted publication date: 19950104 |