公开(公告)号：US08258331B2

公开(公告)日：2012-09-04

申请号：US13087862

申请日：2011-04-15

申请人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu ,  Yu Chang

发明人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu ,  Yu Chang

IPC分类号： C07F7/22 ,  C07C217/00

CPC分类号： C07F7/2208

摘要： A method for preparation of N-methyl-3-(2-tributylstannylphenoxy)-3-phenylpropanamine is provided, which includes formation of N-methyl-3-(2-tributylstannylphenoxy)-3-phenylpropanamine, useful as a precursor of a norepinephrine transporter (NET) contrast label [123Iodine](R)—N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine ([123I]MIPP) with a leaving group Bu3Sn.

摘要翻译： 提供了制备N-甲基-3-（2-三丁基甲锡烷基苯氧基）-3-苯基丙胺的方法，包括形成N-甲基-3-（2-三丁基甲锡烷基苯氧基）-3-苯基丙胺，可用作去甲肾上腺素的前体 转运蛋白（NET）对比标记物[123碘]（R）-N-甲基-3-（2-碘苯氧基）-3-苯基丙胺（[123 I] MIPP）与离去基团Bu 3 Sn。

公开(公告)号：US20100056804A1

公开(公告)日：2010-03-04

申请号：US12203214

申请日：2008-09-03

申请人： Show-Wen LIU ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu ,  Cheng-Hsien Lin ,  Tsai-Yueh Luo ,  Lie-Hang Shen ,  Hwa-Jan Chen

发明人： Show-Wen LIU ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu ,  Cheng-Hsien Lin ,  Tsai-Yueh Luo ,  Lie-Hang Shen ,  Hwa-Jan Chen

IPC分类号： C07D207/30

CPC分类号： C07D207/46 ,  Y02P20/55

摘要： A compound containing carboxylate ester and N2S2 ligand bi-functional groups and a manufacturing method thereof are disclosed. The S in the N2S2 ligand of the compound containing carboxylate ester and N2S2 ligand bi-functional groups includes a protective group so as to avoid to be oxidized and easy storage. In a complex reaction, the protective group is automatically released As to the active carboxylate ester, it is for reacting with compounds having amino groups such as amines, amino acids, peptides, or protein etc while the N2S2 ligand is for bonding with technetium or rhenium so as to form neutral complex. The compound containing carboxylate ester and N2S2 ligand bi-functional groups is applied to radiopharmaceuticals such as contrast agents for tissues and target agents.

摘要翻译： 公开了含有羧酸酯和N 2 S 2配位体双官能团的化合物及其制备方法。 含有羧酸酯和N2S2配位体双官能团的化合物的N2S2配体中的S包括保护基，以避免被氧化并容易储存。 在复杂的反应中，保护基被自动释放对于活性羧酸酯，它是与具有氨基的化合物如胺，氨基酸，肽或蛋白质等反应，而N2S2配体与锝或铼键合 从而形成中性复合物。 含有羧酸酯和N 2 S 2配位体双功能基团的化合物被应用于放射性药物，例如用于组织和靶标的造影剂。

公开(公告)号：US20140066609A1

公开(公告)日：2014-03-06

申请号：US13604353

申请日：2012-09-05

申请人： Kuei-Lin LU ,  Yu CHANG ,  Cheng-Fang HSU ,  Mei-Hui WANG ,  Wuu-Jyh LIN

发明人： Kuei-Lin LU ,  Yu CHANG ,  Cheng-Fang HSU ,  Mei-Hui WANG ,  Wuu-Jyh LIN

IPC分类号： C07H15/04

CPC分类号： C07H15/04 ,  C07H1/00 ,  Y02P20/55

摘要： A novel synthesis method of Glyco-drug radiotracer precursor is revealed. After completing synthesis of Z-Gly-ah (main structure), galactosamine GalNAc(OAc)4 is added to have coupling reaction. Then a product is separated directly from dichloromethane. Thus loss of galactosamine during extraction with liquid chromatography is reduced. Moreover, instead of trifluoroacetyl group, carbobenzoxy (abbreviated as Cbz or Z) is used as a protecting group to ensure uniformity of the phase. The cost and synthesis time are also dramatically reduced.

摘要翻译： 揭示了一种新型的糖 - 放射性示踪剂前体的合成方法。 完成Z-Gly-ah（主要结构）合成后，加入半乳糖胺GalNAc（OAc）4进行偶联反应。 然后将产物直接从二氯甲烷中分离出来。 因此，用液相色谱法提取过程中半乳糖胺的损失降低。 此外，代替三氟乙酰基，使用苄氧羰基（缩写为Cbz或Z）作为保护基，以确保相的均匀性。 成本和合成时间也大大降低。

公开(公告)号：US08551447B2

公开(公告)日：2013-10-08

申请号：US13087664

申请日：2011-04-15

申请人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Yu Chang ,  Cheng-Fang Hsu ,  Tsyh-Lang Lin

发明人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Yu Chang ,  Cheng-Fang Hsu ,  Tsyh-Lang Lin

IPC分类号： A61K38/00

CPC分类号： C07H15/04

摘要： A bifunctional compound with a monosaccharide and a N2S2 ligand, and more particularly, a bifunctional compound with a N2S2 ligand and aminohexylacetyl galactosamine (ah-GalNAc4) is provided. A method for preparing the bifunctional compound with a monosaccharide and a N2S2 ligand is also provided, including activating a carboxyl group in an organic ligand, reacting the activated carboxyl group with a galactopyranoside through amidation, and then hydrolyzing. The bifunctional compound of the present invention is widely useful in nuclear medicine for preparation of liver imaging agents for assisting in correct diagnosis of diseases.

摘要翻译： 提供了具有单糖和N2S2配体的双官能化合物，更具体地，提供了具有N 2 S 2配体和氨基己基乙酰基半乳糖胺（ah-GalNAc 4）的双官能化合物。 还提供了用单糖和N 2 S 2配体制备双功能化合物的方法，包括活化有机配体中的羧基，通过酰胺化使活化的羧基与吡喃半乳糖苷反应，然后水解。 本发明的双功能化合物在制备用于辅助正确诊断疾病的肝成像剂的核医学中广泛有用。

公开(公告)号：US08329879B2

公开(公告)日：2012-12-11

申请号：US12558911

申请日：2009-09-14

申请人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu

发明人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu

IPC分类号： C07F13/00

CPC分类号： C07C323/41 ,  C07F13/005

摘要： H3LMN series compounds used as radioactive agents for treatment of liver cancer and a manufacturing method thereof are revealed. 2-thioethylamine hydrochloride is reacted with triphenylmethanol for protection of thiol to obtain 2-[(triphenylmethyl)thio]ethylamine. Then obtain N-[2-((triphenylmethyl)thio)ethyl]chloroacetamide by a transamidation reaction between 2-[(triphenylmethyl)thio]ethylamine and chloroactyl chloride. Next produce a amine-amide-thiol ligand-N-[2-((triphenylmethyl)thio)ethyl][2-((triphenylmethyl)thio)ethylamino]acetamide by a substitution reaction of N-[2-((triphenylmethyl)thio)ethyl]chloroacetamide and 2-[(triphenylmethyl)thio]ethylamine. After respective reaction with 1-bromotetradecane, 1-bromohexadecane and ethyl 16-bromohexadecanoate, H3LMN series compounds are obtained. These amine-amide-dithiols quadridentate ligands can react with MO3+ (M=Tc or Re) to produce electrically neutral complexes. The complexes have high lipophilicity, allowing them soluble in lipiodol to be applied to radiation therapy for liver cancer.

摘要翻译： 揭示了用作肝癌治疗放射剂的H3LMN系列化合物及其制造方法。 将2-硫代乙胺盐酸盐与三苯基甲醇反应以保护硫醇，得到2 - [（三苯基甲基）硫代]乙胺。 然后通过2 - [（三苯基甲基）硫代]乙胺和氯代酰氯的酰胺化反应获得N- [2 - （（三苯基甲基）硫基）乙基]氯乙酰胺。 接着通过N- [2 - （（三苯基甲基）硫代）的取代反应生成胺 - 酰胺 - 硫醇配体-N- [2 - （（三苯基甲基）硫代）乙基] [2 - （（三苯基甲基）硫基）乙基氨基] ）乙基]氯乙酰胺和2 - [（三苯甲基）硫基]乙胺。 在与1-溴十四烷，1-溴十六烷和16-溴十六烷酸乙酯反应后，得到H3LMN系列化合物。 这些胺 - 酰胺 - 二硫醇三元配体可以与MO3 +（M = Tc或Re）反应以产生电中性络合物。 复合物具有高亲脂性，使其可溶于碘油以适用于放射治疗肝癌。

公开(公告)号：US08048405B2

公开(公告)日：2011-11-01

申请号：US12354815

申请日：2009-01-16

申请人： Tsai-Yueh Luo ,  I-Chung Tang ,  Show-Wen Liu ,  Yu-Lung Wu ,  Cheng-Hsien Lin ,  Cheng-Fang Hsu ,  Kwei-Luen Hsu ,  Chang-Mau Sheng ,  Ching-Jun Liou ,  Te-Sheng Liang

发明人： Tsai-Yueh Luo ,  I-Chung Tang ,  Show-Wen Liu ,  Yu-Lung Wu ,  Cheng-Hsien Lin ,  Cheng-Fang Hsu ,  Kwei-Luen Hsu ,  Chang-Mau Sheng ,  Ching-Jun Liou ,  Te-Sheng Liang

IPC分类号： A61K49/00

CPC分类号： A61K51/0478 ,  A61K49/0438

摘要： A radioactive mixture and a manufacturing method thereof are disclosed. The radioactive mixture (188Re-MN/Lipiodol mixture) is formed by chelating reaction of MN series compounds that are amine-amide-disulfide amine quadric-dentate chelate ligands with TcO4−/or ReO4−, and then dissolved in Lipiodol. Moreover, the 99mTc/or 188Re of the TcO4−/or ReO4− avoids bone marrow injuries caused by free 90Y. By the feature of the Lipiodol that stays in liver tumors for a long period, the radioactive mixture is applied to treat liver cancers by injection so that injuries caused by surgical operations can be prevented. 188Re-MN/Lipiodol is used for liver cancer, breast cancer or other solid tumors treatment. Re-188 MN or Re-188 MN/Lipiodol can be mixed with anticancer drugs, hydrogel, liposome, micelle or other nano-particles to form the multifunctional therapeutic modality.

摘要翻译： 公开了放射性混合物及其制造方法。 通过胺胺 - 二硫化胺胺二齿螯合配体的MN系列化合物与TcO4-或ReO4-螯合反应形成放射性混合物（188Re-MN / Lipiodol混合物），然后溶于Lipiodol中。 此外，TcO4- /或ReO4的99mTc /或188Re避免了由自由90Y引起的骨髓损伤。 通过长时间停留在肝肿瘤中的碘碘醇的特征，通过注射施用放射性混合物来治疗肝癌，从而可以预防外科手术引起的损伤。 188Re-MN / Lipiodol用于肝癌，乳腺癌或其他实体瘤治疗。 Re-188 MN或Re-188 MN / Lipiodol可与抗癌药物，水凝胶，脂质体，胶束或其他纳米颗粒混合，形成多功能治疗方式。

公开(公告)号：US20110065904A1

公开(公告)日：2011-03-17

申请号：US12558911

申请日：2009-09-14

申请人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu

发明人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu

IPC分类号： C07F13/00 ,  C07C237/04 ,  C07C69/003

CPC分类号： C07C323/41 ,  C07F13/005

摘要： H3LMN series compounds used as radioactive agents for treatment of liver cancer and a manufacturing method thereof are revealed. 2-thioethylamine hydrochloride is reacted with triphenylmethanol for protection of thiol to obtain 2-[(triphenylmethyl)thio]ethylamine. Then obtain N-[2-((triphenylmethyl)thio)ethyl]chloroacetamide by a transamidation reaction between 2-[(triphenylmethyl)thio]ethylamine and chloroactyl chloride. Next produce a amine-amide-thiol ligand-N-[2-((triphenylmethyl)thio)ethyl][2-((triphenylmethyl)thio)ethylamino]acetamide by a substitution reaction of N-[2-((triphenylmethyl)thio)ethyl]chloroacetamide and 2-[(triphenylmethyl)thio]ethylamine. After respective reaction with 1-bromotetradecane, 1-bromohexadecane and ethyl 16-bromohexadecanoate, H3LMN series compounds are obtained. These amine-amide-dithiols quadridentate ligands can react with MO3+ (M=Tc or Re) to produce electrically neutral complexes. The complexes have high lipophilicity, allowing them soluble in lipiodol to be applied to radiation therapy for liver cancer.

摘要翻译： 揭示了用作肝癌治疗放射剂的H3LMN系列化合物及其制造方法。 将2-硫代乙胺盐酸盐与三苯基甲醇反应以保护硫醇，得到2 - [（三苯基甲基）硫代]乙胺。 然后通过2 - [（三苯基甲基）硫代]乙胺和氯代酰氯的酰胺化反应获得N- [2 - （（三苯基甲基）硫基）乙基]氯乙酰胺。 接着通过N- [2 - （（三苯基甲基）硫代）的取代反应生成胺 - 酰胺 - 硫醇配体-N- [2 - （（三苯基甲基）硫代）乙基] [2 - （（三苯基甲基）硫基）乙基氨基] ）乙基]氯乙酰胺和2 - [（三苯甲基）硫基]乙胺。 在与1-溴十四烷，1-溴十六烷和16-溴十六烷酸乙酯反应后，得到H3LMN系列化合物。 这些胺 - 酰胺 - 二硫醇三元配体可以与MO3 +（M = Tc或Re）反应，产生电中性络合物。 复合物具有高亲脂性，使其可溶于碘油以适用于放射治疗肝癌。

公开(公告)号：US20110040123A1

公开(公告)日：2011-02-17

申请号：US12540467

申请日：2009-08-13

申请人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu

发明人： Show-Wen Liu ,  Cheng-Hsien Lin ,  Tsyh-Lang Lin ,  Cheng-Fang Hsu

IPC分类号： C07C237/10

CPC分类号： C07C323/41 ,  Y02P20/55

摘要： A bifunctional compound containing an amino group and diaminedithiol ligand and a manufacturing method thereof are revealed, the bifunctional compound includes at least one amino group and a diaminedithiol (N2S2) ligand. The amino groups is for reacting with compounds containing carboxylic acids or halogens while the N2S2 ligand binds with technetium or rhenium so as to form an anion complex. The thiol group in the N2S2 ligand is protected by a protecting group for prevention of oxidation and easy storage. This protecting group is released easily during complex reactions. Due to the bifunctional property, the compound is applied to preparation of radiopharmaceuticals such as imaging agents and targeted agents.

公开(公告)号：US09150602B2

公开(公告)日：2015-10-06

申请号：US13556486

申请日：2012-07-24

申请人： Show-Wen Liu ,  Yu Chang ,  Cheng-Fang Hsu ,  Ming-Che Tsai ,  Tsung-Hsien Chiang ,  Yueh-Feng Deng ,  Kuei-Lin Lu ,  Chih-Yuan Lin ,  Da-Ming Wang ,  Ching-Yun Li

发明人： Show-Wen Liu ,  Yu Chang ,  Cheng-Fang Hsu ,  Ming-Che Tsai ,  Tsung-Hsien Chiang ,  Yueh-Feng Deng ,  Kuei-Lin Lu ,  Chih-Yuan Lin ,  Da-Ming Wang ,  Ching-Yun Li

IPC分类号： C07H15/18 ,  C07H1/00

CPC分类号： C07H15/18 ,  C07H1/00

摘要： A precursor used for labeling hepatocyte receptors and applied to radiotracers for imaging or pharmaceutical compositions for liver cancers is revealed. The precursor is a bifunctional compound. The bifunctional group includes a trisaccharide structure and a diamide dimercaptide (N2S2) ligand. The trisaccharide has high affinity to asialoglycoprotein receptors (ASGPR) on surfaces of hepatocytes while N2S2 ligand reacts with radioisotopes to form neutral complexes. Thus the precursor stays on surfaces of hepatocytes to provide radioisotope labeling or treatment effect of liver cancers.

摘要翻译： 用于标记肝细胞受体并应用于放射性示踪剂以用于肝癌成像的前体或用于肝癌的药物组合物。 前体是双官能化合物。 双官能团包括三糖结构和二酰胺二硫醇（N 2 S 2）配体。 三糖对肝细胞表面的脱唾液酸糖蛋白受体（ASGPR）具有高亲和力，而N2S2配体与放射性同位素反应形成中性复合物。 因此，前体停留在肝细胞的表面，以提供肝癌的放射性同位素标记或治疗效果。

公开(公告)号：US09045513B2

公开(公告)日：2015-06-02

申请号：US13571731

申请日：2012-08-10

申请人： Chih-Yuan Lin ,  Yu Chang ,  Jen-Tsung Wang ,  Cheng-Fang Hsu ,  Wei-Ti Kuo ,  Hung-Wen Yu ,  Wuu-Jyh Lin ,  Mei-Hui Wang

发明人： Chih-Yuan Lin ,  Yu Chang ,  Jen-Tsung Wang ,  Cheng-Fang Hsu ,  Wei-Ti Kuo ,  Hung-Wen Yu ,  Wuu-Jyh Lin ,  Mei-Hui Wang

IPC分类号： C07H15/04 ,  C07H1/06 ,  C07K1/13

CPC分类号： C07H1/06 ,  C07H15/04 ,  C07K1/13

摘要： A method for preparing a precursor used to label hepatocyte receptors is revealed. The precursor contains a bifunctional structure including trisaccharide and DTPA ligand. During synthesis processes of the precursor, silica gel columns and Reverse phase-18 (RP-18) columns are used for purification. Thus both the purification times and cost of each purification are reduced. Moreover, use diethyl ether to facilitate precipitation of products and remove a part of coupling reagent. Removing the coupling reagent helps purification of products. Furthermore, Nα,Nα-bis(carboxymethyl)-L-lysine hydrate and benzyl chloroformate are coupled to form a trisaccharide skeleton so as to ensure the yield rate of trisaccharide structure.

摘要翻译： 揭示了制备用于标记肝细胞受体的前体的方法。 该前体含有包括三糖和DTPA配体的双功能结构。 在前体的合成过程中，使用硅胶柱和反相18（RP-18）柱进行纯化。 因此，每次纯化的纯化时间和成本均降低。 此外，使用乙醚促进产物沉淀并除去一部分偶联剂。 去除偶联剂有助于净化产品。 此外，Nα，Nα-双（羧甲基）-L-赖氨酸水合物和氯甲酸苄酯偶联形成三糖骨架，以确保三糖结构的产率。