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1. 发明专利

JP2000136174A DIPOLYCHELATING AGENT 失效
公开(公告)号：JP2000136174A
公开(公告)日：2000-05-16
申请号：JP19221999
申请日：1999-06-01
申请人： NYCOMED SALUTAR INC
发明人： LOVE DAVID , DAU WILLIAM C , HIMMELSBACH RICHARD J , WATSON ALAN D , ROKKUREEJI SCOTT M
IPC分类号： C07D295/16 , A61K49/00 , A61K49/04 , A61K51/00 , C07C237/06 , C07C237/10 , C07D257/02 , C07F5/00 , C07F7/00
摘要： PROBLEM TO BE SOLVED: To obtain the subject chelating agent having a relatively low toxicity and useful for a diagnostic or therapeutic agent having a beneficial imaging characteristic and specific distributing characteristic in a living body by having a linker part and a specific chelating part. SOLUTION: This dipolychelating agent contains two macrocyclic chelating part connected by a linker part and each capable of forming a complex with metal ions, and the above chelating part and linker part are bonded with an amide part or an ester part, in which carbonyl group is adjacent to the chelating part. The above compound is preferably a compound of the formula: A-L-A [A is the chelating part; L is the linker part and A-L bond is A'CO-XL' (A'CO and XL' are the chelating part A and the linker part L respectively; X is O or a secondary, tertiary or cyclic nitrogen)]. The above chelating part is e.g. a polyaminopolyacetic acid, concretely diethylenetriaminepentaacetic acid, etc., and as the preferable linker compound, 1,2-diaminoethane, etc., can be cited.

2. 发明申请

WO1996040287A2 PREPARATION AND USE OF CONTRAST AGENTS 审中-公开
标题翻译：对比剂的制备和使用
公开(公告)号：WO1996040287A2
公开(公告)日：1996-12-19
申请号：PCT/GB1996001309
申请日：1996-06-03
申请人： NYCOMED SALUTAR, INC. , MATTHEWS, Derek, Peter , FRANOLIC, John , LONG, Jeffrey , HOLM, Richard , DROEGE, Michael , DOWNEY, Shannan
发明人： NYCOMED SALUTAR, INC. , MATTHEWS, Derek, Peter
IPC分类号： A61K49/04
CPC分类号： A61K49/04
摘要： A process for the preparation of multinuclear cluster compounds by reacting a metal carbonyl with iodine, and use of these clusters and clusters derived from them, in diagnostic imaging. Novel multinuclear cluster compounds are also disclosed.
摘要翻译：一种通过使羰基金属与碘反应制备多核簇化合物的方法，以及使用这些衍生自它们的这些簇和簇在诊断成像中的方法。还公开了新的多核簇化合物。

3. 发明申请

WO1993002045A1 HYDROXAMATE AND HYDRAZIDE DERIVATIVES OF POLYAMINES AND THEIR MEDICAL USE AS CHELATING AGENTS 审中-公开
标题翻译：聚氨酯的氢氧化物和氢化衍生物及其作为螯合剂的医药用途
公开(公告)号：WO1993002045A1
公开(公告)日：1993-02-04
申请号：PCT/EP1992001598
申请日：1992-07-16
申请人： COCKBAIN, Julian, Roderick, Michaelson , NYCOMED SALUTAR, INC. , HIMMELSBACH, Richard, J. , RONGVED, Pål , KLAVENESS, Jo , STRANDE, Per , DUGSTAD, Harald
发明人： COCKBAIN, Julian, Roderick, Michaelson , NYCOMED SALUTAR, INC.
IPC分类号： C07C243/34
CPC分类号： C07C243/34 , C07C259/06 , C07D257/02
摘要： The present invention provides a compound of formula (I): A[X(CR R )n]mXA or a chelate complex of salt thereof, for use as therapeutic or diagnostic agent wherein in formula (I), each of the groups R and R may independently represent a hydrogen atom or an alkyl or alkoxy group, optionally carrying one or more substituents selected from hydroxy, alkoxy and aryl groups; each X independently represents an oxygen or sulphur atom or a group NA; each A independently represents a hydrogen atom or an alkyl group optionally substituted by a group Y; each Y represents a hydrogen atom, or a group Z, COZ, SO3R , CSZ, PO2Z or B; or one or more pairs of A groups on different X moieties may together form a group [(CR R )nX ]p (CR R )n or a group A on a mid-chain nitrogen may represent a group [(CR R )nX ]p (CR R )nX A where p represents an integer of 0 to 6, and each X independently represents an oxygen or sulphur atom or a group NA where A is as defined for A but may not form part of a group attached to more than one nitrogen atom; or two adjacent groups R and/or A may together form a homo- or heterocyclic saturated or unsaturated 5-7 membered ring containing 0, 1 or 2 ring heteroatoms selected from oxygen, nitrogen and sulphur; m is an integer of 2 to 8; n is an integer of 2 to 4.
摘要翻译：本发明提供式（I）化合物：A [X（CR 1 R 2）n] m X A或其盐的螯合络合物，其用作治疗或诊断剂，其中式（I）， R 1和R 2中的每一个可以独立地表示氢原子或烷基或烷氧基，任选携带一个或多个选自羟基，烷氧基和芳基的取代基; 每个X独立地表示氧或硫原子或基团NA; 每个A独立地表示氢原子或任选被基团Y取代的烷基; 每个Y表示氢原子，或基团Z，COZ，SO 3 R 6，CSZ，PO 2 Z或B; 或不同X部分上的一对或多对A基团可以一起形成基团[（CR 1 R 2）n X 1] p（CR 1 R 2）n或基团中链氮可以表示基团[（CR 1 R 2）n X 1] p（CR 1 R 2）n X 1 A，其中p表示0至6的整数并且每个X 1独立地表示氧或硫原子或NA <1，其中A 1如对A所定义，但不能形成与多于一个氮原子连接的基团的一部分; 或两个相邻基团R 1和/或A可以一起形成含有0,1或2个选自氧，氮和硫的环杂原子的均聚或杂环饱和或不饱和5-7元环; m为2〜8的整数， n为2〜4的整数。

4. 发明申请

WO1992017215A1 CONTRAST MEDIA 审中-公开
标题翻译：对比媒体
公开(公告)号：WO1992017215A1
公开(公告)日：1992-10-15
申请号：PCT/EP1992000698
申请日：1992-03-27
申请人： COCKBAIN, Julian, R., M. , NYCOMED SALUTAR, INC. , ALMÉN, Torsten , BERG, Arne , CHANG, C., Allen , DROEGE, Michael , DUGSTAD, Harald , FELLMAN, Jere, D. , KIM, Sook-Hui , KLAVENESS, Jo , ROCKLAGE, Scott, M. , RONGVED, Pål , SEGAL, Brent , WATSON, Alan, D.
发明人： COCKBAIN, Julian, R., M. , NYCOMED SALUTAR, INC.
IPC分类号： A61K49/04
CPC分类号： A61K49/0002 , A61K49/06 , A61K51/02 , A61K51/0482 , A61K2123/00 , C07F11/005 , C07F15/025
摘要： An imaging contrast medium comprising a physiologically tolerable multinuclear complex (as defined in claim 1) is disclosed. The multinuclear complex contains at least two, but preferably three or more contrast enhancing atoms. For X-ray or ultrasound imaging techniques heavy metal atoms are used to enhance contrast, whereas in Magnetic Resonance Imaging paramagnetic metal atoms are contrast enhancing. Molybdenum and tungsten are preferred contrast enhancing atoms. The medium may also be used therapeutically.
摘要翻译：公开了一种包含生理上可耐受的多核复合物（如权利要求1所定义）的成像造影剂。多核络合物包含至少两个，但优选三个或更多对比增强原子。对于X射线或超声成像技术，重金属原子用于增强对比度，而在磁共振成像顺磁金属原子是对比度增强。钼和钨是优选的对比度增强原子。培养基也可以治疗使用。

5. 发明申请

WO1995009848A2 POLYAZACYCLOALKANES AS DICHELANTS 审中-公开
标题翻译：聚四环素作为狄更斯
公开(公告)号：WO1995009848A2
公开(公告)日：1995-04-13
申请号：PCT/GB1994002115
申请日：1994-09-29
申请人： NYCOMED SALUTAR, INC. , COCKBAIN, Julian, Roderick, Michaelson , CARVALHO, Joan , FELLMANN, Jere, Douglas , WATSON, Alan, David , KOO, Michael
发明人： NYCOMED SALUTAR, INC. , COCKBAIN, Julian, Roderick, Michaelson
IPC分类号： C07D257/02
CPC分类号： C07D295/15 , A61K49/122 , C07D257/02 , C07D273/08 , C07D403/14 , C07F9/6524
摘要： This invention relates to dichelants, in particular compounds having two macrocyclic chelant groups linked by a bridge containing an ester or amide bond, especially compounds of formula (V) (wherein each X which may be the same or different is NZ, O or S, at least two Xs being NZ; each Z is a group R or a group CR 2Y, at least one Z, and preferably 2 or 3 Zs, on each macrocyclic ring being a group CR 2Y; each Y is a group CO2H, PO3H, SO3H, CONR 2, CON(OR )R , CNS or CONR NR 2, preferably COOH; m is 0 or 1 or 2, preferably 1; each n is 2 or 3, preferably 2; q is 1 or 2, preferably 1; each R which may be the same or different is a hydrogen atom or an alkyl group optionally substituted by one or more hydroxy and/or alkoxy groups; and D is a bridging group, other than an unsubstituted carbonylaminoethylaminocarbonyl group, having a molecular weight of less than 1000, preferably less than 500, joining two macrocyclic rings via at least one amide or ester bond) and salts and metal chelates thereof.
摘要翻译：本发明涉及双耳，特别是具有通过含有酯或酰胺键的桥连接的两个大环螯合剂基团的化合物，特别是具有式（Ⅴ）化合物（其中每个X可以相同或不同的是NZ，O或S，至少两个X为NZ;每个Z为基团R 1或基团CR 1 2Y，至少一个Z，优选2或3个Z，每个大环上为基团CR 2Y; 每个Y是CO 2 H，PO 3 H，SO 3 H，CONR 2，CON（OR 1）R 1，CNS或CONR 1 NR 1，优选COOH; m是0或1或 2，优选1;每个n为2或3，优选2; q为1或2，优选1;每个R 1可以相同或不同，是氢原子或任选被一个或多个羟基和/或烷氧基; D是分子量小于1000，优选小于500的未取代的羰基氨基乙基氨基羰基以外的桥连基，通过至少一个酰胺键或酯键连接两个大环）和盐和金属螯合物。

6. 发明申请

WO1995007270A1 CHELANTS AS CONTRAST ENHANCING AGENTS 审中-公开
标题翻译：作为对比增强剂的CHELANTS
公开(公告)号：WO1995007270A1
公开(公告)日：1995-03-16
申请号：PCT/GB1994001931
申请日：1994-09-06
申请人： NYCOMED SALUTAR, INC. , COCKBAIN, Julian , GARRITY, Martha , CROFTS, Shaun, Paul , CARVALHO, Joan , STRANDE, Per , DUGSTAD, Harald
发明人： NYCOMED SALUTAR, INC. , COCKBAIN, Julian
IPC分类号： C07D257/02
CPC分类号： A61K49/0002 , C07D257/02 , Y10S514/836
摘要： The present invention provides a polychelant compound of formula (VII), (wherein each X which may be the same or different is NZ, O or S, at least two Xs being NZ; B is (CR Y) or -N(CR 2Y)-; each Z is a group R or a group CR 2Y, at least one Z being a group CR 2Y; each Y is a group CO2H, PO3H, SO3H, CONR 2, CON(OR )R , CNS or CONR NR 2; m is 0 or 1 or 2; each n is 2 or 3; q is 0 or 1 when B is (CR Y) and 2 when B is N(CR 2Y); p is an integer having a value of at least 2; each R which may be the same or different is a hydrogen atom or an alkyl, aryl or aralkyl group optionally substituted by one or more hydroxy or alkoxy groups, or two R groups on ring atoms or in Z groups together represent a linker group L; each L which may be the same or different represents a bond or an organic linker group having a molecular weight of less than 1000 and salts and chelates thereof. These compounds, especially the di- and trichelates with paramagnetic or heavy metal ions are especially useful as diagnostic imaging contrast agents.
摘要翻译：本发明提供一种式（Ⅶ）的聚合物化合物，其中每个X可以相同或不同，为NZ，O或S，至少两个X为NZ; B为（CR 1 Y）或-N （CR 1 2Y） - ;每个Z是基团R 1或基团CR 1Y 2，至少一个Z是基团CR 2Y;每个Y是基团CO 2 H，PO 3 H，SO 3 H ，CONR 1，CON（OR 1）R 1，CNS或CONR 1 NR 12，m为0或1或2;每个n为2或3; q为0或 1，当B为（CR 1）Y）时为2，B为N时为2（CR 1 2Y）; p为值至少为2的整数;每个R 1可以相同或不同任选被一个或多个羟基或烷氧基取代的烷基，芳基或芳烷基或环原子上或Z基团中的两个R 1一起表示连接基团L;每个L可以相同或不同的表示分子量小于1000的键或有机连接基团及其盐和螯合物，这些化合物，特别是具有顺磁或重金属离子的二 - 和三 - s作为诊断成像造影剂是特别有用的。

7. 发明申请

WO9628420A3 PREPARATION OF N-ARYLMETHYL AZIRIDINE DERIVATIVES,PREPARATION OF N-ARYLMETHYL AZIRIDINE DERIVATIVES, 1,4,7,10-TETRAAZACYCLODODECANE DERIVATIVES OBTAIN 1,4,7,10-TETRAAZACYCLODODECANE DERIVATIVES OBTAINED THEREFROM AND N-ARYLMETHYL-ETHANOL-AMINE SULPHOED THEREFROM AND N-ARYLMETHYL-ETHANOL-AMINE SULPHONATE ESTERS AS INTERMEDIATES NATE ESTERS AS INTERMEDIATES 审中-公开
标题翻译：制备N-甲基甲基咪唑衍生物，制备N-芳基甲基咪唑衍生物，1,4,7,10-四氮杂十二烷基衍生物，得到由其获得的1,4,7,10-四氮杂环十二烷基衍生物和由其形成的N-芳基甲基 - 乙醇胺作为中间体的N-亚磺酰基 - 乙醇 - 氨基磺酸盐作为中间体
公开(公告)号：WO9628420A3
公开(公告)日：1996-12-12
申请号：PCT/GB9600552
申请日：1996-03-08
申请人： NYCOMED SALUTAR INC , UNIV IOWA RES FOUND , COCKBAIN JULIAN , MESSERLE LOUIS , AMARASINGHE GANDARA , FELLMANN JERE DOUGLAS , GARRITY MARTHA , VARADARAJAN JOHN , VASILEVSKIS JANIS
发明人： MESSERLE LOUIS , AMARASINGHE GANDARA , FELLMANN JERE DOUGLAS , GARRITY MARTHA , VARADARAJAN JOHN , VASILEVSKIS JANIS
IPC分类号： A61K49/00 , A61K49/06 , C07C303/44 , C07C305/06 , C07D203/08 , C07D255/00 , C07D257/02 , C07D259/00 , C07C305/04
CPC分类号： C07D203/08 , A61K49/0002 , A61K49/06 , C07C303/44 , C07D255/00 , C07D257/02 , C07D259/00 , C07C305/06
摘要： Aziridines may be subjected to a cyclooligomerization reaction to produce polyazacycloalkane compounds useful for example in the preparation of chelating agents for use in diagnostic imaging contrast agents. N-benzyl-aziridine in particular is useful as it can be cyclotetramerized and debenzylated to yield cyclen, a key intermediate in chelating agent preparation. The invention provides a particularly attractive route to production of N-benzyl and other N-arylmethyl aziridines of formula (I), (where each R1 independently is hydrogen or a group Ar and Ar is an optionally substituted phenyl group), said process comprising reacting a purified N-arylmethylethanolamine-sulphonate ester with a base. N-arylmethyl-ethanolamine sulphonate ester of the formula: R'NHCH2CH2OSO3H, wherein the N-arylmethyl group R' is an N-(bisarylmethyl) or N-(triarylmethyl) group, as intermediates. In a further aspect the invention provides compounds of formula (II), where Ar and R1 are as hereinbefore defined and at least two differing ArCHR1 moieties are present.
摘要翻译：氮杂环丁烷可以被喷射到环烯化反应中以产生用于例如制备用于诊断成像造影剂的螯合剂的多氮杂环烷烃化合物。特别是N-苄基 - 氮丙啶是有用的，因为它可以进行环化聚合和脱苄基化，以产生螯合剂，螯合剂制备中的关键中间体。本发明提供了生产式（I）的N-苄基和其它N-芳基甲基氮丙啶的特别有吸引力的途径，其中每个R 1独立地为氢或基团AR，Ar为任选取代的苯基。该方法包括使纯化的N-芳基甲基乙醇胺 - 磺酸酯磺酸酯与碱反应。作为中间体，式R'NHCH2CH2OSO3H的N-芳基甲基 - 乙醇胺磺酸酯，其中N-芳基甲基R'是N-（二芳基甲基）或N-（三芳基甲基）基团。在另一方面，本发明提供式（II）的化合物，其中Ar和R 1如上所定义，并且存在至少两个不同的ArCHR 21部分。

8. 发明申请

WO1996028420A2 PREPARATION OF N-ARYLMETHYL AZIRIDINE DERIVATIVES, 1,4,7,10-TETRAAZACYCLODODECANE DERIVATIVES OBTAINED THEREFROM AND N-ARYLMETHYL-ETHANOL-AMINE SULPHONATE ESTERS AS INTERMEDIATES 审中-公开
标题翻译： N-芳基甲基咪唑衍生物的制备，其中获得的1,4,7,10-四氮杂环十二烷基衍生物和作为中间体的N-亚磺酰基 - 乙磺酰胺磺酸盐
公开(公告)号：WO1996028420A2
公开(公告)日：1996-09-19
申请号：PCT/GB1996000552
申请日：1996-03-08
申请人： NYCOMED SALUTAR, INC. , UNIVERSITY OF IOWA RESEARCH FOUNDATION , COCKBAIN, Julian , MESSERLE, Louis , AMARASINGHE, Gandara , FELLMANN, Jere, Douglas , GARRITY, Martha , VARADARAJAN, John , VASILEVSKIS, Janis
发明人： NYCOMED SALUTAR, INC. , UNIVERSITY OF IOWA RESEARCH FOUNDATION , COCKBAIN, Julian
IPC分类号： C07D203/08
CPC分类号： C07D203/08 , A61K49/0002 , A61K49/06 , C07C303/44 , C07D255/00 , C07D257/02 , C07D259/00 , C07C305/06
摘要： Aziridines may be subjected to a cyclooligomerization reaction to produce polyazacycloalkane compounds useful for example in the preparation of chelating agents for use in diagnostic imaging contrast agents. N-benzyl-aziridine in particular is useful as it can be cyclotetramerized and debenzylated to yield cyclen, a key intermediate in chelating agent preparation. The invention provides a particularly attractive route to production of N-benzyl and other N-arylmethyl aziridines of formula (I), (where each R1 independently is hydrogen or a group Ar and Ar is an optionally substituted phenyl group), said process comprising reacting a purified N-arylmethylethanolamine-sulphonate ester with a base. N-arylmethyl-ethanolamine sulphonate ester of the formula: R'NHCH2CH2OSO3H, wherein the N-arylmethyl group R' is an N-(bisarylmethyl) or N-(triarylmethyl) group, as intermediates. In a further aspect the invention provides compounds of formula (II), where Ar and R1 are as hereinbefore defined and at least two differing ArCHR1 moieties are present.
摘要翻译：氮丙啶可以进行环烯基化反应以产生用于例如制备用于诊断成像造影剂的螯合剂的多氮杂环烷烃化合物。特别是N-苄基 - 氮丙啶是有用的，因为它可以进行环化聚合和脱苄基化，以产生螯合剂，螯合剂制备中的关键中间体。本发明提供了生产式（I）的N-苄基和其它N-芳基甲基氮丙啶的特别有吸引力的途径（其中每个R 1独立地为氢或基团Ar，Ar为任选取代的苯基），所述方法包括使纯化的N-芳基甲基乙醇胺 - 磺酸酯与碱。具有下式的N-芳基甲基 - 乙醇胺磺酸酯：R'NHCH2CH2OSO3H，其中N-芳基甲基R'为N-（二芳基甲基）或N-（三芳基甲基）基团，为中间体。在另一方面，本发明提供式（II）化合物，其中Ar和R 1如上所定义，并且存在至少两个不同的ArCHR 1部分。

9. 发明申请

WO9509848A3 POLYAZACYCLOALKANES AS DICHELANTS 审中-公开
标题翻译：聚四环素作为狄更斯
公开(公告)号：WO9509848A3
公开(公告)日：1995-07-27
申请号：PCT/GB9402115
申请日：1994-09-29
申请人： NYCOMED SALUTAR INC , COCKBAIN JULIAN R M , CARVALHO JOAN , FELLMANN JERE DOUGLAS , WATSON ALAN DAVID , KOO MICHAEL
发明人： CARVALHO JOAN , FELLMANN JERE DOUGLAS , WATSON ALAN DAVID , KOO MICHAEL
IPC分类号： G01R33/28 , A61B5/055 , A61K31/395 , A61K31/495 , A61K49/00 , A61K49/06 , A61K51/00 , A61N5/00 , A61P39/00 , A61P39/02 , A61P43/00 , C07D255/02 , C07D257/02 , C07D273/00 , C07D285/00 , C07D401/14 , C07D403/06 , C07D403/14 , C07D405/14 , C07D409/14 , C07F5/00 , C07F9/547 , C07F9/6524 , C07H23/00 , C09K3/00
CPC分类号： C07D295/15 , A61K49/122 , C07D257/02 , C07D273/08 , C07D403/14 , C07F9/6524
摘要： This invention relates to dichelants, in particular compounds having two macrocyclic chelant groups linked by a bridge containing an ester or amide bond, especially compounds of formula (V) (wherein each X which may be the same or different is NZ, O or S, at least two Xs being NZ; each Z is a group R or a group CR 2Y, at least one Z, and preferably 2 or 3 Zs, on each macrocyclic ring being a group CR 2Y; each Y is a group CO2H, PO3H, SO3H, CONR 2, CON(OR )R , CNS or CONR NR 2, preferably COOH; m is 0 or 1 or 2, preferably 1; each n is 2 or 3, preferably 2; q is 1 or 2, preferably 1; each R which may be the same or different is a hydrogen atom or an alkyl group optionally substituted by one or more hydroxy and/or alkoxy groups; and D is a bridging group, other than an unsubstituted carbonylaminoethylaminocarbonyl group, having a molecular weight of less than 1000, preferably less than 500, joining two macrocyclic rings via at least one amide or ester bond) and salts and metal chelates thereof.

10. 发明申请

WO1997043293A1 CONTRAST AGENTS 审中-公开
标题翻译：对比剂
公开(公告)号：WO1997043293A1
公开(公告)日：1997-11-20
申请号：PCT/GB1997001314
申请日：1997-05-14
申请人： NYCOMED SALUTAR, INC. , LONG, Jeffrey , HOLM, Richard , SANDERSON, William , YU, Shi-Bao , ZHENG, Zhiping
发明人： NYCOMED SALUTAR, INC.
IPC分类号： C07F13/00
CPC分类号： A61K49/0433 , A61K49/04 , A61K49/0414 , C07F13/005 , C07F15/008
摘要： Compounds of the formula (I): [M6Q8BnL6-n] where M is Re or Rh; each Q is a bridging atom selected from O, S, Se and Te; B is a monovalent non-bridging atom or moiety; L is a PR3 group in which R is C1-6 alkyl or aryl, optionally substituted on the alkyl or aryl group by one or more water-solubilising groups such as an amine or hydroxidy group, or the three R groups together form a C6-10 trivalent group which may also contain up to three nitrogen or oxygen atoms; n is an integer from 0 to 6; and x is an integer from -2 to +4, representing the overall charge of the cluster, which when non-zero is accompanied by one or more counter ions of equal and balancing charge, and contrast media, particularly X-ray contrast media, containing them.
摘要翻译：式（I）化合物：[M6Q8BnL6-n] x其中M为Re或Rh; 每个Q是选自O，S，Se和Te的桥连原子; B是单价非桥连原子或部分; L是PR 3基团，其中R是C 1-6烷基或芳基，任选地在烷基或芳基上被一个或多个水溶性基团例如胺或羟基基团取代，或三个R基团一起形成C6- 10个三价基团，其也可以含有至多三个氮原子或氧原子; n为0〜6的整数; 并且x是从-2到+4的整数，表示簇的总电荷，当非零伴随着一个或多个相等和平衡电荷的对立离子时，以及对比介质，特别是X射线造影介质，包含它们

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