CN1253507A - 用于用近红外光诊断和用于治疗的酸不稳定的及可酶裂解的染料结构 - Google Patents
用于用近红外光诊断和用于治疗的酸不稳定的及可酶裂解的染料结构 Download PDFInfo
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Abstract
本发明涉及用于用近红外辐射(NIR-辐射)体内和体外诊断的酸不稳定的及可酶裂解的化合物,这些化合物用作光学诊断试剂和治疗剂的应用,以及含有这些化合物的诊断试剂。
Description
本发明涉及用于用近红外辐射(NIR辐射)体内和体外诊断的酸不稳定的及可酶裂解的化合物,这些化合物用作光学诊断试剂和治疗剂的应用,以及含有这些化合物的诊断试剂。
近红外光成象是一种非侵入的诊断方法,其利用生物学组织对波长为650-1000nm的光的高通透性。与紫外光和可见光仅能穿透组织最多几毫米相反,用近红外光能穿透组织达几厘米。光的基本穿透深度很小的原因是内源性染料主要是血红蛋白和水的光吸收,而其在近红外光光谱范围内在650-1000nm具有最小光吸收值。这一最大光学组织透明度范围也因此被称为诊断/治疗窗口(Boulnois,J.,Lasers Med Sci 1986,1:47-66)。因此,在现代成象方法如诊断放射学、磁共振层面X线照相术或超声诊断之外,为诊断医生提供了另一种用于图示组织显现的方法(Haller,E.B.,Time-ResolvedTransillumination and Optical Tomography.J.Biomed Optics 1996,1:7-17)。
通过检测血红蛋白/脱氧血红蛋白的吸收而利用NIR辐射对婴儿大脑中的血流和氧合程度进行位点依赖性记录是已知并应用了许多年的方法(Jobsis,F.F.,科学1977,198:1264-67;Chance,B.;Leigh,J.S.,;Miyake,H.et al.,美国科学院学报1988,85:4971-75;Benaron,D.A.et al.,科学1993,33:396A)。
应用近红外辐射的基本问题是光的强散射,因此即使在不同的光学物理特性情况下,一个物体也不易与另一个边缘分明的物体及其周围区域区分开。当将物体从表面增加移动时,这一问题更突出,并可以认为在透照和检测荧光辐射情况下是最主要的限制因素。作为对比介质的染料可以反映组织的光学性质并导致被检测组织的吸收值和荧光度增加,因此即使位点分辨率较差也可以使检测结果很明确。在这种情况下,这种染料化合物的吸收性质可被用作成象信息。如果染料还具有以荧光辐射的形式发射所吸收的能量的性质,则这一性质也可作为成象信息。在这种情况下,单独检测相对于激发辐射具有向红效应的荧光辐射。这种情况的优势在于组织本身在NIR范围具有极低的固有荧光,因此背景是最小的。(S.Folli等,癌症研究54,2643-9(1994);B.Ballou等,Cancer Immunol.Immunother.41,257-63(1995);X.Li等,SPIE Vol 2389,789-98(1995))。
在荧光检测中,这一方面的前提条件是检测合适的差异即待检测的组织和周围组织之间的荧光发射的差异尽可能地大。原则上这一点可通过在给予物质后一定时间达到荧光染料的浓度差异来实现。尤其是在检测深层组织时,在使用不加限定浓度的物质时这一差异通常是不合适的。
本发明的一个目的在于提供一种克服了现有技术缺点的新化合物。
根据本发明,本发明的目的通过通式(I)的化合物实现:
(F-L)m-A (I)其中
F代表在600-1200nm间具有至少一个最大吸收的染料分子,
L代表连接结构,其含有一个酸不稳定的和/或可酶裂解的键,
m是一个1-80之间的数,
其中若m是一个1-3之间的数,则
A代表在600-1200nm间具有至少一个最大吸收的染料分子,
抗生素活性或细胞抑制活性的分子,生物分子,非生物学大
分子或者化合物B-(L-W)o或D-(L-W)o,其中
D是非生物学大分子,
B是生物分子,
L具有上述含义,
W代表抗生素活性或细胞抑制活性的分子,
o是一个1-20之间的数,
并且若m是一个4-80之间的数,则
A代表生物分子,非生物学大分子或者化合物B-(L-W)o或D-(L-W)o,其中
D,B,L,W和o具有上述含义。
本发明的化合物的针对近红外荧光发射的体内检测的特殊性质在于其具有很少或甚至没有荧光发射,只有在靶位点(例如肿瘤,炎症)这一结构被裂解后或者染料从这一结构中裂解出来之后才发生荧光信号的增强。因此,在待检测组织和周围组织之间荧光信号的有效差异表现在:
a)基于药物动力学机制的浓度差异和
b)在诊断时的荧光量子产额的差异。
已发现当染料分子与另一种分子偶联时(二聚体),染料的荧光猝灭而获得本发明的化合物,即与相应的未结合状态的染料分子相比具有极低的荧光发射。另外还发现当具有芳香结构的其它分子(其可以是染料和活性成分,例如细胞抑制剂或抗生素)与荧光染料偶联时可发生相当的荧光猝灭。令人惊奇的是,当染料与抗体、抗体片段和蛋白质偶联时也发生荧光猝灭。
原则上,作为本发明的化合物的结构成分的染料其单体未缀合形式必须具有高摩尔吸收系数和高荧光量子产额。
本发明的优选的通式I的化合物是F和/或A代表聚甲炔染料、四吡咯染料、四氮杂吡咯染料、黄嘌呤染料、吩噁嗪染料或吩噻嗪染料。
特别优选的是来自聚甲炔类染料的结构,因为其在700-1000nm间的近红外光谱范围具有最大吸收值,摩尔吸收系数非常高(ε高达300000 l mol-1cm-1),这类染料例如花青染料、squarililium染料和croconium染料,以及部花青和oxonol染料。
R1-R4和R7-R10各自独立地代表氟、氯、溴、碘原子或硝基
或基团-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、
-NE1E2、-OE1、-OSO3E1、-SO3E1、-SO2NHE1、-E1,
其中E1和E2各自独立地代表卤素原子、饱和或不饱和的支
链或直链C1-C50烷基链,其中该链或该链的部分任选地
可以形成一或多个芳香或饱和环状C5-C6单位或双环C10
单位,并且其中C1-C50烷基链被0-15个氧原子和/或0
-3个羰基基团间断和/或被0-5个羟基、0-5个酯基、0-
3个羧基、0-3个氨基取代,
并且在每种情况下相邻的基团R1-R4和/或R7-R10可以相互
连接形成六元芳香碳环,
R5-R6各自独立地代表具有上述含义的-E1或代表C1-C4磺烷基链,和/或R1-R10代表一个与L的键合,Q是下列片段
其中
R11代表氢、氟、氯、溴或碘原子或硝基或基团-NE1E2、
-OE1或-E1,其中E1和E2具有上述含义,或者R11代
表一个与L的键合,
R12代表氢原子或具有上述含义的基团E1,
b是数字0、2或3,X和Y各自独立地代表O、S、-CH=CH-或片段其中
R13和R14各自独立地代表氢原子、饱和或不饱和的支链或直
链C1-C10烷基链,其可被至多5个氧原子间断和/或被至
多5个羟基取代,并且R13和R14可以相互连接形成五或
六元环。
本发明的另一个主题是通式(I)的化合物,其中具有治疗活性分子的染料经生理学可裂解的键与生物分子或非生物学载体分子相连,或者染料和活性成分经生理学可裂解的键与生物分子或非生物学载体分子偶联。
特别优选的结构是其中偶联状态的染料的荧光被猝灭,并且活性分子的治疗活性经与染料或载体分子的偶联而被掩蔽(前体药物效应)。键的裂解导致荧光发射的增加并同时伴有活性成分的活性的释放。
在本发明的通式(I)中的活性成分W和/或A是例如下述化合物:
抗生素:阿克拉希霉素、放线菌素F1、氨茴霉素、重氮丝氨酸、博来霉素、放线菌素C、卡柔比星、嗜癌素、色霉素、更生霉素、道诺红菌素、阿霉素、表柔比星、丝裂霉素、霉酚酸、诺加霉素、橄榄霉素、匹来霉素、普卡霉素、紫菜霉素、嘌呤霉素、链黑菌素、杀结核菌素、佐柔比星;
叶酸类似物:二甲叶酸、metothrexate、蝶酰三谷氨酸、trimetrexate;
嘧啶类似物:环胞苷、氮胞苷、6-氮尿苷、氟己嘧啶、阿糖胞苷、doxifluridine、enocitabine、5-氟脱氧尿苷、5-氟尿嘧啶;
嘌呤类似物:fludarabine、6-巯基嘌呤、硫咪嘌呤、硫代鸟嘌呤及上述化合物的衍生物;
烷基化物质:烷基磺酸酯、氮丙啶、乙烯亚胺、甲基蜜胺、硝基脲、氮芥化合物;
激素活性物质如雄激素、抗肾上腺素、抗雄激素、抗雌激素、雌激素、LH-RH类似物和孕激素;以及其它具有抑制细胞活性的物质如紫杉醇和紫杉醇衍生物。
其它活性成分是光动力学活性的物质,它们可经激发后能引起光敏作用形成胞毒性单重态氧和自由基的性质来辨别。这类化合物主要是四吡咯和四氮杂吡咯,例如卟啉、苯并卟啉、氯、红紫素、酞菁、naphthalocyanines和上述化合物的衍生物。其它化合物是膨胀卟啉、porphycenes以及噁嗪和吩噁嗪染料。
通式(I)的连接结构L的化学键的结构组成方式是使得其在某些生理参数即能分辨疾病组织(肿瘤)及与正常组织区域区分开的生理参数情况下被裂解。
文献中描述肿瘤与正常组织相比有低pH。尽管胞内pH基本上是相同的(pH7.4),但是肿瘤的胞外pH降低达0.5pH单位。另外炎症特别是细菌型炎症的pH也降低。pH的测定方法为用微电极测量、用pH敏感的荧光样品进行荧光测量以及用MR探头测量(R.J.Gillieset al.,美国生理学杂志267,pc195-203(1994),G.R.Martin and R.K.Jain,微血管研究46,216-230(1993),L.E.Gerweck and K.Seetharaman,癌症研究56,1194-1198(1996),K.Engin et al.,Int.J.Hyperthermia11(1995)211-216,K.Engin et al.,Int.J.Radiation Oncology Biol.Phys.29(1994)125-132,G.Helmlinger et al.,Nature Medicine 3(1997)177-182.)
因此,本发明的另一主题是具有被降低的生理pH裂解的连接结构L的化合物,这些结构是例如相应于下述片段的烷基腙、酰基腙、芳基腙、磺酰腙、亚胺、肟、缩醛、酮缩醇、原酸酯: 其中p代表2-4之间的数。
除了经降低的pH导致的裂解外,本发明化合物的裂解还可经以升高的浓度存在于待检测组织(例如肿瘤、细菌性炎症)中的酶作用进行。
因此,本发明的另一主题是具有可被酶裂解的连接结构L的化合物,这些可被酶裂解的连接结构是例如被组织蛋白酶、肽酶、羧基肽酶、α-和β-葡糖苷酶、脂酶、氧化酶、磷脂酶、磷酸酶、磷酸二酯酶、蛋白酶、弹性蛋白酶、硫酸酶、还原酶、转移酶和细菌酶如青霉素酰胺酶和β-内酰胺酶裂解的结构(P.D.Senter et al.,Bioconjugates Chem.6(1995),389-94)。
优选的可酶裂解结构是短链肽序列,如含有氨基酸序列Val-Leu-Lys的序列。
在给药后一定时间导致在待检测组织中的浓度或相应的浓度梯度的动力学应与本发明的化合物的裂解的动力学以及释放的染料分子的清除的动力学相关并导致一协同效应。
其它的优选的本发明的通式(I)的化合物是A和/或B代表抗体、其缀合物和片段、特异的肽和蛋白质、受体、酶、酶底物、核苷酸、天然或合成的核糖核酸或脱氧核糖核酸或其化学修饰物、如aptamers或反义寡核苷酸、脂蛋白、凝集素、糖类、单糖、二糖或三糖、直链或支链寡糖或多糖或糖衍生物或葡聚糖。
另外,本发明的通式(I)的化合物优选的是D代表聚乙二醇、聚丙二醇、聚赖氨酸、或聚赖氨酸树状物或其衍生物。
结构元件A、D、B、L和W的连接直接进行或通过通用的官能团进行。这种基团是例如酯、醚、仲胺、叔胺、酰胺、硫脲、脲、氨基甲酸酯基团或马来酰亚胺结构。
本发明的另一主题是本发明的通式I的化合物在用NIR辐射体内诊断和治疗疾病组织中的应用。
本发明还包括在用NIR辐射体内诊断疾病组织区域中所用的光学诊断试剂,其含有至少一种本发明的通式(I)的化合物。
这些试剂根据本领域已知的方法生产,任选地使用通用的佐剂和/或载体及稀释剂等,如生理学相容的电解质、缓冲剂、去污剂、用于匹配渗透性的物质以及用于改善稳定性和溶解性的物质。制药中通用的措施保证了生产中尤其是给药前制剂的无菌性。
染料F和A的合成参照例如下列文献所述的方法进行:
F.M.Hamer,花菁染料及相关化合物,John Wiley and Sons,纽约,1964;
J.Fabian et al.,化学综述92(1992)1197;
L.A.Ernst et al.,细胞计量术10(1989)3-10;
P.L.Southwick et al.,细胞计量术11(1990)418-430;
R.B.Mujumdar et al.,生物缀合物化学4(1993)105-11;
E.Terpetschnig et al.,分析生物化学217(1994)197-204;
J.S.Lindsey et al.,Tetrahedron 45(1989)4845-66,EP-0591820A1;
L.Strekowski et al.,J.Heterocycl.Chem.33(1996)1685-1688;
S.R.Mujumdar et al.,生物缀合物化学7(1996)356-362;
M.Lipowska et al.,Synth.Commun.23(1993)3087-94;
E.Terpetschnig et al.,分析化学282(1993)633-641;
M.Matsuoka and T.Kitao,Dyes Pigm.10(1988)13-22;以及
N.Narayanan and G.Patronay,I.Org.Chem.60(1995)2361-95。
染料合成方法与文献中的方法类似,其具有含酸不稳定的或可酶裂解的键的取代基或者在偶联后从其产生这种键,所述文献例如:
B.M.Mueller et al.,生物缀合物化学1(1990)325-330;
K.Srinvasachar and D.M.Neville,生物化学28(1989)2501-09;
D.M.Neville et al.,生物化学杂志264(1989)14653-61;
T.Kaneko et al.,生物缀合物化学2(1991)133-41;
B.A.Froesch et al.,癌症免疫及免疫治疗42(1996)55-63;以及
J.V.Crivello et al.,聚合物科学杂志:A部:聚合物化学34(1996)3091-3102。
以下实施例解释本发明:
实施例:
1.5-(1-氧乙基)-1,1′-(4-硫丁基)-靛三羰花青钠盐1(图1)的合成
经重氮化并用SnCl2还原从4-氨基苯基-甲基酮合成4-肼基苯基甲基酮(方法类似于T.Gorecki et al.,J.Heterocyclic chem.33(1996)1871-76)。
将4.8克(32mmol)4-肼基苯基甲基酮,5.4克乙酸钠和3.9克(45mmol)3-甲基-2-丁酮在40ml乙酸乙酯中于室温搅拌1小时、在120℃搅拌4小时。反应混合物真空浓缩,加入300ml二氯甲烷,用饱和NaCl溶液洗有机相。在MgSO4上干燥后,获得7.5g棕色油。将其与6.5g(48mmol)1,4-丁砜(butanesulfone)一起在140℃加热5小时,冷却后用丙酮搅拌,然后经色谱纯化沉淀的固体(RP C-18,流动相溶剂甲醇/水)。收率:2.5g(23%)5-(1-氧乙基)-1-(4-硫丁基)-2,3,3-三甲基-3H-假吲哚2。
为生产染料1,将0.5g(1.7mmol)1-(4-硫丁基)-2,3,3-三甲基-3H-假吲哚3与0.47g(1.6mmol)盐酸戊烯二醛二缩苯胺在10ml乙酐于120℃搅拌30分钟。冷却后与0.6g(1.8mmol)2、10ml乙酐、4ml乙酸和0.5g乙酸钠混合并加热至120℃30分钟。冷却深蓝色溶液,与200ml乙醚搅拌,并过滤掉沉淀的固体。色谱纯化(RP C-18,流动相溶剂甲醇/水)并冻干后,获得0.3g(26%)产物1。
元素分析:
Cld:C61.99 H6.33 N3.91 S8.95
Fnd:C61.73 H6.49 N3.80 S8.78
吸收值:λmax(H2O)=748nm(ε=14800 l mol-1cm-1)
2.用酸不稳定的连接结构修饰(图2)
2.1将1与4-羧基苯基磺酰肼反应
将0.2g(0.28mmol)1及74mg(0.34mmol)4-羧基苯基磺酰肼溶于20ml甲醇中,与5μl三氟乙酸混合并在室温搅拌18小时。真空蒸发溶剂,残余物用二氯甲烷洗几次,干燥产物。收率:0.21g4。
2.2将1与4-氨基苯甲酸酰肼反应
类似于2.1将0.2g(0.28mmol)1及51mg(0.34mmol)4-氨基苯甲酸酰肼反应。收率:0.20g5。
2.3将1与4-(氨基甲基)苯甲酸酰肼反应
类似于2.1将0.2g(0.28mmol)1及56mg(0.34mmol)4-氨基甲基苯甲酸酰肼反应。收率:0.22g6。
3.反应性官能团(N-羟基琥珀酰亚胺酯和异硫氰酸酯)的产生(图2)
为了产生相应的N-羟基琥珀酰亚胺酯化合物7,导入在12ml二甲基甲酰胺(DMF)中的0.1g(0.1mmol)4和14mg(0.12mmol)N-羟基琥珀酰亚胺(NHS)并在室温与23mg(0.11mmol)二环己基碳二亚胺在1ml DMF中的溶液混和。搅拌72小时后,用乙醚沉淀产物,过滤并从DMF/乙醚中再沉淀。真空干燥后获得的产物(12mg)无需进一步纯化而使用。
为了产生酸不稳定的异硫氰酸酯化合物8,将0.1g(0.11mmol)5,33mg(0.14mmol)N,N’-硫代羰基二-2(1H)-吡啶酮和15mg(0.15mmol)三乙胺在15ml氯仿中于室温搅拌60分钟。用乙醚沉淀产物,过滤并用HPLC(RP Select B,Merck,流动相溶剂10mmol磷酸盐缓冲液pH8/甲醇)纯化。冻干后获得40mg(40%)8,用二氯甲烷/甲醇分离盐并真空干燥。
4.mAK9.2.27(抗黑素瘤抗体)的标记
4.1用酸不稳定NHS-酯7标记
将在0.5ml 50mmol硼酸盐缓冲液(pH9.2)中的1mg抗体与33μl7(在DMF中的5mmol/l初始溶液)混和并在室温搅拌1小时。经NAP-5柱(用25mmol磷酸盐缓冲液pH7.8,+0.01%NaN3洗脱)分离未结合的染料。将产物mAK9.2.27/4-缀合物在溶液中于4℃保存。
mAK9.2.27/4-缀合物(在磷酸盐缓冲液pH7.8中)的VIS/NIR吸收光谱见图5。
荧光量子产额Q=0.1%(5μmol/l在磷酸盐缓冲液pH7.8中;相对于作为标准的靛花青绿在DMSO中的Q=13%,参见R.C.Benson andH.A.Kues,化学及工程学数据22(1977)379)。
4.2用酸不稳定异硫氰酸酯8标记
将在0.5ml 50mmol硼酸盐缓冲液(pH9.2)中的1mg抗体与6μl8(在DMF中的5mmol/l初始溶液)混和并在室温搅拌15分钟。经NAP-5柱(用25mmol磷酸盐缓冲液pH7.4,+0.01%NaN3洗脱)分离未结合的染料。将产物mAK9.2.27/5-缀合物在溶液中于4℃保存。
5.二聚的靛三羰花青染料的合成
5.1对称螺环二聚体10的产生(图3)
将0.1g(0.47mmol)3,9-二亚乙基-2,4,8,10-四氧杂螺环-[5.5]十一碳烷(根据M.Crivello et al.,聚合物科学杂志:A部分:聚合物化学34(1996)3091-3102所述合成)和0.11g(0.94mmol)6-氨基-1-己醇在15ml乙醚中于室温搅拌24小时,真空蒸发溶剂。残余物在油泵上干燥并无需进一步纯化直接反应。
将0.2g(0.28mmol)5-羧基-双-1,1’-(4-硫丁基)-靛三羰花青钠盐9在15ml二氯甲烷中与0.09g(0.28mmol)TBTU和30mg三乙胺一起搅拌30分钟,并与在2ml二氯甲烷中的0.06g(0.14mmol)上述螺环化合物混和。在室温搅拌18小时后,用乙醚沉淀产物并色谱纯化(RPC-18,流动相溶剂甲醇/10mmol磷酸盐缓冲液pH8)。冻干后,用甲醇/二氯甲烷沉淀产物,获得68mg(26%)产物10。
10(5μmol/l在磷酸盐缓冲液pH8中)的VIS/NIR吸收光谱见图6。
荧光量子产额Q=0.2%(5μmol/l在磷酸盐缓冲液pH8中;相对于作为标准的靛花青绿,见实施例4.1)。
5.2用酸不稳定的腙连接结构6产生染料二聚体(11)
将0.1g(0.14mmol)5-羧基-双-1,1’-(4-硫丁基)-靛三羰花青钠盐9在10ml DMF中与45mg(0.14mmol)TBTU和15mg三乙胺一起搅拌30分钟,并与在2ml DMF中的0.14g(0.16mmol)6混和。在室温搅拌5小时后,加入乙醚结晶产物、过滤并色谱纯化(RP C-18,流动相溶剂甲醇/10mmol磷酸盐缓冲液pH8)。冻干后,用甲醇/二氯甲烷沉淀盐,获得0.13g(59%)产物11。
11(4μmol/l)在磷酸盐缓冲液pH8.0中及37℃24小时后在磷酸盐缓冲液pH6.0中的VIS/NIR吸收光谱见图7。
6.测量作为时间的函数的不同pH值下11的荧光量子产额
在pH为7.4;7.0;6.6;6.0和5.0的50mmol磷酸盐缓冲液中的浓度为4μmol/l的11的溶液于37℃保温,在不同的时间取溶液等份,测定荧光量子产额(SPEX Fluorolog Spectral fluorometer,400W Xe灯,PM958探头,用探头的波长依赖的敏感性校准,数值相对于靛花青,见实施例4.1)。
图8示出了基于作为时间的函数的不同pH值下荧光量子产额的增加的观察到的酸不稳定二聚体11的裂解。
7.具有酸不稳定腙连接结构的阿霉素-靛三羰花青缀合物(13)的合成(图4)
将20mg(34μmol)盐酸阿霉素和11mg(68μmol)4-(氨基甲基)-苯甲酸酰肼在加入2μl三氟乙酸后在3ml无水甲醇中于室温搅拌24小时。用乙腈结晶产物12,离心,用乙腈洗涤并干燥,得18mg(24μmol)粗产物。将14mg(20μmol)5-羧基-双-1,1’-(4-硫丁基)-靛三羰花青钠盐9在0.5ml DMF中与7mg(22μmol)TBTU和20μl三乙胺一起搅拌30分钟。在0℃将这一反应混合物滴加入上述12的溶液(18mg于0.2ml DMF)中并在0℃搅拌3小时。通过加入乙醚沉淀产物并类似于实施例5色谱纯化产物。获得12mg(47%)13。
Claims (12)
1、通式I的化合物
(F-L)m-A (I)其中
F代表在600-1200nm间具有至少一个最大吸收的染料分子,
L代表连接结构,其含有一个酸不稳定的和/或可酶裂解的键,
m是一个1-80之间的数,
其中若m是一个1-3之间的数,则
A代表在600-1200nm间具有至少一个最大吸收的染料分子,
抗生素活性或细胞抑制活性的分子,生物分子,非生物学大
分子或者化合物B-(L-W)o或D-(L-W)o,其中
D是非生物学大分子,
B是生物分子,
L具有上述含义,
W代表抗生素活性或细胞抑制活性的分子,
o是一个1-20之间的数,
并且若m是一个4-80之间的数,则
A代表生物分子,非生物学大分子或者化合物B-(L-W)o或D-(L-W)o,其中
D,B,L,W和o具有上述含义。
2、权利要求1的化合物,其特征在于在通式(I)中,F和/或A代表聚甲炔染料、四吡咯染料、四氮杂吡咯染料、黄嘌呤染料、吩口恶嗪染料或吩噻嗪染料。
3、前述任一项权利要求的化合物,其中在通式(I)中,F和/或A代表花青染料、squarililium染料,croconium染料,部花青染料或oxonol染料。
R1-R4和R7-R10各自独立地代表氟、氯、溴、碘原子或硝基
或基团-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、
-NE1E2、-OE1、-OSO3E1、-SO3E1、-SO2NHE1、-E1,
其中E1和E2各自独立地代表卤素原子、饱和或不饱和的支
链或直链C1-C50烷基链,其中该链或该链的部分任选地
可以形成一或多个芳香或饱和环状C5-C6单位或双环C10
单位,并且其中C1-C50烷基链被0-15个氧原子和/或0
-3个羰基基团间断和/或被0-5个羟基、0-5个酯基、0-
3个羧基、0-3个氨基取代,
并且在每种情况下相邻的基团R1-R4和/或R7-R10可以相互
连接形成六元芳香碳环,
R5-R6各自独立地代表具有上述含义的-E1或代表C1-C4磺
烷基链,
和/或R1-R10代表一个与L的键合,
其中
R11代表氢、氟、氯、溴或碘原子或硝基或基团-NE1E2、
-OE1或-E1,其中E1和E2具有上述含义,或者R11代
表一个与L的键合,
R12代表氢原子或具有上述含义的基团E1,
R13和R14各自独立地代表氢原子、饱和或不饱和的支链或直
链C1-C10烷基链,其可被至多5个氧原子间断和/或被至
多5个羟基取代,并且R13和R14可以相互连接形成五或
六元环。
5、前述任一项权利要求的化合物,其中在通式(I)中,W或A代表抗生素、叶酸类似物、嘧啶类似物、嘌呤类似物、激素活性物质以及其他具有抑制细胞活性的物质。
6、前述任一项权利要求的化合物,其中在通式(I)中,L代表含有下述酸不稳定片段的结构: 其中p代表2-4之间的数。
7、前述任一项权利要求的化合物,其中在通式(I)中,L代表含有可酶裂解的化学键的结构。
8、前述任一项权利要求的化合物,其中在通式(I)中,L代表被组织蛋白酶、肽酶、羧基肽酶、α-和β-葡糖苷酶、脂酶、氧化酶、磷脂酶、磷酸酶、磷酸二酯酶、蛋白酶、弹性蛋白酶、硫酸酶、还原酶、转移酶和细菌酶裂解的结构。
9、前述任一项权利要求的化合物,其中在通式(I)中,A和/或B代表抗体、其缀合物和片段、特异的肽和蛋白质、受体、酶、酶底物、核苷酸、天然或合成的核糖核酸或脱氧核糖核酸或其化学修饰物、如aptamers或反义寡核苷酸、脂蛋白、凝集素、糖类、单糖、二糖或三糖、直链或支链寡糖或多糖或糖衍生物或葡聚糖。
10、前述任一项权利要求的化合物,其中在通式(I)中,D代表聚乙二醇、聚丙二醇、聚赖氨酸、或聚赖氨酸树状物或其衍生物。
11、权利要求1的化合物在用于用NIR辐射体内诊断疾病组织和用于治疗疾病组织中的应用。
12、用于用NIR辐射体内诊断疾病组织的光学诊断试剂,其中其含有至少一种权利要求1的化合物,以及通用的佐剂和/或载体和稀释剂。
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JPH07145148A (ja) * | 1992-06-02 | 1995-06-06 | Bio Sensor Kenkyusho:Kk | ポリメチン系化合物およびそれを用いる測定方法 |
GB9310978D0 (en) * | 1993-05-27 | 1993-07-14 | Zeneca Ltd | Compounds |
DE4445065A1 (de) * | 1994-12-07 | 1996-06-13 | Diagnostikforschung Inst | Verfahren zur In-vivo-Diagnostik mittels NIR-Strahlung |
AU4497096A (en) * | 1995-01-30 | 1996-08-21 | Daiichi Pure Chemicals Co., Ltd. | Diagnostic marker |
US5741657A (en) * | 1995-03-20 | 1998-04-21 | The Regents Of The University Of California | Fluorogenic substrates for β-lactamase and methods of use |
IT1276833B1 (it) | 1995-10-09 | 1997-11-03 | Sorin Biomedica Cardio Spa | Coloranti fluorescenti della famiglia della solfo benz e indocianina |
DE19539409C2 (de) * | 1995-10-11 | 1999-02-18 | Diagnostikforschung Inst | Kontrastmittel für die Nahinfrarot-Diagnostik |
CA2251985A1 (en) * | 1996-04-19 | 1997-10-30 | Alan Lewis Hamilton | Squarate dyes and their use in fluorescent sequencing method |
DE19649971A1 (de) * | 1996-11-19 | 1998-05-28 | Diagnostikforschung Inst | Optische Diagnostika zur Diagnostik neurodegenerativer Krankheiten mittels Nahinfrarot-Strahlung (NIR-Strahlung) |
DE19717904A1 (de) * | 1997-04-23 | 1998-10-29 | Diagnostikforschung Inst | Säurelabile und enzymatisch spaltbare Farbstoffkonstrukte zur Diagnostik mit Nahinfrarotlicht und zur Therapie |
CN1764637A (zh) | 2003-02-28 | 2006-04-26 | 国际壳牌研究有限公司 | 方法 |
-
1997
- 1997-04-23 DE DE19717904A patent/DE19717904A1/de not_active Ceased
-
1998
- 1998-04-02 EP EP98929212A patent/EP0988060B1/de not_active Expired - Lifetime
- 1998-04-02 JP JP54471598A patent/JP5118790B2/ja not_active Expired - Fee Related
- 1998-04-02 WO PCT/DE1998/001001 patent/WO1998047538A2/de active IP Right Grant
- 1998-04-02 DK DK98929212T patent/DK0988060T3/da active
- 1998-04-02 KR KR1019997009757A patent/KR100613306B1/ko not_active IP Right Cessation
- 1998-04-02 HU HU0003132A patent/HU226812B1/hu not_active IP Right Cessation
- 1998-04-02 US US09/403,418 patent/US6534041B1/en not_active Expired - Lifetime
- 1998-04-02 DE DE59814030T patent/DE59814030D1/de not_active Expired - Lifetime
- 1998-04-02 ES ES98929212T patent/ES2289786T3/es not_active Expired - Lifetime
- 1998-04-02 AU AU79057/98A patent/AU733757B2/en not_active Ceased
- 1998-04-02 AT AT98929212T patent/ATE364404T1/de active
- 1998-04-02 CN CN98804489A patent/CN1253507A/zh active Pending
- 1998-04-02 CA CA002287262A patent/CA2287262C/en not_active Expired - Fee Related
- 1998-04-02 PT PT98929212T patent/PT988060E/pt unknown
-
1999
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104395407A (zh) * | 2012-03-30 | 2015-03-04 | 生命科技公司 | 用于检测活性氧的经修饰的结合核酸的花青染料 |
CN104395407B (zh) * | 2012-03-30 | 2016-07-13 | 生命科技公司 | 用于检测活性氧的经修饰的结合核酸的花青染料 |
US9518981B2 (en) | 2012-03-30 | 2016-12-13 | Life Technologies Corporation | Modified nucleic acid binding cyanine dyes for the detection of reactive oxygen species |
CN111494714A (zh) * | 2012-12-21 | 2020-08-07 | 原始G股份有限公司 | 具有微生物功能的可裂解涂层材料 |
CN105492905A (zh) * | 2013-03-15 | 2016-04-13 | 普渡研究基金会 | 炎性疾病的荧光成像 |
CN105492905B (zh) * | 2013-03-15 | 2018-12-07 | 普渡研究基金会 | 炎性疾病的荧光成像 |
CN114748640A (zh) * | 2022-05-06 | 2022-07-15 | 南方医科大学珠江医院 | 一种pH响应性的siRNA递送系统 |
CN114748640B (zh) * | 2022-05-06 | 2024-02-09 | 南方医科大学珠江医院 | 一种pH响应性的siRNA递送系统 |
Also Published As
Publication number | Publication date |
---|---|
US6534041B1 (en) | 2003-03-18 |
DK0988060T3 (da) | 2007-10-15 |
JP2010116413A (ja) | 2010-05-27 |
ATE364404T1 (de) | 2007-07-15 |
ES2289786T3 (es) | 2008-02-01 |
PT988060E (pt) | 2007-08-17 |
HUP0003132A3 (en) | 2003-03-28 |
AU733757B2 (en) | 2001-05-24 |
NO327495B1 (no) | 2009-07-20 |
WO1998047538A2 (de) | 1998-10-29 |
EP0988060A2 (de) | 2000-03-29 |
NO995181L (no) | 1999-10-22 |
JP5118790B2 (ja) | 2013-01-16 |
CY1106860T1 (el) | 2012-05-23 |
JP2001521530A (ja) | 2001-11-06 |
CA2287262A1 (en) | 1998-10-29 |
AU7905798A (en) | 1998-11-13 |
CA2287262C (en) | 2007-02-06 |
EP0988060B1 (de) | 2007-06-13 |
WO1998047538A3 (de) | 1999-01-21 |
HU226812B1 (en) | 2009-11-30 |
NO995181D0 (no) | 1999-10-22 |
KR100613306B1 (ko) | 2006-08-17 |
DE19717904A1 (de) | 1998-10-29 |
DE59814030D1 (de) | 2007-07-26 |
KR20010020183A (ko) | 2001-03-15 |
HUP0003132A2 (hu) | 2001-01-29 |
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