CN1058598A - 新型生物活性缀合物 - Google Patents
新型生物活性缀合物 Download PDFInfo
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- CN1058598A CN1058598A CN91105270A CN91105270A CN1058598A CN 1058598 A CN1058598 A CN 1058598A CN 91105270 A CN91105270 A CN 91105270A CN 91105270 A CN91105270 A CN 91105270A CN 1058598 A CN1058598 A CN 1058598A
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Abstract
通式1的缀合物,其中A-O-为通式A-O-H
药物的残基,
[A-O-W-I]a-T
A-O-H中的-O-H为一级或二级羟基;a为1
至30的整数;W为通式2基团
其中b为1至的整数,B表示含1至3个碳原子的亚
烷基,R1和R2各自独立表示氢原子、卤素、烷基、苯
基或取代苯基;Z为间隔基;T为载体部分。
Description
本发明涉及把具有治疗效用的蒽环类化合物与诸如天然来源或合成来源的多克隆抗体、单克隆抗体、蛋白或多肽缀合的缀合物;涉及这类缀合物的制备方法、含有这类缀合物的制剂配方,以及在一些哺乳类肿瘤治疗中的应用。本发明还涉及新型蒽环衍生物及其制备。
近年来,已经合成了许多高细胞毒性蒽环化合物。例如,分子中含有与糖环的c-3′位相连接的吗啉代或取代吗啉代环的那些蒽环化合物在鼠实验肿瘤模型上,就显示了令人鼓舞的抗肿瘤活性。(见于Bioaetive mokecukes,55-101,vol6,Edi-ted by J.William Lown,Elveiser 1988)。
本发明与新型连接体有关。这类连接体用于从生物活性剂中释放具有治疗效用的药物,以便在人体用药过程中,提高药物的疗效,降低药物毒性。特别要指出,该类生物活性剂包含的药物上连有游离一级羟基或二级羟基、属于诸如抗菌素、抗癌或抗病毒类化疗剂,并且缀合到能够与选择的细胞群作用的抗体上,或者缀合到天然来源或合成来源,可与受体组织作用的蛋白、多肽或高聚物上。
每种药物至少含一个一级羟基或二级羟基,在该一级或二级羟基部位通过一对酸敏感的缩醛键与连接臂结合,再通过连接臂以共价键的方式结合到载体上。本发明的生物活性剂中酸敏感的缩醛键,使之在靶组织的酸性外环境或酸性内环境中释放出活性药物。
据上所述,本发明提供通式1所代表的缀合物,其中A-O-基为通式是A-O-H的药物残基,
而A-O-H中的-O-H为一级或二级羟基;a是从1到30的整数;W是通式2代表的基团:
在通式2中,b是从1到4的整数,B代表含1至3个碳原子的亚烷基,R1和R2分别独立表示氢、卤素、烷基、苯基或取代苯基;Z为一间隔基团;T为载体部分。
a最好是从1到5的整数。B恰切地表示-(CH2)2-。在R1和R2的定义中,卤素为氯、溴或碘较为典型,烷基则可含1至4个碳原子,比如为甲基或乙基。取代苯基可以是卤素取代苯基或烷基取代苯基,在此情况下,卤素和烷基与上面的定义相同。Z基团最好是:
(ⅰ)-NH-;
(ⅱ)-NH-(CH2)c-S-S-,其中c是从1到4的整数;
(ⅲ)-NH-〔C〕d-N=CH-,其中
a)d等于零,
b)d等于1,〔C〕代表-NH-CO(CH2)e-O-(CH2)e-,该式中的e是从2到4的整数,
c)d是从1到4的整数,〔C〕代表-(CH2)f-O-(CH2)f-,该式中的f等于1或2,或者
d)d是从2到6的整数,〔C〕为CH2;
(ⅳ)-NH-〔C〕d-NH-CO-,其中〔C〕和d的定义同上;
(ⅴ)-〔D〕-NH-,其中〔D〕代表-NH-〔CH2〕g-CO-,该式中的g是从2到6的整数;
(ⅵ)-〔E〕-CO-,其中〔E〕代表-NH-(CH2)g-NH-,该式中g是从2到6的整数,或者
在前面的通式1中,药物A-O-H最好代表属于蒽环族的抗肿瘤药,例如阿霉素和它的3′-去氨基-3′-吗啉基衍生物,该衍生物中的吗啉代环选择在2″位以诸如含2到4个碳原子的烷氧基取代;代表嘧啶类似物,例如5-氟去氧尿苷或阿糖胞苷;代表长春花属生物碱的衍生物,例如4-去乙酰长春花碱;或代表其它抗肿瘤药,例如鬼臼脂素或隐陡头菌素族。药物A-O-H亦可选择为抗病毒药,例如3′-叠氮基-3′-去氧-胸腺嘧啶核苷(AZT)、溴乙烯基去氧尿苷(BVDU),9-〔(2-羟乙基)甲基〕鸟嘌呤(acyclovir)或者9-〔(1,3-二羟基-2-丙氧基)甲基〕鸟嘌呤(gancyclovir),或者选择为抗菌素,例如硫霉素或我们的新型青霉烯(penem)衍生物,比如(5R,6S)-2-Carbamcyloxymethyl-6-〔(1R)-hydroxyeth-yl〕-2-penem-3-Carboxylic acld和acetoxy-methyl(5R,6S)-2-Carbamoyloxymethyl-6-〔(1R)-hydroxyethyl〕-2-penem-3-carb-oxylate。
若A-O-部分衍生自蒽环A-O-H,那么A-O-典型地表示
其中R10为氩原子、羟基、或甲氧基;R11和R12中的一个为氢原子,另一个为羟基,或者R11为氩原子或碘原子而R12为氢原子;R13为氨基,或代表包含在吗啉代环中的氮原子。吗啉代环可以是,例如吗啉代(MO)环、3-氰基-4-吗啉代(CM)环,或2-甲氧基-4-吗啉代(MM)环,环中氮原子按下述方式连接于C-3′位:
载体部分T典型地是从多克隆抗体或来自多克隆抗体的包含抗原结合部位的片段选择,它们能够结合到与肿瘤关联的抗原上;或从单克隆抗体或来自单克隆抗体的包含抗原结合部位的片段选择,它们能够优先结合到抗原上,或选择性地表达在肿瘤细胞群上;或者从能够优先或选择性地与肿瘤细胞相结合的多肽或蛋白中选择;以及从高聚载体选择。
最好是从可以表示为T-〔NH2〕x(其中x表示可用于缩合的氨基数目)的化合物中衍生的载体部分,能够从多克隆抗体中选择,该多克隆抗体能够产生抗肿瘤抗原;或者从单克隆抗体中选择,该单克隆抗体能够优先与抗原结合,或选择性地在肿瘤细胞群上表达;或者从天然的或重组的多肽、蛋白或生长因子中选择,它们能优先地或选择性地结合于肿瘤细胞;或者从天然的或合成的高聚载体,例如从聚赖氨酸中选择。该载体部分也可以从上面提取的载体的某一部分衍生。例如从上述抗体的Fab或F(ab′)2片段衍生,或者从上面提到肽或通过重组体DNA技术得到的蛋白质的部分衍生的。
上述抗体和相关治疗应用的代表例是:抗T细胞抗体,如抗体T101〔Royston,I.等人,J.Immunol.1980,125,725〕,抗CD5抗体,如抗体OKT1(Ortho)ATCC CRL 8000(Chronic lymphocytic leukaemias),抗铁传递蛋白抗体,如抗体OKT9(Ortho)ATCC CRL 8021(ovaric和其它肿瘤),抗黑素瘤抗体,如抗体MAb 9.2.27(Bumol,T.F等人,Proc.Natl.Acad.Sci.USA 1982,79,1245)(melanomas),抗癌制造抗体,如抗CEA1116 NS-3d ATCC CRL 8019,抗α-甲胎蛋白OM 3-1.1 ATCC HB 134,791T/36〔Embleton M.J.等人,Br.J.Cancer 1981,43,582)(Osteogenic sarcoma),B72.3〔US-A-4,522,918(1985〕(Colorectal carcinomas和其它肿瘤),抗卵巢癌抗体,如抗体OVB 3 ATCC HB 9147,抗乳房癌抗体,如抗体(HMGF抗原)〔Aboud-Priak,E.等人,Cancer Res.1988,48,3188〕,抗骨癌抗体,如抗体1G3.10〔Yu,D.S.等人,Eur.J.Urol.1987,13,198〕
上面提到的天然或重组来源的生长因子和蛋白的象征性范例是,FGF、EGF、PDGF、TGF-α、α-MS、interleukineS、干扰素、TNF、黑色素(MSH)等。
从可表示为T-〔sH〕X1(其中x1代表可用来缩合的硫羟基数)的化合物衍生的载体部分最好从例如使用N-琥珀酰亚胺基-S-乙酰基硫代乙酸酯(SATA)、N-琥珀酰亚胺基-3-(2-吡啶基硫代)丙酸酯(SPDP)、D.L-高半胱氨酸硫代内酯、N-乙酰基-D,L-高半胱氨酸硫代内酯,或者2-亚氨基硫代内酯获得的硫羟化多克隆抗体或单克隆抗体衍生。
从可表示为7-〔CHO〕X2(其中x2代表可用来缩合的甲酰基总数)的化合物衍生的载体部分最好从那些具有糖基的多克隆或单克隆抗体衍生,糖基最好位于其FC区,并能象US-A-4,671,958中描述的那样,可经化学或酶学方法选择性氧化为醛基。T-〔CHO〕X2载体也可以从适宜的高聚载体甲酰化或氧化衍生,或者从适宜的糖蛋白的糖基氧化成醛基制备。
从可以表示为T-〔COOH〕x3(其中x3代表可用来缩合的羧基总数)的化合物衍生的载体部分最好从聚天冬氨酸或聚谷氨酸衍生;或者从那些衍生自具有下面结构的N-(2-羟丙基)异丁烯酰胺
(HMPA)的可溶性和可生物降解的合成共聚物衍生,HMPA中的〔X〕为-Gly-Phe-Leu-Gly、-NH-(CH2)n-CO-(n为1到5的整数),〔P〕为OH、O-C6H4PNO2,X/Y为(90/10÷95/5mol/mol%),分子量为10000至40000,最好是12000至20000〔见于J.Kopecek“Biodegradation of polymers for biomedical use”in IUPAC Macromolecules,H.Benoit and P.Rempp,Ed.505-520(1982),Pergamon Press.Oxford.England〕;或者从聚(氨基酸)共聚物,例如聚(谷氨酸钠、丙氨酸、酪氨酸)共聚物或分子量为25000至50000道尔顿可用作肺组织靶药的载体(结构见后)〔R.Duncan et al.,Journal of Bioactive and Compatible Polymers,vol.4,July1989〕衍生;或从天然存在于单克隆或多克隆抗体之上的羧基衍生,或从使用双功能基酸酐(例如马来酸酐)处理抗体,用化学方法引入的羧基衍生。
聚(谷氨酸钠、丙氨酸、酪氨酸)
共聚物的结构
本发明进一步提供制备通式1缀合物的程序,该程序包括:把通式3的衍生物与能提供所述通式1缀合物中间隔基Z和载体部分T的一种或数种化合物缩合,借以生成所说的通式1缀合物。
3中A-O-和W与前面的定义相同。缩合反应可以通过活泼衍生物。例如通式3的混合酸酐、叠氮或活泼酯来实施,或者在缩合剂二环己基碳二亚胺的存在下直接进行。一个适宜的程序包括将通式3的衍生物转化成通式4的衍生物,在通式
4中,A-O-及W与前面的定义相同,L代表用于形成酰胺键的活泼基团,例如N-氧琥珀酰亚胺基、它的水溶性衍生物N-氧磺基琥珀酰亚胺基,或者2,4-二硝基苯氧基、2,3,4,5,6-五氟苯氧基,或者叔丁氧羰氧基;和
(ⅰ′)把生成的通式4化合物与前面定义过的通式T-〔NH2〕X的化合物缩合,以便提供具有酰胺键的通式1的生物活性化合物;或者
(ⅱ′)把通式4的化合物与通式为NH2-(CH2)c-SH的硫醇衍生物,例如2-氨基乙硫醇(C=2),缩合,生成通式5的化合物
其中A-O-,W和C的定义与前面相同;再把通式5的生成物与前面定义过的通式T-〔SH〕X1化合物反应,以便制得具有二硫醚键的通式1缀合物;或者
(ⅲ′)把通式4的化合物与肼、丁二酸或己二酸的双肼衍生物,或二氨基化合物反应,生成通式6的化合物,该化合物中的A-O-、W、〔C〕和d的定义与前面相同;再把通式6的生成物与前
面定义过的通式T-〔CHO〕X2化合物缩合,以便制得具有肟键的通式1生物活性化合物。
一个有用的程序包括(ⅳ′)把上面描述的通式为6的化合物与通式为7的化合物在缩合剂的存在下缩合,以便生成通式1的缀合物。通式为7的化合物
通过包含前面定义的通式为T-〔COOH〕X3的载体的反应制备,7式中的y是从1到30的整数,并代表活泼羧基的总数,T是生成的通式1缀合物中的载体部分,L′代表形成酰胺键的羟基或活泼基。反应中随意存在的尚未反应的活化了的羧基,可以用药物上可以接受的氨,比如,1-氨基-2-丙醇,加以封闭。
其它有用的程序包括(ⅴ′)把通式4的化合物与通式为H2N-〔CH2〕g-COOH的氨基衍生物(其中g的定义同前)缩合,借以生成通式8的衍生物:
8式中,A-O-、W和〔D〕的定义同前;通式8的化合物随意地转变为通式9的活泼衍生物:
其中A-O-、W、〔D〕和L的定义同前,而且把生成的通式9的化合物或通式8的化合物在缩合剂的存在下,与前面定义的通式T-〔NH2〕x的化合物缩合,以便生成通式1的生物活性化合物。
其它程序包括(ⅵ′)将通式4的化合物与通式H2N-(CH2)g-NH2(其中g的定义同前)的氨基衍生物反应,借以生成通式10的衍生物:
其中〔E〕的定义同前,或者
(ⅶ′)把通式4的化合物与哌嗪反应,生成通式11的衍生物,并把上面描述的通式10或11的化合物
与前面描述的通式7的化合物缩合,以便生成通式1的缀合物。
例如,把通式3或8的化合物转变为通式4或9衍生物的活化方法是,在乙酸乙酯或N,N-二甲基甲酰胺一类的溶剂中,在N,N′-二环己基碳二亚胺的存在下,将通式3或8的化合物与N-羟基琥珀酰亚胺或它的水溶性3-取代磺酸钠盐反应。在这种情形下,通式4和9中的L代表下面的残基:
其中Ra代表氢原子或磺酸钠基。
把T-〔COOH〕X3类型的载体转变为通式7的化合物的活化方法是,这种载体在N,N′-二环己基碳二亚胺的存在下,在二甲基甲酰胺一类的溶剂中。与对硝基苯酚反应,在这种情形下,L′代表PNO2C6H4-O-;或者在四氢呋喃或二甲基甲酰胺一类的溶剂中,与N-乙氧羰基-2-乙氧基-1,2-二氩苯醌(EEDQ)反应〔见B.Belleau et al.,JACS,90,1651(1968)〕,在这种情形下,7式中的L′代表下面的残基:
另一种程序包括载体T-〔COOH〕X3的碱金属盐,比如钠盐,与烷基-卤素-碳酸酯,例如含1至4个碳的烷基-卤素-碳酸酯,最好是氯代碳酸乙酯(C2H5O-COCl),在水或二甲基甲酰胺一类的溶剂中反应。在这种情形下,式7中的残基L′代表-COOC2H5。
以通式3或8的化合物及具有式T-〔NH2〕x结构的载体为原料,制备通式1的缀合物的缩合反应,是在能够生成酰胺类型共价键以及与载体的结构和谐的条件下进行的。根据载体在水中或有机溶剂中的化学稳定性,可以采用不同的程序进行与通式4、5、6、9、10和11中间体的偶联反应。若载体对有机溶剂敏感,建议的反应条件包括使用PH7至9.5的缓冲水溶液,在4至37℃的温度下,反应数小时至数日。
通过衍生物5和通式T-〔SH〕X1载体缩合,制备通式1缀合物,是在包括使用PH6至7的缓冲水溶液、温度为4℃、反应时间为数小时至数日等条件下进行的。
通过衍生物6与通式T-〔CHO〕X2载体缩合,制备通式1缀合物。是在能够生成肟或腙类型的共价键的条件下进行的,而且该条件与载体的结构协调一致。建议采用的条件包括,使用PH为4至7.5的缓冲水溶液,反应温度4至37℃,反应时间数小时至数日。
通过衍生物6、10或11与通式T-〔CO-L′〕y载体缩合,制备通式1缀合物,是在能够生成酰胺式共价键的条件下进行的,而且该条件与载体的结构协调一致。建议采用的条件包括,使用PH为7至9.5的缓冲水溶液,反应温度4至37℃,反应时间数小时至数日。
其它条件包括使用无水二甲基亚砜或无水二甲基甲酰胺,室温反应1至3小时。
这里提到的“数小时至数日”的反应周期,可以从4小时至5天。
例如,通式4和9的化合物与抗体T-〔NH2〕x之间进行缩合反应的适宜条件是:含1mg/ml单克隆抗体,PH为8的0.1M磷酸钠水溶液和0.1M氯化钠水溶液,与过量30倍摩尔的4或9的10%(w/v)N,N-二甲基甲酰胺溶液,在20℃反应24小时。缀合物在sephadex G-25柱(pharmacia Fine Chemical.Piscataway.N.J.)上通过凝胶过滤纯化,用PBS(磷酸盐-缓冲盐水)洗脱。
通式5的化合物与含硫羟基的功能基化的抗体偶合的适宜条件是,含1mg/ml单克隆抗体,PH为6的0.1M醋酸钠水溶液和0.1M氯化钠水溶液,与过量30倍摩尔浓度为5%(w/v)的相同缓冲液在4℃下反应24小时。生成的缀合物用前面叙述过的凝胶过滤法纯制。
通式6的化合物与T-〔CHO〕x2型载体间的偶合的适宜条件是,含1mg/ml单克隆抗体,PH6至7的0.1M醋酸钠和0.1M氯化钠水溶液,与过量30倍摩尔,浓度为5%(w/v)的6的相同缓冲溶液,在20℃下反应24小时。生成的缀合物用前面叙述过的凝胶过滤法纯制。
通式6、10和11的化合物与通式7的活泼载体缩合的适宜条件是,含5至50mg/ml化合物6、10或11的二甲基甲酰胺一类无水极性溶剂的反应液,与等摩尔的化合物7在20℃下反应24小时。
通式3的化合物,以及通式4、5、6、9、10和11的活化化合物,均为新化合物,因而包括在本发明的范围之内。
化合物3、5、6、10和11具有作为反应中间体和/或作为活性治疗剂的双重功效。应当特别指出,通式3的中间体是通式A-O-H化合物有用的前药。这在前面已经叙述过。通式3的衍生物能用图1所示的程序制备。该程序包括,把通式A-O-H的药物与诸如通式12之一的带有保护羧基的适宜的烯醇醚衍生物缩合,通式 12
中的B、b、R1和R2的定义同前,R3表示一保护基,例如甲基或乙基;然后脱去生成物中的保护基。
图1
抗肿瘤蒽环类表示用于制备通式1的生物活性衍生物的适宜羟基化药物(A-OH),所以没有限制本发明。
在蒽环化合物的类型中,通式(13)的3′-去氨基-3′-吗啉基衍生物,例如3′-去氨基-3′-(4-吗啉基)阿霉素(13a),或3′-去氨基-3′-(2-甲氧基-4-吗啉基)阿霉素(13b)〔见E.M.Acton et al.,Morpholin-yl Anthracyclines,in Bioactive Mokecules,vol 6,Edt.by J.W.Lown,Elsevier,1988〕,代表了选择的化合物。
欲将通式13a,b的蒽环转化为前面定义过的通式3的新型酸敏感衍生物,可以这样进行:按J.A.Landgrebe等在文献J.Org.Chem.43,1244(1975)中描述的方法,将带有酮基的适宜化合物与重氮基乙酸乙酯反应,制备前面表述过的通式12化合物,其中Rx为乙基一类的残基;然后再用12去处理13a,b。蒽环类及其它含一级或二级羟基的化合物与化合物12反应时,优先选择的反应条件是,用磺酸,比如对甲苯磺酸或樟脑磺酸作催化剂,在二甲基甲酰胺一类的极性溶剂中,室温反应数小时至数日。通式3的化合物中蒽环上连接的酸敏感残基的保护羧基转化为通式4化合物的活泼羰基,再由它与适宜的载体偶合,制备新的生物活性剂。通式4的蒽环衍生物,可随意地转变为通式5、6、8、9、10和11的衍生物,并能与适宜的载体反应用以制备通式1的生物活性化合物。具有治疗价值的药物,例如前面描述过的那些药物,也能按蒽环中描述的相同风格,与通式12的化合物反应,并转化为治疗一些乳房疾患的生物活性化合物。
本发明的通式1生物活性化合物由于含有缩醛键,在水合氢离子的催化下水解或“在体内”酶解。便能释放出母体药物A-OH,所以是有用的化疗剂。例如,众所周知,与正常组织比较,恶性肿瘤中的糖基化比率要高。这就导致肿瘤内乳酸产物增加并降低PH值〔见H.M.Rauen et al.,Z.Naturforsch,Teil B 23(1968),1461〕。
按照描述的方法制备的缀合物,采用不同的化学-物理方法检定。例如,在不同波长下使用色谱凝胶过滤操作(Yu,D.S.et al.,J.Urol.,140,415,1988)和凝胶电泳法,分别或同时检测蒽环和抗体,估算出它保持原分子量不变,且不形成聚集体。获得的化合物的总电荷分布,是通过离子交换色谱法估定的。蒽环浓度是采用分光光度滴定,并参照由母体蒽环绘制的标准校正曲线估算的。蛋白浓度是通过比色测定,比如bicinconic acid测定(Smith,P.K.et al.,Anal.Biochem.,150,76,1985〕或Bradford染料测定〔Bradford,M.M.,Anal.Biochem.,72,248,1976〕来估算的。缀合操作之后,抗体的抗原结合活性的保持,是通过FLISA方法〔Yu,D.S.et al.,J.Urol.,140,415,1988〕和细胞荧光法〔Gallego,J.et al.,Int.J.Cancer,33,737,1984〕评价的。与母体药物比较,缀合物的细胞毒性度的评价。是在培养时间长到足以说明极大细胞毒性效应之后〔Dillmann,R.O.,et al.,Concer Res.,48,6097,1988〕,测定靶细胞的3H-胸腺嘧啶脱氧核苷抑制敏度而确定的。
与抗原阴性细胞族相比较,缀合物对抗原阳性细胞族的选择性细胞毒性度,是通过短时间培养后〔Dillmann,R.O.et al.Cancer Res.,48,6096,1988〕,测定抗原阳性细胞族对比抗原阴性细胞族的3H-胸腺嘧啶脱氧核苷抑制敏度而确定的。
缀合物的酸敏感度,是将该化合物在适当的缓冲溶液中培养之后,用前面提到的色谱法进行评价的。
另外,缀合物的抗体部分(125I)和/或蒽环部分(14C)放射性标记。和HPLC分析法,用来评价缀合物在血浆中的稳定性。
生物学活性
化合物3′(按例1制备)在体外进行了抗Lovo(人体结肠腺癌)和Lovo-Doxo-耐药(Lovo/Dx)细胞测定,处理4小时后使用单细胞覆盖技术(溶菌测定),同时与阿霉素及3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素(136)进行比较。50%抑制浓度(IC50),根据浓度-效应曲线计算。表1中报道的数据说明,化合物3′对敏感和耐药两类细胞的毒性均高于阿霉素,但比它的母体化合物136的毒性低15至20倍。
化合物3′在患P388-阿霉素-耐药白血病(P388/DX Johnson)的CDF-1鼠上进行了体内试验,并与阿霉素及化合物136进行了比较。表2中报道的数据表明,化合物3′在肿瘤接种后第一天按0.22mg/kg的剂量腹膜内给药,显示很高的活性(T/C% 184)。
通式1′、1″、1ⅴ、1ⅵ和1ⅶ的缀合物(分别按例5、6、11和12制备)在P388/DX Johnson白血病模型上进行了体内试验,并与阿霉素和游离药物13b进行了比较。这些缀合物中的细胞毒药物3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素残基,是通过酸敏感连接体连接的。表3中报道的数据说明,在肿瘤接种后第一天静脉给药,所有新化合物保持的活性都等于游离药物13b的活性。以LD50-100和最佳剂量间的比值表征的治疗指数,所有缀合物都比游离药物13b高。
表4中报道了在pH3(醋酸盐缓冲液)和37℃下,从缀合物释放3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素(13b)的t50%。
表1:治疗4小时后的细胞毒性度
IC50=ng/ml(1)
(1)IC50=抑制50%菌落生长的浓度
(2)R.I.=耐受性指数=(IC50Lovo/DX)/(IC50Lovo)
表2:P388/DX Johnson白血病的抗肿瘤活性,第一天腹膜内给药
(3)平均存活时间;高出非治疗对照组的%。
(4)依据对死鼠尸解所进行评价。
表3:对P388/DX Johnson白血病的抗肿瘤活性,第一天静脉给药
*最佳剂量
(5)剂量:(ng/kg):以缀合物中13b的含量表示
表4:在PH5,37℃,醋酸盐缓冲液(7)中,从缀合物中释放13b
(6)释放50%游离药13b所需要的时间。通过HPLC法,用化合物13b的校正曲线测定。
(7)离子强度0.05M。
化合物的疗效,以及与它们的母体比较疗效的改善,在人体移植肿瘤的动物模型上进行评估。患有人体肿瘤异种移植癌的裸鼠,用适宜剂量的缀合物,游离药、抗体、药物和抗体的机械性混合物,在同剂量下进行治疗,记录肿瘤生长情况,并在不同的治疗组间进行比较。
按照药剂处方将缀合物与可以药用的载体或稀释剂进行配方。任何合适的载体或稀释剂均可使用。适用的载体和稀释剂包括,生理盐水和Ringers右旋糖苷溶液。
现用下述范列说明本发明,但本发明不受它们的限制。
例1
14-O-(1-羧甲氧基-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素〔3′;A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H〕的制备:
按UK Application No.8928654.6中描述的方法制备的3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素(13b)(0.68g,1mmole),溶于无水二甲基甲酰胺(20ml)中,并在熔融过的对甲苯磺酸(50mg)存在下用2-(环己烯-1-基)-氧乙酸乙酯〔12′:b=1,R3=C2H5,B=-(CH2)2-,R1=R2=H〕(6g,32mmole)处理。混合物在室温下搅拌2小时,然后注入碳酸氢钠水溶液中,用二氯甲烷萃取。有机层用水洗,无水硫酸钠干燥并过滤。减压下蒸除溶剂。残留物在闪式硅胶柱上分离。二氯甲烷/甲醇(98/2 V/V)混合液洗脱,得到标题化合物3′的酯衍生物(R3=C2H5)。
该化合物在0℃、搅拌下,氮气保护,用0.1N氯氧化钠水溶液(200ml)处理1小时。然后用醋酸将混合物的PH调至8.2,並用正丁醇萃取。有机层用水洗,减压下浓缩至小体积,用闪式硅胶柱层析分离,二氯甲烷/甲醇(80/20,V/V)混合液洗脱,得到标题化合物3′(0.35g,收率43%),3′是用等当量盐酸水溶液处理,冷冻干燥后的游离酸衍生物。
TLC用硅胶板(Merck)F254,展开系统的二氯甲烷/甲醇(95/5 V/V),Rf=0.13;
MS-FD:m/e783(M+);
1H NMR(200MHF,DMSO d6)δ:
1.12(d,J=6.4Hz,3H,CH3-5′);1.3-1.9(m,12H, ,CH2-2′);2.0-2.7(m,7H,CH2-8,O-CH2CH2-N,O-CH-CH2-N,H-3′);2.94(s,2H,CH2-10);3.24(s,3H,CH-OHC3);3.40,3.73(two m,2H,NCH2CH2O);3.57(m,1H,H-4′);3.91(s,2H,OCH2COOH);3.97(s,3H,OHC3-4);4.04(dq,J=6.4,1.0Hz,1H,H-5′);4.35(dd,J=2.2,5.2Hz,1H,OCH-OCH3);4.61(s,2H,CH2-14);4.92(m,1H,H-7);5.24(m,1H,H-1′);7.6-7.9(m,3H,H-1,H-2,H-3);13.20(bs,1H,OH-11);14.02(s,1H,0H-6).
例2
14-O-(1-羧甲氧基-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素的N-氧琥珀酰亚胺基衍生物〔4′∶A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、L=-O- 〕的制备:
按例1所述制备的化合物3′(0.2g,0.25mmol)溶于8ml无水二甲基甲酰胺中,冷至0℃,用N-羟基琥珀酰亚胺(0.2g)和二环己基碳二亚胺(0.4g)处理。混合物0℃放置2小时,然后在室温下放置过夜。此后,反应混合物在减压下浓缩至小体积,残留物在闪式硅胶柱上分离,二氯甲烷/甲醇混合溶剂(97/3.V/V)洗脱。含标题化合物的馏分减压浓缩至干,残留物溶入乙酸乙酯中,过滤並在减压下浓缩至小体积。最后加乙醚並在垂熔玻璃漏斗上收集标题化合物4′(0.130g),用乙醚洗、並在氮气保护下保存。
TLC用硅胶板(Merck)F254,展开系统为二氯甲烷/甲醇(95/5.V/V),Rf=0.37。
MS-FD:m/e864(M+)。
例3
14-O-(1-肼基羰基甲氧基-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素〔6′:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、d=O〕的制备:
按例2所述制备的化合物4″(20mg)溶入5ml四氢呋喃中,并加入1M的水合肼的异丙醇溶液。混合物在0℃放置70分钟,然后加二氯甲烷,混合物用冷水洗三次。分出有机层、无水硫酸钠干燥,过滤、减压蒸除溶剂。残留物在闪式硅胶柱上分离,用二氯甲烷/甲醇混合溶剂(99/1,v/v)洗脱。化合物6′,20mg,用乙醚沉淀出来。
TLC用硅胶板(Merck)F254,展开系统为二氯甲烷/甲醇(95/5,v/v),Rf=0.25。
MS-FD:m/e 797(M+)
1HNMR(200MHz,DMSO d6)δ:
1.36(d,J=6.6Hz,3H,CH3-5′);1.4-1.7(m,10H, );1.76(m,2H,CH2-2′);2.30(m,2H,CH2-8);2.50(m,1H,H-3′);2.55(m,4H,N-CH2-CH(OCH3),N-CH2-CH2-O);2.98(d,J=18.8Hz,1H,H-10ax);3.22(dd,J=1.0,18.8Hz,1H,H-10e);3.39(s,3H,CH(OCH3));3.55,3.95(two m,2H,NCH2CH2O);3.70(m,1H,H-4′);3.95(m,1H,H-5′);4.09(s,3H,CH3-O-4);4.10(m,2H,O-CH2CONH);4.50(m,1H,NCH2-CH(OCH3));4.67(s,2H,CH2-14);5.28(m,1H,H-7);5.54(m,1H,H-1′);7.64(bs,1H,CONHNH2);7.78(t,J=7.9Hz,1H,H-2);8.04(d,J=7.9Hz,1H,H-1);13.32(s,1H,OH-11);13.98(s,1H,OH-6).
例4
14-O-〔1-(4-羧基-1-正丁基)氨基甲酰基甲基氧-1-环己基)〕-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素〔8′:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、g=4〕的制备:
r-氨基丁酸(15mg,0.15mmol)溶于PH为716的2.5ml 0.05M的磷酸盐缓冲液中,並加入按例2所述制备的化合物4′(30mg,0.033mmol)与3ml乙腈配成的溶液。混合物室温放置过夜,然后用醋酸调PH至6,並用正丁醇萃取。分出有机层並减压浓缩。残留物用硅胶柱层析分离,二氯甲烷/甲醇(95/5,V/V)混合溶液洗脱,得到20mg标题化合物8′。
TLC用硅胶板(Merck)F254,展开系统为二氯甲烷/甲醇(95/1,V/V).Rf=0.55。
MS-FD:m/e884(M+)。
例5
通式1′的聚谷氨酸缀合物〔1′:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、Z=-NH-NH-CO-、a=2T=聚-L-谷氨酸〕的制备:
分子量为2000至15000的聚-L-谷氨酸(Sigma)(85mg)、按例3所述制备的化合物6′(20mg),溶于2ml二甲基甲酰胺中,并搅拌3小时。然后加入25mgN-乙氧羰基-2-乙氧基-1,2-二氢喹啉。反应混合物搅拌过夜。然后倒入乙醚和石油醚的混合液中。在重熔玻璃漏斗上收集沉淀,用乙醛洗,并溶入到8ml2.5%的碳酸氢钠水溶液中。所得溶液通过-40至63μm(Merck)(30×1.8cm)的RP-8反相柱,并用水和乙腈的混合液洗脱,乙腈从0递增至20%。含缀合物的馏分冷冻干燥并收集于重熔玻璃漏斗上,用甲醇和乙醚洗,得到45mg标题化合物1′。用光谱进行估算,该缀合物含13%通式13b的甲氧吗啉代。
例6
通式1″的聚(谷氨酸钠、丙氨酸、酪氨酸)-缀合物〔1″:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、Z=-NH-NH-CO-、a=2、T=聚(谷氨酸钠、丙氨酸、酪氨酸)〕的制备:
按照例5中描述的相同程序,分子量为25000至50000的聚(谷氨酸钠、丙氨酸、酪氨酸)(1∶1∶1)(Sigma)60mg和按例3所述制备的化合物6′20mg溶于2毫升二甲基甲酰胺中,搅拌3小时并用N-乙氧羰基-2-乙氧基-1,2-二氧喹啉(25mg)处理,经反相柱纯化后得35mg标题化合物1″。
例7
取1ml PH为8,由0.1M NaH2PO4,0.1M NaCl及纯化的小鼠单克隆抗人体黑素瘤抗体EP1〔Giacomini,P.et al.,Int.J.Cancer,39,729(1978)〕的溶液,该黑素瘤抗体溶液浓度为2mg/ml,在搅拌下室温缓慢加例2中描述的10-2M的化合物4′的N,N-二甲基甲酰胺(37.5mcl)溶液。反应混合物在室温下,于黑暗处搅拌过夜,并离心分离。在Sephadex-G25(PD-10,pharmacia)柱上凝胶色谱过滤分离缀合物,用PH为7.3的PBS(Gibco,10X,Cat.N.042-04200M)洗脱。收集洗脱下来的峰(1.5ml),在48nm波长用分光光度计方法检测蒽环组分。用比色蛋白分析(BCA,Pierce)检测蛋白组分。该缀合物含1.27mg/ml抗体,蒽环/蛋白比为11.4/1.0。产物的化学-物理外观,通过HPLC-凝胶过滤分析(Biosil SEC-250柱,0.1M NaH2PO4,0.1M NaCl,PH7.0),双波长(280和480nm)检测,以及SDS-PAGE确定。HPLC表明,有50%的蛋白发生了聚集,从柱的间隙容积流出。SDS-PAGE表明,蒽环吸附和Coomassie-染料蛋白反应二者都定位在160KD分子量,从而证实了共价键的形成,也指出由于非共价键相互作用而形成的聚集。
例8
通式1ⅳ的抗结肠癌缀合物〔1ⅳ:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、Z=-NH-NH-、T=B7213〕的制备:
1ml由PH为6,0.1M NaH2PO4的缓冲溶液和B7213抗体〔US-A-4,522,918〕组成的溶液,抗体浓度为2.6mg/ml,用0.1ml 0.1M NaIO4的水溶液4℃下,在黑暗中处理。1小时后,产品在Sephadex G25柱(PD-10pharmacia)上用凝胶过滤色谱纯化。用0.1M pH为6的NaH2PO4洗脱。
含蛋白的馏分(1.7mg,2ml)用按例3所述制得的化合物6′的相同缓冲液的溶液处理,6′溶液浓度为10%w/v,用量为30摩尔当量。在37℃下,黑暗中反应24小时后,反应混合物按例7中描述的程序纯化。
该缀合物含0.48mg/ml抗体,蒽环/蛋白比率为2.4/1,而且85%为单体。
例9
3-异丁烯酰胺基-2-羟基-丙烷和14-O-{1-〔4-(N-异丁烯酰甘氨酰苯丙氨酰亮氨酰甘氨酰)肼基〕-羰甲氧-环己基}-3′-去氨基-3′-〔2(S)-甲氧-4-吗啉基〕阿霉素共聚物(1ⅴ)〔1ⅴ:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、Z=-NH-NH-CO-、T=HPMA、X=Gly-PHe-Leu-Gly〕的制备:
按〔J.Kopecek et al.,Makromol.Chem.,177,2833-2848(1976)〕中描述的程序,由3-异丁烯酰胺基-2-羟基-丙烷和N-异丁烯酰甘氨酰苯丙氨酰亮氨酰甘氨酸对硝基苯酯的游离基聚合反应,制备的共聚物HPMA〔X=Gly-Phe-Leu-Gly,P=OC6H4PNO2且含量为4.2%(mol/mol %)〕0.58g溶到含衍生物6′(0.1g)的15ml无水二甲基亚砜溶液中,其中6′按例3所述制备。室温反应2天后,加入0.4ml1-氨基-2-丙醇,而且将反应混合物注入300ml丙酮和乙醚1∶1(V/V)的混合液中。收集沉淀,再溶于10ml 95%的乙醇中,用80ml丙酮从该溶液中沉淀出,标题化合物1ⅴ,收集沉淀并用乙醚洗。
产量:0.51g。
按3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素的盐酸盐(13a)计算的蒽环的含量(w/w%)为:3.3%。通式1ⅴ中的百分摩尔比(r∶s∶t)=(95.7∶0.79∶3.52)
例10
14-O-(1-哌嗪基羰甲氧基-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素〔11′:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H〕的制备:
按例2所述制备的化合物4(100mg)溶于20ml无水四氢呋喃中,冷至0℃,并加由50mg哌嗪与2ml无水四氢呋喃配制成的溶液。反应混合物0℃下搅拌15分钟,然后用100ml二氯甲烷稀释,用3×50ml水洗。分出有机层,无水硫酸钠干燥,减压蒸除溶剂。粗产品用硅胶层析柱分离,用二氯甲烷/甲醇(80/20,V/V)混合溶液洗脱。用乙醚沉淀出80mg化合物11′。
TLC用硅胶板(Merck)F254,展开系统为二氯甲烷/甲醇(70/30,V/V),Rf=0.60。
FD-MS:m/z868(100,〔M+H〕+)。
1HNMR(200HMZ,CDCl3)δ:
1.35(d,J=6.6Hz,3H,5′-CH3);1.3-1.9(m,12H,2′-CH2,cyclohexane);2.11(dd,J=4.2,14.6Hz,1H,8ax-H);2.3-2.5(m,5H,8eq-H,3′-H.3″ax-H,5″-CH2);2.60(dd,J=3.9,11.2Hz,1H,3″eq-H);2.86(m,4H,CH2-NH-CH2);3.00(d,J=18.9Hz,1H,10ax-H);3.23(dd,J=1.2,18.9Hz,1H,10eq-H);3.37(s,3H,2″-OCH3);3.4-3.6(m,5H,CON(CH2)2;6″ax-H);3.90(m,1H,6″eq-H);3.98(q,J=6.6Hz,1H,5′-H);4.07(s,3H,4-OCH3);4.18(s,2H,OCH2CON);4.48(dd,J=2.5,3.9Hz,1H,2″eq-H);4.79(m,2H,14-CH2);5.24(m,1H,7-H);5.53(m,1H,1′-H);7.37(d,J=7.7Hz,1H,3-H);7.76(dd,J=7.7,6.8Hz,1H,2-H);8.02(d,J=6.8Hz,1H,1-H);13.30(bs,1H,11-OH);13.98(s,1H,6-OH).
例11
3-异丁烯酰胺基-2-羟基-丙烷和14-O-{1-〔4-(N-异丁烯酰甘氨酰基)哌嗪-1-基〕羰甲氧基-环己基}-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素共聚物(1ⅵ)〔1ⅵ:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、Z=〔1,4-哌嗪基〕-CO-,T=HPMA、X=-HN-CH2-CO-〕的制备:
按〔J.Kopecek et al.,Makromol.Chem.,177,2833-2848(1976)〕中描述的程序,由3-异丁烯酰胺基-2-羟基-丙烷和N-异丁烯酰甘氨酸对硝基苯酯的游基聚合反应,制备的共聚物HPMA〔X=HN-CH2-CO-,P=OC6H4PNO2且含量为7.6%(mol/mol %〕0.42g溶到2.2ml无水二甲基亚砜中,并与按例10所述制备的衍生物11′(0.07g)反应。室温反应2小时后,加入0.05ml 1-氨基-2-丙醇,反应混合物注入到200ml丙酮和乙醚1∶1(V/V)的混合液中。收集沉淀,并再加入10ml95%乙醇中,用80ml丙酮从其中沉淀出标题化合物1ⅵ,收集产物并用乙醚洗。
产量:0.39g。
按3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素盐酸盐(13a)计算的蒽环含量(w/w%)为,9.74%。
通式1ⅵ中的摩尔百分比(r∶s∶t)=(92.4∶2.15∶5.45)。
例12
3-异丁烯酰胺基-2-羟基-丙烷和14-O-{1-〔4-(6-异丁烯酰胺基己酰基)哌嗪基〕-羰甲氧-环己基}-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素共聚物(1ⅶ)〔1ⅶ:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、I=〔1,4-哌嗪基〕-CO-、T=HPMA、X=HN-(CH2)5-CO-〕的制备:
按〔J.Kopecek et al.,Makromol.Chem.,177,2833-2848(1976)〕中描述的程序,由3-异丁烯酰胺基-2-羟基-丙烷和N-异丁烯酰胺基己酸对硝基苯酯的游离基聚合反应,制备的共聚物HPMA〔X=HN-(CH2)5-CO-、P=OC6H4PNO且含量为5.3%(mol/mol %)0.6g溶入3ml无水二甲基亚砜中,并与0.1g按例10所述制备的衍生物11′反应。室温反应2小时后,加入0.1ml 1-氨基-2-丙醇。反应混合物注入到200ml丙酮和乙醚1/1(V/V)的混合溶液中。按照例11中描述的相同程序,得0.58g标题化合物1ⅶ。
按3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素盐酸盐(13a)计算,蒽环的百分含量(w/w%)为9.2%,
通式1ⅶ中的摩尔百分比(r∶s∶t)=(94.7∶2.05∶3.31)。
例13
聚(谷氨酸钠、丙氨酸、酪氨酸)(1∶1∶1)和14-O-(1-哌嗪基羰基甲氧基-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素缀合物(1ⅷ)〔1ⅷ:A-O-=13b′、b=1、B=-(CH2)2-、R1=R2=H、I=〔1,4-哌嗪基〕-CO-、T=聚〔谷氨酸钠、丙氨酸、酪氨酸)〕的制备:
室温搅拌下将分子量为25000至40000的聚(谷氨酸钠、丙氨酸、酪氨酸)(1∶1∶1)(Sigma)0.2g溶入5ml水中。用0.1N盐酸将该溶液酸化至PH3,使对应的游离酸从水溶液中沉淀出来。所得聚(谷氨酸、丙氨酸、酪氨酸)0.17g,真空干燥后溶入10ml无水二甲基甲酰胺中。往该溶液中加入0.035g14-O-(1-哌嗪基羰甲氧基-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素(11′),11′按例10所述制备,和0.08gN-乙氧羰基-2-乙氧基-1,2-二氢喹啉(EEDQ)。三小时后再加另一批EEDQ(0.08g,反应混合物室温搅拌过夜,然后倾入300ml乙醚中。所得沉淀混悬于10ml水中并用14ml 0.1N氢氧化钠处理;用0.1N盐酸调pH至8.5,用Sephadex G10柱分离。水溶液冷冻干燥,得0.16g标题化合物1ⅷ。
按3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素盐酸盐(13a)计算,蒽环的百分含量(w/w%)为10%。
通式1ⅷ化合物中的百分摩尔比(r∶s∶t∶u)=(31.33∶2.01∶33.33∶33.33)。
Claims (31)
2、依据权利要求1的缀合物,其中A-O-部分自通式为A-O-H的蒽环衍生。
3、依据权利要求2的缀合物,其中A-O-部分代表
其中R10为氢原子、羟基或甲氧基,R11和R12中之一为氢原子,另一个为羟基,或者R11为氢原子或碘原子而R12为氢原子,R13为氢原子或代表吗啉代环中的氮原子。
4、依据上述任何一项权利要求的组合物,其中a为1至5的整数。
5、依据上述任何一项权利要求的缀合物,其中B表示-(CH2)2-。
6、依据上述任何一项权利要求的缀合物,其中Z为:
(ⅰ)-NH-;
(ⅱ)-NH-(CH2)c-S-S-,该式中的c是1到4的整数;
(ⅲ)-NH-〔C〕d-N=CH-,在该式中,
(a)d等于O,
(b)d等于1,〔C〕表示-NH-CO(CH2)e-CO-NH-,其中的e是2至4的整数,
(c)d为1至4的整数,〔C〕代表-(CH2)f-O-(CH2)f-,其中f等于1或2,或者
(d)d为2至6的整数,〔C〕代表CH2;
(ⅳ)-NH-〔C〕d-NH-CO-,其中〔C〕和d的定义同上;
(ⅴ)-〔D〕-NH-,其中〔D〕代表-NH-〔CH2〕g-CO-,该式中的g为2至6的整数;
(ⅵ)-〔E〕-CO-,其中〔E〕代表-NH-〔CH2〕g-NH-,该式中的g为2至6的整数,或者
(ⅶ)通式如下的哌嗪羰基:
7、依据上述任何一项权利要求的缀合物,其中载体部分T从多克隆抗体,或者由此而来的包括抗原结合部位能与肿瘤相关抗原结合的它们的片段;从单克隆抗体、或者由此而来的包括抗原结合部位,能优先与抗原结合或在肿瘤细胞群选择性表达的它们的片段;从能优先或选择性地与肿瘤细胞结合的多肽或蛋白;以及从高聚载体中选择。
8、依据权利要求7的缀合物,其中载体部分T从抗T细胞抗体、抗CD5抗体、抗铁传递蛋白受体抗体、抗黑素瘤抗体、抗瘤标记抗体、抗卵巢癌抗体、抗乳腺癌抗体和抗膀胱癌抗体中选择。
9、依据权利要求7的缀合物,其中载体部分T是生长因子。
10、如同权利要求1中定义的通式1缀合物的制备方法,该方法包括把通式3的衍生物与一种或多种能够提供所述间隔基Z和载体部分T的化合物缩合,借以生成所述的缀合物,在
通式3中,A-O-和W的定义与权利要求1同。
11、依据权利要求10的方法,其中缩合反应通过通式3的衍生物的活化衍生物进行,或在缩合剂的存在下直接进行。
12、依据权利要求10的方法,包括把所述通式3的衍生物转化为通式4的活泼衍生物,4
中的A-O-和W的定义同权利要求10,L代表形成酰胺键的活泼基团,而且
(ⅰ′)生成的通式4化合物与通式为T-〔NH2〕X的化合物缩合,该式中T为载体部分,X表示可用来缩合的氨基数,或者
(ⅱ′)通式4化合物与通式为NH2-(CH2)c-SH的硫醇衍生物缩合,该式中C是1至4的整数,并将生成的缩合产物通式5化合物与通式为T-〔SH〕Xi
的化合物缩合,通式5中A-O-、W和c的定义同前,而T-〔SH〕X1中T的定义同前,x1表示能用来缩合的硫羟基数,或者
(ⅲ′)通式4化合物与肼、丁二酰二肼衍生物、己二酰二肼衍生物或二氨基化合物反应,生成通式6的产物:
其中A-O-和W的定义与权利要求1同,〔C〕和d的定义同权利要求6。生成物6与通式T-〔CHO〕X2的化合物缩合,该通式中T为载体部分,x2表示可用来缩合的甲酰基数。
13、依据权利要求10的方法,包括
(ⅳ′)按权利要求12制备的通式6化合物与通式7的化合物缩合:
其中T为载体部分,y为1至30的整数并代表载体上的羧基总数,L′表示羟基或形成酰胺键的活泼基团,缩合反应随意地在缩合剂的存在下进行。
14、依据权利要求10的方法,包括
(ⅴ′)通式3的化合物与通式为H2N-〔CH2〕g-COOH的氨基衍生物缩合,该氨基衍生物通式中的g是2至6的整数,借以生成通式8的衍生物:
其中A-O-和W的定义同权利要求1,〔D〕的定义同权利要求6;通式8的化合物随意地转变为通式9的活泼衍生物:
其中A-O-、W和〔D〕的定义同前,L为形成酰胺键的活泼基团;在缩合剂的存在下。生成的通式9化合物或通式8化合物与通式为T-〔NH2〕X的化合物缩合,T-〔NH2〕X已在权利要求12中定义。
15、依据权利要求10的方法,包括
(ⅵ′)通式4的化合物与权利要求6定义的通式为H2N-(CH2)g-NH2的氨基衍生物反应,借以生成通式10的衍生物:
其中A-O-和W的定义同权利要求10,〔E〕的定义同权利要求6,或者
(ⅶ′)通式4的化合物与哌嗪反应,以便生成通式11的衍生物:
按照前面叙述的,把通式10或11的化合物与按权利要求13中叙述的通式7的化合物反应。
16、包括可以药用的载体或稀释剂,依据从权利要求1至9中任一项的作为活性组分的缀合物,或者依据权利要求10至15中任一项中的程序已经制备的作为活性组分的缀合物的药剂配方。
17、权利要求10中,定义的通式3的衍生物。
18、依据权利要求17的衍生物14-O-(1-羧甲氧基-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素。
20、权利要求12定义的通式4的衍生物。
21、依据权利要求20的衍生物,14-O-(1-羧甲氧-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基)阿霉素N-氧琥珀酰亚胺酯。
22、权利要求20中要求的通式4的衍生物的制备方法,该方法包括把权利要求19中要求的通式3的衍生物转变成所说的通式4的衍生物。
23、权利要求12中定义的通式5的衍生物。
24、制备权利要求23中要求的通式5衍生物的方法,该方法包括使用权利要求10中详述过的方法,从通式3的衍生物制备所述衍生物。
25、权利要求12中定义的通式6的衍生物。
26、依据权利要求25的衍生物,14-O-(1-肼基羰基甲氧-环己基)-3′-去氨基-3′-〔2(S)-甲氧基-4-吗啉基〕阿霉素。
27、权利要求25中要求的通式6的衍生物的制备方法,该方法包括按权利要求12中详述过的方法从通式3的衍生物,制备所述衍生物。
28、权利要求14中定义的通式9的衍生物。
29、权利要求28中要求的通式9衍生物的制备方法,该方法包括按照权利要求14中详述的方法,从通式3的衍生物制备所述衍生物。
30、权利要求15中定义的通式10或11的衍生物。
31、权利要求30中要求的通式10或11的衍生物的制备方法,该方法包括按照权利要求15中详述过的方法,从通式4的衍生物制备所述衍生物。
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DE4236237A1 (de) * | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, ihre Herstellung und Verwendung als Arzneimittel |
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CN1301853C (zh) * | 1998-01-13 | 2007-02-28 | 美国3M公司 | 颜色转变膜 |
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