CN1441678A - 具有氨磺酰基的化合物以及包含这些化合物的药物组合物 - Google Patents
具有氨磺酰基的化合物以及包含这些化合物的药物组合物 Download PDFInfo
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- CN1441678A CN1441678A CN01810337A CN01810337A CN1441678A CN 1441678 A CN1441678 A CN 1441678A CN 01810337 A CN01810337 A CN 01810337A CN 01810337 A CN01810337 A CN 01810337A CN 1441678 A CN1441678 A CN 1441678A
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Abstract
本发明涉及作为前体药物和/或载体可使活性成分摄入至红细胞中和/或使活性成分结合至红细胞上的化合物,其特征在于该化合物摄入至红细胞中和/或化合物结合至红细胞上是通过式-SO2NR1R2的基团实现的,式中R1和R2相互独立地代表氢原子、酰基、烷基、环烷基、芳基、氰基或羟基。通过本发明的前体药物,诸如在治疗上具有有价值的性质及高“首过”作用的内源性物质、天然物质以及合成物质的活性成分具有合理程度的口服利用性,或者显著地提高口服活性。
Description
本发明涉及作为前体药物和/或载体可使活性成分摄入至红细胞中和/或使活性成分结合至红细胞上的化合物。
本发明的目的是使活性成分,例如在治疗上具有有价值的性质并具有高“首过”作用的内源性物质、天然物质及合成物质,具有合理程度的口服利用性或者明显地提高它们的口服活性。
该目的是通过在活性成分中加入任选取代的氨磺酰基,例如作为“锚”,使得摄入红细胞中或者结合至红细胞上成为可能。
这意味着本发明涉及作为前体药物和/或载体可使活性成分摄入至红细胞中和/或使活性成分结合至红细胞上的化合物,其中化合物摄入至红细胞中和/或化合物结合至红细胞上是通过以下基团实现的:
-SO2NR1R2式中R1和R2相互独立地代表氢原子、酰基、烷基、环烷基、芳基、氰基或羟基。
基团R1和R2之一优选代表氢原子;基团R1和R2特别优选两个都代表氢原子。
本发明之N-单取代的化合物或者N,N-二取代的化合物可具有一个或二个N-烷基、N-烯基、N-环烷基、N-酰基或N-芳基取代基,这些取代基分别优选具有最多10个碳原子。R1和/或R2特别代表具有1-6个碳原子的烷基或酰基。实例为甲基、乙基、丙基或异丙基或者相应的酰基衍生物。芳基的例子为苯基或甲苯基。环烷基的例子为环戊基或环己基。
有迹象表明,在口服给药时,如果基团R1和R2两者都不是氢原子,则被断裂掉并被氢原子置换,使得在此情况下不是基团-SO2NR1R2而是基团-SO2NH2被提供摄入红细胞中或结合至红细胞上。图1是显示在口服给药17β-羟基-雌-1,3,5(10)-三烯-3-基-(N-乙酰基)氨基磺酸酯(J1045,14C-标记的酰基取代基和3H-标记的甾族化合物骨架)后氚在红细胞和血浆上的14C周围的不同活性分布。由该图可以看出,在口服给药后,氨基磺酸酯基中14C-标记的酰基取代基不再出现于血液中。该数据还证实根据本发明的物质相对于血浆富集在红细胞腔隙(the erythrocyte compartment)中。
因此,根据本发明优选的氨磺酰基也可首先由N-单取代的或者N,N-二取代的氨磺酰基,例如N-酰基氨磺酰基,在身体中形成。
根据本发明,前体药物(前药)被定义为也是在很大程度上无生理活性的而且仅是在进入身体后反应为实际上的活性成分的药物。除活性成分的作用外,前体药物也可具有其他药理作用。如果这些作用是主要或者完全与治疗相关的作用,则根据本发明的化合物将被认为在临界情况下也是活性成分,而不仅仅是前体药物(“载体”)。
化合物摄入至红细胞中或化合物结合在红细胞上是通过血红蛋白、膜蛋白和/或碳脱水酶(carboanhydrase)如碳脱水酶I(hCAI)和II(hCAII)进行的。
活性成分的储备是通过化合物摄入在红细胞中和/或化合物结合在红细胞上而形成于红细胞中的,由此身体中必要部分的活性成分存在于红细胞中。
根据本发明,术语“储备形成”定义为化合物(或者活性成分)在红细胞中的富集浓度比血浆中的浓度高10-1000倍、优选20-1000倍、特别优选30-1000倍,在此倍数是在通过离心由红细胞和血浆中分离并测定根据本发明的物质在红细胞和血浆中的浓度后测得的。对于雌二醇氨基磺酸酯(J995),发现在任何时间上述倍数都是98∶2。
基本上,所述化合物是在红细胞中发挥其作用的化合物。化合物和/或包含在化合物中的活性成分在此情况下优选预防寄生虫对红细胞的攻击,这在例如疟疾中是疾病的基本方面。
化合物优选具有以下结构:
活性成分-[间隔基团]n-SO2NR1R2式中n代表0或1的数,R1和R2与以上定义相同,而游离形式的活性成分具有至少一个官能团,其中优选基团R1和R2中至少一个为氢原子,并特别优选两个都为氢原子。
如果化合物起到前体药物的作用,则可通过释放、特别是水解断裂产物中包含的活性成分和/或其代谢物来得到治疗上所希望的作用。对于J995,发现该化合物在红细胞中是稳定的,而且仅在血浆或者组织中才由前体药物中释放活性成分。
如果n是0,则官能团优选是:
-OH基团,其与基团-SO2NH2形成基团-O-SO2NH2,
=O基团,其转化为基团=N-OH或=N-NH2并与基团-SO2NH2形成基团=N-O-SO2NH2或=N-NH-SO2NH2,
-NHR基团,其与基团-SO2NH2形成基团-NR-SO2NH2,其中R是氢原子或烷基(优选具有1-4个碳原子),或者NR是杂环体系的一部分,例如象在褪黑素或者一些所述的抗疟药中,或者
-SH基团,其与基团-SO2NH2形成基团-S-SO2NH2。
如果n是1,则官能团优选是基团-COOH或衍生于该基团的基团,如酯基,其与间隔基团和基团-SO2NH2形成基团-C(O)-间隔基团-SO2NH2,其中间隔基团在此情况下是-A-B-(O)s,在此s是0或1的数,A代表S、O或NR3,而R3是氢原子、烷基(优选具有1-4个碳原子)或者酰基(优选具有1-4个碳原子),B选自于亚烷基、亚芳基、亚烷基亚芳基或者亚烷基亚芳基亚烷基,它们可任选被取代。
如果n是1,则官能团还优选是基团-YH,其与间隔基团和基团-SO2NH2一起形成基团-Y-间隔基团-SO2NH2,其中Y代表S、O或NR4,R4是氢原子、酰基(优选具有1-4个碳原子)或烷基(优选具有1-4个碳原子),或NR4是杂环体系的一部分,而间隔基团是以下基团:式中t和p是0或1的数,而E选自于亚烷基、亚芳基、亚烷基亚芳基或者亚烷基亚芳基亚烷基,它们可任选被取代,或者,间隔基团代表以下基团:式中n和q是0或1的数,R5和R6相互独立地代表氢原子或烷基(优选具有1-4个碳原子),而D代表亚芳基,特别是亚苯基,或者,间隔基团代表以下基团:式中r和v是0或1的数,而m代表1-15的数。
根据本发明之化合物的结构简要地基于基团-SO2NH2进行解释。以上对基团-SO2NH2的阐述也相应地适用于基团-SO2NR1R2。
活性成分基本上可以是任何具有至少一个上述官能团之一并任选经由间隔基团通过所述官能团结合至基团-SO2NR1R2上的活性成分。
活性成分优选选自于雄激素、合成代谢药、抗雄激素、雌激素、孕激素、糖皮质激素、杀变形虫药、抗利尿剂、抗促性腺激素、溃疡治疗剂、神经药剂、多巴胺受体拮抗剂、多巴胺、阿朴吗啡、褪黑素以及肽,如GnRH(促性腺激素释放激素)和其他的下丘脑调节活性肽。
活性成分优选是雄激素,如睾酮,其中官能团是雄激素的17-羟基或者3-羰基。
活性成分优选是雌激素,如雌二醇、雌三醇或雌酮,其中官能团是3-、16-或17-羟基或者17-羰基。
活性成分优选是孕激素,如炔诺酮、地诺孕素、屈螺酮或左炔诺酮,其中官能团是17-羟基或者3-羰基。
活性成分特别优选是抗疟药,例如arteether、蒿甲醚、青蒿琥酯、氯喹、帕马喹、伯氨喹、pyrethamine、甲氟喹、氯胍、cinchonidine、cinchonine、羟氯喹、帕马喹、伯氨喹、乙胺嘧啶以及奎宁或奎宁衍生物,如二硫酸奎宁、碳酸奎宁、二氢溴酸奎宁、二盐酸奎宁、碳酸乙酯奎宁、甲酸奎宁、葡糖酸奎宁、氢碘酸奎宁、盐酸奎宁、水杨酸奎宁或硫酸奎宁。
除其药物动力学性质为,这些化合物(前体药物)还使药物具有累积于血红细胞(红细胞)中的能力。这导致以下的治疗相关性质或者优点:
1.仅通过所述的改性,就可使在治疗上具有有价值的性质以及高“首过”作用的内源性物质、天然物质及合成物质具有合理程度的口服利用性,或者显著提高口服活性。根据本发明的物质摄入至红细胞中防止了在由肝脏中(首次)通过时被血液带走,并由此防止了它们的代谢及排泄。
2.根据本发明的改性使这些物质与未取代的起始物质相比在肝脏中的副作用减少。
3.如果在红细胞中的作用是治疗的目的,在红细胞中的浓度成倍于在血浆中的浓度可特别地被利用。在寄生虫攻击红细胞、例如疟疾病中,情况尤为如此。
4.几乎所有的内源性激素、递质物质和许多活性成分由于快速发生的代谢和消除而限制了它们的治疗应用。根据本发明的改性,通过在红细胞中产生的储备,显著地延长了活性物质在肌体中的停留时间。避免了给药后短时间内在血浆中出现非常高的药物浓度。这是有利的,特别是在所有的物质是在中枢神经系统和周围神经系统中发挥作用的情况下。
5.此外,本发明还描述了前体药物。这些前体药物结合在红细胞上。由其前体药物(水解)释放酸,可产生治疗上所希望的作用。
根据本发明的化合物原则上可用于透皮给药、吸入或者注射中。但是,根据本发明之前体药物的治疗相关性质或者优点特别用于口服给药中。
由于本身的性质,药物治疗的成功明确地取决于相应治疗剂的药物动力学和药代动力学性质。另外,分配药物的剂型对于治疗的成功与否也是决定性的。所述剂型通过医师或患者对作用原则的适用性以及患者的“配合性”都有决定性的影响。可确定地认为,口服治疗形式比任何其他给药形式都具有更好的“配合性”。
高度接受口服给药的一个原因是给药的简单性以及治疗的良好控制性。口服给药的优异“配合性”的其他必要原因应与以下因素有关:我们习惯于用嘴摄取食物、液体及刺激剂。其他给药过程可被视为创伤性或者非自然性的,而且从治疗的更长期持续形式而言是不鼓励的。
图1显示了在一次性口服给药后3H/14C-J 1045 vs.3H-J 995的总放射活性分布。
图2基于J995解释了根据本发明的原理。
图3显示了可连接的雌二醇氨基磺酸酯(J1242)的化学合成以及该配体的固定化。
图4和5显示了在蛋白质印迹中亲和层析级分的分析。官能团
官能团可基本上是用其引入基团-SO2NR1R2的任何基团,其中任选通过间隔基团。
如以上所述,根据本发明的化合物优选具有以下结构:
活性成分-[间隔基团]n-SO2NH2式中n代表0或1的数,而游离形式的活性成分具有官能团。
如果n是0,则官能团优选是:
-OH基团,其与基团-SO2NH2形成基团-O-SO2NH2,
=O基团,其转化为基团=N-OH或=N-NH2并与基团-SO2NH2形成基团=N-O-SO2NH2或=N-NH-SO2NH2,
-NHR基团,其与基团-SO2NH2形成基团-NR-SO2NH2,其中R是氢原子或烷基(优选具有1-4个碳原子),或者NR是杂环体系的一部分,或者
-SH基团,其与基团-SO2NH2形成基团-S-SO2NH2。
如果n是1,则官能团优选是基团-COOH(或衍生于该基团的基团,如酯基),其与间隔基团和基团-SO2NH2形成基团-C(O)-间隔基团-SO2NH2。
如果n是1,则官能团还优选是基团-YH,其与间隔基团和基团-SO2NH2一起形成-Y-间隔基团-SO2NH2基团,其中Y代表S、O或NR4,R4是氢原子或烷基(优选具有1-4个碳原子),或NR4是杂环体系的一部分。活性成分
活性成分基本上可以是具有官能团而且通过该官能团以及任选通过间隔基团连接至基团-SO2NR1R2上的任何活性物质。
根据本发明的原理特别适合于在治疗上具有有价值的性质并具有高“首过”作用的内源性物质、天然物质以及合成物质。这些物质通过上述改性具有合理程度的口服利用性,或者口服活性得到显著提高。
具体而言,根据本发明的原理适合于以下活性成分类别或活性成分:
可用以下骨架描述并在分子中具有至少一个基团-SO2NR1R2可连接于其上的官能团的激素,所述官能团优选是上述官能团之一:
优选在3-或17-位具有基团HO-或C=O的代谢合成剂或雄激素,其中代谢合成剂的例子是诺龙、美替诺龙、及群勃龙(官能团:C=O或OH)以及普拉睾酮(官能团:C=O或OH),而雄激素的例子是美睾酮、脱氢表雄酮和睾酮(官能团:C=O或OH)。
抗雄激素,如Casodex(官能团:OH)和环丙孕酮或醋酸环丙孕酮(官能团:OH、C=O)。
优选在3-或17-位具有基团HO-或C=O的孕激素,其例子为地诺孕素、左炔诺酮、羟基孕酮、炔诺酮以及衍生于乙炔雌二醇或17α-羟基孕酮或诺龙的孕激素(官能团:17-OH,3-C=O),以及屈螺酮(官能团:C=O)。
优选具有3-、16-、或17-羟基和/或17-羰基作为官能团的雌激素,如雌二醇、雌三醇或雌酮(官能团:OH基团、C=O基团)。
糖皮质激素,例如可的松、地塞米松和泼尼松龙(官能团:OH、C=O)。
杀变形虫药,如甲硝唑、chlorotetracycline、土霉素、去甲环素、及四环素(官能团:OH)以及氯喹(官能团:NH)。
抗利尿剂,如加压素、去氨加压素、苯赖加压素、赖氨加压素、鸟氨加压素和特利加压素(官能团:NH)。
抗促性腺激素,如达那唑和对羟苯丙酮(官能团:OH)。
溃疡治疗剂,如前列腺素、米索前列腺醇(官能团:OH)。
多巴胺受体激动剂,如多培沙明、利舒来德和培高利特(宫能团:OH和/或NH)以及多巴胺(官能团:OH)。
神经药物和抗癌药。
肽,如GnRH和其他下丘脑调节活性肽。
抗疟药,如arteether、蒿甲醚、青蒿素、青蒿琥酯(官能团:OH、C=O)、氯喹、帕马喹、伯氨喹、pyrethamine(官能团:NH)、甲氟喹(官能团:NH、OH)、氯胍(官能团:C=NH)、cinchonidine、cinchonine(官能团:OH)、羟氯喹(官能团:OH、NH)、帕马喹、伯氨喹、乙胺嘧啶(官能团:NH)以及奎宁或奎宁衍生物,如二硫酸奎宁、碳酸奎宁、二氢溴酸奎宁、二盐酸奎宁、碳酸乙酯奎宁、甲酸奎宁、葡糖酸奎宁、氢碘酸奎宁、盐酸奎宁、水杨酸奎宁或硫酸奎宁(官能团:OH)。间隔基团
根据本发明,术语“间隔基团”定义为在基团-SO2NHR与活性成分的官能团之间的碳链和/或一个或者多个芳基。
由于生物利用度以及跨膜转运,根据本发明的化合物优选具有低于600的分子量。
如果官能团是基团-COOH,则间隔基团优选是基团-A-B-(O)s-,其中s是0或1的数,A代表S、O或NR3,而R3是氢原子、烷基(优选具有1-4个碳原子)或酰基(优选具有1-4个碳原子),以及B选自于亚烷基、亚芳基、亚烷基亚芳基或者亚烷基亚芳基亚烷基,它们可任选被取代。
如果官能团是基团-YH,则间隔基团优选是以下基团:式中t和p是0或1的数,而E选自于亚烷基、亚芳基、亚烷基亚芳基或者亚烷基亚芳基亚烷基,它们可任选被取代,或是以下基团:式中q和n是0或1的数,R5和R6相互独立地代表氢原子或烷基(优选具有1-4个碳原子),而D代表亚芳基,特别是亚苯基,它们可任选被取代,或者是以下基团:式中r和v是0或1的数,而m代表1-15的数。
根据本发明,亚烷基定义为具有1(或2)-20、优选1(或2)-10个碳原子的支链或直链亚烷基,其可任选被取代。取代基可选自于C1-4-烷基、C1-4-烷氧基、C1-4-酰基、卤原子(如氟、氯、溴或碘原子)、羟基或羰基。亚烷基的例子是亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基、亚庚基、亚辛基、亚壬基、亚癸基和亚十一烷基,它们可以是直链或支链的,并可任选被一个或者多个上述取代基取代。
根据本发明,亚烷基还包括具有2(或3)-20、优选2(或3)-10个碳原子的亚烯基和亚炔基,它们可任选被上述取代基取代。亚烯基或亚炔基的例子衍生于上述亚烷基的例子,其中可存在一个或者多个双键或叁键(最多4个)。
根据本发明,术语亚烷基还包括具有5-20、优选5-10个碳原子的环烷基,其可任选被取代。例子包括环戊基或环己基。
根据本发明,亚芳基定义为具有6-20个碳原子并任选被取代的亚芳基。所述一个或多个取代基可选自于卤原子(如氟、氯、溴或碘原子)、羟基、氨基、硝基、C1-4烷氧基、酰基、或C1-4-烷基。亚芳基的例子是亚苯基、卤代亚苯基、羟基亚苯基或亚萘基,其中优选亚苯基。
根据本发明,亚芳基还可定义为具有5-20个碳原子的亚杂芳基,其中1-3个碳原子可被硫原子、氧原子或氮原子替换。亚杂芳基的例子衍生于吡啶、呋喃、噻吩、吡咯、咪唑、吡嗪、嘧啶或哒嗪环。
根据本发明,亚烷基亚芳基定义为与具有6-19个碳原子的亚芳基连接的具有1-14个碳原子的直链或支链亚烷基。对于这两个基团,以上对亚烷基或亚芳基的定义除碳原子数外都适用。亚烷基亚芳基的例子有亚苄基或者取代的亚苄基,其中亚甲基的一个或者多个氢原子交换为C1-4-烷基。
根据本发明,亚烷基亚芳基亚烷基定义为与具有6-18个碳原子的亚芳基连接的具有1-13个碳原子的直链或支链亚烷基,而所述亚芳基又与具有1-13个碳原子的直链或支链亚烷基连接。对于这两种基团,以上对亚烷基或亚芳基的定义除碳原子数外都适用。优选的是以下基团:式中f和i是0或1的数,g和h代表1-5的数,而R7和R8相互独立地代表氢原子或C1-4-烷基。
具有1-4个碳原子的烷基的例子是甲基、乙基、丙基、异丙基、丁基、或叔丁基。
具有1-4个碳原子的烷氧基的例子是甲氧基、乙氧基、丙氧基、异丙氧基和叔丁氧基。
C1-4-酰基的例子是乙酰基、丙酰基或丁酰基。
在本发明中卤原子定义为氟、氯、溴或碘原子。药物组合物
本发明的主题还有包含至少一种根据本发明的化合物以及药物相容性佐剂和/或载体的药物组合物。
本发明的药物是以合适的剂量及本领域已知的方法用常规使用的固体或液体载体和/或稀释剂以及根据所希望的给药类型常规使用的佐剂而制得的。在优选的口服分配剂型中,片剂、薄膜片、包衣片、胶囊、丸剂、散剂、溶液剂或混悬剂还优选制成为缓释剂型。
片状的药物剂型可例如通过混合活性成分和已知的佐剂来制得,所述佐剂例如是葡萄糖、食糖、山梨醇、甘露醇、聚乙烯吡咯烷酮、崩解剂(如玉米淀粉或藻酸)、粘合剂(如淀粉或明胶)、润滑剂(如硬脂酸镁或滑石)。片剂还可由多层组成或者可具有碎裂线(break-line)。
另外,包衣片可通过用片剂包衣中通常使用的物质如聚乙烯吡咯烷酮或紫胶、阿拉伯胶、滑石、二氧化钛或食糖对以类似于片剂的制造方法制得的芯进行包衣来制备。在此情况下,包衣片的外壳也可由多个层组成,其中例如使用如上所述的佐剂。
含有本发明之活性成分的溶液剂或者混悬剂可与诸如糖、甜精或食糖混合和/或与调味剂如香草或柑橘提取物混合,以改善口味。另外,它们可与悬浮助剂如羧甲基纤维素钠或者防腐剂如对羟基苯甲酸混合。
胶囊的制备可通过混合药物活性物质和载体如乳糖或山梨醇、然后将它们引入胶囊中来进行。
栓剂的制备优选通过使活性成分与合适的载体物质如中性油脂或者聚乙二醇或其衍生物混合来进行。
活性成分的高生物利用度可通过储备作用来产生,该储备作用一方面使得可以给药非常低剂量的氨基磺酸酯,另一方面还可以更长的时间间隔给药。
这意味着,如果以前体药物的形式使用,根据本发明的化合物的剂量在口服给药时可以非常低,远低于给药包含于前体药物中的活性成分本身时的剂量,而且活性成分可以更长的时间间隔给药。
对于J995,例如发现,单个剂量单元可以是20-300μg的雌激素氨基磺酸酯,而给药间隔为1-3天;0.5-5.0mg的雌激素氨基磺酸酯,给药间隔为5-10天;或2.0-20mg的雌激素氨基磺酸酯,给药间隔为20-40天。
根据本发明的化合物、活性成分和间隔基团都可市售得到或者根据文献中已知的方法制备[参见例如:S.Schwarz等人,Steroids 61(1996)710-717;Pharmazie[Pharmaceutics]30(1975)17 ff.;WO96/05216;WO97/14712;WO93/05064;DE-A-1203042;Appel,Senkpiel,Chem.Ber.92(1959)1102-1104;G.Weiss,G.Schulze,Justus Liebigs Ann.Chem.729(1969)40-51;M.J.Reed等人,Pharm.Sci.(1996)11-16;U.G.Sahm等人,Pharm.Sci.(1996)17-20]。本发明原理的优点的说明
雌激素氨基磺酸酯是雌激素的前体药物,而且在给药后具有不同于雌激素的药代动力学性质,表现出可与透皮给药时达到的动力学相比的性质。口服给药后,雌二醇氨基磺酸酯被胃肠道重新吸收并摄入至红细胞中或者结合在红细胞上。通过摄入至红细胞中或者结合在红细胞上,防止了在由肝脏(首次)通过期间氨基磺酸酯被血液带走并由此防止代谢及排泄,使得雌二醇氨基磺酸酯表现出低的肝雌激素性。雌二醇氨基磺酸酯富集于红细胞中,其浓度数倍于血浆浓度(倍数98∶2),由此形成雌二醇氨基磺酸酯的储备,使得可以缓慢地向周围组织以及靶组织中释放雌二醇氨基磺酸酯(见图2)。这使得可以延长雌二醇氨基磺酸酯在肌体中的停留时间,并避免在血浆中出现非常高的浓度。
雌二醇氨基磺酸酯具有以下特征:
(a)前体药物摄入至红细胞中或者前体药物结合在红细胞上,以及
(b)前体药物在红细胞中的浓度数倍于血浆浓度(储备作用)
(c)由储备中缓慢释放活性成分。
由此产生以下优点:
-由于储备作用在血液中产生非常均一且长期的活性成分浓
度,
-活性成分的高口服生物利用度,这一方面可允许非常低剂量
的氨基磺酸酯,而另一方面可允许更长间隔的给药时间,
-降低血液浓度的个体变化,以及
-降低肝雌激素性作用。红细胞中雌二醇氨基磺酸酯的特异性载体蛋白的鉴别
在图3中显示了可连接的雌二醇氨基磺酸酯(J1242)的化学合成,其描述在以下文献中:S.Schwarz等人,Steroids 64(1999)460-471。在柱材料(E-AH-琼脂糖凝胶)中使雌二醇氨基磺酸酯衍生物固定化后,在柱上分离红细胞溶胞产物的蛋白质。负责将雌二醇氨基磺酸酯结合于红细胞上的蛋白质被吸附在亲和层析柱的表面上。在用醋酸盐缓冲液洗涤并洗脱存留在柱上的蛋白质后,洗脱物用“Westerm Plot法”进行分析(见图4和5)。
其结果发现,红细胞中的雌二醇氨基磺酸酯结合在碳脱水酶II(hCAII)上。亲和层析显示,红细胞的蛋白质组分特异性地结合,在此该结果不排除雌二醇氨基磺酸酯以及本发明的物质结合在红细胞的其他蛋白质上,如果这些蛋白质与J1242的亲和性落后于与hCA II的亲和性。
Claims (26)
1、作为前体药物和/或载体可使活性成分摄入至红细胞中和/或使活性成分结合至红细胞上的化合物,其特征在于该化合物摄入至红细胞中和/或化合物结合至红细胞上是通过以下基团实现的:
-SO2NR1R2式中R1和R2相互独立地代表氢原子、酰基、烷基、环烷基、芳基、氰基或羟基。
2、如权利要求1所述的化合物,其中化合物摄入至红细胞中和/或结合在红细胞上是通过血红蛋白、膜蛋白和/或碳脱水酶进行的。
3、如权利要求1或2所述的化合物,其中活性成分在红细胞中的储备是通过化合物摄入在红细胞中和/或化合物结合在红细胞上而形成的,由此必要部分的活性成分在身体中存在于红细胞中。
4、如权利要求3所述的化合物,其中化合物在红细胞中的富集浓度超过血浆浓度10-1000倍。
5、如权利要求1-4之一所述的化合物,其中该化合物是在红细胞中发挥其作用的化合物。
6、如权利要求2-5之一所述的化合物,其中该化合物是具有以下结构的前体药物:
活性成分-[间隔基团]n-SO2NR1R2式中n代表0或1的数,R1和R2与权利要求1中的定义相同,而游离形式的活性成分具有官能团。
7、如权利要求6所述的化合物,其中基团R1和R2之一代表氢原子。
8、如权利要求7所述的化合物,其中R1和R2代表氢原子。
9、如权利要求6-8之一所述的化合物,其中该化合物和/或包含在该化合物中的活性成分防止寄生虫对红细胞的攻击。
10、如权利要求9所述的化合物,其中活性成分是抗疟药,例如arteether、蒿甲醚、青蒿琥酯、氯喹、帕马喹、伯氨喹、pyrethamine、甲氟喹、氯胍、cinchonidine、cinchonine、羟氯喹、帕马喹、伯氨喹、乙胺嘧啶以及奎宁或奎宁衍生物,如二硫酸奎宁、碳酸奎宁、二氢溴酸奎宁、二盐酸奎宁、碳酸乙酯奎宁、甲酸奎宁、葡糖酸奎宁、氢碘酸奎宁、盐酸奎宁、水杨酸奎宁或硫酸奎宁。
11、如权利要求1-10之一所述的化合物,其中治疗上所希望的作用是通过释放、特别是水解断裂前体药物中包含的活性成分和/或其代谢物来实施的。
12、如权利要求6-8之一所述的化合物,其中n是0,官能团是:
-OH基团,其与基团-SO2NH2形成基团-O-SO2NH2,
=O基团,其转化为基团=N-OH或=N-NH2并与基团-SO2NH2形成基团=N-O-SO2NH2或=N-NH-SO2NH2,
-NHR基团,其与基团-SO2NH2形成基团-NR-SO2NH2,其中R是氢原子或烷基,或者NR是杂环体系的一部分,或者
-SH基团,其与基团-SO2NH2形成基团-S-SO2NH2。
13、如权利要求6所述的化合物,其中n是1,官能团是基团-COOH,其与间隔基团和基团-SO2NH2形成基团-C(O)-间隔基团-SO2NH2。
14、如权利要求11所述的化合物,其中间隔基团是-A-B-(O)s基团,在此s是0或1的数,A代表S、O或NR3,而R3是氢原子、烷基或者酰基,B选自于亚烷基、亚芳基、亚烷基亚芳基或者亚烷基亚芳基亚烷基,它们可任选被取代。
15、如权利要求8所述的化合物,其中n是1,官能团是基团-YH,其与间隔基团和基团-SO2NH2一起形成基团-Y-间隔基团-SO2NH2,其中Y代表S、O或NR4,R4是氢原子、烷基或酰基,或NR4是杂环体系的一部分。
16、如权利要求15所述的化合物,其中间隔基团是以下基团:式中t和p是0或1的数,而E选自于亚烷基、亚芳基、亚烷基亚芳基或者亚烷基亚芳基亚烷基,它们可任选被取代。
17、如权利要求15所述的化合物,其中间隔基团是以下基团:式中q和n是0或1的数,R5和R6相互独立地代表氢原子或烷基,而D代表亚芳基,特别是亚苯基,它们可任选被取代。
19、如权利要求16-18之一所述的化合物,其中所述官能团是基团-OH。
20、如权利要求6、7、8、9、10、11、12、13、14、15、16、17、18和/或20所述的化合物,其中活性成分选自于雄激素、合成代谢药、抗雄激素、雌激素、孕激素、糖皮质激素、杀变形虫药、抗利尿剂、抗促性腺激素、溃疡治疗剂、神经药剂、多巴胺受体拮抗剂、多巴胺、阿朴吗啡、褪黑素以及肽,如GnRH和其他的下丘脑调节活性肽。
21、如权利要求20所述的化合物,其中活性成分是雄激素,而官能团是雄激素的17-羟基或者3-羰基。
22、如权利要求21所述的化合物,其中雄激素是睾酮。
23、如权利要求20所述的化合物,其中活性成分是雌激素,而官能团是3-、16-或17-羟基或17-羰基。
24、如权利要求23所述的化合物,其中活性成分选自于雌二醇、雌三醇或雌酮。
25、如权利要求20所述的化合物,其中活性成分是孕激素,而官能团是17-羟基或3-羰基。
26、如权利要求25所述的化合物,其中活性成分选自于炔诺酮、地诺孕素、屈螺酮或左炔诺酮。
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CN101987104A (zh) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | 一种杂芳香基氨磺酰基羧酸酯碳酸酐酶抑制剂的眼用组合物 |
CN101987102A (zh) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | 一种糖皮质激素杂芳香基氨磺酰基羧酸酯的眼用抗炎组合物 |
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2000
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2001
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101987104A (zh) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | 一种杂芳香基氨磺酰基羧酸酯碳酸酐酶抑制剂的眼用组合物 |
CN101987102A (zh) * | 2009-08-05 | 2011-03-23 | 天津金耀集团有限公司 | 一种糖皮质激素杂芳香基氨磺酰基羧酸酯的眼用抗炎组合物 |
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