CN1333651A - RAS-法呢基转移酶抑制剂和磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精的复合物及方法 - Google Patents
RAS-法呢基转移酶抑制剂和磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精的复合物及方法 Download PDFInfo
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- CN1333651A CN1333651A CN99815707A CN99815707A CN1333651A CN 1333651 A CN1333651 A CN 1333651A CN 99815707 A CN99815707 A CN 99815707A CN 99815707 A CN99815707 A CN 99815707A CN 1333651 A CN1333651 A CN 1333651A
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- tetrahydrochysene
- benzodiazepine
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- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical class [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract
本发明提供下式(Ⅰ)的ras-法呢基转移酶抑制剂或其药学上可接受的盐和磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精形成的ras-法呢基转移酶抑制剂复合物,在式(Ⅰ)中,n表示0或1;R1选自Cl、Br、苯基、吡啶基或氰基;R2表示芳烷基;R3选自低级烷基、芳基或取代的芳基或杂环;Z1选自CO、SO2、CO2或SO2NR5,R5选自氢、低级烷基或取代的烷基。该复合物具有ras-法呢基转移酶抑制剂意想不到的高水溶性,并且可用于对癌症病人进行静脉内给药。本发明还提供形成该复合物的方法。所述ras-法呢基转移酶抑制剂可用作抗肿瘤药物。
Description
发明领域
本发明涉及水溶性和稳定性提高的ras-法呢基转移酶抑制剂复合物,该复合物是由ras-法呢基转移酶抑制剂如(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂和磺基丁基醚-7-β-环糊精或由(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂和2-羟丙基-β-环糊精组成,以及涉及制备这种复合物的方法。所述ras-法呢基转移酶抑制剂可用作抗肿瘤药物。所述复合物也可用作抗肿瘤药物。
发明背景
环糊精是由淀粉获得的环状低聚糖,由6个葡萄糖单元(α-环糊精)、7个葡萄糖单元(β-环糊精)或8个葡萄糖单元(γ-环糊精)形成。已知它们可与完全或至少部分嵌入5-8A环糊精腔内的小分子形成包含化合物,Saenger,W.,″Cyclodextrin Inclusion Compounds in Researchand Industry,″Angew.Chem.Int.Ed.Engl.19,344-362(1980)。在第351页,Saenger指出α-环糊精与水、甲醇、多碘化合物、碘、氪、n-丙醇、p-碘苯胺、二甲亚砜和甲醇、m-硝基苯酚、甲基橙、前列腺素E、乙酸钾形成复合物;β-环糊精与水、n-丙醇、p-碘苯酚、2,5-二碘苯甲酸、p-硝基N-乙酰苯胺形成复合物;γ-环糊精与丙醇/水和水形成复合物。
除此之外,Saenger在第357页还指出β-环糊精增加苯唑卡因、普鲁卡因、阿托品、阿司匹林、硝酸甘油、蒜素、保泰松、水杨酸、驱蛔萜、2-环戊烯十三烷酸醚酯、亚油酸酯以及消炎痛的稳定性,并且环糊精增加脂肪酸,胺类如普鲁卡因、利多卡因、度冷丁、解痉素,甾类化合物如可的松乙酸盐和睾酮、羟基苯甲酸、苯唑卡因、阿司匹林、p-氨基苯甲酸、四环素、磺胺嘧啶、吗啡、香草醛、麻黄碱、山梨酸、取代的苯基碳酸、酮洛芬、其它解热剂、维生素D3、香豆素抗凝剂、磺胺类和巴比妥酸盐类的水溶性。
然而,β-环糊精具有肾毒性和膜去稳定性。由于对β-环糊精的安全考虑,对该环糊精进行了许多化学修饰。β-环糊精的不同类型包括烷基化环糊精、羟烷基化环糊精、羧甲基环糊精以及磺烷基醚环糊精,所述磺烷基醚环糊精包括在β-环糊精4和7位置上不同取代程度的磺基丁基醚(SBE)β-环糊精。最后一组中的具体产品包括Captisol,SBE 7-β-环糊精(SBE-CD)。羟烷基化环糊精中的具体产品包括2-羟丙基-β-环糊精(HPCD)。
1983年2月1日授予的美国专利第4,371,673号公开了两种类型水溶性维甲酸类多聚体的环糊精复合物以及维甲酸类与环糊精醚型衍生物的复合物。
1986年6月24日授予的美国专利第4,596,795号公开了通过舌下或口颊途径给予其与特定环糊精衍生物复合物或包合物形式的性激素、特别是睾酮、孕酮和雌二醇的,从而将这些激素有效传输入体循环,然后由体内逐渐排除。环糊精的衍生物必须带有一个或几个取代基,每个包含一个或几个羟基。特别优选羟丙基-β-环糊精和多-β-环糊精的复合物。
1988年2月23日授予的美国专利第4,727,064号涉及本身是结晶而且水溶性低的药物组合物转变为药学特性改善的固有无定形的复合物的方法。通过将将上述药物组合物加入到水溶性多组分的环糊精衍生物混合物而完成这种转变。使用的环糊精衍生物是羟丙基-β-环糊精、二羟丙基-β-环糊精、羧甲基-β-环糊精等。
1992年7月28日授予的美国专利第5,134,127号公开了磺烷基醚环糊精衍生物以及它们作为经口、鼻或胃肠外给药的不溶于水的药物的溶剂的作用。还公开了其中一种药物与磺基丁基醚-β-环糊精复合的药用组合物。所述药物选自:异戊巴比妥、氨苄青霉素、阿司匹林、丙酸氯地米松、苯唑卡因、睾酮等。
1994年12月27日授予的美国专利第5,376,645号也公开了磺烷基醚环糊精衍生物以及它们作为经口、鼻或胃肠外给药的不溶于水的药物的溶剂的作用。还公开了其中一种药物与磺基丁基醚-β-环糊精复合的组合物。所用的药物与在美国专利第5,134,127号公开的药物相同。
发明描述
根据本发明,提供由式I的ras-法呢基转移酶抑制剂或其药学上可接受的盐以及磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精形成的新的ras-法呢基转移酶抑制剂复合物或包含化合物,式I中,n表示0或1;R1为Cl、Br、苯基、吡啶基或氰基;R2表示芳烷基;R3为低级烷基、芳基或取代的芳基或杂环;Z1为CO、SO2、CO2、SO2NR5,其中R5为氢、低级烷基或取代的烷基。
术语“烷基”是指1到20个碳原子、优选1到7个碳原子的直链或支链未取代的烃基。表述“低级烷基”是指1到4个碳原子未取代的烷基。
术语“取代的烷基”是指例如被一到四个取代基取代的烷基,所述取代基例如:卤基、三氟甲基、三氟甲氧基、羟基、烷氧基、环烷氧基、杂环氧基、氧代、烷酰基、芳氧基、烷酰氧基、氨基、烷基氨基、芳氨基、芳烷基氨基、环烷基氨基、杂环氨基,其中2个氨基取代基选自烷基、芳基或芳烷基的双取代胺类;烷酰氨基、芳酰氨基、芳烷酰氨基、取代的烷酰氨基、取代的芳氨基、取代的芳烷酰氨基、巯基、烷硫基、芳硫基、芳烷硫基、环烷硫基、杂环硫基、烷基硫羰基、芳基硫羰基、芳烷基硫羰基、烷基磺酰基、芳基磺酰基、芳烷基磺酰基、亚磺酰氨基如SO2NH2、取代的亚磺酰氨基、硝基、氰基、羧基、氨基甲酰基如CONH2、取代的氨基甲酰基如CONH烷基、CONH芳基、CONH芳烷基,或在氮上有两个取代基的情况下选自:烷基、芳基或芳烷基;烷氧基羰基、芳基、取代的芳基、胍基和杂环基如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基等。在上述取代基进一步被取代的情况下,可以由卤素、烷基、烷氧基、芳基或芳烷基进一步取代。
术语“芳基”是指在环的部分具有6到12个碳原子单环或双环芳烃基,例如苯基、萘基、联苯基和二苯基,其中每个芳基都可以是取代的芳基。
术语“芳烷基”是指直接通过一个烷基键合的芳基如苯甲基。
术语“取代的芳基”是指例如被一到四个取代基取代的芳基,所述取代基例如烷基、取代的烷基、卤基、三氟甲氧基、三氟甲基、羟基、烷氧基、环烷氧基、杂环氧基、烷酰基、烷酰氧基、氨基、烷基氨基、芳烷基氨基、环烷基氨基、杂环基氨基、二烷基氨基、烷酰氨基、巯基、烷硫基、环烷硫基、杂环硫基、脲基、硝基、氰基、羧基、羧烷基、氨基甲酰基、烷氧基羰基、烷基硫羰基、芳基硫羰基、烷基磺酰基、亚磺酰氨基、芳氧基等。所述取代基可由卤基、羟基、烷基、烷氧基、芳基、取代的芳基、取代的烷基或芳烷基进一步取代。
术语“杂环基”是指任选取代、完全饱和或不饱和芳香环基或非芳香环基,例如4到7个原子的单环,7到11个原子的双环,或10到15个原子的三环系统,它们在包含至少一个碳原子的环中至少含有一个杂原子。包含一个杂原子的杂环基的每个环可以具有1、2、3或4个杂原子,所述杂原子选自:氮原子、氧原子和硫原子,其中氮和硫杂原子也可以被任选氧化,而氮杂原子还可任选被季铵化。所述杂环基可以于任一杂原子或碳原子连接。
式I的抑制剂可以与多种有机酸和无机酸形成盐。这类盐包括与盐酸、羟基甲磺酸、溴化氢、甲磺酸、硫酸、乙酸、三氟乙酸、马来酸、苯磺酸、甲苯磺酸以及其它各种酸形成的盐,例如硝酸盐、磷酸盐、硼酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、水杨酸盐等。这类盐可以通过抑制剂I在所述盐沉淀的介质或水介质中与等量的所述酸中反应,然后蒸发制成。尽管其它盐例如分离或纯化本发明的抑制剂(化合物I)或其盐中也是有用的,但是优选药学上和生理学上可接受的无毒的盐。
特定的抑制剂有:(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂;(化合物I)或其盐;(R)-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-4-苯基磺酰基)-3-(苯甲基)-1H-1,4-苯并二氮杂-7-腈或其盐;(R)-7-溴-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-4-(甲基磺酰基)-3-(苯甲基)-1H-1,4-苯并二氮杂或其盐;(R)-7-氰基-2,3,4,5-四氢-1-1H-咪唑-4-基甲基)-3-(苯甲基)-4-(丙基磺酰基)-1H-1,4-苯并二氮杂或其盐;以及(R)-7-氰基-4-[(4-氟苯基)磺酰基]-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-1H-1,4-苯并二氮杂或其盐。
除此之外,根据本发明提供新型水溶性稳定形式的式I的ras-法呢基转移酶抑制剂,它包括磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精和式I的ras-法呢基转移酶抑制剂的复合物或包含化合物。已经发现与其它ras-法呢基转移酶抑制剂的制剂相比,ras-法呢基转移酶抑制剂-磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精复合物的水溶性和稳定性显著提高。
评价了ras-法呢基转移酶抑制剂(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂(化合物I)与助溶剂和表面活性剂的多种其它胃肠外制剂。所述抑制剂(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂具有良好溶解性,在包含10%乙醇和10%Cremophor的混合物或仅含10%Tween 80的水制剂中每毫升溶解10毫克以上。但是,这些制剂具有多个缺点:由于提高了对离子的敏感性导致ras-法呢基转移酶抑制剂沉淀而不能进行缓冲;不能进行静脉内给药需要的稀释,并且导致pH变化和抑制剂沉淀以及在临床中前驱给药需要应用的表面活性剂的毒性。前驱给药问题常常与使用表面活性剂(如Tween 80和Cremophor)有关。
其它ras-法呢基转移酶抑制剂的实例有:(R)-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-4-苯基磺酰基)-3-(苯甲基)-1H-1,4-苯并二氮杂-7-腈;(R)-7-溴-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-4-(甲基磺酰基)-3-(苯甲基)-1H-1,4-苯并二氮杂;(R)-7-氰基-2,3,4,5-四氢-1-1H-咪唑-4-基甲基)-3-(苯甲基)-4-(丙基磺酰基)-1H-1,4-苯并二氮杂;以及(R)-7-氰基-4-[(4-氟苯基)磺酰基]-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-1H-1,4-苯并二氮杂,或它们的盐。式I的ras-法呢基转移酶抑制剂以及所述特定的抑制剂通过WO 97/30992中描述的方法合成。所述磺基丁基醚-7-β-环糊精(Captisol)得自美国Cydex公司。2-羟丙基-β-环糊精可自美国American Maize Company获得。
总的来说,本发明的复合物在pH值3到9时所述式I的ras-法呢基转移酶抑制剂与环糊精的摩尔比为1∶2或更高。
所述ras-法呢基转移酶抑制剂和磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精的复合物通过下列步骤制得:形成磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精的水溶液,搅拌下加入所述ras-法呢基转移酶抑制剂的游离碱或各种盐,并用适当的酸或众所周知的水性缓冲液调节pH至需要的pH值。
根据本发明的优选方法,本发明的复合物通过下列步骤制成:5克的磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精在15毫升去离子水中,室温下搅拌30分钟形成水溶液。用盐酸调节溶液的pH至2或3。在该搅拌的溶液中加入500毫克的所述ras-法呢基转移酶抑制剂(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂,加入所述抑制剂后继续搅拌溶液,同时用稀盐酸或氢氧化钠调节pH至4或4.5。然后溶液用0.22微米滤器过滤,回收所述复合物的滤液。
发现本发明优选的ras-法呢基转移酶抑制剂(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂(化合物I)和磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精的复合物的水溶性和稳定性高优于上述其它制剂。例如,当磺基丁基醚-7-β-环糊精存在时,所述抑制剂(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂的水溶性惊人地增高。当pH8时所述抑制剂的溶解性由在水中的<5μg/mL增加到在5%(w/v)SBE-CD溶液中1.2mg/mL,而在40%(w/v)SBE-CD溶液中增加至8mg/mL。同样,在pH4.5时所述抑制剂的溶解性由在水中的0.2mg/mL也增加到在5%(w/v)SBE-CD溶液中~6mg/mL,而在40%(w/v)SBE-CD溶液中增加至~45mg/mL.同样,当2-羟丙基-β-环糊精存在时,所述抑制剂(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂的溶解性也明显提高。在2.5%(w/v)HPCD溶液中所述化合物I的溶解性当pH8时为~0.2mg/ml,pH4.2时为2.7mg/ml。这样,根据溶液的pH和溶液中存在的SBE-CD或HPCD的浓度,发现该抑制剂的水溶性提高了40-1600倍。
除此之外,当有光存在时,所述优选化合物的稳定性惊人地增强。结果表明在大约1000英尺烛光的高强度光下,所述复合物的ras-法呢基转移酶抑制剂(化合物I)降解速率在含20%(w/v)SBE-CD的溶液中降低10倍以上。
所述优选复合物水溶性增强及其有光时的稳定性使其适合用于静脉内制剂,因为它克服了其它含有助溶剂和表面活性剂的制剂的缺点。本发明的优选复合物克服了离子强度的影响,从而允许应用缓冲剂控制pH,并且它是完全可稀释的,因为SBE-CD的作用使所述抑制剂的溶解度线性增加。它还提供对稀释剂的选择如电解质、非电解质,而且它是完全水溶性的。
所述复合物可用于静脉内传递ras-法呢基转移酶抑制剂以治疗人类癌症。
本发明还提供包含式I的ras-法呢基转移酶抑制剂和磺基丁基醚-7-β-环糊精或2-羟丙基-β-环糊精的复合物及其药学上可接受的载体和任选的其它治疗和预防成分一起的药用制剂。所述载体必须是在与该组方的其它成分匹配的意义上可接受的,且对其接受者无害。
所述药用制剂可以是可给予所述复合物的任何制剂,包括适合口、鼻、眼内或胃肠外(肌内和静脉内)给药的制剂。
用于所述药用制剂的载体成分根据情况可以包括稀释剂、缓冲剂、调味剂、粘合剂、增稠剂、润滑剂、防腐剂等。
本发明复合物的优选给药方式是胃肠外给药,包括皮下注射、静脉内、肌内、胸骨内注射或输注技术。本发明的复合物除了治疗如小鼠、大鼠、狗、猫等温血动物外,还可有效治疗人类癌症。
下列实施例为本发明的优选实施方案。除非另有说明,否则所有的温度都为摄氏度。
实施例1
如下所述制备本发明磺基丁基醚-7-β-环糊精和ras-法呢基转移酶抑制剂(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂(化合物I)形成的复合物。
称量5.0克磺基丁基醚-7-β-环糊精(SBE-CD)放入容量瓶中。在室温的搅拌下加入15mL去离子水,用频繁的声处理直至获得澄清的溶液。搅拌该溶液30分钟,然后边搅拌边加入稀盐酸溶液直至该溶液的pH在2到3之间。然后将500mg化合物I加入到该溶液中,将该混合物在室温下用频繁的声处理再搅拌两个小时直至化合物I完全溶解。用稀盐酸或氢氧化钠调节所得到溶液的pH至4到4.5之间。之后用去离子水调节该溶液的体积到25mL。颠倒容量瓶数次使该溶液充分混合,通过0.22μm滤器过滤。澄清的滤液在20%(w/v)SBE-CD溶液中包含20mg/mL化合物I(游离碱的相当量)的所述复合物。
实施例2
用柠檬酸缓冲液制备SBE-CD和化合物I的游离碱的复合物
在室温的搅拌下往装有1.6克柠檬酸一水合物、0.6克二水合柠檬酸钠和40克SBE-CD的混合物的容量瓶中加入170mL去离子水。该混合物用频繁的声处理搅拌30分钟直至获得澄清的溶液。往该溶液中加入4.0克化合物I。再搅拌该混合物2小时直至获得澄清的溶液。之后,用去离子水调节该溶液的体积至200mL,将所得溶液完全混合,通过0.22μm滤器过滤。澄清的滤液在20%(w/v)SBE-CD溶液中包含20mg/mL化合物I(游离碱的相当量)的所述复合物。
实施例3
用柠檬酸缓冲液制备HPCD和化合物I的游离碱的复合物
HPCD和化合物I的游离碱的复合物可以通过用HPCD代替上述实施例2方法中的SBE-CD来制备。
实施例4用柠檬酸缓冲液制备SBE-CD和化合物I的甲磺酸盐(mesylate)的复
合物
在室温的搅拌下往1.2克柠檬酸一水合物、1.2克柠檬酸钠二水合物和40克SBE-CD的混合物中加入170mL去离子水。该混合物用频繁的声处理搅拌30分钟直至获得澄清的溶液。然后往该溶液中加入4-8克化合物I的甲磺酸盐,再搅拌该混合物2小时直至获得澄清的溶液。之后,用去离子水调节该溶液的体积至200mL,将所得溶液充分混合,通过0.22μm滤器过滤。澄清的滤液在20%(w/v)SBE-CD溶液中包含20mg/mL化合物I(游离碱的相当量)的复合物。
Claims (10)
2.权利要求1的复合物,其中所述抑制剂选自:(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂;(R)-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-4-苯基磺酰基)-3-(苯甲基)-1H-1,4-苯并二氮杂-7-腈;(R)-7-溴-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-4-(甲基磺酰基)-3-(苯甲基)-1H-1,4-苯并二氮杂;(R)-7-氰基-2,3,4,5-四氢-1-1H-咪唑-4-基甲基)-3-(苯甲基)-4-(丙基磺酰基)-1H-1,4-苯并二氮杂;以及(R)-7-氰基-4-[(4-氟苯基)磺酰基]-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-1H-1,4-苯并二氮杂。
3.权利要求2的复合物,其中所述抑制剂是(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂。
4.一种ras-法呢基转移酶抑制剂组合物,它包含有效量的权利要求1定义的复合物和其药学上可接受的载体。
5.权利要求4的组合物,其中所述组合物是液体形式。
6.权利要求4的组合物,其中所述载体是柠檬酸缓冲液。
7.权利要求4的组合物,它还包含电解质或非电解质的稀释剂。
8.权利要求4的组合物,其中所述抑制剂是(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂或其药学上可接受的盐。
9.一种胃肠外给药的药用组合物,它包含药学上适合的载体和权利要求1的复合物。
10.权利要求9的组合物,其中所述抑制剂是(R)-7-氰基-2,3,4,5-四氢-1-(1H-咪唑-4-基甲基)-3-(苯甲基)-4-(2-噻吩基磺酰基)-1H-1,4-苯并二氮杂或其药学上可接受的盐。
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WO2007051358A1 (en) * | 2005-11-02 | 2007-05-10 | Nanjing Normal University | HYDROXYPROPYL-SULFOBUTYL-β-CYCLODEXTRIN, THE PREPARATION METHOD,THE ANALYTICAL METHOD AND THE PHARMACUTICAL APPLICATION THEREOF |
CN103037904A (zh) * | 2010-05-26 | 2013-04-10 | 纽柔菲克西亚有限公司 | 2-亚氨基生物素制剂及其应用 |
CN103037904B (zh) * | 2010-05-26 | 2015-04-22 | 纽柔菲克西亚有限公司 | 2-亚氨基生物素制剂及其应用 |
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US9616135B2 (en) | 2010-05-26 | 2017-04-11 | Neurophyxia B.V. | 2-iminobiotin formulations and uses thereof |
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