CN1151836C - 用作传送活性剂的化合物和组合物 - Google Patents

用作传送活性剂的化合物和组合物 Download PDF

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CN1151836C
CN1151836C CNB961929987A CN96192998A CN1151836C CN 1151836 C CN1151836 C CN 1151836C CN B961929987 A CNB961929987 A CN B961929987A CN 96192998 A CN96192998 A CN 96192998A CN 1151836 C CN1151836 C CN 1151836C
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thiazolinyl
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CN1190893A (zh
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A・勒尼一贝
A·勒尼一贝
萨鲁比
K-K·霍
米斯特尼
D·J·萨鲁比
普里斯
S·J·米斯特尼
J·B·普里斯
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Emisphere Technologies Inc
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Emisphere Technologies Inc
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

本发明涉及将修饰氨基酸化合物用于活性剂的传送。活性剂可以是肽如rhGH。本发明还涉及给药方法，如口服，皮下，舌下和鼻内给药，并涉及修饰氨基酸的制备方法。

Description

用作传送活性剂的化合物和组合物
本申请是系列申请08/414,654(申请日1995年3月31日)和系列申请06/003,111(申请日1995年9月1日)的部分继续申请。
技术领域
本发明涉及用于传送活性剂，特别是生物或化学活性剂(如生物活性肽等等)的化合物。这些化合物被用作有利于运载体(cargo)向目标传输的载体。这些载体是修饰氨基酸，并且很适于和生物活性剂形成非共价混合物，用于动物的口服给药。本发明还涉及这类组合物的制备及其给药的方法。
背景技术
常规的传送活性剂方法常常受到生物，化学和物理屏障的严格限制。这些屏障通常受传送所要通过的环境，传送目标的环境或目标本身所影响。
生物或化学活性剂特别容易受到这种障碍的屏障。例如，在向动物传送药物和治疗剂时，屏障受身体影响。物理屏障的实例有皮肤和达到目标之前必须经过的各种器官膜。化学屏障包括但不限于pH变化，双层类脂和降解酶。
这些屏障在设计口服传送系统时非常重要。如果不是由于生物，化学和物理障碍如胃肠(GI)道变化的pH，强力消化酶和活性剂无法渗透的胃肠膜，许多生物或化学活性剂都可以选择口服传送作为给动物给药的途径。在大量典型不适用于口服给药的活性剂中有生物或化学活性肽，如降钙素和胰岛素；多糖类，尤其是粘多糖，包括但不限于肝素；类肝素；抗生素；及其它有机物。这些活性剂在胃肠道中被酸的水解物，酶等等迅速破坏或使之失效。
易损药剂的口服给药的早期方法依赖于辅剂(例如，间苯二酚和非离子表面活性剂如聚氧乙烯油醚和正十六基聚乙烯醚)的联合给药，从而人为地增加肠壁的渗透性，以及与酶抑制剂(例如，胰蛋白酶抑制剂，二异丙基氟磷酸盐(DFF)和抑肽酶)联合给药，从而抑制酶降解。
脂质体被用作胰岛素和肝素的药物传输系统早已有文献描述。例如，参见美国专利4,239,754；Patel等人(1976)，FEBS Letter，第62卷，60页；及Hashimoto等人(1979)，Endocrinology Japan，第26卷，337页。
但是，已经排除了这种药物传输系统被广泛应用的可能性，因为：(1)这些系统要求毒性量的辅剂或抑制剂；(2)不能使用低分子量的运载体即活性剂；(3)该系统表现出较差的稳定性，而且不适于存放；(4)该系统难以制造；(5)该系统不能保护活性剂(运载体)；(6)该系统会有害地改变活性剂；或(7)该系统不允许或不利于活性剂的吸收。
最近，混合氨基酸(类蛋白)的人工聚合物微球体已被用于传输药物。例如，美国专利4,925,673描述了含类蛋白微球体载体药物以及它们的制备和使用方法。这些类蛋白微球被用于大量活性剂的传输。
但是，本领域仍然需要简单便宜的传输系统，它既易于制备又能够传输多种活性剂。
发明内容
本发明提供了用于传输活性剂的组合物。这些组合物包含至少一种活性剂，而且是可传输的(eferably)的生物或化学活性剂，和至少一种下列化合物I-CXXIII或其盐。
Figure C9619299800151
Figure C9619299800161
Figure C9619299800171
Figure C9619299800181
Figure C9619299800191
Figure C9619299800211
Figure C9619299800241
Figure C9619299800251
Figure C9619299800261
Figure C9619299800281
Figure C9619299800321
Figure C9619299800331
已经发现，具有芳香酰胺基，在芳香环的邻位有羟基取代基的，且链上有4-20个碳原子的亲脂链的有机酸化合物及其盐可用作传输活性剂的载体。优选有5-20个碳原子的亲脂链。
含有上述载体化合物和活性剂的组合物已经表现出在将活性剂传输到所选生物系统时是有效的。这些组合物包含至少一种活性剂(最好是生物或化学活性剂)和至少一种下式的载体化合物，
2-HO-Ar-CONR8-R7-COOH
其中
Ar是取代的或未取代的苯基或萘基；
R7选自C4-C20烷基，C4-C20烯基，苯基，萘基，(C1-C10烷基)苯基，(C1-C10烯基)苯基，(C1-C10烷基)萘基，(C1-C10烯基)萘基，苯基(C1-C10烷基)，苯基(C1-C10烯基)，萘基(C1-C10烷基)和萘基(C1-C10烯基)；
R8选自氢，C1-C4烷基，C1-C4烯基，羟基和C1-C4烷氧基；
R7可以任意被C1-C4烷基，C1-C4烯基，C1-C4烷氧基，-OH，-SH和-CO2R9或它们的任意组合取代；
其中R9是氢，C1-C4烷基或C1-C4烯基；
R7可以任意被氧，氮，硫或它们的任意组合间断；条件是这些化合物或其盐不在酸基的a位被氨基取代。
优选的R6基团为C4-C20烷基和C4-C20烯基。最优选的R6基团为C5-C20烷基和C5-C20烯基。
优选的载体化合物具有下列结构式：
Figure C9619299800381
其中R7定义如上。
本发明进一步包含这些组合物的剂量单位形式。
本发明还包括制备这些含有混合了至少一种活性剂和至少一种上述化合物，并且任意含有剂量载体的组合物的方法。
在一具体实例中，这些无毒化合物可以作为转运系统部分给动物口服给药，在给药之前它们与活性剂捏合或混合。
本发明进一步提供了制备下式化合物的方法，
Figure C9619299800382
其中
Y是 或SO2；
R1是C3-C24烷基，C2-C20烯基，C2-C20炔基，环烷基或芳香基：
R2是氢，C1-C4烷基或C2-C4烯基；及
R3是C1-C7烷基，C3-C10环烷基，芳基，噻吩基，吡咯并或吡啶基，这里，R3可任意被一个或多个C1-C5烷基，C2-C4烯基，F，Cl，OH，SO2，COOH或SO3H取代：
所说方法包括
(a)在水中并在碱存在下，将下式化合物
Figure C9619299800384
与下式化合物反应，
R3-Y-X
其中Y，R1，R2和R3定义如上，X是离去基团。
附图说明
图1是给大鼠皮下注射rhGH组合物后的结果的图示说明。
图2是给大鼠舌下(SL)，鼻内(IN)和结肠内(IC)进行rhGH组合物给药后的结果的图示说明。
图3是用化合物XXXI作为载体进行肝素传输结肠内给药的结果的图示说明。
具体来说本发明具体组合物中包括活性剂和修饰氨基酸。这些组合物可用于传送各种活性剂通过各种生物，化学和物理屏障，尤其适用于传送经过环境降解的活性剂。特别地，本发明组合物被用于将生物或化学活性剂传送给或给予任何动物如鸟类；哺乳动物如灵长类，尤其是人类；及昆虫类动物。
本发明另一个优点是使用便于制备和便宜的原料。本发明组合物和配制方法费用合理，简单易行，适合工业规模的商业生产。
这里所说的皮下，舌下和鼻内联合使用活性剂如重组人生长激素(rhGH)和传送剂，特别是蛋白质，将使活性剂的生物利用度比单独使用活性剂有所增加。将鲑降钙素与传送剂给大鼠联合给药可得到类似的结果。支持这些发现的数据可在实施例中找到。
活性剂
适合用于本发明的活性剂包括生物或化学活性剂。化学活性剂包括但不限于香料以及其它活性剂如化妆品。
生物或化学活性剂包括但不限于杀虫剂，药剂和治疗剂。例如，适用于本发明的生物或化学活性剂包括但不限于肽类，特别是小肽；荷尔蒙，特别是依靠其本身不能或只能使一部分所给剂量穿过胃肠内粘膜和/或很容易被胃肠道中的酸和酶化学裂解的荷尔蒙；多糖，尤其是粘液多糖的混合物；碳水化合物；脂类；或上述物质的任意组合。进一步的实例包括但不限于人生长激素；牛生长激素；生长释放激素；干扰素；白介素-1；胰岛素；肝素，特别是小分子量肝素；降钙素；红细胞生成素；心钠素；抗原；单克隆抗体；促生长素抑制素；促肾上腺皮质素，促性腺释放激素；催产素；加压素；色甘酸钠(色甘酸钠或色甘酸二钠)；万古霉素；去铁胺(DFO)；甲状旁腺素抗生素，包括但不限于抗真菌剂；或它们的任意组合。
修饰氨基酸
术语“修饰氨基酸”，“修饰多氨基酸”和“修饰肽”指已经被修饰的氨基酸，或其中至少一种氨基酸被修饰的多氨基酸和肽，修饰是通过用酰化或磺酰化剂与至少存在的游离胺基团之一反应来酰化或磺酰化至少一种游离胺基团实现的。
修饰的氨基酸，多氨基酸和肽可用于传送活性剂，所说活性剂包括但不限于生物或化学活性剂如药剂和治疗剂。
氨基酸是含有至少一种游离胺基团的任意羧酸，氨基酸包括天然和合成氨基酸。
多氨基酸即可以是肽，也可以是由其它可以连接的基团如酯，酐或酐类似物形成的键连接的两个或多个氨基酸。
肽是由肽键连接的两个或多个氨基酸。肽链的长度可以各种各样，可以是由两个氨基酸组成二肽，也可以是由几百个氨基酸组成的多肽。参见Chambers生物学辞典(Chambers Biological Dictionary)，编者Peter M.B.Walker，Cambridge，England：Chambers Cambridge，1989，215页，其中具体谈到二肽，三肽，四肽和五肽的制备。
虽然已经发现化合物I-CXXIII可作为生物或化学活性剂口服传送的载体，但上述文献只提到化合物I-XXXI化合物的制备。
修饰氨基酸的典型制备方法是将其中的氨基酸或酯修饰。许多修饰氨基酸的制备是通过用下式试剂进行酰化或磺酰化反应实现的，
X-Y-R4
其中
R4是在最终产物中产生指定的修饰的适当残基，
Y是 或SO2，及
X是离去基团。典型的离去基团包括但不限于卤素，如氯，溴和碘。此外，用相应的的酐作修饰剂。
对于本发明许多化合物，本领域普通技术人员可以根据现已公开的方法从氨基酸很容易地制备。例如，化合物I-VII是从氨基丁酸衍生的；化合物VIII-X和XXXII-XXXV是从氨基己酸衍生的；及化合物XI-XXVI和XXXVI是从氨基辛酸衍生的。例如，上述修饰氨基酸化合物可以通过单个氨基酸与适当的修饰剂反应来制备，修饰剂与氨基酸中的游离氨基部分反应形成酰胺。可以使用保护剂以避免不需要的副反应发生，这些对于本领域普通技术人员都是已知的。
可以将氨基酸溶解于金属氢氧化物如氢氧化钠或氢氧化钾的碱性水溶液中，并在约5-70℃之间，优选约10-40℃之间加热约1-4小时，优选约2.5小时。对于氨基酸中每一当量NH2(氨基)，所用碱的用量范围通常约为1.25-3毫摩尔，优选约1.5-2.25毫摩尔/每当量NH2。溶液的pH值通常约为8-13，优选约10-12。
此后，将适当氨基修饰剂加到氨基酸溶液中，同时搅拌。混合物的温度通常保持在约5-70℃，优选约10-40℃，反应进行约1-4小时。所用氨基修饰剂的用量与氨基酸数量有关，它取决于氨基酸中全部游离NH2的摩尔数。一般，对于氨基酸中每摩尔当量的全部游离NH2，氨基修饰剂的用量范围在约0.5-2.5摩尔当量之间，优选约0.75-1.25当量。
用适当的酸如浓盐酸调节混合物的pH值，直到pH值达到约2-3，淬灭了反应。将混合物放置于室温放置，混合物分成透明的上层和白色或米白色沉淀。除去上层，通过过滤或滗析从下层中收集修饰氨基酸。然后将粗的修饰氨基酸产物溶解于pH约为9-13，优选约11-13的水中。过滤除去不溶性物质，滤液经真空干燥。所得修饰氨基酸的产率一般约为30-60％，通常约为45％。
如果需要，可用氨基酸酯如氨基酸化合物的苄酯，甲酯或乙酯制备本发明修饰氨基酸。将溶解于适当有机溶剂如二甲基甲酰胺，吡啶或四氢呋喃的氨基酸酯与适当氨基修饰剂在约5-70℃，优选约25℃，反应约7-24小时。用来处理氨基酸酯的氨基修饰剂的用量与用于上述氨基酸的用量相同。该反应可以在有或没有碱如三乙胺或二异丙基乙胺存在下进行。
之后，在负压下除去反应溶剂，通过在约50-80℃，优选约70℃，用适当碱性溶液如1N氢氧化钠水解修饰的氨基酸酯一个足以水解掉酯基的时间来除去酯官能度，得到有游离羧基的修饰氨基酸。然后将水解混合物冷却到室温并酸化，例如，用25％盐酸水溶液，使其pH达到约2-2.5。修饰氨基酸从溶液中沉淀，用常规方法如过滤或滗析方法回收。苄酯可以通过在有机溶剂中用过渡金属催化剂进行氢化而除去。
修饰氨基酸可以通过重结晶或在固体柱载体上分级进行纯化。适当的重结晶溶剂系统包括乙腈，甲醇和四氢呋喃。分馏可以在适当固体柱载体如氧化铝上，用甲醇/正丙醇混合物作流动相；反相柱载体用三氟乙酸/乙腈混合物作流动相；离子交换色谱用水作流动相进行。如果采用阴离子交换色谱，优选采用0-500mM系列氯化钠梯度液来洗脱。
在另一种方法中可通过下列方法制备具有下式的修饰氨基酸
Figure C9619299800421
其中
Y是 或SO2；
R1是C3-C24烷基，C2-C20烯基，C2-C20炔基，环烷基或芳基；
R2是氢，C1-C4烷基或C2-C4烯基；及
R3是C1-C7烷基，C3-C10环烷基，芳基，噻吩基，吡咯并或吡啶基，这里，R3可任意被一个或多个C1-C5烷基，C2-C4烯基，F，Cl，OH，SO2，COOH或SO3H取代；
(a)在水中和碱存在下，将下式化合物
Figure C9619299800423
与下式化合物反应，
 R3-Y-X
其中Y，R1，R2和R3定义如上，X是离去基团。
化合物CXXV可以，例如，采用Olah等人(合成(Synthesis)，537-538(1979))所述方法来制备。
化合物XXXI可按照路线I所述方法从10-十一碳烯-1-醇(1)来制备，三步过程的总产率为31％。在Mitrunobu条件下，用链烷醇(1)对酞酰亚胺进行烷基化，接着与肼反应，得到1-氨基十一碳-10-烯(2)产率66％。将此胺用邻-乙酰基水杨酰氯衍生，所得烯(3)用高锰酸钾氧化成酸。除去乙酸盐，接着由酸性沉淀物中得到基于胺(2)计算的47％产率的化合物XXXI。
                         路线1
传送系统
本发明组合物可包含一种或多种活性剂。
在一个实例中，化合物I-CXXIII或至少含有这些化合物之一的多氨基酸或肽可以在给药之前，经过将一种或多种化合物，多氨基酸或肽与活性剂简单混合，而被直接用作传送载体。
在另一实例中，化合物，多氨基酸或肽可以用来制成含有活性剂的微球。这些化合物，多氨基酸或肽特别适用于某些生物活性剂如小肽激素的口服使用，如果只靠这些活性剂本身，是无法或只有部分所服剂量通过胃肠粘膜和/或易于被胃肠道中的酸和酶进行化学裂解。
如果将修饰氨基酸，多氨基酸或肽转化微球形式，可任意将混合物加热到约20-50℃，优选约40℃，直到修饰氨基酸溶解。最终，每mL溶液中含有约1-2000mg化合物，多氨基酸或肽，优选每mL含有约1-500mg。活性剂在最终溶液中的浓度可以各种各样，这取决于治疗所需要的剂量。如果必要，可以通过，例如，反相HPLC分析测定精确浓度。
如果用化合物，多氨基酸或肽制备微球，另一种可以使用的方法如下：将化合物，多氨基酸或肽溶解于浓度约为75-200mg/ml，优选约100mg/ml，温度约为25-60℃，优选40℃的去离子水中。留在溶液中的颗粒物可用常规方法如过滤方法除去。
然后，将保持温度在约40℃的化合物，多氨基酸或肽溶液以1∶1(v/v)的比例与酸浓度约为0.05-2N，优选约1.7N的酸性水溶液(也是约为40℃)混合。将所得混合物在40℃培养足够长时间，直到用光学显微镜可以观察到已形成微球。在本发明实践中，添加顺序最好是将化合物，多氨基酸或肽加到酸性水溶液中。
适于形成微球的酸包括不会发生下列情况的任何酸：
(a)对修饰氨基酸，多氨酸酸或肽产生不利影响，例如引起或产生传播化学分解；
(b)干扰微球形成；
(c)干扰活性剂运载体的微球联合；以及
(d)与活性剂运载体之间发生不利的作用。
在这方面适合的优选酸包括乙酸，柠檬酸，盐酸，磷酸，苹果酸和马来酸。
可以在制备微球之前将稳定微球的添加剂混入酸性水溶液或掺入化合物或运载体溶液中。在一些活性剂的帮助下这些添加剂的存在将改善溶液中微球的稳定性和/或分散性。
稳定性添加剂的浓度约为0.1-5％(w/v)，优选约0.5％(w/v)。适于作微球稳定添加剂的实例包括但不限于阿拉伯胶，明胶，甲基纤维素，聚乙二醇，聚丙二醇，羧酸及其盐，和多熔素。优选的稳定性添加剂是阿拉伯胶，明胶和甲基纤维素。
在上述条件下，化合物分子，多氨基酸或肽形成中空或固体阵列形式的微球，其中，运载体分布在裹着液体或固体运载体的载体基质中或囊状微球中。如果化合物，多氨基酸或肽在可溶性物质存在下形成微球，例如药剂在上述酸性水溶液中形成，则该物质将被封装在微球中。人们可用这种方式封装药理活性物质如肽，蛋白质和多糖，以及填充有机分子如抗生素，所说抗生素一般通过口服途径给药时生物利用度很差。可以混入微球的药剂的用量取决于多种因素，包括该药剂在溶液中的浓度以及运载体与载体的亲和力。化合物，多氨基酸或肽的微球不改变活性剂的生理和生物性质。而且，封装过程也不改变活性剂的药理性能。任何药剂都可以混装在微球中。该系统的突出优点是传送化学或生物剂，如不采用该系统，这些化学或生物剂在微球到达目标区(即到达此区后微球才释放其内容)之前，可能会在给药的动物体内遭到破坏或者功效降低，和传送在胃肠道中吸收很差的药剂。目标区因所用药物的不同而多种多样。
微球的粒径在决定活性剂于胃肠道的目标区释放方面起着重要作用。优选微球的直径约为≤0.1μm到10μm，优选约0.5-5μm。微球足够小是为了在胃肠道的目标区，譬如胃和空肠之间有效地释放活性剂。也可以将小微球悬浮在适当流体载体(如等渗盐水)中，通过直接注射到循环系统，或者肌肉内或皮下注射来进行胃肠外给药。给药方式的选择当然取决于对所要给予的活性剂的要求。用氨基酸大微球(＞50μm)作口服传送系统将会使其功效降低。
通过将化合物，多氨基酸或肽与水或含有活性剂的水溶液混合而形成的微球的大小可以通过操纵各种物理或化学参数如封装液的pH值，克分子渗透压浓度或离子浓度，溶液中离子的大小以及通过选择封装过程所用的酸来控制。
在临给药之前将载体的水溶液与活性成分的水溶液混合来制成给药混合物。或者，在制剂过程中将载体与生物或化学活性成分混合。该(混合物)溶液可以任意含有添加剂如磷酸盐缓冲剂，柠檬酸，乙酸，明胶和阿拉伯胶。
可将稳定性添加剂加到载体溶液中。这些添加剂与一些药物一起可促进溶液中制剂的稳定性和分散性。
稳定性添加剂的浓度可约为0.1-5％(w/v)，优选约0.5％(w/v)。适于作稳定性添加剂的实例包括但不限于阿拉伯胶，明胶，甲基纤维素，聚乙二醇，羧酸及其盐，和多熔素。优选的稳定性添加剂是阿拉伯胶，明胶和甲基纤维素。
活性剂的用量是能够完成具体活性剂之目的的有效量。在组合物中的量一般是指药理或生物有效量。但是，当组合物是以单位剂量如胶囊剂，片剂或液体形式使用时，其用量可以比药理或生物有效量少，因为单位剂量可以含有多倍载体/生物或化学活性剂组合物，或者可以含有分开的药理或生物有效量。总的有效量可以通过累积单位剂量来实现，其总剂量含有生物或药理活性剂的药理或生物或化学活性的量。
本领域技术人员可以测定将要使用的活性剂，特别是生物或化学活性剂的总量。但是，人们惊奇地发现，对于一些生物或化学活性剂来说，现公开的载体的使用提供了极为有效的传送，特别是在口服，鼻内，舌下，十二指肠内或皮下系统中。因此，可以使用比在以前单位剂量或传送系统更低的生物或化学活性剂用量给患者给药，仍能达到同样的血液浓度和治疗效果。
本发明组合物中载体的用量应该是有效传送的量，并且可以用本领域技术人员已知的方法对任何具体载体或生物或化学活性剂进行测定。
单位剂量也可以包含任何赋形剂；稀释剂；崩解剂；润滑剂；增塑剂；调色剂；以及剂量载体，包括但不限于水，1，2-丙二醇，乙醇，橄榄油，或它们的任意组合。
本发明组合物或单位剂量优选的给药方式是口服或十二指肠内注射。
本发明传送组合物也可以包含一种或多种酶抑制剂。这种酶抑制剂包括但不限于这样的化合物，如放线酰胺素或表放线酰胺素以及它们的衍生物。这些化合物具有以下结构式：
这些化合物的衍生物公开于美国专利5,206,384。放线酰胺素衍生物具有下列结构式：
其中，
R5是亚磺甲基(sulfoxymethyl)或选自甲酰胺，羟氨基羰基和烷氧羰基的羧基或取代的羧基；及
R6是羟基，烷氧基，羟氨基或亚磺氨基(sulfoxyamino)。
其它酶抑制剂包括但不限于抑肽酶(Trasylol)和Bowman-Birk抑制剂。
本发明化合物和组合物可用于将生物或化学活性剂给予任何动物，譬如鸟类；哺乳动物如灵长类，尤其是人类；和昆虫。该系统特别有利于传送化学或生物活剂，如不采用该系统，这些化学或生物剂在到达目标区(即到达此区后传送组合物中的活性剂才释放出来)之前及在要给药的动物体内遭到破坏或者功效降低。特别地，本发明化合物和组合物可用于活性剂的口服给药，特别是那些通常不能口服传送的活性剂。
具体实施方案
下列实施例用于说明本发明而非限制本发明。所有份数均以重量为单位除非另有说明。
实施例1
化合物XIX制备如下：
在一个3L的三颈圆底烧瓶顶部装上机械搅拌器和温度计，并将烧瓶在冰浴中冷却。在圆底烧瓶中加入8-氨基辛酸(100.0g，0.65mol)的2M氢氧化钠水溶液(1.4L)。溶液的温度保持在约5℃，并用7小时分批加入邻乙酰基水杨酰氯(198.6g，0.76mol，1.2当量)。将混合物在5℃搅拌12小时，得到黄色均匀溶液。该溶液用1M盐酸酸化，而将pH调至6.8，然后用乙酸乙酯(2×600mL)萃取。再将水相的pH调至6.3，并用乙酸乙酯(2×600mL)进一步萃取。合并有机相，用无水硫酸钠干燥，过滤并减压蒸发。将剩余物重新溶解于最小体积的2M氢氧化钠水溶液，使溶液的pH在9.5-10之间。搅拌混合物的同时用1M盐酸酸化至约pH6.2，形成固体。滤出固体，用水(3×300mL)洗涤，再用55％甲醇/水(v/v)重结晶，得到化合物XVIII为米色固体(99.7g，57％)。
数据如下：
mp 116-117C.1H NMR(300MHz，DMSO-d6)δ：12.70(1H；brs)，11.95(1H，br s)8.81(1H，t)，7.82(1H，m)，7.38(1H，m)，6.84(2H，m)，2.36(2H，q)，2.18(2H，t)，1.50(4H，br m)，1.28(6H，m)，
元素分析：C15H21NO4：理论值：C，64.50；H，7.58；N，5.02
                         实测值：C，64.26；H，7.81；N，4.93
用类似的的方法制备化合物I，II，III，IV，VI，IX，X，XI，XII，XIII，XIV，XX，XXI，XXIII，XXVII，XXVIII，XXXIII和XXXIV。
数据如下：
化合物I：1H NMR(300MHz，D2O)：δ1：5(2H，m)2.0(2H，t)2.3(2H，t)7.5(2H，t)7.6(1H，m)7.3(2H，m)
化合物II：1H NMR(300MHz，D2O)：δ1.4(8H，m)1.7(6H，m)2.1(2H，t)1.25(1H，m)3.05(2H，t)
化合物III：1H NMR_(300MHz，DMSO-d6)：δ0.7(3H，m)0.9(2H，m)1.1(3H，q)1.6.(5H，m)1.75(2Hr，q)2.1(2H，t)3.0(2H，q)7.9(1H，m)
化合物IV：元素分析计算值：C11H13NO4：C，59.9，H，5.87，N，6.27实测值：C，58.89，H，5.85，N，6.07.
1H NMR(300MHz，DMSO-d6)：δ1.8(2H，m)2.3(2H，t)3.1(2H，q)6.9(2H，t)7.4(1H，t)7.8(1H，d)8.85(1H，t)12.0(1H，s)12.15(1H，s)
化合物VI：1H NMR(300MHz，D2O)：δ0.8(2H，m)1.1(4H，m)1.4(2H，q)1.6(7H，m)2.15(4H，m)3.1(2H，t)
化合物IX：1H NMR(300MHz，DMSO-d6)：δ0.9(q，3H)，1.2(m，7H)，1.3(q，2H)，1.5(q，3H)，1.9(d.2H)，2.0(d，1H)，2.2(t，2H)，3.0(q，3H)，7.7(s，1H)
化合物X：1H NMR(300MHz，DMSO-d6)：δ0.7(d，2H)，0.9(dd，1H)，1.2-1.3(m，7H)，1.5(q，3H)，1.6-1.8(m，5H)，2.15(t，2H)，3.0(m，3H)，7.5(s，1H)，12.0(s，1H)化合物XI：元素分析计算值：C15H20NO3Cl：C，60.48，H，6.78，N，4.70实测值：C，60.4，H，6.68，N，4.53.1H NMR(300MHz，DMSO-d6)：δ1.28(m，6H)1.48(m，4H)2.19(t，2H)3.19(qt，2H)，7.323-7.48(m，4H)，8.39(t，1H)，12.09(s，1H)
化合物XII：元素分析计算值：C17H22NO3：C，66.42，H，7.23，N，4.56实测值：C，65.80，H，7.17，N，4.14.1H NMR(300MHz，DMSO-d6)：δ1.25(m，6H)1.43-1.49(m，4H)2.18(t，2H)3.15(qt，2H)，6.72(d，1H)，7.21-7.26(m，2H)，7.39(t，1H)，7.48(d，1H)，7.65(t，1H)，8.21(t，1H)
化合物XIII：元素分析计算值：C15H19NO3：C，60.18，H，6，41，N，4.67实测值：C，60.26，H，6.53，N，4.61.1H NMR(300MHz，DMSO-d6)：δ1.28(m，6H)，1.45-1.52(m，4H)，2.19(t，2H)，2.22(qt，2H)，7.13(m，2H)，7.43-7.53(m，1H)，8.67(t，1H)12.03(s，1H)
化合物XIV：元素分析计算值：C14H20N2O3：·0.66H2O：C，63.04，H，7.91，N，10.34实测值：C，63.21，7.59，10.53 1H NMR(300MHz，DMSO-d6)：δ1.22-12.8(m，6H)，1.48-1.50(m，4H)，2.18(t，2H)，3.24(qt，2H)，7.48(m，1H)，8.15(d，1H)，8.63-8.69(m，2H)，8.97(d，1H)
化合物XX：元素分析计算值：C15H20NO3F：C，60.09，H，7.19，N，4.98实测值：C，63.82，H，7.23，N，4.94.1H NMR(300MHz，DMSO-d6)：δ1.28(m，6H)1.49(m，4H)2.19(t，2H)3.23(qt，2H)，7.24-7.30(m，2H)，7.49-7.60(m，2H)，11.99(s，1H)
化合物XXI：元素分析计算值：C17H23NO4：C，66.85，H，7.61，N，4.58实测值：C，66.81，H，7.69，N，4.37.1H NMR(300MHz，DMSO-d6)：δ1.26(m，6H)1.42-1.50(m，4)2.18(t，2H)3.13(qt，2H)，6.63(d，1H)，6.80(t，1H)，6.86(d，1H)，7.15(t，1H)，7.39 (d，1H)，7.60(d，1H)，8.03(t，1H)，9，95(s，1H)，12.12(s，1H)
化合物XXIII：元素分析计算值：C15H27NO3：C，66.86，H，10.22，N，5.19实测值：C，66.92，H，10.72，N，5.14.1H NMR(300MHz，DMSO-d8)：δ1.56-1.34(m，13H)1.46(t，2H)1.60-1.68(m，5H)，2.04(t，1H)，2.17(t，2H)，2.97(qt，2H)，7.62(t，1H)，11.98(s，1H)
化合物XXVII：元素分析计算值：C18H27NO4：C，67.25，H，8.48，N，4.36实测值：C，67.23，H，8.57，N，4.20.1H NMR(300MHz，DMSO-d6)：δ1.22-1.26(m，12H)1.45-1.51(m，4H)2.16(t，2H)3.25(qt，2H)，6.85(t，2H)，7.37(t，1H)，7.81(d，1H)，8.79(t，1H)，11.95(s，1H)，12.72(s，1H)
化合物XXVIII：1H NMR(300MHz，DMSO-d6)：δ1.26(8H，br m)，1.49(4H，m)，2.17(2H，t)，3.26(2H，m)，6.86(2H，m)，7.37(1H，m)，7.83(1H，m)，8.80(1H，t)，11.95(1H，s)，12.73(1H，s).
化合物XXXIII：1H NMR(300MHz，DMSO-d6)：δ1.2(a，2H)，1.3(q，2H)，1.3(q，2H)，1.5(q，2H)，2.2(t，2H)，3.0(q，2H)，3.5(s，2H)，7.3(m，5H)，8.0(s，1H)
化合物XXXIV：元素分析计算值：C12H17NO4：C，62.23，H，6.83，N，5.57实测值：C，61.93，H，6.80，N，5.56.1H NMR(300MHz，DMSO-d6)：δ1-.24-1.34(m，2H)，1.491.57(m，4H)2.19(t，2H)3.26(qt，2H)，6.68(t，2H)，7.37(s，1H)，7.83(d，1H)8.81(t，1H)，12.08(s，1H)，12.72(s，1H)
实施例1A
化合物XIX的另一种合成方法如下：
在一个5L三颈圆底烧瓶上装上加热罩，顶部装上机械搅拌器，添加漏斗和温度计。反应在氩气中进行。将羟胺-邻-磺酸(196.7g 1.74mol，1.10当量)和甲酸(1L)加到圆底烧瓶中，搅拌后形成白色浆液。通过添加漏斗向白色浆液中滴加环辛酮(200.0g，1.58mol，1.0当量)的甲酸(600mL)溶液。添加完成后用回流冷凝器替换添加漏斗，然后将反应加热至回流(内部温度约为105℃)1小时，得到棕色溶液。将溶液冷却至室温后将其倒入饱和氯化铵(1.5L)溶液和水(1.5L)的混合物中。所得混合物用氯仿(3×1200mL)萃取。将合并的氯仿相倒入烧杯，慢慢加入饱和碳酸氢钠(2L)。然后分离氯仿相，无水硫酸钠干燥，减压蒸发，得到棕色油。将该油放入一个装有磁性搅拌器的500mL圆底烧瓶中。将圆底烧瓶置于硅油浴，并装上一个头上带有温度计的短径真空蒸馏装置。将一个Cow型接收器连到三个250mL烧瓶上。通过真空蒸馏(馏分的头部温度为80-120℃，压力为3.0-3.4mmHg)得到2-氮杂环壬酮(145g，65％，mp 64-69℃)。
在一个5L三颈圆底烧瓶上装上加热罩，顶部装上机械搅拌器，回流冷凝器和一个29温度计。将2-氮杂环壬酮(83g，0.59mol，1.0当量)的5M水性氢氧化钠(650mL，3.23mol，5.5当量)悬浮液装入圆底烧瓶。混合物被加热回流(内部温度约为110℃)4小时，得到清澈的黄色溶液。除去加热罩和回流冷凝器。溶液冷却到室温后用水(650mL)稀释，然后在冰浴中冷却。在搅拌和继续冷却的同时用1小时在溶液中分批加入精细研磨的邻-乙酰基水杨酰氯(114.7g，0.59mol，1.0当量)。添加后30分钟除去冰浴，并继续在室温搅拌21小时，得到棕黄色溶液。将搅拌的混合物用2M硫酸(约850mL)酸化至约pH1，形成黄色固体。过滤收集固体，并将其溶解于温甲醇(1.7L)。在该甲醇中加入活性炭(约5g)，并将溶液搅拌10分钟。过滤除去活性炭，用300mL甲醇洗涤炭的剩余物。在合并的滤液(即2L甲醇)中加水(2L)，在4℃静置过夜，产生米白色固体沉淀。滤出粗产物，并从65％甲醇/水(v/v)中重结晶，得到化合物XIX(69.1g，42％)为米白色固体。
数据如下：
mp 116-117℃；HPLC，1HNMR和元素分析：C15H21NO4：
理论值：C，64.50；H，7.58；N，5.02
实测值：C，64.26；H，7.81；N，4.93
实施例2
化合物XXXI制备如下：
1-氨基十一碳-10-烯
将10-十一碳烯-1-醇(5.00g，29.36mmol，1当量)，三苯膦(7.70g，29.36mmol，1当量)和酞酰亚胺(4.32g，29.36mmol，1当量)的无水四氢呋喃(THF，30mL)混合物在氩气中剧烈搅拌。用THF(12mL)稀释偶氮二羧酸二乙酯(DEAD，5.11g，29.36mmol，1当量)，然后用注射器滴加到上述混合物中。添加完成后将反应物在室温搅拌4小时。真空除去溶剂，加入乙醚(30mL)使三苯膦氧化物和肼二羧酸酯沉淀，并滤出沉淀。用乙醚(2×30mL)漂洗沉淀物，蒸发合并的滤液，得到黄色固体。黄色固体用温己烷(3×50mL)研制，并过滤。蒸发合并的己烷相，得到1-酞酰亚胺基十一碳-10-烯为黄色蜡。
将黄色蜡溶解于肼水合物(1.47g，1当量，29.36mmol)的乙醇溶液(38mL)中。将混合物加热回流2小时。混合物冷却到室温后加入浓盐酸(30mL)，并用烧结玻璃滤器滤出固体。剩余物用水(50mL)洗涤，蒸发合并的滤液，得到黄色固体。将黄色固体重新溶解于1M NaOH(100mL)，并用乙醚(2×50mL)萃取。干燥并蒸发乙醚，得到黄色油。将该油用Kugelrohr蒸馏方法(约0.1mmHg，100℃)纯化，得到1-氨基十一碳-10-烯(2)为浅黄色油(3.29g，66％)。
数据如下：
1H NMR(300mHz，DMSO-d6)；δ1.23(14H，br m)，1.99(2H，m)，2.48(2H，m)，4.94(2H，m)，5.77(1H，m).
1-(邻-乙酰基水杨酰氨基)十一碳-10-烯
将邻-乙酰基水杨酰氯(3.82g，19.25mmol，1当量)的THF(30mL)放在冰浴中冷却。用注射器先后加入三乙胺(1.95g，19.25mmol，1当量)和1-氨基十一碳-10-烯(3.26g，19.25mmol，1当量)的THF(10mL)液。除去冰浴，在室温搅拌反应物3.5小时。除去溶剂后将剩余物溶解于EtOAc(50mL)，并用水(2×30mL)洗涤。干燥并蒸发有机相，得到6.59g 1-(邻-乙酰基水杨酰氨基)十一碳-10-烯为无色油。
数据如下：
1H NMR(300mHz，DMSO-d6：δ1.26(12H，br s)，1.47(2H，m)，1.99(2H，m)，2.19(3H，s)，3.15(2H，q)，4.95(2H，m)，5.78(1H，m)，7.15(1H，m)，7.30(1H，m)，7.50(2H，m) 8.24(1H，t).
化合物XXXI
将1-(邻-乙酰基水杨酰氨基)十一碳-10-烯(6.59g，19.25mmol，1当量)的二氯甲烷(108mL)液加到水(108mL)，硫酸(9M，13mL)，冰醋酸(2.16mL)和甲基三烷(C8-C10)氯化铵(0.32g)(Adogenò464，得自Aldrich Chemical Co.)的混合物中。将混合物在冰浴中剧烈搅拌，并用1.5小时分批加入高锰酸钾(9.13g，57.75mmol，3当量)。加完后撤除冰浴，在室温搅拌所得紫红色溶液20小时。将溶液在冰浴中冷却，加入亚硫酸氢钠(6.8g)以消耗掉过量高锰酸盐。分离有机相，水相用乙酸乙酯(2×50mL)萃取。合并的有机相用盐水(50mL)洗涤，干燥并蒸发。在剩余物中加入氢氧化钠(2M，50mL)，并搅拌30分钟。溶液用水(50mL)稀释，用乙醚(50mL)洗涤，并用2M盐酸酸化至pH1。过滤收集生成的固体。将固体从65％MeOH/H2O中重结晶，得到化合物XXXI为褐色固体(2.78g，基于胺计算为47％)。
数据如下：
1H NMR(300mHz，DMSO-d6)：δ1.24(10H，br m)，1.51(4H，m)，2.17(2H，t)，3.27(2H，m)，6.86(2H，m)，7.37(1H m)，7.82(1H，m)，8.80(1H，t)，11.95(1H，s)，12.72(1H，s).
实施例3
化合物LXXXVI制备如下：
在一个1L三颈圆底烧瓶上装上磁性搅拌器和冷凝器。在烧瓶内装入3-(4-氨基苯基)丙酸(30g，0.182mol)的二氯甲烷(300mL)溶液，并一批加入三甲基甲硅烷氯化物(46.2mL，0.364mol)。将反应混合物回流1.5小时，冷却至室温后再移至冰水浴。先后加入三乙胺(76.2mL，0.546mol)和2-甲氧基肉桂酰氯(35.8g，0.182mol)。将反应混合物暖至室温，然后搅拌48小时。用旋转蒸发器除去溶剂，在剩余物中加入饱和碳酸氢钠水溶液和乙酸乙酯。分离各相，水相用2N硫酸水溶液酸化至pH1.4，然后用乙酸乙酯(2×400mL)萃取。真空浓缩合并的有机相，剩余物从50％(v/v)甲醇水溶液重结晶，得到的产物为褐色固体(48.57g，82％)。
数据如下：
1H NMR(300MHz，DMSO-d6)：δ12.1(1H，br)，7.8(1H，dd)，7.6(3H，m)，7.4(1H，m)，7.3(2H，m)，7.1(1H，d)，7.0(1H，t)，6.9(1H，d)，3.9(3H，s)，2.8(2H，t)，2.5(4H，m).
元素分析计算值：C19H19NO4：C，70.14；H，5.88；N，4.31.实测值：C，69.76；H，5.91；N，4.21.
实施例4
化合物CXVII制备如下：
在一个3L三颈圆底烧瓶的顶部装上机械搅拌器和温度计。在圆底烧瓶中装入8-氨基辛酸(10.0g，0.054mol)的2M氢氧化钠水溶液(1.4L)，再用7h分批加入邻-硝基苯甲酰氯(12.0g，0.065mol，1.2当量)。将混合物在25℃搅拌12h，得到黄色均匀溶液。用1M盐酸将溶液酸化至约pH2，分离油状剩余物，然后滗析。将该油溶解于搅拌的水(300mL)中，并在冰水浴中冷却。滤出产生的白色固体沉淀，用水(3×300mL)洗涤，并从55％乙腈/水(V/V)中重结晶，得到化合物CXVII为米色固体(7.4g，47％)。mp89-92℃。
数据如下：
1H NMR(300MHz，DMSO-d6)δ：12.0(1H，s)，8.65(1H，t)，8.0(1H，dd)，7.8(1H，m)，7.65(1H，m)，7.5(1H，m)，3.2(2H，q)，2.2(2H，t)，1.5(4H，br m)，1.3(6H，br m).
元素分析计算值：C15H20N2O5：C，58.41；H，6.54；N，9.09.实测值：C，58.50；H，6.71；N，9.14.
本发明其它化合物可按照实施例1-4所述方法来制备。
实施例5-15  大鼠体内评价重组生长激素
按下表1将修饰氨基酸和重组人类生长激素(rhGH)在pH约为7-8的磷酸盐缓冲液中混合来制备剂量组合物。
通过舌下，灌胃，十二指肠内给药或结肠给药给予大鼠剂量组合物。用ELISA测定法对得自Medix Biotech Inc.的rhGH进行传送情况的测定评价。对于结肠内给药，制出样品并以溶于含丙二醇(0-50％)的缓冲液中的25mg/kg载体和1mg/kg rhGH的剂量给予禁食的大鼠。
下面表1中给出测定的结果。
对比实施例5A
灌胃给予大鼠rhGH(6mg/ml)。根据实施例5的方法测定传送情况。
结果列于下面表1。
                                            表1
                                      rhGH的体内传送
  实施例   载体 载体剂量(mg/kg) 药物剂量(mg/kg) 给药方法 rhGH的血清浓度的平均峰值(ng/mL)
    5   I     500     6   口服     26.6±43.83
    5A  无     0     6   口服     ＜10±10
    6  V     500     6   口服     3.22±7.2
    7  VI     500     6   口服     19.34±18.73
    8  VIII     500     6   口服     73.41±70.3
    9  IX     500     6   口服     28.70±41.7
    10  XIII     25     1   结肠     109.52±36.1
    11  XIX     200     3   口服     60.92±26.3
    12  XIX     25     1   结肠     111.52±16.4
    13  XIX     100     3   舌下     119.14±65.6
    14  XIX     25     1   鼻内     92.7±73.2
    15  XXVII     25     1   结肠     73.72±4.9
实施例16-27大鼠体内评价重组生长激素
剂量溶液的制备
将传送剂用蒸馏水稀释，并用盐酸水溶液或氢氧化钠水溶液调至pH7.2-8.0，重新制成传送剂。混合rhGH，D-甘露糖醇和甘油，并将其溶解于2％甘油/水的混合物中，制成rhGH的储藏溶液。然后将该储藏溶液加到传送剂溶液中。研究几种传送剂对活性剂的传送率。
体内实验
将体重为200-250g的雄性Sprague-Dawley大鼠禁食24小时。在给药前15分钟给予大鼠酮胺(44mg/kg)和氯丙嗪(1.5mg/kg)。通过皮下注射，鼻内滴注或舌下滴注给大鼠使用上述药剂溶液之一。不断从大鼠的尾部动脉抽取血样进行血清钙浓度或血清rhGH浓度测定。在本实验中所用rhGh的剂量为0.1mg/kg。
用rhGH酶免疫测定试验试剂盒对血清rhGH浓度进行定量测定。其结果在表2和图1和2中给出。
图2中，圆点代表化合物CXXIII和rhGH水溶液SL给药后的反应。方块代表化合物CXXIII和rhGH水溶液IN给药后的反应。三角代表化合物CXXIII和rhGH水溶液IC给药后的反应。化合物CXXIII的剂量为25mg/kg，rhGH的剂量为1mg/kg。
对比实施例16A
灌胃给予大鼠rhGH(1mg/kg)。根据实施例16的方法测定传送情况。
结果列于下面表2。
                           表2
             通过皮下给药传送剂对重组人生长激素(rhGH)的生物利用度的增强作用
实施例   传送剂   传送剂剂量(mg/kg) rhGH的血清浓度的峰值(ng/mL)
    16  CXXIII     1.0     22±3
    16A     无     0.0     4±2
    17  CXXIII     2.5     25±5
    18  CXXIII     25     30±6
    19     CXI     2.5     16±2
    20   LVIII     1.0     29±10
    21  LXXXVI     1.0     22±7
    22  LXXXVI     2.5     23±5
    23     LXI     2.5     26±5
    24     CX     1.0     15±3
    25     CXV     1.0     25±3
    26     LXVI     1.0     33±5
    27     CIX     1.0     16±3
实施例28-33大鼠体内评价干扰素
按下表3将修饰氨基酸化合物与干扰素a2b在pH约为7-8的Trizmaò盐酸盐缓冲液(Tris-HCl)中混合，制成药剂组合物。如果必要，将丙二醇(0-25％)作为溶解剂加入。
通过灌胃，十二指肠内给药或结肠内给药给予大鼠药剂组合物。用ELISA测定法对得自Biosource Inc.的干扰素a进行传送情况的测定。
下面表3中给出结肠内给药的结果。
对比实施例28A
在大鼠的结肠内给予干扰素a 2b(250mg/kg)。根据实施例14的方法测定传送情况。
结果列于下面表3。
                                     表3
                        结肠内给药干扰素的体内传送
实施例   载体 载体剂量(mg/kg) 干扰素剂量(mg/kg) 干扰素血清浓度的平均峰值(pg/mL)
    28   VII     100     250     5241±2205
    28A    无     0     250     0
    29    XI     100     250     1189±1373
    30   XII     100     250     6955±2163
    31   XIX     100     250     11193±8559
    32   XXI     100     250     4238±2789
    33 XXXIV     100     250     4853±5231
实施例34-37大鼠体内评价鲑鱼降钙素
按下表4将修饰氨基酸与鲑鱼降钙素混合，制成剂量组合物。将400mg载体加到2.9mL 25％丙二醇水溶液中。搅拌所得溶液，用氢氧化钠(1.0N)调至pH7.2.。加水使整个体积达到2.0mL。样品中载体的最终浓度为200mg/mL。将降钙素(10mg)加到溶液中，使整个降钙素的浓度为2.5mg/mL。
对于每一种样品，要将一组禁食的大鼠麻醉。通过灌胃，结肠内滴注或十二指肠内滴注给予大鼠药剂组合物。不断从鼠的尾部动脉抽取血样。通过试验用Calcium Kit(Sigma Chemical Company，St.Louis，Missouri，USA)对血清钙浓度进行测定。
结果在下面表4中给出。
                                        表4
                                   降钙素的体内传送
实施例 载体 载体剂量(mg/kg) 药物剂量(mg/kg) 给药方法 血清钙浓度降低的最大值(基线以下的％)
    34    I     400     10     口服
    35    V     400     10     口服     18.35±2.87
    36  XIX     10     3     结肠     26.49±12.3
    37  XIX     200     7.5     口服     25.48±4.7
实施例38-43大鼠体内评价鲑鱼降钙素
剂量溶液的制备
将传送剂用水稀释，并用盐酸水溶液或氢氧化钠水溶液调至pH7.2-8.0，重新制成传送剂。将sCT溶解于柠檬酸(0.085N)，制成sCT的储藏溶液。然后将该储藏溶液加到传送剂溶液中。研究几种不同的传送剂对活性剂的传送率的影响。
体内实验
将体重为200-250g的雄性Sprague-Dawley大鼠禁食24小时。在给药前15分钟给予大鼠酮胺(44mg/kg)和氯丙嗪(1.5mg/kg)。通过皮下注射给予大鼠上述药剂溶液之一。不断从大鼠的尾部动脉抽取血样进行血清钙浓度测定。
采用邻-甲酚酞氨酸络合剂方法(Sigma)，用UV/VIS分光光度计(PerkinElmer)对血清钙浓度进行定量测定。结果在表5中给出。
实施例38A
给大鼠灌入鲑鱼降钙素。根据实施例38的方法测定传送情况。
结果由下面表5给出。
                           表5
               通过皮下给药传送剂对鲑鱼降钙素(sCT，剂量为0.2mg/kg)的生物利用度的增强作用
实施例   传送剂   传送剂剂量(mg/kg) 血清钙浓度降低的百分比(％)
    38   CXXIII     2     17±3
    38A     无     0     17±2
    39   CXXIII     20     25±4
    40   CXXIII     200     25±5
    41   CXXIII     2000     26±5
    42      CXI     20     21±4
    43     CXIV     20     20±3
实施例44-50大鼠体内评价肝素
按下表6将修饰氨基酸与列于下面表6的肝素混合，制成药剂组合物。在试验试管中，将900mg载体溶解于3mL丙二醇，并将0.299g钠肝素溶解于3mL水。溶液用旋涡方式混合。在所得混合物中加入氢氧化钠(10M)直到形成溶液。然后用浓盐酸将pH调至7.4±0.5。所得溶液在40℃用声波作用30分钟。
通过灌胃给予一组禁食的有知觉的大鼠药剂组合物。给予酮胺(44mg/kg)后，通过心脏穿刺抽取血样。根据Henry，J.B.，(用实验室方法进行临床诊断和处理(Clinical Diagnosis and Management byLaboratory Methods)；Philadelphia，PA；WB Saunders(1979))所述方法，利用活化的局部促凝血时间(actiVated partial thromboplastim time，APTT)对肝素活性进行测定。
结果列于下面表6。
对比实施例44A
灌胃给予大鼠肝素(100mg/kg)。根据实施例44的方法对肝素的活性进行测定。
结果列于下面表6。
                                表6
                      口服给药后干扰素的体内传送
实施例   载体 载体剂量(mg/kg) 药物剂量(mg/kg)     APTT的平均峰值(sec)
    44    II     300     100     25.45±2.8
    44A    无     0     100     20.7±0.17
    45   III     300     100     38.64±17
    46     V     300     100     87.4±34.1
    47   XII     300     100     49.53±17.1
    48   XIX     300     100     119.99±56.3
    49  XXXI     50     25     127.56±22.97
    50  XXXI     50     10     50.85±9.1
实施例51
依照实施例44方法，只是用小分子量肝素代替肝素，并根据需要改变起溶解作用的丙二醇和水的用量。
实施例50-58大鼠体内评价甲状旁腺激素
剂量溶液的制备
将传送剂用蒸馏水和/或丙二醇稀释，并用盐酸水溶液或氢氧化钠水溶液调至pH7.2-8.0，重新配制传送剂。将甲状旁腺激素溶解于水，制成甲状旁腺激素储备溶液。然后将该储备溶液加到传送剂溶液中。研究几种不同的传送剂对活性剂的传送率的影响。
体内实验
将体重为200-250g的雄性Sprague-Dawley大鼠禁食24小时。在给药前15分钟给予大鼠酮胺(44mg/kg)和氯丙嗪(1.5mg/kg)。通过灌胃或结肠内滴注给予大鼠上述药剂溶液之一。不断从大鼠的尾部动脉抽取血样进行甲状旁腺激素的血清浓度测定。用甲状旁腺激素放射性免疫测定试验试剂含对甲状旁腺激素的血清浓度进行定量分析。
体内口服给药
将含有甲状旁腺激素(PTH)和非a-氨基传送剂的溶液给大鼠口服来进行体内试验。结果表明比类似单独使用活性剂相比能显著增加甲状旁腺激素的口服生物利用度。
结果列于下面表7。
                                   表7
               口服传送剂对甲状旁腺激素(PTH)生物利用度的提高作用
实施例   载体 载体剂量(mg/kg) 给药方法 活性剂剂量(mg/kg) PTH血清浓度的峰值(pg/mL)
    51  CXXIII     100   结肠内     25     130±20
    52  CXXIII     250     口服     100     75±25
    53  CXXIII     250     口服     25     20±6
    54   CVIII     100   结肠内     25     115±20
    55   LXXXVI     100   结肠内     25     40±12
    56   LVIII     100   结肠内     25     145±25
    57    CXIV     100   结肠内     25     65±15
    58   LXXXIX     100   结肠内     25     70±15
上面提到的专利，申请，试验方法和公开的文献在这里全部引入本文供参考。
根据上文对本发明详细描述部分，本领域技术人员会对本发明作出许多变化。所有这些显而易见的变化都包括在所附权利要求的范围内。

Claims (24)

1.下列化合物或其盐：
Figure C9619299800021
2.选自下列的化合物或其盐：
3.选自下列的化合物或其盐：
4.选自下列的化合物或其盐：
5.选自下列的化合物或其盐：
6.基本组成为下列组分的组合物：
(a)活性剂；及
(b)下列化合物或其盐：
Figure C9619299800071
7.基本组成为下列组分的组合物：
(a)活性剂；及
(b)下列化合物或其盐：
 8.基本组成为下列组分的组合物：
(a)活性剂；及
(b)下列化合物或其盐：
 9.基本组成为下列组分的组合物：
(a)活性剂；及
(b)下列化合物或其盐：
 10.基本组成为下列组分的组合物：
(a)活性剂；及
(b)下列化合物或其盐：
11.权利要求6定义的组合物，其中所说活性剂选自生物活性剂和化学活性剂。
12.权利要求11定义的组合物，其中所说生物活性剂选自肽，粘多糖，碳水化合物，类脂，农药和它们的任意组合物。
13.权利要求12定义的组合物，其中所说生物活性剂选自人生长激素，牛生长激素，释放生长激素的激素，干扰素，白介素-II，胰岛素，肝素，降钙素，红细胞生成素，心钠素，抗原，单克隆抗体，促生长素抑制素，促肾上腺皮质素，促性腺释放激素，催产素，加压素，色甘酸钠，万古霉素，甲状旁腺激素，去铁胺(DFO)，或它们的任意组合物。
14.权利要求10定义的组合物，包括甲状旁腺激素和化合物CXXIII或其盐。
15.组成为下列组分的剂量单位：
(A)权利要求6定义的组合物；及
(B)任选地包含一或多种下列成分
(a)赋形剂，
(b)稀释剂，
(c)崩解剂，
(d)润滑剂，
(e)增塑剂，
(f)调色剂，或
(g)药剂的载体。
16.根据权利要求15的剂量单位，包括片剂，胶囊剂或液体制剂。
17.权利要求6定义的组合物用于制备为动物输送生物活性剂的药物的用途。
18.一种制备权利要求6组合物的方法，该方法包括将下列组分混合：
(A)至少-种生物活性剂；
(B)至少一种权利要求1定义的化合物；及
(C)可有可无的剂量载体。
19.权利要求6的组合物用于制备为动物输送生物活性剂的药物的用途，其中所述组合物是经口服，鼻内，舌下，十二指肠内，肌肉内或皮下给药的。
20.制备权利要求1-5所述化合物的方法，该方法包括
(a)在水中和碱存在下，将下式化合物
Figure C9619299800111
其中
R1是C3-C24烷基，C2-C20烯基，C2-C20炔基，环烷基或芳基；
R2是氢，C1-C4烷基或C2-C4烯基；
与下式化合物反应，
R3-Y-X
其中
Y是
Figure C9619299800121
或SO2；
R3是C1-C7烷基，C3-C10环烷基，芳基，噻吩基，吡咯并或吡啶基，其中，
R3可任意被一个或多个C1-C5烷基，C2-C4烯基，F，Cl，OH，SO2，COOH或
SO3H取代，X是离去基团，
生成具式CXXIV的化合物，
其中R1，R2，R3和Y的定义同本权利要求中所述。
21.基本组成为下列组分的药物组合物，它包含：
(A)至少一种生物活性剂；及
(B)至少一种下式载体化合物或其盐，
2-HO-Ar-CONR8-R7-COOH
其中
Ar是取代的或未取代的苯基或萘基；
R7选自C4-C20烷基，C4-C20烯基，苯基，萘基，(C1-C10烷基)苯基，(C1-C10烯基)苯基，(C1-C10烷基)萘基，(C1-C10烯基)萘基，苯基(C1-C10烷基)，苯基(C1-C10烯基)，萘基(C1-C10烷基)和萘基(C1-C10烯基)；
R8选自氢，C1-C4烷基，C1-C4烯基，羟基和C1-C4烷氧基；
R8可以任意被C1-C4烷基，C1-C4烯基，C1-C4烷氧基，-OH，-SH和-CO2R9或它们的任意组合基团取代；
其中R9是氢，C1-C4烷基或C1-C4烯基；
R7可以任意被氧，氮，硫或它们的任意组合间断；
条件是这些化合物或其盐不在酸基的α位被氨基取代。
22.权利要求21的药物组合物，其中Ar为未取代苯基，R8为氢。
23.权利要求1中的化合物，其选自下面的化合物或其盐：
24.权利要求6的组合物，其包括：
(a)活性剂；和
(b)选自下面的化合物或其盐
Figure C9619299800132
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