CN1313439C - 用于送递活性剂的化合物和组合物 - Google Patents

用于送递活性剂的化合物和组合物 Download PDF

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CN1313439C
CN1313439C CNB998094382A CN99809438A CN1313439C CN 1313439 C CN1313439 C CN 1313439C CN B998094382 A CNB998094382 A CN B998094382A CN 99809438 A CN99809438 A CN 99809438A CN 1313439 C CN1313439 C CN 1313439C
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salt
heparin
agent
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CN1315936A (zh
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D·盖斯啻耐德尼尔
A·莱昂－贝
E·瓦恩格
L·埃里格
K－K·赫
J·B·普里斯
王乃方
P·坦格
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Emisphere Technologies Inc
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Abstract

提供了送递活性剂的化合物和组合物。还提供了施用和制备的方法。

Description

用于送递活性剂的化合物和组合物
本发明涉及用于送递活性剂(例如生物活性剂或化学活性剂)至靶的化合物。这些化合物很适合与对动物经口、结肠内或其它途径施药的活性剂形成非共价混合物。还公开了制备和施用这样的组合物的方法。
送递活性剂的常规方法时常受生物的、化学的和物理的障碍的严重限制。通常，这些障碍是由下列因素施加的：送递所发生的环境、送递的靶环境和/或靶自身。生物活性剂和化学活性剂特别易受这类障碍的影响。
在对动物送递生物活性的和化学活性的药剂和治疗剂时，障碍是由身体施加的。物理障碍的实例有：皮肤、脂双层和各种器官膜，所述器官膜相对地不透过某些活性剂，但必须在活性剂到达靶(例如循环系统)之前被穿过。化学障碍包括但不限于：胃肠(GI)道中的pH变化和降解酶。
这些障碍在经口送递体系的设计中具有特别的意义。如果没有生物的、化学的和物理的障碍，很多生物活性剂或化学活性剂的经口送递应当是施药所选择的途径。在通常不适合经口施药的许多作用剂中，有生物活性的或化学活性的肽，例如：降钙素和胰岛素；多糖，尤其是粘多糖(包括但不限于肝素)；类肝素；抗生素；以及其它有机物质。这些作用剂在胃肠道中可通过酸解、酶等的作用而迅速变得无效或被破坏。此外，大分子药物的尺寸和结构可能阻止吸收。
经口施用易损坏药剂的早期方法依赖于共同施用佐剂[例如，间苯二酚和非离子型表面活性剂(例如聚氧乙烯油酰醚和正十六烷基聚乙烯醚)]而人为地增大肠壁的渗透性，以及共同施用酶促抑制剂[例如胰腺胰蛋白酶抑制剂、二异丙基氟磷酸酯(DFF)和抑胰肽酶]而抑制酶促降解。还描述了脂质体作为胰岛素和肝素的药物送递体系。例如，参见US 4,239,754；Patel等(1976)，FEBS通讯(FEBSLetters)，Vol.62，pg.60；以及Hashimoto等(1979)，内分泌学(日本)(Endocrinology Japan)，Vol.26，pg.337。然而，这样的药物送递体系的宽范围应用受阻碍，因为：(1)所述体系需要中毒量的佐剂或抑制剂；(2)不可能达到合适的低分子量载荷(即，活性剂)；(3)所述体系表现差稳定性和不足的寿命；(4)所述体系难于生产；(5)所述体系不能保护活性剂(载荷)；(6)所述体系不利地改变活性剂；或者(7)所述体系不允许或不促进活性剂的吸收。
最近，已应用混合氨基酸的人造聚合物微球(类蛋白质)来送递药物。例如，美国专利4,925,673描述了含药物的类蛋白质微球化合物，以及它们的制备方法和应用。这些类蛋白质微球适用于送递一些活性剂。此外，已应用某些改性氨基酸来送递药物。参见例如，US5,629,020；US 5,643,957；US 5,650,386；和US 5,776,888。
然而，仍需要简单的、廉价的送递体系，它们容易制备，而且，它们能通过各种途径送递宽范围的活性剂。
提供了适用于送递活性剂的化合物和组合物。所述化合物包括下列化合物或其盐：
  化合物#   n   m   X
12345678910111213141516171819202122232425104133 333232233322232322323233332 CH2OCH2O0000011000000220000000000 2-OH4-OH2-NH2，5-F2-NH2，5-F2-NH2，5-Cl2-NH2，3，5-Cl2-NHMe4-OH3-OH2-NHMe2-OH，3-F；5-Cl2-OH，3-Cl；5-F2-OH，3，5-Me2-OH，3，5-Me2-OH，3-Br，5-Cl2-OH2-OH2-OH，3，5-F2-OH，3，5-F2-OH，5-F2-OH，5-F2-NHAc2-SO3Na2-OH，3-Me，5-F2-OH，3-Me，5-Cl2-OH，4-Ome2-OH，3-Me，5-Cl
  化合物#   n   X
  26272829303132333435119120121122123124125126127128129130131132   768787477835678124910111277   2-OH，5-Me2-OH2-OH，3，5-Cl2-OH，3，5-Cl2-OH，4-Me2-CH2OH2-OH，4-Me2-OH，4-Me2-OH，5-F2-OH，5-F2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，3，4-F2-OH，4-F
  化合物#   n   m   X
  36373839404142434445464748495051525354555657858687888990919293949596979899100   75777777777777777777799510105333391111111199   00CH2O00000001000001200000000000000000000   2-OH，3-NH2，5-NO22-OH，4-Cl4-OH2-NH2，5-F2-NH2，5-Cl2-OH，3，5-F2-OH，3，4-F2-NHMe2-OH，4-F2-OH，3-F，5-Cl4-OH2-OH，3-Cl，5-F2-OH，3-Br，5-Cl2-OH，3，5-Me2-OMe，6-Cl2-OH，6-Cl3-OH2-OH2-OH，5-F2-OH，3-Me，5-Cl2-OH，3-Me，5-F2-OH，5-Cl2-F2-FH2-FH2-OCH32-CH32-FH2-OCH32-CH32-OCH32-FH2-CH3H
  101102103105106107108109110111112113114116117118   51233591111111456   0000000000000000   2-CH32-OH，4-OMe2-OH2-OH，5-Cl2-OH，4-OMe2-OH，4-OMe2-OH，4-OMe2-OH，4-OMeH2-CH32-OMe2-F2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl
化合物58：
Figure C9980943800121
化合物59：
Figure C9980943800122
化合物60：X＝F
化合物61：X＝OH
化合物62：X＝SO
化合物63：X＝SO2
化合物64
化合物65：X＝Cl；Y＝OMe
化合物66：X＝F：Y＝OH
化合物67：X＝F；Y＝OMe
化合物68：X＝OMe；Y＝OH
化合物69：n＝1
化合物70：n＝2
化合物71：
化合物72：
化合物73：
化合物74：X＝Me
化合物75：X＝OMe
化合物76：X＝Y＝OMe；Z＝H；n＝1
化合物77：X＝OH；Y＝Z＝Cl；n＝1
化合物78 n＝2
化合物134：n＝3
Figure C9980943800153
化合物79：
Figure C9980943800154
化合物80：
化合物81：
化合物82：
Figure C9980943800163
化合物83
Figure C9980943800171
化合物84：R＝C(O)-NH-(CH2)7COOH
化合物135：R＝(CH2)7COOH
本发明的组合物包含至少一种活性剂(优选是生物活性剂或化学活性剂)，以及至少一种本发明的化合物或其盐。还提供了这类组合物的制备方法和施药方法。包含这样的化合物和活性剂的所述组合物适用于送递活性剂到选定的生物体系，并且与单独施用所述活性剂相比，以增大或改善活性剂的生物利用率的方式送递。
本发明的组合物包含一种活性剂和一种送递剂。这些组合物可被用于送递各种活性剂通过各种生物的、化学的和物理的障碍，而且特别适合送递易受环境降解的活性剂。
本发明的其它优点包括容易制备的、廉价原料的应用。本发明的组合物和配制方法成本低，操作简单，而且可在工业规模实现商品化生产。
化合物
所述化合物可呈羧酸和/或它们的盐的形式。盐包括但不限于：有机或无机盐(例如钠盐)。此外，可应用包含这些化合物中的一种或多种的聚氨基酸和肽。
氨基酸是具有至少一个游离氨基的任意羧酸，包括天然氨基酸和合成氨基酸。聚氨基酸是肽(它们是通过肽键连接的两个或多个氨基酸)或者是通过其它基形成的键连接的两个或多个氨基酸(它们可通过例如酯键或酐键连接)。肽在长度上可变，从二肽(具有两个氨基酸)到多肽(具有数百个氨基酸)。参见： 钱伯斯生物词典(Chambers Biological Dictionary)，Peter M.B.编辑，Walker，Cambridge，England：Chambers Cambridge，1989，第215页。一个或多个氨基酸或肽单元可被酰化或磺化。
本文描述的很多化合物可得自氨基酸，并且可通过基于本公开的本领域技术人员能力所及的方法和下列文献中描述的方法容易地从氨基酸制备：WO 96/30036、WO 97/36480、US 5,643,957和US 5,650,386。例如，可这样制备所述化合物：将单一氨基酸与合适的酰化剂或胺-改性剂(它与氨基酸中存在的游离氨基部分反应而形成酰胺)反应。本领域技术人员应知道，可应用保护基来避免不需要的副反应。至于保护基，可参考T.W.Greene， 有机合成中的保护基(Protecting Groups in Organic Synthesis)，Wiley，New York(1981)，它的公开内容并入本文作表考。
所述化合物可通过重结晶或者通过在一种或多种固体色谱载体(独立地或串联)上分级来纯化。合适的重结晶溶剂体系包括但不限于：乙腈、甲醇和四氢呋喃。可这样进行分级：在合适的色谱载体(例如氧化铝)上，应用甲醇/正丙醇混合物作流动相；应用三氟乙酸/乙腈混合物作流动相的反相色谱法；以及应用水或合适的缓冲剂作流动相的离子交换色谱法。当进行阴离子交换色谱法时，优选应用0～500mM氯化钠梯度。
活性剂
适用于本发明的活性剂包括生物活性剂和化学活性剂及其组合，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活性剂包括但不限于：蛋白质；多肽；肽；激素，尤其是自身不通过(或只有一部分施用的剂量通过)胃肠粘膜和/或在胃肠道中易被酸和酶化学分裂的激素；多糖，尤其是粘多糖的混合物；碳水化合物；脂质；其它有机化合物；或其任意组合。
进一步的实例包括但不限于下列物质(包括其合成的、天然的或重组的来源)：生长激素，包括人生长激素(hGH)、重组人生长激素(rhGH)、牛生长激素和猪生长激素；生长激素释放激素；干扰素，包括α-、β-和γ-干扰素；白细胞介素-1；白细胞介素-2；胰岛素，包括猪的、牛的、人的和人的重组的胰岛素，任选具有反离子，包括钠、锌、钙和铵；胰岛素样生长因子，包括IGF-1；肝素，包括未分级的肝素、类肝素、皮肤素、软骨素、低分子量肝素、很低分子量肝素和超低分子量肝素；降钙素，包括鲑鱼的、鳗鱼的和人的降钙素；促红细胞生成素；心钠素(atrial naturetic factor)；抗原；单克隆抗体；促生长素抑制素；蛋白酶抑制剂；促肾上腺皮质激素；促性腺激素释放激素；催产素；促黄体生成激素(leutinizing-hormone)释放激素；促卵泡激素；葡糖脑苷脂酶；血小板生成素；非尔司啶；前列腺素；环孢菌素；血管升压素；色甘酸钠(色甘酸一钠或二钠)；万古霉素；去铁胺(DFO)；甲状旁腺激素(PTH)，包括其片段；抗微生物剂，包括抗真菌剂；这些化合物的类似物、片段、模拟物或聚乙二醇(PEG)改性衍生物；或其任意组合。
在本发明的一个方案中，所述生物活性剂包括：胰岛素、未分级的肝素、低分子量肝素、很低分子量肝素、超低分子量肝素、降钙素、甲状旁腺激素、促红细胞生成素、人生长激素或其组合。
送递体系
本发明的组合物包含送递剂和一种或多种活性剂。在一个实施方案中，一种或多种送递剂化合物、或者这些化合物的盐、或者聚氨基酸或肽(这些化合物或盐形成其单元的一个或多个)可通过在施用前与活性剂混合而被用作送递剂。
施药混合物可这样制备：就在施用前，将所述化合物的水溶液与活性组分的水溶液混合。也可在生产过程中将所述化合物与生物或化学活性组分掺和。
所述溶液可任选包含添加剂(例如磷酸缓冲盐、柠檬酸、二元醇或其它分散剂)。可在所述溶液中掺入稳定添加剂，优选以约0.1～20％(w/v)范围内的浓度掺入。
本发明的送递组合物还可包含一种或多种酶抑制剂。这样的酶抑制剂包括但不限于：化合物，例如放线酰胺素或表放线酰胺素及其衍生物。这些化合物的衍生物被公开于US 5,206,384中。其它酶抑制剂包括但不限于：抑蛋白酶肽(抑胰肽酶)和Bowman-Birk抑制剂。
本发明提供了一种制备组合物的方法，它包括：
混合
(A)至少一种活性剂；
(B)选自化合物1～25、36～61、65～68、73～81、85～114、116～118和133～134及其盐的化合物；以及
(C)任选一种配药载体。
本发明还提供了一种制备组合物的方法，它包括：
混合
(A)至少一种活性剂；
(B)化合物105及其盐或者化合物54及其盐或者化合物116及其盐。
活性剂的量是达到靶指示的特定活性剂的目的的有效量。所述组合物中活性剂的量通常是药物上、生物上、治疗上或化学上的有效量。不过，当以单元剂型(例如胶囊、片、粉末或液体)应用所述组合物时，可以用更少的量，因为单元剂型可能包含许多化合物/生物上或化学上的活性剂组合物或者可能包含均分的药物上、生物上、治疗上或化学上的有效量。然后，就能以累积单元施用总的有效量，所述累积单元总计包含生物活性剂或药物活性剂的药物上、生物上、治疗上或化学上的有效量。
应用的活性剂总量可通过本领域技术人员已知的方法确定。然而，由于所述组合物可能比现有组合物更有效地送递活性剂，所以，可以对受治疗者施用比现有单元剂型或送递体系中应用的更少量的生物活性剂或化学活性剂，但仍达到相同的血液水平和/或治疗效果。
现在公开的化合物送递生物活性剂和化学活性剂，尤其经口、鼻内、舌下、十二指肠内、皮内、经颊、结肠内、经直肠、经阴道、经粘膜、经肺、经皮、皮内、胃肠外、静脉内、肌内和眼系统送递，以及越过血脑屏障送递。
单元剂型还可包含如下物质的任何一种或组合：赋形剂，稀释剂，崩解剂，润滑剂，增塑剂，着色剂，调味剂，风味掩蔽剂，糖，增甜剂，盐，以及配药载体(包括但不限于：水、1，2-丙二醇、乙醇、橄榄油或其任意组合)。
本发明的化合物和组合物适合给任何动物施用生物活性剂或化学活性剂，所述动物包括但不限于：禽类，例如鸡；哺乳动物，例如母牛、猪、狗、猫、灵长目动物(尤其是人)；以及昆虫。所述体系特别有利于送递这样的化学活性剂或生物活性剂：如果用其它方法施用，它们就会被在活性剂到达其靶区(即，送递组合物的活性剂在其中将被释放的区)之前和在它们被施给的动物体内所遇到的条件破坏或变得效果更小。本发明的化合物和组合物还适用于施用活性剂，尤其是通常不能通过特定的途径(特别是经口途径)送递的那些，或者是需要改良送递的那些。可通过在一段时间或者在一段特定的时间(例如引起更迅速的送递)送递更多活性剂来改良送递。
施用后，组合物或单元剂型中存在的活性剂被吸收入循环。作用剂的生物利用率容易通过测定血液中已知药物活性(例如由肝素引起的血液凝固时间增长，或者由降钙素引起的循环钙含量降低)而估测。活性剂自身的循环含量也可被直接测定。
如下实施例阐述了本发明而不是限制它。除非另有说明，所有的份都以重量份给出。
实施例1-化合物制备
方法A：化合物26的制备。在装有磁搅拌器的1L圆底烧瓶中加入2-氨基-对甲酚(1.71g，13.88mmol，1当量)和2M氢氧化钠水溶液(20ml)。在0℃和搅拌下，往溶液中滴加甲基壬二酰氯(3.08g，13.96mmol，1.01eq.)。添加后，使反应混合物暖至室温并在室温下搅拌4～5小时。通过添加20％氢氧化钠将溶液的pH保持在约11～12。然后，用乙酸乙酯(3×30ml)萃取溶液。在硫酸钠上干燥合并的有机层，过滤，真空浓缩。将残余物再溶于THF(50ml)，用2N NaOH(20ml)处理。在室温下搅拌形成的混合物达8小时。TLC指示反应完全。真空浓缩混合物，酸化。收集形成的固体，用甲醇/丙酮/水重结晶而给出2.5g产品。
化合物11～15、18～21、24、25、27～35、48～50、54～56、58、65～68、73、83、110、120和131～133也是应用合适的原料通过该方法制备的。化合物120、122和123也是应用合适的原料通过该方法制备的，不同的是在含THF的体系中进行反应。
方法B：化合物60的制备。用1.45ml(1.24g，11.4mmol)氯化三甲基硅烷处理1.03g(5.62mmol)3-氨基-4-氟氢化肉桂酸和20ml二氯甲烷的浆料并加热至回流达150min。将反应混合物冷却到0℃，用2.4ml(1.74g，17.2mmol)三乙胺处理。搅拌5min后，将所述混合物倾入加料漏斗，缓慢地加到1.21g(6.09mmol)O-乙酰水杨酰氯和10ml二氯甲烷的0℃溶液中。使反应混合物暖至25℃并搅拌18hr。用3％盐酸水溶液(2×20ml)、水(1×20ml)和盐水(1×15ml)洗涤，在硫酸钠上干燥，真空浓缩，给出棕黄色固体。将该固体从15ml65％乙醇/水中重结晶而给出棕色固体。将该固体溶于饱和碳酸氢钠水溶液。搅拌直至分解乙酸酯(通过HPLC检测)后，酸化溶液，引起沉淀形成。通过过滤分离而给出0.58g(38％产率)产品，mp＝202-4℃。
化合物59、61、74～81、107、109和111～113也是应用合适的原料通过该方法制备的。化合物37、42、44和134也可应用合适的原料通过该方法制备。
方法C：化合物1的制备。在装有磁性搅拌棒、氩气驱气管和冷水冷凝器的250ml圆底烧瓶中，将1，4-苯并二_烷-2-酮(4.50g，30mmol)溶于乙腈(75ml)。添加三乙胺(4.17ml，3.03g，30mmol)和4-(4-氨基苯基)丁酸(5.37g，30mmol)。将反应混合物加热至回流达2hr，在25℃下搅拌一夜，真空浓缩。用二氯甲烷吸收棕色残余物，用1N盐酸水溶液洗涤(1×100ml)。通过过滤分离形成的固体，用1N盐酸水溶液和水冲洗。在真空干燥箱中将形成的固体干燥一夜，形成褐色固体化合物(9.19g，93％产率)。
化合物53是通过该方法从二氢香豆素和8-氨基辛酸开始制备的。
方法D：化合物36的制备。应用方法T从3，5-二硝基水杨酸和8-氨基辛酸开始制备了8-(N-3，5-二硝基水杨酰)氨基辛酸。
用70mg 10％Pd/C处理0.7g(1.9mmol)8-(N-3，5-二硝基水杨酰)氨基辛酸和40ml乙酸乙酯的溶液并置于氢气氛中达18hr。通过过滤除去催化剂。真空浓缩滤液。将残余物从甲醇/丙酮/水中重结晶，给出0.4g(62％产率)产品，mp＝156-7℃。
方法E：化合物2的制备。应用方法C通过4-(4-氨基苯基)丁酸与4-苄氧基苯氧基乙酰氯的反应制备了4-(4-(4-苄氧基苯氧基乙酰)氨基)苯基)丁酸。
在氩气中将5.00g(11.9mmol)4-(4-(4-苄氧基苯氧基乙酰)氨基)苯基)丁酸和150ml甲醇的浆料搅拌大约20分钟。一次添加催化量(0.4g)的10％披钯碳。将反应器抽空。在室温下的氢气氛中保持反应一夜。然后，滤去披钯碳，真空浓缩滤液而给出白色固体产品。
化合物8、9和38也是应用合适的原料通过该方法制备的。
方法F：化合物39的制备。将10.82g(59.7mmol)5-氟靛红酸酐、9.50g 8-氨基辛酸、16.8g 50wt％K2CO3/水和40ml二_烷的悬浮液加热至回流。2hr后，反应完全(通过HPLC检测的)。将深紫色溶液冷却到25℃，用3％盐酸水溶液酸化至pH＝4.00，导致形成深色沉淀。通过过滤分离固体，从65％乙醇/水重结晶而给出11.86g(67％产率)黄色固体产品，mp＝108-9℃。
化合物3～7、10、40和43也是应用合适的原料通过该方法制备的。
方法G：化合物62的制备。用1.05 eq 3N亚硝酸钠水溶液处理5℃下4-(4-氨基苯基)丁酸(1.0eq)和6N盐酸水溶液(5.44eq)的混合物(缓慢地添加以便保持温度低于5℃)。添加2.8N碘化钾水溶液(1.01eq)。将反应物搅拌一夜。分层。应用甲醇/二氯甲烷作为洗脱剂通过急骤色谱法纯化有机相，给出4-(4-碘苯基)丁酸。
用2eq碳酸钾、1.5 eq 2-羟基苯硫酚和催化量的乙酸铜(cupericacetate)(0.01eq)处理4-(4-碘苯基)丁酸(0.86M)和二甲基甲酰胺的溶液。将反应混合物回流18hr，冷却到25℃，用含水的酸酸化，用乙酸乙酯萃取。浓缩有机相。应用乙酸乙酯/己烷作为洗脱剂通过急骤色谱法纯化残余物，给出4-(4-(2-羟基苯基)苯硫基)丁酸。
用9.8M过氧化氢水溶液处理4-(4-(2-羟基苯基)苯硫基)丁酸和乙酸乙酯/乙酸的0.33M溶液。搅拌12hr后，分层。浓缩有机相。应用甲苯/丙酮/己烷作为洗脱剂通过急骤色谱法纯化残余物而给出产品。
方法H：化合物82的制备。用2.91g 2-硝基苯基异氰酸酯和10ml二氯甲烷的溶液处理0℃下3.97g(17.8mmol)9-溴-1-壬醇和二氯甲烷的溶液。将反应混合物加热至回流达2hr，在25℃下搅拌16hr，真空浓缩。黄色固体被鉴定为9-溴壬基N-(2-硝基苯基)氨基甲酸酯并被直接应用。
在35℃下，将2.99g(7.72mmol)9-溴壬基N-(2-硝基苯基)氨基甲酸酯、1.61g(23.3mmol)亚硝酸钠、4.50ml(4.72g，78.5mmol)乙酸和15mL二甲亚砜的悬浮液搅拌7hr。用3％盐酸水溶液酸化反应混合物，用乙醚(3×20ml)萃取。用2N氢氧化钠水溶液(3×20ml)萃取合并的有机层。用3％盐酸水溶液酸化碱性水相，导致形成沉淀。通过过滤收集固体，给出0.79g(30％产率)化合物，mp＝90-1℃。
方法I：化合物64的制备。应用方法F从靛红酸酐和4-(4-氨基苯基)丁酸开始制备了4-(4-(2-氨基苯甲酰)氨基苯基)丁酸。
将4.73g(16.0mmol)4-(4-(2-氨基苯甲酰)氨基苯基)丁酸和40ml原甲酸三乙酯的浆料置于氩气氛中，加热至回流达18小时。在回流过程中，反应物变得更清亮。使反应混合物冷却到室温，通过过滤收集形成的固体，给出4.47g(88％产率)产品，mp＝201～204℃。
方法J：化合物63的制备。在0℃下，用4eq间-氯过苯甲酸处理4-(4-(2-羟基苯基)苯硫基)丁酸于二氯甲烷中的0.05M溶液。使反应混合物暖至25℃，搅拌12hr。除去溶剂。应用乙酸乙酯/己烷/乙酸作为洗脱剂通过急骤色谱法纯化残余物而给出产品。
方法K：化合物84的制备。应用方法F，从靛红酸酐和8-氨基辛酸开始制备了8-N-(2-氨基苯甲酰)氨基辛酸。
将6.88g(24.7mmol)8-N-(2-氨基苯甲酰)氨基辛酸和100mL二氯甲烷的浆料冷却到0℃，并且用2.00ml(2.08g，12.4mmol)1，6-己二异氰酸酯和5ml二氯甲烷处理。将反应混合物加热至回流达2hr，冷却到25℃，用20ml乙醇稀释。通过过滤分离形成的固体，从1/2/1乙酸乙酯/乙醇/水中重结晶，得到总计5.15g(57％产率)褐色固体产品，mp＝138～142℃。
化合物135也是应用合适的原料通过该方法制备的。
方法L：化合物51的制备。应用方法A，从2-氯-6-甲氧基苯甲酸和8-氨基辛酸开始制备了8-(N-6-氯-2-甲氧基苯甲酰)氨基辛酸。
将处于氩气氛中的1.27g(3.72mmol)8-(N-6-氯-2-甲氧基苯甲酰)氨基辛酸于200ml二氯甲烷的悬浮液冷却到0℃，用8ml 1.0M三溴化硼于二氯甲烷中的溶液处理。搅拌60min后，TLC指示反应完全。用水骤冷反应混合物并搅拌30min。分层。用二氯甲烷(2×30ml)萃取水层。将合并的有机层在硫酸钠上干燥，过滤，真空浓缩。将形成的白色固体从甲醇/丙酮/水中重结晶而给出0.5g(43％产率)产品，mp＝156-7℃。
方法M：化合物17的制备。在氩气氛中搅拌4.28mL(0.034摩尔)二氢香豆素、75ml乙腈、4.79ml三乙胺(3.48g，0.0343摩尔)和5.62g 3-(4-氨基苯基)丙酸(0.034摩尔)的溶液，将烧瓶加热至回流达18小时。使反应物冷却到室温，真空除去乙腈。在二氯甲烷和1N盐酸水溶液中搅拌残余物，形成白色固体。滤出该固体，用水和二氯甲烷冲洗，然后，在50℃下真空干燥，给出9.17g(86.1％产率)产品，mp＝163～165℃。
化合物16也是应用合适的原料通过该方法制备的。
方法N：化合物52的制备。用6.45ml(68.4mmol)乙酸酐处理10.0g(65.8mmol)3-羟基苯基乙酸于50ml二甲苯中的溶液。将该混合物加热回流约2.5小时直至蒸出大部分二甲苯和乙酸副产物。分离低聚-(3-羟基苯基乙酸)棕色油状物。
将该油状物溶于150ml 1，4-二_烷。往该低聚物溶液中添加9.97g(62.7mmol)8-氨基辛酸和34.5ml 2N NaOH的溶液。将反应混合物加热至回流一夜。然后，在真空下除去二_烷。将棕色残余物吸收入2N NaOH，用两份各100ml乙酸乙酯萃取。接着用2N硫酸溶液酸化水层，再用三份各100ml乙酸乙酯萃取。用活性炭使合并的乙酸乙酯层脱色，用硫酸钠干燥，真空浓缩。然后，通过柱色谱法纯化生成的棕色油，其中应用硅胶柱，以乙酸乙酯∶己烷∶乙酸(60∶40∶1)为流动相。用温水(40～50℃)洗涤形成的白色固体而给出白色固体产物。
化合物41、45和47也是应用合适的原料通过该方法制备的。
方法0：化合物22的制备。3.0g(11.0mmol)3-(4-(2-氨基苯甲酰)氨基苯基)丙酸[3-(4-(2-aminobenzoyl)aminophenyl)proprionic]和10ml二氯甲烷的溶液。在30分钟内滴加乙酸酐(1.12g，1.04ml，11.0mmol)。一旦乙酸酐全部被添加完毕，就在室温下搅拌反应物18hr。通过HPLC确定反应完全。通过过滤分离生成的固体。在真空干燥箱中将生成的白色固体干燥一夜而得产品。
方法P：化合物23的制备。将5.13g(27.9mmol)2-磺基苯甲酸环酐、5.0g(27.9mmol)4-(4-氨基苯基)丁酸和100ml乙腈的混合物搅拌18hr。浓缩该乳白色溶液。将残余物吸收入50ml冷盐酸水溶液，用乙酸乙酯(5×50ml)萃取并浓缩。应用乙腈为洗脱剂通过柱色谱法纯化残余物而给出产品。
方法Q：化合物57的制备。在冰浴中搅拌10g 5-氯-2-羟基苯甲酰胺(58.0mmol)、吡啶(22ml)和乙腈(25ml)的溶液。滴加氯甲酸乙酯(6.1ml，0.0638mol)。在＜10℃下搅拌该粉红色溶液达30分钟。用油浴代替冰浴。将反应混合物加热到95℃而蒸去挥发性物质(43ml)。使反应物冷却到室温，导致形成白色固体。将混合物倾入水(100ml)中，用浓盐酸水溶液酸化。滤出生成的固体，在热乙醇中重结晶而给出9.77g 6-氯-2H-1，3-苯并_嗪-2，4(3H)-二酮。
用1，10-二溴癸烷(52.52g，0.175mol)的溶液处理9.77g 6-氯-2H-1，3-苯并_嗪-2，4(3H)-二酮(50mmol)和60ml DMF的浆料，添加DMF(60ml)。滴加二异丙基乙胺(9.6ml，55mmol)。装上温度计和冷凝器，将烧瓶置于油浴中。将反应物加热到60℃达大约3hrs，冷却到47℃，添加己烷(150ml)。用水(175ml)稀释混合物。通过过滤除去生成的固体。用温己烷洗涤水层。从己烷层滤出形成的固体，从温己烷中重结晶而给出10.39g 6-氯-3-(10-溴癸基)-2H-1，3-苯并_嗪-2，4(3H)-二酮。
在氩气中搅拌6-氯-3-(10-溴癸基)-2H-1，3-苯并_嗪-2，4(3H)-二酮(10.39g，0.025mol)、亚硝酸钠(5.52g，0.08mol)和DMSO(60ml)的混合物。添加乙酸(14.9ml)，将反应物加热到75℃达6hrs。冷却到室温后，再将反应混合物溶于乙酸乙酯，用0.5N HCl(2x)和2NNaOH(2x)洗涤。将氢氧化钠层搅拌2小时又20分钟，用2M H2SO4酸化溶液。然后，过滤固体，从二氯甲烷和己烷中重结晶。产量：3.0g。
方法R：化合物71的制备。在冰(盐)浴中冷却3.22g(18.4mmol)邻苯二甲酸单甲酯、2.90ml(2.11g，20.8mmol)三乙胺和20ml丙酮的溶液，用2.00ml(2.27g，20.9mmol)氯甲酸乙酯和10ml丙酮的溶液处理(在20min内滴加)。搅拌该白色浑浊液达15min，用2.53g(38.9mmol)叠氮化钠和8ml水的溶液处理。搅拌30min后，将仍然浑浊的溶液倾入50ml冰水，用甲苯(3×30ml)萃取。在硫酸钠上干燥甲苯相，加热至回流达80min。将反应混合物冷却到0℃。在5min内分数份添加3.11g(18.8mmol)3-(4-氨基苯基)丙酸。搅拌64hr后，用80ml 3∶1二_烷/水溶液稀释反应混合物，加热至回流达3hr。用2N(1×30ml)和0.5N(2×30ml)氢氧化钠萃取冷却后的混合物。酸化合并的水层，导致形成白色固体。通过过滤分离，溶于乙酸乙酯，滤去不溶性物质，浓缩滤液给出1.13g固体产品。
方法S：化合物69的制备。将3.17g(21.7mmol)4-羟基喹啉并偶氮宁(4-hydroxyquinoazoline)、3滴二甲基甲酰胺和20.0ml亚硫酰氯的浆料加热至回流。150min后，将清亮的黄色溶液冷却到30℃。在50mm真空度下蒸去多余的亚硫酰氯。在1.0mm真空度下15min后，用30ml二氯甲烷吸收烧瓶中的灰白色/黄色内含物，用3.61g(21.9mmol)3-(4-氨基苯基)丙酸和40ml异丙醇的浆料处理。将反应混合物搅拌18hr。通过过滤分离淡黄色固体，在真空干燥箱中干燥而给出产品。
化合物70也是通过该方法制备的，不同的是只酸化到pH 4.56以便分离游离的胺。
方法T：化合物46的制备。将乙酸酐(6.45ml，6.98g，68.4mmol)、4-羟基苯基乙酸(10.00g，65.8mmol)和二甲苯(50ml)加到装有磁性搅拌棒、温度计和具有冷凝器的迪安-斯达克榻分水器的100mL三颈烧瓶中。将烧瓶加热至回流，在约100℃时，反应混合物清亮成黄色溶液。大部分挥发性有机物(二甲苯和乙酸)在两小时中被蒸入迪安-斯达克榻分水器(135～146℃)。继续蒸馏一小时，在此期间，烧瓶温度缓慢地升到190℃，馏出液减慢到成滴地流。趁热将残余物倾入铝盘。冷却时形成棕色蜡状固体。
将2N氢氧化钠(34.4ml，36g，68.7mmol)和8-氨基辛酸(9.94g，62.5mmol)溶液加到低聚(4-羟基苯基乙酸)(11.06g，81.3mmol)和二_烷(150ml)的溶液中(在五分钟内添加)。将反应混合物加热到90℃达5.5小时(此时，通过HPLC确定反应已完成)。将亮橙色反应混合物冷却到40℃。真空除去二_烷。用2N氢氧化钠吸收棕色残余物，用乙酸乙酯(2×100ml)萃取，酸化。用乙酸乙酯(3×100ml)萃取，用炭脱色，在硫酸钠上干燥，真空浓缩而给出棕色油状物。用温水(2倍)研制而给出褐色固体，将它从乙醇/水中重结晶两次而给出2.48g褐色固体产物。
化合物106和108也是应用合适的原料通过该方法制备的。
方法U：化合物72的制备。将4.11g(25.3mmol)4-羟基香豆素、4.54g(25.3mmol)4-(4-氨基苯基)丁酸和20ml乙酸的悬浮液加热至回流达7天。将反应混合物冷却到25℃，导致形成灰白色固体，通过过滤收集。用50ml水稀释滤液，导致形成第二种固体，也通过过滤收集。将两种固体合并，从65％乙醇/水中重结晶而给出0.62g产品。
方法V：化合物85的制备。用6.78mls三甲基氯硅烷(5.80g，53.5mmol)处理5.00g 10-氨基癸酸(26.7mmol)于70mls二氯甲烷中的浆料，使它回流140min。将反应混合物冷却至0℃，然后用5.58mls三乙胺(4.1g，40.1mmol)处理。将该混合物搅拌约20min后，在15min的时间内滴加3.91mls o-氟苯甲酰氯(4.24g，26.7mmol)于10mls二氯甲烷中的溶液至反应混合物中。将该反应混合物在0℃下搅拌30min，再在25℃下搅拌18hrs。真空除去二氯甲烷，在残余物中添加100mls NaOH溶液(2N)。在用盐酸溶液(2M)酸化该混合物至pH＝1之前，将该混合物搅拌1hr。然后，用乙酸乙酯(2×100mls)萃取酸化后的混合物，用活性炭脱色，在硫酸钠上干燥，真空浓缩。将生成的白色固体从50％乙醇/水混合物中重结晶而得到白色固体，在25℃的真空下干燥24hr。产品产量为6.57g(79.5％)，mp＝85～86℃。
由该方法通过合适的氨基酸与合适的酰基氯反应还制备了化合物86～101。
方法W：化合物102的制备。用70.06mls三甲基氯硅烷(59.97g，0.552mol)处理20.72g甘氨酸(0.276mol)于150mls二氯甲烷中的浆料，使它回流2小时。将反应混合物冷却到0℃，然后，用115.41mls三乙胺(83.79g，0.828mol)处理。将该混合物搅拌约20min后，在15min的时间内往反应混合物中滴加20.72g(0.276mol)4-甲氧基-2-乙酰苯甲酰氯(58.70g，0.276mol)于75mls二氯甲烷中的溶液。将反应混合物在0℃下搅拌30min，再在25℃下搅拌18hrs。真空除去二氯甲烷，往残余物中添加200mls NaOH溶液(2N)。在用盐酸溶液(2M)将该混合物酸化到pH＝3之前将混合物搅拌数小时。滤出生成的固体，在40℃下真空干燥。将固体从水/乙醇(3/1)中重结晶而得一种固体，将它在25℃下真空干燥24hr。产品产量为27.35g(44％)mp＝185.5～189℃。
通过溶于150mls温热的乙醇而制备了上述固体的钠盐。将氢氧化钠(4.95g于14.5mL水中)加到所述乙醇溶液中，冷却到室温。滤出生成的固体(应用庚烷帮助过滤并洗涤固体)。干燥后，获得褐色固体(27.73，92.37％)mp＞230℃。关于C10H10N1O5Na·0.40H2O的CHN计算值：C，47.21；H，4.28；N，5.51；Na，9.04；实测值：C，47.14；H，4.32；N，5.36；Na，8.45和2.83％水。
方法X：化合物103的制备。用71.33mls三甲基氯硅烷(61.06g，0.562mol)处理25.0g β-丙氨酸(0.281mol)于300mls二氯甲烷中的浆料，使它回流1.5小时。将反应混合物冷却到0℃，然后，用117.50mls三乙胺(85.30g，0.843mol)处理。将该混合物搅拌约20min后，在15min的时间内往反应混合物中滴加乙酰水杨酰氯(55.73g，0.281mol)于150mls二氯甲烷中的溶液。将反应混合物在0℃下搅拌30min，再在25℃下搅拌18hrs。真空除去二氯甲烷，往残余物中添加200mls NaOH溶液(2N)。在用硫酸(2M)酸化该混合物至pH＝1之前将混合物搅拌一小时。用乙酸乙酯(3×200mLs)萃取生成的油状物，在硫酸钠上干燥，真空除去溶剂。将固体从乙酸乙酯/己烷(1/1)中重结晶而得一种固体，在25℃的真空下将它干燥24hr。产品产量为9.20g(16％)。关于C10H11N1O4的CHN计算值：C，57.03；H，5.27；N，6.67；实测值：C，57.41；H，5.30；N，6.69。通过溶于50mls温热的乙醇而制备了上述固体的钠盐。将氢氧化钠(1.79g于5.25mL水中)加到所述乙醇溶液中，冷却到室温。滤出生成的固体。干燥后，获得一种固体(5.80g)mp 231～235℃。关于C10H10N1O4Na·0.35H2O的CHN计算值：C，50.56；H，4.54；N，5.90；Na，9.68；实测值：C，50.30；H，4.37；N，5.72；Na，9.55和2.68％水。
方法Y：化合物104的制备。在冰浴中，将4-甲氧基水杨酸(98.74g，0.59mol)搅拌溶于二氯甲烷(500ml)。分别滴加三乙胺(123.4ml，1.5eq.)和乙酰氯(46.2ml，1.1eq)。从冰浴中取出溶液，在室温下搅拌两夜。通过HPLC跟踪反应。用0.5N HCl(2×200ml)和水(2×200ml)洗涤反应混合物。在硫酸钠上干燥有机层，真空浓缩。将生成的固体在二氯甲烷/己烷中重结晶。产物是61.72g 4-甲氧基-2-乙酰苯甲酸。通过1H NMR证实了结构。
往4-甲氧基-2-乙酰苯甲酸(20g，0.195mol)和二氯甲烷(100ml)的混合物中添加亚硫酰氯(13.8ml，2eq)和1滴DMF。将混合物回流1.5小时，然后冷却到室温，真空浓缩而得一种油状物。未纯化而直接应用4-甲氧基-2-乙酰苯甲酰氯。
用TMS氯化物(11.2ml)处理4-(4-氨基苯基)丁酸(7.87g，0.044mol)于二氯甲烷(100ml)中的浆料，将它回流1.5小时。将反应混合物冷却到0℃，然后滴加三乙胺(18.4ml)处理。将混合物搅拌约20分钟后，在15分钟期间将上面制备的4-甲氧基-2-乙酰苯甲酰氯(10g)于二氯甲烷(10ml)中的溶液滴加到反应混合物中。撤去冰浴，在室温下将混合物搅拌一夜。真空除去二氯甲烷，往残余物中添加2N NaOH溶液(100ml)。在用2M HCl将该混合物酸化到pH＝1之前将混合物搅拌1小时。然后，用乙酸乙酯(2×100ml)萃取酸化后的混合物，用活性炭脱色，在硫酸钠上干燥，真空浓缩。将生成的白色固体从50％乙醇/水混合物中重结晶而得白色固体，在25℃的真空下将它干燥24小时。关于C18H19NO5的CHN计算值：C，65.54；H，5.81；N，4.25；实测值：C，65.49；H，5.84；N，4.23。产量为7.76g(53.6％)。mp＝177～182℃
方法Z：化合物105的制备。将4-溴丁酸(26.17g，0.16mol)加到甲醇(150ml)中，添加数滴硫酸。将该溶液回流31/4小时。TCL(1∶1EtOAc/Hex)分析表明酯形成的完成。真空浓缩混合物而得一种油状物。将该油状物溶于二氯甲烷，用水、饱和碳酸氢钠和盐水洗涤。在硫酸钠上干燥有机层，真空浓缩。通过1H NMR证实了结构，生成20.26g(4-溴)丁酸甲酯。
在50ml DMA中搅拌6-氯卡沙兰(12.4g，1.12eq)、(4-溴)丁酸甲酯(10.13g，1.0eq)和10.13g碳酸钠(10.13g，1.12eq)。将溶液回流4.5小时，然后冷却到室温一夜。滤出固体，用乙醇洗涤。往滤液中添加水和2N NaOH。将混合物加热2.5小时。HPLC分析表明水解完全。用浓HCl酸化溶液至pH约为1。滤出生成的白色固体，在真空下置于P2O5上一夜。将所述固体在甲醇/水中重结晶，过滤，干燥，给出7.35g化合物。关于C11H12NO4Cl的CHN计算值：C，51.28；H，4.69；N，5.44；实测值：C，50.92；H，4.59；N，5.46。熔点136～140℃。应注意，通过相同方法制备的其它批该化合物(元素分析表明更纯的产品)的熔点在153～155℃范围内。
方法AA：化合物118的制备。将碳酸钠(5.37g，0.0506mol)加到盛有6-氯卡沙兰(10.0g，0.0506mol)和二甲基乙酰胺(50ml)的250ml 3-颈圆底烧瓶中。在搅拌下，往反应混合物中一次性添加5-溴庚酸乙酯(10.91g，0.0460mol)，开始加热反应混合物。将反应温度保持在80℃并加热16hr。停止加热，使反应混合物冷却到室温。将反应混合物真空过滤，用两份各20ml乙醇洗涤滤饼。往滤液中添加水直至看到橙棕色固体沉淀。通过真空过滤分离该固体，先用20mls乙醇、后用20mls庚烷洗涤。将所述固体转入圆底烧瓶，添加200ml2N NaOH。开始加热至回流并继续一小时。然后，将反应物冷却到25℃，用2N HCl溶液酸化反应混合物。通过过滤分离沉淀的白色固体，从30∶70乙醇∶水中重结晶，真空干燥一夜。分离了9.55g(63.0％)产品。熔点：115～116℃。燃烧分析：％C：56.09(计算值)，55.93(实测值)；％H：6.01(计算值)，6.09(实测值)；％N：4.67(计算值)，4.64(实测值)。1H NMR分析：(d6-DMSO)：δ12.7，s，1H(COOH)；δ12.0，s，1H(OH)；δ8.88，t，1H(NH)；δ7.94，d，1H(H，酰胺的邻位)；δ7.42，dd，1H(H，酰胺的对位)；δ6.92，d，1H(H，氢氧化物的邻位)；δ3.27，q，2H(CH2，酰胺的α位)；δ2.20，t，2H(CH2，COOH的α位)；δ1.40，m，4H(CH2，酰胺的β位，CH2，COOH的β位)；δ1.30，m，4H(残余脂族CH2)。
还通过该方法应用合适的原料制备了化合物114、116和117。
方法BB：化合物121的制备。在氮气氛中和回流(110℃)下将2-氨基-4-氯苯酚(17.88g，124.5mmol)、8-乙氧基-8-氧代辛酸(25.19g，124.5mmol)、硼酸(0.385g，6.23mmol)和2-氨基-5-甲基吡啶(0.675g，6.23mmol)于160mL干甲苯中的悬浮液加热达4小时，在此期间，通过在迪安-斯达克榻分离单元中共沸蒸馏除去反应中产生的水(2.5mL)。在硅胶上进行的薄层色谱(洗脱剂：EtOAc/庚烷：1/1)揭示了反应完全。往冷却后的反应混合物中添加2N NaOH水溶液(125mL，250mmol)。回流加热反应物达4h，然后冷却。用乙酸乙酯(300mL)和水(150mL)稀释冷却后的反应混合物。用两份乙酸乙酯(250mL)洗涤水层。小心分离后，骤冷水层，用10％盐酸水溶液(86.20mL，250mmol)酸化而得一种固体，将它过滤，用己烷洗涤，真空干燥。用二氯甲烷研制而得所需的酸(8-(5-氯-2-羟基苯胺基)-8-氧代辛酸)(灰白色固体)(22.39g，60％)：HPLC(柱：Higgins Kromasil 100 C18，水/乙腈/乙酸：950/50/1，3mL/min，220nm)Rt
5.38min.；mp 123-124C；1H NMR(DMSO d6，300MHz)δ：1.28(m，4H)，1.51(m，4H)，2.19(t，2H)，2.39(t，2H)，6.83(d，1H)，6.93(dd，1H)，7.95(d，1H)，9.20(s，1H)，10.10(s，1H)，12.00(brs，1H)；23C NMR(DMSO d6，75MHz)δ：24.29，24.90，28，20，33.58，35.90，116.50，121.02，122.20，123.41，127.74，148.23，171.93，174.26.MS m/z 300(M+1)+.关于C14H18ClNO4的分析计算值：C，56.10；H，6.05；Cl，11.83，N，4.67.实测值：C，56.07，H，6.11，11.98，N，4.64.
通过相同方法应用合适的原料制备了化合物119。还可应用合适的原料通过该方法制备化合物124～130。
实施例2-甲状旁腺激素送递
制备了经口灌胃法(PO)或结肠内(IC)施药的送递剂化合物和甲状旁腺激素残基1～34(PTH)(残基1～38对应于化合物103的溶液)的施药溶液。化合物的溶液是这样制备的：或者用该化合物的钠盐，或者通过将游离酸转化成它的钠盐，即，配制化合物的溶液，搅拌，添加一当量氢氧化钠(1.0N)，用水(就PO溶液来说)或25％丙二醇水溶液(就IC来说)稀释。最终施药溶液是这样制备的：将化合物溶液与PTH储备溶液(通常具有5mg PTH/ml的浓度)混合，再稀释到所需的体积(一般是3.0ml)。将化合物和PTH剂量列于下表1。
将重量为200～250g的雄性Sprague-Dawley大鼠禁食24小时，在施药前15分钟施给氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg)。给大鼠以1ml/kg(就PO来说)或0.5ml/kg(就IC来说)的剂量施用施药溶液之一。逐次从尾动脉采集血样用于血清测定PTH浓度。血清PTH浓度是通过PTH放射免疫测定试剂盒(Kit#RIK 6101，得自PeninsulaLaboratories，Inc.，San Carlos，CA)定量分析的。下表1阐述了结果。
  表1.大鼠内PTH送递-经口(PO)和结肠内(IC)
  化合物   施用方法   化合物剂量(mg/kg)   PTH剂量(μg/kg)   平均峰值血清PTH(pg/mL)
  3   PO   300   100   222±155
  10   PO   300   100   420±335
  79   IC   100   25   731±577
  80   IC   100   25   1456±486
  86   PO   100   200   0
  89   PO   100   200   27±61
  90   PO   100   200   14±21
  91   PO   100   200   5±12
  92   PO   100   200   303±427
  93   PO   100   200   343±155
  94   PO   100   200   17±38
  102   PO   100   200   252.13±230.46
  102   PO   100   200   70.98±81.81
  102   PO   100   200   894.82±702.01
  102   PO   100   200   185.52±59.47
  103   IC   100   25   38.53±30.9
  104   PO   100   200   286.35±191.58
  106   PO   100   200   309.07±289.74
  106   PO   100   200   894.91±1220.06
  106   PO   100   200   1459.71±1041.36
  106   PO   100   200   192.15±48.81
  107   PO   100   200   110.19±142.23
  107   PO   100   200   254.71±191.97
  107   PO   100   200   1302.99±871.82
  107   PO   100   200   304.8±381.39
实施例3-肝素送递
通过混合制备了结肠内施药(IC)组合物，该组合物包含送递剂化合物和肝素钠USP(于25％丙二醇水溶液中)。或者应用化合物的钠盐，或者用一当量氢氧化钠(1.0N)将游离酸转化为钠盐。通常，将化合物与肝素粉末混合，添加25％丙二醇水溶液，添加NaOH溶液，超声处理内含物，然后稀释到3.0的体积。检查pH，如果需要的话，调节到pH＝7～8。将最终化合物和肝素剂量列于下表2。
将重量为200～250g的雄性Sprague-Dawley大鼠禁食24小时，在施药前15分钟施给氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg)。给禁食的大鼠以1ml/kg的体积剂量施用施药溶液。在施用氯胺酮(44mg/kg)后，通过心穿刺采集血样。肝素活性是按Henry，J.B.的方法[“通过实验室方法临床诊断和治疗”(Clinical Diagnosis andManagement by Laboratory Methods)；Philadelphia，PA；W.B.Saunders(1979)]利用活化部分凝血激酶时间(APTT)测定的。下表2给出了结果。
                   表2.结肠内送递肝素
  化合物   施用方法   化合物剂量(mg/kg)   肝素剂量(mg/kg)   平均峰值APTT(sec)
  7   IC   50   25   59±41
  14   IC   50   25   54±21
  28   IC   50   25   55±27
  33   IC   50   25   42±21
  34   IC   50   25   58±31
                    表2.结肠内送递肝素
  化合物   施用方法   化合物剂量(mg/kg)   肝素剂量(mg/kg)   平均峰值APTT(sec)
  35   IC   50   25   154±171
  41   IC   50   25   41±26
  46   IC   50   25   52±34
  48   IC   50   25   75±18
  51   IC   50   25   111±49
  54   IC   50   25   124±137
  55   IC   50   25   125±195
  56   IC   50   25   91±75
  60   IC   50   25   71±43
  72   IC   50   25   50±18
  85   IC   50   25   27±4
  86   IC   50   25   24±1
  86   IC   50   25   31±11
  87   IC   50   25   21±1
  87   IC   50   25   23±3
  88   IC   50   25   59±47
  89   IC   50   25   33±7
  90   IC   50   25   26±7
  91   IC   50   25   24±4
  92   IC   50   25   22±2
  93   IC   25   50   22±0
  94   IC   50   25   50±28
  95   IC   50   25   30±2
  96   IC   50   25   72±63
  97   IC   50   25   33±10
  98   IC   50   25   25±5
  99   IC   50   25   34±7
  100   IC   50   25   31±8
  101   IC   50   25   26±5
  102   IC   50   25   24.8±0.9
  102   IC   50   25   24.7±6.5
  103   IC   50   25   21.9±2.0
  106   IC   50   25   48±16.9
                       表2.结肠内送递肝素
  化合物   施用方法   化合物剂量(mg/kg)   肝素剂量(mg/kg)   平均峰值APTT(sec)
  106   IC   50   25   27.7±12.6
  107   IC   50   25   26.2±6.1
  108   IC   50   25   72.9±28.9
  109   IC   50   25   24.2±1.7
  110   IC   50   25   26.5±4.7
  110   IC   50   25   23.4±0.7
  111   IC   50   25   24.4±3.3
  112   IC   50   25   28.7±11.5
  113   IC   50   25   20.4
  120   IC   50   25   42±34
  131   IC   50   25   58±30
  132   IC   50   25   65±19
实施例4：经口送递重组人生长激素(rhGH)
制备了经口灌胃法(PO)施药的送递剂化合物和rhGH于磷酸盐缓冲剂中的施药溶液。化合物的溶液是这样制备的：或者用该化合物的钠盐，或者通过将游离酸转化成它的钠盐，即，配制化合物的溶液，搅拌，添加一当量氢氧化钠(1.0N)，再用磷酸盐缓冲剂稀释。最终施药溶液是这样制备的：将化合物溶液与rhGH储备溶液(通常具有15mgrhGH/ml的浓度)混合，再稀释到所需的体积(一般是3.0ml)。将化合物和rhGH剂量列于下表3。
将重量为200～250g的雄性Sprague-Dawley大鼠禁食24小时，在施药前15分钟施给氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg)。给大鼠施用1ml/kg的施药溶液。逐次从尾动脉采集血样用于测定血清rhGH浓度。血清rhGH浓度是通过rhGH免疫测定试剂盒(Kit#KIF4015，得自Genzyme Corporation Inc.，Cambridge，MA)定量分析的。
下表3列出了结果。
                表3.在大鼠内经口送递rhGH
  化合物   施用方法   化合物剂量(mg/kg)   rhGH剂量(mg/kg)   平均峰值血清[rhGH](ng/ml)
  3   PO   300   6   72±45
  10   PO   200   3   43±65
  40   PO   300   6   42±80
  45   PO   200   3   49±56
  54   PO   200   3   48±33
  74   PO   200   3   80±44
  76   PO   200   3   40±34
  77   PO   200   3   54±62
实施例5  鲑鱼降钙素(sCT)送递
通过混合制备了送递剂化合物和鲑鱼降钙素(sCT)于水中的经口施药(PO)组合物。用量列于表4。将450mg化合物加到2.0ml水中。或者应用化合物的钠盐，或者将游离酸转化为钠盐：通过搅拌形成的溶液，再添加一当量氢氧化钠(1.0N)，再用水稀释。将90μg sCT加入该溶液。然后，添加水使总体积为3.0ml。所述溶液具有150mg/ml的最终化合物浓度。(就化合物118和123来说，将溶液稀释到6.0ml，体积剂量增加一倍)。总的sCT浓度为30μg/ml。(就化合物123来说，应用不同量的sCT，导致当配制成2.0ml/kg时，最终sCT剂量为100μg/kg)。
将重量为200～250g的雄性Sprague-Dawley大鼠禁食24小时，在施药前15分钟施给氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg)。给大鼠施用1ml/kg的施药溶液。(就化合物118和123来说为2ml/kg)。逐次从尾动脉采集血样。通过用EIA试剂盒(Kit#EIAS-6003，得自Peninsula Laboratories，Inc.，San Carlos，CA)测试而确定血清sCT。至于化合物104和105，改进试剂盒的标准方案如下：在暗处震荡下与50μl肽抗体保温2小时，洗涤平板，添加血清和生物素化肽，用4ml缓冲剂稀释，在暗处震荡一夜。下表4阐述了结果。
               表4.在大鼠内经口送递鲑鱼降钙素(sCT)
  化合物   化合物剂量(mg/kg)   sCT剂量(μg/kg)   血清sCT(pg/ml)±SD(SE)
  104   50   25   287±104
  105   50   25   583±140
  105   150   30   802±669(299)
  116   150   30   724±463(207)
  117   150   30   383±292(131)
  118   150   30   276±319(159)
  119   150   30   95±119(53)
  121   150   30   717±603(301)
  122   150   30   187±79(36)
  123   150   100   0
上述专利、申请、试验方法和出版物都以其整体并入本文作参考。
根据如上详细描述将启示本领域技术人员关于本发明的很多变化。所有这些明显的变化都在附后的权利要求书希望保护的范围之内。

Claims (30)

1.一种选自化合物12、43、54、105和116～118或其盐的化合物：
  化合物#   n   m   X   124354105116117118   2773456   0000000   2-OH，3-Cl；5-F2-NHMe2-OH，5-F2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl2-OH，5-Cl
2.权利要求1的化合物，它是化合物105或其盐。
3.权利要求1的化合物，它是化合物54或其盐。
4.权利要求1的化合物，它是化合物116或其盐。
5.一种组合物，它包含：
(A)一种生物活性剂；以及
(B)一种化合物，它选自如权利要求1中所示的化合物12、43、54、105和116～118或其盐，及其混合物。
6.权利要求5的组合物，其中，所述化合物是化合物105或其盐。
7.权利要求5的组合物，其中，所述化合物是化合物54或其盐。
8.权利要求5的组合物，其中，所述化合物是化合物116或其盐。
9.权利要求5-8任一项的组合物，其中，所述生物活性剂包括：至少一种蛋白质、多肽、肽、激素、多糖、碳水化合物或脂质。
10.权利要求9的组合物，其中，所述多糖是粘多糖。
11.权利要求5-8任一项的组合物，其中，所述生物活性剂选自下组物质：
生长激素，生长激素释放激素，干扰素，白细胞介素-1，白细胞介素-2，胰岛素，胰岛素样生长因子，肝素，类肝素，皮肤素，软骨素，降钙素，促红细胞生成素，心钠素，抗原，单克隆抗体，促生长素抑制素，蛋白酶抑制剂，促肾上腺皮质激素，促性腺激素释放激素，催产素，促黄体生成激素释放激素，促卵泡激素，葡糖脑苷脂酶，血小板生成素，非尔司啶，前列腺素，环孢菌素，血管升压素，色甘酸钠，万古霉素，去铁胺，甲状旁腺激素及其片段，抗微生物剂；及其任意组合。
12.权利要求11的组合物，其中，所述生长激素是人生长激素、重组人生长激素、牛生长激素或猪生长激素。
13.权利要求11的组合物，其中，所述干扰素是α-干扰素、β-干扰素或γ-干扰素。
14.权利要求11的组合物，其中，所述胰岛素是猪胰岛素、牛胰岛素、人胰岛素或人重组胰岛素。
15.权利要求11的组合物，其中，所述胰岛素样生长因子是胰岛素样生长因子-1。
16.权利要求11的组合物，其中，所述肝素是未分级的肝素、低分子量肝素、很低分子量肝素或超低分子量肝素。
17.权利要求11的组合物，其中，所述降钙素是鲑鱼降钙素、鳗鱼降钙素或人降钙素。
18.权利要求11的组合物，其中，所述色甘酸钠是色甘酸一钠或色甘酸二钠。
19.权利要求11的组合物，其中，所述抗微生物剂是抗真菌剂。
20.权利要求5-8任一项的组合物，其中，所述生物活性剂包括：胰岛素、未分级的肝素、低分子量肝素、很低分子量肝素、超低分子量肝素、降钙素、甲状旁腺激素、促红细胞生成素、人生长激素或其组合。
21.权利要求5-8任一项的组合物，其中，所述活性剂是甲状旁腺激素。
22.权利要求5-8任一项的组合物，其中，所述活性剂是肝素。
23.权利要求5-8任一项的组合物，其中，所述活性剂是生长激素。
24.权利要求5-8任一项的组合物，其中，所述活性剂是降钙素。
25.一种单元剂型，它包含：
(A)权利要求5-24任一项的组合物；以及
(B)(a)一种赋形剂，
(b)一种稀释剂，
(c)一种崩解剂，
(d)一种润滑剂，
(e)一种增塑剂，
(f)一种着色剂，
(g)一种配药载体，或者
(h)其任意组合。
26.权利要求25的单元剂型，其中，该单元剂型包含一种配药载体，该单元剂型包括：片、胶囊、粉末或液体。
27.权利要求25的单元剂型，其中，所述配药载体是一种选自下组的液体：水、1，2-丙二醇、乙醇及其任意组合。
28.权利要求1～4任一项的化合物在制备用于给动物施用生物活性剂的组合物中的用途。
29.一种制备组合物的方法，它包括：
混合
(A)至少一种生物活性剂；
(B)权利要求1的化合物；以及
(C)任选一种配药载体。
30.一种制备组合物的方法，它包括：
混合
(A)至少一种生物活性剂；
(B)权利要求2、3或4的化合物。
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US7186414B2 (en) 2007-03-06
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