CN1187821A - 雷帕霉素衍生物 - Google Patents
雷帕霉素衍生物 Download PDFInfo
- Publication number
- CN1187821A CN1187821A CN96194681A CN96194681A CN1187821A CN 1187821 A CN1187821 A CN 1187821A CN 96194681 A CN96194681 A CN 96194681A CN 96194681 A CN96194681 A CN 96194681A CN 1187821 A CN1187821 A CN 1187821A
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- alkyl
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- hydroxyl
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 title description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 206010020718 hyperplasia Diseases 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 7
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Abstract
式(Ⅰ)化合物,其中R2选自式(Ⅱ)或式(Ⅲ),并且X是OH或H,该化合物显示出免疫抑制活性。
Description
本发明涉及雷帕霉素(rapamycin)衍生物，其生产方法，及其作为药物的应用，和含该衍生物的药物组合物。
雷帕霉素是由吸湿链霉菌(streptomyces hygroscopicus)产生的已知大环内酯抗生素，其结构如式A所示：参见McAlpine，J.B.等人，J.Antibiotics(抗菌素杂志)(1991)44：688；Schreiber，S.L.等人，J.Am.Chem.Soc.(美国化学会会志)(1991)113：7433；US 3929992等文献(对雷帕霉素曾提出过各种不同的编号方式，为避免混淆，本文中对具体雷帕霉素衍生物命名时，该名以使用式A编号方式的雷帕霉素为参考给定)。雷帕霉素是一种有效的免疫抑制剂，同时还表现出抗肿瘤活性及杀真菌活性。但是，它作为药物的应用，却因其很低而又多变的生物利用度而受到限制。而且雷帕霉素不溶解且稳定性差，使其很难配制成稳定的盖伦制剂组合物。
很多雷帕霉素衍生物是已知的，某些40-O-取代的雷帕霉素在US 5258389和WO 94/09010(O-烷基雷帕霉素)；WO 92/05179(羧酸酯)；US 5118677(酰胺酯)；US 5118678(氨基甲酸酯)；US 5100883(氟化酯)；US 5151413(乙缩醛)，及US 5120842(甲硅烷基醚)中介绍过。
目前令人惊异地发现某些新型的雷帕霉素衍生物，具有超过雷帕霉素的，得到改善的药理学特性，并显示出更大的稳定性。根据本发明，提供式I化合物，其中
R1是烷基、链烯基、链炔基、羟烷基、羟链烯基、羟链炔基、苄基、烷氧苄基、或氯苄基；
R2选自式II或式III：其中R3选自H、烷基、链烯基、链炔基、芳基、硫代烷基、芳烷基、羟芳烷基、羟芳基、羟烷基、二羟烷基、羟烷氧烷基、羟烷芳烷基、二羟烷芳烷基、烷氧烷基、烷基羰基氧烷基、氨烷基、烷氨烷基、烷氧羰基氨烷基、烷基羰基氨烷基、芳基亚磺酰氨烷基、烯丙基、二羟烷基烯丙基、二氧戊环烯丙基、烷酯烷基、和烷基甲硅烷基；
R4是氢、甲基，或者R4和R3连在一起形成C2-6亚烷基；
R5是R6O-CH2-(其中R6选自H、烷基、链烯基、链炔基、芳基、烷羰基、芳羰基、杂芳羰基、羟烷羰基、氨烷羰基、甲酰基、硫代烷基、芳烷基、羟芳烷基、羟芳基、羟烷基、二羟烷基、羟烷氧烷基、羟烷基芳烷基、二羟烷基芳烷基、烷氧烷基、烷基羰基氧烷基、氨烷基、烷氨烷基、烷氧羰基氨烷基、烷羰基氨烷基、芳基亚磺酰氨烷基、烯丙基、二羟烷基烯丙基、二氧戊环基烯丙基、和烷酯烷基)，R7CO(其中R7选自H、烷基、羟基、烷氧基、芳氧基、氨基、烷氨基、氨基酸残基、或N，N-二取代氨基，其中所述取代基(a)选自烷基、芳基、或芳烷基，或(b)形成杂环结构)，R8NCH-(其中R8是烷基、芳基、氨基、烷氨基、芳氨基、羟基、烷氧基或芳磺酰氨基)，-O-CH-O-，或者取代的二氧次甲基；
Y选自O、(H、OH)和(H、OR9)，其中R9选自C1-4烷基、烷羰基、芳羰基、杂芳羰基、羟烷基羰基、氨基烷羰基、甲酰基或芳基；并且
X是OH或H；
其中“alk”(本文中译为“链”或“烷”)或“alkyl”(本文中译为“烷基”)均指任意由氧链隔断或不隔断的C1-10脂族取代基；“ar”或“aryl”(本文中均译为“芳基”)均指单环、任选杂环，任意被取代(或未被取代)的C4-14芳香取代基，
其先决条件是，若X是OH，R1是烷基、且R2是式II残基时，R3不是H。
上面提到的任何“alk”部份(本文中译为“链”或“烷”)或“alkyl”(本文译为“烷基”)，可以是支链、直链或环状的，优选任意由氧键隔断或不隔断的C1-6脂族取代基，更优选不被氧键隔断者。
上面提到的“ar”或“aryl”(本文均译为“芳基”)及任意被取代的芳基可包括，例如苯基、苄基、甲苯基和吡啶基等等。
若R1是氯苄基或烷氧苄基，该取代基优选位于邻位。
若R7CO-是N，N-二取代氨基甲酰基，它可以是例如N-甲基-N-(2-吡啶-2-基-乙基)-氨基甲酰基、(4-甲基-哌嗪-1-基)-羰基或(吗啉-4-基)-羰基。
若R5是被取代的二氧次甲基，则可以是例如O，O-(亚烷基)-二氧-次甲基，即此处2个氧由一个亚烷基连接。
式I化合物中，下面各情况或者单独的、或者任何结合、次结合情况均属优选：
1.X是OH，并且R1是C3-10链炔基或C3-10羟链炔基，优选C3-10链-2-炔基，或C3-10羟基链-2-炔基，更优选C3-6链-2-炔基；
2.X是H、并且R1是C1-10烷基、C3-10链-2-烯基、C3-10羟基链-2-烯基、C3-10链-2-炔基、C3-10羟基链-2-炔基，或C1-10烷氧基C1-10烷基，优选C1-6烷基或C3-6链-2-炔基，更优选C1-4烷基，最优选甲基；
3.作为R1的C3-6链炔基是2-丙炔基或戊-2炔基，优选戊-2-炔基；
4.Y是O，(H，OH)或(H，C1-4烷氧基)，优选O；
5.R2是式II残基；
6.式II残基中，R3是H、C1-6羟烷基、羟基-C1-6烷氧基-C1-6烷基、(C1-6烷基)-羰基-氨基-C1-6烷基、C1-6烷氧基-C1-6烷氧基或氨基-C1-6烷基、优选H、羟乙基、羟丙基、羟乙氧乙基、甲氧乙基、或乙酰氨乙基；特别是当X是H、或当X是OH且R1是链炔基时，R3为H；
7.式II残基中，R4是甲基；
8.R2是式III残基，其中R5是R6OCH2-，其中R6选自H、C1-6烷基、C3-6链-2-烯基、C3-6链-2-炔基、芳基、C1-6烷基-羰基、芳羰基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基或氨基C1-6烷基；或R5为R7CO-，其中R7选自H、羟基、C1-6烷氧基、氨基、C1-6烷氨基、氨基酸残基，或N，N-二取代氨基，其中所述取代基(a)选自C1-6烷基或芳基，或(b)形成杂环结构；或R5是R8NCH-，其中R8是烷基、芳基、氨基、烷氨基、芳氨基、羟基、烷氧基或芳磺酰氨基；或R5是-O-CH-O-，或者取代的二氧次甲基。
优选化合物是式Ia化合物和式Ib化合物：
其中R1、R2和Y定义同上，优选上述第1和第3-8项所给定的优选含义；
其中R1、R2和Y定义同上，优选上述第2-8项给定的优选含义。
特别优选的化合物包括：
(i)32-脱氧-雷帕霉素；
(ii)16-O-戊-2-炔基-32-脱氧-雷帕霉素；
(iii)16-O-戊-2-炔基-32-脱氧-40-O-(2-羟基-乙基)-雷帕霉素；
(iv)16-O-戊-2-炔基-32(S)-二氢-雷帕霉素；
(v)16-O-戊-2-炔基-32(S)-二氢-40-O-(2-羟乙基)-雷帕霉素；
(vi)32(S)-二氢-40-O-(2-甲氧基)乙基-雷帕霉素；
(vii)32(S)-二氢-40-O-(2-羟乙基)-雷帕霉素。
式I化合物表现出异构现象，因此将存在异构形式。应当明确，本发明包括式I化合物，式I′的单个异构体，以及其异构体混合物；
其中R1、R2、Y和X定义同上。
单个异构体可以用与本领域已知方法类似的方法加以分离。
本发明也提供生产式I化合物的方法，该方法包括：
a)为生产X是H的式I化合物，通过还原，消除式IVa化合物32位的羰基，
其中R1、R2和Y定义同上，式IVa化合物是被保护的、或未被保护的，并且，如果需要，除去带有的保护基；或者
b)为生产X是OH的式I化合物，立体有择性地还原上面定义的式IVa化合物32位的羰基；
c)将R1是烷基的式I化合物加以转化，提供R1是烷基以外其它基团的式I化合物。
方法a)中，优选式IVa化合物是加以保护的，即它可以在不参与该反应的官能团上包含保护基团，所述官能团是例如，28位上的OH，和若R2是式II残基时，任意在40位上的OH、或者R2是式III残基时39位上的OH。
为得到式I的32-脱氧化合物的还原反应a)，可以很方便地以二步完成：
i)将优选保护形式的式IVa化合物与氢化物(例如氢化二异丁基铝，或优选氢化锂三叔丁氧基铝)反应，得到相应的32-二氢化合物，还可以使用本领域还原酮的其它已知方法和试剂，来从相应酮生产32-二氢化合物。这些方法包括，例如加氢化、用金属还原、金属氢化物还原、如Comprehensive Organic Transformations(综合有机转化)(R.C.Larock，VCH Publishers Inc，New York，1989，pp.527-535，Sections 7.1.1-7.1.4)一书所述，以及采用酮不对称还原法，如该书540-547页第7.1.15节所述。该步骤后接着进行第ii)步，
ii)将该32-二氢化合物转化为相应的32-卤代衍生物，例如32-溴代，或优选32-碘代衍生物，然后将其用例如氢化物还原成所需的32-脱氧衍生物，并在需要时将所得化合物去保护基。还可以使用还原卤化物常采用的其它试剂，例如包括低价金属(即锂、钠、镁和锌)和金属氢化物(氢化铝、硼氢化物、硅烷、氢化铜)参见ComprehensiveOrgamc Transformations，R.C.Larock，VCH Publishers Inc.，New York，1989，pp.18-20，Sections 1.5.1和1.5.2。另外，卤化物还原反应还可在存在适当金属催化剂(即阮内镍、金属钯或其配合物、铑或钌的配合物)的条件下，用氢或氢源(即甲酸或其盐)来进行卤化物还原，参见上述书第20-24页，第1.5.3节。而且还可采用将醇转化为相应脱氧化合物所用的已知方法。这些方法，包括例如直接还原法，或中间体磷化合物、磺化物、硫代碳酸酯、硫代氨基甲酸酯、或黄原酸酯的还原法，如该书第27-31页，第1.9.1-1.9.4节所述。
适当的羟基保护基及其形成和除去的方法均属本领域已知，参见Protective Groups in Organic Synthesis(有机合成中的保护基)，Second ed.T.W.Greene和P.G.M.Wuts，John Wiley & Sons，New York，1991，Chapter 2(本文列为参考文献)。优选的OH保护基是例如三有机甲硅烷基，如三(C1-6)烷基甲硅烷基(如三甲基甲硅烷基、三乙基甲硅烷基)、三异丙基甲硅烷基、异丙基二甲基甲硅烷基、叔丁基二甲基甲硅烷基、三芳基甲硅烷基(如三苯基甲硅烷基)或三芳烷基甲硅烷基(如三苄基甲硅烷基)。去保护基反应可以在温和酸性条件下进行。
该还原反应第i)步可在低温下，例如-10至-80℃下进行。
第ii)步中，将任意加以保护的32-二氢化合物，优选32(R)-非对映异构体，转化成酯，优选磺酸酯，例如甲磺酸酯、甲苯磺酸酯、nosylate或triflate，接着用适当的卤化物，如碘化钠、或溴化钠、碘化四丁基铵、或溴化四丁基铵置换，该反应优选在碱例如胺存在下进行。采用已知分离技术例如色谱，可从混合物中分离出32(R)-非对映异构体。
还原32-卤代化合物的适当氢化物包括，例如氢化三丁基锡或三-(三甲基甲硅烷基)硅烷之类的自由基氢化物。还原反应也可以在存在或不存在自由基引发剂，例如2，2′-偶氮二异丁腈，或优选Et3B下，一般在0°-80℃温度下进行。
假如需要，在i)或ii)步还原反应之后，可以加入氧化剂如乙酸铜，使不希望的还原副反应(例如出现在9位的)部位，选择性地再氧化成羰基。
或者，通过本领域已知方法，例如使用与N-溴或N-碘代琥珀酰亚胺、四溴化碳或四碘化碳、1，2-二溴四氯乙烷、2，4，5-三溴或三碘咪唑、碘、1，2-二碘乙烷结合的三苯基磷，或使用亚硫酰溴，或者碘化甲基三苯氧基鏻，也可以将32-二氢衍生物直接转化成卤化物。
也可以通过形成甲苯磺酰腙，然后再用甲硼烷，例如儿茶酚甲硼烷处理，或通过形成二噻烷，然后进行适当的还原反应，例如用阮内镍或氢化物如氢化三丁基锡还原，来实现使32位上的羰基还原成32-脱氧衍生物的转化。还可以采用其它已知的使酮转化成相应烷烃的方法，例如包括直接还原法(参见Comprehensive Organic Transformations一书pp 35-37，Section 1.12.1，该参考书前后已列举过)，或通过腙还原(参见该书pp 37-38，Section 1.12.2)以及通过硫和硒衍生物还原(参见该书pp34-35，Section 1.10和1.11)。
生成式I 32(S)-二氢化合物的还原步骤b)是在选择条件下进行的。优选使用明显有利于还原成32(S)的还原剂，例如三乙基硼氢化钠。在低温下例如-50至-80℃，在惰性溶剂例如THF、乙醚、甘醇二甲醚、二甘醇二甲醚或甲基叔丁基醚中，该还原反应很容易进行。可以采用本领域已知的方法，例如柱色谱、逆相色谱使32(S)-二氢化合物从所产生的少量32(R)-二氢化合物中分离出来。
如果需要，28位上的羟基及40位上任意出现的羟基可以在还原反应前加以保护，并随后去除保护基，例如前面讨论过的。优选还原法b)是在无羟基保护的条件下进行的。
转化步骤c)可以按照本领域已知方法进行，例如，可将R1是烷基(优选甲基)的式I化合物与Rx是链炔基或羟基链炔基的Rx-OH化合物反应，得到R1是链炔基或羟基链炔基的式I化合物，该反应可以在非质子传递溶剂例如二氯甲烷、甲苯、乙腈或IHF中，在酸性条件下进行。
优选32位上的还原反应(特别是还原步骤b))在R1已经是所需基团(例如R1是链炔基)的式IVa化合物上进行，由此避免还原后再进行转化。用作原料的其中R1是链炔基或羟基链炔基的式IVa化合物，可如上所述使用化合物Rx-OH来制备。
用作原料的化合物，可以采用本领域已知和已实施的类似方法来制备，如USP 5258389、WO 94/09010、WO 95/16691、USP 5120842等所公开的方法。
下面的实施例是本发明的举例说明，所有温度是℃，并使用下述简写：
THF＝四氢呋喃
TES＝三乙基甲硅烷基
实施例132-脱氧雷帕霉素(R1＝CH3；R2＝II，其中R3＝H且R4＝CH3；X＝H；Y＝O)
在搅拌下向冷却(-78°)的26.1g(22.85mmol)28，40-双-O-TES雷帕霉素于260ml THF中的溶液里，加入50.3ml(50.3mmol)氢化锂三叔丁氧基铝的1M THF溶液。所得混合物用2小时升温至-15°。然后用冰浴代替冷却浴，使温度达0°，此温度下继续搅拌1小时。将反应混合物倾入含750ml乙酸乙酯和400ml冰冷却的2N柠檬酸水溶液的分液漏斗中，并短暂振摇。分离出水层并用冷乙酸乙酯萃取二次。将有机溶液合并，用冰冷却的2N柠檬酸水溶液、水、饱和碳酸氢钠水溶液依次洗涤，并用饱和盐水再洗二次，然后用无水碳酸钠干燥，过滤并减压浓缩，将由32(R)-二氢-28，40-双-O-TES雷帕霉素和32(R)9，32-双-二氢-28，40-双-O-TES-雷帕霉素混合物组成的残渣，不进一步提纯，溶解于260ml甲醇中。将该溶液冷至0°，用6.85g(34.31mmol)乙酸铜处理。搅拌1小时之后，用甲基叔丁基醚稀释所得悬浮液，用水和饱和盐水依次洗两次。用甲基叔丁基醚反萃取水层。合并有机溶液，用无水硫酸钠干燥，过滤，并减压浓缩。用硅胶色谱(60∶40己烷/甲基叔丁基醚)提纯残渣得到纯的32(R)-二氢-28，40-双-O-TES-雷帕霉素，为白色固体。
1H NMR(CDCl3)4∶1旋转异构体混合物，括号内的化学位移指含量少的旋转异构体，
δ0.72(1H，dd，H-38ax)，1.63(1.60)(3H，s，C17-CH3)，1.66(1.69)(3H，s，C29-CH3)，1.77 and 1.81(H-33)，2.46(1H，m，H-31)，2.82(2.91)(1H，m，H-25)，2.91(1H，m，H-39)，3.13(3H，s，C16-OCH3)，3.26(3H，s，C27-OCH3)，3.41(1H，m，H-40)，3.43(3H，s，C39-OCH3)，3.62(1H，m，H-32)，3.75(3.57)(1H，d，H-27)，4.10(1H，d，H-28)，4.81(1H，broad s，C10-OH)，5.05(1H，d，H-34)，5.27(1H，d，H-30)，5.36(1H，d，H-2)，5.69(1H，dd，H-22)，6.03(5.96)(1H，d，H-18)，6.15(1H，dd，H-21)，6.33(1H，dd，H-20)，6.40(1H，dd，H-19)MS(FAB，LiI matrix)m/z 1150([M+Li]+)(rel.intensity 100)
搅拌下向冷却的(-15°)20.69g(18.10mmol)32(R)-二氢-28，40-双-O-TES-雷帕霉素和7.55ml(54.27mmol)三乙胺的200ml二氯甲烷溶液中，加入2.10ml(27.02mmol)甲磺酰氯。将该混合物搅拌20分钟，然后用乙酸乙酯稀释，并加入饱和碳酸氢钠水溶液。分离各层，用乙酸乙酯萃取水层三次。合并有机相，用饱和碳酸氢钠水溶液及盐水洗涤，用无水硫酸钠干燥、过滤并减压浓缩。用硅胶柱色谱(80∶20己烷/乙酸乙酯)提纯残渣，得到纯的32(R)-二氢-32-O-甲磺酰基-28，40-双-O-TES-雷帕霉素，为白色固体。但按常规，不需进一步提纯，粗产物即可用于下步反应。1H NMR(CDCl3)δ0.77(1H，dd，H-38ax)，1.67(3H，s，C17-CH3)，1.72(3H，s，C29-CH3)，2.77(1H，M，H-25)，2.92(1H，m，H-39)，3.03(3H，s，C16-OCH3)，3.17(3H，s，C27-OCH3)，3.21(3H，s，C39-OCH3)，3.42(1H，m，H-40)，3.45(3H，s，CH3SO3)，3.91(1H，d，H-27)，4.10(1H，d，H-28)，4.72(1H，m，H-32)，4.94(1H，s，C10-OH)，5.12(1H，m，H-34)，5.25(1H，d，H-30)，5.43(1H，d，H-2)，5.88(1H，dd，H-22)，6.03(1H，d，H-18)，6.18(1H，dd，H-21)，6.37(1H，dd，H-20)，6.44(1H，dd，H-19)MS(FAB，LiI matnx)m/z 1228([M+Li]+)(rel.intensity 68)，1132([(M-CH3SO3H)+Li]+)(rel.intensity 100)
将22.35g(18.30mmol)32(R)-二氢-32-O-甲磺酰基-28，40-双-O-TES-雷帕霉素，27.50g(183.33mmol)碘化钠，及6.3ml(36.68mmol)二异丙基乙胺在400ml THF中的混合物加热回流6小时，然后冷却至室温。用乙酸乙酯稀释所得混合物，并用38.4％亚硫酸氢钠处理。分离各层，有机相用饱和碳酸氢钠水溶液洗三次，再用饱和盐水洗1次，然后用无水硫酸钠干燥，过滤，减压浓缩。用硅胶柱色谱(83∶17己烷/乙酸乙酯)提纯残渣，得到纯的32(S)-脱氧-32-碘-28，40-双-O-TES-雷帕霉素。
1H NMR(CDCl3)1.5∶1旋转异构体混合物，括号内的化学位移指含量少的旋转异构体，
δ0.73(1H，dd，H-38ax)，1.68(1.66)(6H，s，C17-CH3and C29-CH3)，2.72(1H，m，H-25)，2.91(2H，m，H-32 and H-39)，3.15(3H，s，C16-OCH3)，3.30(3.31)(3H，s，C27-OCH3)，3.43(3.41)(3H，s，C39-OCH3)，3.77(3.91)(1H，d，H-27)，4.21(4.25)(1H，d，H-28)，4.51(1H，s，C10-OH)，5.45(5.48)(1H，d，H-30)，5.60(5.79)(1H，dd，H-22)，6.02(5.85)(1H，d，H-18)MS(FAB，LiI matrix)m/z 1260([M+Li]+)(rel.intensity 100)
搅拌下向冷却(0°)的16.79g(13.19mmol)32(S)-脱氧-32-碘-28，40-双-O-TES-雷帕霉素的190ml甲苯溶液中加入7ml(26.38mmol)氢化三丁基锡，接着再加入1.3ml(1.30mmol)1M三乙基甲硼烷的己烷溶液。将该混合物搅拌30分钟，用饱和氯化铵水溶液使反应骤停。分离各层，用乙酸乙酯提取水层两次，合并有机相，依次用水、饱和碳酸氢钠水溶液、水洗涤，再用饱和盐水洗3次，然后用无水硫酸钠干燥，过滤并减压浓缩。用硅胶柱色谱(75∶25己烷/甲基叔丁基醚)提纯残渣，得到纯的32-脱氧-28，40-双-O-TES-雷帕霉素，为白色固体。
1H NMR(CDCl3)2.5∶1旋转异构体混合物，括号内的化学位移代表含量少的旋转异构体，
δ0.73(1H，dd，H-38ax)，1.62(1.57)(3H，s，C17-CH3)，1.68(1.72)(3H，s，C29-CH3)，2.77(2.91)(1H，m，H-25)，2.91(1H，m，H-39)，3.15(3H，s，C16-OCH3)，3.27(3.25)(3H，s，C27-OCH3)，3.43(3.45)(3H，s，C39-OCH3)，3.70(3.67)(1H，d，H-27)，4.11(4.07)(1H，d，H-28)，4.57(1H，broad s，C10-OH)，4.87(4.67)(1H，d，H-34)，5.19(5.08)(1H，d，H-30)，5.32(1H，d，H-2)，5.60(5.66)(1H，dd，H-22)，6.01(5.92)(1H，d，H-18)，6.17(1H，dd，H-21)，6.30(1H，dd，H-20)，6.40(1H，dd，H-19)MS(FAB，LiI matrix)m/z 1134([M+Li]+)(rel.intensity 100)
搅拌下向冷却(-15°)的10.73g(9.52mmol)32-脱氧-28，40-双-O-TES雷帕霉素的85ml甲醇溶液中，滴加入9.5ml 2N硫酸水溶液。加完之后，使反应混合物温热至0°，并搅拌1.5小时，然后用乙酸乙酯稀释，用饱和碳酸氢钠水溶液使反应骤停。分离各层，用三份乙酸乙酯提取水层。合并有机相，用饱和碳酸氢钠溶液洗三次，再用盐水洗涤，然后用无水硫酸钠干燥，过滤，减压浓缩。将残渣溶于乙醚中，随后所需的32-脱氧-雷帕霉素结晶出来(无色晶体)。
1H NMR(CDCl3)3∶1旋转异构体混合物，括号内的化学位移代表含量少的旋转异构体，
δ0.70(1H，dd，H-38ax)，1.14 and 1.32(H-32)，1.56(H-33)，1.65(1.62)(3H，s，C17-CH3)，1.68(1.70)(3H，s，C29-CH3)，2.31(2H，m，H-23 and H-31)，2.82(2.95)(1H，m，H-25)，2.95(1H，m，H-39)，3.14(3H，s，C16-OCH3)，3.32(3H，s，C27-OCH3)，3.38(1H，m，H-40)，3.43(3.41)(3H，s，C39-OCH3)，3.61(1H，d，H-27)，4.12(1H，d，H-28)，4.80(4.71)(1H，d，H-34)，5.22(1H，d，H-30)，5.31(1H，d，H-2)，5.56(1H，dd，H-22)，5.95(5.87)(1H，d，H-18)，6.16(1H，dd，H-21)，6.36(1H，dd，H-20)，6.41(1H，dd，H-19)MS(FAB，LiI matnx)m/z 906([M+Li]+)(rel.intensty 100)
实施例216-戊-2-炔氧基-32(S)-二氢雷帕霉素(R1＝戊-2-炔基；R2＝II，其中R3＝H，R4＝CH3；X＝OH；Y＝O)
搅拌下向冷却(0°)的970mg(1.06mmol)32(S)-二氢雷帕霉素和1.39ml(15.00mmol)2-戊炔-l-醇的20ml二氯甲烷溶液中加入0.50ml(6.50mmol)三氟乙酸。该混合物于0°下搅拌3小时，再用饱和碳酸氢钠水溶液使反应骤停。分离各层，用三份乙酸乙酯萃取水层。合并有机溶液，用饱和盐水洗涤，用无水硫酸钠干燥，过滤，减压浓缩。用硅胶柱色谱(20∶80己烷-乙酸乙酯)提纯粗产物混合物，然后经逆相HPLC(RPl8，8l∶19甲醇-水)提纯，得到标题化合物，为白色无定形固体。
1H NMR(CDCl3)2.5∶1旋转异构体混合物，括号内的化学位移代表含量少的旋转异构体，
δ0.71(1H，dd，H-38 ax)，1.13(1.05)(3H，t，CH3CH2CCCH2O)，1.67(3H，s，17-CH3)，1.69(3H，s，29-CH3)，2.21(2H，qt，CH3CH2CCCH2O)，2.96(1H，m，H-39)，3.33(3.37)(3H，s，27-OCH3)，3.41(3.39)(3H，s，39-OCH3)，3.78(1H，dt，CH3CH2CCCHHO)，4.0(1H，dt，CH3CH2CCCHHO)，5.52(5.71)(1H，dd，H-22)，5.98(5.83)(1H，d，H-18)，6.15(1H，m，H-21)，6.30(1H，dd，H-20)，6.40(1H，dd，H-19)MS(FAB)m/z 974([M+Li]+)
实施例316-戊-2-炔氧基-32(S)-二氢雷帕霉素(另一种合成路线)
用与实施例2类似方法使雷帕霉素与2-戊炔-1-醇反应，得到16-戊-2-炔氧基-雷帕霉素。
搅拌下向冷却(-77°)的17.5g(18.1mmol)16-脱甲氧基-16-戊-2-炔氧基-雷帕霉素的180ml THF溶液中，加入21.7ml(21.7mmol)1M三乙基硼氢化钠的THF溶液。于-77°1小时之后，用10％柠檬酸水溶液使该反应骤停并中和。然后使该反应混合物回复到室温，减压蒸发除去大部份THF。用乙酸乙酯提取所得溶液二次，合并有机相，用硫酸钠干燥。蒸出溶剂后，用硅胶色谱，以己烷/丙酮7/3洗脱，提纯粗产物。用制备HPLC(RP-18，76∶24甲醇∶水)完成最后纯化步骤，得到标题化合物，为白色无定形固体。
光谱数据与用其它反应路线所得产物之数据相同。
实施例432(S)-二氢-40-O-(2-甲氧基)乙基-雷帕霉素(R1＝CH3；R2＝II，其中R3＝2-甲氧基-乙基，且R4＝CH3；X＝OH；Y＝O)
搅拌下向冷却(0°)的2.17g(2.00mmol)40-O-(2-甲氧基)乙基-28-O-TES-雷帕霉素的20ml THF溶液中，滴加入4.4ml(4.4mmol)1M L-Selectride的THF溶液。于0°将所得黄色溶液搅拌3小时，加入2ml MeOH使过剩的氢化物试剂骤停反应。用甲基叔丁基醚稀释该溶液，加入饱和Rochelle氏盐水溶液。使该混合物升至室温，继续搅拌15分钟。分离各层，用冷1N HCl、饱和盐水、1N碳酸氢钠依次洗涤有机溶液，再用盐水洗涤。用甲基叔丁基醚反萃取含水洗液。合并有机相，用无水硫酸钠干燥，过滤，并减压浓缩，得到32-二氢-40-O-(2-甲氧基)乙基-28-O-TES-雷帕霉素的32S和32R异构体的粗产物混合物。
将上述粗产物溶于20ml乙腈中，并冷却至0°。向所得溶液中加入2ml HF·吡啶复合物，继续搅拌1小时，加入1N碳酸氢钠。用甲基叔丁基醚提取该混合物三次。合并有机相，用1N碳酸氢钠和饱和盐水洗涤，用无水硫酸钠干燥，过滤，并减压浓缩。用逆相HPLC(RP18，5μm，50∶50-100∶0乙腈-水60分钟洗脱)提纯，得到32(S)-二氢-40-O-(2-甲氧基)乙基-雷帕霉素，及32(R)-二氢-40-O-(2-甲氧基)乙基-雷帕霉素副产物。
32(S)-二氢-40-O-(2-甲氧基)乙基-雷帕霉素：1HNMR(CDCl3)2∶1旋转异构体混合物，括号内的化学位移代表含量少的旋转异构体，δ 0.77(1H，dd，H-38 ax)，
1.67(6H，s，C17-CH3 and C29-CH3)，2.50(1H，m，H-31)，3.01(1H，m，H-25)，3.12(2H，m，H-39 and H-40)，3.14(3.15)(3H，s，OCH3)，3.28(1H，m，H-32)，3.36(3.34)(3H，s，OCH3)，3.39(3.38)(3H，s，OCH3)，3.48(3.46)(3H，s，OCH3)，3.55 and 3.75(4H，2m，OCH2CH2O)，3.84(1H，m，H-14)，4.12(4.16)(1H，d，H-28)，4.73(1H，s，C10-OH)，5.03(1H，m，H-34)MS(FAB)m/z 980([M+Li]+)
实施例532(S)-二氢-40-O-(2-羟基)乙基-雷帕霉素(R1＝CH3；R2＝II，其中R3＝-CH2CH2OH，且R4＝CH3；X＝OH；Y＝O)
按照实施例4的方法，但使用适当的原料，获得标题化合物。
32(S)-二氢-40-O-(2-羟基)乙基-雷帕霉素：1H NMR(CDCl3)1.7∶1旋转异构体混合物，括号内的化学位移代表含量少的旋转异构体，δ0.76(1H，dd，H-38ax)，2.50(1H，m，H-31)，3.10(1H，m，H-39)，3.13(3.14)(3H，s，C16-OCH3)，3.20(1H，m，H-40)，3.28(1H，m，H-32)，3.36(3.38)(3H，s，C27-OCH3)，3.45(3.43)(3.41)(3H，s，C39-OCH3)，3.50(1H，d，H-27)，3.58 and 3.70(4H，m，OCH2CH2OH)，4.12(4.16)(1H，d，H-28)，5.06(1H，m，H-34)，5.60(1H，dd，H-22)，5.99(1H，d，H-18)，6.17(1H，dd，H-21)，6.33(1H，dd，H-20)，6.42(1H，dd，H-19)MS(FAB，LiI matnx)m/z 966([M+Li]+)(rel.mtensity 100)
实施例616-戊-2-炔氧基-32-脱氧-雷帕霉素(R1＝戊-2-炔基；R2＝II，其中R3＝H，且R4＝CH3；X＝H；Y＝O)
按照实施例1和2或3的方法，但使用适当原料，获得标题化合物。1H NMR(CDCl3)δ0.70(1H，dd，H-38ax)，1.23(3H，t，CH3CH2CCCH2O)，2.21(2H，ddq，CH3CH2CCCH2O)，2.78(1H，m，H-25)，2.94(1H，m，H-39)，3.31(3H，s，C27-OCH3)，3.42(3H，s，C39-OCH3)，3.62(1H，d，H-27)，3.78(1H，ddd，CH3CH2CCCH2O)，4.02(1H，ddd，CH3CH2CCCH2O)，4.12(1H，d，H-28)，4.79(1H，m，H-34)，5.20(1H，d，H-30)，5.28(1H，broad d，H-2)，5.50(1H，dd，H-22)，5.97(1H，d，H-18)，6.14(1H，dd，H-21)，6.30(1H，dd，H-20)，6.38(1H，dd，H-19)MS(FAB，LiI matrix)m/z 958([M+Li]+)(rel.intensity 100)
式I化合物显示出药学活性，因此适于用作药物。
具体地说，式I化合物具有免疫抑制和抗增生活性，正如下面的体内、体外实验法所显示的：
1.混合淋巴细胞反应(MLR)
混合淋巴细胞反应实验最初与同种移植术相连系而得以创立，用于评估可能的器官供体和受体之间的组织相容性，并且是已建立的体外免疫反应最佳模型之一。例如，由T.Meo在“Immunological Methods(免疫学方法)”(L.Lefkovits和B.Pernis，Eds.，Academic Press，N.Y.pp.227-239(1979))一书中所述的鼠模型MLR，被用来证明式I化合物的免疫抑制效果。将来自Bal b/c小鼠(雌性，8-10周龄)的脾细胞(2×105/孔)与来自CBA小鼠(雌性，8-10周龄)经0.5×106照射(2000rads)或经自力霉素C处理的脾细胞，在微滴板上共保温5天。该照射过的同种细胞对Bal b/c脾细胞诱导出增生反应，该被诱导细胞可通过标记前体掺入DNA来加以测定。因为刺激物细胞被照射过(或用自力霉素处理过)，它们不对Bal b/c细胞有应答而引起增生，但确实保留其抗原性。在不同稀释度条件下测定式I化合物对Bal b/c细胞的抗增生效果，并计算使细胞增生得到50％抑制时的浓度(IC50)。该试验样品的抑制能力可与雷帕霉素相比较，以相对IC50表示(即IC50试验化合物/IC50雷帕霉素)。发现实施例1和2化合物在该试验中的相对IC50分别为0.3和0.08。
2.IL-6介导的增生(IL-6 PROL)
使用白细胞介素-6(IL-6)依赖性小鼠杂交瘤细胞系，来评估式I化合物影响与信号通道相联系的生成因子的能力。该试验在96孔微滴板上进行。在补充有1ng重组体IL-6/ml的无血清培养基中(如M.HSchreier和R.Tees在Immunological Methods(免疫学方法)，I.Lefkovits和B.Pernis，Eds.，Academic Press 1981，Vol.II，pp.263-275中所述)培养5000细胞/孔。在存在或不存在试验样品的条件下，经66小时保温之后，再用1μCi(3-H)胸苷/孔搏动这些细胞6小时，收集细胞并用液体闪烁计数器计数。(3-H)胸苷对DNA的掺入与细胞数量增加相关，因此是一种细胞增生的测量法。检测试验样品的一系列稀释液，可计算出对细胞增生产生50％抑制作用的浓度(IC50)。试验样品的此种抑制能力可与雷帕霉素相比较，以相对IC50表示(即IC50试验样品/IC50雷帕霉素)。发现实施例1和2的化合物在该试验中相对IC50分别为0.2和0.09。
3.Macrophilin结合试验(MBA)
雷帕霉素及结构上相关的免疫抑制剂FK-506，在体内与Macrophilin-12(也称为FK-506结合蛋白或FKBP-12)结合都是已知的，并且认为此种结合与这些化合物的免疫抑制活性有关。式I化合物与Macrophilin也很强地结合，正如竞争结合试验所证明的一样。该试验中，用与BSA偶联的FK-506包涂微滴孔。使生物素化重组人Macrophilin-12(biot-MAP)，在存在或不存在试验样品的条件下，与该固定的FK-506结合。洗涤后(除去非特异性结合的Macrophilin)，将其与抗生蛋白链菌素-碱性磷酸酶结合物一起保温，评估结合的biot-MAP。接着洗涤并随后加入磷酸对硝基苯酯作为底物。于405nm波长处读出OD，试验样品与biot-MAP的结合引起biot-MAP与FK-506的结合量降低，因此OD 405便降低。试验一系列试验样品稀释液，测定出对biot-MAP与固定的FK-506结合产生50％抑制作用时的浓度(IC50)。将该试验样品的抑制能力，与作为标准的游离FK-506的IC50相比较，以相对IC50表示(即IC50试验样品/IC50游离FK 506)。该试验中，发现实施例1、2和5的化合物的相对IC50分别为1、2.8和2.5。
4.局部的移植物对抗宿主(GvH)反应
以一种适当的动物模型，证明式I化合物的体内效力，如Ford等人在Transplantation(移植)10(1970)258中所述。将来自6周龄雌性Wistar/Furth(WF)鼠的脾细胞(1×107)经皮下注射入体重约100g的雌性(F 344×WF)F1大鼠的左后爪，此时定为0天。该动物被连续处理4天，在第7天取出腘淋巴结，并称重。两淋巴节重量之差作为评价该反应的参数。
5.鼠的肾同种移植反应
采用末端对末端吻合术，将DA(RT1a)或Brown-Norway(BN)(RT1n)供体鼠的一只肾移植入单侧(左侧)肾切除的(Lewis RT11)受体鼠的肾管上。输尿管吻合也是末端对末端。移植之日起开始治疗，并连接治疗14天。移植7天以后实行对侧肾切除，受体便只能依赖供体肾运作。移植物受体的存活，作为移植物功能的参数。
6.实验性诱导大鼠的过敏性脑脊髓炎(EAE)
采用Levine & Wenk AMER J.PATH(美国病理学杂志)47(1965)61；McFarlin等人，J.IMMUNOL(免疫学杂志)113(1974)712；Borel，TRANSPLANT & CLIN IMMUNOL(移植物与临床免疫)13(1981)3等文献所述方法，测定式I化合物对EAE的效力。EAE对多发性硬化症来说是广泛被接受的模型。将牛脊髓和完全弗氏佐剂的混合物注射入雄性Wistar鼠的后爪中。通常在16天内出现发病症状(尾和两后腿麻痹)。记录发病动物数及发病时间。
7.弗氏佐剂关节炎
采用Wmter & Nuss，ARTHRITIS & RHE UMATISM(关节炎与风湿病)9(1966)394；Billingham & Davies，HANDBOOK OFEXPERIMENTAL PHARMACOL(实验药理学手册)(Vane &Ferreira Eds.，Sprmger-Verlag，Berlin)50/II(1979)108-144等文献所述方法，证明对抗实验性诱导关节炎效力。将含0.6mg冻干的热杀死分支杆菌属Smegmatis的0.1ml矿物油，经皮内注射入OFA和Wistar大鼠(雄性或雌性，150g体重)的尾根部或后爪中。在发生关节炎模型中，注射佐剂之后立即开始治疗(第1-18天)，而在建立关节炎模型中，治疗于第14天开始，此时继发性炎症确实发生(第14-20天)。实验结束时，用微卡尺测量关节的肿胀程度。ED50是质肿胀(原发或继发性)缩小到对照物的一半所需的口服剂量，以mg/kg表示。
8.抗肿瘤及MDR活性
在体外给多药抗性细胞和药物敏感细胞，或给患有多药抗性或药物过敏性肿瘤或感染的动物，施用抗癌剂，例如秋水仙素或鬼臼乙叉甙，分别共服或不共服欲试验的式I化合物，并单独施用式I化合物，由此来证明式I化合物的抗肿瘤活性，以及其通过减弱多药抗性来提高抗肿瘤药剂效能的能力。
体外试验中，采用适当的药物抗性细胞系和对照(亲本)细胞系，例如按Ling等人，J.Cell.Physiol(细胞生理学杂志)83，103-116(1974)和Bech-Hansen等人，J.Cell.Physiol(细胞生理学杂志)88，23-32(1976)等文献所述产生的细胞。挑选的具体克隆是多药物抗性(如秋水仙素抗性)系CHR(亚克隆C5S3.2)和亲本，敏感系AUX B1(亚克隆AB1 S11)。
以注射多药抗性和药物敏感性癌细胞的小鼠来证明体内抗肿瘤和抗MDR活性。
按照Slater等人在J.Clin.Invest.(临床检查杂志)，70，1131(1982)中所述方法，通过连续转移EA细胞给BALb/c宿主小鼠的后代，而产生对药物DR、VC、AM、ET、TE或CC有抗性的Ehrlich腹水癌细胞亚系。
在设计相仿的试验模型中，采用式I化合物可获同样的结果，例如在体外进行，或利用以抗药性和药物敏感性病毒株感染，以抗生素(如青霉素)抗性和敏感性细菌菌株感染，以抗真菌抗性和敏感性真菌菌株感染，以及用药物抗性原生动物株(抗疟疾药物抗性的疟原虫株等，如天然出现的疟原虫属falciparum的亚株，显示获得过化学疗法)感染的试验动物来进行。
9.Mip和类Mip因子抑制作用
此外，式I化合物结合并阻隔各种Mip(巨噬细胞传染性增效剂)和类Mip因子，该因子结构上与Macrophilin相似。Mip和类Mip因子是很广泛围内各种病原菌产生的毒性因子，包括Chlamidia属(如Chlamidia trachomatis)、Neisseria属(如Neisseria meningitidis)、和Legionella属(如Legionella pneumophilia)产生的此种因子，以及立克次体目的专性寄生体所产生的此种因子，这些因子对引起胞内感染起关键作用。式I化合物对降低产生Mip或类Mip因子的病原菌传染性之效力，可通过分别在存在或不存在该大环内酯的条件下进行细胞培养，将两种情况下病原菌的传染性加以比较，来得到证实，例如使用Lundemose等人，在Mol.Microbiol(分子微生物学)(1993)7：777中所述方法。
10.慢性同种移植排斥作用
将雄性DA(RT1a)大鼠的肾常位移植进雄性Lewis(RT11)受体。总共24只动物被移植。移植开始14天中以7.5mg/kg/天的剂量，口服环孢素A(cyclosporine A)治疗所有动物，预防急性细胞排斥。不进行对侧肾切除。用不同剂量式I化合物治疗、或用安慰剂治疗的每个实验组包括6只动物。
移植后的第53-64天开始，用式I化合物或者用安慰剂口服治疗受体动物69-72天。移植后的14天，以肾灌注测定法，借助磁共振成像(MRI)，对动物进行移植物评估(将移植肾与对侧自己的肾进行比较)。该评估在移植后第53-64天，和实验结束时再重复进行。然后对动物进行尸检。测定排斥参数，例如MRI记分、移植肾的相对灌注速度、以及肾同种移植物对细胞排斥和肾管改变的组织学记分，并进行统计学分析。该鼠肾同种移植模型中，以0.5-2.5mg/kg剂量施用式I化合物，例如实施例1或2的化合物，使所有上述排斥参数均降低。
11.血管成形术
基本上按Powell等人(1989)所述，进行充气导管插入术，订为第0天，在异氟烷麻醉下，将Fogarty 2F导管通过外部颈动脉插入左颈总动脉，并充气膨胀(扩张约10μl H2O体积)。充气气球沿颈总动脉长度撤出三次，后两次同时还轻轻扭曲，以便均匀地去除皮内愈合作用。然后除掉该导管，围绕外部颈动脉用结扎线结扎，防止出血，使动物康复。
此实验使用2组12只RoRo大鼠(400g，约24周龄)：一组是对照组，一组施用欲试验化合物。所有操作、实验程序和分析中，这些大鼠是完全随机的。
在充气切口前3天(第-3天)开始，直至实验结束，即充气切口后14天(第+14天)均口服(管饲法)欲试验化合物。这些大鼠于笼内独处，随意喂给食物和水。然后将鼠用异氟烷麻醉，将灌注导管通过左心室插入，并固定在主动脉弓，而将抽吸套管插入右心室。在150mmHg灌注压力下，一开始给动物灌注0.1M磷酸盐缓冲盐水溶液(PBS，pH7.4)1分钟，然后灌注2.5％戊二醛的磷酸盐缓冲液(pH 7.4)15分钟。套管顶端处灌注压力为150mmHg(颈动脉中是约100mmHg，将连有压力传感器的套管插入外颈动脉作预备实验，测定出该压力)。然后切下颈动脉，与周围组织分开，浸入含7％蔗糖的0.1M二甲基胂酸盐缓冲液(pH 7.4)中，并于4℃保温过夜。下一天将该颈动脉浸入0.05％KMnO4在0.1M二甲基胂酸盐的溶液中并于室温下振荡1小时。然后将该组织在一系列分级乙醇液中脱水：在75％乙醇中2×10分钟、85％乙醇中2×10分钟、95％乙醇中3×10分钟、100％乙醇中3×10分钟。然后根据厂商的推荐将该脱水颈动脉嵌入Technovit 7100中，将该嵌埋介质置于通氩气的保干器中使其聚合过夜，因为发现氧能抑制该聚合块适当硬化。
用硬金属刀在旋转切片机上，将各颈动脉从中部切成厚1-2μm的切片，并用Giemse染剂染色。由此从各颈动脉制备约5个切片，借助影像分析系统(MCID，Toronto，Canada)，对该介质的横截面，新内膜及腔体等进行形态测量学评估。该试验中，当口服日剂量0.5-2.5mg/kg式I化合物时，例如实施例1或2化合物，便能抑制肌内膜增生。
式I化合物还可用于检测Macrophilin结合化合物是否存在，或其存在量的试验中，例如用于为诊断或筛选之目的的竞争试验中。因此，另一实施方案中，本发明提供式I化合物作为筛选工具，测定实验溶液中(例如欲筛选的血液、血清、或试验液体培养基)是否存在结合macrophilin的化合物之应用。优选将式I化合物固定于微滴孔中，然后在存在或不存在试验溶液的条件下，使其与经标记的macrophilin-12(FKBP-12)结合。另外，还可将FKBP-12固定于微滴孔中，在存在或不存在试验溶液的条件下，使其与被标记过(例如经氟标记、酶标记、或放射性标记，比如R1含有标记基团的式I化合物)的式I化合物结合。洗涤平板，测定结合标记化合物之量。试验溶液中macrophilin结合物的量大致与结合标记化合物之量成反比。为进行定量分析，使用一系列macrophilin结合化合物已知浓度绘制标准结合曲线。
因此，在下述情况下使用式I化合物：
a)治疗和预防急性或慢性器官或组织移植排斥，例如治疗心脏、肺、心脏-肺结合、肝、肾、胰、皮肤、或角膜等移植的受体。它们也能预防移植物对抗宿主症，例如骨髓移植后引起的疾病。
b)治疗和预防移植血管病变，例如动脉硬化症。
c)治疗和预防平滑肌细胞增生和迁移引起的血管内膜增厚、血管阻塞、栓塞性冠状动脉硬化、心瓣再狭窄等疾病。
d)治疗和预防自身免疫症，及炎性病症特别是伴有包括关节炎(例如类风湿性关节炎、关节炎慢性进行症、及关节炎变形症等)和风湿症等在内的自身免疫成份病原学的炎性症状。可以采用式I化合物治疗的具体自身免疫症，包括自身免疫血液学失调症(如溶血性贫血、再生障碍贫血、纯红细胞贫血和特发性血小板减少症等)、系统性红斑狼疮、多软骨炎、硬皮病、Wegener肉芽肿、皮肤肌炎、慢性自身肝炎、重症肌无力、牛皮癣、Steven-Johnson综合症、特发口炎性腹泻、自身免疫炎性肠病(包括溃疡性结肠炎和Crohn氏症等)、内分泌眼病、Graves症、肉样瘤、多发性硬化症、原发性胆囊肝硬变、青少年糖尿病(I型糖尿病)、眼色素层炎(前层和后层)、干性角膜结膜炎、春季角膜结膜炎、间质性肺纤维化、牛皮癣患者关节炎、肾小球性肾炎(并发或不并发肾病综合症，例如特发性肾病综合症或最小变化肾病等)，以及青少年皮肤肌炎。
e)治疗和预防哮喘病。
f)治疗多药抗性(MDR)，式I化合物抑制P-糖蛋白(Pgp)，所述糖蛋白是与MDR关联的膜转移分子。MDR对于用常规化学疗法不起作用的癌症患者及爱滋病患者是特别严重的问题，因为在这些病人中，药物会使Pgp排出细胞外。因此，式I化合物被用于治疗和控制多药抗性症状，例如多药性抗癌症或多药抗性爱滋病，从而提高其它化疗药剂的效力。
g)治疗增生性失调症，例如肿瘤、高增生皮肤失调症等等。
h)治疗真菌感染。
i)治疗和预防炎症，特别是能起类固醇的作用。
j)治疗和预防感染，特别是带有Mip或类Mip因子的病原菌感染。
对于上述适应症，当然，其所需剂量会随所治疾病的症状(例如病的类型、或抗性性质等)、所期望的效果、及施用方式等而有所不同。但一般来说，口服剂量在0.05-5，或高至10mg/kg/天数量级，例如0.1-2，或直至7.5mg/kg/天，服用一次、分剂量每天2-4次、或者肠道外给药，例如静脉滴注或灌注剂量在0.01-2.5，直至5mg/kg/天数量级，具体如0.05-0.1，直至1.0mg/kg/天数量级，均能达到满意效果。因此对病人适宜日剂量为口服500mg数量级，具体如5-100mg数量级、静脉注射0.5-125mg，直至250mg数量级，具体如2.5-50mg数量级。
此外更为优选的是以提供预定的槽型血液水平(如由RIA技术决定的)的特定方式来安排患者的剂量。由此可以调节患者剂量，以便成功地调节保持槽型血液水平，正如由RIA测定为50-150，直至500，或1000ng/ml，即类似目前由Ciclosporin免疫抑制治疗所采用的剂量法。
式I化合物可以作为唯一活性成份给药，也可与其它药物一起给药。例如在预防和治疗移植物对抗宿主症、移植排斥、或自身免疫疾病之类的免疫抑制应用，该式I化合物可以与环孢素(cyclosporin)或子囊霉素(或其免疫抑制类似物，例如环孢素A、环孢素G、FK-506等)、皮质甾类、环磷酰胺、咪唑硫嘌呤、氨甲喋呤、brequinar、来氟米特、咪唑立宾、霉酚酸、mycophenolate mofetil、免疫抑制单克隆抗体(例如对MHC、CD2、CD3、CD4、CD7、CD25、CD28、CTLA4、B7、CD45或CD58之类的白细胞受体或其配位体的单克隆抗体)，或其它免疫调节化合物结合使用。对于抗炎症应用，式I化合物可与消炎剂如皮质甾族化合物一起作用。对于抗感染应用，式I化合物可以与抗感染剂如抗病毒药或抗生素一起使用。
式I化合物采用常规途径给药，特别是经胃肠道给药，例如口服，可以以溶液形式饮用，或制成片剂或胶囊，或者肠道外给药，比如配成可注射的溶液或悬浮液。口服用适宜的单位剂量形式，例如含1-50mg式I化合物，通常1-10mg。含式I化合物的药物组合物可由常规方式制备，例如用类似于配制雷帕霉素药物组合物的方法，如EPA 0041795所介绍的。
优选药物组合物含式I化合物及载体介质，所述介质包含亲水相，亲油相和表面活性剂。可将其配成乳液，微乳液预浓缩物，如UK专利申请2278780A所公开的。优选亲油相含载体介质重量的10-85％，表面活性剂含载体介质重量的5-80％，而亲水相含载体介质重量的10-50％。式I化合物优选占2-15％重量。
特别优选的药物组合物包含下面所述的微乳化状浓缩液载体介质：
i)蓖麻油和环氧乙烷的反应产物，
ii)植物油和甘油的酯基转移产物，主要包括亚油酸或油酸、单、二、或三甘油酯，或多氧烷基化植物油，
iii)1，2-丙二醇，和
iv)乙醇。
根据前面的介绍，本发明还提供：
A.用作药物的式I化合物，例如用于预防和治疗上面所述疾病。
B.含式I化合物及药物学上可接受的稀释剂或载体的药物组合物。
C.针对需要此种治疗的个体预防和治疗上面所述疾病的方法，该方法包括给所述个体施用有效量的式I化合物。
D.用于上面所述免疫抑制、炎症或感染的药盒或药包，包括含有式I化合物的药物组合物，及包括含有免疫抑制剂或免疫调节药剂，或者含抗炎剂或抗感染剂的药物组合物。
令人惊异地发现X是OH的式I化合物，即32(S)-二氢化合物活性得到改善，如上面的试验所揭示的，并且比其相应的对映体，即32(R)-二氢化合物更稳定，比如若进行下面的试验可看出：
将试验化合物在大鼠血清中保温，经不同的保温时间之后，以MBA测试法，测定其与FKBP 12的结合亲和力。当亲和力降低时，则名义上IC50提高。亲和力的降低一般归因于化合物在大鼠血清中的不稳定性。
Claims (10)
1.式I化合物：
其中
R1是烷基、链烯基、链炔基、羟烷基、羟链烯基、羟链炔基、苄基、烷氧苄基、或氯苄基；
R2选自式II或式III：
其中R3选自H、烷基、链烯基、链炔基、芳基、硫代烷基、芳烷基、羟芳烷基、羟芳基、羟烷基、二羟烷基、羟烷氧烷基、羟烷芳烷基、二羟烷芳烷基、烷氧烷基、烷基羰基氧烷基、氨烷基、烷氨烷基、烷氧羰基氨烷基、烷基羰基氨烷基、芳基亚磺酰氨烷基、烯丙基、二羟烷基烯丙基、二氧戊环 烯丙基、烷酯烷基、和烷基甲硅烷基；
R4是氢、甲基，或者R4和R3连在一起形成C2-6亚烷基；
R5是R6O-CH2-(其中R6选自H、烷基、链烯基、链炔基、芳基、烷羰基、芳羰基、杂芳羰基、羟烷羰基、氨烷羰基、甲酰基、硫代烷基、芳烷基、羟芳烷基、羟芳基、羟烷基、二羟烷基、羟烷氧烷基、羟基烷芳烷基、二羟烷基芳烷基、烷氧烷基、烷基羰基氧烷基、氨烷基、烷氨烷基、烷氧羰基氨烷基、烷羰基氨烷基、芳基亚磺酰氨烷基、烯丙基、二羟烷基烯丙基、二氧戊环基烯丙基、和烷酯烷基)，R7CO(其中R7选自H、烷基、羟基、烷氧基、芳氧基、氨基、烷氨基、氨基酸残基、或N，N-二取代氨基，其中所述取代基(a)选自烷基、芳基、或芳烷基，或(b)形成杂环结构)，R8NCH-(其中R8是烷基、芳基、氨基、烷氨基、芳氨基、羟基、烷氧基或芳磺酰氨基)，-O-CH-O-，或者取代的二氧次甲基；
Y选自O、(H、OH)和(H、OR9)，其中R9选自C1-4烷基、烷羰基、芳羰基、杂芳羰基、羟烷基羰基、氨基烷羰基、甲酰基或芳基；并且
X是OH或H；
其中“alk”(本文中译为“链”或“烷”)或“alkyl”(本文中译为“烷基”)均指任意由氧键隔断或不隔断的C1-10脂族取代基；“ar”或“aryl” (本文中均译为“芳基”)均指单环、任选杂环，任意被取代(或未被取代)的C4-14芳香取代基，
其先决条件是，若X是OH，R1是烷基、且R2是式II残基时，则R3不是H。
2.式Ia化合物：其中R1是C3-10链-2-炔基或C3-10羟基链-2-炔基，
R2是权利要求1定义的式II或III残基，并且Y是O。
3.式Ib化合物：
其中R1是C1-10烷基、C3-10链烯基、C3-10羟基链烯基、C3-10链-2-炔基、C3-10羟基链-2-炔基、或C1-10烷氧基C1-10烷基，
R2是权利要求1定义的式II或式III残基，并且Y是O。
4.化合物16-戊-2-炔氧基-32(S)-二氢-雷帕霉素或16-戊-2-炔氧基-32(S)-二氢-40-O-(2-羟乙基)-雷帕霉素。
5.化合物32-脱氧-雷帕霉素，或16-戊-2-炔氧基-32-脱氧-雷帕霉素。
6.根据权利要求1的式I化合物的制备方法，该方法包括：
a) 为生产X是H的式I化合物，将式IVa化合物32位上的羰基还原消除，
其中R1和Y定义同上，式IVa化合物是被保护或未被保护的，如果需要，除去存在的保护基；
b)为生产X是OH的式I化合物，将上面定义的式IVa化合物32位上的羰基进行立体有择还原；
c)将R1是烷基的式I化合物转化，提供R1是烷基以外其它基团的式I化合物。
7.根据权利要求1-5任意之一的化合物，用作药物。
8.一种药物组合物，其中含有权利要求1-5任意之一的化合物，与其药物学上可接受的稀释剂或载体相结合。
9.用于免疫抑制，炎症或感染的药盒或药包，其中包括含有权利要求1-5任意之一化合物的药物组合物，并包括含有免疫抑制剂或免疫调节剂，或者抗炎剂或抗感染剂的药物组合物。
10.针对需要治疗的个体，预防或治疗急、慢性器官或组织移植排斥，移植血管病变，平滑肌细胞增生及迁移导致的血管内膜增厚或肿瘤的方法，该方法包括给所述个体施用有效量权利要求1-5任意之一的化合物。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101522691B (zh) * | 2006-11-27 | 2012-08-22 | 泰尔茂株式会社 | O-烷基化雷帕霉素衍生物的制备方法及o-烷基化雷帕霉素衍生物 |
| CN103739616A (zh) * | 2013-12-27 | 2014-04-23 | 福建省微生物研究所 | 含噻唑基雷帕霉素类衍生物及其应用 |
| CN103739616B (zh) * | 2013-12-27 | 2015-12-30 | 福建省微生物研究所 | 含噻唑基雷帕霉素类衍生物及其应用 |
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