[4-[2-(1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl)propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate | 162635-04-3

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: [4-[2-(1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl)propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
• CAS: 162635-04-3
• 化学式: C₅₆H₈₇NO₁₆
• 分子量: 1030.3
• InChiKey: CBPNZQVSJQDFBE-UHFFFAOYSA-N

物化性质

• 熔点：
  99-101°C
• 沸点：
  1048.4±75.0 °C(Predicted)
• 密度：
  1.21
• 闪点：
  587.8℃
• 溶解度：
  易溶于可溶于氯仿、甲醇。
• 颜色/状态：
  White to off-white powder
• 解离常数：
  No ionizable functional groups

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  73
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  242
• 氢给体数：
  4
• 氢受体数：
  16

ADMET

代谢

西罗莫司是替西莫司的活性代谢物，是人类静脉给药后主要的代谢物。其余代谢物在血浆中的放射性不到10%。

Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the metabolites account for less than 10% of radioactivity in the plasma.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Temsirolimus通过水解代谢为西罗莫司，后者是主要的活性代谢物。Temsirolimus和西罗莫司均通过细胞色素P-450（CYP）同工酶3A4进行代谢。尽管Temsirolimus代谢为西罗莫司，但Temsirolimus本身具有抗肿瘤活性，并不被认为是一种前药。

Temsirolimus is metabolized by hydrolysis to sirolimus, the principal active metabolite. Both temsirolimus and sirolimus also are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外代谢替西罗莫司（雷帕霉素-42-[2,2-双(羟甲基)]-丙酸酯），一种抗肿瘤药物，使用人肝微粒体以及重组人细胞色素P450酶，即CYP3A4、1A2、2A6、2C8、2C9、2C19和2E1进行了研究。通过液相色谱（LC）-串联质谱（MS/MS或MS/MS/MS）检测到15个代谢物。CYP3A4被确定为主要负责该化合物代谢的酶。与重组CYP3A4孵育的替西罗莫司产生了从人肝微粒体孵育中检测到的大多数代谢物，用于大规模制备代谢物。通过硅胶色谱法随后是半制备反相色谱高效液相色谱，分离和纯化了各个代谢物，以进行结构鉴定和生物活性研究。通过正负质谱（MS）和MS/MS光谱方法，将小代谢物（峰1-7）鉴定为羟基化或去甲基化的大环内酯环开环的替西罗莫司衍生物。由于这些化合物不稳定且仅以微量存在，因此未进行进一步的研究。六种主要代谢物被鉴定为36-羟基替西罗莫司（M8）、35-羟基替西罗莫司（M9）、11-羟基替西罗莫司开环的半缩酮环（M10和M11）、N-氧化物替西罗莫司（M12）和32-O-去甲基替西罗莫司（M13），使用结合LC-MS、MS/MS、MS/MS/MS和NMR技术。与母体化合物相比，这些代谢物对LNCaP细胞增殖的活性显著降低。

The in vitro metabolism of temsirolimus, (rapamycin-42-[2,2-bis-(hydroxymethyl)]-propionate), an antineoplastic agent, was studied using human liver microsomes as well as recombinant human cytochrome P450s, namely CYP3A4, 1A2, 2A6, 2C8, 2C9, 2C19, and 2E1. Fifteen metabolites were detected by liquid chromatography (LC)-tandem mass spectrometry (MS/MS or MS/MS/MS). CYP3A4 was identified as the main enzyme responsible for the metabolism of the compound. Incubation of temsirolimus with recombinant CYP3A4 produced most of the metabolites detected from incubation with human liver microsomes, which was used for large-scale preparation of the metabolites. By silica gel chromatography followed by semipreparative reverse-phase high-performance liquid chromatography, individual metabolites were separated and purified for structural elucidation and bioactivity studies. The minor metabolites (peaks 1-7) were identified as hydroxylated or desmethylated macrolide ring-opened temsirolimus derivatives by both positive and negative mass spectrometry (MS) and MS/MS spectroscopic methods. Because these compounds were unstable and only present in trace amounts, no further investigations were conducted. Six major metabolites were identified as 36-hydroxyl temsirolimus (M8), 35-hydroxyl temsirolimus (M9), 11-hydroxyl temsirolimus with an opened hemiketal ring (M10 and M11), N- oxide temsirolimus (M12), and 32-O-desmethyl temsirolimus (M13) using combined LC-MS, MS/MS, MS/MS/MS, and NMR techniques. Compared with the parent compound, these metabolites showed dramatically decreased activity against LNCaP cellular proliferation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清转氨酶升高发生在30%到40%接受替西罗利姆治疗的病人中，碱性磷酸酶升高发生在60%到70%的病人中，但这些异常通常是轻微的、无症状的，并且是自限性的，很少需要调整剂量或停药。肝酶升高超过正常上限5倍的情况只发生在1%到3%的病人中。自从批准并广泛临床使用以来，没有报告过归因于替西罗利姆使用的明显临床肝损伤的案例。替西罗利姆像西罗利姆一样具有免疫抑制作用，乙肝病毒的再激活被认为是治疗的可能并发症。然而，尽管有超过10年的临床使用，没有报告过归因于替西罗利姆治疗的乙肝病毒再激活的情况。因此，由于替西罗利姆引起的急性肝损伤和黄疸可能非常罕见，如果真的发生的话。对替西罗利姆输注的过敏反应并不少见（因此推荐使用抗组胺药进行预处理），并且已经报告过史蒂文斯-约翰逊综合征的病例。

Serum aminotransferase elevations occur in 30% to 40% and alkaline phosphatase in 60% to 70% of patients receiving temsirolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Elevations of liver enzymes above 5 times the upper limit of normal occur in only 1% to 3% of patients. Since approval and wide spread clinical use, there have been no case reports of clinically apparent liver injury attributed to temsirolimus use. Temsirolimus, like sirolimus, is immunosuppressive, and reactivation of hepatitis B is considered a possible complication of therapy. Yet despite more than 10 years of clinical use, there have been no reports of reactivation of hepatitis B attributed to temsirolimus therapy. Thus, acute liver injury with jaundice due to temsirolimus is probably quite rare, if it occurs at all. Hypersensitivity reactions to temsirolimus infusions are not uncommon (for which reason premedication with an antihistamine is recommended) and instances of Stevens Johnson syndrome have been reported.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：替西罗利姆是一种西罗利姆的前药。由于缺乏关于替西罗利姆或西罗利姆在哺乳期间使用的信息，可能更倾向于使用另一种药物，特别是在哺乳新生儿或早产儿时。制造商建议在替西罗利姆治疗期间及最后一次给药后3周内停止哺乳。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ Summary of Use during Lactation:Temsirolimus is a prodrug of sirolimus. Because no information is available on the use of temsirolimus or sirolimus during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. The manufacturer recommends that breastfeeding be discontinued during temsirolimus therapy and for 3 weeks following the last dose. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

CYP3A4抑制剂：潜在的药代动力学相互作用（主要活性代谢物西罗莫司的血浆浓度增加）。应避免与强效CYP3A4抑制剂同时使用；如果没有替代品，应考虑调整替西罗莫司的剂量。

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of the principal active metabolite sirolimus). Concomitant use with a potent CYP3A4 inhibitors should be avoided; if no alternative is available, consideration should be given to temsirolimus dosage adjustment.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

CYP3A4诱导剂：可能存在药代动力学相互作用（降低主要活性代谢物西罗莫司的血药浓度）。应避免与强效CYP3A4诱导剂同时使用；如果没有替代方案，应考虑调整坦西莫司的剂量。

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of the principal active metabolite sirolimus). Concomitant use with potent CYP3A4 inducers should be avoided; if no alternative is available, consideration should be given to temsirolimus dosage adjustment.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在同时使用血管紧张素转换酶（ACE）抑制剂治疗期间观察到的血管性水肿型反应。建议谨慎使用。

Angioedema-type reactions observed during concomitant therapy with angiotensin-converting enzyme (ACE) inhibitors. Caution is advised.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在癌症患者中单次给予25毫克替西罗利姆后，全血中替西罗利姆的平均Cmax为585 ng/mL（变异系数，CV=14%），血液中的平均AUC为1627 ng·hr/mL（CV=26%）。通常Cmax发生在输注结束时。在1毫克到25毫克的剂量范围内，替西罗利姆的暴露量呈小于剂量比例的方式增加，而西罗利姆的暴露量则与剂量成比例增加。在癌症患者中单次静脉注射25毫克后，西罗利姆的AUC是替西罗利姆AUC的2.7倍，这主要是由于西罗利姆的半衰期更长。

Following administration of a single 25 mg dose of temsirolimus in patients with cancer, mean temsirolimus Cmax in whole blood was 585 ng/mL (coefficient of variation, CV =14%), and mean AUC in blood was 1627 ng.hr/mL (CV=26%). Typically Cmax occurred at the end of infusion. Over the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予单次25毫克静脉注射后，患有癌症的患者全血中替西罗利姆的稳态分布体积为172升。替西罗利姆和西罗利姆都广泛地分布在形成的血细胞中。

Following a single 25 mg intravenous dose, mean steady-state volume of distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在癌症患者中，单次服用25毫克坦西莫利布斯后，坦西莫利布斯的平均（变异系数）系统清除率为16.2（22%）升/小时。

Following a single 25 mg dose of temsirolimus in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

不知道西罗莫司是否会被分泌到人乳中...

It is not known whether temsirolimus is excreted into human milk...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射单次放射性标记的替西罗莫司剂量后，大约78%的总放射性在14天内通过粪便回收，4.6%通过尿液回收。

Following IV administration of a single radiolabeled dose of temsirolimus, approximately 78% of the total radioactivity is recovered in feces and 4.6% in urine within 14 days.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  3
• 海关编码：
  29349990
• 储存条件：
  -20°C 冰箱

制备方法与用途

概述

替西罗莫司（temsirolimus），又称西罗莫司酯化物，是由辉瑞医药研发的一种靶向性抗肿瘤药物，用于治疗进展性肾癌。它是首个针对肾癌的靶向治疗药物，并且是唯一上市的特异性抑制mTOR激酶的药物。

相关研究

mTOR激酶在调节细胞增殖、生长和存活方面起着重要作用。体外研究表明，替西罗莫司通过抑制mTOR激酶导致血管内皮生长因子（VEGF）水平下降，进而阻止新生血管的发展，最终导致癌细胞死亡。

应用

在我国尚未上市，但国外的临床试验结果显示，替西罗莫司对晚期肾癌有较好的疗效，具有广阔的应用前景。

药理作用

mTOR是一种多功能激酶，属于磷脂酰肌醇3激酶（PI3K）蛋白激酶家族成员。作为PI3K/AKT信号通路的下游效应蛋白，其底物主要控制与细胞生长和增殖密切相关的蛋白质合成。肾透明细胞癌中普遍存在PI3K-AKT-mTOR信号传导通路的过度激活。

制备

1. 坦罗莫司半成品制备：将8.3g粗品（纯度75.68%，西罗莫司3.47%，异构体16.48%）溶解于25mL乙酸乙酯中，上样至正相硅球填料柱进行梯度洗脱。在20℃条件下收集组分，并在30℃下减压浓缩至干，得到纯度为84.78%，西罗莫司0.02%，异构体13.28%的半成品。

2. 进一步精制：通过后续处理，最终获得高纯度的替西罗莫司产品。

体内与体外研究

• 体外研究：替西罗莫司抑制核糖体蛋白S6磷酸化。在PTEN阳性的DU145细胞中比在PTEN阴性的PC-3细胞中更为有效，且能够显著抑制细胞生长和克隆存活，作用呈浓度依赖性。对原代人淋巴细胞性白血病（ALL）细胞的处理也显示了显著抑制增殖并诱导凋亡的效果。

• 体内研究：替西罗莫司以20 mg/kg剂量腹腔注射，每周5天，能够显著延迟DAOY移植瘤生长。在较高剂量（100 mg/kg）下单独给药一周内，肿瘤体积下降37%。处理两周也延缓了对Rapamycin耐受的U251移植瘤生长。此外，在患Huntington疾病的小鼠模型中，替西罗莫司能够抑制mTOR并改善多种行为任务表现。它还能够在皮下诱导显著的抗癌反应，并在携带人ALL的NOD/SCID移植瘤模型中降低外周血膨胀和脾肿大。

这些研究结果表明替西罗莫司具有良好的治疗潜力，特别是在抗肿瘤方面显示出显著效果。

反应信息

• 作为产物：
  描述：

  生成 [4-[2-(1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl)propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
  参考文献：
  名称：

  一种坦西莫司的制备方法

  摘要：

  本发明属于坦西莫司的制备方法技术领域。本发明中坦西莫司的制备方法包括如下步骤：1）将2,2-二（羟甲基）丙酸、有机碱和氯硅烷加入有机溶剂中反应得化合物Ⅰ；2）将化合物Ⅰ和碱溶于有机溶剂中，加入2,4,6-三氯苯甲酰氯，反应后将反应液加入化合物A和4-（N，N-二甲氨基）吡啶的有机溶剂中，反应生成化合物B；3）化合物B与酸反应得坦西莫司。本发明的制备方法相对于现有技术，制备路线短、收率高，且操作简单、成本低廉，更适合工业化生产。

  公开号：

  CN102796115A

文献信息

• 一种替西罗莫司的手性合成方法
  申请人：惠州市莱佛士制药技术有限公司

  公开号：CN103664999A

  公开（公告）日：2014-03-26

  本发明涉及有机化合物合成领域，具体涉及一种替西罗莫司的手性合成方法。一种替西罗莫司的手性合成方法，包括如下步骤：利用雷帕霉素与手性化合物反应生成合成替西罗莫司前体，然后利用替西罗莫司前体水解为替西罗莫司。在本发明中，利用手性酯化合物直接与雷帕霉素反应，利用手性化合物的空间效应，使得反应在单一的反应点进行，使得整个反应具有选择性。因此，本发明提供了一种步骤简单，高产率，低成本且适合工业化生产的替西罗莫司合成方法。
• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF TEMSIROLIMUS AND ITS INTERMEDIATES<br/>[FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION DU TEMSIROLIMUS ET DE SES INTERMÉDIAIRES
  申请人：FRESENIUS KABI ONCOLOGY LTD

  公开号：WO2011092564A2

  公开（公告）日：2011-08-04

  Intermediates, process for their preparation and their use in the preparation of therapeutically effective antineoplastic agents, in particular Temsirolimus of formula (I).

  中间体，其制备过程及其在制备治疗有效的抗肿瘤药物，特别是式（I）的替米罗斯中的使用。
• PROCESS FOR THE PREPARATION OF TEMSIROLIMUS AND ITS INTERMEDIATES
  申请人：Gupta Nitin

  公开号：US20110184167A1

  公开（公告）日：2011-07-28

  Novel intermediates, process for their preparation and their use in the preparation of therapeutically effective antineoplastic agents, in particular Temsirolimus of formula (I).

  小说中间体，其制备方法及其在制备具有治疗作用的抗肿瘤制剂中的使用，特别是在制备式（I）的替米沙坦中的使用。
• [EN] RAPAMYCIN HYDROXYESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM<br/>[FR] HYDROXYESTERS DE RAPAMICYNE, LEUR PROCEDE D'OBTENTION ET PREPARATIONS PHARMACEUTIQUES LES CONTENANT
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：WO1995028406A1

  公开（公告）日：1995-10-26

  (EN) A compound of structure (I) wherein R1 and R2 are each, independently, hydrogen or -CO(CR3R4)b(CR5R6)dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl, alkenyle, alkynyl, trifluoromethyl, or -F; R5 and R6 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, -F, or -CO2R11, or R5 and R6 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with -(CR3R4)fOR10; R7 is hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, -F, or -CO2R11; R8 and R9 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, -F, or -CO2R11, or R8 and R9 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with -(CR3R4)fOR10; R10 is hydrogen, alkyl, alkenyl, alkynyl, tri-(alkyl)silyl, tri-(alkyl)silylethyl, triphenylmethyl, benzyl, alkoxymethyl, tri-(alkyl)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; R11 is hydrogen, alkyl, alkenyl, alkynyl, or phenylalkyl; X is 5-(2,2-dialkyl)[1,3]dioxanyl, 5-(2-spiro-cycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]dioxanyl, 4-(2-spiro-cycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]-dioxalanyl, or 4-(2-spiro-cycloalkyl)[1,3]dioxalanyl; b = 0-6; d = 0-6; and f = 0-6 with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one -(CR3R4)fOR10, X, or -(CR3R4)fOR10 substituted cycloalkyl group, or a pharmaceutically acceptable salt thereof which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.(FR) Composé de structure (I) dans lequel: R1 et R2 sont chacun indépendamment hydrogène ou -CO(CR3R4)b(CR5R6)dCR7R8R9; R3 et R4 sont chacun indépendamment hydrogène, alkyle, alcényle, alcynyle, trifluorométhyle ou -F; R5 et R6 sont chacun indépendamment hydrogène, alkyle, alcényle, alcynyle, -(CR3R4)fOR10, -CF3, -F ou -CO2R11, ou bien R5 et R6 peuvent être réunis pour former X ou un cycle cycloalkyle pouvant optionnellement être mono, di ou tri-substitué par -(CR3R4)fOR10; R7 est hydrogène, alkyle, alcényle, alcynyle, -(CR3R4)fOR10, -CF3, -F ou CO2R11; R8 et R9 sont chacun indépendamment hydrogène, alkyle, alcényle, alcynyle, -(R3R4)fOR10, -CF3, -F ou CO2R11, ou bien R8 et R9 peuvent être réunis pour former X ou un cycle cycloalkyle pouvant optionnellement être mono, di ou tri-substitué par -(CR3R4)fOR10; R10 est hydrogène alkyle, alcényle, alcynyle, tri-(alkyl)silyle, tri-(alkyl)silyléthyle, triphénylméthyle, benzyle, alcoxyméthyle, tri-(alkyl)silyléthoxyméthyle, chloroéthyle, ou tétrahydropyranyle; R11 est hydrogène alkyle, alcényle, alcynyle ou phénylalkyle; X est 5-(2,2-dialkyl)[1,3]dioxanyle, 5-(2-spiro-cycloalkyl)[1,3]dioxanyle, 4(2,2-dialkyl)[1,3]dioxanyle, 4(2-spiro-cycloalkyl)[1,3]dioxanyle, 4(2,2-dialkyl)[1,3]dioxalamyle, 4(2-spiro-cycloalkyl)[1,3]dioxalamyle; b = 0-6; d = 0-6; et f = 0-6 sous réserve que R1 et R2 ne soient ni l'un ni l'autre hydrogène et que R1 et R2 contiennent au moins un -(CR3R4)fOR10, un X ou un groupe cycloalkyle à substitution -(CR3R4)fOR10 ou un de leurs sels pharmaceutiquement acceptables servant d'immunosuppresseur, d'anti-inflammatoire, d'antifongique, d'antiproliférant, et d'antitumoral.

  化合物的结构式为(I)，其中R1和R2各自独立地为氢或-CO(CR3R4)b(CR5R6)dCR7R8R9；R3和R4各自独立地为氢、烷基、烯基、炔基、三氟甲基或-F；R5和R6各自独立地为氢、烷基、烯基、炔基、-(CR3R4)fOR10、-CF3、-F或-CO2R11，或者R5和R6可以结合形成X或者一个环烷基，该环烷基可以选择性地单、双或三取代为-(CR3R4)fOR10；R7为氢、烷基、烯基、炔基、-(CR3R4)fOR10、-CF3、-F或-CO2R11；R8和R9各自独立地为氢、烷基、烯基、炔基、-(CR3R4)fOR10、-CF3、-F或-CO2R11，或者R8和R9可以结合形成X或者一个环烷基，该环烷基可以选择性地单、双或三取代为-(CR3R4)fOR10；R10为氢、烷基、烯基、炔基、三(烷基)硅烷基、三(烷基)硅基乙基、三苯甲基、苄基、烷氧基甲基、三(烷基)硅基乙氧基甲基、氯乙基或四氢吡喃基；R11为氢、烷基、烯基、炔基或苯基烷基；X为5-(2,2-二烷基)[1,3]二氧杂环己烷基、5-(2-螺环烷基)[1,3]二氧杂环己烷基、4-(2,2-二烷基)[1,3]二氧杂环己烷基、4-(2-螺环烷基)[1,3]二氧杂环己烷基、4-(2,2-二烷基)[1,3]二氧杂丙烷基或4-(2-螺环烷基)[1,3]二氧杂丙烷基；b = 0-6；d = 0-6；f = 0-6，条件是R1和R2均不为氢，并且R1或R2中至少含有一个-(CR3R4)fOR10、X或-(CR3R4)fOR10取代的环烷基，或其药学上可接受的盐，用作免疫抑制剂、抗炎症、抗真菌、抗增殖和抗肿瘤剂。
• Rapamycin hydroxyesters
  申请人：American Home Products Corporation

  公开号：US05362718A1

  公开（公告）日：1994-11-08

  A compound of the structure ##STR1## wherein R.sup.1 and R.sup.2 are each, independently, hydrogen or --CO(CR.sup.3 R.sup.4).sub.b (CR.sup.5 R.sup.6).sub.d CR.sup.7 R.sup.8 R.sup.9 ; R.sup.3 and R.sup.4 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, or --F; R.sup.5 and R.sup.6 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, --(CR.sup.3 R.sup.4).sub.f OR.sup.10, --CF.sub.3, --F, or --CO.sub.2 R.sup.11, or R.sup.5 and R.sup.6 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with --(CR.sup.3 R.sup.4).sub.f 0R.sup.10 ; R.sup.7 is hydrogen, alkyl, alkenyl, alkynyl, --(CR.sup.3 R.sup.4).sub.f OR.sup.10, --CF.sub.3, --F, or --CO.sub.2 R.sup.11 ; R.sup.8 and R.sup.9 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, --(CR.sup.3 R.sup.4).sub.f OR.sup.10, --CF.sub.3, --F, or --CO.sub.2 R.sup.11, or R.sup.8 and R.sup.9 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with --(CR.sup.3 R.sup.4).sub.f OR.sup.10 ; R.sup.10 is hydrogen, alkyl, alkenyl, alkynyl, tri-(alkyl)silyl, tri-(alkyl)silylethyl, triphenylmethyl, benzyl, alkoxymethyl, tri-(alkyl)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; R.sup.11 is hydrogen, alkyl, alkenyl, alkynyl, or phenylalkyl; X is 5-(2,2-dialkyl)[1,3]dioxanyl, 5-(2,2-dicycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]dioxanyl, 4-(2,2-dicycloalkyl)[1,3]dioxanyl, 4-(2,2dialkyl)[1,3]dioxalanyl, or 4-(2,2-dicycloalkyl)[1,3]dioxalanyl; b=0-6; d=0-6; and f=0-6 with the proviso that R.sup.1 and R.sup.2 are both not hydrogen and further provided that either R.sup.1 or R.sup.2 contains at least one --(CR.sup.3 R.sup.4).sub.f OR.sup.10, X, or --(CR.sup.3 R.sup.4).sub.f OR.sup.10 substituted cycloalkyl group, or a pharmaceutically acceptable salt thereof which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.

  结构式为##STR1##的化合物，其中R.sup.1和R.sup.2各自独立地为氢或--CO（CR.sup.3R.sup.4）.sub.b（CR.sup.5R.sup.6）.sub.dCR.sup.7R.sup.8R.sup.9；R.sup.3和R.sup.4各自独立地为氢，烷基，烯基，炔基，三氟甲基或--F；R.sup.5和R.sup.6各自独立地为氢，烷基，烯基，炔基，--（CR.sup.3R.sup.4）.sub.fOR.sup.10，--CF.sub.3，--F或--CO.sub.2R.sup.11，或者R.sup.5和R.sup.6可以结合形成X或一个环烷基环，该环烷基环可以选择性地单取代，双取代或三取代--（CR.sup.3R.sup.4）.sub.fOR.sup.10；R.sup.7为氢，烷基，烯基，炔基，--（CR.sup.3R.sup.4）.sub.fOR.sup.10，--CF.sub.3，--F或--CO.sub.2R.sup.11；R.sup.8和R.sup.9各自独立地为氢，烷基，烯基，炔基，--（CR.sup.3R.sup.4）.sub.fOR.sup.10，--CF.sub.3，--F或--CO.sub.2R.sup.11，或者R.sup.8和R.sup.9可以结合形成X或一个环烷基环，该环烷基环可以选择性地单取代，双取代或三取代--（CR.sup.3R.sup.4）.sub.fOR.sup.10；R.sup.10为氢，烷基，烯基，炔基，三（烷基）硅基，三（烷基）硅基乙基，三苯甲基，苄基，烷氧甲基，三（烷基）硅基乙氧甲基，氯乙基或四氢吡喃基；R.sup.11为氢，烷基，烯基，炔基或苯基烷基；X为5-（2,2-二烷基）[1,3]二氧杂环戊基，5-（2,2-二环戊基）[1,3]二氧杂环戊基，4-（2,2-二烷基）[1,3]二氧杂环戊基，4-（2,2-二环戊基）[1,3]二氧杂环戊基，4-（2,2-二烷基）[1,3]二氧杂环丁基或4-（2,2-二环戊基）[1,3]二氧杂环丁基；b=0-6；d=0-6；f=0-6，但R.sup.1和R.sup.2均不为氢，并且进一步提供R.sup.1或R.sup.2至少包含一个--（CR.sup.3R.sup.4）.sub.fOR.sup.10，X或--（CR.sup.3R.sup.4）.sub.fOR.sup.10取代的环烷基团，或其药学上可接受的盐，其可用作免疫抑制剂，抗炎剂，抗真菌剂，抗增殖剂和抗肿瘤剂。