CN1059905C - 雷怕霉素羟基酯,它们的制备方法及其药用组合物 - Google Patents

雷怕霉素羟基酯,它们的制备方法及其药用组合物 Download PDF

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CN1059905C
CN1059905C CN95193325A CN95193325A CN1059905C CN 1059905 C CN1059905 C CN 1059905C CN 95193325 A CN95193325 A CN 95193325A CN 95193325 A CN95193325 A CN 95193325A CN 1059905 C CN1059905 C CN 1059905C
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J·S·施康尼基
C·L·利昂尼
G·A·施泽
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Abstract

结构式(Ⅰ)的化合物或其药学上可接受的盐：
其中：
R1和R2每个独立地是氢或-CO(CR3R4)b(CR5R6)dCR7R8R9；R3和R4每个独立地是氢，烷基，链烯基，炔基，三氟甲基或-F；R5和R6独立地是氢，烷基，链烯基，炔基，-(CR3R4)fOR10，-CF3，-F，或-CO2R11，或者R5和R6可以一起形成X或环烷环，它们可以被-(CR3R4)fOR10单，双或三非强制性地取代；R7是氢，烷基，链烯基，炔基，-(CR3R4)fOR10，-CF3，-F，或-CO2R11；R8和R9独立地是氢，烷基，链烯基，炔基，-(CR3R4)fOR10，-CF3，-F，或-CO2R11，或者R8和R9可以一起形成X或环烷环，它们可以被-(CR3R4)fOR10单，双或三非强制性地取代；R10是氢，烷基，链烯基，炔基，三(烷基)甲硅烷基，三(烷基)甲硅烷基乙基，三苯甲基，苄基，烷氧甲基，三(烷基)甲硅烷基乙氧甲基，氯乙基或四氢吡喃基，R11是氢，烷基，链烯基，炔基或苯基烷基；X是5-(2，2-二烷基)[1，3]二烷基，5-(2-螺-环烷基)[1，3]二烷基，4-(2，2-二烷基)[1，3]二烷基，4-(2-螺-环烷基)[1，3]二烷基，4-(2，2-二烷基)[1，3]二氧杂环戊烷基，或4-(2-螺-环烷基)[1，3]二氧杂环戊烷基；b＝0-6；d＝0-6；以及f＝0-6，其条件是R1和R2两者不同时是氢，另一条件是R1或者R2至少含一个-(CR3R4)fOR10，X，或-(CR3R4)fOR10取代的3-8个碳原子的环烷基。它们可以用作免疫抑制，抗炎，抗真菌，抗增生和抗肿瘤剂。

Description

雷怕霉素羟基酯，它们的制备方法及其药用组合物
发明的背景
本发明涉及雷怕霉素羟基酯，使用它们诱发免疫抑制的方法以及治疗移植排斥，对宿主的移植物疾病(graft vs.host disease)，自身免疫疾病，炎症，成人T-细胞白血病/淋巴瘤，实体瘤，真菌感染及血管过度增生疾病。
雷怕霉素是由链霉菌属Streptomyces hygroscopicus生产的大环三烯类抗生素，发现它有抗真菌活性，尤其是在体外及体内抗白色念珠菌的活性(C.Vezina等人，抗生素杂志(J.Antibiot.)，28，721(1975)；S.N.Sehgal等人，抗生素杂志，28，727(1975)；H.A.Baker等人，抗生素杂志，31，539(1978)；美国专利3,929,992；和美国专利3,993,749)。
雷怕霉素单独(美国专利4,885,171)或者和溶链菌结合(美国专利4,401,653)具有抗肿瘤活性；R.Martel等人〔加拿大生理学与药理学杂志(Can.J.Physiol.Pharmacol.)55，48(1977)〕公开了雷怕霉素在试验过敏性脑脊髓炎模型，一种多发性硬化症模型及在佐剂性关节炎(adjuvant arthritis)模型，一种类风湿性关节炎模型中是有效的，并且能有效地抑制类IgE抗体的形成。
雷怕霉素的免疫抑制效果已经公开在FASEB 3，3411(1989)中，环孢菌素A和FK-506，另一种大环分子作为免疫抑制剂也是有效的，因此可用于预防移植排斥〔FASEB 3，3411(1989)；FASEB 3，5256(1989)；R.Y.Calne等人，Lancet 1183(1978)；美国专利5,100,899〕。
雷怕霉素也用于预防或治疗系统性红斑狼疮；〔美国专利5,078,999〕；肺炎〔美国专利5,080,899〕，胰岛素依赖型糖尿病〔炎性疾病研究协会第五次国际会议(Fifth Int.Conf.Inflamm.Res.Assoc.)121(摘要)，(1990)〕，平滑肌细胞增生及血管损伤引起的内膜变厚〔Morris，R.J.心肺移植(Heart Lung Transplant)11(pt.2)；197(1992)〕，成年人T细胞白血病/淋巴瘤〔欧洲专利申请525,960A1〕和眼炎〔欧洲专利申请532,862A1〕。
雷怕霉素的单或双酰基衍生物(在28和43位酯化)已显示出可用于抗真菌(美国专利4,316,885)以及用于制成雷怕霉素的水溶性氨酰基前药(美国专利4,650,803)。最近，关于雷怕霉素的常规编号变化了，因此，按照C.A命名法，上述酯处在31-和42-位。
发明的详细描述：
本发明提供了一种雷怕霉素衍生物或其药学上可接受的盐，它可用作免疫抑制，抗炎，抗真菌，抗增生和抗肿瘤剂，其结构如下：
Figure C9519332500061
其中：R1和R2每个独立地是氢或-CO(CR3R4)b(CR5R6)dCR7R8R9；R3和R4每个独立地是氢，1-6个碳原子的烷基，2-7个碳原子的链
烯基，2-7个碳原子的炔基，三氟甲基或-F；R5和R6每个独立地是氢，1-6个碳原子的烷基，2-7个碳原子的链
烯基，2-7个碳原子的炔基，-(CR3R4)fOR10，-CF3，-F或-CO2R11，
或者R5和R6可以一起形成X或3-8个碳原子的环烷环，它们可
以被-(CR3R4)fOR10单，双或三非强制性地取代；R7是氢，1-6个碳原子的烷基，2-7个碳原子的链烯基，2-7个
碳原子的炔基，-(CR3R4)fOR10，-CF3，-F或-CO2R11；R8和R9每个独立地是氢，1-6个碳原子的烷基，2-7个碳原子的链
烯基，2-7个碳原子的炔基，-(CR3R4)fOR10，-CF3，-F，或-CO2R11，
或者R8和R9可以一起形成X或3-8个碳原子的环烷环，它们可
以被-(CR3R4)fOR10单，双或三非强制性地取代；R10是氢，1-6个碳原子的烷基，2-7个碳原子的链烯基，2-7个
碳原子的炔基，三(1-6个碳原子的烷基)甲硅烷基，三(1-6
个碳原子的烷基)甲硅烷基乙基，三苯甲基，苄基，2-7个碳原
子的烷氧甲基，三(1-6个碳原子的烷基)甲硅烷基乙氧甲基，
氯乙基，或四氢吡喃基；R11是氢，1-6个碳原子的烷基，2-7个碳原子的链烯基，2-7个
碳原子的炔基，或苯基烷基(7-10个碳原子)；X是5-(2，2-二(1-6个碳原子的烷基))[1，3]二噁烷基，5-
(2-螺(3-8个碳原子的环烷基))[1，3]二噁烷基，4-(2，2
-二(1-6个碳原子的烷基))[1，3]-二噁烷基，4-(2-螺
(3-8个碳原子的环烷基))[1，3]二噁烷基，4-(2，2-二(1
-6个碳原子的烷基))[1，3]二氧杂环戊烷基，或4-(2-螺(3
-8个碳原子的环烷基))[1，3]二氧杂环戊烷基；b是0-6；d是0-6；及f是O-6其条件是R1和R2两者不同时是氢，另一条件是R1或者R2至少含一个-(CR3R4)f-OR10，X，或是被-(CR3R4)f-OR10取代的3-8个碳原子的环烷基。
药学上可接受的盐是从无机阳离子如钠，钾等得到的，或者是从有机碱如每个烷基是1-6个碳原子的单-，双-或三烷基胺以及每个烷基是1-6个碳原子的单-，双-或三-羟基烷基胺得到的。
术语1-6个碳原子的烷基，2-7个碳原子的链烯基和2-7个碳原子的炔基包括直链的及支链的碳链。因为本发明化合物可含一个以上的-(CR3R4)fOR10基团，R3，R4，f和R10可以相同或不同；同样，当其它一般取代基在同一结构中重复的时候，它们也可以相同或不同。
对于其中R1含R8和R9一起形成X的化合物，当X是5-(2，2-二(1-6个碳原子的烷基))[1，3]二噁烷基，X的烷基含1个碳原子，且d＝0时，R1有以下结构：
同样，对于其中R1含R8和R9一起形成X的化合物，当X是4-(2-螺(3-8个碳原子的环烷基))[1，3]二噁烷基，X的环烷基含6个碳原子且d＝0时，R1有以下结构：
Figure C9519332500082
对于含X的化合物，优选的化合物包括其中X的烷基，如果存在的话，是甲基，以及X的环烷基，如果存在的话，是环己基的化合物。
当R10不是氢，烷基，链烯基或炔基时，是指R10是可作为醇保护基的基团，因之，这种基团是未羟基化化合物的中间体并且本身是有生物学活性的。R10包括三(1-6个碳原子的烷基)甲硅烷基，三(1-6个碳原子的烷基)甲硅烷基乙基，三苯甲基，苄基，2-7个碳原子的烷氧甲基，三(1-6个碳原子的烷基)甲硅烷基乙氧甲基，氯乙基和四氢吡喃基。其它的醇保护基是本领域技术人员公知的，并且可以看作是本发明的一部分。
在本发明的化合物中，优选其中R2是氢的化合物；R2是氢，而且b＝0及d＝0的化合物；R2是氢，b＝0，d＝0，而且R8和R9每个独立地是氢，烷基或是-(CR3R4)fOR10，或者一起形成X的化合物。
在42或31，42位有酯基-CO(CR3R4)b(CR5R6)dCR7R8R9的本发明化合物可以通过用保护的羟基及多羟基酸，已被活化的烷氧基或多烷氧基羧酸使雷怕霉素酰化来制备，随后如果需要的话，除去醇保护基。某些羧酸酯活化的方法是本领域公知的，但优选的方法是使用碳化二亚胺，混合酸酐或酰氯。例如，适当取代的羧酸能以混合酸酐活化，用如2，4，6-三氯苯甲酰氯的酰基活化。雷怕霉素在温和的碱性条件下用混合酸酐处理可提供所需的化合物。另外，酰化反应可用1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐和二甲氨基吡啶实现。42-和31，42-酯的混合物可用色谱法分离。
因之，本发明提供了制备本发明的雷怕霉素化合物的方法，具体地说，本发明提供了制备雷怕霉素羟基酯，包括上述定义的式I化合物的方法，该方法包括：a)用酰化剂酰化雷怕霉素或其官能衍生物或其类似物；或b)连续用两种酰化剂酰化雷怕霉素，或其官能衍生物或其类似物；所述酰化剂选自下式(II)或其活性衍生物：
          HO-CO(CR3R4)b(CR5R6)dCR7R8R9     (II)其中R3-R9，b和d的定义如上述，条件是，假如需要用适当的保护基保护雷怕霉素或其官能衍生物的42位时，将游离羟基保护起来，如果需要，反应后再除去任何保护基。
反应可在偶联剂存在下进行，如适当取代的碳化二亚胺偶联剂。本发明上述化合物也能用式II酸的活性衍生物如酸酐，混合酸酐或酰卤如酰氯通过酰化反应制备。
本发明的31-酯-42-羟基化合物可以通过用保护基如叔丁基二甲基甲硅烷基保护雷怕霉素42位醇，随后用上述方法酯化31位而制备。制备雷怕霉素42-甲硅烷基醚记载于美国专利Bl5,120,842中，本文结合其内容作为参考。除去保护基得到31位酯化的化合物。在叔丁基二甲基甲硅烷基保护基情况下，脱保护可在温和的酸性条件下，如乙酸/水/THF中完成。脱保护方法记载于美国专利5,118,678的实施例15中，本文结合其内容作为参考。
完成31位酯化和42位脱保护之后，42位可用与和31位醇反应不同的酰化剂进行酯化，因而得到在31位和42位有不同酯的化合物。另外上述制备的42位酯化的化合物，能和不同的酰化剂反应，得到在31位和42位有不同酯的化合物。
本发明也包括其它雷怕霉素的类似的羟基酯，例如但不限于29-去甲氧雷怕霉素〔美国专利4,375,464，C.A命名法是32-去甲氧雷怕霉素〕；其中1，3，和/或5位的双键是被还原的雷怕霉素衍生物〔美国专利5,023,262〕；29-脱甲基雷怕霉素〔美国专利5,093,339，C.A命名法是32-脱甲基雷怕霉素〕；7，29-双脱甲基雷怕霉素〔美国专利5,093,338，C.A命名法是7，32-双脱甲基雷怕霉素〕以及15-羟基雷怕霉素〔美国专利5,102,876〕，上述美国专利公开本文结合在本文中作为参考。
本发明代表化合物的免疫抑制活性用体外标准的药理学试验方法测定抑制淋巴细胞的增生(LAF)和两种体内标准的药理学试验方法评价。点状皮肤移植试验方法测定试验化合物的免疫抑制活性以及试验化合物抑制和治疗移植排斥的能力。佐剂性关节炎标准药理学试验方法测定试验化合物抑制免疫调节的炎症的能力。佐剂性关节炎试验方法对于类风湿性关节炎是一种标准的药理学试验方法，这些标准药理学试验方法的程序如下述。
Comitogen诱发的胸腺细胞增生方法(LAF)用作体外测定代表性化合物的免疫抑制效果的方法。简要地说，正常BALB/c鼠的胸腺细胞用PHA和IL-1培养72小时，于最后6小时用氚化的胸苷起搏。细胞用及不用各种浓度的雷怕霉素，环孢菌素A或试验化合物培养。收集细胞，测定结合的放射性。和对于未用药物处理的对照组比较计算每分钟百分数的变化，评价淋巴增生的抑制。为了评价每一个化合物，也对雷怕霉素进行评价作为比较，得到各试验化合物及雷怕霉素的IC50值。当作为比较物评价本发明的代表性化合物时，雷怕霉素的IC50范围是0.6-1.5nM。所得结果提供了IC50以及在0.1μm时T细胞增生的百分抑制。本发明的代表性化合物所得结果也作为与雷怕霉素相比的比率表示。正的比率指出免疫抑制活性。大于1的比率说明试验化合物比雷怕霉素能在更大程度上抑制胸腺细胞的增生。比率的计算如下：
Figure C9519332500101
在体内试验方法中，测定从雄性BALB/c供者移植到雄性C3H(H-2K)受者的点状移植皮片的存活时间，以评价本发明代表性化合物。采用Billingham R.E.和Medawar P.B.，实验生物学杂志(J.Exp.Biol.)28：385-402(1951)中所述方法。简要地说，供者的点状移植皮片作为同种移植移植到受者的背部，并且以在同一区域的同系移植作为对照，受者用不同浓度的试验化合物腹膜内或口服给药，雷怕霉素用作试验对照，未处理的受者作为排斥对照。每天监视移植物，记录观察结果，直到移植物变干并形成变黑的痂。这天被认为是排斥日。药物处理组的平均移植物存活时间(天数±S.D.)和对照组比较，下表显示出得到的结果。结果以平均存活时间的天数表示。未处理的(对照)点状移植皮片一般在6-7天内被排斥。化合物的试验剂量是4mg/kg。
佐剂性关节炎标准药理学试验方法测定试验化合物预防免疫调节炎症的能力及抑制和治疗类风湿性关节炎的能力。下面简要描述所用的试验方法：一组鼠(雄性近亲繁殖Wistar Lewis鼠)用被试验的化合物预处理(抗原前1小时)，然后用Freud’s Complete Adjuvant(FCA)注射在右后爪，以诱发关节炎。对鼠从第0-14天于星期一，星期三，星期五的日程按日共口服给药7个剂量。于第16，23和第30天测量两只后爪。测定第16天与第0天爪体积的差数，得到与对照组比较的百分变化。T细胞调节炎症引起左后爪(未注射的爪)发炎，并记录于上表中(与对照组比较的％变化)。另一方面，非特异性炎症引起右后爪发炎。试验化合物剂量是5mg/kg。结果以未注射的爪在第16天对于对照组百分变化表示。百分变化越是负值，化合物就越有效。雷怕霉素对于对照的变化是-70％--90％，说明雷怕霉素治疗的鼠比对照鼠少70-90％免疫诱发的炎症。
在制备试验的特定化合物的方法之后获得这些标准药理学试验方法得到的结果。
这些标准药理学试验方法的结果说明本发明化合物在体外及体内均有免疫抑制活性。LAF试验方法得到的结果说明对T细胞增生的抑制，因而阐明了本发明化合物的免疫抑制活性。皮肤移植和佐剂性关节炎标准药理学试验方法得到的结果进一步显示本发明化合物作为免疫抑制剂的效用。另外，皮肤移植试验方法得到的结果进一步说明本发明化合物治疗和抑制移植排斥的能力。佐剂性关节炎标准药理学试验方法得到的结果进一步说明本发明化合物治疗和抑制类风湿性关节炎的能力。
基于上述标准药理学试验方法的结果，本发明化合物可用于治疗和抑制移植排斥，如肾，心脏，肝，肺，骨髓，胰腺(胰岛细胞)，角膜，小肠和皮肤的异体移植和心脏辨膜的异种移植。治疗和抑制自身免疫疾病如狼疮，类风湿性关节炎，糖尿病，重症肌无力和多发性硬化症，以及炎性疾病如牛皮癣，皮炎，湿疹，皮脂溢，肠发炎，肺炎(包括气喘，慢性阻塞性肺病，肺气肿，急性呼吸困难综合症，支气管炎等)以及眼色素层炎。
根据得到的上述活性概况，本发明化合物也被认为有抗肿瘤，抗真菌和抗增生活性。本发明化合物因此还可用于治疗实体瘤，成人T细胞白血病/淋巴瘤，真菌感染和过度增生的血管病如再狭窄和动脉粥样硬化。当用于再狭窄时，本发明化合物优选用于治疗出现在血管形成术后的再狭窄，当用于此目的时，可将本发明化合物在术前，手术期间或手术后，或上述各种情况结合的方式使用。
当治疗和抑制上述疾病时，本发明化合物可以给哺乳动物经口，非肠道，鼻内，支气管内，透皮，局部，阴道内或直肠使用。
可以期望，本发明化合物用作免疫抑制或抗炎剂时，它们能和一种或几种其它免疫调节剂一起使用。所述其它免疫调节剂包括，但不限于是硫唑嘌呤，皮质甾醇如强的松和甲基强的松龙，环磷酰胺，雷怕霉素，环孢菌素A，FK-506，OKT-3和ATG。将本发明化合物和上述其它药剂结合使用以诱发免疫抑制和治疗炎症，每种药剂仅需要较少的剂量就可达到希望的效果。Stepkowski建立了这种结合治疗的基础，他的研究结果表明在低治疗剂量下结合使用雷怕霉素和环孢菌素A大大延长了心脏同种移植的存活时间〔Transplantation Proc.23：507(1991)〕。
本发明化合物能单独地或和药用载体一起配成制剂用于需要治疗的哺乳动物。药用载体可以是固体或液体。当配制口服药剂时，发现于PHOSAL PG-50(带1，2-丙二醇的磷脂浓缩物A.Nattermann &Cie.GmbH)中的0.01％的吐温80提供了一种可接受的口服配方。
固体载体可包括一种或多种物质，它们可以作为调味剂，润滑剂，增溶剂，悬浮剂，填充剂，滑动剂，压缩助剂，粘合剂或片剂崩解剂，也可以是胶囊化材料。在粉剂中，载体是能和精细分散的活性成份混合的精细分散的固体。在片剂中，活性成份和适当比例的有需要的压缩性能的载体混合，并压缩成需要的形状和大小。粉剂和片剂优选含直到99％的活性成份。合适的固体载体例如包括：磷酸钙，硬脂酸镁，滑石，蔗糖，乳糖，糊精，淀粉，明胶，纤维素，甲基纤维素，羧甲基纤维素钠，聚乙烯吡咯烷，低熔点蜡和离子交换树脂。
液体载体用于制备溶液，悬浮液，乳液，糖浆，酏剂和加压的组合物。活性成份可溶解于或悬浮于药学可接受的液体载体中如水，有机溶剂，两者的混合物或药学上可接受的油或脂肪中。液体载体可以含有其它合适的药学上可接受的添加剂如增溶剂，乳化剂，缓冲剂，防腐剂，甜味剂，调味剂，悬浮剂，增稠剂，着色剂，粘度调节剂，稳定剂或渗透调节剂。对于口服和非肠道给药的液体载体的合适的实例包括水(部分含有上述添加剂如纤维素衍生物，优选羧甲基纤维素钠溶液)，醇类(包括单羟基醇和多羟基醇如甘醇)及它们的衍生物，以及油(例如精馏的椰子油和花生油)。对于非肠道给药，载体可以是油的酯如油酸乙酯和十四烷酸异丙酯。无菌液体载体可用于非肠道给药的无菌液体形式的组合物。加压组合物的液体载体可以是卤代烃及其它药学上可接受的推进剂。
无菌溶液或悬浮液的液体药用组合物例如可以用于肌肉内，腹膜内及皮下给药。无菌溶液也可以用于静脉给药。化合物也能以固体或液体组合物的形式口服给药。
本发明化合物能以常规的栓剂形式直肠给药。对于鼻内或支气管内吸入或吹入法给药，本发明化合物可以配制成水的或部分水的溶液，它们能以气雾剂的形式被使用。本发明化合物还可以通过使用含活性化合物和载体的透皮补片进行透皮给药，载体应是对活性化合物隋性的对皮肤无毒并能将全身吸收的药物通过皮肤输送至血流中。载体可以是各种形式如乳膏，软膏，糊剂，凝胶及包藏装置。乳膏和软膏可以是水包油或油包水型的粘性液体或半固体乳液。含有分散于含活性成份的石油或亲水石油中的吸收粉末的糊剂也是可用的。各种包藏装置可以将活性成份释放到血液系统，如半透膜复盖在含有或无载体的活性成份的贮器上，或复盖在含活性成份的基质上，其它包藏装置是文献中已知的。
此外，本发明化合物还可以通过用药学上可接受的赋形剂配制成溶液，乳膏或洗剂使用，其中含0.1-5％，优选2％的活性成份，它们可以用于真菌侵害的部位。
剂量要求随使用的具体组合物，给药方式，病症的严重程度及被治疗的具体对象改变。根据标准药理学试验方法得到的结果，活性化合物的日投药剂量是0.1μg/kg-100mg/kg，优选0.001-25mg/kg，更优选0.01-5mg/kg。治疗一般从少于化合物最佳剂量的较小剂量开始，随后在未治愈情况下增加剂量直到最佳效果。口服，非肠道，鼻内或支气管内给药的精确剂量取决于用药医生根据对每个被治疗患者的经验。药用组合物优选单位剂量形式，例如片剂或胶囊。在此种情况下，组合物被细分成含适当量活性成份的单位剂量；单位剂量形式可以是包装的组合物，例如：包装的粉剂，小瓶，安瓿，预先装好的含液体的注射器或含液体的袋剂。单位剂量形式可以例如是胶囊或片剂本身，或者是各种包装形式的任何上述组合物。
下述实施例阐明本发明代表性化合物的制备方法及生物活性。
                     实施例1(四氢吡喃-2-基氧基)乙酸雷怕霉素42-酯
于0℃及氮气氛下，将2，4，6-三氯苯甲酰氯(0.55ml，3.51mmol)用注射器加入到乙醇酸THP-醚(0.562g，3.51mmol)和三乙胺(0.49ml，3.51mmol)的THF(10ml)溶液中，室温搅拌混合物4小时，形成白色沉淀，真空过滤除去白色沉淀，用氮气流和温水浴浓缩滤液，残留物溶于10ml苯中，加入雷怕霉素(2.92g，3.19mmol)和DMAP(0.429g，3.51mmol)，将混合物于室温搅拌过夜。混合物用EtOAc稀释，用冷的1N HCl水溶液，饱和NaHCO3水溶液及食盐水洗涤，用MgSO4干燥，过滤，浓缩得到油状黄色固体，经快速色谱法提纯(2X 65％EtOAc-己烷)，得到标题化合物(1.114g，33％)，为白色固体。(-)FAB-MS m/z 1055.5(M-)，590.3(S(southern)碎g)，463.2(N(northern)碎片)1H NMR(400MHz，d-6 DMSO)δ4.60(m，1H，C(42)H)，4.66(m，1H)，4.14(s，2H)，3.73(m，1H)，3.42(m，1H).13C NMR(100.6MHz，d-6 DMSO)δ169.2，97.4，63.5，61.2，29.7，24.8，18.8.
                     实施例2羟乙酸雷怕霉素42-酯
于0℃将对甲苯磺酸(10mg)加入到实施例1产品(306mg，0.29mmol)于10ml CH3OH中的溶液中，室温搅拌该溶液2小时，用饱和NaHCO3停止反应，水相用3X EtOAc萃取，合并的有机相用食盐水洗涤，用MgSO4干燥，过滤，浓缩得到白色固体，用快速色谱法提纯(2X，EtOAc)，得到标题化合物(145mg，51％)，为白色固体。(-)FAB-MS m/z 971.3 M-)，590(S碎片)，379.1(N碎片).1H NMR(400MHz，d-6 DMSO)δ4.60(m，1H，C(42)H)，3.98(s，2H).13C NMR(100.6MHz.，d-6 DMSO)δ172.1，59.7.标准药理学试验方法得到的结果：LAF IC50：1.80nMLAF比率：0.83
在佐剂性关节炎实验中对对照组的百分变化为-88％
                     实施例32，2-二甲基-3-(四氢吡喃-2-基氧基)丙酸雷怕霉素42-酯
于0℃及氮气氛下，往2，2-二甲基-3-羟基丙酸THP-醚(0.319g，1.58mmol)和三乙胺(0.22ml，1.58mmol)于5ml无水THF中的溶液中通过注射器滴加2，4，6-三氯苯甲酰氯(0.25ml，1.58mmol)，于室温搅拌混合物4.5小时，真空过滤除去白色沉淀，用氮气流及温水浴浓缩滤液，残留物溶于5ml苯中，加入雷怕霉素(1.31g，1.43mmol)和DMAP(0.193g，1.58mmol)，室温搅拌混合物过夜，用EtOAc稀释，用1N HCl水溶液，饱和NaHCO3水溶液，水及食盐水洗涤，MgSO4干燥，过滤并浓缩得到黄色油性固体，用快速色谱法提纯(1X60％EtOAc-己烷，1X 55％EtOAc-己烷)，得到标题化合物(0.356g，23％)，为白色固体。(-)FAB-MS m/z 1097.7(M-)，590.4(S碎片)，505.3(N碎片).1H NMR(400MHz，d-6 DMSO)δ4.55(m，1H，C(42)H)，4.55(m，1H)，3.69(m，1H)，3.60(m，2H)，3.42(m，1H)，1.13(s，3H)，1.11(s，3H).13C NMR(100.6MHz，d-6 DMSO)δ175.0，98.0，73.8，60，7，42.6，30.0，24.9，22.0，21.6，18.7.标准药理学试验方法得到的结果：LAF IC50：7.10nMLAF比率：0.34
                     实施例43-羟基-2，2-二甲基丙酸雷怕霉素42-酯
将对甲苯磺酸(10mg)加入到于0℃下的实施例3产品(250mg，0.23mmol)于10ml CH3OH中的溶液中，室温搅拌该溶液2小时，用饱和NaHCO3溶液停止反应，水相用3X EtOAc萃取，合并的有机相用食用盐水洗涤，用MgSO4干燥，过滤并浓缩得到白色固体。用快速色谱法提纯(2X 75％EtOAc-己烷)，得到标题化合物(103mg，45％)，为白色固体。(-)FAB-MS m/z 1013.3(M-)，590.2(S碎片)，421.1(N碎片)1H NMR(400MHz，d-6 DMSO)δ4.48(m，1H，C(42)H)，3.39(d，2H)，1.06(s，6H).13C NMR(100.6MHz，d-6 DMSO)δ175.5，68.0，44.1，21.7.标准药理学试验方法得到的结果：LAF IC50：0.80nMLAF比率：1.25皮移植物存活时间：10.7±0.5天
                     实施例5和62，2-二甲基[1，3]二氧杂环戊烷-4-羧酸雷怕霉素42-酯(实施例5)2，2-二甲基[1，3]二氧杂环戊烷-4-羧酸雷怕霉素31，42-双酯(实施例6)
于0℃及氮气氛下，将2，4，6-三氯苯甲酰氯(0.56ml，3.61mmol)通过注射器加入到2，3-二羟基丙酸异亚丙基缩酮(0.527g，3.61mmol)和三乙胺(0.50ml，3.61mmol)于10ml THF中的溶液中，室温搅拌混合物4小时，真空过滤除去白色沉淀，用氮气流和温水浴浓缩滤液，残留物溶于15ml苯中，先加入雷怕霉素(3.00g，3.28mmol)，再加入DMAP(0.441g，3.61mmol)，室温搅拌混合物过夜，用EtOAc稀释混合物，用冷的1N HCl水溶液，饱和NaHCO3水溶液和食盐水洗涤，用MgSO4干燥，过滤并浓缩得到黄色泡沫状物，用硅胶快速色谱法提纯(梯度洗脱：50-60-75-100％EtOAc-己烷，4X 65％EtOAc-己烷)，得到标题化合物。极性较小的31，42-双酯(0.415g)先洗脱下来，极性较大的单酯(0.601g，16％)后洗脱下来，为白色固体。实施例5(-)FAB-MS m/z 1041.4(M-)，590.3(S碎片)，449.2(N碎片)1H NMR(400MHz，d-6 DMSO)δ4.6(m，1H，C(42)H)，4.6(m，1H)，4.20(dd，1H)，3.96(m，1H)，1.36(s，3H)，1.30(s，3H).13C NMR(100.6MHz，d-6 DMSO)δ170.5，110.2，73.4，66.6，25.7，25.4.实施例6(-)FAB-MS m/z 1169.6(M-).1H NMR(400MHz，d-6 DMSO)δ5.3(m，1H，C(31)H)，4.6(m，1H，C(42)H)，4.6(m，2H)，4.19(t，1H)，4.13(t，1H)，3.9(m，2H)，1.36(s，3H)，1.33(s，3H)，1.30(s，3 H)，1.28(s，3H).13C NMR(100.6MHz，d-6 DMSO)δ170.5，169.2，110.3，110.2，73.4，66.6，66.5，25.8，25.7，25.4，25.1.标准药理学试验方法得到的结果：实施例5LAF IC50：1.20nMLAF比率：0.74实施例6LAF IC50：1.30nMLAF比率：0.5
                     实施例72，3-二羟基丙酸雷怕霉素42-酯
实施例5产品(351mg，0.34mmol)在10ml THF和10ml 1N HCl中的溶液于室温下搅拌6小时，混合物用EtOAc稀释，用饱和NaHCO3溶液和食盐水洗涤，用MgSO4干燥，过滤并浓缩成油状物。用快速色谱法提纯(1X EtOAc，1X 10％MeOH-CH2C12，1X 5％MeOH-EtOAc)，得到标题化合物(78mg，23％)，为白色固体。(-)FAB-MS m/z 1001.2(M-)，590.2(S碎片)，409.1(N碎片)1H NMR(400MHz，d-6 DMSO)δ4.5(m，1H，C(42)H)，3.60(m，1H)，3.45(m，2H).标准药理学试验方法得到的结果：LAF IC50：1.4nMLAF比率：0.40
                     实施例82，2-二甲基[1，3]二噁烷-5-羧酸雷怕霉素42-酯
于0℃及氮气氛下将2，4，6-三氯苯甲酰氯(0.98ml，6.27mmol)通过注射器加到2-(羟甲基)-3-羟基丙酸异亚丙基缩酮(1.000g，6.24mmol)和三乙胺(0.90ml，6.46mmol)于20ml THF中的溶液中，将混合物于室温搅拌4小时，形成白色沉淀，真空过滤除去白色沉淀，用氮气流和温水浴浓缩滤液，残留物溶于20ml苯中，加入雷怕霉素(5.70g，6.24mmol)和DMAP(0.762g，6.24mmol)，于室温将混合物搅拌过夜。用EtOAc稀释混合物，用H2O和食盐水洗涤，用MgSO4干燥，过滤并浓缩，得到黄色固体，快速色谱法提纯(75％EtOAc-己烷)得到标题化合物(4.17g，63％)，为白色固体。(-)FAB-MS m/z 1055.8(M-)，590.5(S碎片)，463.4(N碎片)1H NMR(400MHz，d-6 DMSO)δ4.55(m，1H，C(42)H)，3.95(m，4H)，130(s，6H).13C NMR(100.6MHz，d-6 DMSO)δ170.1，97.4，59.5，24.8，22.5.标准药理学试验方法得到的结果：LAF IC50：0.76nMLAF比率：0.45
                     实施例93-羟基-2-羟甲基丙酸雷怕霉素42-酯
实施例8产品(3.30g，3.12mmol)于50ml THF和25ml 1N HCl中的溶液于室温搅拌2小时，用饱和NaHCO3溶液稀释，用EtOAc萃取(3X)，合并的有机相用饱和NaCl水溶液洗涤，用MgSO4干燥，过滤并浓缩得到黄色泡沫状物。用快速色谱法提纯(1X EtOAc，2X 5％EtOH-EtOAc)，得到标题化合物(1.68g，53％)，为白色固体。(-)FAB-MS m/z 1015.5(M-)，590.3(S碎片)，423.3(N碎片)1H NMR(400MHz.d-6DMSO)δ4.6(br s，2H)，4.55(m，1H，C(42)H)，3.55(m，4H)，2.57-2.53(m，1H).13C NMR(100.6MHz，d-6 DMSO)δ172.2，59.3，51.5标准药理学试验方法得到的结果：LAF IC50：0.84nMLAF比率：0.57
                     实施例102，2，5-三甲基[1，3]二噁烷-5-羧酸雷怕霉素42-酯
于0℃及氮气氛下，往2，2-双(羟甲基)丙酸异亚丙基缩酮(1.041g，5.98mmol)(按照Bruice，美国化学会志(J.Am.Chem.Soc.)89：3568(1967)方法制备)和三乙胺(0.83ml，5.98mmol)于20ml无水THF中的溶液中加入2，4，6-三氯苯甲酰氯(0.93ml，5.98mmol)，室温下将所得白色悬浮液搅拌5小时，真空过滤除去沉淀，再用10ml无水THF淋洗烧瓶和滤饼，旋转蒸发浓缩滤液，得到白色固体。残留物溶于20ml无水苯中，加入雷怕霉素(5.47g，5.98mmol)和DMAP(0.731g，5.98mmol)，室温搅拌过夜，用EtOAc稀释混合物，用水和饱和NaCl水溶液洗涤，用MgSO4干燥，过滤并蒸发得到黄色油状物。用快速色谱法提纯(5X 60％EtOAc-己烷)，得到标题化合物(2.2g，34％)，为白色固体。(-)FAB-MS m/z 1069.5(M-)，590.3(S碎片)，477.2(N碎片).1H NMR(400MHz，d-6 DMSO)δ4.57(m，1H，C(42)H)，4.02(d，2H)，3.60(d，2H)，1.34(s，3H)，1.24(s，3H)，1.06(s，3H).13C NMR(100.6MHz，d-6 DMSO)δ173.2，99.0，65.0，22.2，18.1.标准药理学试验方法得到的结果：LAF IC50：4.90nMLAF比率：0.41皮移植物存活时间：11.0±1.3天
                        实施例112，2-双(羟甲基)丙酸雷怕霉素42-酯
实施例10产品(2.8g，2.65mmol)于50ml THF和25ml 1N HCl中的溶液于室温下搅拌4小时，用水稀释混合物，用EtOAc萃取三次。合并的有机相用饱和NaHCO3溶液，饱和NaCl溶液洗涤，用MgSO4干燥，过滤并蒸发得到黄色油状固体物。用快速色谱法提纯(3X EtOAc)，得到标题化合物(1.6g，59％)。(-)FAB-MS m/z 1029.6(M-)，590.4(S碎片)，437.3(N碎片).1H NMR(400MHz，d-6 DMSO)δ4.5(m，1H，C(42)H)，3.45(s，4H)，1.04(s，3H).13C NMR(100.6MHz，d-6 DMSO)δ174.2，63.7，63.6，49.9，16.8.标准药理学试验方法得到的结果：LAF IC50：0.80和1.80nMLAF比率：1.00和0.44皮移植物存活时间：11.4±1.5和12.0±1.1天佐剂性关节炎对对照组的百分变化：-88％
                    实施例122，2-二甲基-5-(2-三甲基硅烷基乙氧甲基)[1，3]-二噁烷-5-羧酸雷怕霉素42-酯
于0℃及氮气氛下，将2，4，6-三氯苯甲酰氯(0.14ml，0.86mmol)通过注射器加入到2，2-双(羟甲基)-2-(2-三甲基甲硅烷基乙氧)丙酸异亚丙基缩酮(0.250g，0.86mmol)和三乙胺(0.12ml，0.86mmol)于2ml THF中的溶液中，室温下搅拌混合物4小时，形成白色沉淀，真空过滤除去白色沉淀，用氮气流和温水浴浓缩滤液。残留物溶于2ml苯中，加入雷怕霉素(0.786g，0.86mmol)和DMAP(0.105g，0.86mmol)，室温下将混合物搅拌过夜，用EtOAc稀释混合物，用水和食盐水洗涤，用MgSO4干燥，过滤并浓缩得到黄色固体。快速色谱法提纯(梯度洗脱：40-60-80-100％EtOAc-己烷)，得到标题化合物(0.559g，54％)，为白色固体。(-)FAB-MS m/z 1185.2(M-)，590.1(S碎片)，593(N碎片).1H NMR(400MHz，d-6 DMSO)δ4.55(m，1H，C(42)H)，3.73(m，4H)，3.57(s，2H)，3.43(t，2H)，1.29(s，6H)，0.79(t，2H)，-0.04(s，9H).13C NMR(100.6MHz，d-6 DMSO)δ171.1，97.7，70.2，68.1，61.3，46.0，24.6，22.1，14.6，-1.3.标准药理学试验方法得到的结果：LAF IC50：7.20nMLAF比率：0.05
                   实施例13和143-甲基-1，5-二氧杂-螺[5，5]十一烷-3-羧酸雷怕霉素42-酯(实施例13)3-甲基-1，5-二氧杂-螺[5，5]十一烷-3-羧酸雷怕霉素31，42-二酯(实施例14)
于0C及氮气氛下，将2，4，6-三氯苯甲酰氯(0.16ml，1.0mmol)通过注射器加入到2，3-二羟基丙酸亚环己基缩酮(0.214g，1.0mmol)和三乙胺(0.14ml，1.0mmol)于2.5ml THF中的溶液中。室温搅拌混合物4小时，真空过滤除去白色沉淀，用氮气流和温水浴浓缩滤液。残留物溶于3ml苯中，依次加入雷怕霉素(0.457g，0.5mmol)和DMAP(0.061g，0.5mmol)，室温搅拌混合物过夜，用EtOAc稀释混合物，用冷的1N HCl水溶液，饱和NaHCO3水溶液和食盐水洗涤，用MgSO4干燥，过滤并浓缩，得到黄色泡沫状物。硅胶快速色谱法提纯(45-50％EtOAc-己烷)，得到标题化合物。先洗脱下31，42-二酯(0.168g，26％)，后洗脱下的是极性更大的42-单酯(0.301g，52％)，分离产品，为白色固体。实施例13(-)FAB-MS m/z 1109.5(M-)，590.3(S碎片)，517.3(N碎片)1H NMR(400MHz，d-6 DMSO)δ4.55(m，1H，C(42)H)，3.61(t，4H)，1.04(s，3H).13C NMR(100.6MHz，d-6 DMSO)δ173.3，97.2，64.2.实施例14(-)FAB-MS m/z 1305.6(M-).1H NMR(400MHz，d-6 DMSO)δ5.25(m，1H，C(31)H)，4.55(m，1H，C(42)H)，3.64-3.54(m，8H)，1.05(s，3H)，0.97(s，3H).13C NMR(100.6MHz，d-6 DMSO)δ173.2，172.1，97.3，97.2，64.3，64.2，63.9.标准药理学试验方法得到的结果：实施例13LAF IC50：0.6nMLAF比率：2.00实施例14LAF：在0.1μM下抑制T细胞增生43％

Claims (21)

1.下述结构式的化合物或其药学上可接受的盐：其中：R1和R2每个独立地是氢或-CO(CR3R4)b(CR5R6)dCR7R8R9；R3和R4每个独立地是氢或1-6个碳原子的烷基；R5和R6独立地是氢、1-6个碳原子的烷基、-(CR3R4)fOR10、-CF3，或者R5和R6可以一起形成X；R7是氢、1-6个碳原子的烷基、-(CR3R4)fOR10或-CO2R11；R8和R9独立地是氢、1-6个碳原子的烷基、-(CR3R4)fOR10或-CO2R11，或者R8和R9可以一起形成X；R10是氢、1-6个碳原子的烷基、三(1-6个碳原子的烷基)甲硅烷基乙基或四氢吡喃基；R11是氢、1-6个碳原子的烷基、2-7个碳原子的链烯基、2-7个碳原子的炔基或7-10个碳原子的苯基烷基；X是5-(2，2-二(1-6个碳原子的烷基))[1，3]二噁烷基、5-(2-螺(3-8个碳原子的环烷基))[1，3]二噁烷基、4-(2，2-二(1-6个碳原子的烷基))[1，3]二噁烷基、4-(2-螺(3-8个碳原子的环烷基))[1，3]二噁烷基、4-(2，2-二(1-6个碳原子的烷基))[1，3]二氧杂环戊烷基或4-(2-螺(3-8个碳原子的环烷基))[1，3]二氧杂环戊烷基；b＝0-6；d＝0-6；以及f＝0-6，其条件是R1和R2两者不同时是氢，另一条件是R1或者R2至少含一个-(CR3R4)fOR10或X。
2.按照权利要求1的化合物或其药学上可接受的盐，其中R2是氢。
3.按照权利要求1的化合物或其药学上可接受的盐，其中b＝0，d＝0。
4.按照权利要求3的化合物或其药学上可接受的盐，其中R8和R9每个独立地是氢、烷基或-(CR3R4)fOR10或者一起形成X。
5.按照权利要求1的化合物，它是(四氢吡喃-2-基氧基)乙酸雷帕霉素42-酯或其药学上可接受的盐。
6.按照权利要求1的化合物，它是羟基乙酸雷帕霉素42-酯或其药学上可接受的盐。
7.按照权利要求1的化合物，它是2，2-二甲5-3-(四氢吡喃-2-基氧基)丙酸雷帕霉素42-酯或其药学上可接受的盐。
8.按照权利要求1的化合物，它是3-羟基-2，2-二甲基丙酸雷帕霉素42-酯或其药可接受的盐。
9.按照权利要求1的化合物，它是2，2-二甲基[1，3]二氧杂环戊烷-4-羧酸雷帕霉素42-酯或其药学上可接受的盐。
10.按照权利要求1的化合物，它是2，2-二甲基[1，3]二氧杂环戊烷-4-羧酸31，42-二酯或其药学上可接受的盐。
11.按照权利要求1的化合物，它是2，3-二羟基丙酸雷帕霉素42-酯或其药学上可接受的盐。
12.按照权利要求1的化合物，它是2，2-二甲基[1，3]二噁烷-5-羧酸雷帕霉素42-酯或其药学上可接受的盐。
13.按照权利要求1的化合物，它是3-羟基-2-羟甲基丙酸雷帕霉素42-酯或其药学上可接受的盐。
14.按照权利要求1的化合物，它是2，2，5-三甲基[1，3]二噁烷-5-羧酸雷帕霉素42-酯或其药学上可接受的盐。
15.按照权利要求1的化合物，它是2，2-双(羟甲基)丙酸雷帕霉素42-酯或其药学上可接受的盐。
16.按照权利要求1的化合物，它是2，2-二甲基-5-(2-三甲基硅烷基乙氧甲基)[1，3]二噁烷-5-羧酸雷帕霉素42-酯或其药学上可接受的盐。
17.按照权利要求1的化合物，它是3-甲基-1，5-二氧杂-螺[5.5]十一烷-3-羧酸雷帕霉素42-酯或其药学上可接受的盐。
18.按照权利要求1的化合物，它是3-甲基-1，5-二氧杂-螺[5.5]十一烷-3-羧酸雷帕霉素31，42-二酯或其药学上可接受的盐。
19.权利要求1的化合物的应用，用于制备治疗哺乳动物的移植排斥、宿主移植物疾病、真菌感染、风湿性关节炎、再狭窄或肺炎的药物
20.药物组合物，它包含权利要求1的化合物或其药学上可接受的盐和药物载体。
21.制备权利要求1的式I雷帕霉素羟基酯的方法，包括：a)用酰化剂酰化雷帕霉素或其官能衍生物或类似物；或b)用两种酰化剂连续酰化雷帕霉素或其官能衍生物或类似物；所述酰化剂选自下式酸或其活性衍生物：
      HO-CO(CR3R4)b(CR5R6)dCR7R8R9       (II)其中R3-R9、b和d定义如权利要求1，条件是假如需要用适当的保护基保护雷帕霉素或其官能衍生物的42位的话，应保护游离羟基，需要的话，反应后除去任何保护基。
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CN104086564A (zh) * 2014-07-30 2014-10-08 江苏奥赛康药业股份有限公司 一种高纯度坦罗莫司的制备方法
CN104086564B (zh) * 2014-07-30 2019-02-05 江苏奥赛康药业股份有限公司 一种高纯度坦罗莫司的制备方法

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