CN1189465C - 具有双c-20侧链的维生素d3类似物 - Google Patents
具有双c-20侧链的维生素d3类似物 Download PDFInfo
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- CN1189465C CN1189465C CNB988045818A CN98804581A CN1189465C CN 1189465 C CN1189465 C CN 1189465C CN B988045818 A CNB988045818 A CN B988045818A CN 98804581 A CN98804581 A CN 98804581A CN 1189465 C CN1189465 C CN 1189465C
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Electroplating Methods And Accessories (AREA)
- Electroplating And Plating Baths Therefor (AREA)
Abstract
本发明提供了式(I)的维生素D3类似物,其中:X是H2或CH2;Y是氢、羟基或氟;Z是羟基;R1和R2是(C1-C4)烷基或氟代烷基,或者R1和R2与C25一起形成(C3-C6)环烷基或氟代环烷基;R3和R4是(C1-C4)烷基或氟代烷基,或者R3和R4与C25,一起形成(C3-C6)环烷基或氟代环烷基;A是单键或双键;B1是单键、E-双键、Z-双键或三键;和B2是单键、E-双键、Z-双键或三键;和它们的前药,制备这些类似物的中间体和方法,含有这些类似物的药物组合物,治疗骨质疏松症、甲状旁腺功能亢进和自动免疫疾病的方法,以及治疗和预防肿瘤形成性疾病的方法。
Description
本发明涉及维生素D3类似物,中间体和制备它们的方法,含有所述类似物的药物组合物,和这些类似物在治疗骨质疏松症,原发和继发性甲状旁腺功能亢进,自动免疫疾病以及治疗和预防肿瘤形成疾病中的应用。
骨质疏松症是骨代谢疾病的最常见的形式,并且被认为是症状性的,是骨质损失的骨折阶段(骨质减少)。虽然骨质疏松症也可以由于一些潜在疾病引起而是继发性的,但90%的情况是自发的。绝经后的妇女有自发产生骨质疏松症的危险(绝经骨质疏松症或I型骨质疏松症);其它自发发生骨质疏松症的高危群体是各种性别的老年人(老年或II型骨质疏松症)。骨质疏松症还与皮质类固醇的使用、固定或长期的卧床休息、酗酒、糖尿病、性激素毒性(gonadotoxic)化学疗法、高催乳素血症、神经型厌食症、原发或继发的闭经、器官移植免疫抑制和卵巢切除术有关。绝经期骨质疏松症的特征是脊柱骨折,而股骨颈骨折是老年性骨质疏松症的主要特征。
在骨质疏松症中骨质损失的机理被认为是涉及到骨骼本身再生过程中的不平衡。此过程被称为骨质重建,发生在一系列分离的活性囊中。这些囊出现在骨骼基质中,对给定的骨骼表面而言是骨吸收的位置。破骨细胞(骨质溶解或再吸收的细胞)会造成部分正常密度骨质的再吸收。在再吸收过程之后会出现成骨细胞(骨质形成细胞),然后把破骨细胞留下的空洞由新的骨质再充满。
在健康的成人体内,破骨细胞和成骨细胞都发挥功能,因此骨质的形成和再吸收之间是平衡的。但是,在骨质疏松症者体内的骨质重建过程出现了不平衡,使骨质的替代速度减慢,因此造成了骨损失。虽然在某种意义上,大多数个体中这种不平衡随年龄增大而出现,但是,出现在较年轻的人群中的绝经期骨质疏松症,卵巢切除术后的骨质疏松症,或是医原型的病症如由于皮质类固醇治疗或器官移植后的免疫抑制所引起的骨质疏松症就更为严重。
建议用来增加人体骨质的各种方法可用于治疗骨质疏松症,包括施用雄激素、氟盐、甲状旁腺激素和修饰的甲状旁腺激素。另外,还建议施用双膦酸盐、降钙素、钙、1,25-二羟基维生素D3和它的某些类似物、和/或雌激素,它们可单独或结合施用,用来维持正常的骨质。
维生素D3是钙代谢中的关键因素,能够促进肠对钙和磷的吸收,使血浆保持适当的钙和磷的水平,刺激钙在骨骼中的流出流进。维生素D3在体内被羟基化,生成1α,25-二羟基代谢物,是活性物质。用1,25-二羟基维生素D3进行的动物试验表明它具有骨骼合成代谢活性。Aerssens等人在Calcif Tissue Int.,55:443-450(1994)中报道了在进行或没有进行皮质类固醇治疗时,1α-羟基维生素D3在生长期大鼠中对骨骼强度和组成的影响。但是由于治疗比不够好(高钙尿和高钙血,以及肾毒),人体使用受到抗再吸收的限制。
Dechant和Goa在“骨化三醇,在治疗绝经期骨质疏松症和可能用于皮质类固醇诱导的骨质疏松症方面的综述”(骨化三醇。A reviewof its use in the treatment of postmenopausal osteoporosis andits potential in corticosteroid-induced osteoporosis),DrugsAging[NEW ZEALAND,5(4):300-17(1994)]报道了1,25-二羟基维生素D3(骨化三醇)在治疗绝经期骨质疏松症(和用于皮质类固醇诱导的骨质疏松症)时的效力,该文是以622例患有绝经期骨质疏松症的妇女的临床试验为基础的。患有轻度至中等程度疾病(但不是有严重疾病的患者)的患者在用骨化三醇(0.25微克,一天二次)治疗三年后与施用1000mg/天钙的患者相比,出现新的椎骨骨折的比例显著下降,下降达到3倍。用强的松或强的松龙长期治疗的患者,用骨化三醇0.5-1.0μg/天加上1000mg钙/天,并且加或不加鼻内给药400IU降钙素/天可以预防类固醇诱导的骨质损失。总的来说,骨化三醇具有很好的耐受性。在推荐施用的剂量下,高钙血的情况很少出现,并且较轻,通常与钙吸收的减少和/或骨化三醇的剂量相吻合。但是,需要进行骨化三醇治疗的狭窄范围要求对它的使用应当适当控制,应该定期测量血浆中的钙和肌酸酐的水平。此研究清楚地说明骨化三醇治疗的关键性限制是治疗和毒性剂量极为接近。
Baggiolini等人在欧洲专利公开号580,968中公开了维生素D3类似物,包括1α-氟-25-羟基-16-烯-23-炔-26,27-六氟维生素D3,用于治疗皮肤的增生性疾病,用于治疗癌症和白血病,以及用于治疗皮脂腺疾病。美国专利申请号08/560,080公开和要求保护此化合物用于骨质疏松症的骨质和/或密度恢复。审查中的美国专利申请60/018,219和美国专利申请“氟代维生素D3类似物”(申请日1997.3.19)也公开了某些维生素D3类似物用于治疗骨质疏松症。
继发性的甲状旁腺功能亢进通常发生于慢性肾衰竭患者。已经确定肾中1,25-二羟基维生素D3(骨化三醇)合成的减少是导致这些患者出现继发性甲状旁腺功能亢进的基本的机理之一,已经证明骨化三醇对PTH的合成有直接的抑制作用。因此,对这些患者推荐使用骨化三醇,用于治疗继发性甲状旁腺功能亢进。但是,正如上文所述,骨化三醇有可能导致高钙血的效果,从而使其治疗范围狭窄,这限制了它的应用,特别是在高剂量时更是如此。因此需要有其它不会导致这些不良效果的治疗甲状旁腺功能亢进的方法。
流行病学研究表明太阳或紫外线接触会降低各种恶性肿瘤如乳癌、结肠癌和前列腺癌的发病率。对受试者研究的证据表明除了典型靶器官如肠、肾和骨骼以外,维生素D受体(VDR)存在于人体的各类正常细胞系和癌细胞系以及新的组织中。维生素D或1,25-二羟基维生素D3的生长抑制经常不会在体内转化成有效的治疗效果。体内的早期研究集中于1,25-二羟基维生素D3和其类似物在小鼠白血病模型中的抗增生效果,在此情况下,1,25-二羟基维生素D3不仅显示出抗增生效果,而且还有分化效果。由于用高剂量亲代1,25-二羟基维生素D3治疗时出现了高血钙的情况,因此它在体内的质量效果受到限制。其结果是研究开发出了能够具有很好的抗癌作用而又不产生高血钙的类似物。
这里公开的在C20上带有两个侧链的维生素D3类似物以前从来没有公开过,也没有公开过它们在治疗骨质疏松症,原发和继发性甲状旁腺功能亢进,自动免疫疾病以及治疗和预防肿瘤形成疾病如白血病和癌症中的应用。
本发明提供了式I的维生素D3类似物:
其中:
X是H2或CH2;
Y是氢、羟基或氟;
Z是羟基;
R1和R2是(C1-C4)烷基或氟代烷基,或者R1和R2与C25一起形成(C3-C6)环烷基或氟代环烷基;
R3和R4是(C1-C4)烷基或氟代烷基,或者R3和R4与C25’一起形成(C3-C6)环烷基或氟代环烷基;
A是单键或双键;
B1是单键、E-双键、Z-双键或三键;和
B2是单键、E-双键、Z-双键或三键。
本发明还提供了含有药用载体和上文定义的式I的维生素D3类似物的组合物。
本发明涉及式I化合物在治疗骨质疏松症、甲状旁腺功能亢进、自动免疫疾病以及在治疗和预防肿瘤形成疾病中的应用。
本文中所用的术语“(C1-C4)烷基”是指具有1至4个碳原子的,完全饱和的直链烃基,或具有3至4个碳原子的,完全饱和的支链烃基;术语“(C1-C4)氟代烷基”是指上述定义的烷基基团中有一个或多个连接于碳骨架上的氢原子被一个或多个氟原子所取代。
本文中所用的术语“(C3-C6)环烷基”是指具有3至6个碳原子的,完全饱和的环状烃基,例如环丙基、环戊基等;术语“(C3-C6)氟代环烷基”是指上述定义的环烷基基团中有一个或多个连接于碳骨架上的氢原子被一个或多个氟原子所取代。
本文中使用的术语“E”表示碳-碳双键的立体化学构型是连接于不同碳原子上的两个氢原子处于碳-碳双键相反的侧面上;术语“Z”表示碳-碳双键的立体化学构型是连接于不同碳原子上的两个氢原子处于碳-碳双键的同一侧面上。
“前药”是指在把这些前药施用于哺乳动物之后,能够在体内释放出式I的活性母体药物的任何化合物。式I化合物的前药可通过对式I化合物上的官能团进行修饰来制备,这样,经过如此修饰的化合物在体内裂解释放出母体化合物。前药包括其中的羟基基团键合有可在体内裂解而产生游离羟基的任何基团的式I化合物。前药的实例包括,但不限定于式I化合物的酯类(如乙酸酯、甲酸酯和苯甲酸酯衍生物),氨基甲酸酯类(如N,N-二甲氨基羰基),和羟基官能团的醚类,等等。本领域的熟练技术人员可用常规技术,通过将母体化合物分子的羟基酰化或醚化制备出这些化合物。
“治疗有效量”是指为了治疗或预防疾病给哺乳动物的用药量足以能够达到治疗或预防这种疾病的效果。根据施用的化合物,疾病,其严重程度和需要治疗的哺乳动物的年龄、体重等改变“治疗有效量”。
本发明化合物通常可按照维生素D3分子片段的反应和结合的方法制备。在这方面,Shiuey等人在J.Org.Chem.,55:243(1990)中描述的合成方法可用来制备和结合维生素D3的分子片段。式I化合物和中间体本身的制备由下面的反应流程说明。
式I化合物可由下面的式II化合物制备:
其中的R1、R2、R3、R4、A、B1和B2如上文定义,R5是氢或三甲基甲硅烷基,
使其与式III化合物反应:
其中X如上文定义,Y是氢、氟或羟基保护基团,而Z是叔丁基-二甲基硅烷氧基,
接着除去甲硅烷基保护基团。
通常使式III化合物与正丁基锂和式II化合物反应,反应在己烷和四氢呋喃的混合物中,于-78℃进行,除去甲硅烷基保护基团之后可得到式I化合物,除去保护基团的反应是在四氢呋喃溶剂中与四丁基氟化铵反应。
值得注意的是,虽然典型的是把带有羟基的中间体以甲硅烷基醚保护起来,但是本发明包括了使用下述文献中提到的其它的羟基保护基团:T.W.Greene,“Protective Groups in Organic Synthesis”(有机合成中的保护基团),Wiley,纽约,(1991),和J.F.McOmie,“Protective Groups in Organic Chemistry”(有机化学中的保护基团),Plenum Press,伦敦,(1973),以及其它的脱保护方法。
式III化合物的合成和纯化是本领域已知的和常规的,可参见例如下述文献:USP 5,086,191和5,616,759,DeLuca等人;5,087,619,Baggiolini等人;5,384,314,Doran等人;5,428,029,Doran等人;5,451,574,Baggiolini等人;EPO 808 832 A2,WO96/31216,Brasitus等人;Shiuey等人,J.Org.Chem.(有机化学杂志),55:243-247(1990);Kiegel,J.等人,Tetr.Lett.(四面体杂志),32:6057-6060(1991);Perlman,K.L.等人,Tetr.Lett.(四面体杂志),32:7663-7666(1991)。
反应流程1说明了式Ia化合物的制备方法,其中的B1和B2是单键;R1-R4各自是CH3;X是CH2;以及Y和Z是OH。
在反应流程1中,式IV化合物是由相应的前体醇脱水而制备的已知化合物,例如参见Wovkulich,P.M.等人,Tetrahedron,40:2283(1984)。在路易斯酸如二氯化乙基铝存在下,通过使式IV化合物与丙酸乙酯反应,可使其转化成式V化合物。反应在氯代烃溶剂如二氯甲烷中,于室温下进行。在催化剂如10%钯-碳存在下使式V化合物氢化,从而转化成式VI化合物。反应在一个大气压下,于室温,在酯类溶剂如乙酸乙酯中进行。在醚类溶剂如乙醚和四氢呋喃的混合物中,于室温,使式VI化合物与甲基溴化镁反应,转化成式VII化合物。以乙腈和四氢呋喃的混合物为溶剂,于室温使式VII化合物与30%氟硅酸水溶液反应,转化成式VIII化合物。在氯代烃溶剂如二氯甲烷中,于室温下使式VIII化合物与重铬酸吡啶鎓反应,氧化成为式IX化合物。以二氯甲烷为溶剂,使化合物IX与三甲基甲硅烷基咪唑反应得到化合物IIa。使化合物IIIa与正丁基锂以及化合物IIa于己烷和四氢呋喃混合物中于-78℃一起反应,在四氢呋喃溶剂中与四丁基氟化铵反应除去甲硅烷基保护基团之后,得到式Ia化合物。
其中A是单键或双键,B1和B2是双键或三键的式I化合物,是通过使相应的式II前体类似物与式III化合物反应制备的。相应的式II前体类似物可按照本领域熟练技术人员已知的方法制备。合成路线的实例见反应流程2。
B1和B2是反式双键(E)的式II化合物可通过将式VI化合物用二异丙基氨化锂和苯基氧硒基氯化物(phenylselenylchloride)处理,接着用过氧化氢氧化和用氧化硒消除,使其转化成相应的二不饱和酯X来制备。通过如流程1所示的反应使二不饱和酯X转化成B1和B2是反式双键(E)的式IIa前体类似物。
B1和B2是顺式双键(Z)的式II化合物可通过下述方法获得:用试剂如臭氧或四氧化锇/偏高碘酸钠使式X化合物的双键氧化分解,生成式XI的醛;然后使式XI的醛与膦酸内鎓盐(CF3CH2O)2P(O)CH2C(O)OEt进行Wittig-Horner反应,用Still修饰缩合,得到双不饱和酯XII,其中双键的立体构型是顺式的(Z)。通过流程1所示的反应将双不饱和酯XII转化成B1和B2是顺式双键(Z)的前体类似物IIa。
B1和B2是三键的式II化合物可通过下述方法获得:使式X或XII的不饱和酯脱氢,得到含三键的相应酯,接着按反应流程1所示,与有机金属试剂缩合,得到式IIa的类似化合物。也可以通过将式X或XII化合物的双键进行溴化/脱氢溴化作用形成三键。另外,将式XI的醛用丁基锂和三苯膦/四溴化碳处理,经过Corey-Fuchs反应得到乙炔化物阴离子XIII,使其与酮缩合后得到类似于VII的相应炔醇XIV。
类似的,以A是双键的化合物VI类似物为原料,可得到类似于IIa的和A是双键的前体。
带有不同烷基和氟代烷基的R1-R4的式II化合物可由适当的有机金属试剂如烷基锂或格利雅试剂与如V、VI、X和XII中的C-25酯进行缩合来制备。另外,也可以由中间体如XIII衍生的乙炔化物阴离子与适当的酮或氟代酮(如六氟丙酮)缩合以引入这些基团。
在某些优选的实施方案中,B1和B2是双键或三键。
在其它优选的实施方案中,A是双键。
在其它优选的实施方案中,A是单键。
优选的实施方案还包括其中X是CH2而Y是氟或羟基的化合物。
其它优选的实施方案是其中的R1-R4是烷基或氟代烷基,优选三氟甲基的化合物。
本发明的另一方面包括式I化合物的前药。
上面已经给出了一系列不同取代基的优选取代基,用这些优选取代基得到的本发明化合物比不是使用优选取代基的化合物更为优选。虽然有些优选基团是相互排斥的,但是这些取代基的优选基团通常是相互独立的,因此,在这些优选取代基中,使用了较多优选取代基的化合物比使用了一个或较少优选取代基的化合物更优选。
本发明化合物可用于预防和治疗哺乳动物由于骨质损失而表现出来的各种症状。特别是本发明化合物可用于对哺乳动物的骨质疏松症和骨质减少进行预防性和治疗性的处理而不会出现高钙尿和高钙血,或肾毒。这里所说的“高钙尿”是指在尿中过量的钙,在人体中相当于排泄量大于4/mg/kg/天。这种情况常常会引起肾石病(肾结石)。“高钙血”是指在血浆中有超浓度的钙,就人(和大鼠)而言,相当于高于大约10.5mg/dl。“不能耐受的高钙血”通常是指血浆中的钙浓度大于大约12mg/dl,这和情绪不稳定、精神错乱、谵妄、精神病、木僵和昏迷有关。
预期本发明化合物可用于治疗I型(绝经期)、II型(老年性)和III型(医原性)骨质疏松症,包括和用于器官移植的免疫抑制药物有关的骨质疏松症,以及用于治疗由于肾透析和甲状旁腺功能亢进引起的骨营养不良。
本发明化合物还可用于治疗由甲状旁腺激素水平提高引起的疾病。一方面,本发明化合物可用于治疗与肾衰竭有关的,特别是与逆转或减少由于肾功能不全引起的骨损失有关的继发性甲状旁腺功能亢进。另一方面包括治疗与晚期继发性甲状旁腺功能亢进有关的肾病性骨营养不良。其它方面还包括治疗原发的甲状旁腺功能亢进。
式I化合物还可用于治疗肿瘤形成性疾病如白血病、结肠癌、乳癌和前列腺癌。
式I化合物还可用于治疗免疫抑制和自动免疫疾病。这些疾病包括,但不限于多发性硬化、系统性红斑狼疮、糖尿病、甲状腺炎和同种移植排斥。特别是本发明式I化合物用于治疗由维生素D3受体(VDR)活性调节的疾病。这些化合物在体内的应用可用这些疾病的小鼠模型来证明,这些模型是本领域已知的,参见Lemire等,自动免疫(Autoimmunity),12:143-148(1992);Lemire等临床研究杂志(J.Clin.Invest.),87:1103-1107(1991);Lemire等内分泌学(Endocrinology),135:2818(1994);Lemire等细胞生物学杂志(J.Cellular.Biochem.),49:26-31(1992)。
一般来说,本发明化合物不会出现在使用其它维生素D3类似物如1,25-二羟基维生素D3时观察到的钙水平提高,因此提供了改进的治疗比率和对上述疾病更好的治疗方法。
通常本发明化合物可以大约每天0.0002-0.5mg/kg体重的量施用,优选每天施用0.001至大约0.1mg/kg体重,最优选每天施用0.002至大约0.02mg/kg体重。对一个50公斤的人来说,每天的剂量大约0.01至大约25μg活性成分,优选大约0.05至大约10μg活性成分,最优选大约1.0至大约10μg活性成分。此剂量可以一次施用,多次施用或控制释放的常用药物组合物给药,以达到最有效的结果,优选每天一次或二次口服。在某些情况下,要达到理想的治疗效果,隔天给药也是适当的。
准确的剂量和组合物,以及最适当的给药方式的选择特别受到药物制剂的性能、所治疗的疾病的性质和严重的程度、患者的身体状况和精神敏度的影响。在治疗皮质类固醇引起的骨质减少时,预计需要的剂量应大于或高于皮质类固醇的剂量。
代表性的给药方式包括口服、肠胃外(包括皮下、肌内和静脉内)、直肠、含剂(包括舌下)、肺部、经皮和鼻内给药,最优选口服。可以连续或间隙(例如快速浓注)给药。
本发明的另一方面涉及药物组合物,该组合物含有本发明化合物作为活性成分,并与药用,无毒的载体结合。如上文所述,这些组合物可以制成用于肠胃外(包括皮下、肌内和静脉内)给药的剂型,特别是溶液或悬浮液的形式;用于口服或含剂给药,特别是片剂和胶囊;用于肺部和鼻内给药,特别是粉剂、滴鼻剂或气雾剂;以及用于直肠或经皮施用的制剂。
组合物通常以单位剂量形式给药,并可用药学领域已知的任何方法,例如雷明顿药物科学(Remington’s Pharmaceutical Sciences),第17版,Mack Publishing Company,Easton,PA.(1985)中所述的方法制备。肠胃外用药的制剂可含有赋形剂无菌水或盐水、亚烷基二醇如丙二醇、聚亚烷基二醇如聚乙二醇、油如植物油、氢化萘等。用于鼻内给药的制剂可以是固体,并可含有赋形剂如乳糖或或葡聚糖,或是做滴鼻剂使用的水或油的溶液或定量使用的喷雾剂。含剂用药的典型赋形剂包括蔗糖、硬脂酸钙、硬脂酸镁、预凝胶化的淀粉等。
口服用药的组合物可包括一种或多种生理上可接受的载体和/或赋形剂,可以是液体或是固体的形式。片剂或胶囊优选和下述物质一起制备:粘合剂如糖浆、金合欢胶、明胶、山梨糖醇、黄蓍胶或聚乙烯吡咯烷酮;填充剂如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸;润滑剂如硬脂酸镁、滑石、聚乙二醇或二氧化硅;表面活性剂如十二烷基硫酸钠。液体组合物可含有常规的添加剂,例如悬浮剂如山梨糖醇糖浆、甲基纤维素、蔗糖糖浆、明胶、羧甲基纤维素或可食用的脂肪;乳化剂如卵磷脂或金合欢胶;植物油如杏仁油、椰子油、鱼肝油或花生油;防腐剂如丁基化的羟基苯甲醚(BHA)和丁基化的羟基甲苯(BHT)。液体组合物可装入胶囊如明胶胶囊以得到单位剂量形式。
优选的固体口服制剂包括片剂、两片的硬胶囊和软的,有弹性的明胶(SEG)胶囊。SEG胶囊是特别好的,因为它具有与其它两种形式不同的优点(参见Seager,H.,“Soft gelatin capsules:a solutionto many tableting problem”(软明胶胶囊解决多种压片问题的方法),Pharmaceutical Technology(药学技术),9(1985))。使用SEG胶囊的一些优点是:a)SEG胶囊的剂量均匀性是最佳的,因为药物被溶解或被分散于可被准确计量地装入胶囊的液体中;b)被制成SEG胶囊的药物具有良好的生物利用率,因为药物被溶解、增溶或被分散于能和水混溶的或油状液体中,因此在身体中释放时溶液被溶解或乳化,从而生成高表面的药物分散液;和c)在长期储存过程中能防止对氧化敏感的药物降解,因为干燥的软明胶壳体提供了一个防止氧扩散的屏障。
干燥壳体制剂典型地包括大约40%-60%浓度的明胶,大约20%-30%浓度的增塑剂(如甘油、山梨糖醇或丙二醇)和大约30%-40%浓度的水。也可存在其它材料如防腐剂、染料、遮光剂和香料。液体填充材料包括被溶解、增溶或分散的固体药物(加入分散剂如蜂蜡、氢化的蓖麻油或聚乙二醇4000),或在载体或载体如矿物油、植物油、甘油三酯、二醇、多元醇与表面活性剂的混合物中的液体药物。
下面的实施例能使本领域熟练技术人员更清楚的理解和实践本发明,它们仅仅是说明和代表,而不能构成对本发明保护范围的限制。
实验
实施例1
[1R-[1α(2E,4E,7E),3aβ,4α,7aα]]-5-[4-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]八氢-7a-甲基-1H-茚-1-基]-2,4,7-三烯壬二酸二乙酯(V)
在搅拌着的3.08g(10.0mmol)[1R-(1α,3aβ,4α,7aα)]-(1,1-二甲基乙基)二甲基[[八氢-7a-甲基-1-(1-甲基乙烯基)-1H-茚-4-基]氧基]甲硅烷和3.92g(40.0mmol)丙酸乙酯的20ml二氯甲烷溶液中加入40ml(40.0mmol)1.0M的二氯乙基铝的己烷溶液。混合物于室温,氩气中搅拌24小时,用981mg(10mmol)丙酸乙酯和7.5ml(7.50mmol)1.0M的二氯乙基铝的己烷溶液进行处理,再搅拌18小时。将得到的桔红色溶液分批加入200ml乙酸乙酯和100ml 50%盐水的混合物,在嘶嘶声结束后,收集有机相,水相用3×100ml乙酸乙酯再萃取。合并的有机萃取液用2×100ml 50%的盐水洗涤,(Na2SO4)干燥和蒸发,得到5.76g带有红色的胶体,在120g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以10%乙酸乙酯的己烷溶液做洗脱液,每20ml作为一个级分收集。将第21-32份级分合并,蒸发后得到2.18g粗制的产物。用HPLC(15-30μm筛目的硅胶,50cm×50mm柱,流速70ml/min)进一步纯化,以7.5%乙酸乙酯的己烷溶液做洗脱液,得到1.62g(32%)的标题化合物,RT为25分钟,为浅黄色胶体。
[α]25 D+83.50°(EtOH,c=0.98);UV(MeOH)284(ε=28,173),207(ε=16,884)nm;IR(CHCl3)1708,1651,1628cm-1;1H NMR(CDCl3)δ0.006(6H,s),0.80,3H,s),0.88(9H,s),1.16(1H,t,J=7.6Hz),1.28(6H,重叠t,J=7Hz),1.67-1.78,(6H,m),2.16(1H,t,J=9Hz),3.00,(1H,dd,J=6,16,Hz),3.35(1H,dd,J=16,4Hz),4.02(1H,s),4.16(4H,重叠 q,J=7Hz),5.75(1H,d,J=16Hz),5.84(1H,d,J=15Hz),6.17(1H,d,J=11Hz),6.88(1H,dt,J=16,6Hz),7.50(1H,dd,J=11,15,Hz);MS(EI)m/z 504(M+,23).
元素分析,C29H48O5Si
计算值:C,69.00;H,9.58;Si,5.56;
实测值:C,68.94;H,9.69;Si,5.67。
实施例2
[1R-(1α,3αβ,4α,7aα)]-5-[4-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]八氢-7a-甲基-1H-茚-1-基]壬烷二酸二乙酯(VI)
室温,大气压下,将搅拌着的1.009g(2.0mmol)[1R-[1α(2E,4E,7E),3aβ,4α,7aα]]-5-[4-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]八氢-7a-甲基-1H-茚-1-基]-2,4,7-三烯壬二酸二乙酯的50ml乙酸乙酯溶液用200mg 10%的钯-碳氢化,直到停止吸收氢气(在2.5小时内吸收了140ml氢气)。混合物经硅藻土垫过滤,用4×50ml乙酸乙酯洗涤,合并滤液和洗涤液,蒸发得到1.07g无色油。将其在60g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以12%乙酸乙酯的己烷溶液做洗脱液,每20ml作为一个级分收集。将第7-12份级分合并,蒸发后得到964mg(94%)标题化合物,为无色油。 [α]D 25+32.1°(CHCl3,c=1.04);IR(CHCl3)
1726cm-1;1H NMR(CDCl3)δ0.00(3H,s),0.01(3H,s),0.87(9H,s),0.88(3H,s),1.27(6H,t,J=7Hz),1.28-1.90(21H,m),2.25(4H,brt),3.9g(1H,s),4.11(4H,q,J=7Hz);MS(FAB)m/z 511(M++1,100).
元素分析,C29H54O5Si
计算值:C,68.11;H,10.66;Si,5.50;
实测值:C,68.21;H,10.85;Si,5.43。
实施例3
[1R-(1α,3aβ,4α,7aα)]-6-[4-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]八氢-7a-甲基-1H-茚-1-基]-2,10-二甲基-2,10-十一烷二醇(VII)
冰浴冷却下,在搅拌着的868mg(1.7mmol)[1R-(1α,3aβ,4α,7aα)]-5-[4-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]八氢-7a-甲基-1H-茚-1-基]壬烷二酸二乙酯的12ml无水THF溶液中滴加5.0ml(15mmol)3.0M甲基溴化镁的乙醚溶液。混合物于室温搅拌45分钟,冷却至5℃,滴加3.0ml饱和NH4Cl使反应停止。在嘶嘶声结束后,再滴加15ml乙酸乙酯和15ml饱和NH4Cl,继续搅拌20分钟。将混合物倾入100ml乙酸乙酯和50ml饱和NH4Cl。收集有机相,水相用3×60ml乙酸乙酯再萃取。合并的有机萃取液用2×100ml 50%的盐水洗涤,(Na2SO4)干燥和蒸发,得到814mg无色的胶体,将其在100g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以50%乙酸乙酯的己烷溶液做洗脱液,每20ml作为一个级分收集。将第19-20份级分合并,蒸发,高真空干燥(17小时),得到763mg(93%)的标题化合物,为无色泡沫。
[α]D 25+35.8°(EtOH,c=1.02);IR(CHCl3)3608cm-1;1HNMR(CDCl3)δ0.00(6H,s),0.88(9H,s),0.90(3H,s),1.20(12H,s),1.23-1.90(27 H,m),3.99(1H,s);MS(EI)m/z 482(3,M+).
元素分析,C29H58O3Si
计算值:C,72.14;H,12.11;Si,5.82;
实测值:C,72.18;H,11.99;Si,5.69。
实施例4
[1S-(1α,3aβ,4α,7aα)]八氢-1-[5-羟基-1-(4-羟基-4-甲基戊基)-5-甲基己基]-7a-甲基-4H-茚-4-醇(VIII)
在聚四氟乙烯容器中装有搅拌着的700mg(1.45mmol)[1R-(1α,3aβ,4α,7aα)]-6-[4-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]八氢-7a-甲基-1H-茚-1-基]-2,10-二甲基-2,10-十一烷二醇于5ml无水THF和15ml CH3CN混合物中的溶液,向其中滴加3.0ml 30%左右的氟代硅酸水溶液(按照A.S.Pilcher和P.DeShong,J.Org.Chem.,1993,58,5130所述的方法制备),反应混合物于室温,氩气中搅拌1.0小时。然后,以小时为间隔,分批加入4份(每份2.0ml)氟代硅酸溶液,加入试剂的总量11ml,时间是5小时。小心地将反应混合物倾入125ml乙酸乙酯和75ml饱和的碳酸氢钾水溶液的混合物。在嘶嘶声结束后,收集有机相,水相用3×75ml乙酸乙酯再萃取。有机萃取液用125ml 50%的盐水洗涤,(Na2SO4)干燥和蒸发,得到534mg胶体,将其在70g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以70%乙酸乙酯做洗脱液,每20ml作为一个级分收集,将第17-30份级分合并,过滤和蒸发,残余物在高真空中放置4小时,得到458mg(85%)的标题化合物,为无色泡沫。[α]D 25+26.2°(CHCl3,c=0.76);IR(CHCl3)3608cm-1;1H NMR(CDCl3)δ0.93(3H,s),1.21(12H,s),1.24-1.60(24H,m),1.79-1.95(4H,m),4.07(1H,s);MS(FAB)m/z369(M++H).
实施例5
[1S-(1α,3aβ,7aα)]八氢-1-[5-羟基-1-(4-羟基-4-甲基戊基)-5-甲基己基]-7a-甲基-4H-茚-4-酮(IX)
在搅拌着的400mg(1.08mmol)[1S-(1α,3aβ,4α,7aα)]八氢-1-[5-羟基-1-(4-羟基-4-甲基戊基)-5-甲基己基]-7a-甲基-4H-茚-4-醇的8.0ml二氯甲烷溶液中加入1.30g(3.45mmol)重铬酸吡啶鎓,反应混合物于室温搅拌4.75小时。用20ml二丙醚稀释,再搅拌15分钟,用硅藻土塞过滤。硅藻土用4×40ml二丙醚洗涤,蒸发合并的滤液和洗液,得到405mg浅黄色胶体,将其在70g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以75%乙酸乙酯的己烷溶液做洗脱液,每20ml作为一个级分收集,将第17-30份级分合并,蒸发后得到无色胶体,残余物在高真空中放置4.5小时,得到372mg(94%)的标题化合物,为无色胶体。
[α]D 25 0.45°(EtOH,c=0.92);IR(CHCl3)3608,1706cm-1;1H NMR(CDCl3)δ0.63(3H,s),1.22(12H,s),1.30-2.10(22H,m),2.20-2.28(2H,m),2.45(1H,dd,J=7.6,11Hz;MSm/z 348(M+-18).
实施例6
[1S-(1α,3aβ,7aα)八氢-7a-甲基-1-[5-甲基-1-[4-甲基-4-[(三甲基甲硅烷基)氧基]戊基]-5-[(三甲基甲硅烷基)氧基]己基]-4H-茚-4-酮(IIa)
在搅拌着的366.6mg(1.0mmol)[1S-(1α,3aβ,7aα)]八氢-1-[5-羟基-1-(4-羟基-4-甲基戊基)-5-甲基己基]-7a-甲基-4H-茚-4-酮的10.0ml二氯甲烷溶液中加入1.25ml(8.5mmol)1-(三甲基甲硅烷基)咪唑,反应混合物于室温,氩气中搅拌4.25小时。用7.0ml水稀释,再搅拌15分钟,将其倾入75ml乙酸乙酯和50ml 50%的盐水混合物。收集有机相,水相用3×50ml乙酸乙酯再萃取,合并的有机相用3×75ml 50%盐水洗涤,(Na2SO4)干燥和蒸发,得到无色油,将其在65g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以20%乙酸乙酯的己烷溶液做洗脱液,每20ml作为一个级分收集,将第5-7份级分合并,浓缩至大约5ml,通过0.45μm的过滤器(Millex-HV)过滤,蒸发后得到无色油,残余物在高真空中放置18小时,得到469mg(91%)的标题化合物。
[α]D 25-3.21°(CHCl3,c=0.87);IP(CHCl3);1706cm-1;1H NMR(CDCl3)δ0.01(18H,s),0.63(3H,s),1.20(6H,s),1.21(6H,s),1.26-1.49(14H,m),1.50-2.10(8H,m),2.21-2.31(2H,m),2.46(1H,dd,J=12,11Hz);MS(EI)m/z495(M+-15).
元素分析,C29H58O3Si2
计算值:C,68.17;H,11.44;Si,10.99;
实测值:C,68.19;H,11.41;Si,11.07。
实施例7
(1α,3β,5Z,7E)-21-(3-羟基-3-甲基丁基)-9,10-断胆甾-5,7,10,(19)-三烯-1,3,25-三醇(Ia)
在搅拌着的466mg(0.8mmol)试剂[3S-(1Z,3α,5β)]-[2-[3,5-双[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-2-亚甲基-亚环己基]乙基]二苯基氧化膦的4.0ml无水THF冷(-78℃)溶液中加入0.5ml 1.6M正丁基锂己烷溶液。将得到的深红色溶液在-78℃搅拌7分钟,用204mg(0.40mmol)[1S-(1α,3aβ,7aα)八氢-7a-甲基-1-[5-甲基-1-[4-甲基-4-[(三甲基甲硅烷基)氧基]戊基]-5-[(三甲基甲硅烷基)氧基]己基]-4H-茚-4-酮的3.0ml无水THF溶液处理,在-78℃搅拌3小时。使混合物温热至室温,加入5ml 1∶1的2N罗谢尔(Rochells)盐溶液和2N碳酸氢钾溶液的混合物使反应停止,再搅拌15分钟,将其倾入80ml乙酸乙酯和50ml 1∶1的2N Rochells盐溶液和2N碳酸氢钾溶液的混合物。收集有机相,水相用3×60ml乙酸乙酯再萃取,合并的有机相用3×75ml 50%盐水洗涤,(Na2SO4)干燥和蒸发,得到1.29g胶体。将其在60g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以8%乙酸乙酯的己烷溶液做洗脱液,每20ml作为一个级分收集,将第5和6份级分合并,蒸发得到208mg无色胶体。将后者溶于4.0ml THF,用4.0ml 1.0M四丁基氟化铵的THF溶液处理,溶液在氩气中搅拌17小时。用5.0ml水稀释,再搅拌15分钟,将其倾入80ml 80%乙酸乙酯的己烷溶液和50ml水的混合物。收集有机相,水相用4×80ml 80%乙酸乙酯的己烷溶液再萃取,合并的有机相用4×80ml 50%盐水洗涤,(Na2SO4)干燥和蒸发,得到139mg半固体,将其在60g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以6%2-丙醇的乙酸乙酯溶液做洗脱液,每20ml作为一个级分收集,将第17-25份级分合并,蒸发得到108mg无色泡沫。将该产物进一步用HPLC(15-30μm筛目的硅胶,50cm×50mm柱,流速70ml/min)进一步纯化,以3% 2-丙醇的乙酸乙酯溶液做洗脱液,收集RT为35分钟的洗出物,蒸发溶剂后得到无色半固体。将其溶于15ml无水甲酸甲酯,通过0.45μm的过滤器(Millex-HV)过滤,浓缩,残余物在高真空中放置4小时,得到82mg标题化合物,为无色的无定形固体。 [α]D 25+13.8°(EtOH,c=0.5);UV(MeOH)263(ε=17,545),212(ε=14,702)nm;IR(CHCl3)3608cm-1;1HNMR(CDCl3)δ0.53(3H,s),1.21(12H,s),1.26-2.17(32H,m),2.30(1H,dd,J=10,7Hz),2.59(1H,d,J=11Hz),2.83(1H,d,J=13Hz),5.00(1H,s),5.33(1H,s),6.02(1H,d,J=11Hz),6.37(1H,d,J=11Hz);HRMS(EI):C32H54O2:计算值:m/z 502.4022,实测值:m/z 502.4024。
实施例8
21-(3-羟基-3-甲基丁基)-1α-氟-25羟基维生素D3
在搅拌着的320mg(0.67mmol)试剂[S-反式-1-氟-5-[[二甲基-(1,1-二甲基乙基)甲硅烷基]氧基-2-亚甲基-3-[(二苯基膦基)亚乙基]环己烷的4.0ml无水THF冷(-78℃)溶液中,加入0.42ml(0.67mmol)1.6M正丁基锂己烷溶液。得到的深红色溶液在-78℃搅拌7分钟,用118mg(0.23mmol)[1R-(1α,3aβ,7aα)八氢-7a-甲基-1-[5-甲基-1-[4-甲基-4-[(三甲基甲硅烷基)氧基]戊基]-5-[(三甲基甲硅烷基)氧基]己基]-4H-茚-4-酮的2.0ml无水THF溶液处理,在-78℃搅拌4.5小时。使混合物温热至室温,再搅拌20分钟,加入5ml 1∶1的1N Rochelle盐溶液和1N碳酸氢钾溶液的混合物使反应停止。15分钟后,将反应混合物倾入50ml 1∶1的IN Rochells盐溶液和1N碳酸氢钾溶液的混合物。分离有机相,水相用3×40ml乙酸乙酯再萃取,合并的有机萃取物用100ml 10%盐水洗涤,(Na2SO4)干燥和蒸发,得到426mg无色胶体。将其在40g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以5%乙酸乙酯的己烷溶液做洗脱液,每15ml作为一个级分收集,将第5-7份级分合并,蒸发得到144mg无色胶体。将后者溶于3.0ml THF,用2.0ml 1.0M四正丁基氟化铵的THF溶液处理,溶液于室温在氩气中搅拌17小时。用5.0ml水稀释,再搅拌10分钟,将其倾入50ml乙酸乙酯和40ml水的混合物。分离有机相,水相用3×50ml乙酸乙酯再萃取,合并的有机相用5×100ml水洗涤,(Na2SO4)干燥和蒸发,得到78mg胶体,将其在40g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以90%乙酸乙酯的己烷溶液做洗脱液,每15ml作为一个级分收集,将第14-20份级分合并,蒸发得到57mg无色的半固体。将该产物溶于20ml无水的甲酸甲酯,通过0.4μm的过滤器过滤,浓缩滤液,在0℃放置1.0小时,过滤收集结晶,得到42mg标题化合物。mp 96-98℃;[α]+38.6°(MeOH,c=0.5);UV(MeOH)270(ε=14,136),242(ε=14,350),210(ε=13,564)nm;IR(CHCl3)3610cm-1;1H NMR(CDCl3)δ0.54(3H,s),1.21(12H,s),1.22-1.60(21H,m),1.69(2H,m),1.80(1H,m),2.0(3H,m),2.17(1H,m),2.31(1H,m),2.62(1H,d,J=12Hz),2.82(1H,d,J=12Hz),4.22(1H,brs),5.07(1H,brt),5.10(1H,s),5.19(1H,brt),5.39(1H,s),6.02(1H,d,J=11Hz),6.40(1H,d,J=11Hz);MS(FAB)m/z 504.5(M+,60).
实施例9
21-(3-羟基-3-甲基丁基)-1,25-二羟基-19-降维生素D3
在搅拌着的571mg(1.0mmol)试剂[3R-(3α,5β,Z)-3,5-双[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]亚环己基]乙基]-二苯膦氧化物的6.0ml无水THF冷(-78℃)溶液中,加入0.65ml(1.04mmol)1.6M正丁基锂己烷溶液。得到的深红色溶液在-78℃搅拌10分钟,用204.4mg(0.4mmol)[1R-(1α,3aβ,7aα)八氢-7a-甲基-1-[5-甲基-1-[4-甲基-4-[(三甲基甲硅烷基)氧基]戊基]-5-[(三甲基甲硅烷基)氧基]己基]-4H-茚-4-酮的2.5ml无水THF溶液处理,在-78℃搅拌3.0小时。使混合物温热至室温,再搅拌15分钟,加入15ml 1∶1的1N Rochelle盐溶液和1N碳酸氢钾溶液的混合物使反应停止。10分钟后,将反应混合物倾入70ml乙酸乙酯与40ml 1∶1的1N Rochelle盐溶液和1N碳酸氢钾溶液的混合物组成的混合物。分离有机相,水相用3×70ml乙酸乙酯再萃取,合并的有机萃取物用100ml 10%盐水洗涤,(Na2SO4)干燥和蒸发,得到760mg无色胶体。将其在60g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以5%乙酸乙酯的己烷溶液做洗脱液,每15ml作为一个级分收集,将第5-10份级分合并,蒸发得到304mg无色胶体。后者溶于4.0ml THF,用5.0ml 1.0M四正丁基氟化铵的THF溶液处理,溶液于室温在氩气中搅拌42小时。用15ml水稀释,再搅拌15分钟,将其倾入75ml乙酸乙酯和50ml 10%盐水的混合物。分离有机相,水相用3×70ml乙酸乙酯再萃取,合并的有机相用5×100ml水洗涤,(Na2SO4)干燥和蒸发,得到186mg半固体,将其在50g硅胶(40-65μm筛目,3.5cm直径的柱)上用快速色谱纯化,以7.5%2-丙醇的乙酸乙酯溶液做洗脱液,每15ml作为一个级分收集,将第11-29份级分合并并蒸发。残余物溶于20ml无水的甲酸甲酯,溶液通过0.4μm的过滤器过滤,蒸发滤液,得到154mg标题化合物,为无色固体。 [a]+50.93°(MeOH,c=0.32);1H NMR(CDCl3)δ0.54(3H,s),1.21(12H,s),1.2-2.0(27H,m),2.20(2H,m)2.48(1H,d,J=12Hz),2.25(2H,m),2.82(1H,s),4.06(1H,br s)4.10(1H,br s),5.85(1H,d,J=12Hz),6.30(1H,d,J=12Hz);MS(FAB)m/z 490.4(M+,30).
实施例10
在大鼠肾功能不全的模型中维生素D3类似物对继发性甲状旁腺功能亢进的作用
本发明的维生素D3类似物对甲状旁腺激素的抑制活性用由于肾衰竭而患有继发性甲状旁腺功能亢进的大鼠进行实验,所述的肾衰竭是由于7/8肾切除诱导的大鼠肾衰竭模型(Kidney International,M.Fukugawa等人,39:874-881(1991))。
试验材料:
式Ia化合物
1,25-二羟基维生素D3(对照)
载体-Miglyol 812
对雌性Sprague Dawley大鼠进行麻醉,切除右肾和2-3支左肾动脉以达到7/8的肾切除。给予高磷饮食(0.6%的钙和0.8%的磷)。差不多在手术后的3-6周,大鼠开始水肿,对血浆的PHT水平进行筛选,选择PHT水平为100-500pg/ml的大鼠进行研究。
将大鼠分成五组,分别按照下表进行处理。
组别 | 大鼠数量 | 处理 |
1 | 6 | 式Ia,10μg/kg/天,po |
2 | 6 | 式Ia,1μg/kg/天,po |
3 | 6 | 式Ia,0.1μg/kg/天,po |
4 | 5 | 1,25(OH)2 vit.D3,0.2μg/kg/天,po |
5 | 5 | 载体,po |
预取血(T=0),每天以管饲法口服式Ia化合物(剂量为10,1或0.1μg/kg/天)、载体对照或1,25-二羟基维生素D3阳性对照,共7天。将化合物预先溶于乙醇,用载体(Miglyol 812)稀释,接着蒸发乙醇。
在给药的最后一天,再取血(T=1)并处死动物。用NicholsInstitute Diagnostic Kit #40-2240进行血浆中的PTH试验。按照Sigma Diagnostic Kit #587,用邻甲酚酞进行血浆钙的试验。按照SigmaDiagnostic Kit#1600-320,用钼酸铵进行血浆肌酸酐的试验。
组别 | PHT pg/ml,T=1-T=0 | 最后的钙水平(mg/ml) |
式Ia(10μg/kg) | -132 | 11.97 |
式Ia(1μg/kg) | -124 | 10.35 |
式Ia(0.1μg/kg) | 112 | 10.20 |
1,25(OH)2 vit.D3(0.1μg/kg) | -66 | 10.82 |
载体 | 156 | 9.69 |
结果表明,在抑制甲状旁腺激素水平提高而又不会引起钙水平提高上式Ia化合物比1,25(OH)2 vit.D3更有效。
实施例11
大鼠的骨合成代谢
将3个月大的大鼠进行卵巢切除术(Ovx),并从卵巢切除后3周开始每天一次口服施用1,25-二羟基维生素D3(表中的vit.)或一种本发明化合物,一直用药到卵巢切除后6周时将大鼠处死。对照组是假的(大鼠不进行卵巢切除)和Ovx,只给予载体。在手术后4周和6周时收集2次血样和尿样,测定血钙和尿钙。在手术后6周处死时测定最后的股骨钙。
右股骨的骨矿物密度用High Resolution Software Package用QDR-1000W骨密度仪Bone Densito meterTM(Hologic,Waltham,MA)测定。以仰卧的位置将动物放在扫描板上进行扫描,这样就能使右腿垂直于躯干,胫骨垂直于股骨。
在治疗有效量内,就骨骼增加生长而又不引起高钙尿、肾毒或高钙血方面,本发明化合物比1,25-二羟基维生素D3更有效。
实施例12
大鼠的自动免疫模型
维生素D3类似物治疗自动免疫疾病的能力用大鼠免疫试验(脑脊髓炎EAE)模型进行体内试验说明。
通过爪垫注射,使雌性Lewis大鼠用豚鼠脊柱索匀浆和改进的Freund弗氏完全佐剂(在Freund的不完全佐剂中含4mg/ml M.结核)的1∶1混合物免疫。从进行免疫后的第5天开始,经皮下或经口服给药化合物或载体12天。观察动物的一系列症状:EAE-尾张力丧失、下肢发软、蹒跚步态、麻痹等。
在减少大鼠模型的EAE症状方面,式I化合物是有效的。
实施例13
用MCF-7乳癌细胞进行细胞增殖试验
MCF-7细胞是人体乳癌细胞,对雌激素受体反应阳性。维生素D3类似物对乳癌的抑制活性由在培养中对MCF-7细胞增生的抑制进行评价。
将MCF-7细胞以每孔5000细胞/孔放于96孔板上,于37C,在5%CO2/95%空气中,和在含有10%胎牛血清、700nM胰岛素、2mM谷氨酰胺、0.1mM MEM非必需氨基酸和1mM丙酮酸钠的Dulbecco’sModified Eagle培养基中温育。在绝对乙醇中以10mM的浓度制成维生素D3类似物的储备液,并储存在-20℃,氩气中。在铺板后1天,再在MCF-7中加入对照培养基或含有各种不同浓度的维生素D3类似物的培养基。培养7天后,按照F.Denizot和R.Lang,J.ImmunologicalMethods,Vol.89:271-277(1986)所述的方法,由染料MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物)的还原检测每孔中的MCF-7细胞数。将MTT加入每孔中,最后浓度1mg/ml,使细胞孵化3小时,之后,用95%乙醇萃取还原的MTT,在波长570nm时测定光密度。
对各种维生素D3类似物,以其在波长570nm时相对于使用浓度的光密度图测定出IC50值。IC50值定义为在波长570nm相对于最大的吸收值减少一半时维生素D3类似物的浓度。
维生素D3类似物 IC50,nM
1,25-二羟基维生素D3 40
21-(3-羟基-3-甲基)丁基-1,25-二羟基维生素D3 0.8
上述试验表明,在抑制MCF-7乳癌细胞生长方面,21-(3-羟基-3-甲基)丁基-1,25-二羟基维生素D3比1,25-二羟基维生素D3的效力大差不多50倍。
实施例14
用ZR-75乳癌细胞进行细胞增殖试验ZR-75细胞是人体乳癌细胞,对雌激素受体反应阳性。维生素D3类似物对乳癌的抑制活性由在培养中对ZR-75细胞增生的抑制进行评价。
将ZR-75细胞以每孔12500细胞/孔放于24孔板上,于37℃,在5%CO2/95%空气中,和在含有10%胎牛血清和2mM谷氨酰胺的RPMI培养基中温育。在绝对乙醇中以10mM的浓度制成维生素D3类似物的储备液,并储存在-20℃,氩气中。在铺板后1天,再在ZR-75中加入对照培养基或含有各种不同浓度维生素D3类似物的培养基。培养10天后,按照F.Denizot和R.Lang,J.Immunological Methods,Vol.89:271-277(1986)所述的方法,由染料MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物)的还原检测每孔中的ZR-75细胞数。将MTT加入每孔中,最后浓度为1mg/ml,把细胞培养3小时,之后,用95%乙醇萃取还原的MTT,在波长570nm时测定光密度。
对各种维生素D3类似物,以其在波长570nm时相对于使用浓度的光密度图测定出IC50值。IC50值定义为在波长570nm相对于最大的吸收值减少一半时维生素D3类似物的浓度。
维生素D3类似物 IC50,nM
1,25-二羟基维生素D3 13
21-(3-羟基-3-甲基)丁基-1,25-二羟基维生素D3 0.3
上述试验表明,在抑制ZR-75乳癌细胞生长方面,21-(3-羟基-3-甲基)丁基-1,25-二羟基维生素D3比1,25-二羟基维生素D3的效力大差不多40倍。
实施例15
口服剂量形式软明胶胶囊
口服制剂的胶囊在氮气中,于淡黄色光线下配制,将0.01-25.0mg一种本发明化合物置于150mg分级后的椰子油中,加入0.015mg丁基化的羟基甲苯(BHT)和0.015mg丁基化的羟基苯甲醚(BHA),将它们装入软明胶胶囊。
为了更加清楚和容易理解,前述发明已经通过说明和实施例的方式进行了比较详细的描述。很显然,本领域普通技术人员可在本发明要求保护的范围内进行变化和改进,因此可以理解的是,上述说明书仅仅是为了进行说明,而不是限制。本发明的范围参考所附的权利要求书来决定,同时提出了与此权利要求书等同的整个范围。
在此申请中引用的专利、专利申请和专利公开全部引用作为参考,通常来说每个单个的专利、专利申请或专利公开是单独指明的。
Claims (14)
2.权利要求1的化合物,其中A是单键。
3.权利要求1的化合物,其中Y是氟。
4.权利要求1的化合物,其中Y是羟基。
5.权利要求1的化合物,其中B1和B2是双键。
6.权利要求1的化合物,其中B1和B2是三键。
7.权利要求1的化合物,其R1-R4是C1-C4氟代烷基。
8.权利要求1定义的式I化合物的前药,该前药为甲酸酯、乙酸酯、苯甲酸酯、氨基甲酸酯或者为羟基官能团的醚。
9.含有权利要求1-8任意一项化合物和治疗上惰性的载体的药物。
12.权利要求1-8任意一项的化合物在制备治疗原发和继发性甲状旁腺功能亢进、肾病性骨营养不良和自动免疫疾病的药物中的应用。
13.权利要求1-8任意一项的化合物在制备治疗多发性硬化和狼疮的药物中的应用。
14.权利要求1-8任意一项的化合物在制备治疗和预防肿瘤形成性疾病的药物中的应用。
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US4466197P | 1997-04-28 | 1997-04-28 | |
US60/044,661 | 1997-04-28 | ||
US7214098P | 1998-01-22 | 1998-01-22 | |
US60/072,140 | 1998-01-22 |
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CN1253557A CN1253557A (zh) | 2000-05-17 |
CN1189465C true CN1189465C (zh) | 2005-02-16 |
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CNB988045818A Expired - Fee Related CN1189465C (zh) | 1997-04-28 | 1998-04-22 | 具有双c-20侧链的维生素d3类似物 |
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EP (1) | EP0980354B1 (zh) |
JP (1) | JP3479310B2 (zh) |
KR (1) | KR100351490B1 (zh) |
CN (1) | CN1189465C (zh) |
AT (1) | ATE219483T1 (zh) |
AU (1) | AU732331B2 (zh) |
BR (1) | BR9809313B1 (zh) |
CA (1) | CA2287881C (zh) |
DE (1) | DE69806152T2 (zh) |
DK (1) | DK0980354T3 (zh) |
ES (1) | ES2178217T3 (zh) |
HK (1) | HK1026705A1 (zh) |
MA (1) | MA26485A1 (zh) |
PT (1) | PT980354E (zh) |
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WO (1) | WO1998049138A2 (zh) |
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US6479474B2 (en) * | 1999-07-08 | 2002-11-12 | Wisconsin Alumni Research Foundation | Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis |
EP1622455A4 (en) * | 2003-04-30 | 2009-12-16 | Bioxell Spa | GEMINI VITAMIN D3 COMPOUNDS AND METHOD FOR THEIR USE |
AU2004203436A1 (en) | 2003-09-24 | 2005-04-14 | Bioxell Spa | Compound and use in treatment |
WO2005074389A2 (ja) * | 2004-02-03 | 2005-08-18 | Chugai Pharmaceutical Co Ltd | ビタミンd化合物及びそれらの合成中間体の合成方法 |
WO2005082375A2 (en) | 2004-03-01 | 2005-09-09 | Bioxell Spa | Treatment of interstitial cystitis with vitamin d compounds |
JP2008538114A (ja) * | 2005-03-23 | 2008-10-09 | ビオクセル エッセ ピ ア | 20−アルキル、ジェミニビタミンd3化合物及びその使用方法 |
CN114276284A (zh) * | 2021-12-30 | 2022-04-05 | 正大制药(青岛)有限公司 | 一种氟骨化醇的制备方法 |
CN114957068A (zh) * | 2022-04-19 | 2022-08-30 | 正大制药(青岛)有限公司 | 一种氟骨化醇20s异构体的制备方法 |
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US5145846A (en) * | 1988-01-20 | 1992-09-08 | Hoffmann-La Roche Inc. | Vitamin D3 analogs |
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- 1998-04-22 DK DK98924177T patent/DK0980354T3/da active
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Publication number | Publication date |
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JP2000510875A (ja) | 2000-08-22 |
PT980354E (pt) | 2002-10-31 |
AU732331B2 (en) | 2001-04-12 |
BR9809313A (pt) | 2000-07-04 |
TR199902639T2 (xx) | 2000-07-21 |
HK1026705A1 (en) | 2000-12-22 |
CA2287881C (en) | 2008-09-09 |
KR20010020343A (ko) | 2001-03-15 |
EP0980354B1 (en) | 2002-06-19 |
CA2287881A1 (en) | 1998-11-05 |
ATE219483T1 (de) | 2002-07-15 |
EP0980354A2 (en) | 2000-02-23 |
ES2178217T3 (es) | 2002-12-16 |
DE69806152T2 (de) | 2003-02-06 |
CN1253557A (zh) | 2000-05-17 |
MA26485A1 (fr) | 2004-12-20 |
BR9809313B1 (pt) | 2010-11-16 |
WO1998049138A2 (en) | 1998-11-05 |
DE69806152D1 (de) | 2002-07-25 |
KR100351490B1 (ko) | 2002-09-05 |
DK0980354T3 (da) | 2002-10-14 |
WO1998049138A3 (en) | 1999-01-28 |
AU7646898A (en) | 1998-11-24 |
JP3479310B2 (ja) | 2003-12-15 |
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