CN1129577C - 维生素d3衍生物 - Google Patents
维生素d3衍生物 Download PDFInfo
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- CN1129577C CN1129577C CN97180993A CN97180993A CN1129577C CN 1129577 C CN1129577 C CN 1129577C CN 97180993 A CN97180993 A CN 97180993A CN 97180993 A CN97180993 A CN 97180993A CN 1129577 C CN1129577 C CN 1129577C
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- tetraene
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Abstract
具有式(I)的化合物,其中Q为C1-C6亚烃基二基;Y为单键,羰基或者为亚甲基,亚乙基,-CH(OH)-,-O-(C6H4)-(邻,间,对)或-S-(C6H4)-(邻,间,对)二基;R1和R2可以相同也可以不同,代表氢或C1-C6烃基;或R1和R2与带有基团Z的碳原子(式I中用星号标出)一起构成C3-C6碳环;且Z为氢或羟基;条件是当Q为亚乙基,Y为亚甲基,R1和R2代表甲基或三氟甲基,且Z为羟基时,或者当Q为亚乙基,Y为羰基或-CH(OH)-,R1和R2代表甲基,且Z为羟基时,C-20的构型不能为E。化合物显示出抗炎和免疫调节作用以及较强的诱导一些细胞分化并抑制其不需要的增殖的活性。
Description
本发明涉及迄今为止尚未知晓的一类化合物,它们在诱导一些细胞(包括癌细胞和皮肤细胞)的分化以及抑制其不期望的增殖方面具有强的活性,这类化合物还具有抗炎和免疫调节作用。本发明还涉及含有这些化合物的药物制剂,这类制剂的剂量单位,并涉及它们在治疗和预防甲状旁腺机能亢进(尤其是与肾衰有关的次级甲状旁腺机能亢进),以异常的细胞分化和/或增殖为特征的疾病,例如癌症,白血病,骨髓纤维变性,以及牛皮癣,一系列疾病状态,包括糖尿病,高血压,痤疮,脱发,皮肤老化,AIDS,神经变性失调,例如Alzheimer’s疾病,宿主对移植物的反应,移植排斥,炎症疾病,例如风湿性关节炎和哮喘方面的用途,以及在预防和/或治疗类固醇诱导的皮肤萎缩和促进骨生成并治疗骨质疏松方面的用途。
由通式I表示的本发明化合物,其中式Q为C1-C6亚烃基二基;Y为单键,羰基或为亚甲基,亚乙基,-CH(OH)-,-O-(C6H4)-(邻,间,对)或-S-(C6H4)-(邻,间,对)二基;R1和R2可以相同也可以不同,代表氢或C1-C6烃基;或R1和R2与带有基团Z的碳原子(式I中用星号标出)一起构成C3-C6碳环;且Z为氢或羟基;条件是当Q为亚乙基,Y为亚甲基,R1和R2代表甲基或三氟甲基,且Z为羟基时,或者当Q为亚乙基,Y为羰基或-CH(OH)-,R1和R2代表甲基,且Z为羟基时,C-20的构型不能为R。
在本发明的内容中,烃基基团(亚烃基二基)的是指从直链、支链或环状的饱和或不饱和的烃类上去掉1(2)氢原子后的残基。
Q的实施例有(但不限于此)亚甲基,亚乙基,三,四和五亚甲基,-C=C-,-CH=CH-CH=CH-,-CH=CH-C≡C-,-CH=CH-CH-,-CH2-(C6H4)-(邻,间,对),-C≡C-,-C≡C-CH2-,-CH(R)-(CH2)2-,-CH(R)-CH=CH-,以及CH(R)-C≡C-,其中R为羟基,C1-C4烷氧基或C1-C4烷基。其中Q为-(CH2)n-,n为1-4的整数,或代表带有一或两个(后一种情况属共轭)双键或三键的直链碳链,或代表CH(R)-C≡C-(R的定义同上)的式I化合物是特别优选的。
当分别考虑时,R1和R2的实施例包括(但不限于)氢,甲基,乙基,乙烯基,正、异和环丙基以及三氟甲基。
当一起考虑时,R1和R2的实施例包括二、三、四和五亚甲基。
本发明化合物包含一种以上的立体异构体形式(例如C-20的
R或
S构型;当基团Q中存在双键时的
E或
Z构型)。本发明包含所有这些立体异构体的纯品以及其混合物。
另外,其中带有一或多个以掩蔽形式存在且其在体内能转化为羟基基团的式I前药也包括在本发明范围内。
式I中Z为羟基的化合物也可作为前药,因为这些化合物在体外是相对不具活性的的,但它们在给予患者后可以通过酶促羟基化反应转化为活性的式I化合物。
已有显示,1α,25-二羟基维生素D3(1,25-(OH)2D3)影响白细胞介素(interleukins)的作用和/或生成(Muller,K.等人,免疫学通讯,
17,361-366(,1988))。这一结果表明,该化合物在治疗以免疫系统失调为特征的疾病方面具有潜在的用途,例如自身免疫,AIDS,宿主对移植物的反应,移植排斥或其它以异常白细胞介素-1生成为特征的疾病,象风湿性关节炎和哮喘类的炎症疾病。
文献中已发现1,25-(OH)2D3可以促进细胞分化并抑制过度的细胞增殖(Abe,E.等人,美国国家科学院院报,
78,4990-4994(1981)),这一结果表明该化合物可以用来治疗以异常细胞增殖和/或细胞分化为特征的疾病,例如白血病,骨髓纤维变性以及牛皮癣。
另外还有人建议用1,25-(OH)2D3或其前药1α-OH-D3来治疗高血压(Lind,L.等人,斯堪的纳维亚药物学院,
222,423-427(1987))和糖尿病(Inomata,S.等人,Bone Mineral.,
1,187-192(1986))。有关1,25-(OH)2D3的另一个适应症是基于最近观察到的遗传维生素D耐性与脱发之间的联系:用1,25-(OH)2D3可以促进头发的生长(Editorial,Lancet,March 4,p.478(1989))。另外局部应用1,25-(OH)2D3可以减小雄性Syrian仓鼠耳中皮脂腺的体积大小,这一结果表明该化合物可以用来治疗痤疮(Malloy V.L.等人,TheTricontinental Meeting for investigative Dermatology,华盛顿,(1989))。
然而,这些适应症的治疗可能性被众所周知的1,25-(OH)2D3对钙代谢较强的影响作用所强烈限制;升高的血钙浓度将迅速引起高血压,因此,该化合物及其一系列潜在的合成类似物用来作为治疗诸如牛皮癣,白血病或作为治疗需要以较高剂量持续给药的免疫疾病的药物并不是十分满意。
最近对一系列维生素D类似物进行了描述,相对于其在体内对钙代谢的影响(可从血清钙浓度增高和/或尿钙分泌增加测得)而言,这些类似物在体外对细胞分化诱导/细胞增殖抑制显示出某种程度的选择性。因此其对剂量限制不严格并可以安全地给药。在这种选择性的基础上,首先开发出了这类化合物中的钙泊三醇(INN)或钙泊三烯(calcipotriene)(USAN),并且,现已广泛地认识到它们可安全且有效地用作局部治疗牛皮癣的药物。
对另一个基于这一基础而选择的类似物(EB1089)的研究支持了这样一个观点:系统给予维生素D类似物可以在亚毒性剂量下抑制体内乳腺癌细胞的分化(Colston K.W.等人,生化药理学,
44,2273-2280(1992)以及Mathiasen,I.S.等人,甾类生化、分子生物学杂志Molec.Biol.,
46,365-371(1993))。
文献(Binderup,L.,生化药理学,
43,1885-1892(1992))综述了维生素D类似物的免疫抑制活性。因此,对于体外T-淋巴细胞的活化作用来说,一系列20-表-维生素D类似物被鉴定为是强的抑制剂(Binderup,L.等人,生化药理学,
42,1569-1575(1991))。系统地给予实验动物模型这一类似物中的两个化合物MC1288和KH1060,它们显示出体内免疫抑制活性。与低剂量的环孢菌素A(cyciosporin A)联合给药可以观察到加合或协同的作用。单独或与环孢菌素A联合使用KH1060也显示出可以防止糖尿病NOD小鼠上移植物小岛的自身免疫破坏(Bouillon R.等人,维生素D,一种多能甾体激素:结构研究,分子内分泌学和临床应用;Norman,A.W.,BouillonR.,Thomasset,M.,Eds.;de Gruyter,berlin,1994,pp.551-552)。MC1288可以延长大鼠心脏和小肠移植物的存活时间(Johnsson,C.等人,维生素D,一种多能甾体激素:结构研究,分子内分泌学和临床应用;Norman,A.W.,Bouillon R.,Thomasset,M.,Eds.;de Gruyter,Berlin,1994,pp.549-550)。然而在所有这些研究中,可以产生显著免疫抑制的类似物的剂量也可以诱导血清钙水平的提高,因此,对寻找新的带有可接受的延缓治疗活性与最小毒性适当结合的类似物有持续的需求。
本发明提供了迄今为止尚未公开的带有强免疫抑制和细胞增殖抑制活性的16-脱氢-1α,25-二羟基维生素D3类似物。式I化合物是以在五员D环中存在16,17-双键为特征的,它们在C-20上的绝对构型为
R或者
S。
D环中存在16,17-双键的维生素D类似物并非新化合物。例如Hoffmann-La Roche Inc.在美国专利5,087,619/1992和5,145,846/1992中公开了25-羟基-和1α,25-二羟基-16-烯-维生素D3,它们的23-烯和23-炔类似物以及相应的26,26,26,27,27,27-六氟衍生物的合成和用途。Uskokovic,M R等人描述了1,25-二羟基维生素D3-16-烯类似物的合成和生物活性(维生素D:Gene Regulation,结构-功能分析和临床应用;Norman,A.W.,Bouillon R.,Thomasset,M.,Eds.;de Gruyter,Berlin,1991,pp.139-145)。Hoffmann-LaRoche A.G.在欧洲专利申请0580968/1993中公开了了25-羟基-和1α,25-二羟基-以及1α-氟-25-羟基-16-烯-23-炔-维生素D3以及它们相应的19-去甲衍生物的26,26,26,27,27,27六氟类似物合成和用途。Mclane,J.A.等人描述了1,25-二羟基-16-烯-维生素D3(美国专利5,401,733/1995)稳定和活性的代谢。然而应该注意到的是,这些和其它先有技术的16-脱氢-维生素D3化合物均是以C-20甲基的天然维生素D构型存在为特征的。进一步地,作为其余的侧链(C-20上的其它取代基),它们均具有天然维生素D3侧链的脂肪六碳骨架结构。最后,这些化合物任意地含有23,24-双键或三键。
本发明化合物在C-20侧链的骨架上不同于先有技术的16-脱氢维生素D3类似物,其不限于脂肪或六碳环,并且任意双键或三键位置可以不局限在23和24碳原子之间的。另外,C-20上的构型即可以为
R(天然维生素D3的构型)也可以为
S。
为了证明式I化合物的有效性,表A中的信息用“HaCaT,rel.”,“MLR,rel.”,以及“Calc.,rel.”来表示;下面将解释它们的含义。
一项有用的评价受试化合物抗皮肤细胞增殖活性(例如抗牛皮癣作用)速度的分析即是采用HaCaT(一种自发无限增殖的非致瘤人类皮肤角质化细胞系(Mork Hansen,C.等人,J.Invest.Dermatol.1,44-48(1996))进行的体外分析,用以测定3H-胸腺嘧啶的摄取。
一项用来评价受试化合物免疫抑制活性速度的体外实验是混合淋巴细胞反应分析,“MIR”,指测定小鼠脾淋巴细胞的同种异体刺激:用与7.5×106/ml细胞(得自CB6F1小鼠(诱导者))共培养的5×106/ml细胞(得自BALB/C小鼠(反应者))对得自BALB/C和CB6F1小鼠脾脏的淋巴细胞进行刺激。将混合的淋巴细胞培养物与受试化合物一起培养72小时。通过在DNA上引入3H-胸腺嘧啶,分析细胞DNA合成。
通常,1,25-(OH)2D3对有机体中钙平衡的分类活性作用(包括血钙和尿钙活性)在本发明的维生素D类似物中是不需要的,其中例如对一些细胞增殖抑制和/或免疫抑制活性的选择性则是本发明所需要的。
按照前述的方法(Binderup,L.,Bramm,E.,生化药理学,
37,889-895(1988)),在大鼠体内对化合物的钙活性进行了测定。在表A“Calc.,rel.”栏中,列出了选择的化合物(与1,25-(OH)2D3有关)的血钙活性;正如所述的,一般来说,本发明化合物的低数值是优选的。
表A显示,选择的化合物107和111在HaCaT-分析中(牛皮癣模型)比1,25-(OH)2D3具有更大的活性,而其血钙活性与1,25-(OH)2D3相似。
关于本发明化合物的其它重要性质以及它们的免疫抑制活性可从表A“MLR,rel.”这一栏中看出,选择的化合物107和111具有强的作用。表A:
化合物I和参考化合物的生物实验 表A注释*分子的其余部分与式I相同。**数值与1,25-(OH)2D3有关;数值大于1表示在分析中该化合物的活性比1,25-(OH)2D3大。¤用1,25-(OH)2D3的IC50值与化合物的IC50值的比例计算而得。IC50值是指与对照物相比,导致50% 3H-胸腺嘧啶引入抑制的浓度。#1,25=1,25-(OH)2D3=1,25-(OH)2-维生素D3。n.d.=未测定Ref.=对照化合物
已有报道,式I化合物可以从C-20差向异构体醇
3和
4来制备,醇3和4的合成是从维生素D衍生物醛1(Calverley,M.J.,Tetrahedron,
43,4609-4619(1987))经20-酮化合物2来制备的(Hansen,K,等人:维生素D:Gene Regulation,结构-功能分析和临床应用;Norman,A.W.,Bouillon R.,Thomasset,M.,Eds.;de Gruyter,Berlin,1991,pp.161-162),例如采用路线1和2中的通用方法。
更具体讲,路线1中给出了从上述起始物质合成式I化合物的重要中间体——16-脱氢甲苯磺酸盐(酯)
13/
14和类似醛
15/
16的制备方法,路线2给出了上述关键中间体向式I化合物的进一步转化。
结构单元V至VIII或它们的类似物的侧链合成可按文献/国际专利申请WO87/00834,WO89/10351。WO/91/00271,WO/91/00855,WO/91/15475,WO/93/19044以及WO/95/02577中描述的标准方法进行。
本专利说明书中通篇使用下列标准缩写:DMF=N,N-二甲基甲酰胺;DMSO=二甲基亚砜;Et=乙基;Hal=卤素;“HF”=5%氟化氢的乙腈∶水(7∶1,v/v);Me=甲基,Ph=苯基;PPTS=对甲基苯磺酸吡啶鎓;TBAF=氟化四正丁基铵三水合物;TBDMS=叔丁基二甲基甲硅烷基;THF=四氢呋喃;THP=四氢-4H-吡喃-2-基;TMS=三甲基甲硅烷基;Ts=对甲苯磺酰基(tosyl)。路线1 路线1注释
a)在吡啶中用氯化氧磷脱水;0℃/1h以及20℃/16-18h。
b)在二氯甲烷/水中用二氧化硫保护三烯系统;20℃/45-90分钟;色谱分离C-6差向异构体。
c)在二氯甲烷中用多聚甲醛/三氟化硼的醚合物进行羰基-烯反应;0℃/5-20分钟。
d)在甲苯/水中,用碳酸氢钠进行二氧化硫加成物的脱保护;90℃/1-2h。
e)在吡啶中用对甲苯磺酰氯进行对甲苯磺酰化;0-5℃/16-18h。
f)用草酰氯/DMSO在二氯甲烷中进行Swern氧化;-78℃/20分钟。路线2 Q,Y,R1,R2和Z如上定义;Z1为羟基或保护的醇,如TMS-O,TBDMS-D或THP-O;x为O或S;n为2,3或4。路线2注释
a)在碱(氢化钠)存在下,于DMF中用侧链结构单元V(H-X-R3,见下)进行烷基化;20℃/0.5-22小时。
b)在Li2CuCl4存在下,于THF中,与衍生自侧链结构单元VI(R4-Hal,见下)的格氏试剂R4-Mg-Hal进行反应;0℃/2h,然后8-10℃/16-20h。
c)在碱(双(三甲基甲硅烷基)氨基化锂)存在下,于THF中,与衍生自侧链结构单元VII(A-R5,见下)的A1-R5内鎓盐进行反应,-45℃/0.5-1.5小时。
d)在升高的温度下,于甲苯中,与衍生自侧链结构单元VIII(A1-R6,见下)的A1-R6内鎓盐进行反应,90-110℃/2-8小时。
e)式II化合物侧链上任意功能基团的修饰。
f)在三重增感剂(例如蒽或9-乙酰基蒽)的存在下,用紫外光使式IIa和III化合物异构化成相应的式IV化合物。
g)用例如TBAF或“HF”处理,使式IV化合物脱保护,生成相应的式I化合物。V H-X-R3 R3=-(C6H4)-C(R1)(R2)-Z1(邻-,间-,对-)VI R4-Hal R4=-CH2-(CH2)n-C(R1)(R2)-Z1
Hal=Cl或BrVII A-R5 A=Ph3P+--CH2或(EtO)2P(O)-CH2-
R5=-CH=CH-CO-OmeVIII A-R6 A的含义如上所述
在A1-R5和A1-R6中,A1代表Ph3P+--CH-或(EtO)2P(O)-CHLi-,R5和R6的定义同上。
本发明化合物意在用于能够局部或系统治疗上述人类和畜类失调的药物组合物。
本发明化合物可与其它制药或治疗方法联合使用。在治疗牛皮癣时,本发明化合物可与类固醇或其它治疗方法(例如光或紫外光治疗或PUVA治疗)联合使用。在治疗癌症时,本发明化合物可与其它抗癌药物或抗癌治疗方法(例如放疗)联合使用,在预防移植物排斥或移植物对抗宿主反应或在治疗自身免疫疾病时,本发明化合物优选与其它免疫抑制/免疫调节药物和治疗方法(例如环孢菌素A)联合使用。
当然,产生治疗效果所需的式I化合物(下文中称为活性成分)的量根据特定的化合物,给药途径以及接受治疗的哺乳动物的情况而变化。本发明化合物可经非肠道,关节内,经肠或局部给药等途径给药。当经肠途径给药时,吸收较好,因此,这是优选的治疗系统失调的给药途径。在治疗如牛皮癣等皮肤失调或眼部疾病时,局部或肠道给药是优选的。
虽然活性成分可以粗化合物形式单独给药,但优选是以其药物制剂的形式使用。通常,制剂中包含0.1ppm-0.1%(重量比)的活性成分。
因此,用于畜用和人类药物的本发明制剂包括与药用载体混合的活性成分以及任意其它的治疗成分。载体必须是“可接受的”,其含义是可与制剂中的其它成分相容并不损害接受该药物者。
制剂包括适合于口服,眼部,直肠,非肠道(包括皮下,肌内和静脉),透皮,关节内以及局部,鼻腔或颊部给药的剂型。
术语“剂量单位”是指一个单元,即可以给予病人的单一剂量,其控制和包装都很方便,既包含了活性成分本身或与固体或液体药用稀释剂或载体的混合物,又保持了其物理和化学上的稳定。
通常制剂以剂量单位形式存在,并且可以用制药领域内已知的任何方法进行制备,所有的方法均包括将活性成分引入有关载体这一步骤,上述载体由一或多种附加成分组成。一般的制备方法如下:均匀并紧密的将活性成分引入液体载体或细分的固体载体或两者的混合物中,然后,如需要,将产品成型至所需制剂。
适合于口服给药的本发明制剂可以独立的单位形式存在,例如胶囊,小药囊,片剂或锭剂,其中的每一种均含有预定剂量的活性成分;粉剂或颗粒剂;水或非水液体的溶液或悬浮液;或水包油乳剂或油包水乳剂。活性成分可以大丸剂,干药糖剂或膏剂形式给药。
用于直肠给药的制剂可采用栓剂形式,其中引入了活性成分和载体,或者以灌肠剂的形式给药。
用于非肠道给药的制剂通常含有活性成分的无菌油性或水性制剂,其与接受者的血液等渗。透皮制剂可以药膏形式给药。
适合于关节内或眼部给药的制剂可制成活性成分的无菌水性制剂,活性成分可是微晶形式,例如,水合微晶悬浮液。脂质体制剂或可生物降解的聚合物系统也可用于本发明活性成分,通过关节内和眼部进行给药。
适合于局部或眼部给药的制剂包括液体或半液体制剂,例如搽剂,洗剂,凝胶剂,敷剂,水包油乳剂或油包水乳剂(例如霜剂),软膏剂或药膏;或溶液或悬浮液(例如滴剂)。
适合于鼻腔或颊腔给药的制剂包括粉剂,自推进剂和喷雾剂,例如气溶胶和雾化剂。
除了前述的成分之外,本发明制剂还可以含有一或多种附加成分,例如稀释剂,粘合剂,防腐剂等。
组合物进一步含有其它通常用于治疗上述病理状态的治疗活性化合物,例如其它用于免疫疾病治疗的免疫抑制剂,或用于皮肤病治疗的类固醇。
本发明进一步涉及治疗患有上述疾病之一患者的方法,该方法包括给予所需治疗的患者有效剂量的一或多个式I化合物,它们可以是单独的,也可以与一或多个通常用于治疗上述疾病的其它治疗活性化合物联合使用。本发明化合物和/或与其它治疗活性化合物的联合使用可以同时,也可以分开。
在系统治疗中,每日剂量从0.001-2μg/kg体重,优选0.002-0.3μg/kg哺乳动物体重,例如给予0.003-0.3μg式I化合物/kg,典型地,相当于一个成人的每日剂量为0.2-25μg。在皮肤失调的局部治疗中,给予含有0.1-500μg/g,优选0.1-100μg/g式I化合物的软膏剂,霜剂或洗剂。对于局部使用的眼用软膏剂、滴剂或凝胶剂来说,是给予0.1-500μg/g,优选0.1-100μg/g式I化合物。口服组合物通常配成每剂量单位含有0.05-50μg,优选0.1-25μg的式I化合物的片剂,胶囊或滴剂。
下文将进一步描述本发明。通用步骤,制备和实施例 一般内容
实施例化的式I化合物列于表5,其中中间体5-16以及通式II,III和IV列于表1-4。
对于核磁共振光谱(300MHz)而言化学位移值(δ)是相对于与内标四甲基硅烷(δ=0)或氯仿(δ=7.25)有关的氘代氯仿溶液得到的。对于多重峰的数值而言,无论是有定义的(双锋(d),三重峰(t),四重峰(q)还是没有定义的(m)的,除非给出的是范围(s=单峰,b=宽峰),数值均取自约中点的位置。偶合常数(J)用Hertz(Hz)表示,有时接近于最近的单位。
醚是指乙醚,经金属钠干燥。THF经二苯(甲)酮钠干燥。石油醚指戊烷成分。除非另有说明,反应通常在氩气室温下进行。处理步骤包括用指定的溶剂(否则是有机反应溶剂)进行稀释,依次用水和盐水提取,无水硫酸镁干燥,减压浓缩,得到残余物。用硅胶进行色谱。表1 式5-16中间体(路线1)化合物序号 制备序号 通用步骤5 1 17a 3 27b 4 29a 7 39b 8 311 11 413 13 515 15 66 2 18a 5 28b 6 210a 9 310b 10 312 12 414 14 516 16 6表2 通式IIa-d中间体(路线2)
基团通式I 化合物序号 制备序号 通用步骤 C20构型
X n R1 R2 Z1IIa 201 17 7
S O - Me Me OHIIa 202 18 7
R O - Me Me OHIIa 203 19 7
S S - Me Me OHIIa 204 20 7
R S - Me Me OHIIb 205 21 8
R - 2 Me Me OTMSIIb 206 22 8
S - 2 Me Me OTMSIIb 207 23 8
R - 3 Et Et OTMSIIb 208 24 8
R - 3 Et Et OTMSIIc 209 25 9
R - - - - -IIc 210 26 9
S - - - - -IId 213 27 10
R - - - - -IId 214 28 10
S - - - - -表3 通式III中间体(路线2)
基团化合物序号 制备序号 通用步骤 C20构型
Q Y R1 R2 Z305 29 11
R (CH2)3 单键 Me Me OH306 30 11
S (CH2)3 单键 Me Me OH307 31 11
R (CH2)4 单键 Et Et OH308 32 11
S (CH2)4 单键 Et Et OH309 33 12
R (CH=CH)2 a 单键 Me Me OH310 34 12
S (CH=CH)2 a 单键 Me Me OH311 35 12
R (CH=CH)2 a 单键 Et Et OH312 36 12
S (CH=CH)2 a 单键 Et Et OH表3(续) 通式III中间体(路线2)
基团化合物序号 制备序号 通用步骤 C20构型
Q Y R1 R2 Z313 37 13
R (CH=CH)a CH(OH)b CH2-CH2 H314 38 13
S (CH=CH)a CH(OH)b CH2-CH2 H315 39 13
R (CH=CH)a CH(OH)c CH2-CH2 H316 40 13
S (CH=CH)a CH(OH)c CH2-CH2 Ha
E-(
E,
E-)双键的构型b 该C原子
S构型c 该C原子为
R构型表4 通式IV中间体(路线2)
基团化合物序号 制备序号 C20构型No. No. Q Y R1 R2 Z401 41
S CH2 O-C6H4(间) Me Me OH402 42
R CH2 O-C6H4(间) Me Me OH403 43
S CH2 S-C6H4(间) Me Me OH404 44
R CH2 S-C6H4(间) Me Me OH405 45
R (CH2)3 单键 Me Me OH406 46
S (CH2)3 单键 Me Me OH407 47
R (CH2)4 单键 Et Et OH408 48
S (CH2)4 单键 Et Et OH409 49
R (CH=CH)2 a 单键 Me Me OH410 50
S (CH=CH)2 a 单键 Me Me OH表4(续) 通式IV中间体(路线2)
基团化合物序号 制备序号 C20构型
Q Y R1 R2 Z411 51
R (CH=CH)2 a 单键 Et Et OH412 52
S (CH=CH)2 a 单键 Et Et OH413 53
R (CH=CH)a CH(OH)b CH2-CH2 H414 54
S (CH=CH)a CH(OH)b CH2-CH2 H415 55
R (CH=CH)a CH(OH)c CH2-CH2 H416 56
S (CH=CH)a CH(OH)c CH2-CH2 Ha
E-(
E,
E-)双键的构型b 该C原子
S构型c 该C原子为
R构型表5 实施例化合物1
基团化合物序号 实施例号 C20构型
Q Y R1 R2 Z101 1
S CH2 O-C6H4(间) Me Me OH102 2
R CH2 O-C6H4(间) Me Me OH103 3
S CH2 S-C6H4(间) Me Me OH104 4
R CH2 S-C6H4(间) Me Me OH105 5
R (CH2)3 单键 Me Me OH106 6
S (CH2)3 单键 Me Me OH107 7
R (CH2)4 单键 Et Et OH108 8
S (CH2)4 单键 Et Et OH109 9
R (CH=CH)2 a 单键 Me Me OH110 10
S (CH=CH)2 a 单键 Me Me OH表5(续) 实施例化合物1
基团化合物序号 实施例号 C20构型No. No. atC20 Q Y R1 R2 Z111 11
R (CH=CH)2 a 单键 Et Et OH112 12
S (CH=CH)2 a 单键 Et Et OH113 13
R (CH=CH)a CH(OH)b CH2-CH2 H114 14
S (CH=CH)a CH(OH)b CH2-CH2 H115 15
R (CH=CH)a CH(OH)c CH2-CH2 H116 16
S (CH=CH)a CH(OH)c CH2-CH2 Ha
E-(
E,
E-)双键的构型b 该C原子
S构型c 该C原子为
R构型通用步骤 通用步骤1:
化合物4和3的脱水得到相应的无水化合物5和6(制备 1-2)
将化合物
4(或
3)(2.81g,5mmol)吡啶溶液(40ml)冷却至0℃,于5分钟内伴随搅拌滴加氯化氧磷(4.6ml,50mmol)。低温搅拌1小时后,再于室温下搅拌16小时,将反应混合物倾入冰冷的乙酸乙酯(120ml)中,搅拌下,小心地加入水(40ml)。用4N的盐酸(80ml)调节此混合物的表观pH至2.8,分离各相。用乙酸乙酯(60ml)对水层进行提取后,合并有机层并进行处理,得到的粗产品不必经纯化(化合物
5)直接用于下一步,也可以用乙醚-甲醇进行重结晶纯化(化合物
6)用于下一步。通用步骤2:
化合物5和6与二氧化硫反应得到相应的二氧化硫加成 物7a/7b和8a/8b(制备3-6)
在剧烈搅拌下,向粗化合物
5(或纯品
6)(5mmol)的二氯甲烷(25ml)和水(10ml)的溶液中加入冰冷的约1.5M二氧化硫的二氯甲烷(100ml)溶液。混合物在室温下搅拌45分钟,倾入冰水(100ml)中。用2N的氢氧化钠(62ml)调节此混合物的表观pH至5.6,分出有机层。再对水层进行提取(二氯甲烷,25ml),对有机层进行处理。残余物进行色谱(洗脱液:5%-10%乙醚/石油醚),从而分离6(S)和6(R)SO2-加成物7a和7b(或9a和9b)。通用步骤3:使SO2-加成物7a,7b,8a和8b与多聚甲醛进行烯反应生成相应的SO2-保护的16-脱氢醇9a,9b,10a和10b(制备7-10)
0℃及搅拌下,向化合物
7a(
7b,
8a,
8b)(2.42g,4mmol)的二氯甲烷(80ml)溶液中加入多聚甲醛(0.60g,20mmol),再加入三氟化硼的醚合溶液(0.10ml,0.4当量)。0℃搅拌15分钟后,用1/15M的磷酸缓冲液终止反应(pH=6.5)(60ml),处理混合物。残余物进行色谱(洗脱液:10%-15%乙酸乙酯的石油醚溶液),从极性较大的标题化合物(
9a或
9b,
10a,
10b)中分出少量极性较小的起始物质。通用步骤4:使SO2-加成物9a/9b以及10a/10b脱保护得到相应的16-脱氢醇11和12(制备11-12)
向化合物
9a(
9b)(1.27g,2mmol)的甲苯溶液(20ml)中加水(10ml)和碳酸氢钠(0.67g,8mmol),混合物于85-90℃下搅拌1.5h。冷却至室温后。处理反应混合物(甲苯)得到化合物
11,其为泡沫状物。
相似地处理化合物
10a(或
10b),得到化合物
12,其为无定型粉末。通用步骤5:
16-脱氢醇11和12的甲苯磺酰化生成相应的甲苯磺酸酯 (盐)13和14(制备13-14)
0℃下,向搅拌着的化合物
11(或
12)(2mmol)的吡啶(10ml)溶液中加入对甲苯磺酰氯(0.76g,4mmol),混合物在0-5℃下搅拌2小时,然后在冰箱中放置过夜(16h)。将反应混合物倾入冰冷的乙酸乙酯(40ml)和水的混合物中,用4N盐酸调pH至2.6。分出水相后,用乙酸乙酯提取,对合并的有机层进行处理。。残余物经色谱纯化(洗脱液:5%乙醚的石油醚溶液)得到纯品
13(或
14)。通用步骤6:
16-脱氢醇11和12的氧化生成相应的醛15和16(Swern 氧化)(制备15-16)
搅拌下,将草酰氯(0.45ml,5mmol)的干燥二氯甲烷溶液冷却至-78℃,用注射器加入2N二甲基亚砜的无水二氯甲烷(5.6ml,11.2mmol)溶液。低温搅拌10分钟后,加入
11(或
12)(4mmol)的无水二氯甲烷溶液(12ml)(注射器)。继续搅拌20分钟,用三乙胺(2.1ml,15mmol)终止反应。移去冷却浴,,使混合物升温至室温,搅拌约45分钟,处理(二氯甲烷)后得到粗化合物
15(或
16),其无须进一步纯化可直接用于下一步反应。通用步骤7:
化合物13和14烷基化得到式IIa化合物(制备17-20)
向合适的烷基化试剂HXR3(1.5mmol)的无水DMF(10ml)溶液中加入氢化钠(2.25mmol),混合物搅拌20分钟。用注射器将化合物13(或
14)的无水THF溶液(5ml)加入其中,继续搅拌30-40分钟(S-烷基化),或16-22小时(O-烷基化)。冷却至0-5℃,滴加水(0.5-1.0ml)分解过量的试剂,处理反应混合物(乙酸乙酯)。残余物经硅胶色谱纯化(洗脱液:5-10%乙醚的石油醚溶液),得到相应的化合物IIa。通用步骤8:
化合物13和14与衍生自侧链结构单元II(R 4 Hal)格氏 试剂R 4 MgHal反应得到式IIb化合物(制备21-24)
向镁屑(220mg,1.1原子当量)的无水烧瓶中,于氩气并搅拌下,滴加合适的化合物VI(8.25mmol)的无水THF(7.5ml)溶液,加热下搅拌回流45分钟。0℃并搅拌下,用氯化锂(32mg)溶液和无水氯化铜(50mg)的无水THF(5ml)溶液对格氏试剂进行处理,15分钟后用化合物
13(或
14)的无水THF(5ml)溶液进行处理。5-10℃搅拌18小时后,处理反应混合物(乙醚)。粗品经色谱纯化,得到所需的化合物IIb。通用步骤9:
醛15和16与衍生自侧链结构单元VII(AR 5 )的内鎓盐 A 1 R 5 进行反应得到式IIc化合物(制备25-26)
-50℃并搅拌下,向醛
15(或
16)(1.0mmol)以及合适的化合物VII(1.8mmol)的无水THF(5ml)溶液中经注射器滴加1M的双(三甲基甲硅烷基)氨化锂的无水THF溶液(1.5ml)。低温继续搅拌1小时,然后使混合物升温至-10℃(15-20分钟)。滴加少量水终止反应,对其进行处理(乙醚)。残余物经硅胶色谱纯化,得到所需的化合物IIc。通用步骤10:
醛15和16与衍生自侧链结构单元VIII(A 1 R 6 )的内鎓 盐A 1 R 6 进行反应得到式IId化合物(制备27-28)
向醛
15(或
16)(1.8mmol)的无水甲苯(20ml)溶液中加入合适的化合物VIII(3.6mmol),混合物于90-110℃下搅拌2-4小时。冷却至0℃后,过滤混合物,浓缩滤液,色谱纯化,得到所需化合物IId。通用步骤11:
用PPTS使化合物IIb脱保护得到相应的化合物III(制 备29-32)
向合适的化合物IIb(0.5mmol)的无水THF(3ml)溶液和乙醇(6ml)中加入PPTS(15mg),混合物搅拌1小时,乙酸乙酯处理,得到的粗品经硅胶色谱纯化,得到所需化合物III。通用步骤12:
用烷基锂与化合物IIc反应得到相应的化合物III(制 备33-36)
-78℃下,将预冷却(-15℃)的烷基锂乙醚溶液(3-4摩尔当量)经注射器滴加到合适的化合物IIc(0.5mmol)的无水THF(6ml)溶液中。-78℃下搅拌45分钟后,滴加少量水终止反应,升温至20℃,对其进行处理(乙醚)。残余物经硅胶色谱纯化,得到所需的化合物III。通用步骤13:
化合物IId还原得到相应的化合物III(制备37-40)
0℃并搅拌下,向合适的化合物IId(0.8mmol)的THF(4ml)溶液中加入0.4MCeCl3.7H2O的乙醇(2ml)溶液,再加入硼氢化钠(76mg,2mmol)。搅拌下于10分钟内加入甲醇(4ml),混合物搅拌20分钟,乙酸乙酯处理,得到的残余物经色谱纯化,得到所需化合物III。通用步骤14:
化合物IIa和III异构化得到相应的化合物IV(制备 41-56)
将合适的化合物IIa或III(0.28mmol)的溶液,蒽(0.10g,0.56mmol)以及三乙胺(0.20ml,1.4mmol)的二氯甲烷(16ml)溶液置于25ml的圆底Pyrex烧瓶中,在约10℃及搅拌下,用来自高压紫外灯(型号TQ760Z2(Hanau))的UV-光照射该烧瓶30分钟。减压浓缩反应混合物,残余物用石油醚处理(2×2ml)并过滤。浓缩滤液,得到的残余物经色谱纯化,得到标题化合物。通用步骤15:用“HF”处理使化合物IV脱保护得到相应的化合物I(实施例1-8和13-16)
搅拌下,向合适的化合物IV(0.25mmol)的乙酸乙酯溶液(1.5ml)中加入乙腈(6ml),再加入5%氟氢酸的乙腈-水7∶1(2.0ml)溶液。继续搅拌45-60分钟后,加入1M碳酸氢钾溶液(10ml),用乙酸乙酯处理混合物。残余物经色谱纯化(洗脱液:30%戊烷的乙酸乙酯溶液),得到所需化合物I。通用步骤16:
用氟化四正丁基铵处理使化合物IV脱保护得到相应的 化合物I(实施例9-12
向合适的化合物IV(0.18mmol)的THF溶液(4.5ml)中加入TBAF三水合物(0.29g,0.9mmol),混合物搅拌加热回流1小时。加入0.2M碳酸氢钠溶液(5ml),用乙酸乙酯处理混合物。残余物经色谱纯化(洗脱液:50%乙酸乙酯的戊烷溶液),得到标题化合物。制备
制备1:
化合物5
方法:通用步骤1
起始物质:化合物4
1H NMR δ 0.06(m,12H),0.76(s,3H),0.85(s,9H),0.89(s,9H),1.66(m,3H),1.45-2.50(m,13H),2.56(dd,1H),2.86(m,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.98(m,1H),5.19(m,1H),5.85(d,1H),6.44(d,1H).
制备2:
化合物6
方法:通用步骤1
起始物质:化合物3
m.p.87-88℃
元素分析:C33H58O2Si2 理论值:C73.00,H 10.77
实测值:C72.90,H 10.82
1H NMR 50.06(m,12H),0.62(s,3H),0.86(s,9H),0.90(s,9H),1.56(d,3H),1.20-2.10(m,10H),2.32(m,3H),2.57(dd,1H),2.89(m,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.99(m,1H),5.08(m,1H),5.86(d,1H),6.45(d,1H).
制备3:
化合物7a
方法:通用步骤2
起始物质:化合物5
m.p.117-118℃
元素分析:C33H58O4SSi2 理论值:C65.29,H 9.63,S 5.28
实测值:C65.12,H 9.54,S 5.22
1H NMR δ 0.05(m,12H),0.86(s,9H),0.87(s,9H),0.87(s,3H),1.66(m,3H),1.40-2.50(m,14H),2.60(m,1H),3.60(bd,1H),3.93(m,1H),4.19(m,1H),4.36(m,1H),4.64(d,1H),4.74(d,1H),5.17(m,1H).
制备4:
化合物7b
方法:通用步骤2
起始物质:化合物5
1H NMR δ 0.06(m,12H),0.78(s,3H),0.87(s,9H), 0.88(s,9H),1.66(m,3H),1.45-2.45(m,14H),2.56(m,1H),3.63(bd,1H),3.92(bd,1H),4.15(m,1H),4.38(m,1H),4.62(d,1H),4.84(d,1H),5.19(m,1H).
制备5:
化合物8a
方法:通用步骤2
起始物质:化合物6
m.p.117-118℃
元素分析:C33H58O4SSi2 理论值:C65.29,H 9.63,S 5.28
实测值:C65.14,H 9.54,S 5.08
1H NMR δ 0.06(m,12H),0.72(s,3H),0.87(s,9H),0.88(s,9H),1.36(m,1H),1.55(d,3H),1.45-2.05(m,10H),2.10-2.45(m,3H),2.63(m,1H),3.60(bd,1H),3.93(m,1H),4.18(m,H),4.36(m,1H),4.65(d,1H),4.75(d,1H),5.10(m,1H).
制备6:
化合物8b
方法:通用步骤2
起始物质:化合物6
1H NMR δ 0.06(m,12H),0.64(s,3H),0.86(s,9H),0.88(s,9H),1.55(d,3H),1.20-1.95(m,10H),2.08(dd,1H),2.30(m,3H),2.60(m,1H),3.63(bd,1H),3.92(bd,1H),4.16(m,1H),4.38(m,1H),4.62(d,1H),4.85(d,1H),5.10(m,1H).
制备7:
化合物9a
方法:通用步骤3
起始物质:化合物7a
m.p.115-116℃
元素分析:C34H60O5SSi2 理论值:C64.10,H 9.49,S 5.03
实测值:C63.78,H 9.55,S 5.00
1H NMR δ 0.06(m,12H),0.82(s,3H),0.87(s,9H),0.88(s,9H),1.06(d,3H),1.35-2.50(m,14H),2.61(m,1H),3.57(m,3H),3.93(m,1H),4.18(m,1H),4.37(m,1H),4.63(d,1H),4.82(d,1H),5.43(m,1H).
制备8:
化合物9b
方法:通用步骤3
起始物质:化合物7b
m.p.131-132℃
元素分析:C34H60O5SSi2 理论值:C64.10,H 9.49
实测值:C64.18,H 9.46
1H NMR δ 0.05(m,12H),0.72(s,3H),0.85(s,9H),0.87(s,9H),1.06(d,3H),1.35-2.02(m,9H),2.10-2.65(m,6H),3.58(m,3H),3.92(bd,1H),4.15(m,1H),4.38(m,1H),4.62(d,1H),4.92(d,1H),5.45(m,1H).
制备9:
化合物10a
方法:通用步骤3
起始物质:化合物8a
m.p.125-126℃
元素分析:C34H60O5SSi2 理论值:C64.10,H 9.49,S 5.03
实测值:C63.98,H 9.46,S 4.82
1H NMR δ 0.06(m,12H),0.81(s,3H),0.87(s,9H),0.88(s,9H),1.11(d,3H),1.40-2.50(m,14H),2.60(m,1H),3.47(dd,1H),3.58(dd,1H),3.60(bd,1H),3.93(m,1H),4.19(m,1H),4.37(m,1H),4.64(m,1H),4.82(m,1H),5.45(m,1H).
制备10:
化合物10b
方法:通用步骤3
起始物质:化合物8b
m.p.129-130℃
1H NMR δ 0.06(m,12H),0.72(s,3H),0.86(s,9H),0.88(s,9H),1.11(d,3H),1.35-2.00(m,9H),2.10-2.50(m,5H),2.57(dd,1H),3.46(dd,1H),3.59(dd,1H),3.64(bd,1H),3.92(bd,1H),4.16(m,1H),4.38(m,1H),4.62(d,1H),4.93(d,1H),5.48(m,1H).
制备11:
化合物11
方法:通用步骤4
起始物质:化合物9a或9b
元素分析:C34H60O3SSi2 理论值:C71.27,H 10.55
实测值:C71.00,H 10.59
1H NMR δ 0.05(m,12H),0.71(s,3H),0.85(s,9H),0.90(s,9H),1.06(d,3H),1.35-2.00(m,8H),2.09(m,1H),2.28(m,2H),2.41(m.2H),2.58(dd,1H),2.87(m,1H),3.55(m,2H),4.22(m,1H),4.54(m,1H),4.95(m,1H),4.99(m,1H),5.46(m,1H),5.92(d,1H),6.45(d,1H).
制备12:
化合物12
方法:通用步骤4
起始物质:化合物10a或10b
1H NMR δ 0.06(m,12H),0.70(s,3H),0.85(s,9H),0.90(s,9H),1.11(d,3H),1.40-1.90(m,7H),1.93(m,1H),2.10(m,1H),2.20-2.50(m,4H),2.58(dd,1H),2.86(m,1H),3.48(m,1H),3.57(m,1H),4.22(m,1H),4.54(m,1H),4.95(m,1H),4.99(m,1H),5.48(m,1H),5.92(d,1H),6.45(d,1H).
制备13:
化合物13
方法:通用步骤5
起始物质:化合物11
m.p.77-78℃
元素分析:C41H66O5SSi2 理论值:C67.72,H9.15,S4.41
实测值:C67.50,H9.07,S4.67
1H NMR δ 0.06(m,12H),0.60(s,3H),0.86(s,9H),0.89(s,9H),1.04(d,3H),1.30-1.85(m,6H),1.91(m,1H),2.02(m,1H),2.10-2.38(m,3H),2.44(s,3H),2.40-2.62(m,2H),2.84(m,1H),3.84(t,1H),4.04(dd,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.98(m,1H),5.31(m,1H),5.88(d,1H),6.43(d,1H),7.33(d,2H),7.78(d,2H).
制备14:
化合物14
方法:通用步骤5
起始物质:化合物12
m.p.89-90℃
元素分析:C41H66O5SSi2 理论值:C67.72,H9.15
实测值:C67.73,H9.36
1H NMR δ 0.06(m,12H),0.63(s,3H),0.85(s,9H),0.90(s,9H),1.09(d,3H),2.44(s,3H),2.56(dd,1H),0.75-2.50(m,12H),2.83(m,1H),3.73(t,1H),4.03(dd,1H),4.22(m,1H),4.53(m,1H),4.95(m,1H),4.98(m,1H),5.37(m,1H),5.88(d,1H),6.42(d,1H),7.33(d,2H),7.78(d,2H).
制备15:
化合物15
方法:通用步骤6
起始物质:化合物11
1H NMR δ 0.06(m,12H),0.69(s,3H),0.85(s,9H),0.90(s,9H),1.21(d,3H),1.40-2.00(m,7H),2.14(m,1H),2.31(m,2H),2.44(dd,1H),2.58(m,1H),2.87(m,1H),3.05(m,1H),4.22(m,1H),4.53(m,1H),4.95(m,1H),4.99(m,1H),5.52(m,1H),5.92(d,1H),6.44(d,1H),9.45(d,1H).
制备16:
化合物16
方法:通用步骤6
起始物质:化合物12
1H NMR δ 0.06(m,12H),0.70(s,3H),0.85(s,9H),0.89(s,9H),1.24(d,3H),1.00-2.00(m,7H),2.14(m,1H),2.29(m,2H),2.46(m,1H),2.57(dd,1H),2.86(m,1H),3.05(m,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.99(m,1H),5.56(m,1H),5.92(d,1H),6.44(d,1H),9.45(d,1H).
制备17:
化合物201
方法:通用步骤7
起始物质:化合物13
烷基化剂:3-(1-羟基-1-甲基)乙基苯酚
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.72(s,3H),0.85(s,9H),0.90(s,9H),1.20(d,3H),1.57(s,6H),1.15-2.00(m,8H),2.09(m,1H),2.28(m,2H),2.43(m,1H),2.60(m,2H),2.87(m,1H),3.81(t,1H),4.00(dd,1H),4.23(m,1H),4.53(m,1H),4.95(m,1H),4.99(m,1H),5.48(m,1H),5.93(d,1H),6.46(d,1H),6.76(m,1H),7.03(m,2H),7.24(t,1H).
制备18:
化合物202
方法:通用步骤7
起始物质:化合物14
烷基化剂:3-(1-羟基-1-甲基)乙基苯酚
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.72(s,3H),0.85(s,9H),0.90(s,9H),1.23(d,3H),1.57(s,6H),1.40-2.00(m,8H),2.09(m,1H),2.29(m,2H),2.42(m,1H),2.60(m,2H),2.87(m,1H),3.67(t,1H),4.01(dd,1H),4.23(m,1H),4.54(m,1H),4.95(m,1H),4.99(m,1H),5.51(m,1H),5.93(d,1H),6.46(d,1H),6.78(m,1H),7.04(m,2H),7.24(t,1H).
制备19:
化合物203
方法:通用步骤7
起始物质:化合物13
烷基化剂:3-(1-羟基-1-甲基)乙基苯酚
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.70(s,3H),0.86(s,9H),0.90(s,9H),1.19(d,3H),1.56(s,6H),1.15-1.87(m,7H),1.92(m,1H),2.07(m,1H),2.20-2.50(m,4H),2.57(dd,1H),2.85(d,1H),2.86(dd,1H),3.20(dd,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.99(m,1H),5.44(m,1H),5.91(d,1H),6.45(d,1H),7.15-7.30(m,3H),7.46(m,1H).
制备20:
化合物204
方法:通用步骤7
起始物质:化合物14
烷基化剂:3-(1-羟基-1-甲基)乙基硫代苯酚
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMRδ 0.05(m,12H),0.67(s,3H),0.85(s,9H),0.90(s,9H),1.22(d,3H),1.56(s,6H),1.40-1.87(m,7H),1.93(m,1H),2.08(m,1H),2.25(m,2H),2.40(m,2H),2.58(dd,1H),2.79(dd,1H),2.84(m,1H),3.18(dd,1H), 4.22(m,1H),4.53(m,1H),4.95(m,1H),4.99(m,1H),5.47(m,1H),5.90(d,1H),6.44(d,1H),7.15-7.30(m,3H),7.48(m,1H).
制备21:
化合物205
方法:通用步骤8
起始物质:化合物13
烷基化剂:4-溴-2-甲基-2-三甲基甲硅烷氧基丁烷
色谱洗脱剂:1%乙醚的戊烷溶液
1H NMR δ 0.07(m,21H),0.68(s,3H),0.85(s,9H),0.90(s,9H),1.02(d,3H),1.18(s,6H),1.10-2.45(m,18H),2.60(dd,1H),2.85(m,1H),4.22(m,1H),4.53(m,1H),4.95(m,1H),4.99 (m,1H),5.30(m,1H),5.92(d,1H),6.46(d,1H).
制备22:
化合物206
方法:通用步骤8
起始物质:化合物14
烷基化剂:4-溴-2-甲基-2-三甲基甲硅烷氧基丁烷色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.10(s,9H),0.69(s,3H),0.85(s,9H),0.90(s,9H),1.05(d,3H),1.19(s,6H),1.10-2.45(m,18H),2.59(dd,1H),2.85(m,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.99(m,1H),5.33(m,1H),5.92(d,1H),6.46(d,1H).
制备23:
化合物207
方法:通用步骤8
起始物质:化合物13
烷基化剂:6-溴-2-乙基-3-三甲基甲硅烷氧基己烷
色谱洗脱剂:1%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.08(s,9H),0.68(s,3H),0.80(t,6H),0.85(s,9H),0.90(s,9H),1.01(d,3H),1.44(q,4H),0.75-2.45(m,20H),2.58(dd,1H),2.85(m,1H),4.22(m,1H),4.54(m,1H),4.95(m,1H),4.99(m,1H),5.30(m,1H),5.92(d,1H),6.46(d,1H).
制备24:
化合物208
方法:通用步骤8
起始物质:化合物14
烷基化剂:6-溴-3-乙基-3-三甲基甲硅烷氧基己烷
色谱洗脱剂:1%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.08(s,9H),0.69(s,3H),0.80(t,6H),0.85(s,9H),0.90(s,9H),1.04(d,3H),1.15-2.45(m,20H),1.44(q,4H),2.59(dd,1H),2.86(m,1H),4.22(m,1H),4.54(m,1H),4.95(m,1H),4.99(m,1H),5.32(m,1H),5.92(d,1H),6.46(d,1H).
制备25:
化合物209
方法:通用步骤9
起始物质:化合物15
色谱洗脱剂:2.5%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.65(s,3H),0.85(s,9H),0.89(s,9H),1.19(d,3H),1.15-1.87(m,6H),1.93(m,1H),2.06(m,1H),2.25(m,2H),2.38(dd,1H),2.58(dd,1H),2.84(m,1H),3.00(m,1H),3.73(s,3H),4.22(m,1H),4.52(m,1H),4.95(m,1H),4.98(m,1H),5.41(m,1H),5.81(d,1H,J=15.4Hz),5.90(d,1H),6.03(dd,1H,J=15.2Hz and 7.8Hz),6.16(dd,1H),J=15.2Hz and 10.5Hz),6.44(d,1H),7.27(dd,1H,J=15.4Hz and 10.5Hz).
制备26:
化合物210
方法:通用步骤9
起始物质:化合物16
色谱洗脱剂:2.5%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.69(s,3H),0.85(s,9H),0.89(s,9H),1.20(d,3H),1.35-1.87(m,6H),1.93(m,1H),2.07(m,1H),2.25(m,2H),2.41(dd,1H),2.58(dd,1H),2.84(bd,1H),2.98(m,1H),3.73(s,3H),4.22(m,1H),4.54(m,1H),4.95(m,1H),4.98(m,1H),5.41(m,1H),5.80(d,1H,J=15.4Hz),5.91(d,1H),6.11(m,2H),6.44(d,1H),7.27(dd,1H,J=15.4Hz and 9.9Hz).
制备27:
化合物213
方法:通用步骤10
起始物质:化合物15
色谱洗脱剂:2.5%乙醚的石油醚溶液
1H NMR δ 0.05(m,12H),0.67(s,3H),0.85(s,9H),0.90(s,9H),0.80-0.95(m,2H),1.07(m,2H),1.22(d,3H),1.45-2.35(m,11H),2.41(dd,1H),2.58(dd,1H),2.85(m,1H),3.06(m,1H),4.22(m,1H),4.53(m,1H),4.95(m,1H),4.98(m,1H),5.44(m,1H),5.90(d,1H),6.20(dd,1H,J=1.0 and 15.8Hz),6.44(d,1H),6.82(dd,1H,J=7.9 and 15.8Hz).
制备28:
化合物214
方法:通用步骤10
起始物质:化合物16色谱洗脱剂:2.5%乙醚的石油醚溶液
1H NMR δ 0.05(m,12H),0.70(s,3H),0.85(s,9H),0.90(s,9H),0.82-0.95(m,2H),1.07(m,2H),1.24(d,3H),1.35-2.50(m,12H),2.58(dd,1H),2.84(bd,1H),3.04(m,1H),4.22(m,1H),4.53(m,1H),4.95(m,1H),4.98(m,1H),5.46(m,1H),5.91(d,1H),6.18(dd,1H,J=1.0 and 15.8Hz),6.44(d,1H),6.85(dd,1H,J=7.7 and 15.8Hz).
制备29:
化合物305
方法: 通用步骤11
起始物质:化合物205
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.68(s,3H),0.85(s,9H),0.89(s,9H),1.02(d,3H),1.19(s,6H),1.10-2.45(m,19H),2.58(dd,1H),2.85(m,1H),4.22(m,1H),4.53(m 1H),4.94(m,1H),4.98(m,1H),5.31(m,1H),5.92(d,1H),6.45(d,1H).
制备30:
化合物306
方法:通用步骤11
起始物质:化合物206
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.69(s,3H),0.85(s,9H),0.89(s,9H),1.05(d,3H),1.20(s,6H),1.10-2.45(m,19H),2.58(dd,1H),2.85(m,1H),4.22(m,1H),4.54(m,1H),4.94(m,1H),4.99(m,1H),5.33(m,1H),5.91(d,1H),6.45(d,1H).
制备31:
化合物307
方法:通用步骤11
起始物质:化合物207
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.67(s,3H),0.84(t,6H),0.85(s,9H),0.90(s,9H),1.01(d,3H),1.44(q,4H),0.80-2.45(m,21H),2.58(dd,1H),2.85(m,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.98(m,1H),5.29(m,1H),5.91(d,1H),6.45(d,1H).
制备32:
化合物308
方法:通用步骤11
起始物质:化合物208
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.68(s,3H),0.85(s,6H),0.85(t,9H),0.90(s,9H),1.04(d,3H),1.45(q,4H),1.15-2.45(m,21H),2.59(dd,1H),2.86(m 1H),4.22(m,1H),4.54(m,1H),4.94(m,1H),4.99(m,1H),5.32(m,1H),5.91(d,1H),6.46(d,1H).
制备33:
化合物309
方法:通用步骤12
起始物质:化合物209
有机金属试剂:甲基锂
色谱洗脱剂:5%乙醚的石油醚溶液
制备34:
化合物310
方法:通用步骤12
起始物质:化合物210
有机金属试剂:甲基锂
色谱洗脱剂:2.5%乙醚的石油醚溶液
制备35:
化合物311
方法:通用步骤12
起始物质:化合物209
有机金属试剂:乙基锂
色谱洗脱剂:5%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.67(s,3H),0.85(t,6H),0.85(s,9H),0.89(s,9H),1.16(d,3H),1.10-1.87(m,1H),1.92(m,1H),2.04(m,1H),2.25(m,2H),2.38(dd,1H),2.59(dd,1H),2.89(m,2H),4.22(m,1H),4.53(m,1H),4.94(m,1H),4.98(m,1H),5.38(m,1H),5.54(d,1H,J=15.3Hz),5.59(dd,1H,J=14.9Hz and 8.0Hz),5.90(d,1H),6.02(dd,1H,J=14.9Hz and10.3Hz),6.17 dd,1H,J=15.3Hz and 10.3Hz),6.45(d,1H).
制备36:
化合物312
方法:通用步骤12
起始物质:化合物210
有机金属试剂:乙基锂
色谱洗脱剂:5%乙醚的戊烷溶液
0.06(m,12H),0.69(s,3H),0.85(s,9H),0.86(t,6H),0.90(s,9H),1.17(d,3H),1.25-1.87(m,11H),1.93(m,1H),2.05(m,1H),2.26(m,2H),2.42(dd,1H),2.59(dd,1H),2.86(m,2H),4.22(m,1H),4.54(m,1H),4.95(m,1H),4.99(m,1H),5.38(m,1H),5.54(d,1H,J=15.3Hz),5.64(dd,1H,J=15.0Hz and7.7Hz),5.91(d,1H),6.01(dd,1H,J=15.0Hz and 10.3Hz),6.18(dd,1H,J=15.3Hz and 10.3Hz),6.45(d,1H).
制备37:
化合物313
方法:通用步骤13
起始物质:化合物213
色谱洗脱剂:10%乙醚的石油醚溶液
1H NMR δ 0.05(m,12H),0.22(m,1H),0.32(m,1H),0.49(m,2H),0.68(s,3H),0.85(s,9H),0.86(s,9H),0.97(s,1H),1.15(d,3H),1.40-2.10(m,9H),2.15-2.45(m,3H),2.58(dd,1H),2.87(m,2H),3.42(m,1H),4.22(m,1H),4.53(m,1H),4.94(m,1H),5.00(m,1H),5.37(m,1H),5.54(m,2H),5.90(d,1H),6.44(d,1H).
制备38:
化合物314
方法:通用步骤13
起始物质:化合物214
色谱洗脱剂:10%乙醚的石油醚溶液
制备39:
化合物315
方法:通用步骤13
起始物质:化合物213
色谱洗脱剂:10%乙醚的石油醚溶液
1H NMR δ 0.05(m,12H),0.23(m,1H)0.32(m,1H),0.51(m,2H),0.68(s,3H),0.85(s,6H),0.90(s,9H),0.98(m,9H),1.15(d,3H),1.45-2.10(m,9H),2.17-2.45(m,3H),2.58(dd,1H),2.87(m 2H),3.46(m,1H),4.22(m,1H),4.54(m,1H),4.94(m,1H),4.98(m,1H),5.37(m,1H),5.58(m,2H),5.90(d,1H),6.45(d,1H).
制备40:
化合物316
方法:通用步骤13
起始物质:化合物214
色谱洗脱剂:10%乙醚的石油醚溶液
制备41:
化合物401
方法:通用步骤14
起始物质:化合物201
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.71(s,3H),0.86(s,9H),0.87(s,9H),1.19(d,3H),1.56(s,6H),1.15-2.70(m,14H),2.82(m,1H),3.80(t,1H),4.00(dd,1H),4.19(m,1H),4.37(m,1H),4.87(m,1H),5.18(m,1H),5.45(m,1H),6.10(d,1H),6.23(d,1H),6.77(m,1H),7.03(m,2H),7.23(t,1H).
制备42:
化合物402
方法:通用步骤14
起始物质:化合物202
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.71(s,3H),0.87(s,18H),1.22(d,3H),1.57(s,6H),1.40-2.15(m,9H),2.23(m,2H),2.37(m,1H),2.45(dd,1H),2.61(m,1H),2.82(m,1H),3.66(t,1H),4.01(dd,1H),4.19(m,1H),4.38(m,1H),4.88(m,1H),5.18(m,1H),5.48(m,1H),6.11(d,1H),6.23(d,1H),6.77 m,1H),6.95-7.10(m,2H),7.24(t,1H).
制备43:
化合物403
方法:通用步骤14
起始物质:化合物203
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.69(s,3H),0.87(s,18H),1.18(d,3H),1.55(s,6H),1.15-2.50(m,14H),2.80(m,1H),2.86(dd,1H),3.20(dd,1H),4.18(m,1H),4.38(m,1H),4.87(m,1H),5.19(m,1H),5.41(m,1H),6.09(d,1H),6.22(d,1H),7.15-7.30(m,3H),7.46(m,1H).
制备44:
化合物404
方法:通用步骤14
起始物质:化合物204
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.66(s,3H),0.86(s,9H),0.87(s,9H),1.21(d,3H),1.56(s,6H),1.30-2.50(m,14H),2.78(dd,1H),2.80(m,1H),3.18(dd,1H),4.18(m,1H),4.37(m,1H),4.86(m,1H),5.18(m,1H),5.44(m,1H),6.08(d,1H),6.22(d,1H),7.15-7.30(m,3H),7.47(m,1H).
制备45:
化合物405
方法:通用步骤14
起始物质:化合物305
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.67(s,3H),0.87(s,9H),0.88(s,9H),1.01(d,3H),1.18(s,6H),0.80-2.27(m,18H),2.35(m,1H),2.45(dd,1H),2.80(m,1H),4.19(m,1H),4.37(m,1H),4.87(m,1H),5.18(m,1H),5.28(m,1H),6.09(d,1H),6.23(d,1H).
制备46:
化合物406
方法:通用步骤14
起始物质:化合物306
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.68(s,3H),0.87(s,9H),0.88(s,9H),1.04(d,3H),1.20(s,6H),1.10-2.40(m,19H),2.45(d,1H),2.80(m,1H),4.18(m,1H),4.38(m,1H),4.87(m,1H),5.18(m,1H),5.30(m,1H),6.10(d,1H),6.23(d,1H).
制备47:
化合物407
方法:通用步骤14
起始物质:化合物307
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.66(s,3H),0.84(t,6H),0.87(s,18H),1.00(d,3H),1.44(q,4H),0.75-2.27(m,20H),2.34(m,1H),2.44(dd,1H),2.80(m,1H),4.19(m,1H),4.38(m,1H),4.87(m,1H),5.18(m,1H),5.27(m,1H),6.09(d,1H),6.22(d,1H).
制备48:
化合物408
方法:通用步骤14
起始物质:化合物308
色谱洗脱剂:10%乙醚的戊烷溶液
1H NMR δ 0.06(m,12H),0.68(s,3H),0.87(t,6H),0.87(s,9H),0.88(s,9H),1.02(d,3H),1.44(q,4H),1.15-2.50(m,22H),2.80(m,1H),4.19(m,1H),4.38(m,1H),4.87(m,1H),5.18(m,1H),5.29(m,1H),6.09(d,1H),6.23(d,1H).
制备49:
化合物409
方法:通用步骤14
起始物质:化合物309
色谱洗脱剂:5%乙醚的石油醚溶液
制备50:
化合物410
方法:通用步骤14
起始物质:化合物310
色谱洗脱剂:5%乙醚的戊烷溶液
制备51:
化合物411
方法:通用步骤14
起始物质:化合物311
色谱洗脱剂:5%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.66(s,3H),0.85(t,6H),0.85(s,9H),0.86(s,9H),1.15(d,3H),1.10-1.92(m,12H),1.99(m,1H),2.18(m,2H),2.33(dd,1H),2.45(dd,1H),2.77(dd,1H),2.90(m,1H),4.18(m,1H),4.37(m,1H),4.87(m,1H),5.17(m,1H),5.35(m,1H),5.53(d,1H,J=15.3Hz),5.58(dd,1H,J=14.9Hz and 8.0Hz),5.95-6.27(m,4H).
制备52:
化合物412
方法:通用步骤14
起始物质:化合物312
色谱洗脱剂:5%乙醚的戊烷溶液
1H NMR δ 0.05(m,12H),0.68(s,3H),0.86(s,9H),0.87(s,9H),0.83-0.95(t,6H),1.16(d,3H),1.10-2.30(m,15H),2.36(dd,1H),2.44(dd,1H),2.79(m,1H),2.88(m,1H),4.18(m,1H),4.37(m,1H),4.87(m,1H),5.17(m,1H),5.35(m,1H),5.53(d,1H,J=15.4Hz),5.64(dd,1H,J=7.7 and 15.0Hz),5.92-6.25(m,4H).
制备53:
化合物413
方法:通用步骤14
起始物质:化合物313
色谱洗脱剂:10%乙醚的石油醚溶液
1H NMR δ 0.05(m,12H),0.23(m,1H),0.31(m,1H),0.50(m,2H),0.67(s,3H),0.86(s,9H)0.87(s,9H),0.97(s,1H),1.14(d,3H),1.30-2.07(m,9H),2.20(m,2H),2.32(m,1H),2.44(dd,1H),2.79(m,1H),2.89(m,1H),3.42(m,1H),4.19(m,1H),4.37(m,1H),4.87(m,1H),5.17(m,1H),5.35(m,1H),5.54(m,2H),6.08(d,1H),6.22(d,1H).
制备54:
化合物414
方法:通用步骤14
起始物质:化合物314
色谱洗脱剂:10%乙醚的石油醚溶液
制备55:
化合物415
方法:通用步骤14
起始物质:化合物315
色谱洗脱剂:10%乙醚的石油醚溶液
1H NMR δ 0.05(m,12H),0.23(m,1H),0.31(m,1H),0.50(m,2H),0.67(s,3H),0.86(s,9H),0.87(s,9H),1.14(d,3H),0.90-2.05(m,10H),2.19(m,2H),2.33(m,1H),2.44(dd,1H),2.79(m,1H),2.89(m,1H),3.46(m,1H),4.18(m,1H),4.36(m,1H),4.87(m,1H),5.17(m,1H),5.34(m,1H),5.57(m,2H),6.08(d,1H),6.22(d,1H).
制备56:
化合物416
方法:通用步骤14
起始物质:化合物316
色谱洗脱剂:10%乙醚的石油醚溶液
实施例
实施例1:
1(S),3(R)-二羟基-20(S)-(3-(1-羟基-1- 甲基-乙基)苯氧甲基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(化合物101)
方法:通用步骤15
起始物质:化合物401
色谱洗脱剂:30%戊烷的乙酸乙酯溶液
1H NMR δ 0.73(s,3H),1.20(d,3H),1.57(s,6H),1.15-1.97(m,9H),2.04(m,2H),2.17-2.45(m,3H),2.60(m,2H),2.83(dd,1H),3.81(t,1H),4.00(dd,1H),4.23(m,1H),4.43(m,1H),5.01(m,1H),5.33(m,1H),5.45(m,1H),6.12(d,1H),6.37(d,1H),6.77(m,1H),7.04(m,2H),7.24(t,1H).
实施例2:
1(S),3(R)-二羟基-20(R)-(3-(1-羟基-1- 甲基-乙基)苯氧甲基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(化合物102)
方法:通用步骤15
起始物质:化合物402
色谱洗脱剂:30%戊烷的乙酸乙酯溶液
1H NMR δ 0.73(s,3H),1.23(d,3H),1.57(s,6H),1.45-1.97(m,9H),2.05(m,2H),2.15-2.45(m,3H),2.60(m,2H),2.83(m,1H),3.67(t,1H),4.00(dd,1H),4.23(m,1H),4.43(m,1H),5.02(m,1H),5.34(m,1H),5.49(m,1H),6.12(d,1H),6.37(d,1H),6.77(m,1H),7.04(m,2H),7.24(t,1H).
实施例3:
1(S),3(R)-二羟基-20(S)-(3-(1-羟基-1- 甲基-乙基)苯硫基甲基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(化合物103)
方法:通用步骤15
起始物质:化合物403
色谱洗脱剂:30%戊烷的乙酸乙酯溶液
1H NMR δ 0.71(s,3H),1.19(d,3H),1.56(s,6H),1.15-2.50(m,15H),2.58(dd,1H),2.81(dd 1H),2.87(dd,1H),3.19(dd,1H),4.23(m,1H),4.43(m,1H),5.00(m,1H),5.33(m,1H),5.42(m,1H),6.11(d,1H),6.36(d,1H),7.15-7.30(m,3H),7.46(m,1H).
实施例4:
1(S),3(R)-二羟基-20(R)-(3-(1-羟基-1- 里基-乙基)苯硫基甲基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(化合物104)
方法:通用步骤15
起始物质:化合物404
色谱洗脱剂:30%戊烷的乙酸乙酯溶液
1H NMR δ 0.68(s,3H),1.22(d,3H),1.57(s,6H),1.30-2.50(m,15H),2.60(dd,1H),2.80(dd,1H),2.82(m,1H),3.18(dd,1H),4.23(m,1H),4.44(m,1H),5.00(m,1H),5.33(m,1H),5.46(m,1H),6.10(d,1H),6.36(d,1H),7.15-7.30(m,3H),7.48(m,1H).
实施例5:
1(S),3(R)-二羟基-20(R)-(4-羟基-4-甲基- 戊-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯(化 合物105)
方法:通用步骤15
起始物质:化合物405
色谱洗脱剂:40%戊烷的乙酸乙酯溶液
1H NMR δ 0.69(s,3H),1.02(d,3H),1.19(s,6H),0.80-2.40(m,21H),2.60(dd,1H),2.82(m,1H),4.22(m,1H),4.44(m,1H),5.02(m,1H),5.29(m,1H),5.34(m,1H),6.11(d,1H),6.38(d,1H).
实施例6:
1(S),3(R)-二羟基-20(S)-(4-羟基-4-甲基- 戊-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯(化 合物106)
方法:通用步骤15
起始物质:化合物406
色谱洗脱剂:30%戊烷的乙酸乙酯溶液
1H NMR δ 0.70(s,3H),1.05(d,3H),1.21(s,6H),1.15-2.40(m,21H),2.60(m,1H),2.82(m,1H),4.24(m,1H),4.42(m,1H),5.01(m,1H),5.33(m,2H),6.10(d,1H),6.37 (d,1H).
实施例7:
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基- 庚-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯(化 合物107)
方法:通用步骤15
起始物质:化合物407
色谱洗脱剂:40%戊烷的乙酸乙酯溶液
1H NMR δ 0.68(s,3H),0.85(t,6H),1.01(d,3H),1.45(q,4H),0.80-2.45(m,23H),2.60(m,1H),2.82(m,1H),4.23(m,1H),4.44(m,1H),5.02(m,1H),5.28(m,1H),5.34(m,1H),6.11(d,1H),6.38(d,1H).
实施例8:
1(S),3(R)-二羟基-20(S)-(5-乙基-5-羟基- 庚-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯(化 合物108)
方法:通用步骤15
起始物质:化合物408
色谱洗脱剂:40%戊烷的乙酸乙酯溶液
1H NMR δ 0.70(s,3H),0.85(t,6H),1.03(d,3H),1.45(q,4H),1.00-2.40(m,23H),2.60(dd,1H),2.81(m,1H),4.23(m,1H),4.43(m,1H),5.01(m,1H),5.31(m,1H),5.33(m,1H),6.11(d,1H),6.37(d,1H).
实施例9:
1(S),3(R)-二羟基-20(R)-(5-羟基-5-甲基- 己-1(E),3(E)-二烯-1-基)-9,10-断-孕甾-5(Z),7(E), 10(19),16-四烯(化合物109)
方法:通用步骤16
起始物质:化合物409
实施例10:
1(S),3(R)-二羟基-20(S)-(5-羟基-5-甲基 -己-1(E),3(E)-二烯-1-基)-9,10-断-孕甾-5(Z),7(E), 10(19),16-四烯(化合物110)
方法:通用步骤15
起始物质:化合物410
实施例11:
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基 -庚-1(E),3(E)-二烯-1-基)-9,10-断-孕甾-5(Z),7(E), 10(19),16-四烯(化合物111)
方法:通用步骤16
起始物质:化合物411
1H NMR δ 0.68(s,3H),0.86(t,6H),1.16(d,3H),1.56(q,4H),1.35-2.43(m,14H),2.59(dd,1H),2.80(dd,1H),2.91(m,1H),4.23(m,1H),4.43(m,1H),5.00(m,1H),5.33(m,1H),5.37(m,1H),5.55(d,1H,J=15.4Hz),5.58(dd,1H,J=14.9Hz and 8.0Hz),5.95-6.25(m,3H),6.36(d,1H).
实施例12:
1(S),3(R)-二羟基-20(S)-(5-乙基-5-羟基- 庚-1(E),3(E)-二烯-1-基)-9,10-断-孕甾-5(Z),7(E), 10(19),16-四烯(化合物112)
方法:通用步骤16
起始物质:化合物412
1H NMR δ 0.71(s,3H),0.86(t,6H),1.17(d,3H),0.83-2.45(m,18H),2.60(dd,1H),2.80(m,1H),2.89(m,1H),4.23(m,1H),4.44(m,1H),5.01(m,1H),5.33(m,1H),5.37(m,1H),5.55(d,1H,J=15.3Hz),5.64(dd,1H,J=7.7and 15.0Hz),6.01(dd,1H,J=10.3 and 15.0Hz),6.11(d,1H),6.18(dd,1H,J=10.3 and 15.3Hz),6.37(d,1H).
实施例13:
1(S),3(R)-二羟基-20(R)-(3-环丙基-3-羟 丙-1(E)-烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(24(S)-异构体)(化合物113)
方法:通用步骤16
起始物质:化合物413
1H NMR δ 0.23(m,1H),0.32(m,1H),0.51(m,2H),0.70(s,3H),0.99(m,1H),1.15(d,3H),1.10-2.40(m,14H),2.59(dd,1H),2.80(dd,1H),2.90(m,1H),3.42(m,1H),4.23(m,1H),4.43(m,1H),5.00(m,1H),5.33(m,1H),5.37(m,1H),5.55(m,2H),6.10(d,1H),6.36(d,1H).
实施例14:
1(S),3(R)-二羟基-20(S)-(3-环丙基-3-羟 丙-1(E)-烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(24(S)-异构体)(化合物114)
方法:通用步骤16
起始物质:化合物414
实施例15:
1(S),3(R)-二羟基-20(R)-(3-环丙基-3-羟 丙-1(E)-烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(24(R)-异构体)(化合物115)
方法:通用步骤16
起始物质:化合物415
1H NMR δ 0.23(m,1H),0.32(m,1H),0.51(m,2H),0.70(s,3H),0.99(m,1H),1.15(d,3H),1.12-2.45(m,14H),2.60(bd,1H),2.80(m,1H),2.90(m,1H),3.46(m,1H),4.23(m,1H),4.44(m,1H),5.00(m,1H),5.33(m,1H),5.36(m,1H),5.58(m,2H),6.10(d,1H),6.36(d,1H).
实施例16:
1(S),3(R)-二羟基-20(S)-(3-环丙基-3-羟 丙-1(E)-烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19), 16-四烯(24(R)-异构体)(化合物116)
方法:通用步骤16
起始物质:化合物416
实施例17:
含有化合物111的胶囊
将化合物111溶于花生油中,使之最终浓度达到1μg化合物/ml油。将10份明胶(重量比),5份甘油(重量比),0.08份山梨酸钾(重量比)以及14份蒸馏水(重量比)一起混合加热,形成软明胶胶囊。向其中填充100μl化合物111的油溶液,这样每个胶囊中含有0.1μg化合物111。
实施例18:
含有化合物111的皮肤霜
将0.05mg化合物111溶于1g杏仁油中。向此溶液中加入40g矿物油和20g自身乳化蜂蜡。将此溶液加热至液体状。加入40ml热水,充分混合。生成的每克霜中大约含有0.5μg化合物111。
Claims (12)
2、权利要求1化合物的非对映异构体,其为纯品形式或为非对映异构体的混和物。
3、权利要求1中的化合物,它们是:
a)1(S),3(R)-二羟基-20(S)-(3-(1-羟基-1-甲基乙基)苯氧甲基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或相应的20(R)异构体,
b)1(S),3(R)-二羟基-20(S)-(4-羟基-4-甲基-戊-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯,
c)1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基-庚-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或相应的20(S)异构体,
d)1(S),3(R)-二羟基-20(R)-(3-环丙基-3-羟丙-1(E)-烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯(24(S)-异构体)或相应的24(R)异构体。
4、制备权利要求1中式I化合物的方法,其包括:
a)从1(S),3(R)-双(叔丁基二甲基甲硅烷氧基)-20-对甲苯磺酰氧甲基-9,10-断-孕甾-5(E),7(E),10(19),16-四烯的20(S)和20(R)异构体进行下面反应制备式I化合物中与C-20相连的侧链,
(i)在碱存在下于溶剂中,与侧链结构单元H-X-R3进行反应,其中X为O或S,R3为间-C6H4-CR1R2Z1,且Z为羟基或保护羟基,或者
(ii)在Li2CuCl4存在下,于溶剂中,与格氏试剂R4-Mg-Hal进行反应,其中R4为-CH2-(CH2)n-CR1R2Z1,n为2,3,或4,Z1的定义同上,Hal为Cl或Br,并且
b)上述得自步骤a)的化合物可以任意地进行(i)从外消旋体中分离,(ii)用三重增感剂使之进行光异构化,得到5(Z)异构体,(iii)去甲硅烷基化以及(iv)脱保护;这些反应的顺序可以任选。
5、权利要求4所述的方法,其中步骤a)(i)中的碱为NaH.
6、权利要求4所述的方法,其中步骤a)(ii)中的溶剂为THF。
7、制备权利要求1中式I化合物的方法,其包括:
a)从1(S),3(R)-双(叔丁基二甲基甲硅烷氧基)-20-甲酰基-9,10-断-孕甾-5(E),7(E),10(19),16-四烯的20(S)和20(R)异构体进行下面反应制备式I化合物中与C-20相连的侧链,
(i)与Wittig-型试剂进行反应,然后再使生成的酯与有机金属试剂进行反应,或
(ii)与wittig-型试剂进行反应,随后在CeCl3的存在下,再使生成的酮与还原剂进行反应,并且,b)上述得自步骤a)的化合物可以任意地进行(i)从外消旋体中分离,(ii)用三重增感剂使之进行光异构化,得到5(Z)异构体,(iii)去甲硅烷基化以及(iv)脱保护;这些反应的顺序可以任选。
8、权利要求7所述的方法,其中步骤a)(ii)中的还原剂为NaBH4。
9、用于合成式I化合物和其类似物的中间体,它们是:
a)1(S),3(R)-双(叔丁基二甲基甲硅烷氧基)-20(S)-羟甲基-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或相应的20(R)异构体,
b)1(S),3(R)-双(叔丁基二甲基甲硅烷氧基)-20(S)-对甲苯磺酰基甲基-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或相应的20(R)异构体,
c)1(S),3(E)-双(叔丁基二甲基甲硅烷氧基)-20(S)-甲酰基-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或相应的20(R)异构体。
10、含有有效剂量的至少一种权利要求1-3中任一项所述化合物以及药用非毒性的载体和/或辅助剂的药物组合物。
11、权利要求10中的药物组合物,其为剂量单位形式,剂量单位中含有重量比为0.1ppm至0.1%的式I化合物。
12、权利要求1-3中任一要求的化合物用于制备治疗和预防牛皮癣的药物的用途。
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CA2588396C (en) | 2004-11-22 | 2013-04-23 | Wisconsin Alumni Research Foundation | 17,20(e)-dehydro vitamin d analogs and their uses |
US8222236B2 (en) | 2008-07-10 | 2012-07-17 | Wisconsin Alumni Research Foundation | 2-methylene-(20E)-20(22)-dehydro-19-nor-vitamin D analogs |
US7893043B2 (en) | 2008-07-10 | 2011-02-22 | Wisconsin Alumni Research Foundation | 2-methylene-(17Z)-17(20)-dehydro-19,21-dinor-vitamin D analogs |
US7888339B2 (en) | 2008-07-10 | 2011-02-15 | Wisconsin Alumni Research Foundation | 2-methylene-20(21)-dehydro-19-nor-vitamin D analogs |
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US5087619A (en) * | 1988-01-20 | 1992-02-11 | Hoffman-La Roche Inc. | Vitamin D3 analogs |
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US5401733A (en) * | 1993-10-01 | 1995-03-28 | Hoffmann-La Roche Inc. | Stable and active metabolites of 1,25-dihydroxy-16-ene-cholecalciferol |
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EP0944592A1 (en) | 1999-09-29 |
WO1998024762A1 (en) | 1998-06-11 |
EP0944592B1 (en) | 2005-01-26 |
AU5117198A (en) | 1998-06-29 |
ATE287873T1 (de) | 2005-02-15 |
AU719081B2 (en) | 2000-05-04 |
CZ198399A3 (cs) | 1999-10-13 |
DE69732369D1 (de) | 2005-03-03 |
NZ335862A (en) | 2000-11-24 |
JP2001506610A (ja) | 2001-05-22 |
HK1023991A1 (en) | 2000-09-29 |
GB9625271D0 (en) | 1997-01-22 |
PT944592E (pt) | 2005-04-29 |
PL189092B1 (pl) | 2005-06-30 |
CN1241999A (zh) | 2000-01-19 |
CA2272148A1 (en) | 1998-06-11 |
HUP9904603A3 (en) | 2000-09-28 |
US20020103172A1 (en) | 2002-08-01 |
HUP9904603A2 (hu) | 2000-06-28 |
KR20000057417A (ko) | 2000-09-15 |
DE69732369T2 (de) | 2006-05-11 |
ES2236830T3 (es) | 2005-07-16 |
RU2175318C2 (ru) | 2001-10-27 |
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