CN1201452A - 24-高-26,27-六氟-胆钙化甾醇 - Google Patents
24-高-26,27-六氟-胆钙化甾醇 Download PDFInfo
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- CN1201452A CN1201452A CN96198019A CN96198019A CN1201452A CN 1201452 A CN1201452 A CN 1201452A CN 96198019 A CN96198019 A CN 96198019A CN 96198019 A CN96198019 A CN 96198019A CN 1201452 A CN1201452 A CN 1201452A
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Abstract
本发明涉及式(Ⅰ)化合物,其中A为具有立体化学构型E或Z的碳双键,即分别为式(a)和式(b),R为羟基且R1为氢或=CH2,或R为氢或氟且R1为=CH2。式(Ⅰ)化合物诱导某些皮肤细胞系和癌细胞系分化并抑制其增生。因此,式(Ⅰ)化合物可用作治疗过度增生性皮肤病如牛皮癣的药物。式(Ⅰ)化合物也可用作治疗肿瘤如白血病的药物。
Description
式I化合物促使某些皮肤细胞系和癌细胞系分化并抑制其增生。因此,式I化合物可用作治疗过度增生性皮肤病(如牛皮癣)的药剂。式I化合物也可用作治疗肿瘤疾病(如白血病)的药剂。
这里所用的术语“低级烷基”指含1-4个碳原子的直链或支链烷基,例如甲基,乙基,丙基,异丙基,丁基,叔丁基等。术语“芳基-低级烷基”为对甲苯基,苄基,苯乙基,苯丙基等。术语“芳基”是指从芳香烃衍生出来的基团,其可以是未取代的或被一个或多个低级烷基取代。芳基的实例为苯基和对甲基苯基。术语“卤素”指卤素原子,即溴,氯,氟或碘。
本发明涉及含有一种式I化合物或两种或多种式I化合物的混合物的组合物。
本发明也涉及通过以一种式I化合物或两种或多种式I化合物的混合物给药来治疗上述疾病的方法。
本发明也涉及制备式I化合物及式X,XI,XII和V中间体的方法。
在式I化合物的优选的实施例中,R为羟基且R1为=CH2。在式I的另一化合物中,R1为氢。
最优选的式I化合物为:1,25-二羟基-22E,24Z-二烯-24-高-26,27-六氟胆钙化甾醇;1,25-二羟基-22E,24E-二烯-24-高-26,27-六氟胆钙化甾醇;1,25-二羟基-22E,24Z-二烯-24-高-19-去甲26,27-六氟胆钙化甾醇;1,25-二羟基-22E,24E-二烯-24-高-19-去甲26,27-六氟胆钙化甾醇;1α-氟-25-羟基-22E-24Z-二烯-24-高-26,27-六氟胆钙化甾醇;和1α-氟-25-羟基-22E-24E-二烯-24-高-26,27-六氟胆钙化甾醇。
参考下面结构式流程图I-III和实施例,按下述方法通过从相应的受保护的化合物中除去式-Si:(R4,R4,R6)保护基来制备式I的化合物。
在上面结构式流程图I中,式II的化合物通过与相应的式III化合物反应转变成式IVa、IVb、或IVc的化合物其中Ph为苯基,R1,R4,R5和R6的定义如上所述,R7为氢,氟或其中R4,R5和R6如上所述。
该反应于-60℃--90℃,优选-78℃,在极性非质子有机溶剂(如无水乙醚或更优选无水四氢呋喃)中,在强碱(如烷基锂象丁基锂)的存在下进行。
式III化合物是已知的或可按已知方法制备。
通过在极性有机熔剂(如醚,或更优选四氢呋喃)中与氟盐(如氟化四丁基铵)反应除去式IVa、IVb或IVc化合物的保护基,得到相应的式Ia、Ib或Ic化合物。
上述的式II的中间体可按下述方法并具体参考下面的结构式流程图II来制备。
在上面结构式流程图II中,当制备其中A为的式I化合物时,在非质子有机溶剂(如无水醚或更优选无水四氢呋喃)中,优选在碱金属烷氧化物(如甲醇钠)存在下,在回流温度(对四氢呋喃约为80℃)下使式V化合物与还原剂(如氢化锂铝)反应约2.5小时部分氢化,冷却至约0℃,用常规方法处理,得到相应的式VI化合物。
通过在室温下在非质子溶剂(如无水四氢呋喃或更优选无水二氯甲烷)中用氧化剂如氯化铬酸2,2′-二吡啶鎓或重铬酸吡啶鎓处理将所得的式IV化合物氧化成式VII化合物。
使式VII化合物在非质子有机溶剂(如无水四氢呋喃或更优选无水二氯甲烷)中与(三烷基甲硅烷)咪唑(如(三甲基甲硅烷基)咪唑)反应,转变成式II化合物。用常规方法(如萃取后再用色谱处理)处理式II化合物。
参考下面结构式流程图III按如下所述制备式V的化合物。
在上面结构式流程图III中,使已知化合物式VIII的化合物(Wovkulich,P.M.等人,Proceedings of the 6th Workshop of VitaminD,1985,755-764页),在非质子溶剂(如无水四氢呋喃或更优选无水二氯甲烷)中,在氩气氛下,与氧化剂(如氯化铬酸2,2′-二吡啶鎓或氯化铬酸吡啶鎓)作用,转变成式IX化合物。
使式IX的化合物在非质子溶剂(如无水四氢呋喃或无水二氯甲烷)中与维悌希试剂(如溴化(3-三甲基-甲硅烷基-2-丙炔基)-三苯基磷)和碱(如丁基锂)反应,转化为式X的化合物。反应于-78℃下进行。
式X化合物通过与硝酸银在醇溶剂(如乙醇)中反应转变为式XI化合物。
式XI化合物通过与氟代丙酮(如六氟丙酮)反应,转变成式XII化合物。反应于-78℃下进行。
式XII的化合物通过在有机溶剂(如乙腈和四氢呋喃的混合物)中与二甲硅烷基化试剂(disilylating reageat)(如氢氟酸)反应,转化成式V的化合物。
可以口服方式将上述式I化合物向需要这种治疗的温血动物给药以治疗肿瘤疾病如白血病。更具体地说,可以每天0.05-50μg的剂量将上述式I化合物向成年人口服给药以治疗肿瘤疾病如白血病。
可以口服方式将上述式I化合物向需要这种治疗的温血动物给药以治疗过度增生性皮肤病如牛皮癣,基底细胞癌,角蛋白疾病和角化病。更具体地说,可以每天大约0.5-50μg的剂量口服方式将上述式I化合物向成人给药以治疗过度增生性皮肤病如牛皮癣,基底细胞癌,角蛋白疾病和角化病。这些化合物可以每天大约0.05-50μg,优选0.5-50μg的剂量口服给药用来治疗痤疮。
可将上述式I的化合物向需要这种治疗的温血动物局部给药来治疗过度增生的皮肤病如牛皮癣,基底细胞癌,角蛋白疾病和角化病,更具体地说,可以每天每克局部应用制剂大约为0.5-大约50μg的剂量将上述式I化合物局部给药以治疗过度增生性皮肤病如牛皮癣,基底细胞癌,角蛋白疾病和角化病。
下面的试验方法可证明式I化合物具有治疗肿瘤疾病的药物活性。HL-60细胞分化
通过还原氮蓝四唑(NBT)测量它们的氧化突变电位来测定HL-60细胞分化的诱导
在添加有10%胎牛血清(FCS),2mML-谷氨酰胺,1mM丙酮酸钠,1%非必需氨基酸,50U/ml青霉素和50μg/ml链霉素的RPMI1640培养基中培养HL-60细胞。把HL-60细胞(在90μlRPMI补充培养基中的30,000细胞)接种到平底微升孔中。接种后,立即将10μl在RPMI补充培养基中稀释的下表I所列试验化合物加到各孔中,使最终浓度在10-11和10-6M之间(自10-3M的乙醇储备液开始并于-20℃避光贮存)。3天后,用多道吸量管从孔中除去培养基,并用100μlNBT溶液(含200nM肉豆蔻酸佛波醇酯乙酸盐的1mg/ml磷酸盐缓冲液)置换。于37℃再培养1小时后,除去NBT溶液,加入100μl 10%十二烷基硫酸钠的0.01N HCl溶液。用自动平板读数器于540 nm以光度计法定量测定还原的NBT量。计算3个孔的平均值。S.E.M在5和10%之间。在用100-1000nm钙化三醇进行的相同实验中将值表示成最大分化的百分数。用图谱法确定达到最大值的50%的浓度(nM),在表I中以ED50给出。
表I
化合物 | ED50(nM) |
1,25-二羟基-胆钙化甾醇 | 6.0 |
1,25-二羟基-22E,24Z-二烯-24-高-26,27-六氟-胆钙化甾醇 | 1.6 |
1,25-二羟基-22E,24E-二烯-24-高-26,27-六氟-胆钙化甾醇 | 0.9 |
从上面结果可以看出式I化合物促使HL-60细胞分化,并因此阻止这些癌细胞生长。因此,式I化合物可用于治疗肿瘤和白血病。
通过下面的试验可证明式I化合物具有用作治疗过度增生性皮肤病的药物的活性。角质化细胞增生的抑制
使用HaCaT细胞系-未死的人细胞系HaCaT(起初从N.E.Fusening,德国癌症研究中心,Heidelberg,德国获得)。在试验化合物存在下培养6天后测量按指数增长的培养基中3H-胸苷结合数。
细胞培养:在含有4.5g葡萄糖和哈姆F12营养物,3∶1(体积/体积)的混合物的Dulbecco改性的Eagle培养基中培养HaCaT。该混合物中补充有10%FCS,2mM L-谷氨酰胺,50UI/ml青霉素,50μg/ml链霉素,10ng/ml EGF,400ng/ml氢化可的松,8.5ng/ml霍乱毒素和5ng/ml胰岛素。将细胞保持在含5%CO2和95%空气的潮湿气氛中并每隔3-4天换一次气。
3H-胸苷摄入的抑制:将HaCaT细胞(在180μl的具有添加物的混合物中有250个细胞)接种到96孔培养板中,并于37℃用5%CO2和95%空气保温接种后立即将用20μl含有1%乙醇的具有添加物的混合物稀释的下表II列出的试验化合物加到孔中,使终浓度在10-9到10-6M之间(从1mM的乙醇中的储备液开始,于-20℃避光保存)。6天后,向孔中加入1μCi/孔的浓度的3H-胸苷(5Ci/mmol)。脉冲标记细胞最后6小时的生长期。然后于37℃在剧烈搅动下让细胞受胰蛋白酶作用10分钟,并用细胞收集器把细胞收集到96-孔过滤板上。于40℃真空干燥20-30分钟后,加入20μl闪烁体,计算结合到过滤板上的放射活性。
把该值表示成对照(无试验化合物的样品)的百分数。用图谱法确定达到对照值的50%的浓度,并将该值表达为表II中的IC50(抑制浓度)。
表II
化合物 | IC50(nM) |
1,25-二羟基-胆钙化甾醇 | 55.0 |
1,25-二羟基-22E,24Z-二烯-24-高-26,27-六氟-胆钙化甾醇 | 2.1 |
1,25-二羟基-22E,24E-24-高-二烯-26,27-六氟-胆钙化甾醇 | 5.1 |
从上面结果可以看出:式I化合物抑制角质化细胞的增生。因此,式I化合物可用于治疗过度增生性皮肤病如牛皮癣。鼠的钙耐受性试验
体内钙平衡的大辐度改变强烈地影响鼠体重增长。
每天给鼠(体重25-30g)皮下注射化合物,连续4天。仅在5天疗程之前和之后记录体重。在这个疗程中引起体重零增长的剂量为“最高耐受剂量”(HTD)。结果示于表III中
表III
化合物 | HTD(μg/kg) |
1,25-二羟基-胆钙化甾醇 | 0.5 |
1,25-二羟基-22E,24Z-24-高-26,27-六氟-胆钙化甾醇 | 0.4 |
1,25-二羟基-22E,24E-24-高-23E-二烯-26,27-六氟-胆钙化甾醇 | 0.8 |
从上面结果可以看出,式I化合物显示出与1,25-二羟基胆钙化甾醇近似相同的HTD值。
下面实施例进一步描述本发明,但丝毫不限定本发明。
包含本发明式I化合物的口服剂型可与可药用载体物质一起包含在胶囊,片剂等之内。
可包含在胶囊之内的可药用载体的实例如下:粘合剂如黄蓍胶,阿拉伯胶,玉米淀粉,或明胶;赋形剂如磷酸二钙;崩解剂如玉米淀粉;马铃薯淀粉,藻酸等;润滑剂如硬脂酸镁,甜味剂如蔗糖,乳糖或糖精;调味剂如薄荷,冬青油或樱桃油。其它各种物质可作为涂层或用来改变剂型的物理形式。例如,片剂可涂有紫胶,糖或两者。糖浆或酏剂可含有活性化合物,作为甜味剂的蔗糖,作为防腐剂的对羟苯甲酸甲酯和对羟苯甲酸丙酯,颜料和调味剂(如樱桃或橙子调味料)。
含本发明的式I化合物的可局部应用的剂型包括:含有具有油状的、可吸收的、水溶性的和乳化型基料(如黄凡士林、羊毛脂、聚乙二醇等)的配方的软膏和乳膏。
洗剂为液体制剂,包括从简单的溶液到含细分散物质的各种水制剂或醇水制剂。洗剂可含悬浮剂或分散剂,例如,纤维素衍生物(如乙基纤维素,甲基纤维素等);把活性成分包裹在由水、醇、甘油等组成的赋形剂中的明胶或树胶。
凝胶是通过使活性成分的溶液或悬浮液在载体赋形剂中凝结而形成的半固体制剂。把含水或不含水的赋形剂用凝胶剂(如羧基聚亚甲基)将其凝结,用碱(如氢氧化钠和胺如聚乙烯可可胺)将其中和到适当的凝胶稠度。
这里所用的术语“局部应用的”指包含掺合在适当药物载体中,且在受感染部位使用的以施加局部作用的活性成分的用途。因此,可局部应用的组合物包括与皮肤直接接触的外部应用的那些化合物药物形式。局部应用剂型包括凝胶剂,乳膏,洗剂,软膏,粉末剂,气雾剂及通过将式I化合物与已知的局部应用的药物载体物质混合得到的可将药物应用于皮肤的其它常用剂型。除了用于皮肤外,本发明的局部应用的组合物也可用于治疗粘膜炎症,其中这样的膜易于接近局部用药。例如局部应用组合物可用于嘴或结肠下部的粘膜内层。
实施例1
[1R-[1α(S*),3aβ,4α,7aα]]-4-[[(1,1-二甲基乙基)二甲基甲硅烷基]-氧基]八氢-β,7α-二甲基-1H-茚-1-乙醛
在氩气氛和搅拌下,向5.37g(25mmol)氯铬酸吡啶鎓的50ml无水二氯甲烷的悬浮液中滴加溶于15ml无水二氯甲烷中的3.26g(10mmol)[1R-[1α(S*),3aβ,4α,7aα]]-4-[[(1,1-二甲基乙基)二甲基甲硅烷基]-氧基]八氢-β,7α-二甲基-1H-茚-1-乙醇。搅拌该反应混合物1小时,然后用120ml乙醚稀释,在100g Florosil柱上纯化,得到3.04g(94%)的标题化合物。
1H-NMR(CDCL3):δ0.02(s,6H,2CH3),0.88(s,9H,3CH3),1.09(d,3H,J=7Hz,CH3),4.02(宽的多重峰,1H,CH)9.58(d,1H,J=3Hz,CH)。
实施例2
[1R-[1α(1R*,2E),3aβ,4α,7aα]]-(1,1-二甲基乙基)二甲基-[[8氢-7a-甲基-1-[1-甲基-5-(三甲基甲硅烷基)-2-戊烯-4-炔基]-1H-茚-4-基]氧基]硅烷
在-78℃、搅拌下,向1g(2.2mmol)溴化(3-三甲基甲硅烷基-2-丙炔基)-三苯基-鏻在20ml无水四氢呋喃中的悬浮液中加入1.4ml(2.2mmol)1.6M正丁基锂的己烷溶液。加完后,加热混合物至40℃,搅拌0.5小时,混合物变成红色溶液。然后把溶液冷却到-78℃,加入溶于6ml无水四氢呋喃中的478mg(1.47mmol)[1R-[1αS*],3aβ,4α,7aα]]-4-[[(1,1-二甲基乙基)]二甲基甲硅烷基]氧基]8氢-β,7a-二甲基-1H-茚-1-乙醛,然后于室温下搅拌1小时,加水使反应停止。用乙酸乙酯萃取完全。用水和盐水洗涤合并的萃取液,并在硫酸钠上干燥,蒸干。用乙烷研制残余物,用乙烷通过急骤式色谱纯化可溶性部分,得到396mg(64%)标题化合物。用己烷通过制备性的HPLC纯化分析样品,并在乙醇中结晶,熔点81-83℃。
[α]25D+80.5℃(c0.2)CHCL3);UVλ(己烷):肩峰227nm(ε17,000,max 236-237nm(ε21,800),肩峰295nm(ε16,000);1H-NMR(CDCL3):δ0.01(s,6H,3CH3),0.19(s,9H,3CH3),0.89(s,9H,3CH3),0.93(s,3H,CH3),1.02(d,3H,J=6.7Hz,CH3),1.80(m,1H,CH2的CH),1.91(dm,1H,J偕=12.5Hz,CH2的CH),2.11(m,1H,CH),3.99(m,1H,CH),5.42(d,1H,J反位15.9Hz,CH),6.06(dd,1H,J连位=8.8Hz,J反位=15.9CH)。
用X-射线分析证实该化合物的结构。分析:C25H46OSi2的
计算值C,71.70,H11.07
实测值C,71.23,H11.04。
实施例3
[1R-[1α(1R*,2E),3aβ,4α,7aα]]-(1,1-二甲基乙基)二甲基[[8氢-7α-甲基-1-[1-甲基-2-戊烯-4-炔基]-1H-茚-4-基]-氧基]硅烷
在室温搅拌下,向1.5g(3.58mmol)[1R[1α(1R*,2E),3aβ,4α,7aα]]-(1,1-二甲基乙基)二甲基-[[8氢-7α-甲基-1-[1-甲基-5-(三甲基甲硅烷基)-2-戊烯-4-炔基]-1H-茚-4-基]氧基]硅烷在9ml无水四氢呋喃和60ml乙醇中的悬浮液中滴加3.65g(21.4mmol)硝酸银在72ml 3∶1乙醇-水中的溶液。生成黄白色沉淀,搅拌所形成的混合物1小时。随后加入60ml水中的4.19g(64.4mmol)氰化钾,此时沉淀溶解。0.5小时后,薄层色谱显示反应进行完全。用500ml水和盐水(1∶1)稀释混合物,用乙酸乙酯彻底萃取。用水和盐水洗涤合并的萃取液,在硫酸钠上干燥,蒸干。用乙烷通过急骤式色谱纯化粗产物,再用乙烷通过使用YMC柱(50mm×50cm)的制备HPLC纯化,得到1.26g(100%)标题化合物。
1H-NMR(CDCL3):δ0.001(s,6H,2CH3),0.89(s,9H,3CH3),0.94(s,3H,3CH3),1.02(d,3H,J=7Hz,CH3),2.13(m,1H,CH),2.75(d,1H,J=2.5Hz,CH),3.99(宽单重峰,1H,CH),5.25(dd,1H,J连位=2.5Hz,J反 位=16Hz,CH),6.09(dd,1H,J连位=8Hz,J反位=16Hz,CH)。
实施例4
[1R-[1α(1R*,2E),3aβ,4α,7aα]]-7-[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]-1,1,1-三氟-2-(三氟甲基)-5-辛烯-3-炔-2-醇
向-78℃搅拌下的0.91g(2.63mmol)[1R-(1α(1R*,2E),3aβ,4α,7aα]]-(1,1-二甲基乙基)-二甲基-[八氢-7a-甲基-1-(1-甲基-2-戊稀-4-炔基]-1H-茚-4-基]氧基]硅烷在15ml无水四氢呋喃中的悬浮液中加入1.65ml 1.6M正丁基锂的己烷溶液。搅拌混合物0.5小时,此时用分散管用2分钟时间引入气态六氟丙酮,再搅拌反应混合物1.5小时,此时薄层色谱显示反应已进行完全。用400ml水稀释反应混合物,用己烷彻底萃取。用水和盐水洗涤合并的萃取液在硫酸钠上干燥,蒸干。用己烷-乙酸乙酯(19∶1)通过急骤式色谱纯化粗产物,得到1.27g(95%)标题化合物。
1H-NMR(CDCL3):δ0.00(s,6H,2CH3),0.88(s,9H,3CH3),1.03(d,3H,CH3),2.18(m,1H,CH),4.00(宽的单重峰,1H,CH),5.42(d,1H,J反 位=16Hz,CH),6.26(dd,1H,J连位=9Hz,J反位=16Hz,CH)。
实施例5
[1R-(1α(1R*,2E),3aβ,4α,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2-庚烯-4-炔基]-1H-茚-4-醇
在室温和搅拌下,向1.648g(3.21mmol)[1R-[1α(1R*,2E),3aβ,4α,7aα]]-7-[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]-1,1,1-三氟-2-(三氟甲基)-5-辛烯-3-炔-2-醇在30ml乙腈和24ml无水四氢呋喃的溶液中加入30ml 49%氢氟酸,搅拌所得的反应混合物3小时。然后用400ml水稀释,用乙酸乙酯彻底萃取。用2N碳酸氢钾和水,最后用盐水洗涤,合并的萃取液在硫酸钠上干燥,蒸干。用己烷-乙酸乙酯(2∶1)通过急骤式色谱纯化粗产品,从乙醚-石油醚(2∶25)中结晶,得到标题化合物1.087g(85%),熔点108-109℃。
[α]25D+47℃(c0.2CHCL3);UVλ(EtOH):最大峰224nm(ε20,060),肩峰230-231nm(ε18,600);1H-NMR(CDCL3):δ0.96(s,3H,CH3),1.05(d,3H,J=6.41Hz,CH3),1.96(宽峰,1H,J偕=13Hz,CH2的CH),2.19(m,1H,CH),4.10(宽单重峰,1H,CH),5.44(d,1H,J反位=16Hz,CH),6.25(dd,1H,J连位=8.9Hz,J反式=16Hz,CH)。
分析:C19H24F6O2的计算值:C 57.28 H 6.07;
测定值:C 57.29 H6.19。
实施例6
[1R-[1α(1R*,2E,4E),3aβ,4α,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟-甲基)-2,4-庚二烯基]1H-茚-4-醇
向装有滴液漏斗,冷凝器和氩气导入管的100ml三颈烧瓶中加入悬浮在1.5ml无水四氢呋喃中的143mg(3.75mmol)氢化铝锂。在冰浴中冷却烧瓶,随着搅拌先小心地加入203mg(3.75mmol)固体甲醇钠,然后滴加300mg(0.753mmol)[1R-[1α(1R*,2E,4E),3aβ,4α,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟-甲基)-2-庚烯-4-炔基]1H-茚-4-醇在6ml无水四氢呋喃中的溶液。加完后除去冰浴,于80℃回流加热反应混合物2.5小时。然后在冰浴中冷却,用1ml水和1ml 2N氢氧化钠使反应停止,加20ml乙醚,搅拌0.5小时,加2.2g MgSO4,搅拌0.5小时,过滤,用乙醚洗涤过滤器,将滤液蒸干。用己烷-乙酸乙酯(4∶1)通过制备性的HPLC纯化粗产物,用二氯甲烷-己烷混合物重结晶后,得到251mg(83.2%)标题化合物结晶,熔点146-148℃。
UVλmax(EtOH):228-229mm(ε32,100),1H-NMR(CDCL3):δ0.907(s,3H,CH3),1.05(d,3H,J=6.5Hz,CH3),1.69(m,1H,CH),1.98(宽峰,1H,J偕=13Hz,CH2的CH),2.17(m,1H,CH),4.09(宽的单重峰,1H,CH),5.59(d,1H,J反位=15.4Hz,CH),5.79(dd,1H,J连位=8.6Hz,J反位=15.3,Hz,CH),6.05(dd,1H,J连位=10.5Hz,J反位=15.3Hz,CH),6.68(dd,1H,J连位=10.6Hz,J反位=15.3Hz,CH)。
分析:C19H26F6O2的计算值:C56.99,H6.55;
测定值:C56.64,H6.41
实施例7
[1R-[1α(1R*,2E,4E),3aβ,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2,4-庚二烯基]-4H-茚-4-酮
搅拌下向300mg(0.75mmol)[1R-[1α(1R*,2E,4E)-3aβ,4α,7aα]]-八氢-7α-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2,4-庚二烯]-4H-茚-4-醇在15ml无水二氯甲烷的溶液中加入1.465g(3.9mmol)重铬酸吡啶鎓,于室温下搅拌3.5小时。加25ml乙醚并搅拌15分钟后,通过硅藻土填料层过滤混合物,用3×25ml乙酸乙酯洗涤填料层用2N碳酸氢钾,水和盐水洗涤合并的滤液,在硫酸钠上干燥,蒸干。用己烷-乙酸乙酯(3∶1)通过急骤式色谱纯化粗产品,得到267mg(89.5%)标题化合物。
1H-NMR(CDCL3):δ0.66(s,3H,CH3),1.08(d,3H,J=6.5Hz,CH3),2.46(dd,1H,J=8和11Hz,CH),5.58(d,1H,J反位=15Hz,CH),5.57(dd,1H,J连位=8.5Hz,J反位=15Hz,CH),6.04(dd,1H,J连位=10.5Hz,J反位=15Hz,CH),6.68(dd,1H,J连位=10.5Hz,J反位=15Hz,CH).
实施例8
[1R-[1α(1R*,2E,4E)-3aβ,7aα]]-8氢-7a-甲基-1-[7,7,7-三氟-1-甲基-6-(三氟甲基)-6-[(三甲基甲硅烷基)氧基]-2.4-庚二烯]-4H-茚-4-酮
搅拌下向267mg(0.67mmol)[1R[1α(1R*,2E,4E),3aβ,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2,4-庚二烯]-4H-茚-4-酮在10ml无水二氯甲烷中的溶液中加入0.885ml(6.03mmol)1-(三甲基-甲硅烷基)咪唑,于室温下搅拌过夜。然后加入水使反应停止,用乙酸乙酯萃取。用水和盐水洗涤合并的萃取液,在硫酸钠上干燥,蒸干。用己烷-乙酸乙酯(5∶1)通过急骤式色谱纯化粗产物,得到307mg(97.3%)标题化合物。
1H-NMR(CDCL3):δ0.02(s,9H,3CH3),0.66(s,3H,3CH3),1.10(d,3H,J=6.5Hz,CH3),2.45(dd,1H,J=8和11Hz,CH2的CH),5.55(dd,1H,J反位=15Hz,CH),5.73(dd,1H,J连位=8.5Hz,J反位=15Hz,CH),6.01(dd,1H,J连位=10Hz,J反位=15Hz,CH),6.51(dd,1H,J连位=10Hz,J反位=15Hz,CH)。
实施例9
1,25-二羟基-22E,24E-二烯-26,27-六氟-24-高-胆钙化甾醇
在-78℃搅拌下向0.608g(1.04mmol)[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]二苯基氧化磷在10ml无水四氢呋喃的溶液中加入0.652ml(1.04mmol)1.6M正丁基锂的己烷溶液。溶液变红,在加入在8ml无水四氢呋喃中的307mg(0.652mmol)[1R[1α(1R*,2E,4E),3aβ,7aα]]八氢-7a-甲基-1-[7,7,7-三氟-1-甲基-6-(三氟甲基)-6-[(三甲基甲硅烷基)氧基]-2,4-庚二烯基]-4H-茚-4-酮的全部过程中颜色不变。于-78℃搅拌反应混合物0.5小时,然后用水使反应停止。用4×50ml乙酸乙酯萃取。用水和盐水洗涤合并的萃取液,在硫酸钠上干燥,蒸干。用己烷-乙酸乙酯(10∶1)通过急骤式色谱纯化粗产物,得到337mg三甲硅烷基化的中间体。
在室温搅拌及氩气气氛下向337mg三甲硅烷基化中间体在8ml无水四氢呋喃中的溶液中分批加入3ml(3mmol)1M四丁基氟化铵的四氢呋喃溶液。反应混合物搅拌过夜,然后用水稀释,用乙酸乙酯萃取。用水和盐水洗涤合并的萃取液,在硫酸钠上干燥并蒸干。用己烷-乙酸乙酯(1∶3)的急骤式色谱和己烷-乙酸乙酯(1∶4)的制备性的HPLC纯化粗产物,得到235mg(67.4%)白色泡沫状的标题化合物,
[α]25D+64.5℃(c0.2,EtOH);UVλmax(EtOH):229nm(ε40,500)262-263nm(ε17,600);1H-NMR(CDCL3):δ0.57(s,3H,CH3),1.08(d,3H,J=6.5Hz,CH3),2.18(m,1H,CH),2.32,2.60(ABX的AB,2H,J连位=6.5and 3Hz,J偕=13Hz,CH2),2.83(宽的双峰,1H,J偕=12.5Hz,CH2的CH),4.23(宽的多重峰,1H,CH),4.44(宽的多重峰,1H,CH),5.00,5.23(2s,2H,CH2),5.60(d,1H,J反位=15.5Hz,CH),5.82(dd,1H,J连位=9Hz,J反 位=15Hz,CH),6.01,6.36(AB,2H,J连位=11Hz,CHCH),6.05(dd,1H,J连位=10.5Hz,J反位=15Hz,CH),6.69(dd,1H,J连位=10.5Hz,J反位=15.5Hz,CH).
分析:C28H36F6O3的计算值:C6291,H6.79;
测定值:C61.83,H7.02
实施例10
[1R-[1α(1R*,2E,4Z),3aβ,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2,4-庚二烯基]-1H-茚-4-醇
在1个大气压和室温下把392mg(0.98mmol)[1R-[1α(1R*,2E),3aβ,4α,7aα]]-八氢-7α-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2-庚烯-4-炔基]-1H-茚-4-醇],5ml乙酸乙酯,12.5ml己烷,0.35ml无水乙醇,0.017ml和63mg林德拉催化剂(CaCO3上承载5%的Pd)的混合物氢化2小时。通过硅藻土填料层过滤反应混合物,用己烷洗涤填料层。用稀酸,盐水,2N碳酸氢钾和水洗涤合并的滤液,在硫酸钠上干燥,蒸干。用己烷重结晶粗产物。用己烷-乙酸乙酯(3∶1)通过制备性的HPLC分离纯化。第一步得到的产物和母液,最终得到220mg(56%)标题化合物,熔点140-141℃;
UVλmax(EtOH):231-232nm(ε30,600);1H-NMR(CDCl3):δ0.97(s,3H,CH3),1.05(d,3H,J=6.7Hz,CH3),1.98(宽峰,1H,J偕=13Hz,CH2的CH),2.21,(m,1H,CH),4.08(宽的单峰,1H,CH),5.25(d,1H,J顺位=11.5Hz,CH),5.75(dd,1H,J连位=8.8Hz,J反位=15Hz,CH),6.43(t,1H,J连位和J顺位=11.5Hz,CH),6.71(dd,1H,J连位=11.5Hz,J反位=15Hz,CH)。
分析:C19H26F6O2的计算值:C56.99,H6.55;
测定值:C57.03,H6.69
实施例11
[1R[1α(1R*,2E,4E),3aβ,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2,4-庚二烯基]-4H-茚-4-酮
在室温和搅拌下向202mg(0.52mmol)[1R-[1α(1R*,2E,4Z),3aβ,4α,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-2,4-庚二烯基]-1H-茚-4-醇在10ml无水二氯甲烷中的溶液中加入886mg(2.36mmol)重铬酸吡啶鎓,搅拌0.5小时。然后加入25ml乙醚,搅拌15分钟,通过硅藻土填料层过滤。用3×25ml乙酸乙酯洗涤填料层。用2N碳酸氢钾,水和盐水洗涤合并的滤液,在硫酸钠上干燥,蒸干。用二氯甲烷-乙酸乙酯(20∶1)通过急骤式色谱纯化粗产物,得到196mg(96%)标题化合物。
1H-NMR(CDCL3):δ0.67(s,3H,CH3),1.10(d,1H,J=6.5Hz,CH3),2.45(dd,1H,J=8和11Hz,CH),5.26(d,1H,J顺位=11.5Hz,CH),5.76(dd,1H,J连位=8.5Hz,J反位=15Hz,CH),6.43(t,1H,J连位和J顺位=11.5Hz,CH),6.73(dd,1H,J连位=11.5Hz,J反位=15Hz,CH)。
实施例12
[1R[1α(1R*,2E,4Z),3aβ,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-1-甲基-6-(三氟甲基)-6-[(三甲基甲硅烷基)氧基]-2,4-庚二烯基]-4H-茚-4-酮
在氩气气氛和搅拌下向196mg(0.49mmol)[1R-[1α(1R*,2E,4Z),3aβ,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-6-羟基-1-甲基-6-(三氟甲基)-2,4-庚二烯基]-4H-茚-4-酮在10ml无水二氯甲烷中的溶液中加入0.67ml(4.42mmol)1-(三甲基甲硅烷基)-咪唑,然后于室温下将所得的反应混合物搅拌过夜。然后用乙酸乙酯稀释,用水和盐水洗涤,在硫酸钠上干燥,蒸干。用己烷-乙酸乙酯(5∶1)通过急骤式色谱纯化粗产物,得到229mg(99%)标题化合物。
实施例13
1,25-二羟基-22E,24Z-二烯-26,27-六氟-24-高-胆钙化甾醇
在-78℃和搅拌下,向467mg(0.80mmol)[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]二苯基氧化磷在10ml无水四氢呋喃中的溶液中加入0.5ml(0.80mmol)1.6M正丁基锂的己烷溶液。溶液变红,在加入溶于8ml无水四氢呋喃中的229mg(0.486mmol)[1R[1α(1R*,2E,4Z),3aβ,7aα]]-八氢-7a-甲基-1-[7,7,7-三氟-1-甲基-6-(三氟甲基)-6-[(三甲基甲硅烷基)氧基]-24-庚二烯基]-4H-茚-4-酮的整个过程中颜色不变。于-78℃搅拌反应混合物1.5小时,用水使反应停止。用乙酸乙酯彻底萃取。用水和盐水洗涤合并的萃取液,在硫酸钠上干燥,蒸干。用己烷-乙酸乙酯(10∶1)通过急骤式色谱纯化粗残留物,得到310mg三甲硅烷基化的中间体。
在室温搅拌及氩气氛下向310mg三甲硅烷基化中间体溶于8ml无水四氢呋喃中的溶液中分批加入4.5ml 1M氟化四丁基铵的四氢呋喃溶液。搅拌反应混合物48小时,然后用水稀释,用乙酸乙酯彻底萃取。用水和盐水洗涤合并的萃取液,在硫酸钠上干燥,蒸干。先通过使用己烷-乙酸乙酯(1∶3)的急骤式色谱和使用己烷-乙酸-乙酯(1∶4)的制备性的HPLC,再通过使用己烷-乙酸乙酯(1∶4)的制备性的HPLC纯化粗产物,得到206mg(79.2%)白色泡沫状的标题化合物。
[α]25D+17.5℃(c0.2,EtOH);UVλ(EtOH):max 232-233nm(ε38,700),肩峰265nm(ε17,200);1H-NMR(CDCl3):δ0.57(s,3H,CH3),1.07(d,3H,J=6.5Hz,CH3),2.22(m,1H,CH),2.32,2.60(ABX的AB,2H,J连位=6.5和3.5Hz,J偕=13Hz,CH2),2.84(dd,1H,J连位=4Hz,J偕=12.5Hz,CH2的CH),4.23(宽的多重峰,1H,CH),4.43(宽的多重峰,1H,CH),5.00,5.33(2s,2H,CH2)5.25(d,1H,J连位=12Hz,CH),5.76(dd,1H,J连 位=8.5Hz,J反位=15Hz,CH),6.02,6.38(AB,2H,J连位=11.3Hz,CHCH),6.43(t,1H,J连位和J反位=12Hz,CH),6.71(dd,1H,J连位=12Hz,J反位=15Hz,CH)。
分析:C28H36F6O3的计算值:C62.91,H6.79;
测定值:C61.73,H6.74
实施例14
口服剂型:软胶囊
mg/胶囊 | |
1,25-二羟基-22E,24E-二烯-24-高-26,27-六氟-胆钙化甾醇 | 0.0005-0.050 |
丁基化羟基甲苯(BHT) | 0.016 |
丁基化羟基苯甲醚(BHA) | 0.016 |
Myglyol-812加至足量 | 160 |
1.把BHT和BHA悬浮在Myglyol-812中,加热至大约50℃,搅拌直到溶解。
2.把化合物A溶于步骤1的溶液中。
3.把步骤2得到的溶液装入软明胶帽中。
所有步骤都在氮气氛下避光进行。
实施例15口服剂型:软胶囊
mg/胶囊 | |
化合物A | 0.0005-0.050 |
α-生育酚 | 0.016 |
Myglyol-812足量 | 160 |
1.把α-生育酚悬浮在Mygloyol-812中,加热至大约50℃,搅拌直到溶解。
2.把化合物A溶于步骤1的溶液中。
3.把步骤2得到的溶液装入软明胶帽中。
以上各步都在氮气氛下避光进行。
实施例16
局部应用的剂型:乳膏
%体积/体积 | |
化合物A | 0.00005-5.0 |
十六烷醇 | 1.50 |
十八烷醇 | 2.50 |
脱水山梨醇单酯酸酯(司班60) | 2.00 |
矿物油 | 2.00 |
单硬酯酸甘油酯和聚氧乙烯乙二醇硬脂酸酯的混合物(Arlacel 165) | 4.00 |
多乙氧基醚60(吐温60) | 1.00 |
辛酸/癸酸甘油三酯 | 5.00 |
山梨醇溶液 | 4.00 |
乙二胺四乙酸二钠 | 0.10 |
丁基化的羟基苯甲醚(BHA) | 0.02 |
山梨酸 | 0.20 |
山梨酸钾 | 0.1-0.2 |
水 加到 | 100.00 |
1.搅拌化合物A直到溶解。
2.加热十六烷醇、十八烷醇、司班60、矿物油、Arlacel 165、吐温60和BHA的混合物至大约70-75℃,形成油状溶液。
3.把步骤1的溶液加到步骤2的溶液中,同时混合均匀。
4.把水、山梨醇溶液、乙二胺四乙酸二钠、山梨酸和山梨酸钾的混合物加热到70-75℃。
5.把步骤3的溶液加到步骤4的溶液中,同时用高速混合器乳化。
6.把步骤5乳液到室温冷却,直到乳液凝固。
实施例17
局部应用剂型:凝胶
%体积/体积 | |
化合物A | 0.00005-5.0 |
丁基化的羟基苯甲醚(BHA) | 0.02 |
羟丙基纤维素 | 3.00 |
乙醇,USP | 45.00 |
水,加至 | 100.00 |
1.把BHA溶于乙醇和水的混合物中。
2.把化合物A溶于步骤1的溶液中。
3.把羟丙基纤维素分散在步骤2的溶液中。
实施例18
局部应用剂型:溶液
%体积/体积 | |
化合物A | 0.00005-5.0 |
丙二醇 | 10.00 |
辛酸/癸酸甘油三酯 | 30.00 |
丁基化的羟基苯甲醚(BHA) | 0.02 |
无水乙醇加至 | 100.00 |
1.把化合物A溶于乙醇中。
2.把BHA加到步骤1的溶液中并溶解。
3.把丙二醇和辛酸/癸酸甘油三酯加到步骤2的溶液中并混合直至溶液变清。
Claims (22)
- 3.权利要求2的化合物,其中R为羟基。
- 4.权利要求2的化合物,其中R为氟。
- 5.权利要求2的化合物,其中R1为=CH2。
- 6.权利要求3的化合物,其中R1为氢。
- 7.权利要求3的化合物为1,25-二羟基-22E,24E-二烯-26,27-六氟-24-高-胆钙化甾醇。
- 8.权利要求6的化合物为1,25-二羟基-22E-24E-二烯-19-去甲-26,27-六氟-24-高-胆钙化甾醇。
- 9.权利要求4的化合物为1α-氟-25-羟基-22E,24E-二烯-26,27-六氟-24-高-胆钙化甾醇。
- 10.权利要求1的化合物,其中A为
- 11.权利要求10的化合物,其中R为羟基。
- 12.权利要求10的化合物,其中R为氟。
- 13.权利要求10的化合物,其中R1为=CH2。
- 14.权利要求11的化合物,其中R1为氢。
- 15.权利要求11的化合物为1,25-二羟基-22E,24Z-二烯-26,27-六氟-24-高-胆钙化甾醇。
- 16.权利要求14的化合物为1,25-二羟基-22E-24Z-二烯-19-去甲-26,27-六氟-24-高-胆钙化甾醇。
- 17.权利要求12的化合物为1α-氟-25-羟基-22E,24Z-二烯-26,27-六氟-24-高-胆钙化甾醇。
- 19.一种药物组合物,特别用于诱导某些皮肤细胞系和癌细胞系的分化和抑制其增生,特别用于治疗过度增生性皮肤病,如牛皮癣,和肿瘤如白血病,其包括:(a)有效量的权利要求1中的式I的化合物,和(b)惰性载体。
- 20.权利要求1-17的化合物,用作诱导某些皮肤细胞系和癌细胞系分化并抑制其增生的药物,特别是用作治疗过度增生性皮肤病如牛皮癣,和用作治疗肿瘤如白血病的药物。
- 21.权利要求1-17的化合物在生产诱导某些皮肤细胞系和癌细胞系分化并抑制其增生,特别是在生产治疗过度增生性皮肤病如牛皮癣和治疗肿瘤和白血病的药物中的用途。
- 22.这里所具体阐述的新化合物,中间体,制剂、工艺和方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US712595P | 1995-10-31 | 1995-10-31 | |
US60/007,125 | 1995-10-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1201452A true CN1201452A (zh) | 1998-12-09 |
Family
ID=21724362
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96198019A Pending CN1201452A (zh) | 1995-10-31 | 1996-10-23 | 24-高-26,27-六氟-胆钙化甾醇 |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0874813A1 (zh) |
JP (1) | JPH10512297A (zh) |
KR (1) | KR19990067173A (zh) |
CN (1) | CN1201452A (zh) |
AU (1) | AU7297496A (zh) |
CA (1) | CA2235584A1 (zh) |
MX (1) | MX9803345A (zh) |
WO (1) | WO1997016423A1 (zh) |
ZA (1) | ZA968953B (zh) |
Cited By (1)
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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 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8915770D0 (en) * | 1989-07-10 | 1989-08-31 | Leo Pharm Prod Ltd | Chemical compounds |
US5206230A (en) * | 1991-06-05 | 1993-04-27 | Daikin Industries, Ltd. | Fluorine-containing vitamin D3 analogues and pharmaceutical composition containing the same |
US6017907A (en) * | 1993-07-09 | 2000-01-25 | Laboratoire Theramex S.A. | Structural analogues of vitamin D |
-
1996
- 1996-10-23 AU AU72974/96A patent/AU7297496A/en not_active Abandoned
- 1996-10-23 CA CA002235584A patent/CA2235584A1/en not_active Abandoned
- 1996-10-23 CN CN96198019A patent/CN1201452A/zh active Pending
- 1996-10-23 JP JP9517038A patent/JPH10512297A/ja active Pending
- 1996-10-23 WO PCT/EP1996/004592 patent/WO1997016423A1/en not_active Application Discontinuation
- 1996-10-23 EP EP96934788A patent/EP0874813A1/en not_active Withdrawn
- 1996-10-23 KR KR1019980703124A patent/KR19990067173A/ko not_active Application Discontinuation
- 1996-10-24 ZA ZA968953A patent/ZA968953B/xx unknown
-
1998
- 1998-04-28 MX MX9803345A patent/MX9803345A/es unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
Also Published As
Publication number | Publication date |
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ZA968953B (en) | 1997-07-30 |
KR19990067173A (ko) | 1999-08-16 |
CA2235584A1 (en) | 1997-05-09 |
JPH10512297A (ja) | 1998-11-24 |
EP0874813A1 (en) | 1998-11-04 |
MX9803345A (es) | 1998-09-30 |
WO1997016423A1 (en) | 1997-05-09 |
AU7297496A (en) | 1997-05-22 |
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