CN1662245A - (20S)－1α－羟基－2α－甲基和2β－甲基－19－去甲－维生素D3及它们的用途 - Google Patents

(20S)－1α－羟基－2α－甲基和2β－甲基－19－去甲－维生素D3及它们的用途 Download PDF

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CN1662245A
CN1662245A CN038146169A CN03814616A CN1662245A CN 1662245 A CN1662245 A CN 1662245A CN 038146169 A CN038146169 A CN 038146169A CN 03814616 A CN03814616 A CN 03814616A CN 1662245 A CN1662245 A CN 1662245A
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赫克托·F.·德鲁卡
拉法尔·R.·西钦斯基
帕维尔·K.·格日瓦奇
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Abstract

本发明公开了(20S)－ 1α－羟基－2α－甲基－19－去甲－维生素D3和(20S)－1α－羟基－2β－甲基－19－去甲－维生素D3及其药学用途。这些化合物在抑制未分化细胞增殖和诱导它们分化为单核细胞方面显示出明显的活性，因此表明其作为抗癌药的用途和治疗皮肤病如银屑病，以及皮肤病况如皱纹、皮肤松弛、皮肤干燥和皮脂分泌不足的用途。这些化合物还具有非常显著的钙活性，因此可以用于治疗人的免疫疾病和代谢性骨病如骨质疏松症。

Description

(20S)-1α-羟基-2α-甲基和2β-甲基-19-去甲-维生素D3及它们的用途
背景技术
本发明涉及维生素D化合物，更具体而言涉及前药(20S)-1α-羟基-2α-甲基和2β-甲基-19-去甲-维生素D3及它们的药学用途。
已知天然激素，1α，25-二羟维生素D3及其麦角固醇系列类似物，即1α，25-二羟维生素D2是动物和人的钙体内稳态的强力调节剂，也已经明确了它们在细胞分化方面的活性，Ostrem等人，Proc.Natl.Acad.Sci.USA， 84，2610(1987)。已经制备并测试了这些代谢产物的许多结构类似物，包括1α-羟维生素D3、1α-羟维生素D2、各种侧链确认的(homologated)维生素和氟化类似物。这些化合物中的一些在细胞分化和钙调节方面显示出令人感兴趣的活性分离。此种活性差异对于治疗多种疾病，如肾性骨营养不良症、维生素D抗性佝偻病、骨质疏松症、银屑病和某些癌可能是有用的。
近来，业已发现一类新的维生素D类似物，即所谓的19-去甲-维生素D化合物，其特征在于维生素D系统典型的A-环环外亚甲基(碳19)被两个氢原子替换。对此19-去甲-类似物(例如，1α，25-二羟-19-去甲-维生素D3)的生物学测试表明，它具有高效诱导细胞分化和极低钙动员活性的选择性活性特征。因此，这些化合物作为治疗癌或治疗各种皮肤病的治疗剂可能有用。已经描述了两种不同的合成此19-去甲-维生素D类似物的方法(Perlman等人，Tetrahedron Lett. 31，1823(1990)；Perlman等人，Tetrahedron Lett. 32，7663(1991)，以及DeLuca等人，美国专利5,086,191)。
在美国专利4,666,634中，Chugai研究小组已经描述并且检测了作为用于骨质疏松症的可能药物和作为抗肿瘤药的1α，25-二羟维生素D3的2β-羟基和烷氧基(例如，ED-71)类似物。请参阅Okano等人，Biochem.Biophys.Res.Commun.163，1444(1989)。也已经制备并且测试了1α，25-二羟维生素D3的其它2-取代(用羟烷基取代，如ED-120，和氟烷基取代)A-环类似物(Miyamoto等人，Chem.Pharm.Bull. 41，1111(1993)；Nishii等人，Osteoporosis Int.Suppl. 1，190(1993)；Posner等人，J.Org.Chem. 59，7855(1994)，以及J.Org.Chem. 60，4617(1995))。
最近，也已合成了1α，25-二羟-19-去甲-维生素D3的2-取代类似物，即在2-位有羟基或烷氧基取代的化合物(DeLuca等人，美国专利5,536,713)，有2-烷基取代的化合物(DeLuca等人，美国专利5,945,410)，有2-亚烷基取代的化合物(DeLuca等人，美国专利5,843,928)，它们显示令人感兴趣的选择性活性特征。所有这些研究表明，维生素D受体中的结合位点可以适应在合成维生素D类似物中C-2位的不同取代基。
在探究药理学上重要的19-去甲类维生素D化合物的继续努力中，已合成并测试了以碳2(C-2)上甲基取代基的存在以及侧链中碳25(C-25)上羟基不存在为特征的两个类似物。这两个类似物的特征在于碳1位的羟基和甲基以非自然(unnatural)或表(epi)取向连接于碳20的维生素D3侧链，即(20S)-1α-羟基-2α-甲基和2β-甲基-19-去甲-维生素D3。这些维生素D类似物似乎是令人感兴趣的靶，因为在C-2位相对小的甲基应当不会干扰维生素D受体。而且，分子力学研究似乎表明，此种分子修饰在实质上改变环己二醇环A的构象，使其构象平衡移向C-2位上的甲基取代基平伏取向的椅式。
发明内容
本发明涉及前药(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3(下式Ia)和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3(下式Ib)、它们的生物活性和这些化合物的各种药学用途。
这些2α-甲基和2β-甲基19-去甲类似物的结构分别以下示式Ia和Ib为特征：
Figure A0381461600151
上述两个化合物显示所期望的和高度有利的生物活性特征。这些化合物并不结合到维生素D受体上，或者与维生素D受体弱结合。然而，与1α，25-二羟维生素D3相比，该2α-甲基化合物具有较高的肠钙转运活性，并且与1α，25-二羟维生素D3相比，具有较高的从骨动员钙的能力。该2β-甲基化合物具有与1α，25-二羟维生素D3大致相同的肠钙转运活性和骨钙动员活性。因此，这些化合物的特征可以为具有很强的钙活性(calcemic activity)，并且在它们的钙活性中是高度特异性的。它们从骨动员钙的活性和高或正常的肠钙转移活性使体内给予这些化合物能够治疗骨损失为主要问题的代谢性骨病。由于它们对骨的活性，这些化合物是治疗期望骨形成的疾病如骨质疏松症，特别是低骨更新骨质疏松症(low bone turnover osteoporosis)、类固醇诱导的骨质疏松症、老年性骨质疏松症或经绝后骨质疏松，以及骨软化症的优选治疗剂。
还已发现本发明的化合物特别适用于治疗和预防以免疫系统失衡为特征的人的疾病，例如自体免疫疾病，包括多发性硬化、狼疮(lupis)、糖尿病、宿主抗移植物反应和器官移植物排斥反应；另外，用于治疗炎性疾病如类风湿性关节炎、哮喘和炎性肠病如乳糜泻和克罗恩病。用本发明的化合物可以治疗痤疮、脱发和高血压。
上述化合物还以高的或显著的细胞分化活性为特征。因此，这些化合物也提供用于治疗银屑病的治疗剂，或者作为抗癌药，尤其是抗白血病、结肠癌、乳癌和前列腺癌。此外，由于它们相对高的细胞分化活性，这些化合物提供用于治疗各种皮肤病况的治疗剂，所述皮肤病况包括皱纹，缺乏适度真皮水合，即皮肤干燥，缺乏适度皮肤坚韧性，即皮肤松弛，和皮脂分泌不足。因此，这些化合物的使用不仅导致皮肤的湿润，而且改善皮肤的屏障功能。
该化合物可以存在于治疗上述疾病和病症的组合物中，其量为约0.01μg/gm至约100μg/gm组合物，并且可以局部、经皮、口服或者胃肠外给药，给药剂量可以为约0.01μg/日至约100μg/日。
附图说明
图1是说明(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3、(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3和1α，25-二羟维生素D3与[3H]-1，25-(OH)2-D3竞争结合维生素D猪肠核受体的相对活性的图；
图2是说明作为(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3、(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3和1α，25-二羟维生素D3的浓度的函数的HL-60细胞分化百分比的图。
具体实施方式
合成并测试了(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3。在结构上，这些19-去甲类似物分别以本文前述的式Ia和Ib为特征。
通过常用的一般方法，即二环Windaus-Grundmann型酮II与烯丙型氧化膦III缩合成相应的2-亚甲基-19-去甲-维生素D类似物IV，其后在后一化合物的C-1和C-3位脱保护；然后接着是化合物V中C-2位上外亚甲基的选择性还原，以提供2α-甲基异构体(Ia)和2β-甲基异构体(Ib)，可以完成具有结构Ia和Ib的(20S)-1α-羟基-2α-甲基-和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3的制备：
在结构III和IV中，基团Y1和Y2是羟基保护基，优选叔丁基二甲基硅基团，还应理解，可能对缩合反应敏感，或者干扰缩合反应的任何官能团均如本领域众所周知地予以适当保护。上述方法代表汇集合成概念的应用，其已经有效地用于制备维生素D化合物[例如Lythgoe等人，J.Chem.Soc.Perkin Trans.I，590(1978)；Lythgoe，Chem.Soc.Rev. 9，449(1983)；Toh等人，J.Org.Chem. 48，1414(1983)；Baggiolini等人，J.Org.Chem. 51，3098(1986)；Sardina等人，J.Org.Chem. 51，1264(1986)；J.Org.Chem. 51，1269(1986)；DeLuca等人，美国专利5,086,191；DeLuca等人，美国专利5,536,713]。
结构II的茚烷酮(Hydrindanone)是新化合物，它可以通过修饰的已知方法由商品维生素D2制备。因此，由商品维生素D2通过3步制备起始醇1(方案1)。将所得的C-22醇1氧化成醛2，然后使其在C-20位平衡。将(20R)-和(20S)-醛的混合物还原，并通过色谱法分离(20R)-醇3。依次将其甲苯磺酰化，并使甲苯磺酸酯4和格氏试剂5在四氯铜酸二锂存在下偶联。将获得的茚烷醇6氧化成新的(20S)-格伦德曼酮类似物II。
为了制备所需的一般结构III的氧化膦，已经开发了从甲基奎尼酸(methyl quinicate)衍生物开始的新的合成路线，所述甲基奎尼酸衍生物如Perlman等人，Tetrahedron Lett. 32，7663(1991)和DeLuca等人，美国专利5,086,191所述，容易地从商品(1R，3R，4S，5R)-(-)-奎尼酸获得。
该方法的最后一步是维生素V中碳2上的外亚甲基单元在三(三苯基膦)氯化铑(I)[Wilkinson’s催化剂，(Ph3P)3RhCl]存在下有效地进行选择性均相催化氢化。这样的还原条件只使C(2)＝CH2单元还原，而C(5)-C(8)丁二烯部分不受影响。分离的物质是在C-2处构型不同的2-甲基-19-去甲-维生素Ia和Ib的差向异构体混合物(约1∶1)。如果需要，混合物可以不经分离而使用，单个2α-和2β-异构体可以通过有效HPLC系统分离。
在题为“2-烷基-19-去甲-维生素D化合物”的美国专利5,945,410中对化合物Ia和Ib的整个合成方法作了更完整的说明和描述，该文献特别地引入本文作参考。
具体而言，茚烷酮II的制备在下文中进行描述并且在方案1中得到说明。汇集合成的最后一步，即该化合物和氧化膦7偶联，接着在维生素D化合物8中羟基脱保护，2-亚甲基-19-去甲-维生素D化合物V中外亚甲基单元的还原/氢化也在下文中进行描述并且在方案2中得到说明。
制备(20S)-脱-A，B-8β-苯甲酸基-20-(羟甲基)孕甾烷(1)
起始醇1根据J.C.Hanekamp，R.B.Rookhuizen，H.J.T.Bos，L.Brandsma Tetrahedron，1992，48，9283-9294公开的方法由商品维生素D2制备，收率70％。
使臭氧在-78℃下通过维生素D2(3g，7.6mmol)在甲醇(250mL)和吡啶(2.44g，2.5mL，31mmol)中的溶液，持续50分钟。接着用氧气将反应混合物冲洗15分钟以除去残余的臭氧，用NaBH4(0.75g，20mmol)处理溶液。20分钟后，加入第二部分NaBH4(0.75g，20mmol)，使混合物暖至室温。接着加入第三部分NaBH4(0.75g，20mmol)，并将反应混合物搅拌18小时。用水(40mL)终止反应，并减压浓缩溶液。用乙酸乙酯(3×80mL)萃取残余物，用1M盐酸水溶液、饱和碳酸氢钠水溶液洗涤合并的有机相，用硫酸钠干燥，并减压浓缩。用己烷/乙酸乙酯(75∶25)对残余物进行硅胶色谱分离，得到(20S)-脱-A，B-20-(羟甲基)孕甾烷-8β-醇(1.21g，收率75％)，为白色晶体。
在0℃下向8β，20-二醇(1.2g，5.7mmol)和DMAP(30mg，0.2mmol)在无水吡啶(20mL)中的溶液中加入苯甲酰氯(2.4g，2mL，17mmol)。将反应混合物在4℃下搅拌24小时，用二氯甲烷(100mL)稀释，用5％盐酸水溶液、饱和碳酸氢钠水溶液洗涤，用硫酸钠干燥，并减压浓缩。用氢氧化钾(1g，15.5mmol)在无水乙醇(30mL)中的溶液在室温下处理残余物(3.39g)。将反应混合物搅拌3小时后，加入冰和5％盐酸水溶液，直到pH＝6。用乙酸乙酯(3×50mL)萃取溶液，用饱和碳酸氢钠水溶液洗涤合并的有机相，用硫酸钠干燥，并减压浓缩。用己烷/乙酸乙酯(75∶25)对残余物进行硅胶色谱分离，得到醇1(1.67g，收率93％)，为无色油：[α]D+56.0(c0.48，CHCl3)；1H NMR(400MHz，CDCl3+TMS)δ8.08-8.02(2H，m，o-HBz)，7.59-7.53(1H，m，p-HBz)，7.50-7.40(2H，m，m-HBz)，5.42(1H，d，J＝2.4Hz，8α-H)，3.65(1H，dd，J＝10.5，3.2Hz，22-H)，3.39(1H，dd，J＝10.5，6.8Hz，22-H)，1.08(3H，d，J＝5.3Hz，21-H3)，1.07(3H，s，18-H3)；13C NMR(125MHz)δ166.70(s，C＝O)，132.93(d，p-CBz)，131.04(s，i-CBz)，129.75(d，o-CBz)，128.57(d，m-CBz)，72.27(d，C-8)，67.95(t，C-22)，52.96(d)，51.60(d)，42.15(s，C-13)，39.98(t)，38.61(d)，30.73(t)，26.81(t)，22.91(t)，18.20(t)，16.87(q，C-21)，13.81(q，C-18)；MS(EI)m/z 316(5，M+)，301(3，M+-Me)，299(1，M+-OH)，298(2，M+-H2O)，285(10，M+-CH2OH)，257(6)，230(9)，194(80)，135(84)，105(100)；C20H28O3的准确计算分子量为316.2038，
实测值为316.2019。
制备(20S)-脱-A，B-8β-苯甲酸基-20-甲酰孕甾烷(2)
将醇1(1.63g，5.2mmol)、重铬酸吡啶鎓(6.05g，16.1mmol)和对甲苯磺酸吡啶鎓(100mg，0.4mmol)在无水二氯甲烷(30mL)中的混合物于室温下搅拌12小时。将所得悬浮液通过C盐薄层过滤。用乙醚洗涤吸附物质，减压除去溶剂，并用己烷/乙酸乙酯(90∶10)对残余物进行硅胶色谱分离，得到醛2(1.36g，收率83％)，为油；1H NMR(400MHz，CDCl3+TMS)δ9.60(1H，d，J＝3.1Hz，CHO)，8.05(2H，m，o-HBz)，7.57(1H，m，p-HBz)，7.45(2H，m，m-HBz)，5.44(1H，s，8α-H)，2.39(1H，m，20-H)，2.03(2H，dm，J＝11.5Hz)，1.15(3H，d，J＝6.9Hz，21-H3)，1.10(3H，s，18-H3)；MS(EI)m/z 314(1，M+)，299(0.5，M+-Me)，286(1，M+-CO)，285(5，M+-CHO)，257(1，M+-C3H5O)，209(10，M+-PhCO)，192(38)，134(60)，105(100)，77(50)；C20H26O3的准确计算分子量为314.1882，实测值为314.1887。
制备(20R)-脱-A，B-8β-苯甲酸基-20-(羟甲基)孕甾烷(3)
将醛2(1.36g，4.3mmol)溶于二氯甲烷(15mL)中，加入40％n-Bu4NOH水溶液(5.6mL，5.57g，8.6mmol)。将所得混合物在室温下搅拌16小时，用二氯甲烷(30mL)稀释，用水洗涤，用硫酸钠干燥，并减压浓缩。用己烷/乙酸乙酯(95∶5)对残余物进行硅胶色谱分离，得到醛2及其20-差向异构体的混合物(730mg，收率53％)，比率约为1∶1.7(由1H NMR测定)。
将该醛混合物(730mg，2.3mmol)溶于THF(5mL)中，加入NaBH4(175mg，4.6mmol)，接着滴加乙醇(5mL)。将反应混合物在室温下搅拌30分钟，用NH4Cl水溶液终止反应。用乙醚(3×30mL)萃取混合物，用水洗涤合并的有机相，用硫酸钠干燥，并减压浓缩。用己烷/乙酸乙酯(95∶5→80∶20)对残余物进行硅胶色谱分离，得到期望的纯(20R)-醇3(366mg，收率52％)为油，以及3及其20-差向异构体1的混合物(325mg，收率45％)，比率约为1∶4(由1H NMR测定)。
3：[α]D+43.0(c0.54，CHCl3)；1H NMR(500MHz，CDCl3+TMS)δ8.10-8.00(2H，m，o-HBz)，7.60-7.53(1H，m，p-HBz)，7.48-7.41(2H，m，m-HBz)，5.42(1H，br s，8α-H)，3.75(1H，dd，J＝10.6，3.5Hz，22-H)，3.48(1H，dd，J＝10.6，7.0Hz，22-H)，1.069(3H，s，18-H3)，0.973(3H，d，J＝6.7Hz，21-H3)；13C NMR(125MHz)δ166.70(s，C＝O)，132.94(d，p-CBz)，131.05(s，i-CBz)，129.76(d，o-CBz)，128.59(d，m-CBz)，72.28(d，C-8)，66.95(t，C-22)，52.94(d)，51.77(d)，41.96(s，C-13)，39.56(t)，37.78(d)，30.75(t)，26.67(t)，22.71(t)，18.25(t)，16.76(q，C-21)，14.14(q，C-18)；MS(EI)m/z 316(16，M+)，301(5，M+-Me)，299(2，M+-OH)，298(3，M+-H2O)，285(9，M+-CH2OH)，257(5)，242(11)，230(8)，194(60)，147(71)，105(100)；C20H28O3的准确计算分子量为316.2038，实测值为316.2050。
制备(20R)-脱-A，B-8-苯甲酸基-20-[(对甲苯磺酰基)氧甲基]孕甾烷(4)
在0℃下向搅拌的醇3(393mg，1.24mmol)、DMAP(10mg，0.08mmol)和Et3N(0.7mL，0.51g，5.04mmol)在无水二氯甲烷(10mL)中的溶液中加入对甲苯磺酰氯(320mg，1.68mmol)。使反应混合物暖至室温(4小时)，并继续再搅拌22小时。加入二氯甲烷(60mL)，并用饱和碳酸氢钠水溶液洗涤混合物，用硫酸钠干燥，并减压浓缩。用己烷/乙酸乙酯(95∶5)对残余物进行硅胶色谱分离，得到甲苯磺酸酯4(533mg，收率91％)，为无色油：[α]D＝+15.0(c0.54，CHCl3)；1H NMR(500MHz，CDCl3+TMS)δ8.02(2H，m，o-HBz)，7.80(2H，d，J＝8.2Hz，o-HTs)，7.55(1H，m，p-HBz)，7.44(2H，m，m-HBz)，7.35(2H，d，J＝8.2Hz，m-HTs)，5.39(1H，br s，8α-H)，4.15(1H，dd，J＝9.4，3.4Hz，22-H)，3.83(1H，dd，J＝9.4，7.1Hz，22-H)，2.457(3H，s，MeTs)，1.98(1H，m)，0.978(3H，s，18-H3)，0.898(3H，d，J＝6.6Hz，21-H3)；13C NMR(125MHz)δ166.60(s，C＝O)，144.87(s，p-CTs)，133.35(s，i-CTs)，132.98(d，p-CBz)，130.94(s，i-CBz)，129.97(d，m-CTs)，129.72(d，o-CBz)，128.58(d，m-CBz)，128.13(d，o-CTs)，74.21(t，C-22)，72.03(d，C-8)，52.44(d)，51.52(d)，41.82(s，C-13)，39.30(t)，35.00(d)，30.75(t)，26.56(t)，22.54(t)，21.85(q，MeTs)，18.12(t)，16.85(q，C-21)，14.09(q，C-18)；MS(EI)m/z 470(1，M+)，365(33，M+-PhCO)，348(64，M+-PhCOOH)，193(52)，176(71)，134(72)，105(100)；C27H34O5S的准确计算分子量为470.2127，实测值为470.2091。
制备(20S)-脱-A，B-胆甾烷-8β-醇(6)
将镁屑(1.32g，55mmol)、1-氯-3-甲基丁烷(3.3mL，2.9g，27.2mmol)和碘(2个晶体)在无水THF(18mL)中回流10小时。将形成的格氏试剂5的溶液冷却至-78℃，并在-78℃下经套管将其滴加入甲苯磺酸酯4(348mg，0.74mmol)在无水THF(5mL)中的溶液中。接着在向-78℃下经套管向反应混合物中滴加6mL Li2CuCl4[通过将无水LiCl(232mg，5.46mmol)和无水CuCl2(368mg，2.75mmol)溶于无水THF(27mL)中而制备]的溶液。移除冷却浴，并将混合物在室温下搅拌20小时，接着倾入含冰(约100g)的1M硫酸水溶液(25mL)中。用二氯甲烷(3×50mL)萃取混合物，并用饱和NH4Cl水溶液、饱和碳酸氢钠水溶液洗涤合并的有机层，用硫酸钠干燥，并减压浓缩。用氯仿对残余物进行硅胶色谱分离，得到醇6(149mg，收率76％)，为无色油：1H NMR(400MHz，CDCl3+TMS)δ4.07(1H，d，J＝2.2Hz，8α-H)，1.98(1H，dm，J＝13.1Hz)，0.93(3H，s，18-H3)，0.86(6H，d，J＝6.6Hz，26-和27-H3)，0.81(3H，d，J＝6.6Hz，21-H3)；13C NMR(125MHz)δ69.41(d，C-8)，56.27(d)，52.62(d)，41.84(s，C-13)，40.28(t)，39.38(t)，35.40(t)，34.83(d)，33.51(t)，28.03(d)，27.10(t)，23.93(t)，22.72(q，C-26/27)，22.63(q，C-26/27)，22.40(t)，18.53(q，C-21)，17.47(t)，13.73(q，C-18)；MS(EI)m/z 266(7，M+)，251(6，M+-Me)，248(2，M+-H2O)，233(4，M+-Me-H2O)，163(6)，152(11)，135(38)，111(100)；C18H34O的准确计算分子量为266.2610，实测值为266.2601。
制备(20S)-脱-A，B-胆甾烷-8-酮(II)
向醇6(15mg，56μmol)和对甲苯磺酸吡啶鎓(2mg，8μmol)在无水二氯甲烷中的溶液中加入重铬酸吡啶鎓(90mg，239μmol)。将所得悬浮液在室温下搅拌3.5小时。将反应混合物过滤通过Waters硅胶Sep-Pak短柱(2g)，并进一步用氯仿洗涤。除去溶剂后，得到酮II(13mg，收率88％)，为无色油：1H NMR(400MHz，CDCl3+TMS)δ2.46(1H，dd，J＝11.5，7.6Hz)，0.89(6H，d，J＝6.6Hz，26-和27-H3)，0.87(3H，d，J＝6.1Hz，21-H3)，0.65(3H，s，18-H3)；MS(EI)m/z 264(41，M+)，249(37，M+-Me)，246(3，M+-H2O)，231(3，M+-Me-H2O)，221(50，M+-C3H7)，152(34)，125(100)，111(69)；C18H32O的准确计算分子量为264.2453，实测值为264.2454。
制备(20S)-1α-羟基-2-亚甲基-19-去甲维生素D3(V)
在氩气氛和搅拌下于-20℃下向氧化膦7(34mg，58μmol)在无水THF中的溶液中缓慢加入PhLi(1.7M环己烷-乙醚，75μL，128μmol)。溶液变成深橙色。30分钟后，将混合物冷却至-78℃，并缓慢加入预冷的(-78℃)酮(II)(12mg，45μmol)在无水THF(200+100μL)中的溶液。将混合物在-78℃和氩气氛下搅拌3小时，并在0℃下搅拌18小时。加入乙酸乙酯，用盐水洗涤有机相，用硫酸钠干燥，并蒸发。将残余物溶于己烷中，并施加到Waters硅胶Sep-Pak短柱(2g)上。用己烷和己烷/乙酸乙酯(99.5∶0.5)洗涤短柱，得到19-去甲维生素衍生物8(12mg)。接着用己烷/乙酸乙酯(96∶4)洗涤Sep-Pak以回收未改变的C，D-环酮II(7mg)，用乙酸乙酯洗涤以回收二苯基氧化膦7(19mg)。通过HPLC(10×250mm Zorbax-硅胶柱，4mL/min)使用己烷/2-丙醇(99.9∶0.1)溶剂系统进一步纯化保护的维生素8。当Rv＝15mL时洗脱纯化合物8(10mg，收率36％)，为无色油：UV(己烷中)λmax262.5，252.5，243.5nm；1H NMR(500MHz，CDCl3)δ6.21和5.82(1H和1H，各自是d，J＝11.1Hz，6-和7-H)，4.95和4.90(1H和1H，各自是s，＝CH2)，4.41(2H，m，1β-和3α-H)，2.80(1H，dd，J＝11.9，3.5Hz，9β-H)，2.49(1H，dd，J＝13.2，6.0Hz，10α-H)，2.44(1H，dd，J＝12.7，4.6Hz，4α-H)，2.32(1H，dd，J＝13.2，3.1Hz，10β-H)，2.16(1H，dd，J＝12.7，8.2Hz，4β-H)，1.98(2H，m)，1.84(1H，m)，0.876(9H，s，Si-t-Bu)，0.851(6H，d，J＝6.0Hz，26-和27-H3)，0.845(9H，s，Si-t-Bu)，0.820(3H，d，J＝6.5Hz，21-H3)，0.521(3H，s，18-H3)，0.060，0.046，0.029和0.006(各自是3H，各自是s，4×Si-CH3)；MS(EI)m/z 628(3，M+)，613(1，M+-Me)，571(3，M+-t-Bu)，496(63，M+-t-BuMe2SiOH)，383(4，M+-t-BuMe2SiOH-C8H17)，366(21)，234(20)，129(41)，75(100)；C39H72O2Si2的准确计算分子量为628.5071，实测值为628.5068。
将保护的维生素8(10mg，16μmol)溶于无水THF(3mL)中，加入四丁基氟化铵(1M在THF中，160μL，160μmoL)，接着加入新活化的分子筛4A(300mg)。将混合物在氩气氛和室温下搅拌2小时，接着用2mL己烷/乙酸乙酯(6∶4)稀释，并施加到Waters硅胶Sep-Pak短柱(2g)上。用相同的溶剂系统洗脱，得到粗产物V，并进一步通过HPLC(10×250mm Zorbax-硅胶柱，4mL/min)使用己烷/2-丙醇(9∶1)溶剂系统进一步纯化粗产物V。在Rv＝32mL时收集分析纯的2-亚甲基-19-去甲维生素V(3.3mg，收率52％)，为无色油：UV(乙醇中)λmax261.5，251.5，243.5nm；1H NMR(500MHz，CDCl3+TMS)δ6.36和5.88(1H和1H，各自是d，J＝11.3Hz，6-和7-H)，5.11和5.09(各自是1H，各自是s，＝CH2)，4.47(2H，m，1β-和3α-H)，2.85(1H，dd，J＝13.4，4.6Hz，10β-H)，2.81(1H，br d，J＝13.9Hz，9β-H)，2.58(1H，dd，J＝13.2，3.7Hz，4α-H)，2.33(1H，dd，J＝13.2，6.1Hz，4β-H)，2.29(1H，dd，J＝13.4，8.4Hz，10α-H)，1.99(2H，m)，1.86(1H，m)，0.867(6H，d，J＝6.6Hz，26-和27-H3)，0.839(3H，d，J＝6.5Hz，21-H3)，0.547(3H，s，18-H3)；MS(EI)m/z 400(100，M+)，385(5，M+-Me)，382(16，M+-H2O)，367(6，M+-Me-H2O)，349(3，M+-Me-2H2O)，315(46)，287(56，M+-C8H17)，269(52)，247(42)；C27H44O2的准确计算分子量为400.3341，实测值为400.3346。
制备(20S)-1α-羟基-2α-甲基-19-去甲维生素D3(Ia)和(20S)-1α-羟基-2β-甲基-19-去甲维生素D3(Ib)
将三(三苯基膦)氯化铑(I)(3.5mg，3.8μmol)加入用氢气预饱和的无水苯(2.5mL)中。在室温下搅拌混合物直到形成均相溶液(约45分钟)。接着加入维生素V(1.8mg，4.5μmol)在无水苯中的溶液(400+400μL)，使反应在持续通入氢气流下进行3小时。在真空下除去苯，将残余物重新溶于己烷/乙酸乙酯(1∶1)中，并施加到Waters硅胶Sep-Pak短柱(2g)上。用相同的溶剂系统洗脱2-甲基维生素的混合物。通过HPLC(10×250mm Zorbax-硅胶柱，4mL/min)使用己烷/2-丙醇(9∶1)溶剂系统进一步纯化化合物。2-甲基-19-去甲维生素Ia和Ib的混合物在Rv＝34mL时给出单峰。两个差向异构体的分离通过反相HPLC(10×250mm Chromegabond C18柱，3mL/min))使用甲醇/水(9∶1)溶剂系统实现。在Rv＝47mL时收集2β-甲基维生素Ib(280μg，收率15％)，在Rv＝51mL时收集其2α-差向异构体Ia(382μg，收率21％)。
Ia：UV(乙醇中)λmax 260.5，250.5，242.5nm；1H NMR(500MHz，CDCl3+TMS)δ6.37和5.82(1H和1H，各自是d，J＝11.1Hz，6-和7-H)，3.96(1H，m，w/2＝14Hz，1β-H)，3.61(1H，m，w/2＝20Hz，3α-H)，2.80(2H，br m，9β-和10α-H)，2.60(1H，dd，J＝13.0，4.5Hz，4α-H)，2.22(1H，br d，J＝12.8Hz，10β-H)，2.13(1H，～t，J＝13.0Hz，4β-H)，1.133(3H，d，J＝6.8Hz，2α-CH3)，0.866(6H，d，J＝6.6Hz，26-和27-H3)，0.833(3H，d，J＝6.4Hz，21-H3)，0.530(3H，s，18-H3)；MS(EI)m/z 402(100，M+)，387(4，M+-Me)，384(7，M+-H2O)，369(3，M+-Me-H2O)，317(24)，289(60，M+-C8H17)，271(33)，259(40)，247(63)；C27H46O2的准确计算分子量为402.3498，实测值为402.3496。
Ib：UV(乙醇中)λmax 260.5，250.0，242.0nm；1H NMR(500MHz，CDCl3+TMS)δ6.26和5.87(1H和1H，各自是d，J＝11.3Hz，6-H和7-H)，3.90(1H，m，w/2＝14Hz，3α-H)，3.50(1H，m，w/2＝26Hz，1β-H)，3.08(1H，dd J＝12.6，4.3Hz，10β-H)，2.80(1H，dd，J＝12.5，3.8Hz，9β-H)，2.43(1H，br d，J＝约14Hz，4α-H)，2.34(1H，dd，J＝13.9，3.0Hz，4β-H)，1.143(3H，d，J＝6.8Hz，2β-CH3)，0.867(6H，d，J＝6.6Hz，26-和27-CH3)，0.839(3H，d，J＝6.5Hz，21-H3)，0.543(3H，s，18-H3)；MS(EI)m/z 402(100，M+)，387(8，M+-Me)，384(8，M+-H2O)，369(5，M+-Me-H2O)，317(42)，289(88，M+-C8H17)，271(52)，259(55)，247(66)；C27H46O2的准确计算分子量为402.3498，实测值为402.3486。
方案1
方案2
Figure A0381461600281
(20S)-1α-羟基-2α-甲基和2β-甲基-19-去甲-维生素D3的生物活性
2β-甲基-(20S)-1α-羟基维生素D3不结合到维生素D受体上，而2α-甲基-(20S)-1α-羟基维生素D3结合到受体上，但是其亲合力比1α，25-二羟维生素D3(1，25-(OH)2D3)(图1)低100倍。这些化合物中没有25-羟基在很大程度上是该活性降低的原因(参阅Eisman，J.A.和H.F.Deluca，Steroids  30，245-257，1977)。重要的是，在结合受体方面，2α-甲基衍生物优于2β-甲基类似物。
令人惊奇地，图2阐明，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3对HL-60分化几乎和1，25(OH)2D3一样有效，使其成为治疗银屑病和癌症，特别是抗白血病、结肠癌、乳癌和前列腺癌的优异的候选药。此外，由于其相对高的细胞分化活性，该化合物提供用于治疗各种皮肤病况的治疗剂，所述皮肤病况包括皱纹，缺乏适度真皮水合，即皮肤干燥，缺乏适度皮肤坚韧性，即皮肤松弛，和皮脂分泌不足。因此，该化合物的使用不仅导致皮肤的湿润，而且改善皮肤的屏障功能。2β衍生物的活性比1，25(OH)2D3弱100倍，使其在这些领域中有效性较小。表1中的数据表明，与天然激素1，25-(OH)2D3相比，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3在刺激肠钙转运方面具有高活性。(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3在刺激肠钙转运方面也具有显著活性，其活性约与1，25-(OH)2D3相同。
表1中的数据还阐明，与1，25-(OH)2D3相比，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3具有更高的骨钙动员活性。(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3也具有显著的骨钙动员活性，其活性约与1，25-(OH)2D3相同。
这些类似物的非常重要的特征是它们与维生素D受体结合弱或根本不结合，但是具有高于或等于1，25-(OH)2D3的生物活性。这表明这些类似物是前药。也就是说，它们通过被25-羟基化而在体内活化。一旦25-羟基化，它们就能够结合到维生素D受体上并提供活性。这些结果表明，由于这些化合物在体内缓慢活化，提供更好控制且持久的活性，因而它们可能优于最终的药物。
因此，表1中的数据阐明了(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3的特征可能为具有大于1，25-(OH)2D3的显著而极为有效的钙活性，而(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3也具有约与1，25-(OH)2D3相同的显著而极为有效的钙活性。
通过Dame等人描述的方法(Biochemistry， 25，4523-4534，1986)进行类似物与猪肠受体的竞争性结合。
如Ostrem等人所述(J.Biol.Chem. 262，14164-14171，1987)测定HL-60前髓细胞向单核细胞的分化。
如Perlman等人所述(Biochemistry 29，190-196，1990)测定肠钙转运。
                           数据解释
测定低钙饮食大鼠血清钙的体内测试提供对(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3的成骨细胞或骨活性的了解。表1中的数据表明，在通过刺激成骨细胞提高血浆中的钙方面，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3的效力显著高于1，25(OH)2D3。同时，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3对肠钙转运的活性也显著高于1，25(OH)2D3(表1)。因此，这些数据表明，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3对骨具有比1，25(OH)2D3高的显著而极为有效的活性。
表1中的数据还表明，在通过刺激成骨细胞提高血浆中的钙方面，(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3的效力只比1，25(OH)2D3稍弱些。同时，(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3对肠钙转运的活性约与1，25-(OH)2D3相同(表1)。因此，这些数据表明，(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3对骨具有约与1，25(OH)2D3相等的显著而极为有效的活性。
化合物Ia和Ib表现出期望的高度有利的生物活性模式。这些化合物的特征在于与1α，25-二羟维生素D3相比相对高的肠钙转运活性，同时也表现出与1α，25-二羟维生素D3相比相对高的骨钙动员活性。因此，这些化合物具有高度特异性的钙活性。它们的骨钙动员活性和高或正常的肠钙转运活性使体内给予这些化合物能用于治疗其中骨损失是主要问题的代谢性骨病。由于它们对骨的钙活性，这些化合物将是治疗其中期望骨形成的疾病，如骨质疏松症，特别是低骨更新骨质疏松、类固醇诱导的骨质疏松、老年性骨质疏松或经绝后骨质疏松，以及骨软化症的优选治疗剂。
在与维生素D受体结合方面，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3比1，25(OH)2D3的活性低得多(图1)，而它们在引起前髓细胞HL-60向单核细胞分化方面也比1，25-(OH)2D3活性仅稍低(图2)。该结果提示，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3将对银屑病非常有效，因为它们在引起细胞分化以及在抑制细胞生长方面具有直接的细胞活性。这也表明，它们将具有作为抗癌药的显著活性，尤其是抗白血病、结肠癌、乳癌和前列腺癌，以及对抗皮肤病况如皮肤干燥(缺乏真皮水合)、过度皮肤松弛(皮肤坚韧性不足)、皮脂分泌不足和皱纹。这些结果也阐明，(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3都是多种人治疗的优异的候选药，除癌症和银屑病以外，它们可能对多种情况如自体免疫疾病有用。
给雄性刚断奶的Sprague-Dawley大鼠喂以食物11(0.47％Ca)+AEK，持续11天，接着喂以食物11(0.02％Ca)+AEK，持续31天。在处死前7天开始给药(i.p.)。给药以每日为基础进行，间隔24小时。为了进行肠转运研究，收集肠的前10cm，为了进行骨Ca动员分析，收集血清。结果报告在表1中。
                               表1
肠钙转运和血清钙(骨钙动员)活性对1，25-(OH)2D3和(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3和(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3长期给药的反应
    化合物     量(pmol/日)     钙转运S/M(平均±SEM)   血清钙(平均±SEM)
无药物(对照)     0   4.5±0.40   4.4±0.07
1α，25-(OH)2D3     130260   5.3±0.426.5±0.84   5.0±0.055.5±0.16
(20S)-1α-(OH)-2α-甲基-19-去甲-D3     130260   8.6±0.906.7±0.68   10.0±0.2012.7±0.15
(20S)-1α-(OH)-2β-甲基-19-去甲-D3     130260   6.8±0.735.7±0.45   4.8±0.045.1±0.04
*以上数据是来自5只动物的平均值和标准误差(SE)。
为了治疗目的，根据本领域已知的常规方法，由式Ia和Ib定义的本发明的化合物可以配方成以下形式用于药学应用：在无毒溶剂中的溶液，或者在适宜溶剂或载体中的乳剂、混悬剂或分散体，或者与固体载体一起的丸剂、片剂或胶囊剂。任何这种配方还可以含有其它药学可接受和无毒的赋形剂，如稳定剂、抗氧化剂、粘合剂、着色剂或乳化剂或矫味剂。
化合物可以口服、局部、胃肠外或经皮给予。化合物有利地通过注射或通过静脉输注或适宜的无菌溶液给予，或者以液体或固体剂量形式经由消化道给予，或者以乳膏剂、软膏剂、贴剂或适于经皮施用的类似载体的形式给予。0.01μg至100μg每日剂量的化合物适于治疗目的，该剂量如本领域所熟知的那样根据要治疗的疾病、其严重程度以及受试者的反应而加以调整。由于化合物显示特异性作用，因此它们各自可以适宜地单独给予，或者在发现其中不同程度骨盐动员和钙转运刺激有利的情况下，与分级剂量的另一活性维生素D化合物一例如1α-羟维生素D2或D3，或1α，25-二羟维生素D3一起给予。
供上述治疗之用的组合物包含有效量的作为活性成分的由上述式Ia和Ib定义的(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3或(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3和适宜的载体。本发明所用的这种化合物的有效量是每gm组合物约0.01μg至约100μg，并且可以以约0.01μg/日至约100μg/日的剂量局部、经皮、口服或胃肠外给予。
化合物可以配方成乳膏剂、洗剂、软膏剂、局部用贴剂、丸剂、胶囊剂或片剂，或在药学无毒并可接受的溶剂或油中的溶液、乳剂、分散体或混悬剂的液体形式，这种制剂可以另外含有其他药学无毒或有益的组分，如稳定剂、抗氧化剂、乳化剂、着色剂、粘合剂或矫味剂。
化合物有利地以足以实现前髓细胞向正常巨噬细胞分化的量给予。上述剂量是适宜的，应当懂得，给药量将如本领域所熟知的那样根据疾病的严重程度和受试者的情况和反应而加以调整。
本发明的配方包含活性成分与药学可接受的载体，并且任选地包含其它治疗成分。载体必须是“可接受的”，其含义是与配方的其它成分相容并且对其接受者无毒。
适于口服给药的本发明的配方可以是如胶囊剂、小袋、片剂或锭剂的分立单位形式，各自含有预定量的活性成分；可以是散剂或颗粒剂的形式；可以是在含水液体或非水液体中的溶液剂或混悬剂的形式；或者可以是水包油型乳剂或油包水型乳剂的形式。
用于直肠给药的配方可以是掺入活性成分和载体如可可脂的栓剂的形式，或者是灌肠剂的形式。
适于胃肠外给药的配方方便地包含活性成分的无菌油性或含水制剂，其优选与接受者的血液等渗。
适于局部给药的配方包括液体或半流体制剂，如搽剂、洗剂、涂剂(applicants)、水包油型或油包水型乳剂如乳膏剂、软膏剂或糊剂；或者溶液或混悬剂如滴剂；或者如喷雾剂。
为了治疗哮喘，可以使用用喷壶、喷雾器或者雾化器发送的粉末吸入、自推进的或者喷雾配方。当发送时，配方优选具有10至100μ的粒径。
配方可以方便地以剂量单位形式存在并且可以用药学领域众所周知的任何方法制备。术语“剂量单位”是指一个单元，即包含等量活性成分或者活性成分与固体或液体药物稀释剂或载体的混合物的单一剂量，其能够作为物理和化学上稳定的单位剂量给予患者。

Claims (77)

1.治疗银屑病的方法，所述方法包括给予患有银屑病的患者有效量的具有下式结构的(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3：
Figure A038146160002C1
2.权利要求1的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素口服给予。
3.权利要求1的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素胃肠外给予。
4.权利要求1的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素经皮给予。
5.权利要求1的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素局部给予。
6.权利要求1的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素以约0.01μg/日至约100μg/日的剂量给予。
7.治疗选自白血病、结肠癌、乳癌或前列腺癌的疾病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2α-甲基-19-去甲-维生素：
Figure A038146160003C1
8.权利要求7的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3口服给予。
9.权利要求7的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3胃肠外给予。
10.权利要求7的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3经皮给予。
11.权利要求7的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
12.治疗选自多发性硬化、狼疮、糖尿病、宿主对移植物反应和器官移植物排斥反应的自体免疫疾病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3：
Figure A038146160003C2
13.权利要求12的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3口服给予。
14.权利要求12的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3胃肠外给予。
15.权利要求12的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3经皮给予。
16.权利要求12的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
17.治疗选自类风湿性关节炎、哮喘和炎性肠病的炎性疾病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3：
18.权利要求17的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3口服给予。
19.权利要求17的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3胃肠外给予。
20.权利要求17的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3经皮给予。
21.权利要求17的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
22.具有下式结构的(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3：
Figure A038146160005C1
23.治疗选自皱纹、缺乏适度皮肤坚韧性、缺乏适度皮肤水合和皮脂分泌不足的皮肤病况的方法，所述方法包括给予患有所述皮肤病况的患者有效量的具有下式结构的(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3：
Figure A038146160005C2
24.权利要求23的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3口服给予。
25.权利要求23的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3胃肠外给予。
26.权利要求23的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3经皮给予。
27.权利要求23的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3局部给予。
28.权利要求23的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
29.治疗需要维持或增加骨量的代谢性骨病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3：
Figure A038146160006C1
30.权利要求29的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3口服给予。
31.权利要求29的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3胃肠外给予。
32.权利要求29的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3经皮给予。
33.权利要求29的方法，其中将(20S)-1α-羟基-2α-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
34.权利要求29的方法，其中该疾病是老年性骨质疏松。
35.权利要求29的方法，其中该疾病是经绝后骨质疏松。
36.权利要求29的方法，其中该疾病是类固醇诱导的骨质疏松症。
37.权利要求29的方法，其中该疾病是低骨更新骨质疏松症。
38.权利要求29的方法，其中该疾病是骨软化症。
39.治疗银屑癣的方法，所述方法包括给予患有银屑癣的患者有效量的具有下式结构的(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3：
Figure A038146160007C1
40.权利要求39的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3口服给予。
41.权利要求39的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3胃肠外给予。
42.权利要求39的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3经皮给予。
43.权利要求39的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3局部给予。
44.权利要求39的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
45.治疗选自白血病、结肠癌、乳癌或前列腺癌的疾病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3：
Figure A038146160008C1
46.权利要求45的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3口服给予。
47.权利要求45的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3胃肠外给予。
48.权利要求45的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3经皮给予。
49.权利要求45的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
50.治疗选自多发性硬化、狼疮、糖尿病、宿主对移植物反应和器官移植物排斥反应的自体免疫疾病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3：
Figure A038146160008C2
51.权利要求50的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3口服给予。
52.权利要求50的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3胃肠外给予。
53.权利要求50的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3经皮给予。
54.权利要求50的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
55.治疗选自类风湿性关节炎、哮喘和炎性肠病的炎性疾病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3：
56.权利要求55的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3口服给予。
57.权利要求55的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3胃肠外给予。
58.权利要求55的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3经皮给予。
59.权利要求55的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
60.具有下式结构的(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3：
61.治疗选自皱纹、缺乏适度皮肤坚韧性、缺乏适度皮肤水合和皮脂分泌不足的皮肤病况的方法，所述方法包括给予患有所述皮肤病况的患者有效量的具有下式结构的(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3：
Figure A038146160010C2
62.权利要求61的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3口服给予。
63.权利要求61的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3胃肠外给予。
64.权利要求61的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3经皮给予。
65.权利要求61的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3局部给予。
66.权利要求61的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
67.治疗需要维持或增加骨量的代谢性骨病的方法，所述方法包括给予患有所述疾病的患者有效量的具有下式结构的(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3：
68.权利要求67的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3口服给予。
69.权利要求67的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3胃肠外给予。
70.权利要求67的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3经皮给予。
71.权利要求67的方法，其中将(20S)-1α-羟基-2β-甲基-19-去甲-维生素D3以约0.01μg/日至约100μg/日的剂量给予。
72.权利要求67的方法，其中该疾病是老年性骨质疏松。
73.权利要求67的方法，其中该疾病是经绝后骨质疏松。
74.权利要求67的方法，其中该疾病是类固醇诱导的骨质疏松症。
75.权利要求67的方法，其中该疾病是低骨更新骨质疏松症。
76.权利要求67的方法，其中该疾病是骨软化症。
77.具有下式结构的化合物：
Figure A038146160012C1
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