CN1217664C - 2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3增加骨强度的用途 - Google Patents
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Abstract
本发明提供2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3的药学用途。该化合物以高的骨钙动员活性为特征,显示出对骨的优势活性。此结果导致用于治疗期望骨形成的疾病,尤其是骨质疏松症的新治疗剂。该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也显示出明显的活性,因而表明其作为抗癌药的用途以及治疗皮肤病如银屑病的用途。该化合物也增加骨的断裂强度和破碎强度,证明它们的与骨置换手术如髋和膝置换有关的用途。
Description
技术领域
本发明涉及维生素D化合物,更具体而言涉及2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3的药学用途。
背景技术
已知天然激素,1α,25-二羟维生素D3及其麦角骨化醇系列类似物,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,最近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益的。
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。已经公开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),其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)上亚甲基取代基的存在为特征的类似物。其中特别关注的是以碳20(C-20)甲基的非天然构型为特征的类似物,即2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3。该维生素D类似物似乎是令人感兴趣的靶,因为在C-2位相对小的亚甲基应当不会干扰维生素D受体。而且,对1α-羟基-2-亚甲基-19-去甲-维生素模型进行的分子力学研究表明,此种分子修饰基本上不改变环己二醇环A的构象。然而,将2-亚甲基引入19-去甲-维生素D碳骨架中则改变其1α-和3β-A-环羟基的特性。两个羟基对于环外亚甲基都是烯丙型的,类似于天然激素分子1α,25-(OH)2D3中的1α-羟基(对于生物活性至关重要)。
发明内容
本发明涉及2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3、其生物活性和该化合物的各种药学用途。
该19-去甲类似物的结构以下示通式I为特征:
连于C-20位甲基取代基的实心楔形线代表碳20具有S构型。
上述化合物显示所期望的和高度有利的生物活性特征。该化合物以类似于1α,25-二羟维生素D3的肠钙转运活性为特征,但是与1α,25-二羟维生素D3相比,其在从骨动员钙方面显示极高的活性。因此,该化合物在其钙活动(calcemic activity)方面具有高度特异性。其从骨动员钙的优势活性使得可以体内给予该化合物来治疗以骨损失为主要问题的代谢性骨病。由于其对骨的优势活性,该化合物将是治疗那些期望骨形成的疾病的优选治疗剂,所述疾病如骨质疏松症,尤其是低骨转换(bone turnover)骨质疏松症、类固醇诱导的骨质疏松症、老年性骨质疏松症或者绝经后骨质疏松症,以及骨软化症和肾性骨营养不良症。治疗可以是经皮、口服或者胃肠外给药。化合物在组合物中的量可以为组合物的约0.1μg/gm至约50μg/gm,给药剂量可以为约0.1μg/天至约10μg/天。
本发明的化合物还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,例如自身免疫性疾病,包括多发性硬化、糖尿病、宿主抗移植物反应和移植物排斥反应;另外,用于治疗炎性疾病如类风湿性关节炎和哮喘,以及用于促进骨折愈合和改善骨移植。本发明的化合物可以治疗的其它病症是痤疮、脱发、皮肤病症如干燥皮肤(缺少真皮水合作用)、过度皮肤松弛(皮肤结实度不足)、皮脂分泌不足和皱纹,以及高血压。
上述化合物还以高的细胞分化活性为特征。因此,该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。化合物在治疗银屑病的组合物中的量可以为组合物的约0.01μg/gm至约50μg/gm,并且可以以约0.01μg/天至约10μg/天的剂量局部、经皮、口服或胃肠外给予。
也已发现,该化合物增加骨的断裂强度(皮质强度)以及破碎强度(小梁强度)。因此,该化合物也可以用于骨置换过程如髋置换、膝置换等。
附图说明
图1是说明2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3、2-亚甲基-19-去甲-1α,25-二羟维生素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2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3与1α,25-二羟维生素D3相比较的肠钙转运活性的图;
图3是说明2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3与1α,25-二羟维生素D3相比较的骨钙动员活性的图;
图4是说明作为用2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3治疗的结果,与用1α,25-二羟维生素D3治疗相比,切除卵巢的老年雌性大鼠中的骨盐密度的图;
图5是说明作为2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3、2-亚甲基-19-去甲-1α,25-二羟维生素D3和1α,25-二羟维生素D3浓度的函数的HL-60细胞分化百分比的图;
图6a是说明作为用2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3治疗的结果,与用1α,25-二羟维生素D3治疗相比,切除卵巢的老年雌性大鼠中骨修复和建构的直方图;
图6b是说明作为用2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3治疗的结果,与用1α,25-二羟维生素D3治疗相比,切除卵巢的老年雌性大鼠中骨强度的增加的直方图;
图7是说明在6周不同剂量的2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3治疗后,与1α,25-二羟维生素D3治疗相比,切除卵巢的老年雌性大鼠中血清钙水平的直方图;和
图8是说明在2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3的不同剂量下,与1α,25-二羟维生素D3相比,切除卵巢的老年雌性大鼠的生长的直方图。
具体实施方式
合成并测试了2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3(本文称为2MD)。该19-去甲类似物的结构以本文前述的通式I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,可以完成具有基本结构I的2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3的制备:
在结构II、III和IV中,基团Y1和Y2是羟基保护基,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的予以适当保护。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]。
一般结构II的茚烷酮(Hydrindanones)是已知的,或者可以通过已知方法制备。
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。
在1998年12月1日公布的名称为“2-亚烷基-19-去甲-维生素D化合物”的美国专利5,843,928中,对化合物I的整个合成过程作了更完整的说明和描述,该专利说明书特别地引入本文做参考。
2-亚甲基-20(S)-19-去甲-1,25-(OH)2D3的生物活性
向19-去甲-1,25(OH)2D3的20(S)异构体的2-位引入亚甲基对于与猪肠维生素D受体的结合几乎没有或没有影响。与标准1,25-(OH)2D3相比,该化合物同样好地与猪受体结合(图1)。由这些结果可以预期,该化合物将具有相等的生物活性。然而,令人惊奇地,2-亚甲基和20(S)取代产生高度选择性的类似物,其对骨具有主要作用。
图2显示,在刺激肠钙转运方面,2MD具有类似于天然激素-1,25-二羟维生素D3(1,25(OH)2D3)的活性。
图3清楚地表明,对骨的作用,即骨钙动员,2MD比1,25(OH)2D3强100倍。
图4显示,与天然激素相比,在切除卵巢的大鼠中,2MD在建构骨量(bone mass)方面特别有效,而不增加血清钙浓度。这是迄今为止对维生素D化合物的空前新发现。
图5说明,对于HL-60分化,2MD比1,25(OH)2D3的作用强50-100倍,使得2MD成为用于治疗银屑病和癌症,尤其是抗白血病、结肠癌、乳癌和前列腺癌的优异的候选药。
表1和图6a说明,2MD在每周给药2次32pmol下与1,25(OH)2D3高剂量每周给药3次相比,在修复切除卵巢的老年雌性大鼠的骨方面非常有效。注:2MD也提高股骨中的灰分%。
表2和图6b显示,2MD提高表1所示动物中的股骨断裂强度(皮质强度)和椎骨破碎强度(小梁强度)。
图7和8显示在大鼠中进行的六周毒性研究,该研究证明2MD在达30pmol/天下仍显得安全。此外,在恒河猴中,27μg的一次口服剂量并不引起明显的血清钙浓度上升,提示在灵长类中的更大安全性。
通过Dame等人(Biochemistry
25,4523-4534,1986)描述的方法进行此类似物与猪肠受体的竞争性结合。
如Ostrem等人(J.Biol.Chem.
262,14164-14171,1987)所述测定HL-60前髓细胞向单核细胞的分化。
数据解释
对零钙饮食大鼠进行增加血清钙的体内测试,以观察2MD的成骨细胞活性或骨活性。剂量反应曲线表明,在通过刺激成骨细胞而提高血浆钙方面,2MD至少比1,25(OH)2D3的作用强80倍(图3)。同时,在肠钙转运方面,2MD的活性与1,25-(OH)2D3近似相等(图2)。因此,这些数据表明,2MD对骨具有选择活性。
在与维生素D受体结合方面,2MD与1,25(OH)2D3活性近似(图1)。然而,在引起前髓细胞HL-60向单核细胞分化方面,2MD比1,25(OH)2D3有效10-100倍(图5)。该结果提示,2MD将对银屑病非常有效,因为它在引起分化以及在抑制生长方面具有直接的细胞活性。这也表明,它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。
然而,最重要的结果是,2MD不仅在修复切除卵巢的老年雌性种畜大鼠的骨量方面极为有效,如图4和6以及表1和2所示,而且它引起骨量增加,超过假手术(sham-operated)对照。这说明2MD很可能具有对骨的合成代谢作用或增加骨形成。重要的是,由2MD提供的骨量增加转化为骨强度的显著提高。股骨的抗骨折强度增加表明皮质强度增加,而椎骨的抗粉碎骨折强度增加表明小梁骨强度增加(表2和图6a和6b)。有趣的是,2MD甚至另外使灰分百分比出乎意料地增加。极为重要的是,在本研究中所用的剂量水平下,动物的血清钙没有变化,这表明骨量显著提高。这说明在使用2MD增加骨盐含量和2MD升高血清钙作用之间存在一安全窗口。
两个不同时机进行的初步安全测试已经揭示,进食高钙食物的雌性大鼠耐受30pmol/天而不升高血清钙或者引起肾的矿化(参见图7和8)。此外,在恒河猴中的初步研究表明,灵长类对2MD具有相当好的耐受,因为将多达27μg的该化合物以单剂量给予10Kg的恒河猴没有出现明显的血清钙浓度升高。这些及其它测试表明,灵长类对2MD将具有极好的耐受,这可能在人中给出在有效和高钙血症危险之间的非常大的窗口。
这些结果说明,2MD是抗骨质疏松症治疗的优异的候选药,它可能对多种其它病症如自身免疫性疾病、癌症和银屑病有用。
表1
用1,25-(OH)2D3和2MD治疗切除卵巢的大鼠
组 | 治疗 | 治疗时间(周) | BMD(g/cm2) | BMC(g) | 体重(g) | BMC/体重(mg/g) | 血清钙(mg/dl) | 股骨灰分(%) | 股骨灰分(mg) |
OVX对照 | 油载体/5X/周 | 81730 | 0.294±0.0040.296±0.0030.296±0.003 | 8.64±3.309.34±0.509.41±0.45 | 414±15422±19404±24 | 21.4±1.2022.3±1.6923.4±1.60 | ------11.1±0.17 | ------59.2±0.82 | ------386±21.6 |
假手术 | 油载体/5X/周 | 81730 | 0.302±0.0030.300±0.0020.297±0.004 | 9.34±0.389.14±0.549.20±0.53 | 356±14351±15340±13 | 26.3±0.7626.4±0.8226.7±1.20 | 11.8±0.20 | 81.5±1.20 | 400±18.0 |
1,25(OH)2D3 | 250pmol/d/5X/周 | 81730 | 0.297±0.0010.308±0.0080.310±0.007 | 8.90±0.409.6±0.3910.1±0.30 | 399±9.3394±11392±16 | 22.4±0.4824.5±0.8726.1±0.97 | 11.4±0.21 | 60.8±1.1 | 417±23 |
1,25(OH)2D3 | 500pmol/d/5X/周3X/周3X/周 | 81730 | 0.312±0.0050.331±0.0080.328±0.003 | 10.2±0.4011.5±0.2511.8±0.23 | 397±14.2421±12.8432±23.0 | 26.3±0.5727.6±0.6828.0±0.69 | 11.9±0.20 | 61.4±1.3 | 478±7.5 |
2MD | 32pmol/d/2X/周 | 81730 | 0.295±0.0090.313±0.0110.331±0.006 | 8.4±0.139.7±0.1911.6±0.40 | 375±8.2373±11.0346±11.0 | 22.4±0.6426.2±0.9233.4±1.60 | 10.8±0.22 | 65.6±1.7 | 462±21.4 |
2MD | 65pmol/d/1X/周 | 81730 | 0.293±0.0040.312±0.0050.310±0.009 | 8.5±0.239.6±0.2410.2±0.33 | 408±10.5402±11.3393±15.0 | 22.2±0.5324.0±0.8026.0±1.10 | 10.7±0.46 | 62.5±0.57 | 443±11.6 |
除假手术的对照动物之外,所有动物均被切除卵巢。数值表示为平均值±SEM。
表2
股骨和椎骨对机械应力的强度
组 | 治疗 | 应力值股骨 | 应力值椎骨 |
OVX对照 | 油载体/5X/周 | 109.31±19.60 | 14.26±3.58 |
假手术 | 油载体/5X/周 | 121.36±12.5 | 13.67±1.79 |
1,25(OH)2D3 | 250pmol/天/5X/周 | 118.21±19.85 | 19.24±5.66 |
1,25(OH)2D3 | 500pmol/天/3-5X/周 | 116.47±16.20 | 17.14±0.52 |
2MD | 32pmol/天/2X/周 | 134.84±14.12 | 23.93±6.59 |
2MD | 65pmol/天/1X/周 | 133.71±14.06 | 17.07±5.73 |
为了治疗目的,根据本领域已知的常规方法,由式I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。0.1μg至10μg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受治疗的疾病、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。
供上述银屑病及其它癌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I定义的2-亚甲基-20(S)-19-去甲-维生素D化合物和适宜的载体。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50μg,并且可以以约0.1μg天至约10μg天的剂量局部、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影响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组分。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制剂可以是如胶囊剂、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被给予患者。
Claims (7)
1.具有下式结构的2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3在制备用于增加骨强度的药物中的用途:
2.权利要求1的用途,其中骨强度是皮质强度。
3.权利要求1的用途,其中骨强度是小梁强度。
4.权利要求1的用途,其中该药物为打算供口服给药用的剂型。
5.权利要求1的用途,其中该药物为打算供胃肠外给药用的剂型。
6.权利要求1的用途,其中该药物为打算供经皮给药用的剂型。
7.权利要求1的用途,其中该药物含有0.1μg/g至50μg/g的量的2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3。
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US61616400A | 2000-07-14 | 2000-07-14 | |
US09/616,164 | 2000-07-14 | ||
US09/616164 | 2000-07-14 |
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CN1455672A CN1455672A (zh) | 2003-11-12 |
CN1217664C true CN1217664C (zh) | 2005-09-07 |
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CN018155324A Expired - Fee Related CN1217664C (zh) | 2000-07-14 | 2001-07-10 | 2-亚甲基-19-去甲-20(S)-1α,25-二羟维生素D3增加骨强度的用途 |
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US (3) | US7115594B2 (zh) |
EP (1) | EP1301189A2 (zh) |
JP (1) | JP2004505022A (zh) |
KR (1) | KR100572957B1 (zh) |
CN (1) | CN1217664C (zh) |
AU (2) | AU2001278888B2 (zh) |
BR (1) | BR0112454A (zh) |
CA (1) | CA2416194C (zh) |
HK (1) | HK1060304A1 (zh) |
IL (2) | IL153907A0 (zh) |
MX (1) | MXPA03000406A (zh) |
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US20030195175A1 (en) * | 2002-03-25 | 2003-10-16 | Deluca Hector F. | Use of carbon-2-modified-vitamin D analogs to induce the formation of new bone |
WO2004076468A1 (ja) | 2003-02-25 | 2004-09-10 | Kobe Tennenbutsu Kagaku Kabushiki Kaisha | ビタミンd誘導体を合成するための新規な中間体 |
WO2005027930A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | 2-alkylene-19-nor-vitamin d derivatives for the treatment of osteosarcoma |
WO2005027919A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | 2-alkylidene-19-nor-vitamin d derivatives for the treatment of a second hip fracture |
WO2005027920A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | 2-alkylidene-19-nor-vitamin d derivatives for the treatment of rickets or vitamin d deficiency |
BRPI0414448A (pt) * | 2003-09-19 | 2006-11-14 | Pfizer Prod Inc | composições farmacêuticas e métodos compreendendo combinações de derivados de 2-alquilideno-19-nor-vitamina d e um agonista/antagonista de estrogênio |
US7214670B2 (en) * | 2003-09-24 | 2007-05-08 | Wisconsin Alumni Research Foundation | Use of 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D3 to increase the life expectancy of human beings |
US7214671B2 (en) * | 2004-02-19 | 2007-05-08 | Wisconsin Alumni Research Foundation | Use of 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D3 for the prophylaxis of bone diseases |
US7713951B2 (en) * | 2004-04-09 | 2010-05-11 | Wisconsin Alumni Research Foundation | 2-alkylidene-18,19-dinor-vitamin D compounds |
EP1812011A1 (en) | 2004-11-12 | 2007-08-01 | Bioxell S.p.a. | Combined use of vitamin d derivatives and anti-proliferative agents for treating bladder cancer |
DE602005021245D1 (de) * | 2004-11-22 | 2010-06-24 | Wisconsin Alumni Res Found | 2-methylen-19,26,27-trinor-(20s)-1-alpha-hydroxyvitamin d3 and dessen verwendungen |
WO2006061683A1 (en) * | 2004-12-09 | 2006-06-15 | Pfizer Products Inc. | 2-alkylidene-19-nor-vitamin d derivatives for the treatment of osteogenesis imperfecta |
US8193169B2 (en) | 2006-04-06 | 2012-06-05 | Wisconsin Alumni Research Foundation | (20R)-2α-methyl-19,26,2-trinor-vitamin D analogs |
WO2008035228A2 (en) * | 2006-04-06 | 2008-03-27 | Wisconsin Alumni Research Foundation | 2- substituted-1alpha, 25-dihydroxy-19,26,27-trinor vitamin d analogs and uses thereof |
WO2011017165A1 (en) * | 2009-08-03 | 2011-02-10 | Wisconsin Alumni Research Foundation | Method of preventing renal disease and treating symptoms thereof |
JP5931845B2 (ja) * | 2010-03-23 | 2016-06-08 | ウイスコンシン アラムニ リサーチ ファンデーション | 2−メチレン−19−ノル−22−メチル−1α,25−ジヒドロキシビタミンD3のジアステレオマー |
US8604009B2 (en) * | 2010-03-23 | 2013-12-10 | Wisconsin Alumni Research Foundation | (20S)-2-methylene-19-nor-22-dimethyl-1α,25-dihydroxyvitamin D3 and (20R)-2-methylene-19-nor-22-dimethyl-1α,25-hydroxyvitamin D3 |
US8664206B2 (en) | 2010-03-23 | 2014-03-04 | Wisconsin Alumni Research Foundation | Diastereomers of 2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D3 |
US9205096B2 (en) | 2012-06-29 | 2015-12-08 | Wisconsin Alumni Research Foundation | Use of 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 to treat secondary hyperparathyroidism |
US10369161B2 (en) | 2014-12-30 | 2019-08-06 | Wisconsin Alumni Research Foundation | Use of 2-methylene-19-NOR-(20S)-1-alpha,25-dihydroxyvitamin D3 to treat primary hyperparathyroidism |
US9539264B2 (en) | 2014-12-30 | 2017-01-10 | Wisconsin Alumni Research Foundation | Use of 2-methylene-19-nor-(20S)-1-alpha,25-dihydroxyvitamin D3 to treat secondary hyperparathyroidism in patients previously treated with calcimimetics |
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US4666634A (en) * | 1984-12-05 | 1987-05-19 | Chugai Seiyaku Kabushiki Kaisha | vitamin D3 derivatives having a substituent at 2-position |
CA1333616C (en) | 1989-03-09 | 1994-12-20 | Hector F. Deluca | 19-nor-vitamin d compounds |
US5086191A (en) * | 1991-05-28 | 1992-02-04 | Wisconsin Alumni Research Foundation | Intermediates for the synthesis of 19-nor vitamin D compounds |
DE69400495T2 (de) * | 1993-04-05 | 1997-04-30 | Wisconsin Alumni Res Found | 19-Nor-vitamin-D3-Verbindung mit einem Substituent an die 2. Stelle |
US5843928A (en) * | 1997-03-17 | 1998-12-01 | Wisconsin Alumni Research Foundation | 2-alkylidene-19-nor-vitamin D compounds |
US6306844B1 (en) * | 1997-03-17 | 2001-10-23 | Wisconsin Alumni Research Foundation | Use of 2α-methyl-19-nor-20(S)-1α, 25-dihydroxyvitamin D3 to increase bone strength |
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EP1301189A2 (en) | 2003-04-16 |
KR20030016403A (ko) | 2003-02-26 |
CN1455672A (zh) | 2003-11-12 |
US20060135493A1 (en) | 2006-06-22 |
US7115594B2 (en) | 2006-10-03 |
AU7888801A (en) | 2002-01-30 |
MXPA03000406A (es) | 2003-06-06 |
IL153907A (en) | 2009-08-03 |
WO2002005823A2 (en) | 2002-01-24 |
US20060135492A1 (en) | 2006-06-22 |
IL153907A0 (en) | 2003-07-31 |
BR0112454A (pt) | 2003-07-29 |
CA2416194A1 (en) | 2002-01-24 |
JP2004505022A (ja) | 2004-02-19 |
KR100572957B1 (ko) | 2006-04-24 |
US20040068129A1 (en) | 2004-04-08 |
CA2416194C (en) | 2009-10-06 |
AU2001278888B2 (en) | 2005-04-07 |
HK1060304A1 (en) | 2004-08-06 |
WO2002005823A3 (en) | 2002-05-23 |
NZ537036A (en) | 2006-07-28 |
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