CN1379675A - 24-羟基-维生素d及其类似物和应用 - Google Patents
24-羟基-维生素d及其类似物和应用 Download PDFInfo
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- CN1379675A CN1379675A CN99806763A CN99806763A CN1379675A CN 1379675 A CN1379675 A CN 1379675A CN 99806763 A CN99806763 A CN 99806763A CN 99806763 A CN99806763 A CN 99806763A CN 1379675 A CN1379675 A CN 1379675A
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Abstract
本发明提出了24-羟基维生素D类化合物以及它们在治疗和预防甲状旁腺机能亢进和过度增殖性疾病、调节免疫和炎性反应及治疗骨损耗性疾病中的应用。
Description
发明背景
本发明涉及24-羟基维生素D类化合物以及它们在治疗和预防甲状旁腺机能亢进和过度增殖性疾病、调节免疫和炎性反应及治疗骨损耗性疾病中的应用。
长期以来,有关维生素D在骨及矿物质代谢中所起的重要生物作用已为人所熟知。例如,在促进钙的吸收以及调节钙的代谢中维生素D起到至关重要的作用。同时,并非维生素D本身而是其在体内的代谢产物起到调节钙代谢作用的论点也已为人所熟知。维生素D的活性形式(M.F.Holick等人,68 Proc.Natl.Acad.Sci.USA,803-804(1971);G.Jones等人,14Biochemistry,1250-1256(1975))以及其它活性维生素D类似物(M.F.Holick等人,180 Science 190-191(1973);H.Y.Lam等人,186 Science1038-1040(1974))的发现造成了很多的轰动以及对这些维生素D类化合物治疗骨损耗性疾病的思考。
动物实验检查了这些活性维生素D类化合物,特别是作为维生素D3激素活性形式的1α,25-二羟基维生素D3的作用,实验表明这些化合物有助于钙平衡的恢复。早期的临床研究表明对一组绝经后妇女口服给药0.5μg/天的1α,25-二羟基维生素D3改善了肠道钙吸收以及钙平衡。基于这一发现,第4,225,596号美国专利(“′596专利”)对于1α,25-二羟基维生素D3用于增加钙吸收和保持作了描述并申请了专利,即、在促进肠道钙吸收以及从骨中再吸收钙(即骨代谢)方面该化合物高度有效。
但是在防止或治疗损耗性骨疾病中,维生素D化合物效能的最佳指示是骨本身而非钙吸收或钙平衡。最近的临床学数据表明在′596专利所规定的剂量范围内,对于防止或恢复骨质或骨矿物质含量损失方面1α,25-二羟基维生素D3最多仅有中等效能(S.M.Ott和C.H.Chesnut,110 Ann.Int.Med.267-274(1 989);J.C.Gallagher等人,113 Ann.Int.Med.649-655(1990);J.Aloia等人,84 Amer.J.Med.40 1-408(1988))。
这些有关1α,25-二羟基维生素D3的临床研究、以及另一有关1α-羟基维生素D3的临床研究(M.Shiraki等人,32 Endocrinol.Japan 305-315(1985))表明,这两种维生素D化合物恢复骨质或骨矿物质含量流失的能力是剂量依赖的。这些研究也表明在这两种化合物真正发挥效力所要求的剂量范围内,高血钙症和尿钙过多等毒性作用成为主要问题。具体而言,将1α,25-二羟基维生素D3剂量增至0.5μg/天以上经常导致毒性作用的出现。而剂量低于0.5μg/天时,对骨质或矿物质含量无效。(参见,G.F.Jensen等人,16 Clin.Invest.515-524(1982);C.Christiansen等人,11 Eur.J.Chlin.Invest.305-309(1981))。
日本一钙摄入量低人群的临床数据表明,当给药1μg/天时,1α-羟基维生素D3有效(M.Shiraki等人,32 Endocrinol.Japan.305-315(1985);H.Orimo等人,3 Bone and Mineral 47-52(1987))。已经发现2μg/天的1α-羟基维生素D3在老年骨质疏松症病人中有增加骨质的功效(O.H.Sorensen等人,7 Clin.Endocrinol.169S-175S(1977))。但是,当1α-羟基维生素D3剂量为2μg/天时,在约67%的患者中表现出毒性作用,而当剂量为1μg/天时,这一比例约为20%。因此,由于其固有的血钙活性,1α-羟基化维生素D3类化合物可造成危险性的高血钙浓度。
由于其毒性,所制定的1α-羟基化维生素D3口服剂量在防止或治疗骨质或骨矿物质含量流失方面最多仅能取得中等疗效。事实上,Aloia建议寻找其它给药途径,使得毒性问题可以避免并且可允许使用更高的剂量水平(J.Aloia等人,84 Amer.J.Med.401-408(1988))。尽管有报道称1α-羟基维生素D3和1α,25-二羟基维生素D3有毒性,对于很多骨损耗性疾病,这两种药物仍是很好的药物。
尽管这两种药物现今并未被所有的主要药物市场所批准,但对于治疗和预防由晚期肾病继发的甲状旁腺机能亢进,这两种药物是仅有的被批准的1α-羟基化维生素D3类药物。甲状旁腺机能亢进是1种或多种甲状旁腺分泌过多的甲状旁腺激素(PTH)所导致的疾病的总称。因此,其特征在于甲状旁腺激素的血浓高。
典型的情况是,一种或多种甲状旁腺表现为明显增大。在原发性甲状旁腺机能亢进时,腺体增大通常是由于新生物或者肿瘤。如果是继发性甲状旁腺机能亢进,甲状旁腺增生通常是由于对激素代谢作用的耐受性。
继发性甲状旁腺机能亢进发生在罹患肾衰减、骨软化症、肠吸收障碍综合症的患者中。在原发性和继发性甲状旁腺机能亢进中,骨异常如骨质流失或矿物质含量降低是最常见的,而且有可能发生肾损伤。因此,甲状旁腺机能亢进还具有异常的钙、磷和骨代谢的特征。
最近,除调节体内钙平衡作用外,维生素D的其它生物效应也已被发现。在与钙平衡无关的多种器官的细胞中已经发现了1α,25-二羟基维生素D3的特异性核受体。例如,Miller等人(52 Cancer Res.(1992)515-520)已经证明在人前列腺癌细胞系LNCaP中存在生物活性的特异性1α,25-二羟基维生素D3的受体。
现已表明某些维生素D类化合物及类似物是恶性肿瘤细胞增殖的强效抑制剂以及细胞分化的诱导剂/促进剂。例如,Suda等人的第4,391,802号美国专利公开了1α-羟基维生素D类化合物、具体而言为1α,25-二羟基维生素D3和1α-羟基维生素D3,由于诱导恶性肿瘤细胞(具体而言如白血病细胞)分化成非恶性的巨噬细胞(单核细胞)而具有强烈抗白血病活性,并可用于白血病的治疗。此外,Skowronski等人(136Endocrinology 20-26(1995))报道了1α,25-二羟基维生素D3及其它维生素D类似物对前列腺癌细胞系的抗增殖及细胞分化作用。
如上所述的文献中进行的增殖研究仅集中在维生素D3化合物。虽然该化合物的确可以有效地在培养基中分化恶性细胞,但是由于其具有与影响钙代谢的药物相同高的效力,严重地限制了它们在作为抗癌药物的分化治疗中的实际应用。在体内有效所需的剂量下,如作为抗白血病药物,因其固有的血钙活性使这些化合物可诱导出显著且具有潜在危险性的高血钙浓度。也就是说,临床使用1α,25-二羟基维生素D3和其它维生素D3类似物作为抗癌药物由于高血钙症的危险是有障碍的,或严重受限的。
维生素D的其它作用包括免疫响应调节(参见,如Truitt等人的第4,749,710号美国专利;Gates等人的第5,559,107号美国专利;Daynes等人的第5,540,919、5,518,725和5,562,910号美国专利)以及炎性反应(参见,如Hansen等人的第5,589,471号美国专利)。
考虑到维生素D的多种生物活性及其作为治疗药物的可能性,对于具有更强特异性和选择性的化合物,即具有抗细胞增殖和细胞分化作用,但与治疗剂量下的已知维生素D类化合物或类似物相比血钙活性较低的维生素D类化合物存在着需求。
发明简述
本发明提供将在以下描述的由通式(I)表示的24-羟基维生素D类化合物,其中C-17侧链是饱和或不饱和、取代或未取代、直链、支链或环状C4-C18烃基,其中在C-24位或等价位置是羟基化的。本发明还提供使用该化合物治疗或预防某些疾病和紊乱的方法。所述疾病和紊乱包括:(i)通过降低(或者维持低的)血清甲状旁腺激素浓度来治疗的甲状旁腺机能亢进;(ii)过度增殖性疾病;(iii)免疫应答不平衡;以及(iv)骨损耗紊乱。
式(I)的化合物是24-羟基维生素D化合物,其具强效生物活性,但与维生素D3的活性形式相比具有低的血钙活性。此等化合物优选为24-羟基化前药,该前药在体内在C-1位被羟基化形成1,24-二羟基化的化合物。
在此所用的术语“维生素D化合物”是指具有维生素激素活性并在式(I)的总结构范围之内的化合物。还应注意的是,通常使用缩写来表示D激素,例如1α-羟基维生素D2可简单地表示为1α-OH-D2。
在另一个方面中,本发明提供一种药物组合物,其中式(I)化合物是活性成分。此等组合物适当地以单元剂量剂型存在,其中包括有效量的式(I)维生素D化合物和药物学上可接受的赋形剂。
本发明的治疗方法是作为常规使用1α,25-二羟基维生素D3或者1α-羟基维生素D3的治疗方法的替代方法。本发明方法的特征在于提供具有相等生物活性但比常规治疗方法毒性更低的式(I)化合物。
在阅读以下附图、优选实施方案详述和所附权利要求后可了解本发明的其它优点,并对本发明的特征作较全面的了解。应深刻认识到附图仅起描述和解释作用,并不是用来对本发明进行界定。
附图简述
以下以附图为参考对本发明示例性的优选实施方案进行描述,其中全文采用相同的符号指示相同的部件,其中:
图1为制备24-羟基-维生素D2的示例性反应图;
图2为制备24-羟基-25-烯-维生素D2的示例性反应图;
图3为24(S)-羟基维生素D2的IR谱;以及
图4为图3化合物的NMR谱。
发明详述
本发明涉及24-羟基-维生素D化合物。本发明的化合物最适合用于治疗和预防某些疾病和紊乱,如过度增殖性疾病、甲状旁腺机能亢进和某些免疫应答病症。所述过度增殖性疾病包括皮肤、乳腺、结肠和前列腺癌和牛皮癣。甲状旁腺机能亢进包括原发性和继发性甲状旁腺机能亢进。免疫应答病症包括自体免疫糖尿病、多发性硬化和移植物排斥。因此,本发明将在这些方面进行详细的描述,但是本领域技术人员还应认识到,本发明的这些描述仅是说明性的,而绝非对其范围的限制。
本发明提供具有药物价值24-羟基维生素D类化合物。这些化合物适合用作1α,24-二羟基化维生素D化合物的前药,其在体内在1α位被羟基化,形成维生素D的活性形式。作为前药,这些化合物有效地避免了调节肠道钙吸收的肠维生素D受体结合的首过效应,与相似剂量的已知活性维生素D化合物如1α,25-二羟基维生素D3相比,使高血钙症减轻或消失。
在以下对本发明的方法的描述中,除非另有说明,各步骤都是在室温和大气压下进行的。
在此所用术语“基本上纯”或者“基本上没有”是指至少90%的纯度。术语“基本上低于”是指与对比物质相比至少低25%。同样,作为烷基、链烯基、氟代烷基、氟代链烯基或环烷基的修饰词,术语“低级”指含1至4个碳原子的直链、支链或环状、饱和或不饱和烃基。这些烃基的具体例子为甲基、乙基、丙基、异丙基、丁基、异丁基、特丁基、乙烯基、丙烯基、丁烯基、异丁烯基、异丙烯基、甲酰基、乙酰基、丙酰基、丁酰基或环丙基。此处术语“烃片断”用于指直链、支链或环状、饱和或不饱和的C1-C4烃基,如低级烷基、低级链烯基或低级环烷基。此处术语“等价位置”,如C-24或等价位置,是指在维生素D类化合物C-17侧链上的特定碳原子,其中碳可为24-位碳,但是指同系列侧链中的等同位置。
在一个方面中,可用于本发明中的维生素D化合物可用通式(I)表示:其中Z代表饱和或不饱和、取代或未取代、直链、支链或环状C4-C18烃基,其中C-24或等价位置被羟基化;如果与Y是双键连接在A环上的,则Y为亚甲基,或者如果与Y为单键,则Y为甲基或氢,即当Y为氢时,式(I)化合物是一种19-降化合物;而X为氢、低级烷基或低级氟代烷基。应注意的是,如果X是氢,则式(I)的化合物是一种18-降化合物。
优选地,Z是以下式(IIA)表示的侧链:其中m是0或1;沿侧链的虚线表示任选添加的C-C键;R1和R2分别是低级烷基、低级氟代烷基、低级链烯基、低级氟代链烯基、低级环烷基,或者与它们所连接的碳(如m=0时的C-25碳)一起形成C3-C8环烃基;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;R5和R6分别为氢或者一起形成在C-22和C-23之间的双键。对于m所指的键,该键可以是单、双或叁键,换言之,-CH2-、-CH=CH-或者-C≡C-。
例如,Z包括式(IIB)表示的侧链:其中R5和R6分别为氢或者一起形成在C-22和C-23之间的双键;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;而R1和R2分别是氢、低级烷基、低级氟代烷基、低级链烯基、低级氟代链烯基、低级环烷基,或者与它们所连接的碳(如C-25碳)一起形成C3-C8环烃基;。
Z还包括式(IIC)表示的侧链:其中n为选目1或2的整数;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4和R7分别为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;A为碳、氧、硫或氮;当A为氮时,r为1而s为0;当A为碳时,r和s为1;当A为硫或氧时,r和s为0;以及R9和R10分别为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基。对于m所指的键,该键可以是-CH2-或-CH=CH-。
例如,Z包括其中n是1、A是碳、r和s为1的侧链,并可用式(IID)表示:其中R3、R9和R10分别为氢、低级烷基、低级氟代烷基、和低级氟代链烯基,而R4和R7为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基。
同样,Z还包括式(IIE)表示的侧链:其中侧链上的虚线表示任选添加的C-C键;q为0或选自1或2的整数;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4和R7为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;A为碳、氧、硫或氮;当A为氮时,r为1而s为0;当A为碳时,r和s为1;当A为硫或氧时,r和s为0;R9和R10分别为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基。对于任选添加的键,例如,如果q=0,C-22和C-23间的键可为单键、双键或三键。而q所表示的基团为-CH2-。
例如,Z包括其中q是0、A是碳、r和s是1;R3、R9和R10分别为氢、低级烷基、低级氟代烷基、低级链烯基和低级氟代链烯基,而R4和R7为氢、低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基的侧链,并可用式(IIF)表示:
本发明范围的维生素D化合物还包括其中适当地包括与如上所述相同的Z侧链的24-羟基维生素D化合物,所述侧链包括那些式(IIA)、(IIB)、(IIC)、(IID)、(IIE)和(IIF)表示的并在C-24位或等价位置被羟基取代者。前维生素D是相应维生素D类化合物的热异构体,如24-羟基前维生素D2是24-羟基维生素D2的热异构体,并存在于其热平衡中。根据本发明的24-羟基前维生素D化合物可适当地用式(III)表示:其中X、Y和Z都如上所定义。
优选的式(I)化合物为作为1α,24-双羟化维生素D前药的24-羟基化合物。式(I)化合物的例子为:
24-羟基维生素D2[24-(OH)-D2]
24-羟基-25-氟维生素D2[24-(OH)-25-F-D2]
24-羟基-25-烯-维生素D2[24-OH-25-烯-D2]
24-羟基-25-羰基-维生素D2[24-OH-25-羰基-D2]
24-羟基维生素D4[24-(OH)-D4]
24-羟基-25-氟维生素D4[24-(OH)-25-F-D4]
24-羟基-25-烯-维生素D4[24-OH-25-烯-D4]
24-羟基-25-羰基-维生素D4[24-OH-25-羰基-D4]
优选的式(III)化合物为24-羟基前维生素D类化合物,它们也是1α,24-双羟基化维生素D的前药和异构体。式(III)化合物的例子为:
24-羟基前维生素D2[24-(OH)-前D2]
24-羟基-25-氟前维生素D2[24-(OH)-25-F-前D2]
24-羟基-25-烯-前维生素D2[24-OH-25-烯-前D2]
24-羟基-25-羰基-前维生素D2[24-OH-25-羰基-前D2]
24-羟基前维生素D4[24-(OH)-前D4]
24-羟基-25-氟前维生素D4[24-(OH)-25-F-前D4]
24-羟基-25-烯-前维生素D4[24-OH-25-烯-前D4]
24-羟基-25-羰基-前维生素D4[24-OH-25-羰基-前D4]
对于侧链中具有手性中心如C-20或C-24位的化合物,应认识到两种非对映体(如R和S)及其混合物均在本发明范围之内。
式(I)的化合物通常用图1所示的示例性反应方法来制备。图1显示了使用麦角甾醇作为起始物来制备24-羟基维生素D2的方法,其中形成的24-羟基维生素D2然后分离,如果需要立体化学纯的,则制备24(S)-羟基维生素D2非对映体和24(R)-羟基维生素D2非对映体。除非另有说明,以下在说到24-羟基化合物时,该化合物是R和S形式的非对映体混合物。
具体而言,麦角甾醇通过六步法转化为24-羟基麦角甾醇(5,7,22麦角三烯-3β,24-二醇(7))。然后照射24-羟基麦角甾醇,并用本领域已知的方法热转化,产生24-羟基维生素D2,并由其分离非对映体。
如图1所示,麦角甾醇被乙酰化,形成3β-乙酸酯(2)。3β-乙酸酯与三唑啉二酮反应,由此与麦角甾醇结构的B环形成加成物(3)。加成物(3)然后被臭氧化,以截短侧链,形成C-21醛(4)。所得醛与合适的酮基化合物反应产生24-烯酮(5),从而使侧链重新组成。将烯酮转化为24-甲基,3β,24-二羟基加成物(6)。该加成物与氢化铝锂反应,使加成物脱保护,并产生24-羟基麦角甾醇(7)。然后照射并热处理24-羟基麦角甾醇,形成24-羟基维生素D2(8)。24-羟基维生素D2进行反相高压液相色谱分离,以分离两种非对映体,然后回收本发明的非对映体形式,24(S)-羟基维生素D2(9)和24(R)-羟基维生素D2(10)。
其中侧链用式(IIC)或(IIE)表示的式(I)化合物通常用图2所示的示例性方法制备。图2显示了使用维生素D2作为起始物并形成25-烯-维生素D2来制备24-羟基-25-烯-维生素D2的方法,其中使得自于人肝瘤细胞的经培养的细胞如HEP3B或HEPG2与25-烯-维生素D2温孵,产生代谢物24-羟基-25-烯-维生素D2,然后用高压液相色谱分离并纯制。
如图2所示,维生素D2(11)与SO2反应,而且C-3位的羟基官能团用特丁基二甲基甲硅烷氧基氯(TBDMSCl)保护,生成中间体(12)。臭氧分解并还原得到醇(13)。挤出SO2,异构化,然后用已知的Swern氧化法氧化得到醛(14)。醛(14)与Wittig试剂或者苯基砜反应引入侧链,得到25-烯-维生素D2化合物(15)。25-烯化合物(15)然后与得自于人肝瘤细胞的细胞系一起温孵,并提取和纯制24-羟基-25-烯-维生素D2(16)。制备24-羟基-25-烯-维生素D的方法也描述在共同未决并共同拥有的题目为“制备羟基-25-烯-维生素D化合物的方法”的专利申请中,其在此并入作为参考。
式(III)化合物一般可采用图1和2列举的方法制备,其中可利用如Pauli等人的第5,252,191号美国专利;Coethals等人的第5,035,783和4,388,243号美国专利中的示例性反应方法制备起始原料前维生素,此处引用这些专利作为参考。式(I)的19-降化合物一般也可由此处给出的示例性反应方法制备,19-降起始原料可按第5,710,294号美国专利中给出的方法制备,此处引用该专利作为参考,其使用合适的维生素D起始物。
本发明的化合物可在药物组合物中用作活性成分,其与活性形式的维生素D3相比具有更少的副作用和低毒性。这些化合物特别适合局部和全身治疗以及预防具有以下特征的疾病:(i)异常细胞增殖和/或细胞分化例如癌症,如皮肤、乳腺、结肠和前列腺癌,以及皮肤疾病如牛皮癣;(ii)免疫系统失衡例如自体免疫疾病,如多发性硬化和糖尿病,以及移植物的排斥;(iii)异常白介素-1产生例如炎性反应疾病,如类风湿性关节炎和哮喘;(iv)异常甲状旁腺激素产生,例如甲状旁腺机能亢进,包括原发性和继发性的;以及(v)骨质或者骨矿物质含量流失。
本发明的24-羟基维生素D化合物具有较低的产生非所希望的高钙血症和/或高钙尿症副作用的趋势或者没有此能力。换言之,本发明的化合物可以如下剂量给药:该剂量使它们在与恶性或者其他过度增殖性细胞接触时起到抗增殖剂和细胞分化剂的作用,而不会显著地改变钙代谢。该作用的选择性和特异性使本发明的24-羟基维生素D化合物可用于并优选作为安全抑制过度增殖并促进恶性或者增生性细胞分化的药物。因此,本发明的24-羟基维生素D化合物克服了上述已知活性维生素D3化合物的缺陷,而且可以优选作为用于控制和治疗以下疾病的药物:恶性疾病如前列腺癌以及良性前列腺增生,皮肤疾病如皮肤癌和牛皮癣,乳腺癌和结肠癌,免疫和炎性反应疾病,以及甲状旁腺机能亢进。例如对于后者,当给药于甲状旁腺机能亢进患者时,式(I)的类似物的毒性基本上比它们的维生素D3相应物低。对于使用口服磷酸钙黏合剂的患者,以高于维生素D3化合物时的剂量给药式(II)的类似物可在治疗甲状旁腺机能亢进时产生比前者更高的效力。
本发明的药理学活性化合物适合使用药学领域的常规方法来处理,以制备用于给药于患者的药物组合物,所述患者例如是哺乳动物,包括人。所述组合物是活性化合物与药物学上可接受的有机或无机载体物质的混合物,并任选包括其他治疗成分,其中所述载体物质不损害性地与活性化合物反应。可使用任何合适的给药途径来给药根据本发明的化合物的优选剂量。例如,可使用口服、直肠、局部、非胃肠道、静脉、肌肉内、皮下、眼、鼻、颊部等途径。
治疗和预防性组合物是那些适用于上述各种给药途径的组合物,但是最合适的途径在任何情况下都取决于待治疗病症的性质和严重程度、以及活性成分的性质。它们通常为单元剂量剂型。
适用于本发明的组合物和方法的合适的药物学上可接受的载体包括但不限于水、盐溶液(如缓冲液)、醇包括苄醇、阿拉伯胶、矿物和植物油(如玉米油、棉籽油、花生油、橄榄油、椰子油)、鱼肝油、油性酯(如Polysorbate 80)、聚乙二醇和丙二醇、明胶、碳水化合物(如乳糖、支链淀粉或淀粉)、硬脂酸镁、滑石、硅酸、黏性石蜡、脂肪酸单甘油酯和二甘油酯、季戊四醇脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷酮等。
药物制剂可以是无菌的,而且如果需要,可与辅剂混合,例如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、增加渗透压的盐、缓冲剂、着色剂和调味剂。如果使用固体载体,本发明化合物的剂型可以是片剂、胶囊、粉末、栓剂或锭剂。如果使用液体载体,则剂型可以是软明胶胶囊、透皮药贴、气雾喷雾剂、局部用乳膏、糖浆剂或者混悬剂、乳剂或者溶液剂。
但是应注意的是,24-羟基前维生素D的剂型最优选用以下载体配制:淀粉、乳糖或支链淀粉,它们不损害性地与活性化合物反应。制剂可制成为片剂、胶囊、粉末或者锭剂。但是,在使用任何配制方法时,应注意避免与溶剂或热接触,因为在这些条件下24-羟基前维生素D会转化为24-羟基维生素D,即、式(III)的化合物优选以无溶剂、晶体、热稳定的形式配制。因为要避免热和溶剂,所以优选的片剂配制方法是干燥制粒法。
对于胃肠道给药时,特别合适的是可注射的无菌溶液,优选油或水溶液,以及混悬剂、乳剂、或植入剂,包括栓剂。安瓿是常规的单元剂量。根据本发明的类似物在非胃肠道给药时的剂量通常为1-30μg,每周给药1-3次。
如上所述,在肠道给药时,特别合适的是片剂、糖衣片、液体、滴剂、栓剂或胶囊剂。可以使用糖浆剂、甘香酒剂等,其中使用甜味载体。
在直肠给药时,化合物配制成包含栓剂基质如可可油或其他三甘油酯的药物组合物。为延长储存期,组合物可有利地包含抗氧剂,如抗坏血酸、丁基化羟基茴香醚或氢醌。
在局部使用时,也可以使用非喷雾剂型、黏性至半固体剂型,其包括与局部使用相匹配的载体,并优选具有比水更大的动态黏性。合适的局部用制剂包括透皮给药装置、溶液、混悬剂、乳剂、气雾剂、乳膏、软膏、涂抹剂、油膏剂、洗剂、粉尘剂等,而且如果需要,这些制剂可进行灭菌或者与辅剂混合如防腐剂等。
本发明化合物的预防或治疗剂量可根据待治疗病症的性质和严重程度、具体的组合物以及给药途径来变化。优选口服给药本发明的药物组合物。
通常情况下,根据本发明的化合物的剂量为约0.025-7.5nmol/kg患者体重,优选为0.025-1nmol/kg。本发明的化合物通常用在药物学可接受的载体中的单元剂量剂型来分配,每单元剂量在药物学上可接受的载体中包含约0.25-50.0μg所述化合物。根据本发明的化合物的剂量通常为3.5-1000μg/周,优选为10-500μg/周。
在治疗过度增殖性疾病如癌症和牛皮癣时,本发明化合物的肠道剂量为每单元剂量1-100nmol,在治疗甲状旁腺机能亢进时为每单元剂量约0.5-50nmol,在治疗炎性疾病时为每单元剂量1-150nmol,在免疫应答调节时为每单元剂量1-150nmol。因此,日有效剂量为0.01-3.0μg/kg体重/天。
另外,本领域技术人员还可认识到,所述剂量可进行包胶以随时间释放,例如持续释放、缓释或直接释放给药系统,如脂质体给药系统,具有缓慢释放机制的多糖,salistic或其他聚合植入物或微球,以及其中活性成分被适当地用一种或多种具有不同分解性的包衣保护者,例如微包胶、肠溶包衣、多层包衣等,以及可连续给药所包含组分的装置。例如,肠溶包衣是一种可以耐受胃液崩解的合适装置。还可以冻干活性成分,然后使用所得到的冻干物例如制备注射产品。
还可以认识到,活性类似物的实际优选用量在具体情况下可根据所用的具体化合物、具体配制的组合物、给药方式、以及待治疗的具体部位来变化。可使用常规方法来确定剂量,例如通过常规对比目标化合物和已知药物的不同活性,或者通过合适的常规药代动力学方法。
对于每个具体患者的具体用量取决于许多因素,例如具体给药化合物的效力、患者的年龄、体重、总的健康状况、性别、饮食、给药的时间和方式、排泄速率、以及组合使用的药物和具体疾病的严重程度。
如以上所述,本发明的化合物优选以口服制剂给药于人(或者动物)患者。随着根据本发明的化合物从口服制剂中释放,其可经由肠被吸收到血液中。本发明的化合物然后在维生素环结构的D环的1α-位进行羟基化,由此产生维生素D化合物的活性形式,其是1α,24-二羟基化的。对于式(I)的化合物,希望几乎没有或者没有与肠维生素D受体的首过相互反应,由此几乎没有或者不产生对肠钙吸收的刺激作用。如果是式(III)的24-羟基前维生素D化合物,因为这些化合物被动物或人的内部温度温热,所以它们转化为相应的1-羟基维生素D,然后被24-羟基化,形成1,24-二羟基化合物。应注意的是,24-羟基前维生素D化合物在热和代谢活化之前不与肠维生素D受体相互作用,并因此不会刺激首过肠钙吸收。
制剂也可包含辅剂以及其他治疗有用的物质,或者可混合包含一种以上的在此所述化合物。
因此,本发明范围的其他方面是与其他激素或者其他在治疗所述疾病中具有效力的药物共同给药有效剂量的本发明化合物。
例如,本发明的化合物可合适地与已知用于改善骨疾病的药物共同给药。此等骨剂可包括结合雌激素或其等价物、抗雌激素、降钙素、双膦酸酯、钙添加剂、钙受体激动剂、钴胺、百日咳毒素、硼、脱氢异雄酮(DHEA)和其他骨生长因子如转化生长因子β、苯丙酸诺龙或者骨形态发生蛋白。这些共同给药的药物的可能剂量范围见表1所示。
表1
各种可以与1α-羟基维生素D2共同给药的药物的可能口服剂量范围
药剂 | 剂量范围 | ||
宽的范围 | 优选范围 | 最优选范围 | |
结合雌激素或等价物(mg/天) | 0.3-5.0 | 0.4-2.4 | 0.6-1.2 |
氟化钠(mg/天) | 5-150 | 30-75 | 40-60 |
降钙素(IU/天) | 5-800 | 25-500 | 50-200 |
钙受体激动剂(mg/天) | 4-1000 | 20-800 | 50-60 |
双膦酸酯(μg/天) | 50-20000 | 100-15000 | 250-10000 |
钙添加剂(mg/天) | 250-2500 | 500-1500 | 750-1000 |
钴胺(μg/天) | 5-200 | 20-100 | 30-50 |
百日咳毒素(mg/天) | 0.1-2000 | 10-1500 | 100-1000 |
硼(mg/天) | 0.10-3000 | 1-250 | 2-100 |
抗雌激素如TamoxifenTM已知不仅是骨剂而且还是抗增殖药物,而且适于与本发明的24-羟基维生素D和24-羟基前维生素D化合物共同给药。
虽然上述例子详细地描述了口服剂量,当应理解的是,药物的组合也可以其他方式给药,包括鼻内、透皮、直肠内、阴道内、皮下、静脉、以及肌肉内给药。
本发明还提供与已知细胞毒性剂共同给药的化合物。此等细胞毒性剂包括雌莫司汀、磷酸酯、泼尼莫司汀、顺铂、5-氟尿嘧啶、美法仑、羟基脲、丝裂霉素、伊达比星、甲氨蝶呤、阿霉素和柔红霉素。可以预期的是,与各种抗癌药物组合使用的式(II)或(III)维生素D可显著增强对癌细胞的细胞毒性作用,因此增加治疗效果。具体而言,因为与单独使用抗癌药物的治疗方案相比,如上所述组合使用较低浓度的抗癌药物也可得到明显增强的生长抑制作用,所以有可能使治疗中与抗癌药物有关的副作用与单独大剂量使用时正常观察到的副作用相比显著下降。这些共同给药的第二抗癌药物的可能剂量范围是0.1-1μg/kg/天。
根据本发明的化合物也适合于与已知抗炎药物共同给药。此等抗炎药物包括甾体(如皮质类甾醇)和非甾体(如水杨酸酯、萘普生)抗炎药。可以预期的是,与各种抗炎药物组合使用的本发明化合物可显著增强抗炎活性,因此增加治疗效果。
共同给药本发明的化合物和已知免疫应答增强剂也包括在本发明的范围内。此等免疫应答增强剂包括环孢菌素、DHEA和DHEA衍生物如DHEA-硫酸酯、16α-溴-DHEA、7-氧-DHEA、16α-溴-DHEA硫酸酯和7-氧-DHEA硫酸酯。可以预期的是,与各种免疫应答增强药物组合使用的本发明化合物可显著增强免疫调节活性,因此增加治疗效果。
将根据以下实施例进一步描述本发明,但这些实施例不是用于限制本发明的范围。实施例1:合成24-羟基维生素D2[24-OH-D2](22E)-5,7,22-三麦角甾三烯-3β-基乙酸酯(2)
向50g(0.13mol)麦角甾醇(1)在300ml无水吡啶的溶液中添加33.3ml(0.35mol)乙酸酐。室温下搅拌混合物过夜,然后添加水(600ml)。过滤沉淀并用200ml乙腈洗涤3次,然后空气干燥,得到42.0g(74%)的(2)22-氧-5α,8α-(4-苯基-3,5-二氧-1,2,4-三唑啉-1,2-二基)23,24-二降-6-胆烯-3β-基-乙酸酯(4)向33.0(0.075mol)麦角甾醇乙酸酯(2)在1000ml氯仿中的溶液内添加13.2g(0.075mol)的4-苯基-1,2,4-三唑啉-3,5-二酮。将所形成的溶液(3)在室温下搅拌30分钟,然后添加5ml吡啶。将溶液冷却至-78℃,然后在-78℃下用臭氧-氧混合物处理2小时,接者用氮气彻底清洗。添加50ml的二甲基亚砜,并用300ml水洗涤混合物,然后用200ml的2N盐酸和300ml的水洗涤。分离有机层,在无水硫酸镁上干燥,然后真空浓缩至干。残留物在硅胶柱上用30%乙酸乙酯的己烷溶液洗脱进行纯制,得到16.0g泡沫固体状的标题化合物
1H NMR(400MHz,CDCl3)δppm:0.85(3H,s,18CH3),1.10(3H,s,19-CH3),1.15(3H,d,21-CH3),1.99(3H,s,3β-CH3CO),5.45(1H,m,3α-H),6.26(1H,d,7-H),6.40(1H,d,6-H),7.42(5H,m,Ph),9.58(1H,d,HCO)22(E)5α,8α-(4-苯基-3,5-二氧-1,2,4-三唑啉-1,2-二基)胆甾-6,22-二烯-3β-基-乙酸酯(5)
在搅拌和氮气下将丁基锂(1.6M在己烷中的溶液,8.94ml,0.014mol)添加在二异丙基胺(1.45g,0.014mol)于无水四氢呋喃(20ml)中的0℃溶液内。在15分钟的时间内于0℃下滴加3-甲基丁烷-2-酮(1.23g,0.014mol)在无水四氢呋喃(6ml)中的溶液。在0℃下搅拌该溶液1小时,然后冷却至-70℃,并添加醛(4)(6.0g,0.011mol)在无水四氢呋喃(60ml)中的溶液。温度升高至-20℃,并在该温度下保持3小时。在-20℃下添加冰乙酸(20ml),然后使溶液达到室温。添加醚(800ml)和水(400ml),分离有机层,用10%盐酸(2×300ml)、饱和碳酸氢钠水溶液(2×300ml)、和水(2×300ml)洗涤。浓缩得到粗产物(7.5g),将其溶解在四氢呋喃(100ml)中,该四氢呋喃中包含1.5N盐酸(12ml)。回流1.5小时后,用醚(600ml)稀释混合物,用5%碳酸钠水溶液(2×200ml)和水(2×200ml)洗涤,然后干燥(无水硫酸镁)。减压浓缩,得到粗产物(7.0g)。在硅胶上进行色谱分离(50%乙酸乙酯的己烷溶液)得到烯酮(5)4.0g(59%)
1H NMR(400MHz,CDCl3)δppm:0.83(3H,s,18CH3),0.99(3H,s,19-CH3),1.09(6H,dd,26和27-CH3),1.12(3H,d,21-CH3),2.0(3H,s,3β-CH3CO),2.84(1H,m,25-H),5.45(1H,m,3α-H),6.06(1H,d,23-H),6.24(1H,d,7-H),6.39(1H,d,6-H),6.71(1H,dd,22-H),7.42(5H,m,Ph)22(E)-5α,8α-(4-苯基-3,5-二氧-1,2,4-三唑啉-1,2-二基)-6,22-麦角甾二烯-3β,24-二醇(6)
将烯酮(5)(3.5g,5.7mmol)在干燥乙醚(100ml)中的溶液冷却至0℃,然后滴加甲基溴化镁(3.0M,乙醚溶液,6.8ml,0.02mol)。在0℃下1小时后,添加饱和氯化铵(100ml)。分离有机层。含水层用乙醚(2×200ml)萃取。合并的醚相用无水硫酸镁干燥,然后真空浓缩至干,得到粗产物(6)3.0g(90%)。(22E)-5,7,22-麦角甾三烯-3β,24-二醇(7)
向3.0g(5.1mmol)的(6)无水四氢呋喃(250ml)中的溶液内添加氢化铝锂3.6g(0.09mol)。在回流下加热混合物3小时,用冰浴冷却,然后小心滴加冰水(5ml)使反应混合物分解。过滤混合物,滤液真空浓缩,以除去大多数的四氢呋喃。残留物溶解在200ml的乙酸乙酯中,并用饱和氯化钠溶液(2×200ml)洗涤两次,用无水硫酸镁干燥,然后真空浓缩。残留物在硅胶柱上用30%乙酸乙酯己烷溶液纯制,得到1.5g(71%)的(7)。
1H NMR(400MHz,CDCl3)δ ppm:0.64(3H,s,18-H),0.88(6H,dd,26和27-CH3),0.93(3H,s,19-CH3),1.06(3H,d,21-CH3),1.19(3H,s,28-CH3),3.55(1H,m,3α-H),5.36(1H,d,7-H),5.42(2H,m,22和23-H),5.52(1H,d,6-H).UV(乙醇):λmax:282nm24-羟基维生素D2(8)
将1g(2.4mmol)的(7)溶解在250ml的乙醚和苯(4∶1)中,在氮气和搅拌下在水冷却的石英浸没井中使用Hanovia中等压力的UV灯照射2小时。真空浓缩溶液,重新溶解在100ml乙醇中,然后在回流下加热过夜。真空浓缩溶液至干,残留物在硅胶柱上用30%乙酸乙酯己烷溶液纯制,得到0.55g(55%)的(8)。
1H NMR(400MHz,CDCl3)δppm:0.57(3H,s,18-CH3),0.92(6H,dd,26和27-CH3),1.06(3H,d,21-CH3),1.20(3H,s,28-CH3),3.93(1H,m,3-H),4.79(1H,m(尖),19-H),5.01(1H,m(尖),19-H),5.43(2H,m,22和23-H),6.02(1H,d,7-H),6.22(1H,d,6-H).UV(乙醇):λmax:265nm实施例2:合成24(S)-羟基维生素D2(9)[24(S)-OH-D2]
在Zorbax-SIL柱(用己烷/异丙醇/甲醇91∶7∶2洗脱)或者反相SupelcoC-8制备柱(25cm×21.2mm,粒径12μm,其溶剂系统为乙腈∶水60∶40,10ml/min)上对产物(8)进行高于液相色谱(HPLC)纯制。洗脱出非对映体(9)和(10)。
24(S)-羟基维生素D2表征如下:[α]D 24.0℃=+120.4(c=1.0,乙醇),m.p.:123-126℃;TLC∶Rf=0.10(4∶1己烷∶乙酸乙酯,硅胶,Whitman No.4500-101);元素分析:计算值c=81.50,H=10.75;实测值c=81.62,H=10.66。红外光谱(IR)(KBr)见图3所示,而核磁共振(NMR)谱(300MHz,1H在CDCl3)见表4所示。实施例3:由24(S)-OH-D2体内产生1α,24(S)-二羟基维生素D2
将24-OH-D2给药(口服或者腹膜内添加)于维生素D缺乏的大鼠。制备血浆的脂质提取物,然后使用以下所述用于合成标准生物1α,24-(OH)2D2的方法(Horst,R.L.,Koszewski,N.J.和Reinhardt,T.A.,Biochem.,29:578-82(1990),并在此并入作为参考)纯制代谢物。
标准生物1α,24-(OH)2-D2体外如下由24-OH-D2来合成:在包含5ml的20%由维生素D缺乏鸡制得的肾匀浆的烧杯中温孵10μg的24-OH-D2。该反应的产物通过HPLC纯制,并用质谱鉴别。在给药维生素D或者24-OH-D2的维生素D缺乏大鼠的血浆的脂质提取物中,发现分离出的一种代谢物在HPLC中与1α,24-(OH)2-D2一起移动这表明是1α,24-(OH)2-D2是维生素D2的天然代谢物。相反地,在给药维生素D3的对比鼠中没有检测到24-OH-D3。实施例4:由24(S)-OH-前维生素D2体内产生1α,24(S)-(OH)2-D2
向雄性刚断奶的鼠喂以维生素D缺乏和正常钙(0.47%)的饲料。四周后,将鼠分为两个组,并口服给药在载体如乳糖中的24-OH-前D2(0.25μg/kg)或者载体(对照)。给药后4小时,杀死鼠,并使用标准技术测量1α,24-(OH)2-D2的血液浓度。
该方法表明1α,24-(OH)2-D2的浓度显著增加。实施例5:在给药24-OH-25-烯-D2的骨质疏松症妇女中产生1α,24(S)-(OH)2-25-烯-D2
已被诊断患有骨质疏松症的女性患者每日给药25μg/天的24-OH-25-烯-D2共1周。收集血液,并分析代谢物1α,24(S)-(OH)2-25-烯-D2。从血液中提取脂质,使用标准方法用HPLC纯制代谢物,并用Incstar(Stillwater,Minnesota)制造的放射受体分析进行定量。在最后给药25μg那天,结果表明血液中有显著量的1α,24(S)-(OH)2-25-烯-D2。实施例6:用24(S)-OH-前D2治疗骨质疏松
用年龄在55-75岁之间的绝经后妇女进行临床研究。该研究涉及120位患者,它们随机分为三个治疗组,并持续24个月。两个治疗组接受恒定剂量的口服给药的24-OH-前D2(u.i.d.,两种5.0μg以上的不同剂量),而另一个组接受匹配量的安慰剂。所有患者保持正常的饮食钙摄入(500-800mg/天),但限制使用钙添加剂。在以下方面通过患者组治疗前和治疗后的对比来评估效力:(a)用X射线吸收计(DEXA)测量的总的身体、桡骨、股骨和/或脊椎骨的矿物密度;(b)髂骨的骨活组织检查;以及(c)测定血清骨钙蛋白。通过对比羟基脯氨酸的尿排泄、血清和尿钙浓度、肌酸清除、血尿氮、和其他常规检查来评估安全性。
该研究表明,通过口服给药24-OH-前D2治疗的患者与用安慰剂治疗的患者相比表现出显著更高的总身体、桡骨、股骨和/或脊椎骨骨密度。经治疗的患者还表现显著升高的血清骨钙蛋白。治疗患者的骨活组织检查表明,24-OH-前D2刺激正常的骨形成。所监测的安全参数证实24-OH-前D2导致不明显的高钙血症或高钙尿症的发生率、或者任何其他代谢紊乱。实施例7:用24(S)-OH-D2预防性治疗的绝经后骨质疏松妇女中的骨质流失
用年龄在55-75岁之间的绝经后妇女进行临床研究。该研究涉及120位患者,它们随机分为三个治疗组,并持续24-36个月。两个治疗组接受恒定剂量的口服给药的24(S)-OH-25-烯-D2(u.i.d.,两种5.0μg或者以上的不同剂量),而另一个组接受匹配量的安慰剂。所有患者保持正常的饮食钙摄入(500-800mg/天),但限制使用钙添加剂。在以下方面通过患者组治疗前和治疗后的对比来评估效力:(a)总的身体钙保留;以及(b)用双光子吸收计(DPA)或者双能X射线吸收计(DEXA)测量的桡骨和脊椎骨的矿物密度。通过对比羟基脯氨酸的尿排泄、血清和尿钙浓度、肌酸清除、血尿氮、和其他常规检查来评估安全性。
该研究表明,通过口服给药24(S)-OH-25-烯-D2治疗的患者与用安慰剂治疗的患者相比表现出显著更高的总身体钙、以及桡骨和脊椎骨骨密度。所监测的安全参数证实24(S)-OH-25-烯-D2导致不明显的高钙血症或高钙尿症的发生率、或者任何其他代谢紊乱。实施例8:用24-OH-D2治疗牛皮癣
在一个双盲研究中评估包含24-OH-D2的口服制剂对治疗皮炎(接触和异位)的效力。所评估的制剂包含10.0-20.0μg的24-OH-D2。对照制剂是相同的,但其不包含24-OH-D2。患者在门诊临床中进行治疗,并分为实验组和对照组。指示他们每天服药一次,在早饭之前的早晨。
在每个患者(实验和对照)中,所选择的包含损伤的皮肤面积通常被衣服覆盖,并指示患者不要将所选择用于研究的皮肤面积暴露于阳光。损伤面积进行估算并记录,然后对损伤照相。记录照相程序的相关细节,以在下一次照相时重复进行(距离、孔径、角度、背景等)。
医师以每周间隔对红斑、鳞屑和厚度进行评估。最终的评估通常在治疗4-6周结束时进行。该研究的结果表明,与对照患者相比,每日口服给药24-OH-D2显著降低红斑、鳞屑和厚度的程度。实施例9:用24(S)-OH-前D2治疗牛皮癣
在一个双盲研究中评估包含24(S)-OH-前D2的口服制剂对治疗皮炎(接触和异位)的效力。所评估的制剂包含10.0-20.0μg的24(S)-OH-前D2。对照制剂是相同的,但其不包含24(S)-OH-前D2。患者在门诊临床中进行治疗,并分为实验组和对照组。指示他们每天服药一次,在早饭之前的早晨。
在每个患者(实验和对照)中,所选择的包含损伤的皮肤面积通常被衣服覆盖,并指示患者不要将所选择用于研究的皮肤面积暴露于阳光。损伤面积进行估算并记录,然后对损伤照相。记录照相程序的相关细节,以在下一次照相时重复进行(距离、孔径、角度、背景等)。
医师以每周间隔对红斑、鳞屑和厚度进行评估。最终的评估通常在治疗4-6周结束时进行。该研究的结果表明,与对照患者相比,每日口服给药24(S)-OH-前D2显著降低红斑、鳞屑和厚度的程度。实施例10:用24-OH-D2治疗前列腺癌
患有晚期非雄激素依赖性前列腺癌的患者参加24-OH-D2的开标研究中。符合要求的患者为至少40岁,表现出前列腺癌的组织学证据,而且具有以前应答激素治疗的进行性疾病。在允许参加该研究时,患者开始口服24-OH-D2的治疗,疗程为26周,同时停止任何以前使用的钙添加剂、维生素D添加剂、和维生素D激素替代治疗。在治疗期间,以固定间隔监测:(1)高钙血症、高磷血症、高钙尿症、高磷尿症和其他毒性;(2)转移疾病发展变化的证据;以及(3)对预定测试药物剂量的顺应性。
该研究进行两期。在第一期中,每日口服24-OH-D2的最大耐受剂量(MTD)是通过向连续组的患者给药逐渐增高的剂量来确定的。所有剂量都是在早餐之前的早晨给药。第一组患者用25.0μg的24-OH-2-D2治疗。随后组的患者用50.0、75.0和100.0μg/天治疗。在研究期间不间断地连续给药,除非血清钙超过11.6mg/dl,或者观察到3或4级的其他毒性,在此情况下中止给药,直至所观察的毒性作用解除,然后以降低10.0μg的剂量重新开始。
该研究的第一期结果表明,24-OH-D2的MTD是25.0μg/天以上,其是用1α,25-(OH)2-D3时所达到的浓度的10-50倍。分析从参加患者中定期收集的血样,其表明24-(OH)-D2的循环浓度与给药剂量成比例地增加,在最高剂量时升高至100pg/ml以上的最大浓度,而且1α,25-(OH)2-D3的循环浓度受到抑制,通常至检测不到的水平。血清和尿钙剂量依赖性地升高。用MTD的24-OH-D2治疗患者至少6个月表明,与转移疾病有关的骨痛显著消失。
在第二期中,患者用24-OH-D2以0.5和1.0倍于MTD的剂量治疗24个月。在治疗1和2年后,用于评估转移疾病的发展的CAT扫描、X射线和骨扫描都表明,以低剂量治疗的许多患者中疾病稳定或者部分康复,而以高剂量治疗的许多患者中疾病稳定以及部分或者完全康复。实施例11:用24-OH-前D2治疗前列腺癌
用维生素D化合物重复实施例8的研究。第一期研究的结果表明,用MTD的24-OH-前D2治疗患者至少6个月,与转移疾病有关的骨痛显著消失。第二期研究的结果表明,2年后用于评估转移疾病的发展的CAT扫描、X射线和骨扫描都表明以低剂量治疗的许多患者中疾病稳定或者部分康复,而以高剂量治疗的许多患者中疾病稳定以及部分或者完全康复。实施例12:用24-OH-D4治疗由于继发性甲状旁腺机能亢进而具有高血PTH的老年患者
用患有继发性甲状旁腺机能亢进的40位患者进行12个月双盲安慰剂对照临床实验。所选患者的年龄为60-100岁,而且具有继发性甲状旁腺机能亢进史。患者还有股颈骨质稀少(股颈骨矿物密度小于等于0.70g/cm2)。
所有患者进行6周的对照期,之后他们随机分为两个治疗组:一组接受恒定剂量为15μg/天的24-OH-D4,而另一个组接受匹配的安慰剂。两个组都保持正常的饮食钙摄入,但不使用钙添加剂。在以下方面比较治疗前和治疗后的患者进行效力评估:(a)完整的PTH(iPTH);(b)桡骨、股骨和脊椎骨的矿物密度;以及(c)骨特异性尿标记物(如吡啶翁交联物)。安全性用(a)血清钙和磷、以及(b)尿钙和磷来评估。
临床数据分析表明,24-OH-D4显著降低iPTH和骨特异性尿标记物。用该化合物治疗的患者与基线值相比表现出正常的血清钙浓度和稳定的桡骨和脊椎骨密度。相反,用安慰剂治疗的患者没有表现出iPTH和骨特异性尿标记物的下降。而且在治疗组中观察到高钙血症不显著的发生率。实施例13:用24-OH-前D2治疗由于继发性甲状旁腺机能亢进而具有高血PTH的老年患者
用患有继发性甲状旁腺机能亢进的40位患者进行12个月双盲安慰剂对照疗程实验。所选患者的年龄为60-100岁,而且具有继发性甲状旁腺机能亢进史。患者还有股颈骨质稀少(股颈骨矿物密度小于等于0.70g/cm2)。
所有患者进行6周的对照期,之后他们随机分为两个治疗组:一组接受恒定剂量为15μg/天的24-OH-前D2,而另一个组接受匹配的安慰剂。两个组都保持正常的饮食钙摄入,但不使用钙添加剂。在以下方面比较治疗前和治疗后的患者进行效力评估:(a)完整的PTH(iPTH);(b)桡骨、股骨和脊椎骨的矿物密度;以及(c)骨特异性尿标记物(如吡啶翁交联物)。安全性用(a)血清钙和磷、以及(b)尿钙和磷来评估。
临床数据分析表明,24-OH-前D2显著降低iPTH和骨特异性尿标记物。用该化合物治疗的患者与基线值相比表现出正常的血清钙浓度和稳定的桡骨和脊椎骨密度。相反,用安慰剂治疗的患者没有表现出iPTH和骨特异性尿标记物的下降。而且在该治疗组中观察到高钙血症不显著的发生率。实施例14:用24-OH-D2治疗晚期肾疾病中继发性甲状旁腺机能亢进的患者
30位肾病患者参加研究原发性甲状旁腺机能亢进的研究。患者的iPTH浓度大于1000pg/ml。这些大大升高的浓度表明疾病的一部分是腺体原发性的以及一部分是肾功能丢失导致的继发性的。根据需要增加(最大为100μg/天,3次/周)或者降低24-OH-D2的初始剂量(50μg 3次/周),以实现并保持150-300pg/ml范围的iPTH。治疗11-12周后,患者的iPTH浓度降低至低于1000pg/ml,而在许多情况下低于500pg/ml。在研究期间患者几乎没有高钙血症发生。实施例15:用24-OH-前D2治疗原发性甲状旁腺机能亢进
20位肾病患者参加研究原发性甲状旁腺机能亢进的研究。患者的iPTH浓度大于200pg/ml。根据需要增加(最大为10μg/天)或者降低24-OH-前D2的初始剂量(2-4μg/天),以实现并保持正常范围的iPTH。治疗11-12周后,患者的iPTH浓度降低至低于100pg/ml,而在许多情况下低于60pg/ml。在研究期间患者几乎没有高钙血症发生。实施例16:24-OH-D2的免疫学测试
使用9-12周龄的雌性C57BL/6小鼠。小鼠随意给以食物和水,而且保持12小时光照和12小时黑暗的循环。
制备已知的平衡盐溶液(BSS),并用HEPES缓冲液补充至0.01摩尔浓度。
测试化合物24-OH-D2溶解在二甲基亚砜中,至最终浓度为0.2或0.4mg/ml。当与维生素D化合物一起作用时,使用减少光照的条件。
小鼠每4只分为一组,并腹膜内接种3×106同种异体P815肿瘤细胞,并在10天后评估所得的细胞毒性胸腺衍生的淋巴细胞(CTL)活性。通过腹膜内途径用溶解在二甲基亚砜中的测试化合物或者仅用二甲基亚砜(载体对照)25微升处理小鼠。在实验1中,从免疫接种前1天开始,每天给药5微克24-OH-D2对小鼠进行处理,然后持续至分析前那天。在实验2中,小鼠仅用10微克24-OH-D2处理两次:开始免疫接种前那天和免疫接种那天。
使小鼠免疫接种P815细胞后10天,使脾由钢网中通过进入BSS,然后用BSS洗涤两次,由此制备单个脾细胞悬浮液。进一步处理脾细胞、用Cr标记P815靶细胞、分析机理、以及用CTL计算结果都是已知的,而且描述在第4,749,710号美国专利中,其在此并入作为参考。单独地由每组动物的脾细胞测定细胞毒性T淋巴细胞活性,结果用每组的平均CTL活性(百分特异性Cr释放)±标准偏差来表示。
结果表明,在载体对照组中,用P815细胞免疫接种的小鼠在10天内产生显著的CTL活性。在用24-OH-D2处理的两个组中都观察到CTL活性在统计学上显著性地降低,由此证明在给药于动物时该化合物的免疫抑制活性。
还应理解的是,虽然上述实施例具体地使用了具体的24-OH-D和24-OH-前D类化合物,在本发明范围内的其他化合物也可容易地用于本发明的治疗中,而且具有基本上等价的结果。
总而言之,本发明提供了24-羟基-维生素D类化合物及其在某些疾病和紊乱中的治疗方法,包括甲状旁腺机能亢进、过度增殖性疾病以及骨损耗性疾病、免疫和炎性应答条件,而且具有显著低的高钙血症和高磷血症。
虽然采用一些具体内容已对本发明作了描述和举例,本领域技术人员应认识到对于已描述的内容可以有多种改动,包括改变,添加或删减。因此,这些改动也应包含在本发明之中,本发明的范围仅由最广义的解释作界定,其中最广义的解释依据于具有法律效力的所附权利要求。
Claims (27)
1、维生素D化合物在制备用于治疗或预防骨质或骨矿物质含量流失和/或甲状旁腺机能亢进、和/或细胞过度增殖、和/或调节免疫和炎性应答的药物中的应用,其中所述维生素D化合物是24-羟基维生素D或者24-羟基前维生素D。
4、如权利要求1所述的应用,其中,Z是式(IIA)表示的侧链:其中沿侧链的虚线表示任选添加的C-C键;m是0或1;R1和R2分别是低级烷基、低级氟代烷基、低级链烯基、低级氟代链烯基、低级环烷基,或者与它们所连接的碳一起形成C3-C8环烃基;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;R5和R6分别为氢或者一起形成在C-22和C-23之间的双键。
5、如权利要求1所述的应用,其中,Z是括式(IIB)表示的侧链:其中R5和R6分别为氢或者一起形成在C-22和C-23之间的双键;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;而R1和R2分别是氢、低级烷基、低级氟代烷基、低级链烯基、低级氟代链烯基、低级环烷基,或者与它们所连接的碳一起形成C3-C8环烃基。
6、如权利要求5所述的应用,其中,所述24-羟基维生素D是24-羟基维生素D2、24(S)-羟基维生素D2、24-羟基维生素D4、和24(R)-羟基维生素D4。
10、如权利要求9所述的应用,其中,所述24-羟基维生素D化合物是24-OH-25-烯-D2和24-OH-25-羰基-D2。
11、维生素D化合物在制备用于增加或保持骨质或骨矿物质含量、和/或降低或保持甲状旁腺激素水平、和/或抑制过度增殖作用、和/或诱导或增强调节免疫应答的细胞分化、和/或调节炎性应答的药物中的应用,其中,所述维生素D化合物是24-羟基维生素D或者24-羟基前维生素D。
13、如权利要求11所述的应用,其中,所述24-羟基前维生素D是式(III)的化合物:其中Z代表饱和或不饱和、取代或未取代、直链、支链或环状C4-C18烃基,其中C-24或等价位置被羟基化;Y为甲基或氢;而X为氢、低级烷基或低级氟代烷基。
14、维生素D化合物在制备用于治疗骨质疏松、和/或甲状旁腺机能亢进、和/或牛皮癣、和/或皮肤癌、和/或乳腺癌、和/或结肠癌、和/或前列腺癌、和/或前列腺增生、和/或免疫应答受损的药物中的应用,其中,所述维生素D化合物是24-羟基维生素D或者24-羟基前维生素D。
15、一种包含有效量的、基本上纯的、经合成的24-羟基维生素D或者24-羟基前维生素D以及药物学上可接受的载体、辅剂或赋形剂的药物组合物。
16、如权利要求15所述的组合物,其中,组合物可口服给药。
17、如权利要求1所述的应用,其中,所述24-羟基维生素D化合物的给药剂量为3.5-1000μg/周。
18、如权利要求15所述的组合物,其中,所述药物还包括骨剂、细胞毒性剂、免疫应答调节剂、抗炎剂或它们的组合。
19、24-羟基维生素D化合物,其是式(I)表示的化合物:其中Z代表饱和或不饱和、取代或未取代、直链、支链或环状C4-C18烃基,其中C-24或等价位置被羟基化;如果与Y是双键连接在A环上的,则Y为亚甲基,或者如果与Y为单键,则Y为甲基或氢,条件是式(I)的化合物不是24-羟基维生素D2;而X为氢、低级烷基或低级氟代烷基,条件是式(I)的化合物不是24-羟基维生素D2。
20、一种24-羟基前维生素D,其是式(III)的化合物:其中Z代表饱和或不饱和、取代或未取代、直链、支链或环状C4-C18烃基,其中C-24或等价位置被羟基化;Y为甲基或氢;而X为氢、低级烷基或低级氟代烷基。
21、如权利要求19所述的化合物,其中,Z是式(IIC)表示的侧链:其中n为选自1或2的整数;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4和R7分别为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;A为碳、氧、硫或氮;当A为氮时,r为1而s为0;当A为碳时,r和s为1;当A为硫或氧时,r和s为0;以及R9和R10分别为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基。
22、如权利要求19所述的化合物,其中,Z是式(IIE)表示的侧链:其中侧链上的虚线表示任选添加的C-C键;q为0或选自1或2的整数;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4和R7为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;A为碳、氧、硫或氮;当A为氮时,r为1而s为0;当A为碳时,r和s为1;当A为硫或氧时,r和s为0;R9和R10分别为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基。
24、如权利要求20所述的化合物,其中,Z是式(IIE)表示的侧链:其中侧链上的虚线表示任选添加的C-C键;q为0或选自1或2的整数;R3为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基;R4和R7为低级烷基、低级氟代烷基、低级链烯基或低级氟代链烯基;A为碳、氧、硫或氮;当A为氮寸,r为1而s为0;当A为碳时,r和s为1;当A为硫或氧时,r和s为0;R9和R10分别为氢、低级烷基、低级链烯基、低级氟代烷基或低级氟代链烯基。
25、作为制成品的片剂,以在给药后的时间中测量的维生素D的血浓计,其具有相当高的维生素D吸收速率,其包括维生素D化合物以及药物学上可接受的载体、辅剂或赋形剂的药物,其中所述维生素D化合物是4-羟基维生素D或者24-羟基前维生素D。
26、如权利要求1所述的应用,其中,所述药物还包括骨剂、细胞毒性剂、免疫应答调节剂、抗炎剂或它们的组合。
27、如权利要求26所述的应用,其中,所述骨剂是其他维生素D化合物、结合雌激素、氟化钠、双膦酸酯、钴胺、钙受体激动剂、百日咳毒素、硼或DHEA。
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-
1998
- 1998-05-29 US US09/086,969 patent/US6242434B1/en not_active Expired - Lifetime
-
1999
- 1999-05-28 CA CA002332146A patent/CA2332146A1/en not_active Abandoned
- 1999-05-28 AU AU43243/99A patent/AU757740B2/en not_active Ceased
- 1999-05-28 BR BR9910671-0A patent/BR9910671A/pt not_active Application Discontinuation
- 1999-05-28 NZ NZ507855A patent/NZ507855A/en unknown
- 1999-05-28 JP JP2000550810A patent/JP2002516299A/ja active Pending
- 1999-05-28 IL IL13935599A patent/IL139355A/xx not_active IP Right Cessation
- 1999-05-28 CN CN99806763A patent/CN1379675A/zh active Pending
- 1999-05-28 DE DE69911596T patent/DE69911596T2/de not_active Expired - Lifetime
- 1999-05-28 WO PCT/US1999/012084 patent/WO1999061398A2/en active IP Right Grant
- 1999-05-28 EP EP99953332A patent/EP1080055B1/en not_active Expired - Lifetime
- 1999-05-28 AT AT99953332T patent/ATE250566T1/de not_active IP Right Cessation
- 1999-05-28 ES ES99953332T patent/ES2209518T3/es not_active Expired - Lifetime
-
2001
- 2001-01-03 US US09/753,697 patent/US7122530B2/en not_active Expired - Fee Related
-
2006
- 2006-06-02 US US11/421,968 patent/US20060211661A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108902985A (zh) * | 2018-06-08 | 2018-11-30 | 唐飞 | 25-羟基维生素d3在制备保健食品中的应用 |
Also Published As
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IL139355A0 (en) | 2001-11-25 |
US6242434B1 (en) | 2001-06-05 |
JP2002516299A (ja) | 2002-06-04 |
DE69911596T2 (de) | 2004-07-01 |
IL139355A (en) | 2005-08-31 |
US20060211661A1 (en) | 2006-09-21 |
WO1999061398A2 (en) | 1999-12-02 |
US7122530B2 (en) | 2006-10-17 |
ES2209518T3 (es) | 2004-06-16 |
US20010002397A1 (en) | 2001-05-31 |
EP1080055B1 (en) | 2003-09-24 |
CA2332146A1 (en) | 1999-12-02 |
BR9910671A (pt) | 2001-06-19 |
NZ507855A (en) | 2003-11-28 |
AU4324399A (en) | 1999-12-13 |
AU757740B2 (en) | 2003-03-06 |
ATE250566T1 (de) | 2003-10-15 |
DE69911596D1 (de) | 2003-10-30 |
WO1999061398A3 (en) | 2000-11-23 |
EP1080055A2 (en) | 2001-03-07 |
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