CN105853993A - 3,5-二羟基戊酸的类似物用于成骨作用 - Google Patents
3,5-二羟基戊酸的类似物用于成骨作用 Download PDFInfo
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- CN105853993A CN105853993A CN201610051593.3A CN201610051593A CN105853993A CN 105853993 A CN105853993 A CN 105853993A CN 201610051593 A CN201610051593 A CN 201610051593A CN 105853993 A CN105853993 A CN 105853993A
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Abstract
本发明揭示一种3,5-二羟基戊酸的类似物，其组成具有改善成骨作用，可不经由甲羟戊酸途径。
Description
技术领域
本发明揭示一种具备成骨作用药物及其活性的应用，特别涉及3,5-二羟基戊酸的类似物，可不经由甲羟戊酸途径。
背景技术
利用非经由脂质代谢相关途径的效果，或多发性效用(pleiotropic effects)的影响，可让他汀类(Statins)药物表现出骨质代谢活性。虽然他汀类药物包含着3,5-二羟基戊酸(3,5-dihydroxypentanoic acid)的母体基团或衍生基团，一直被认为经由甲羟戊酸(mevalonate,MVA)途径模仿3-羟基-3-甲基戊二酰-辅酶A还原酶(3-hydroxy-3-methylglutaryl-coenzyme A reductase,HMG-CoA reductase)受质而中断脂质合成，可成为降低胆固醇的药物。此甲羟戊酸途径对于骨骼的影响已被证实可调控蚀骨细胞活性而抑制骨骼再吸收(bone resorption)，而且发现临床所用的3-羟基-3-甲基戊二酰-辅酶A还原酶抑制剂的他汀类药物还具有诱导成骨作用(bone formation)，其可能通过许多的替代途径。而且他汀类具成骨作用的必要结构需求，目前尚不清楚，亦缺乏策略促使他汀类药物减少在肝组织的分布而增加骨组织亲和。此等事实阻碍着他汀类药物，作为骨骼同化制剂的发展。
3-羟基-3-甲基戊二酰-辅酶A还原酶(HMG-CoA reductase)主要分布在肝脏，进行着脂质的合成。高效的降血脂化合物需与肝脏中的3-羟基-3-甲基戊二酰-辅酶A还原酶呈现高亲和力，且具有肝细胞选择性。因此，如要提高骨组织分布比率，采用降低3-羟基-3-甲基戊二酰-辅酶A还原酶的抑制活性策略，可能防止此类化合物集中在肝脏作用。
他汀类衍生物的相关制剂，最近成为针对骨质疾患治疗的药物。虽然他汀类已经报导在动物实验和局部投予使用模式下可促进骨质增生。但多年来，不论是运用随机对照试验或系统性的评价，显示绝经后妇女投予他汀类药物衍生物，无法防止骨折或增加骨密度，因而认为在人体的全身投予模式下，其效果仍有争议。因此，药物结构仍有改善空间，必须研发能全身使用和具骨选择性的他汀类药物衍生物。
本案申请人鉴于现有技术中的不足，经过悉心试验与研究，并一本锲而不舍的精神，终构思出本案发明「3,5-二羟基戊酸的类似物用于成骨作用」，且能够克服先前技术的不足，以下为本案的简要说明。
发明内容
为了克服先前技术的缺点，本发明经由实验，探讨二羟基戊酸的类似物的医药品及或/食品用途。
本发明的目的即在于提供一种如结构式I所示二羟基戊酸的类似物，
其中，X为氮原子或碳原子；
R为氢基或C1-C4烷基；
Ra选自下列其中之一：(a1)C1-C10烷基，(a2)取代的C1-C10烷基，(a3)C3-C8环烷基，(a4)取代的C3-C8环烷基，(a5)苯胺基(phenylamino)，(a6)取代的苯胺基，(a7)苯基C1-C10烷胺基(phenyl C1-10 alkylamino)，(a8)取代的苯基C1-C10烷胺基，(a9)双磷酸盐类(bisphosphonate)，(a10)四环素(tetracycline)，(a11)胺基酸(amino acid)，(a12)酸性寡胜肽(acidic oligopeptides)，(a13)骨标靶胜肽(bone targeting peptide)，(a14)
Rb选自下列其中之一：无取代基、乙酰基(acetyl group)、显像基团(imaging moiety)；
表示单键或双键；
Rh选自下列结构式(A)，(B)，(C)，(D)，(E)和(F)其中之一：
Rk为C1-C5烷基；
Rm为C1-C5烷基或羟基；
Rn为C1-C5烷基或羟基。
根据本发明的一些实施例，3,5-二羟基戊酸的衍生物还具有成像基团，可用于包括在人类或动物的影像检查的诊断方法。其是包括经由投予包含3,5-二羟基戊酸的衍生物的显像剂注射、输液或任何其他已知的方法而成像。
本发明尚有一目的是在于提供一种制造包括结构式I的3,5-二羟基戊酸的类似物，通过添加剂、赋形剂达到增加骨质作用(bone mass)活性，以治疗哺乳动物病症。
本发明的另一目的在于提供一种组合疗法用途，其是用于投予包括结构式I所示的3,5-二羟基戊酸的类似物的医药组合物与/或食品组合物，以治疗哺乳动物病症。
本发明再有另一目的在于提供一种制造结构式I所示的3,5-二羟基戊酸的类似物的方法，是在于提供芴甲氧羰基(Fmoc)反应物，进行固相多肽合成(solid-phase peptide synthesis,SPPS)方法。其包括提供(a)甘氨酸与王树脂(Wang resin)预载的中间产物，令赖氨酸加以连接。(b)经由水解内酯环，让辛伐他汀酸(simvastatin acid)与赖氨酸的α-氨基酸基团，形成共轭的酰胺键。(c)固相多肽合成过程，必须高于100℃温度下，采取150W以上的微波照射100分钟左右。
附图说明
图1为化合物1-F的制备方法流程；
图2为化合物2-F的制备方法流程；
图3为3,5-二羟基戊酸的类似物的制备方法流程；
图4为化合物1与钙离子以等温滴定量热卡计测试结合能力的结果；
图5为化合物1影响氢氧基磷灰石的沉降的结果，其中，(A)为化合物1+氢氧基磷灰石，(B)为氢氧基磷灰石；
图6为化合物1-F结合至氢氧基磷灰石的荧光显微镜监测结果，其中，(a)为白光照亮区，(b)为暗视野区；
图7为辛伐他汀与化合物1-F对人类脂肪干细胞的诱导矿化结果；
图8为辛伐他汀与化合物4～11对D1细胞的诱导矿化结果；
图9为斑马鱼骨靶向与促骨生成试验结果，其中，(a)为喂食calcein给斑马鱼后，以荧光显微镜观察暗视野，(b)为喂食化合物2-F给斑马鱼后，以荧光显微镜观察暗视野，(c)为喂食化合物1-F、2-F与辛伐他汀给不同斑马鱼后，观察斑马鱼骨头生长情形；
图10为化合物7促进斑马鱼骨头生成的结果。
具体实施方式
本案将可由以下的实施例说明而得到充分了解，使得本领域技术人员可以据以完成，然而本案的实施并非可由下列实施例而被限制其实施型态，本领域技术人员仍可依据除既揭露的实施例的精神推演出其他实施例，该等实施例皆当属于本发明的范围。
为达成前述发明目的，上述结构式I所示二羟基戊酸的类似物，Ra取代基其中(a2)取代的C1-C10烷基可以被下列取代基其中之一所取代：氢基、C1-C10烷基、C1-C10烷氧基、C1-C5烷氧羰基(alkoxycarbonyl)、C1-C5酰氧基(acyloxyl)、C3-C8环烷基(cycloalkyl)、苯基。
上述Ra取代基其中(a4)取代的C3-C8环烷基、(a6)取代的苯胺基、(a8)取代的苯基C1-C10烷胺基可以各自独立的被下列取代基其中之一所取代：C1-C5烷基、氟原子、氯原子、溴原子、碘原子、含氧原子之的5元芳香环、含氧原子的6元芳香环、含氮原子的5元芳香环、含氮原子的6元芳香环。
上述Ra取代基其中(a12)酸性寡胜肽为选自下列其中之一：-Lys-(Asp)m-Lys-PEG、D/L-Aspm、D/L-Glun，其中，m和n各自独立地为1至10的正整数。
上述Ra取代基其中(a13)骨标靶胜肽为选自下列其中之一：Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val，Leu-Leu-Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr-Gly-Gly-Gly-Ser，Lys-Glu-Ile-Pro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser-Gly-Gly-Gly-Ser，Asn-Asn-Val-Ser-Gln-Lys-Trp-Gln-Gln-Arg-Leu-Ile-Gly-Gly-Gly-Ser，Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His-Gly-Gly-Gly-Ser，Gly-Ile-His-Val-Pro-Trp-Met-Pro-Pro-Val-Ala-Phe-Gly-Gly-Gly-Ser，Gln-Arg-Ser-Trp-Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met-Gly-Gly-Glu-Ser，Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser，Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp-Gly-Gly-Gly-Ser，Asp-Ser-Ser-Asn-Pro-Ile-Phe-Trp-Arg-Pro-Ser-Ser-Gly-Gly-Gly-Ser，Asn-Thr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro-Gly-Gly-Gly-Ser，Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser，Ala-Thr-Trp-Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu-Gly-Gly-Gly-Ser，Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser，Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val，Leu-Leu-Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr，Lys-Glu-Ile-Pro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser，Asn-Asn-Val-Ser-Gln-Lys-Trp-Gln-Gln-Arg-Leu-Ile，Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His，Gly-Ile-His-Val-Pro-Trp-Met-Pro-Pro-Val-Ala-Phe，Gln-Arg-Ser-Trp-Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met，Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn，Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp，Asp-Ser-Ser-Asn-Pro-Ile-Phe-Trp-Arg-Pro-Ser-Ser，Asn-Tyr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro，Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn，Ala-Thr-Trp-Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu，Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser。
上述Ra取代基其中(a14)中的U是选自下列其中之一：–Lys、-Lys-(Asp-NHAc)J、-NHAc、-Lys-(Asp-)k-NHAc、(Asp-NHAc)J，而J为1或2，K为正整数且20≥K≥1。
于适当实施例本发明的术语“烷基”，是指饱和直链或含有支链的烃基，而C1-C10烷基是指该饱和直链或含有支链烃基链上拥有1个至10个碳原子。因此，C1-C10烷基是指甲基、乙基、丙基、丁基、异丁基、仲丁基、戊基、2-甲基丁基、3-甲基丁基、己基、庚基、辛基、壬基、癸基。而“不饱和烷基”是指含有双键直链、三键直链或含有双键、三键支链的烃基。“苯胺基(phenylamino)”以-NHPh表示于苯基结构上含有胺基的取代基。
而于适当实施例，结构式I的3,5-二羟基戊酸的类似物的制备，是运用如图1所示的合成路径所示标准态芴甲氧羰基(Fmoc)的保护战略以及固相胜肽合成(solid-phase peptidesynthesis,SPPS)方法。以预先置入甘氨酸的王树脂(Gly-preloaded Wang resin)为起始原料，分别合成上Fmoc-Lys(ivDde)-OH)和辛伐他汀，可获得化合物12。再利用联胺(hydrazine)移除ivDde保护基，合成上连续6个Fmoc-Asp-(tBu)-OH，可获得化合物13。同样地，合成上Fmoc-Lys(ivDde)-OH可获得化合物14。之后，合成上聚乙二醇(化合物15)和氟硫氰酸荧光素(FITC)，再经CLE步骤可得化合物1-F。另外，如化合物14合成上聚乙二醇(化合物15)和乙烯基，可得化合物1。
运用如图2所示的合成路径，以Rink amide树脂为起始原料，合成上连续6个Fmoc-Asp-(tBu)-OH，可获得化合物16。同样地，合成上Fmoc-Lys(ivDde)-OH、聚乙二醇(化合物15)和氟硫氰酸荧光素(FITC)，再经CLE步骤可得化合物2-F。
3,5-二羟基戊酸的类似物，运用图3所示的合成路径，于室温下在干燥四氢呋喃(tetrahydrofuran,THF)中，令异丙基格林那试剂(isopropyl Grignard reagent)与辛伐他汀反应可加以制备。
于适当实施例，辛伐他汀酸衍生化合物为于结构式I，Rh选自下列结构式(A),(B),(C),(D),(E),(F)其中之一。而部分辛伐他汀酸衍生化合物如结构式II所示，其中Rt选自下列其中之一：C1-C10烷基、羟基、C1-C10烷胺基、-NH-(C1-C10)烷基-Rz、-NH-(C1-C5)烷基-O-(C1-C5)烷基-Rz、-NH-胺基；Rz选自下列其中之一：C1-C10不饱和烷基、羟基、胺基、含氧原子的5元芳香环、含氧原子的6元芳香环、含氮原子的5元芳香环、含氮原子的6元芳香环。
图3所示的合成路径是以结构式II所示制备部分辛伐他汀酸衍生化合物，而辛伐他汀酸(化合物4)及衍生化合物5-9，亦可比照此合成路径加以制备，其是在室温下与二氯甲烷、甲醇或干燥四氢呋喃中与各类胺类化合物反应。
根据上述本发明的制备路径流程，其中胜肽链的合成可运用图1或图2所示的合成路径，而3,5-二羟基戊酸的类似物的制备则是经由图3所示的合成路径。于3,5-二羟基戊酸的类似物的合成路径，亦可经由辛伐他汀衍生物作为起始原料，则其中辛伐他汀衍生物是选自市售或已知的他汀类药物。例如阿托伐他汀(Atorvastatin)的化学名称为(3R,5R)-7-[2-(4-氟苯基)-3-苯基-4-(苯基氨基甲酰基)-5-异丙基-吡咯-1-基]-3,5-二羟基庚酸((3R,5R)-7-[2-(4-Fluoro-phenyl)-3-phenyl-4-(phenyl-carbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxy-heptanoic acid)；西立伐他汀(Cerivastatin)的化学名称为(3R,5S,6E)-7-[4-(4-氟苯基)-2,6-二异丙基-5-甲氧甲基-吡啶-3-基]-3,5-二羟基-6-庚烯酸((3R,5S,6E)-7-[4-(4-fluoro-phenyl)-5-(methoxymethyl)-2,6-bis(propan-2-yl)pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid)；氟伐他汀(Fluvastatin)的化学名称为(3R,5S,6E)-7-[3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基]-3,5-二羟基-6-庚烯酸((3R,5S,6E)-7-[3-(4-Fluorophenyl)-1-(1-methyl ethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid)；罗瓦斯达汀(Lovastatin)的化学名称为(1S,3R,7S,8S,8ΑR)-1,2,3,7,8,8Α-六氢-3,7-二甲基-8-[2.[(2R,4R)-四氢-4-羟基-6-氧代-2H-吡喃-2-基]乙基]-1-萘基(S)-2-甲基丁酸酯((1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl(2S)-2-methylbutanoate)；美伐他汀(Mevastatin)的化学名称为2-甲基丁酸[1S-[1-Α(R*),7-Β,8-Β(2S*,4S*),8A-Β]]-1,2,3,7,8,8A-六氢-7-甲基-8-[2-(四氢-4-羟基-6-氧-2H-吡喃-2-基)乙基]-1-萘酯((1S,7R,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl(2S)-2-methylbutanoate)；匹伐他汀(Pitavastatin)的化学名称为(3R,5S,6E)-7-[2-环丙基-4-(4-氟代苯基)喹啉-3-基]-3,5-二羟基-6-庚烯酸((3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-di-hydroxy-6-heptenoic acid)；普伐他汀(Pravastatin)的化学名称为(+)-(3R,5R)-3,5-二羟基-7-[(1S,2S,6S,8S,8aR)-6-羟基-2-甲基-8-[(S)-2-甲基丁酰氧基]-1,2,6,7,8,8a-六氢-1-萘]-庚酸((3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoic acid)；瑞舒伐它汀(Rosuvastatin)的化学名称为(3R,5S,6E)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)-5-嘧啶]-3,5-二羟基-6-庚烯酸((3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonyl-amino)pyrimidin-5-yl]-3,5-di-hydroxy-6(E)-heptenoic acid)；辛伐他汀(Simvastatin)的化学名称为(3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-(2,2-二甲基丁酰氧基)-1,2,6,7,8,8a-六氢-2,6-二甲基-1-萘基]-3,5-二羟基庚酸铵((1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl2,2-dimethylbutanoate)。
术语“治疗”、“治疗中”及其类似术语是指缓减、改善、消减或消除目前患者所处病症或该病症相关的任何症状的方法，以及预防该病症或其他涉及该症状的方法。而术语“有效剂量(therapeutically effective amount)”是代表足以改善或防止医学症状或生物体状态恶化的剂量。有效地剂量亦说明投予化合物的剂量足够用于诊断的剂量。除非说明书另有叙述，否则“活性化合物”以及“医药活性化合物”于此均可替换使用，是指称一具有制药学、药理学或治疗效果的物质。
术语“赋形剂(excipients)”或称为“药学上可接受的载体或赋形剂”、“生物可利用的载体或赋形剂”，是包括溶媒、分散剂、包衣、抗菌或抗真菌剂，保存或推迟吸收剂等任何用于制备成剂型的已知适当化合物。通常此类载体或赋形剂，本身不具备治疗疾病的活性，且将本技术所揭示的衍生物，搭配选用各种药学上可接受的载体或赋形剂，制备成各剂型，投予动物或人类亦不致于造成不良反应、过敏或其它不适当反应。因而本技术所揭示的衍生物，搭配药学上可接受的载体或赋形剂，适用于临床及人类。
术语“药学上可接受之赋形剂”，包括但不限于，聚合物、树脂、增塑剂、填料、润滑剂、稀释剂、黏合剂、崩解剂、溶剂、共一溶剂、界面活性剂、防腐剂、甜味剂、调味剂、药学级的染料或颜料、及黏度剂至少一者。
术语“医药组成物(pharmaceutical composition)”为一种固体或液体组成物，其形式、浓度和纯度程度适合投予给病患(如人类或动物病患)，在投予之后，其可诱发所欲生理变化。医药组成物典型地为无菌及/或非发热性者(non-pyrogenic)。
该载体随各剂型而调整，无菌注射的组成物可溶解或悬浮于无毒的静脉注射稀释液或溶剂中，此类溶剂如1,3－丁二醇。其间可接受的载体可为甘露醇(mannitol)或水。此外以固定油脂、合成的甘油酯或双甘油酯，是一般常用的溶剂。脂肪酸，如油酸(oleic acid)、橄榄油或蓖麻油等甘油酯衍生物之类，尤其经含氧乙基化的型态(oxy-acetylated types)皆可作为制备注射剂并为天然的医药可接受油类。此等油类溶液或悬浮液可包含长链的醇稀释液或分散剂、羧甲基纤维素或类似的分散剂。其他常用的接口活性剂如吐温、Spans，或其他类似的乳化剂，或一般医药制造业所使用于医药可接受的固态、液态或其他生物可利用促进剂(enhancing agent)，可用于医药剂型的开发。
用于口服投药的组成物是采用任何一种口服可接受的剂型，其剂型包括胶囊、锭剂、片剂、乳剂(emulsion)、含水悬浮液(aqueous suspension)、分散剂、溶剂。口服剂型通常所使用的载体，以锭剂为例的基本添加物可为乳糖、玉米淀粉、润滑剂，以及硬脂酸镁。而胶囊使用的稀释剂(diluent)包括乳糖与干燥的玉米淀粉。制成水悬浮液或乳化剂剂型，是将活性物质悬浮或溶解于已经混和着乳化剂或悬浮剂的油性接口活性剂，视需要添加适度的甜味剂，风味剂或是色素。
鼻用喷雾剂(aerosol)或吸入剂(inhalation)组成物，可根据已知的制剂技术进行制备。例如，将组成物溶于生理食盐水中，添加苯甲醇或其他适合的防腐剂，或促进吸收剂以增强其生物可利用性。本发明所揭示的化合物亦可制成栓剂，采取直肠或阴道的投药方式。
本发明所揭示化合物亦可运用注射投药，其包括经由皮下、腹腔、静脉、肌肉，或关节腔内、颅内、关节液内、脊髓内注射，主动脉注射，胸腔注射，疾病部位内注射，或其他适合的投药技术。
于适当实施例，对患者运用组合疗法(combination therapies)投予含有结构式I成分，所制备的单一剂量口服组成物，如片剂、胶囊，或口服结构式I成分的食品。投予结构式I成分化合物的不同剂型的组合疗法，其先后依序投予或是间隔短暂时间方式，可随病患的情况和年龄变化，而选用各种剂型，例如舌下或口腔含片的口服剂型，直肠给药，鼻腔用药、干燥粉末或喷雾的吸入剂，甚至于阴道给药，皮下、肌肉、静脉和皮内的注射剂，局部给药(topical)等等，例如护手霜(mist)、喷雾、溶液剂(solution)、乳液(lotion)、胶冻(gel)、乳霜(cream)、软膏、糊剂(paste)、油膏(unguent)、乳液霜(emulsion)和悬浮剂，更可包括口服或注射投药。间隔短暂时间方式投予，通常以前后3小时内完成投予。
本说明书所叙述的所有技术性及科学术语，除非另外有所定义，皆隶属于本领域技术人员可共同了解的意义。
为化合物1-F与1的结构将辛伐他汀酸的3,5-二羟基戊酸以天门冬胺酸寡肽和聚乙二醇修饰，化合物1-F更有荧光基团的键结，相对地，对照化合物2-F，其结构不含辛伐他酸，只有天门冬胺酸寡肽、聚乙二醇和荧光基团。化合物1-F与1的结构中，辛伐他汀的内酯基被天门冬胺酸寡肽的胺基开环，以酰胺键方式结合在3,5-二羟基戊酸的羧基。
如化合物1-F与1，辛伐他汀的内酯基也可被含有胺基之非寡肽分子以酰胺键键结方式所开环修饰，甚至是以不含胺基的化合物，以成为酮基的结合形式开环，制备了辛伐他汀衍生化合物3～11。
辛伐他汀酸(化合物4)和衍生物1-F、5～11经测试对3-羟基-3-甲基戊二酰-辅酶A还原酶的抑制能力。结果如表一显示，所有辛伐他汀衍生物的有效抑制浓度均高于辛伐他汀本身，至少是辛伐他汀的5倍以上，甚至化合物1-F与9的有效抑制浓度高于辛伐他汀的500倍以上；因而得知辛伐他汀的内酯基被开环并改为酰胺键结，可有效下降对3-羟基-3-甲基戊二酰-辅酶A还原酶的抑制能力。
表一
| 化合物 | IC50(nM) |
| 辛伐他汀 | 56.1±2.1 |
| 辛伐他汀酸(4) | 263.2±83.4 |
| 1-F | >30000 |
| 5 | 1024.5±50.9 |
| 6 | 1127.9±89.5 |
| 7 | 171.2±9.2 |
| 8 | 950±80.1 |
| 9 | >30000 |
| 10 | 26620±620.2 |
| 11 | 21560±330.2 |
化合物1对钙离子(Ca2+)的结合亲和力(binding affinity)，运用等温滴定量热卡计(isothermal titration calorimetry,ITC)测量。结果如图4显示，化合物1可以与约两个钙离子结合，并且有强的结合能力，结合常数为278.1kM-1。
因氢氧基磷灰石(hydroxyapatite,HAP)为骨头的无机物组成，研究中以氢氧基磷灰石为仿生性骨骼材料。化合物1对氢氧基磷灰石的结合测试，其结果如图5显示。以光线穿透值的百分比(％T)表现氢氧基磷灰石在有或无化合物参与的沉降延迟情形。与无添加化合物1组别相比，添加化合物1组别可见氢氧基磷灰石的沉降被延迟达120秒。
如以化合物1-F结合至氢氧基磷灰石，可以荧光显微镜进行监测。结果如图6显示，化合物1-F因结合至氢氧基磷灰石表面，致使氢氧基磷灰石粒子呈现荧光。
以人类脂肪干细胞为细胞毒性测试的材料，发现投予化合物1-F后的细胞存活率远高于投予辛伐他汀组别，换算成IC50表示，可见化合物1-F的IC50为辛伐他汀的300倍，明显地得知化合物1-F在细胞安全性上高于辛伐他汀，IC50结果见表二)
表二 测试化合物于人类脂肪干细胞的细胞毒性
| 化合物 | IC50(μM) |
| 辛伐他汀 | 3.25±0.31 |
| 1-F | >1000 |
如以老鼠骨母前趋细胞(rat bone marrow stem cells)D1为测试材料，评估辛伐他汀衍生物的细胞毒性。结果如表三显示，所有辛伐他汀衍生物的使用浓度均可被提高，表示辛伐他汀衍生物对D1细胞的安全性都比辛伐他汀高。尤其化合物7的IC50更比辛伐他汀高83倍。
表三
| 化合物 | IC50(μM) |
| 辛伐他汀 | 3.25±0.31 |
| 辛伐他汀酸(4) | 29.40±1.02 |
| 5 | 117.00±8.07 |
| 6 | 161.08±3.76 |
| 7 | 269.13±1.04 |
| 8 | 105.7±3.3 |
| 9 | 97.3±7.9 |
| 10 | 92.2±2.1 |
| 11 | 94.1±10.6 |
接着测试化合物对D1细胞的诱导矿化能力。结果如图7显示，浓度15μM以下的辛伐他汀和化合物1-F，两者均可诱导D1细胞矿化。然而辛伐他汀因具有细胞毒性导致细胞死亡情形随浓度增加而越发严重，因此呈现矿质程度下降，可由图7辛伐他汀组的红色染色淡化得知。相较之下，化合物1-F则可以稳定地诱导细胞矿化；当浓度提升至大于20μM，只有化合物1-F组可以成功地诱导D1细胞矿化，而辛伐他汀组别的细胞皆死亡。综合细胞毒性与矿化的分析，化合物1-F相对于辛伐他汀能呈现安全且有效地诱导细胞矿化效果。
辛伐他汀酸(化合物4)及化合物5～11诱导D1细胞矿化能力的测试，则固定浓度为1与4μM，分别比较矿化达9、11、13天的结果。如图8a显示，在第9天，化合物5与7(1μM)都能明显地诱导细胞矿化。在第11天，化合物5、6、7(1μM)均有优异诱导细胞矿化的能力，化合物7尤其显著(图8b)。在第13天，如图8c显示，各化合物均有诱导细胞矿化的能力。而辛伐他汀会造成细胞死亡，无法诱导细胞矿化，1μM的辛伐他汀则具有优异的诱导能力，相较之下，辛伐他汀酸(化合物4)则需在浓度4μM条件下才能有效诱导矿化。我们推测该差异是因为两化合物进入细胞能力不同所导致。其中，水溶性优于辛伐他汀的化合物7也在浓度4μM条件下呈现明显诱导细胞矿化能力，且相当于辛伐他汀(1μM)和辛伐他汀酸(4μM)。
Fleming团队指出斑马鱼的骨骼的基因类型、生理特征与生长模式均相似于人类，且相似度都高于老鼠，适合做为造骨药物的筛选平台。本发明也以斑马鱼为测试骨生成的动物模型，评估了衍生化合物1-F、2-F、7与辛伐他汀的促进造骨能力，更分析化合物2-F于斑马鱼活体的骨靶向能力，结果见图9和图10。
以calcein为正向控制组(其为生物体活体标本的矿物质的染色选择)。斑马鱼在喂食calcein后，可经由荧光显微镜的观察在骨骼上的荧光呈色(图9a的斑马鱼侧面与正面观察)；如图9b显示，斑马鱼喂食化合物2-F后，骨骼上也有荧光呈色，证明化合物2-F可以标靶至骨骼。
投予化合物1-F、2-F与辛伐他汀，测试化合物对于成长中斑马鱼的骨头生成影响。结果发现，化合物1-F可促进骨头生长，并相较于未投药组别(control)增生了50％，辛伐他汀组和不含辛伐他汀的化合物2-F组都无法促进骨头生长；如图9c所示，比较化合物1-F和2-F，其结构差异为有或无3,5-二羟基戊酯衍生物基团，因此推论化合物1-F促进骨头生长的来源应为3,5-二羟基戊酯衍生物基团。再者，Fleming也曾报导辛伐他汀对于斑马鱼骨头无法呈现任何生长效益，或许呼应了辛伐他汀对人体骨骼影响不一之说。本发明也再度观察到相同现象，同时，证明修饰有骨靶向胜肽的化合物1-F不仅能成功地靶向至骨头，对于人类骨头生长的促进应极具潜力。
由前述实验中选出整体表现最优异的非寡肽衍生物7，在斑马鱼骨质提升研究中，被证实不论以0.1与1μM浓度处理，均可促进斑马鱼的骨头生长，较未投药组别增加范围在30～50％之间；如图10所示，显然地，虽未具有靶向载体仍可促进骨质增生，显然3,5-二羟基戊酸的酰胺类似物确实可以达到造骨的功效。
结果表明，以聚天冬氨酸肽修饰的3,5-二羟基戊酸酰胺类似物，可增强骨质的选择性和骨质生成能力，并具有减轻毒性的效果。此类衍生物改善他汀类药物的骨质增生能力，此外化合物1-F和7对于斑马鱼的骨骼具有具体的骨质增加作用，表明了3,5-二羟基戊酸酰胺类似物对于人类骨质增加的潜力。3,5-二羟基戊酸的类似物可成为新颖的骨质同化制剂，用于治疗人类骨质低下疾病。相较于辛伐他汀抑制HMG-CoA还原酶作用，化合物1-F则以强化3,5-二羟基戊酸的类似物影响骨质途径并非经由甲羟戊酸(MVA)途径。本研究是首次以化学结构需求论及，HMG-CoA还原酶抑制作用不是骨形成的必要条件。
实验方法(Materials and methods)
细胞存活率性测定(Cytotoxicity assay)
化合物1-F以含有3-(4,5-二甲基吡啶-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑鎓(3-(4,5-dimethyl-thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,MTS)方式分析细胞毒性。96孔板中，人类脂肪干细胞(hADSC)以每孔6x103个为初始培养密度，培养在k培养液(Keratinocyte-SFM,GIBCO-InvitrogenCorporation)；细胞满盘后，含有化合物1-F的k培养液当作实验组，未含有化合物1-F的为空白试验组，以此在37℃下培养3天；加入MTS试剂培养3小时，再移除k培养液且以磷酸盐缓冲液(phosphate buffered saline,PBS)清洗，并加入100μL二甲基亚砜(dimethylsulfoxide,DMSO)至孔板中，帮助甲腊(formazan)溶解，吸取出含有甲腊的二甲基亚砜溶液，以波长490nm检测吸收值，数值大小得以判断细胞的存活。
化合物4～11以MTT方式分析细胞毒性。D1细胞以每孔5x 103个为初始培养密度，培养在骨培养液。该骨培养液为含有10％胎牛血清(Fetal bovine serum,FBS)、100U/mL盘尼西林(penicillin)、100μg/mL链霉素(streptomycin)、100mg/mL抗坏血酸(ascorbic acid)、1％非必需氨基酸(non-essential amino acids,NEAA)、1.5g碳酸氢钠(sodium bicarbonate)的DMEM培养液基。细胞满盘后，含有化合物4～11的骨培养液当作实验组，未含有化合物4～11的为空白试验组，以此在37℃下培养3天；加入MTT试剂培养3小时，再移除骨培养液且以PBS缓冲液清洗，并加入100μL DMSO至孔板中，帮助甲腊溶解，吸取出含有甲腊的二甲基亚砜溶液，以波长595nm检测吸收值，数值大小得以判断细胞的存活。
3-羟基-3-甲基戊二酰-辅酶A还原酶抑制作用(HMG-CoA reductase inhibition)：配制含有100μM 3-羟基-3-甲基戊二酰-辅酶A还原酶、330μM原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、2％二甲基亚砜(DMSO)、BSA(1mg/mL)的0.1M磷酸缓冲液，在放入不同浓度的化合物1与4～11后，混合5分钟，再加入HMG-CoA还原酶(最终浓度为17.4nM)；之后，以340nm检测其吸收值，再用软件Sigma 10以nonlinear least-squares分析IC50，以此判断化合物是否抑制HMG-CoA还原酶的作用。
D1细胞的成骨诱导培养(Procedures for culture and osteoinduction of D1 cells)：经由美国(American Type Culture Collection,ATCC)购买的D1细胞，将D1细胞以400μL骨培养液(BM prepared with DMEM,10％FBS,100U/mL penicillin,100μg/mL streptomycin,100mg/mL ascorbic acid,1％NEAA,1.5g sodium bicarbonate)培养在48孔板，初始培养的细胞密度于每孔为3x104个；待细胞满盘后，置换含有化合物1的骨培养液，对空白试验组为没有添加化合物1的培养液，培养3天后，再置换诱导成骨细胞矿化培养液。该成骨细胞矿化培养液包括10-2Mβ-甘油磷酸(β-glycerophosphate)、10-7M dexamethasone，每2天更换一次诱导成骨细胞矿化培养液；在设定培养天数下，将孔板中的培养液移除且以PBS缓冲液清洗，再以10％福尔马林(formalin)固定细胞，时间为30分钟；之后，移除福尔马林且以水清洗细胞，直至无福尔马林味道，并静置和干燥12小时，再以200μL的10％醋酸水溶液混合30分钟，取其上清液且测定415nm的吸收值，此读值的空白与试验组的比较为诱导细胞矿化的能力差异。
化合物4～11的诱导细胞矿化的能力则如前所述方法进行评估，但是诱导成骨细胞矿化培养液内不添加地塞米松(dexamethasone)。
化合物的骨标靶作用(Bone Targeting of test compounds)：以AB strain的斑马鱼仔鱼为测试对象，在28℃下以Hank缓冲液(13.7mM NaCl,540μM KCl,25μM Na2HPO4,44μMKH2PO4,300μM CaCl2,100μM MgSO4,420μM NaHCO3,pH 7.4)培养；2dpf的仔鱼被培养在含3.2mM测试化合物的24孔板中，5天后，以3-胺基苯甲酸乙酯甲基磺酸盐(tricaine-methanesulfonate)进行牺牲仔鱼，再将仔鱼以3％羟丙甲纤维素(methyl-cellulose)水溶液固定于载玻片上，利用Leica DM-6000CS荧光显微镜(Leica Instruments Inc.,Wetzlar,Germany)进行影像拍摄，快门设定为60秒。
化合物诱发的成骨作用(Bone formation induced by test compounds)：孵化2天的斑马鱼仔鱼被培养在24孔板，并投予欲测试的化合物，经过5天后，孵化7天的斑马鱼仔鱼被移除24孔板至6公分的圆盘中，以缓冲液清洗仔鱼表面；将仔鱼放入含有0.2％calcein水溶液中，10分钟后，取出仔鱼并清洗仔鱼表面，再将仔鱼放入水中10分钟，让未染于骨头的calcein扩散出仔鱼体内；随后，以3-胺基苯甲酸乙酯甲基磺酸盐(tricaine-methane-sulfonate)进行牺牲仔鱼，再将仔鱼以3％羟丙甲纤维素(methyl-cellulose)水溶液固定于载玻片上，利用Leica Z16APO显微镜进行影像拍摄，快门设定为200ms，图像以NIH Image J的方式计算荧光量(NIH open software with Macbiophotonics plugins)，计算新生成的骨头量以相对于空白试验组的百分比呈现。
统计分析(Statistical analysis)：实验结果，皆以平均值加减标准误差(Mean±SEM)表示。统计间的差异，在非配对及配对样本中分别采用非相依性的Student’s t-test。当多个治疗组与对照组相比较，采用单因子变异数分析(one way ANOVA)，或双因子重复测量变异数分析(two way repeated measures ANOVA)。当变异数分析(Analysis of variance，ANOVA)呈现统计学差异时，采用Dunnett′s或Student-Newman-Keuls test。P值小于0.05，表示实验值具有统计学上显著性差异。数据和图面的分析，在IBM计算机运用SigmaPlot软件(版本8.0，Chicago,IL,U.S.A.)和SigmaStat(版本2.03，Chicago,IL,U.S.A.)。
本发明以下面的实施例予以示范阐明，但本发明不受下述实施例所限制。本发明所用的药物、生物材料皆市售易于取得，下列仅为示例可取得的管道。
实施例1：
化合物1-F的制备：使用芴甲氧羰基(Fmoc)的保护策略进行固相胜肽合成方法，合成胜肽。一般来说，先秤取芴甲氧羰基-甘氨酸预载于王树脂(0.79mmol/g)于反应容器中，再添加5毫升二甲基甲酰胺(Dimethylformamide,DMF)，浸泡1小时后再进行后续步骤。配置20％的呱啶于二甲基甲酰胺中，其为去芴甲氧羰基的保护基的试剂，以下均以DEP为简称；待移除原先5毫升二甲基甲酰胺，即加入DEP进行芴甲氧羰基保护基的去保护，经过10分钟反应后，芴甲氧羰基保护基顺利被移除；配制两倍过量的氨基酸和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(Benzotriazol-1-yl-oxytri-pyrrolidinophosphonium-hexafluoro-phosphate,PyBOP)于反应瓶中，再配制0.4M N-甲基吗啉(N-methyl morpholine)于二甲基甲酰胺中，其为固相胜肽合成的活化试剂，以下均以ACT为简称，ACT也同被置入反应瓶中，反应的时间为所设定的时间；待结束后，将已配制好的终止试剂，其为100μL乙酸酐(Ac2O)于2mL二甲基甲酰胺中，反应30分钟即可完成。进而，配制移除试剂，其组成为95％的三氟乙酸(Trifluoroacetic acid,TFA)水溶液，以下简称CLE，在完成所有的反应条件后，取出所有树脂且与CLE反应90分钟，再移除CLE后可获得胜肽出产物。反应过程中，以含有茚三酮(Ninhydrin)的凯萨试剂进行监测。配制凯萨试剂以便监测反应的进行，其组成为0.28M茚三酮于乙醇溶液、42.37M苯酚于乙醇溶液和吡啶。反应过程中，取些许树脂以凯萨试剂检测，树脂上的胜肽如有胺基会呈现蓝色，称之为正向结果﹙positive result﹚，反之，树脂上的胜肽没有胺基会呈现微淡黄色。取移除芴甲氧羰基后的0.251g(0.2mmol)树脂与N-芴甲氧羰基-N′-[1-(4,4-二甲基-2,6-二氧代环己基亚甲基)-3-甲基丁基]-L-赖氨酸(N-α-Fmoc-N-ε-1-(4,4-dimethyl-2,6-dioxo-cyclohex-1-ylidene)-3-methylbutyl-L-lysine,Fmoc-Lys(ivDde)-OH)反应，4小时后反应顺利结束，再以ACT终止反应；经DEP移除芴甲氧羰基后，0.162g(0.4mmol)的辛伐他汀搭配10％二异丙基乙基胺(diisopropyl-ethylamine)的二甲基甲酰胺溶液进行反应，在200W的微波照射下，温度控制在105℃，经过100分钟后可完成反应，再以ACT终止反应，获得化合物12。随后使用4％联胺(hydrazine)的二甲基甲酰胺溶液移除ivDde保护基，经过20分钟后，ivDde保护基可顺利被移除，再依序合成六个天门冬胺酸，其方法如之前所介绍的固相胜肽合成方法，反应时间分别为30、45、60、80、80和90分钟，获得化合物13。同样地，赖氨酸也被合成上序列，反应时间为4小时，获得化合物14；然后，移除芴甲氧羰基保护基，合成上聚乙二醇，反应时间为2小时；再者，移除ivDde保护基，合成上氟硫氰酸荧光素(Fluorescein isothiocyanate,FITC)，反应时间为1小时，再经CLE步骤可得化合物1-F。
实施例2：
化合物1的制备：比照化合物1-F的实施例步骤，制备到化合物14；再以2小时合成上聚乙二醇，之后，以30分钟修饰上乙烯基，经CLE步骤后可得化合物1。
实施例3：
化合物2-F的制备：取移除芴甲氧羰基后的0.251g(0.2mmol)树脂依序合成六个天门冬胺酸，反应时间分别为30、45、60、80、80和90分钟，获得化合物16。赖氨酸也被合成上序列，反应时间为4小时；随后，再分别修饰上聚乙二醇与氟硫氰酸荧光素，反应时间依序为2与1小时，再经CLE步骤可得化合物2-F。
实施例4：
化合物1的纯化：配制冲提液为甲醇的水溶液(CH3OH：H2O＝7：3)，且含有0.1％三氟乙酸，将初产物溶于1mL冲提液中，再注射进入中压液相层析系统，其中管柱内容物为C18，经不同时间点下收集，经薄层层析鉴定，收集Rf为0.4(CH3OH：H2O＝7：3)的单一产物，可获得化合物1，产率为25％。高效能液相层析分析中，管柱内容物也为C18，冲提液为0.1％三氟乙酸的甲醇溶液，流速为每分钟0.2mL，紫外光侦测波长为220nm，得化合物1的滞留时间为7分钟，纯度为95％。
1H-NMR(400MHz,D2O):δ5.32(m,5H),4.15(m,8H),4.02(br,2H),3.61(m,44H),3.32(s,3H),3.10(m,4H),2.83(m,12H),1.91(s,3H),1.68(m,10H),1.46(br,12H),1.35(br,12H),1.19(m,10H).
Mass(MALDI-TOF):found for 2024Da(M+H+)；calcd.for C89H145N11O41:2023.96Da.
实施例5：
化合物1-F的纯化：冲提液为甲醇，将初产物溶于1mL冲提液中，再注射进入LH20管柱，经不同时间点下收集，经薄层层析鉴定，收集Rf为0.1(CH3OH：H2O＝1：1)的单一产物，可获得化合物1-F，产率为24％。高效能液相层析分析中，管柱内容物为C18，冲提液为0.1％三氟乙酸的甲醇溶液，流速为每分钟0.4mL，紫外光侦测波长为220和496nm，得化合物1-F的滞留时间为8.2分钟，纯度为95％。
1H-NMR(400MHz,acetone-d6):δ8.50(br,1H),7.92(m,1H),7.16(m,3H),6.71(m,11H),4.74(m,6H),4.30(s,2H),4.13(m,6H),3.58(m,44H),3.30(m,3H),2.89(m,12H),1.84(m,16H),1.53(br,8H),1.27(m,18H),0.88(m,2H).
Mass(MALDI-TOF):found for 2469Da(M+H2O+NaCl+Na+)；calcd.forC108H154N12O45S:2369.00.
实施例6：
化合物2-F的纯化：冲提液为水，将初产物溶于1mL冲提液中，再注射进入LH20管柱，经不同时间点下收集，经薄层层析鉴定，收集Rf为0.6(CH3CN：H2O＝1：1)的单一产物，可获得化合物2-F，产率为26％。高效能液相层析分析中，管柱内容物为C18，冲提液为0.1％三氟乙酸的甲醇溶液，流速为每分钟0.4mL，紫外光侦测波长为220和496nm，得化合物2-F的滞留时间为6.4分钟，纯度为95％。
1H-NMR(400MHz,D2O):δ7.63(br,1H),7.53(m,1H),7.23(m,2H),7.04(m,2H),6.47(m,5H),4.46(m,5H),4.05(m,2H),3.88(m,2H),3.53(m,44H),3.25(s,3H),2.56(m,12H),1.61(m,2H),1.05(m,4H).
Mass(MALDI-TOF):found for 1765Da(M+H+)；calcd.for C76H104N10O36S:1764.63Da.
实施例7：
化合物3的制备：辛伐他汀(0.050g,0.1mmole)溶解在10mL的无水四氢呋喃溶液中，再加入0.1mL异丙基格林那试剂(isopropyl Grignard reagent)，浓度也为0.1mmole，反应64小时后，经减压浓缩移除溶剂后，得无色油状物的初产物；初产物以二氯甲烷(CH2Cl2)和饱和食盐水进行萃取，重复操作3次，经移除溶剂后，可得0.055g的白色固体，即为化合物3，产率为36％。
实施例8：
化合物4的制备：辛伐他汀(0.052g,0.1mmole)溶解在10mL的乙醇中，再加入1mL氢氧化钠(NaOH)0.1N水溶液，在室温下反应10分钟可结束反应；将乙醇移除后加入0.1N盐酸水溶液，直至pH值为6，再进行冷冻干燥而获得白色固体；取丙酮加入白色固体中，使得氯化钠以固体方式析出，取出上清液且移除溶剂，最后，可以获得0.042g的白色固体，产率为80％。
1H NMR(400MHz,CDCl3):5.95(d,J＝10Hz,1H),5.75(m,1H),5.47(br,1H),5.33(br,1H),4.17(br,1H),3.67(br,1H),2.40(m,3H),2.22(m,2H),1.92(br,2H),1.543(m,5H),1.30(m,2H),1.08(m,11H),0.86(d,J＝6Hz,3H),0.80(t,J＝8Hz,3H).
Mass(ESI,m/z):437(M+H)+.
实施例9：
化合物5的制备：辛伐他汀(0.102g,0.2mmole)与乙醇胺(0.025g,0.2mmole)溶解在5mL的二氯甲烷中，并加入N-甲基吗啉(0.2mL,1.9mmole)，室温下反应4小时，反应可顺利结束；经减压浓缩移除溶剂后，可得黄色油状物的初产物。初产物以些许二氯甲烷溶解，放入分液漏斗中，且补充二氯甲烷，二氯甲烷的总体积为30mL，再加入30mL的饱和食盐水，进行萃取而留下二氯甲烷溶液，此后，再操作2次萃取，总次数为3次；最后，利用无水硫酸钠干燥溶液中的水，再移除硫酸钠固体和溶剂，可得0.091g的白色固体，即为化合物5，产率为80％。
1H NMR(400MHz,CDCl3).:7.16(t,J＝6Hz,1H),5.94(d,J＝9Hz,1H),5.74(q,J＝4and 6Hz,1H),5.46(br,1H),5.33(br,1H),4.24(m,2H),3.67(m,4H),3.37(m,2H),2.30(m,5H),1.91(m,2H),1.52(m,5H),1.12(m,13H),0.84(d,J＝7Hz,3H),0.79(t,J＝7Hz,3H).
13C-NMR(CDCl3,100MHz):δ178.4,172.7,133.0,131.5,129.4,128.2,71.8,69.1,68.2,61.2,43.5,42.9,42.7,42.1,37.5,36.3,34.8,32.9,30.4,27.2,24.7,24.6,24.2,23.0,13.8,9.2.
Mass(ESI,m/z):502(M+Na)+.HRMS cald.for C27H45NO6Na:502.3144；found:502.3142.
实施例10：
化合物6的制备:比照化合物5的制备过程，将乙醇胺改为丙醇胺(0.018g,0.2mmole)，反应时间同为4小时，可得0.101g的白色固体，产率为86％。
1H-NMR(400MHz,CDCl3):δ6.95(br,1H),5.96(d,J＝10Hz,1H),5.76(br,1H),5.48(br,1H),5.38(m,1H),4.19(br,1H),3.75(br,1H),3.63(m,3H),3.38(br,2H),2.31(m,5H),1.92(m,2H),1.69(m,2H),1.53(m,5H),1.13(m,13H),0.85(d,J＝7Hz,3H),0.80(t,J＝8Hz,7H).
13C-NMR(CDCl3,100MHz):δ178.4,172.8,133.0,131.5,129.5,128.2,72.0,69.3,68.2,59.4,43.4,43.0,42.5,37.7,36.3,36.1,34.7,33.0,32.9,31.9,30.4,27.2,24.8,24.1,23.1,13.9,9.3.
Mass(ESI,m/z):516(M+Na)+.HRMS cald.for C28H47NO6Na:516.3300；found:516.3297.
实施例11：
化合物7的制备：比照化合物5的制备过程，将乙醇胺改为聚乙二醇胺(0.025g,0.2mmole)，反应时间为2小时，可得0.113g的白色固体，产率为90％。
1H-NMR(400MHz,CDCl3):δ7.14(br,1H),5.95(d,J＝10Hz,1H),5.75(dd,J＝6and 6Hz,1H),5.47(br,1H),5.36(m,1H),4.20(br,,1H),3.72(m,4H),3.55(m,5H),3.44(m,2H),2.30(m,5H),1.92(m,2H),1.52(m,5H),1.12(m,11H),0.84(d,J＝7Hz,3H),0.79(t,J＝8Hz,3H).
13C-NMR(CDCl3,100MHz):δ178.3,172.2,133.0,131.5,129.4,128.2,72.2,72.0,69.5,69.4,68.2,61.4,43.3,42.9,42.5,39.1,37.6,36.2,34.7,33.0,30.4,27.2,24.7,24.6,24.2,23.0,13.8,9.3.
Mass(ESI,m/z):546(M+Na)+.HRMS cald.for C29H49NO7Na:546.3407；found:546.3404.
实施例12：
化合物8的制备：辛伐他汀(0.051g,0.1mmole)溶解在4mL的乙醇中，再加入联胺(60μL,5.0mmole)，在室温下反应2天，则可将溶液移除溶剂而获得黄色油状物的初产物；将初产物以二氯甲烷和饱和食盐水进行萃取，在移除溶剂后可得0.038g的白色固体，产率为70％。
1H NMR(400MHz,CDCl3):5.98(d,J＝10Hz,1H),5.77(m,1H),5.49(m 1H),5.48(br,1H),4.20(br,1H),3.78(m,1H),2.45(br,1H),2.34(m,3H),2.23(d,J＝10Hz,1H),1.87(m,2H),1.58(m,5H),1.21(m,2H),1.12(m,11H),0.86(d,J＝7Hz,3H),0.82(t,J＝8Hz,3H).
13C NMR(100MHz,CDCl3):.178.6,132.9,131.4,129.6,128.3,125.9,72.1,69.3,68.1,43.0,42.3,37.9,35.7,34.7,33.3,32.9,30.3,27.2,24.8,24.7,23.8,23.1,13.9,9.3.
Mass(ESI,m/z):473(M+Na)+.HRMS cald.for C25H42N2O5Na:473.2986；found:473.2987.
实施例13：
化合物9的制备：辛伐他汀(0.051g,0.1mmole)和2-胺甲基吡啶(11μL,0.11mmole)溶解在12mL的1,4-环氧己烷中，室温下反应7天，则可收起反应且移除溶剂，可得黄色油状物的初产物；将初产物以正向硅胶管柱分离，在不同时间点下收集，经薄层层析鉴定，收集Rf为0.25(CH2Cl2：CH3OH＝10：0.2)的单一产物，可获得化合物9，产率为35％。
1H NMR(400MHz,CDCl3):8.51(d,J＝4Hz,1H),7.68(td,J＝8and 2Hz,1H),7.27(br,1H),7.21(m,2H),6.97(t,J＝6Hz,1H),5.98(d,J＝9Hz,1H),5.78(dd,J＝6Hz,1H),5.49(t,J＝3Hz,1H),5.39(qui,J＝2and 3Hz,1H),4.69(dd,J＝6Hz,1H),4.50(dd,J＝5Hz,1H),4.25(m,1H),3.80(m,1H),2.43(m,4H),2.23(m,1H),1.94(m,2H),1.56(m,7H),1.14(m,11H),0.87(d,J＝7Hz,3H),0.82(t,J＝7Hz,3H).
13C NMR(100MHz,CDCl3):.178.1,172.3,156.2,148.9,137.0,133.2,131.7,129.5,128.3,122.5,122.0,72.3,69.9,68.1,44.2,43.8,43.0,42.5,37.7,36.2,34.7,33.0,30.5,27.3,24.8,24.2,23.1,13.9,9.3.
实施例14：
化合物10的制备：辛伐他汀(0.051g,0.1mmole)和丙基胺(18μL,0.3mmole)溶解在12mL的四氢呋喃(Tetrahydrofuran,THF)中，室温下反应7天，则可收起反应且移除溶剂，可得黄色油状物的初产物；将初产物以正向硅胶管柱分离，在不同时间点下收集，经薄层层析鉴定，收集Rf为0.25(CH2Cl2：CH3OH＝8：0.2)的单一产物，可获得化合物10，产率为48％。
1H NMR(400MHz,CDCl3):6.28(br,1H),5.98(d,J＝10Hz,1H),5.83(m,2H),5.49(br,1H),5.43(q,J＝3Hz,1H),5.17(m,1H),4.72(br,1H),4.21(qua,J＝5and 7Hz,1H),3.89(t,J＝4Hz,2H),3.79(m,1H),3.62(br,1H),2.39(m,4H),2.23(m,1H),1.79(m,2H),1.56(m,7H),1.08(m,11H),0.86(d,J＝7Hz,3H),0.82(t,J＝7Hz,3H).
13C NMR(100MHz,CDCl3):.178.4,171.7,134.0,133.0,131.4,129.6,128.2,116.4,72.3,69.6,68.1,43.0,42.9,42.3,41.7,37.9,35.8,34.6,33.2,32.9,30.3,27.2,24.8,24.7,23.9,23.1,13.9,9.3.
Mass(ESI,m/z):498(M+Na)+.HRMS cald.for C28H45NO5Na:498.3190；found:498.3189.
实施例15：
化合物11的制备：辛伐他汀(0.051g,0.1mmole)和丙基胺(18μL,0.3mmole)溶解在12mL的四氢呋喃中，室温下反应7天，则可收起反应且移除溶剂，可得黄色油状物的初产物；将初产物以正向硅胶管柱分离，在不同时间点下收集，经薄层层析鉴定，收集Rf为0.3(CH2Cl2：CH3OH＝10：0.2)的单一产物，可获得化合物11，产率为60％。
1H NMR(400MHz,CDCl3):6.23(t,J＝3Hz,1H),5.97(d,J＝10Hz,1H),5.76(dd,J＝4and 6Hz,1H),5.48(br,1H),5.40(qui,J＝2and 3Hz,1H),4.80(br 1H),4.19(m,1H),3.74(m,2H),3.21(m,2H),2.27(m,5H),1.93(m,2H),1.54(m,7H),1.15(m,11H),0.94(t,J＝7Hz,3H),0.83(m,6H).
13C NMR(100MHz,CDCl3):.178.3,171.9,133.0,131.5,129.5,128.2,72.3,69.6,68.1,43.0,42.3,41.0,37.8,35.9,34.6,33.1,32.9,30.4,27.2,24.8,24.6,24.023.1,22.7,13.9,11.3,9.3.
Mass(ESI,m/z):500(M+Na)+.HRMS cald.for C28H47NO5Na:500.3346；found:500.3348.
本发明实属难能的创新发明，深具产业价值，援依法提出申请。此外，本发明可以由本领域技术人员做任何修改，但不脱离如所附申请专利范围所要保护的范围。
其他实施例
实施例1.一种改善生物个体内骨质低下所介导病症或疾病的组成物，其包括结构式I所示的3,5-二羟基戊酸(3,5-dihydroxypentanoic acid)衍生物。
实施例2.一种改善生物个体内骨质低下所介导病症或疾病的组成物，其包括结构式II所示化合物，其中Rt选自下列其中之一：C1-C10烷基、羟基、取代的C1-C10烷胺基、–N-(C1-C10)烷基-OH、–N-(C1-C10)烷基–胺基、–NH-胺基；–N-(C1-C10)不饱和烷基、含氧原子的5元芳香环、含氧原子的6元芳香环、含氮原子的5元芳香环、含氮原子的6元芳香环。
Claims (9)
1.组合物在制备药物或食品中的用途，所述药物或食品用于治疗哺乳动物骨质低下，其中，所述组合物包括结构式I所示的3,5-二羟基戊酸衍生物，
其中，X为氮原子或碳原子；
R为氢基或(C1-C4)烷基；
Ra选自下列其中之一：C1-C10烷基、取代的C1-C10烷基、C3-C8环烷基、取代的C3-C8环烷基、苯胺基、取代的苯胺基、苯基C1-C10烷胺基、取代的苯基C1-C10烷胺基、双磷酸盐类、四环素、胺基酸、酸性寡胜肽、骨标靶胜肽和
Rb选自下列其中之一：无取代基、乙酰基、显像基团；
表示单键或双键；
Rh选自下列结构式(A)，(B)，(C)，(D)，(E)和(F)其中之一：
Rk为C1-C5烷基；
Rm为C1-C5烷基或羟基；
Rn为C1-C5烷基或羟基。
2.根据权利要求1所述的用途，其特征在于，Ra为取代的C1-C10烷基，其中，取代基选自下列其中之一：氢基、C1-C10烷基、C1-C10烷氧基、C1-C5烷氧羰基、C1-C5酰氧基、C3-C8环烷基、苯基和取代的苯基。
3.根据权利要求1所述的用途，其特征在于，Ra为取代的C3-C8环烷基、取代的苯胺基、取代的苯基C1-C10烷胺基之一，其中，取代基各自独立地选自下列其中之一：C1-C5烷基、氟原子、氯原子、溴原子、碘原子、含氧原子的5元芳香环、含氧原子的6元芳香环、含氮原子的5元芳香环、含氮原子的6元芳香环。
4.根据权利要求1所述的用途，其特征在于，Ra为酸性寡胜肽，所述酸性寡胜肽为选自下列其中之一：-Lys-(Asp)m-Lys-PEG、D/L-Aspm、D/L-Glun，其中，m和n各自独立地为1至10的正整数。
5.根据权利要求1所述的用途，其特征在于，Ra为骨标靶胜肽，所述骨标靶胜肽选自下列其中之一：
Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val，
Leu-Leu-Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr-Gly-Gly-Gly-Ser，
Lys-Glu-IlePro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser-Gly-Gly-Gly-Ser，
Asn-Asn-Val-Ser-Gln-Lys-Trp-Gln-Gln-Arg-Leu-Ile-Gly-Gly-Gly-Ser，
Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His-Gly-Gly-Gly-Ser，
Gly-Ile-His-Val-Pro-Trp-Met-Pro-Pro-Val-Ala-Phe-Gly-Gly-Gly-Ser，
Gln-Arg-Ser-Trp-Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met-Gly-Gly-Glu-Ser，
Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser，
Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp-Gly-Gly-Gly-Ser，
Asp-Ser-Ser-Asn-Pro-Ile-Phe-Trp-Arg-Pro-Ser-Ser-Gly-Gly-Gly-Ser，
Asn-Thr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro-Gly-Gly-Gly-Ser，
Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser，
Ala-Thr-Trp-Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu-Gly-Gly-Gly-Ser，
Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser，
Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val，
Leu-Leu-Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr，
Lys-Glu-Ile-Pro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser，
Asn-Asn-Val-Ser-Gln-Lys-Trp-Gln-Gln-Arg-Leu-Ile，
Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His，
Gly-Ile-His-Val-Pro-Trp-Met-Pro-Pro-Val-Ala-Phe，
Gln-Arg-Ser-Trp-Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met，
Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn，
Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp，
Asp-Ser-Ser-Asn-Pro-Ile-Phe-Trp-Arg-Pro-Ser-Ser，
Asn-Tyr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro，
Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn，
Ala-Thr-Trp-Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu，
Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser。
6.根据权利要求1所述的用途，其特征在于，Ra为其中，U选自下列其中之一：–Lys、-Lys-(Asp-NHAc)J、-NHAc、-Lys-(Asp-)k-NHAc、(Asp-NHAc)J，J为1或2，K为正整数且20≥K≥1。
7.组合物在制备药物中的用途，所述药物用于改善生物个体内骨质低下所介导病症或疾病的组成物，其中，所述组合物包括结构式II所示化合物，
其中，Rt选自下列其中之一：C1-C10烷基、羟基、C1-C10烷胺基、–NH-(C1-C10)烷基-Rz、–NH-(C1-C5)烷基-O-(C1-C5)烷基–Rz、–NH-胺基；
Rz选自下列其中之一：C1-C10不饱和烷基、羟基、胺基、含氧原子的5元芳香环、含氧原子的6元芳香环、含氮原子的5元芳香环、含氮原子的6元芳香环。
8.一种化合物，其特征在于，所述化合物为结构式I所示的3,5-二羟基戊酸衍生物，
其中，X为氮原子或碳原子；
R为氢基或(C1-C4)烷基；
Ra选自下列其中之一：C1-C10烷基、取代的C1-C10烷基、C3-C8环烷基、取代的C3-C8
环烷基、苯胺基、取代的苯胺基、苯基C1-C10烷胺基、取代的苯基C1-C10烷胺基、双磷
酸盐类、四环素、胺基酸、酸性寡胜肽、骨标靶胜肽和
Rb选自下列其中之一：无取代基、乙酰基、显像基团；
表示单键或双键；
Rh选自下列结构式(A)，(B)，(C)，(D)，(E)和(F)其中之一：
Rk为C1-C5烷基；
Rm为C1-C5烷基或羟基；
Rn为C1-C5烷基或羟基。
9.一种化合物，其特征在于，所述化合物为结构式II所示化合物，
其中，Rt选自下列其中之一：C1-C10烷基、羟基、C1-C10烷胺基、–NH-(C1-C10)烷基-Rz、–NH-(C1-C5)烷基-O-(C1-C5)烷基–Rz、–NH-胺基；
Rz选自下列其中之一：C1-C10不饱和烷基、羟基、胺基、含氧原子的5元芳香环、含氧原子的6元芳香环、含氮原子的5元芳香环、含氮原子的6元芳香环。
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