TWI542569B - ３，５－二羥基戊酸的類似物用於成骨作用 - Google Patents
３，５－二羥基戊酸的類似物用於成骨作用 Download PDFInfo
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- TWI542569B TWI542569B TW104104625A TW104104625A TWI542569B TW I542569 B TWI542569 B TW I542569B TW 104104625 A TW104104625 A TW 104104625A TW 104104625 A TW104104625 A TW 104104625A TW I542569 B TWI542569 B TW I542569B
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Description
本發明揭示一種具備成骨作用藥物及其活性的應用，特別涉及3,5-二羥基戊酸的類似物，可不經由甲羥戊酸途徑。
利用非經由脂質代謝相關途徑的效果，或多發性效用(pleiotropic effects)的影響，可讓他汀類(Statins)藥物表現出骨質代謝活性。雖然他汀類藥物包含著3,5-二羥基戊酸(3,5-dihydroxypentanoic acid)的母體基團或衍生基團，一直被認為經由甲羥戊酸(mevalonate,MVA)途徑模仿3-羥基-3-甲基戊二醯-輔酶A(3-hydroxy-3-methylglutaryl-coenzyme A reductase,HMG-CoA reductase)受質而中斷脂質合成，可成為降低膽固醇的藥物。此甲羥戊酸途徑對於骨骼之影響已被證實可調控蝕骨細胞活性而抑制骨骼再吸收(bone resorption)，而且發現臨床所用的3-羥基-3-甲基戊二醯-輔酶A還原酶抑制劑之他汀類藥物還具有誘導成骨作用(bone formation)，其可能通過許多的替代途徑。而且他汀類具成骨作用的必要結構需求，目前尚不清楚，亦缺乏策略促使他汀類藥物減少在肝組織的分佈而增加骨組織親和。此等事實阻礙著他汀類藥物，作為骨骼同化製劑的發展。
3-羥基-3-甲基戊二醯-輔酶A還原酶(HMG-CoA reductase)主要分佈在肝臟，進行著脂質的合成。高效的降血脂化合物需與肝臟中的3-羥基-3-甲基戊二醯-輔酶A還原酶呈現高親和力，且具有肝細胞選擇性。因此，如要提高骨組織分佈比率，採降低3-羥基-3-甲基戊二醯-輔酶A還原酶的抑制活性策略，可能防止此類化合物集中在肝臟作用。
他汀類衍生物的相關製劑，最近成為針對骨質疾患治療的藥物。雖然他汀類已經報導在動物實驗和局部投與使用模式下可促進骨質增生。但多年來，不論係運用隨機對照試驗或系統性的評價，顯示絕經後婦女投予他汀類藥物衍生物，無法防止骨折或增加骨密度，因而認為在人體的全身投與模式下，其效果仍有爭議。因此，藥物結構仍有改善空間，必須研發能全身使用和具骨選擇性的他汀類藥物衍生物。
本案申請人鑑於習知技術中的不足，經過悉心試驗與研究，並一本鍥而不捨之精神，終構思出本案發明「3,5-二羥基戊酸的類似物用於成骨作用」，且能夠克服先前技術的不足，以下為本案之簡要說明。
為了克服先前技術的缺點，本發明經由實驗，探討二羥基戊酸的類似物之醫藥品及或/食品用途。
本發明之目的即在於提供一種如結構式I所示二羥基戊酸的類似物，
其中X選自下列取代基其中之一：氮原子與碳原子；R選自下列取代基其中之一：氫基與(C1-C4)烷基；Ra選自下列取代基其中之一：(a1)(C1-C10)烷基；(a2)取代之(C1-C10)烷基；(a3)(C3-C8)環烷基；(a4)取代之(C3-C8)環烷基；(a5)苯胺基(phenylamino)；(a6)取代之苯胺基；(a7)苯基(C1-C10)烷胺基(phenyl C1-10 alkylamino)；(a8)取代之苯基(C1-C10)烷胺基；(a9)雙磷酸鹽類(bisphosphonate),(a10)四環素(tetracycline),(a11)胺基酸(amino acid),(a12)酸性寡胜肽(acidic oligopeptides),(a13)骨標靶胜肽(bone targeting peptide)(a14)U-Lys(U)-Lys(U)-Gly-OH；Rb選自下列取代基其中之一：無取代基、乙醯基(acetyl group)、顯像集團(imaging moiety)；Rf-Rh間之鍵結為單鍵或雙鍵，Rf為碳原子；Rh選自下列結構式(A),(B),(C),(D),(E),(F)其中之一：
Rk選自下列取代基其中之一：(C1-C5)烷基；Rm選自下列取代基其中之一：(C1-C5)烷基、羥基；Rn選自下列取代基其中之一：(C1-C5)烷基、羥基。
根據本發明，於適當實施例，3,5-二羥基戊酸的衍生物還具有成像基團，可用於包括在人類或動物的影像檢查的診斷方法。其係包括經由投予包含3,5-二羥基戊酸的衍生物的顯像劑注射、輸液或任何其他已知的方法，而成像。
本發明尚有一目的係在於提供一種製造包括結構式I之3,5-二羥基戊酸的類似物，藉由添加劑、賦形劑達到增加骨質作用(bone mass)活性，以治療哺乳動物病症。
本發明之另一目的係在於提供一種組合療法用途，其係用於投予包括結構式I之3,5-二羥基戊酸的類似物之醫藥組合物與/或食品組合物，以治療哺乳動物病症。
本發明再有另一目的係在於提供一種製造結構式I之3,5-二羥基戊酸的類似物之方法，係在於提供芴甲氧羰
基(Fmoc)反應物，進行固相多肽合成(solid-phase peptide synthesis,SPPS)方法。其係包括提供(a)甘氨酸與王樹脂(Wang resin)預載之中間產物，令賴氨酸加以連接。(b)經由水解內酯環，讓辛伐他汀酸(simvastatin acid)於賴氨酸之α-氨基酸基團，形成共軛之醯胺鍵結。(c)固相多肽合成過程，必須高於100℃溫度下，採取150W以上之微波照射100分鐘左右。
圖一 為製備方法流程A(Scheme A)
圖二 為製備方法流程B
圖三 為製備方法流程C
圖四 化合物1與鈣離子以等溫滴定量熱卡計測試結合能力
圖五 化合物1影響氫氧基磷灰石的沉降(A)化合物1+氫氧基磷灰石(B)氫氧基磷灰石
圖六 化合物1-F結合至氫氧基磷灰石(a)白光照亮區(b)暗視野區
圖七 辛伐他汀與化合物1-F對人類脂肪幹細胞的誘導礦化
圖八 辛伐他汀與化合物4~11對D1細胞的誘導礦化結果
圖九 斑馬魚骨靶向與促骨生成試驗(a)餵食calcein給斑馬魚後，以螢光顯微鏡觀察暗視野(b)餵食化合物2-F給斑馬魚後，以螢光顯微鏡觀察暗視野(c)餵食化合物1-F、2-F與辛伐他汀給不同斑馬魚後，觀察斑馬魚骨頭生長情形。
圖十 化合物7促進斑馬魚骨頭生成的結果
本案將可由以下的實施例說明而得到充分瞭解，使得熟習本技藝之人士可以據以完成之，然而本案之實施並非可由下列實施例而被限制其實施型態，熟習本技藝之人士仍可依據除既揭露之實施例的精神推演出其他實施例，該等實施例皆當屬於本發明之範圍。
為達成前述發明目的，上述結構式I所示二羥基戊酸的類似物，Ra取代基其中(a2)取代之(C1-C10)烷基係選自下列取代基其中之一：氫基、(C1-C10)烷基、(C1-C10)烷氧基、(C1-C5)烷氧羰基(alkoxycarbonyl)、(C1-C5)醯氧基(acyloxyl)、(C3-C8)環烷基(cycloalkyl)、苯基。
上述Ra取代基其中(a4)取代之(C3-C8)環烷基、(a6)取代之苯胺基、(a8)取代之苯基(C1-C10)烷胺基，該取代基係各自選自下列取代基其中之一：(C1-C5)烷基、氟原子、氯原子、溴原子、碘原子、含氧原子之5元芳香環、含氧原子之6元芳香環、含氮原子之5元芳香環、含氮原子之6元芳香環。
上述Ra取代基其中(a12)酸性寡胜肽係選自下列取代基其中之一：-Lys-(Asp)m-Lys-PEG、D/L-Aspm、D/L-Glun，而m與n均為1至10之正整數。
上述Ra取代基其中(a13)骨標靶胜肽係選自下列取代基其中之一：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)U-Lys(U)-Lys(U)-Gly-OH之U係選自下列取代基其中之一：-Lys、
-Lys-(Asp-NHAc)J、-NHAc、-Lys-(Asp-)k-NHAc、(Asp-NHAc)J，而J為1至2之正整數，K為正整數20K1。
於適當實施例本發明的術語“烷基”，係指飽和直鏈或含有支鏈的烴基，而(C1-C10)烷基係指該飽和直鏈或含有支鏈烴基鏈上擁有1個至10個的碳原子。因此，(C1-C10)烷基係指甲基、乙基、丙基、丁基、異丁基、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“不飽和烷基”係指含有雙鍵直鏈、三鍵直鏈或含有雙鍵、三鍵支鏈的烴基。“苯胺基(phenylamino)”以-NHPh表示於苯基結構上含有胺基之取代基。
而於適當實施例，結構式I的3,5-二羥基戊酸的類似物的製備，係運用如圖一合成路徑所示標準態芴甲氧羰基(Fmoc)的保護戰略以及固相胜肽合成(solid-phase peptide synthesis,SPPS)方法。以預先置入甘氨酸的王樹脂(Gly-preloaded Wang resin)為起始原料，分別合成上Fmoc-Lys( iv Dde)-OH)和辛伐他汀，可獲得化合物12。再利用聯胺(hydrazine)移除 iv Dde保護基，合成上連續6個Fmoc-Asp-(tBu)-OH，可獲得化合物13。同樣地，合成上Fmoc-Lys( iv Dde)-OH可獲得化合物14。之後，合成上聚乙二醇(化合物15)和氟硫氰酸螢光素(FITC)，再經CLE步驟可得化合物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。
運用如圖二合成路徑，以Rink amide樹脂為起始原料，合成上連續6個Fmoc-Asp-(tBu)-OH，可獲得化合物16。同樣地，合成上Fmoc-Lys( iv Dde)-OH、聚乙二醇(化
合物15)和氟硫氰酸螢光素(FITC)，再經CLE步驟可得化合物2-F。
3,5-二羥基戊酸的類似物，運用圖三合成路徑，於室溫下在乾燥四氫呋喃(tetrahydrofuran,THF)，令異丙基格林那試劑(isopropyl Grignard reagent)與辛伐他汀反應可加以製備。
於適當實施例，辛伐他汀酸衍生化合物係於結構式I，Rh選自下列結構式(A),(B),(C),(D),(E),(F)其中之一。而部分辛伐他汀酸衍生化合物如結構式II所示，其中Rt選自下列取代基其中之一：(C1-C10)烷基、羥基、(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選自下列取代基其中之一：(C1-C10)不飽和烷基、羥基、胺基、含氧原子之5元芳香環、含氧原子之6元芳香環、含氮原子之5元芳香環、含氮原子之6元芳香環。
圖三合成路徑係以結構式II所示製備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，亦可比照此合成路徑加以製備，其係在室溫下與二氯甲烷、甲醇或乾燥四氫呋喃中與各類胺類化合物反應。
根據上述本發明的製備路徑流程，其中胜肽鏈之合成可運用圖一或二的合成路徑，而3,5-二羥基戊酸的類似
物的製備則係經由圖三的合成路徑。於3,5-二羥基戊酸的類似物之合成路徑，亦可經由辛伐他汀衍生物作為起始原料，則其中辛伐他汀衍生物係選自市售或習知的他汀類藥物。例如阿托伐他汀(Atorvastatin)的化學名稱為(3R,5R)-7-[2-(4-氟苯基)-3-苯基-4-(苯基氨基甲醯基)-5-異丙基-吡咯-1-基]-3,5-二羥基庚酸((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)的化學名稱為(3R,5S,6E)-7-[4-(4-氟苯基)-2,6-二異丙基-5-甲氧甲基-吡啶-3-基]-3,5-二羥基-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)的化學名稱為(3R,5S,6E)-7-[3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基]-3,5-二羥基-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)；羅瓦斯達汀(Lovastatin)的化學名稱為(1S,3R,7S,8S,8AR)-1,2,3,7,8,8A-六氫-3,7-二甲基-8-[2.[(2R,4R)-四氫-4-羥基-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)的化學名稱為2-甲基丁酸[1S-[1-A(R*),7-B,8-B(2S*,4S*),8A-B]]-1,2,3,7,8,8A-六氫-7-甲基-8-[2-(四氫-4-羥基-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)的化學名稱為(3R,5S,6E)-7-[2-環丙基-4-(4-氟代苯基)喹啉-3-基]-3,5-二羥基-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)的化學名稱為(+)-(3R,5R)-3,5-二羥基-7-[(1S,2S,6S,8S,8aR)-6-羥基-2-甲基-8-[(S)-2-甲基丁醯氧基]-1,2,6,7,8,8a-六氫-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)的化學名稱為(3R,5S,6E)-7-[4-(4-氟苯基)-6-異丙基-2-(N-甲基-N-甲磺醯胺基)-5-嘧啶]-3,5-二羥基-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)的化學名稱為(3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-(2,2-二甲基丁醯氧基)-1,2,6,7,8,8a-六氫-2,6-二甲基-1-萘基]-3,5-二羥基庚酸銨((1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8 a-hexahydronaphthalen-1-yl2,2-dimethylbutanoate)。
術語“治療”、“治療中”及其類似術語係指緩減、改善、消減或消除目前患者所處病症或該病症相關之任何症狀的方法，以及預防該病症或其他涉及該症狀的方法。而術語『有效劑量(therapeutically effective amount)』係代表足以改善或防止醫學症狀或生物體狀態惡化之劑量。有效地劑量亦說明投與化合物之劑量足供用於診斷之劑量。除非說明書另有敘述，否則『活性化合物』以及『醫
藥活性化合物』於此均可替換使用，係指稱一具有製藥學、藥理學或治療效果之物質。
術語『賦形劑(excipients)』或稱為『藥學上可接受之載體或賦形劑』、『生物可利用之載體或賦形劑』，係包括溶媒、分散劑、包衣、抗菌或抗真菌劑，保存或延緩吸收劑等任何用於製備成劑型之習知適當化合物。通常此類載體或賦形劑，本身不具備治療疾病之活性，且將本技術所揭示之衍生物，搭配選用各種藥學上可接受之載體或賦形劑，製備成各劑型，投與動物或人類亦不致於造成不良反應、過敏或其它不適當反應。因而本技術所揭示之衍生物，搭配藥學上可接受之載體或賦形劑，係適用於臨床及人類。
術語“藥學上可接受之賦形劑”，包括但不限於，聚合物、樹脂、增塑劑、填料、潤滑劑、稀釋劑、黏合劑、崩解劑、溶劑、共一溶劑、界面活性劑、防腐劑、甜味劑、調味劑、藥學級的染料或顏料、及黏度劑至少一者。
術語“醫藥組成物(pharmaceutical composition)”為一種固體或液體組成物，其形式、濃度和純度程度適合投予給病患(如人類或動物病患)，在投予之後，其可誘發所欲生理變化。醫藥組成物典型地為無菌及/或非發熱性者(non-pyrogenic)。
該載體隨各劑型而調整，無菌注射之組成物可溶解或懸浮於無毒之靜脈注射稀釋液或溶劑中，此類溶劑如1,3-丁二醇。其間可接受之載體可為甘露醇(mannitol)或水。此外以固定油脂、合成之甘油酯或雙甘油酯，係一般習用之溶劑。脂肪酸，如油酸(oleic acid)、橄欖油或蓖
麻油等甘油酯衍生物之類，尤其經含氧乙基化之型態(oxy-acetylated types)皆可作為製備注射劑並為天然之醫藥可接受油類。此等油類溶液或懸浮液可包含長鏈之醇稀釋液或分散劑、羧甲基纖維素或類似之分散劑。其他常用之介面活性劑如Tween、Spans，或其他類似之乳化劑，或一般醫藥製造業所使用於醫藥可接受之固態、液態或其他生物可利用促進劑(enhancing agent)，可用於醫藥劑型之開發。
用於口服投藥之組成物係採用任何一種口服可接受之劑型，其劑型包括膠囊、錠劑、片劑、乳劑(emulsion)、含水懸浮液(aqueous suspension)、分散劑、溶劑。口服劑型通常所使用之載體，以錠劑為例之基本添加物可為乳糖、玉米澱粉、潤滑劑，以及硬脂酸鎂。而膠囊使用之稀釋劑(diluent)包括乳糖與乾燥之玉米澱粉。製成水懸浮液或乳化劑劑型，係將活性物質懸浮或溶解於已經混和著乳化劑或懸浮劑之油性介面活性劑，視需要添加適度之甜味劑，風味劑或是色素。
鼻用噴霧劑(aerosol)或吸入劑(inhalation)組成物，可根據習知之製劑技術進行製備。例如，將組成物溶於生理食鹽水中，添加苯甲醇或其他適合之防腐劑，或促進吸收劑以增強其生物可利用性。本發明所揭示之化合物亦可製成栓劑，採取直腸或陰道之投藥方式。
本發明所揭示化合物亦可運用注射投藥，其係包括經由皮下、腹腔、靜脈、肌肉，或關節腔內、顱內、關節液內、脊髓內注射，主動脈注射，胸腔注射，疾病部位內注射，或其他適合之投藥技術。
於適當實施例，對患者運用組合療法(combination therapies)投與含有結構式I成分，所製備之單一劑量口服組成物，如片劑、膠囊，或口服結構式I成分之食品。投與結構式I成分化合物之不同劑型之組合療法，其先後依序投與或是間隔短暫時間方式，可隨病患的情況和年齡變化，而選用各種劑型，例如舌下或口腔含片之口服劑型，直腸給藥，鼻腔用藥、乾燥粉末或噴霧之吸入劑，甚至於陰道給藥，皮下、肌肉、靜脈和皮內之注射劑，局部給藥(topical)等等，例如護手霜(mist)、噴霧、溶液劑(solution)、乳液(lotion)、膠凍(gel)、乳霜(cream)、軟膏、糊劑(paste)、油膏(unguent)、乳液霜(emulsion)和懸浮劑，更可包括口服或注射投藥。間隔短暫時間方式投與，通常以前後3小時內完成投與。
本說明書所敘述之所有技術性及科學術語，除非另外有所定義，皆隸屬於該所屬領域之具有通常技藝者可共同瞭解的意義。
為化合物1-F與1的結構將辛伐他汀酸的3,5-二羥基戊酸以天門冬胺酸寡肽和聚乙二醇修飾，化合物1-F更有螢光基團的鍵結，相對地，對照化合物2-F，其結構不含辛伐他酸，只有天門冬胺酸寡肽、聚乙二醇和螢光基團。
化合物1-F與1的結構中，辛伐他汀的內酯基被天門冬胺酸寡肽之胺基開環，以醯胺鍵方式結合在3,5-二羥基戊酸之羧基。
如化合物1-F與1，辛伐他汀的內酯基也可被含有胺基之非寡肽分子以醯胺鍵鍵結方式所開環修飾，甚至是以不含胺基之化合物，以成為酮基的結合形式開環，製備了
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經測試對3-羥基-3-甲基戊二醯-輔酶A還原酶的抑制能力。結果如表一顯示，所有辛伐他汀衍生物的有效抑制濃度均高於辛伐他汀本身，至少是辛伐他汀的5倍以上，甚至化合物1-F與9的有效抑制濃度高於辛伐他汀的500倍以上；因而得知辛伐他汀的內酯基被開環並改為醯胺鍵結，可有效下降對3-羥基-3-甲基戊二醯-輔酶A還原酶的抑制能力。
化合物1對鈣離子(Ca2+)的結合親和力(binding affinity)，係運用等溫滴定量熱卡計(isothermal titration calorimetry,ITC)測量。結果如圖四顯示，化合物1可以與約兩個鈣離子結合，並且有強的結合能力，結合常數為278.1kM-1。
因氫氧基磷灰石(hydroxyapatite,HAP)為骨頭的無機物組成，研究中以氫氧基磷灰石為仿生性骨骼材料。化合物1對氫氧基磷灰石的結合測試，其結果如圖五顯示。
以光線穿透值之百分比(%T)表現氫氧基磷灰石在有或無化合物參與之沉降延遲情形。與無添加化合物1組別相比，添加化合物1組別可見氫氧基磷灰石的沉降被延遲達120秒。
如以化合物1-F結合至氫氧基磷灰石，可以螢光顯微鏡進行監測。結果如圖六顯示，化合物1-F因結合至氫氧基磷灰石表面，致使氫氧基磷灰石粒子呈現螢光。
以人類脂肪幹細胞為細胞毒性測試的材料，發現投與化合物1-F後的細胞存活率遠高於投與辛伐他汀組別，換算成IC50表示，可見化合物1-F之IC50為辛伐他汀的300倍，明顯地得知化合物1-F在細胞安全性上高於辛伐他汀。(表二)
如以老鼠骨母前趨細胞(rat bone marrow stem cells)D1為測試材料，評估辛伐他汀衍生物之細胞毒性。結果如表三顯示，所有辛伐他汀衍生物的使用濃度均可被提高，表示辛伐他汀衍生物對D1細胞的安全性都比辛伐他汀高。尤其化合物7之IC50更比辛伐他汀高83倍。
表三
接著測試化合物對D1細胞的誘導礦化能力。結果如圖七顯示，濃度15μM以下的辛伐他汀和化合物1-F，兩者均可誘導D1細胞礦化。然而辛伐他汀因具有細胞毒性導致細胞死亡情形隨濃度增加而越發嚴重，因此呈現礦質程度下降，可由圖七辛伐他汀組的紅色染色淡化得知。相較之下，化合物1-F則可以穩定地誘導細胞礦化；當濃度提升至大於20μM，只有化合物1-F組可以成功地誘導D1細胞礦化，而辛伐他汀組別之細胞皆死亡。綜合細胞毒性與礦化的分析，化合物1-F相對於辛伐他汀能呈現安全且有效地誘導細胞礦化效果。
辛伐他汀酸(化合物4)及化合物5~11誘導D1細胞礦化能力之測試，則固定濃度為1與4μM，分別比較礦化達9、11、13天的結果。如圖八a顯示，在第9天，化合物5與7(1μM)都能明顯地誘導細胞礦化。在第11
天，化合物5、6、7(1μM)均有優異誘導細胞礦化的能力，化合物7尤其顯著(圖八b)。在第13天，如圖八c顯示，各化合物均有誘導細胞礦化的能力。而辛伐他汀會造成細胞死亡，無法誘導細胞礦化，1μM的辛伐他汀則具有優異的誘導能力，相較之下，辛伐他汀酸(化合物4)則需在濃度4μM條件下才能有效誘導礦化。我們推測該差異是因為兩化合物進入細胞能力不同所導致。其中，水溶性優於辛伐他汀的化合物7也在濃度4μM條件下呈現明顯誘導細胞礦化能力，且相當於辛伐他汀(1μM)和辛伐他汀酸(4μM)。
Fleming團隊指出斑馬魚的骨骼的基因類型、生理特徵與生長模式均相似於人類，且相似度都高於老鼠，適合做為造骨藥物之篩選平台。本發明也以斑馬魚為測試骨生成之動物模型，評估了衍生化合物1-F、2-F、7與辛伐他汀的促進造骨能力，更分析化合物2-F於斑馬魚活體的骨靶向能力。(圖九、十)
以calcein為正向控制組(其為生物體活體標本之礦物質的染色選擇)。斑馬魚在餵食calcein後，可經由螢光顯微鏡的觀察在骨骼上的螢光呈色(圖九a的斑馬魚側面與正面觀察)；如圖九b顯示，斑馬魚餵食化合物2-F後，骨骼上也有螢光呈色，證明化合物2-F可以標靶至骨骼。
投與化合物1-F、2-F與辛伐他汀，測試化合物對於成長中斑馬魚的骨頭生成影響。結果發現，化合物1-F可促進骨頭生長，並相較於未投藥組別(control)增生了50%，辛伐他汀組和不含辛伐他汀的化合物2-F組都無法促進骨頭生長；如圖九c所示比較化合物1-F和2-F，其結
構差異為有或無3,5-二羥基戊酯衍生物基團，因此推論化合物1-F促進骨頭生長的來源應為3,5-二羥基戊酯衍生物基團。再者，Fleming也曾報導辛伐他汀對於斑馬魚骨頭無法呈現任何生長效益，或許呼應了辛伐他汀對人體骨骼影響不一之說。本發明也再度觀察到相同現象，同時，證明修飾有骨靶向胜肽的化合物1-F不僅能成功地靶向至骨頭，對於人類骨頭生長之促進應極具潛力。
由前述實驗中選出整體表現最優異的非寡肽衍生物7，在斑馬魚骨質提升研究中，被證實不論以0.1與1μM濃度處理，均可促進斑馬魚之骨頭生長，較未投藥組別增加範圍在30~50%之間；如圖十所示顯然地，雖未具有靶向載體仍可促進骨質增生，顯然3,5-二羥基戊酸的醯胺類似物確實可以達到造骨之功效。
結果表明，以聚天冬氨酸肽修飾的3,5-二羥基戊酸醯胺類似物，可增強骨質的選擇性和骨質生成能力，並具有減輕毒性的效果。此類衍生物改善他汀類藥物的骨質增生能力，此外化合物1-F和7對於斑馬魚的骨骼具有具體的骨質增加作用，表明了3,5-二羥基戊酸醯胺類似物對於人類骨質增加之潛力。3,5-二羥基戊酸的類似物可成為新穎的骨質同化製劑，用於治療人類骨質低下疾病。相較於辛伐他汀抑制HMG-CoA還原酶作用，化合物1-F則以強化3,5-二羥基戊酸的類似物影響骨質途徑並非經由甲羥戊酸(MVA)途徑。本研究係首次以化學結構需求論及，HMG-CoA還原酶抑制作用不是骨形成的必要條件。
實驗方法(Materials and methods)
細胞存活率性測定(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)方式分析細胞毒性。96孔盤中，人類脂肪幹細胞(hADSC)以每孔6x103為初始培養密度，培養在k培養液(Keratinocyte-SFM,GIBCO-Invitrogen Corporation)；細胞滿盤後，含有化合物1-F的k培養液當作實驗組，未含有化合物1-F的為空白試驗組，以此在37℃下培養3天；加入MTS試劑培養3小時，再移除k培養液且以磷酸鹽緩衝液(phosphate buffered saline,PBS)清洗，並加入100μL二甲基亞碸(dimethyl sulfoxide,DMSO)至孔盤中，幫助甲臘(formazan)溶解，吸取出含有甲臘之二甲基亞碸溶液，以波長490nm偵測吸收值，數值大小得以判斷細胞的存活。
化合物4~11以MTT方式分析細胞毒性。D1細胞以每孔5 x 103為初始培養密度，培養在骨培養液。該骨培養液以含有10%胎牛血清(Fetal bovine serum,FBS)、100U/mL盤尼西林(penicillin)、100μg/mL鏈黴素(streptomycin)、100mg/mL抗壞血酸(ascorbic acid)、1%非必需氨基酸(non-essential amino acids,NEAA)、1.5g碳酸氫鈉(sodium bicarbonate)之DMEM培養液基。細胞滿盤後，含有化合物4~11的骨培養液當作實驗組，未含有化合物4~11的為空白試驗組，以此在37℃下培養3天；加入MTT試劑培養3小時，再移除骨培養液且以PBS緩衝液清洗，並加入100μL DMSO至孔盤中，幫助甲臘溶解，吸取出含有甲臘之二甲基亞碸溶液，以波長595nm
偵測吸收值，數值大小得以判斷細胞的存活。
3-羥基-3-甲基戊二醯-輔酶A還原酶抑制作用(HMG-CoA reductase inhibition)：配製含有100μM 3-羥基-3-甲基戊二醯-輔酶A還原酶、330μM原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、2%二甲基亞碸(DMSO)、BSA(1mg/mL)之0.1M磷酸緩衝液，在放入不同濃度的化合物1與4~11後，混合5分鐘，再加入HMG-CoA還原酶(最終濃度為17.4nM)；之後，以340nm偵測其吸收值，再用軟體Sigma 10以nonlinear least-squares分析IC50，以此判斷化合物是否抑制HMG-CoA還原酶的作用。
D1細胞的成骨誘導培養(Procedures for culture and osteoinduction of D1 cells)：經由美國(American Type Culture Collection,ATCC)購買的D1細胞，將D1細胞以400μL骨培養液(BM prepared with DMEM,10% FBS,100U/mL penicillin,100μg/mL streptomycin,100mg/mL ascorbic acid,1% NEAA,1.5g sodium bicarbonate)培養在48孔盤，初始培養之細胞密度於每孔為3x104；待細胞滿盤後，置換含有化合物1的骨培養液，對空白試驗組為沒有添加化合物1的培養液，培養3天後，再置換誘導成骨細胞礦化培養液。該成骨細胞礦化培養液包括10-2M β-甘油磷酸(β-glycerophosphate)、10-7M dexamethasone，每2天更換一次誘導成骨細胞礦化培養液；在設定培養天數下，將孔盤中的培養液移除且以PBS緩衝液清洗，再以10%福馬林(formalin)固定細胞，時間為30分鐘；之後，移除福馬林且以水清洗細胞，直至無福馬林味道，並靜置和乾燥12小時，再以200μL之10%醋酸水溶液混合30
分鐘，取其上清液且測定415nm的吸收值，此讀值之空白與試驗組的比較為誘導細胞礦化的能力差異。
化合物4~11的誘導細胞礦化的能力則如前所述方法進行評估，但是誘導成骨細胞礦化培養液內不添加dexamethasone。
化合物的骨標靶作用(Bone Targeting of test compounds)：以AB strain的斑馬魚仔魚為測試對象，在28℃下以Hank緩衝液(13.7mM NaCl,540μM KCl,25μM Na2HPO4,44μM KH2PO4,300μM CaCl2,100μM MgSO4,420μM NaHCO3,pH 7.4)培養；2dpf的仔魚被培養在含3.2mM測試化合物的24孔盤中，5天後，以3-胺基苯甲酸乙酯甲基磺酸鹽(tricaine-methanesulfonate)進行犧牲仔魚，再將仔魚以3%羥丙甲纖維素(methyl-cellulose)水溶液固定於載玻片上，利用Leica DM-6000 CS螢光顯微鏡(Leica Instruments Inc.,Wetzlar,Germany)進行影像拍攝，快門設定為60秒。
化合物誘發的成骨作用(Bone formation induced by test compounds)：孵化2天的斑馬魚仔魚被培養在24孔盤，並投予欲測試的化合物，經過5天後，孵化7天的斑馬魚仔魚被移除24孔盤至6公分的圓盤中，以緩衝液清洗仔魚表面；將仔魚放入含有0.2% calcein水溶液中，10分鐘後，取出仔魚並清洗仔魚表面，再將仔魚放入水中10分鐘，讓未染於骨頭的calcein擴散出仔魚體內；隨後，以3-胺基苯甲酸乙酯甲基磺酸鹽(tricaine-methane-sulfonate)進行犧牲仔魚，再將仔魚以3%羥丙甲纖維素(methyl-cellulose)水溶液固定於載玻片上，利用Leica Z16 APO顯
微鏡進行影像拍攝，快門設定為200ms，圖像以NIH Image J的方式計算螢光量(NIH open software with Macbiophotonics plugins)，計算新生成的骨頭量以相對於空白試驗組的百分比呈現。
統計分析(Statistical analysis)：實驗結果，皆以平均值加減標準誤(Mean±SEM)表示。統計間的差異，在非配對及配對樣本中分別採用非相依性的Student’s t-test。當多個治療組與對照組相比較，採用單因子變異數分析(one way ANOVA)，或雙因子重複測量變異數分析(two way repeated measures ANOVA)。當變異數分析(Analysis of variance，ANOVA)呈現統計學差異時，採用Dunnett's或Student-Newman-Keuls test。P值小於0.05，表示實驗值具有統計學上顯著性差異。資料和圖面的分析，在IBM電腦運用SigmaPlot軟體(版本8.0，Chicago,IL,U.S.A.)和SigmaStat(版本2.03，Chicago,IL,U.S.A.)。
本發明係以下面的實施例予以示範闡明，但本發明不受下述實施例所限制。本發明所用之藥物、生物材料皆市售易於取得，下列僅為示例可取得之管道。
實施例1 化合物1-F之製備：使用芴甲氧羰基(Fmoc)的保護策略進行固相胜肽合成方法，合成胜肽。
一般來說，先秤取芴甲氧羰基-甘氨酸預載於王樹脂(0.79mmol/g)於反應容器中，再添加5毫升二甲基甲醯胺(Dimethylformamide,DMF)，浸泡1小時後再進行後續步驟。配置20%的呱啶於二甲基甲醯胺中，其為去芴甲氧羰基之保護基的試劑，以下均以DEP為簡稱；待移除原先5毫升二甲基甲醯胺，即加入DEP進行芴甲氧羰基保
護基的去保護，經過10分鐘反應後，芴甲氧羰基保護基順利被移除；配製兩倍過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)於反應瓶中，再配製0.4M N-甲基嗎啉(N-methyl morpholine)於二甲基甲醯胺中，其為固相胜肽合成的活化試劑，以下均以ACT為簡稱，ACT也同被置入反應瓶中，反應的時間為所設定之；待結束後，將已配製好的終止試劑，其為100μL乙酸酐(Ac2O)於2mL二甲基甲醯胺中，反應30分鐘即可完成。進而，配製移除試劑，其組成為95%的三氟乙酸(Trifluoroacetic acid,TFA)水溶液，以下簡稱CLE，在完成所有的反應條件後，取出所有樹脂且與CLE反應90分鐘，再移除CLE後可獲得胜肽出產物。反應過程中，以含有茚三酮(Ninhydrin)之凱薩試劑進行監測。
配製凱薩試劑以便監測反應的進行，其組成為0.28M茚三酮於乙醇溶液、42.37M苯酚於乙醇溶液和吡啶。反應過程中，取些許樹脂以凱薩試劑檢測，樹脂上之胜肽如有胺基會呈現藍色，稱之為正向結果(positive result)，反之，樹脂上之胜肽沒有胺基會呈現微淡黃色。取移除芴甲氧羰基後的0.251g(0.2mmol)樹脂與N-芴甲氧羰基-N'-[1-(4,4-二甲基-2,6-二氧代環己基亞甲基)-3-甲基丁基]-L-賴氨酸(N-α-Fmoc-N-ε-1-(4,4-dimethyl-2,6-dioxo-cyclohex-1-ylidene)-3-methylbutyl-L-lysine,Fmoc-Lys( iv Dde)-OH)反應，4小時後反應順利結束，再以ACT終止反應；經DEP移除芴甲氧羰基後，0.162g(0.4mmol)的辛伐他汀搭配10%二異丙基乙基胺(diisopropyl-
ethylamine)之二甲基甲醯胺溶液進行反應，在200W的微波照射下，溫度控制在105℃，經過100分鐘後可完成反應，再以ACT終止反應，獲得化合物12。隨後使用4%聯胺(hydrazine)之二甲基甲醯胺溶液移除ivDde保護基，經過20分鐘後，ivDde保護基可順利被移除，再依序合成六個天門冬胺酸，其方法如之前所介紹的固相胜肽合成方法，反應時間分別為30、45、60、80、80和90分鐘，獲得化合物13。同樣地，賴氨酸也被合成上序列，反應時間為4小時，獲得化合物14；然後，移除芴甲氧羰基保護基，合成上聚乙二醇，反應時間為2小時；再者，移除ivDde保護基，合成上氟硫氰酸螢光素(Fluorescein isothiocyanate,FITC)，反應時間為1小時，再經CLE步驟可得化合物1-F。
實施例2 化合物1之製備：比照化合物1-F之實施例步驟，製備到化合物14；再以2小時合成上聚乙二醇，之後，以30分鐘修飾上乙烯基，經CLE步驟後可得化合物1。
實施例3 化合物2-F之製備：取移除芴甲氧羰基後的0.251g(0.2mmol)樹脂依序合成六個天門冬胺酸，反應時間分別為30、45、60、80、80和90分鐘，獲得化合物16。賴氨酸也被合成上序列，反應時間為4小時；隨後，再分別修飾上聚乙二醇與氟硫氰酸螢光素，反應時間依序為2與1小時，再經CLE步驟可得化合物2-F。
實施例4 化合物1之純化：配製沖提液為甲醇的水溶液(CH3OH：H2O=7：3)，且含有0.1%三氟乙酸，將初產物溶於1mL沖提液中，再注射進入中壓液相層析
系統，其中管柱內容物為C18，經不同時間點下收集，經薄層層析鑑定，收集Rf為0.4(CH3OH：H2O=7：3)的單一產物，可獲得化合物1，產率為25%。高效能液相層析分析中，管柱內容物也為C18，沖提液為0.1%三氟乙酸的甲醇溶液，流速為每分鐘0.2mL，紫外光偵測波長為220nm，得化合物1的滯留時間為7分鐘，純度為95%。
1H-NMR(400MHz,D2O)：δ 5.32(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.
實施例5 化合物1-F之純化：沖提液為甲醇，將初產物溶於1mL沖提液中，再注射進入LH20管柱，經不同時間點下收集，經薄層層析鑑定，收集Rf為0.1(CH3OH：H2O=1：1)的單一產物，可獲得化合物1-F，產率為24%。高效能液相層析分析中，管柱內容物為C18，沖提液為0.1%三氟乙酸的甲醇溶液，流速為每分鐘0.4mL，紫外光偵測波長為220和496nm，得化合物1-F的滯留時間為8.2分鐘，純度為95%。
1H-NMR(400MHz,acetone-d6)：δ 8.50(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.for C108H154N12O45S：2369.00.
實施例6 化合物2-F之純化：沖提液為水，將初產物溶於1mL沖提液中，再注射進入LH20管柱，經不同時間點下收集，經薄層層析鑑定，收集Rf為0.6(CH3CN：H2O=1：1)的單一產物，可獲得化合物2-F，產率為26%。
高效能液相層析分析中，管柱內容物為C18，沖提液為0.1%三氟乙酸的甲醇溶液，流速為每分鐘0.4mL，紫外光偵測波長為220和496nm，得化合物2-F的滯留時間為6.4分鐘，純度為95%。
1H-NMR(400MHz,D2O)：δ 7.63(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.
實施例7 化合物3之製備：辛伐他汀(0.050g,0.1mmole)溶解在10mL的無水四氫呋喃溶液中，再加入0.1mL異丙基格林那試劑(isopropyl Grignard reagent)，濃度也為0.1mmole，反應64小時後，經減壓濃縮移除溶劑後，得無色油狀物的初產物；初產物以二氯甲烷(CH2Cl2)和飽和食鹽水進行萃取，重複操作3次，經移除溶劑後，可得0.055g的白色固體，即為化合物3，產率為36%。
實施例8 化合物4之製備：辛伐他汀(0.052g,0.1mmole)溶解在10mL的乙醇中，再加入1mL氫氧化鈉(NaOH)0.1N水溶液，在室溫下反應10分鐘可結束反應；將乙醇移除後加入0.1N鹽酸水溶液，直至pH值為
6，再進行冷凍乾燥而獲得白色固體；取丙酮加入白色固體中，使得氯化鈉以固體方式析出，取出上清液且移除溶劑，最後，可以獲得0.042g的白色固體，產率為80%。
1H NMR(400MHz,CDCl3)：δ 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)+.
實施例9 化合物5之製備：辛伐他汀(0.102g,0.2mmole)與乙醇胺(0.025g,0.2mmole)溶解在5mL的二氯甲烷中，並加入N-甲基嗎啉(0.2mL,1.9mmole)，室溫下反應4小時，反應可順利結束；經減壓濃縮移除溶劑後，可得黃色油狀物的初產物。初產物以些許二氯甲烷溶解，放入分液漏斗中，且補充二氯甲烷，二氯甲烷的總體積為30mL，再加入30mL的飽和食鹽水，進行萃取而留下二氯甲烷溶液，此後，再操作2次萃取，總次數為3次；最後，利用無水硫酸鈉乾燥溶液中的水，再移除硫酸鈉固體和溶劑，可得0.091g的白色固體，即為化合物5，產率為80%。
1H NMR(400MHz,CDCl3)：δ 7.16(t,J=6Hz,1H),5.94(d,J=9Hz,1H),5.74(q,J=4 and 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)：δ 178.4,172.7,133.0,
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.
實施例10 化合物6之製備：比照化合物5的製備過程，將乙醇胺改為丙醇胺(0.018g,0.2mmole)，反應時間同為4小時，可得0.101g的白色固體，產率為86%。
1H-NMR(400MHz,CDCl3)：δ 6.95(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)：δ 178.4,172.8,133.0,131.5,129.5,128.2,72.0,69.3,68.2,59.4,43.4,43.0,42.5,37.7,36.3,36.1,34.7,33.0,32.9,31.9,30.4,27.2,24.8,24.1,23.1,13.9,9.3.
Mass(ESI,m/z)：516(M+Na)+.HRMS cald.for C28H47NO6Na：516.3300；found：516.3297.
實施例11 化合物7之製備：比照化合物5的製備過程，將乙醇胺改為聚乙二醇胺(0.025g,0.2mmole)，反應時間為2小時，可得0.113g的白色固體，產率為90%。
1H-NMR(400MHz,CDCl3)：δ 7.14(br,1H),5.95(d,J=10Hz,1H),5.75(dd,J=6 and 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)：δ 178.3,172.2,133.0,131.5,129.4,128.2,72.2,72.0,69.5,69.4,68.2,61.4,43.3,42.9,42.5,39.1,37.6,36.2,34.7,33.0,30.4,27.2,24.7,24.6,24.2,23.0,13.8,9.3.
Mass(ESI,m/z)：546(M+Na)+.HRMS cald.for C29H49NO7Na：546.3407；found：546.3404.
實施例12 化合物8之製備：辛伐他汀(0.051g,0.1mmole)溶解在4mL的乙醇中，再加入聯胺(60μL,5.0mmole)，在室溫下反應2天，則可將溶液移除溶劑而獲得黃色油狀物的初產物；將初產物以二氯甲烷和飽和食鹽水進行萃取，在移除溶劑後可得0.038g的白色固體，產率為70%。
1H NMR(400MHz,CDCl3)：δ 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)：δ 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.
實施例13 化合物9之製備：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-環氧己烷中，室溫下反應7天，則可收起反應
且移除溶劑，可得黃色油狀物的初產物；將初產物以正向矽膠管柱分離，在不同時間點下收集，經薄層層析鑑定，收集Rf為0.25(CH2Cl2：CH3OH=10：0.2)的單一產物，可獲得化合物9，產率為35%。
1H NMR(400MHz,CDCl3)：δ 8.51(d,J=4Hz,1H),7.68(td,J=8 and 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=2 and 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)：δ 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.
實施例14 化合物10之製備：辛伐他汀(0.051g,0.1mmole)和丙基胺(18μL,0.3mmole)溶解在12mL的四氫呋喃(Tetrahydrofuran,THF)中，室溫下反應7天，則可收起反應且移除溶劑，可得黃色油狀物的初產物；將初產物以正向矽膠管柱分離，在不同時間點下收集，經薄層層析鑑定，收集Rf為0.25(CH2Cl2：CH3OH=8：0.2)的單一產物，可獲得化合物10，產率為48%。
1H NMR(400MHz,CDCl3)：δ 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=5 and 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)：δ 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.
實施例15 化合物11之製備：辛伐他汀(0.051g,0.1mmole)和丙基胺(18μL,0.3mmole)溶解在12mL的四氫呋喃中，室溫下反應7天，則可收起反應且移除溶劑，可得黃色油狀物的初產物；將初產物以正向矽膠管柱分離，在不同時間點下收集，經薄層層析鑑定，收集Rf為0.3(CH2Cl2：CH3OH=10：0.2)的單一產物，可獲得化合物11，產率為60%。
1H NMR(400MHz,CDCl3)：δ 6.23(t,J=3Hz,1H),5.97(d,J=10Hz,1H),5.76(dd,J=4 and 6Hz,1H),5.48(br,1H),5.40(qui,J=2 and 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)：δ 178.3,171.9,133.0,131.5,129.5,128.2,72.3,69.6,68.1,43.0,42.3,41.0,37.8,35.9,34.6,33.1,32.9,30.4,27.2,24.8,24.6,24.0 23.1,22.7,13.9,11.3,9.3.
Mass(ESI,m/z)：500(M+Na)+.HRMS cald.for C28H47NO5Na：500.3346；found：500.3348.
本發明實屬難能的創新發明，深具產業價值，援依法提出申請。此外，本發明可以由本領域技術人員做任何修改，但不脫離如所附申請專利範圍所要保護的範圍。
其他實施例
實施例1. 一種改善生物個體內骨質低下所介導病症或疾病的組成物，其特徵係包括結構式I所示3,5-二羥基戊酸(3,5-dihydroxypentanoic acid)衍生物。
實施例2. 一種改善生物個體內骨質低下所介導病症或疾病的組成物，其特徵係包括結構式II所示化合物，其中Rt選自下列取代基其中之一：(C1-C10)烷基、羥基、取代之(C1-C10)烷胺基、-N-(C1-C10)烷基-OH、-N-(C1-C10)烷基-胺基、-NH-胺基；-N-(C1-C10)不飽和烷基、含氧原子之5元芳香環、含氧原子之6元芳香環、含氮原子之5元芳香環、含氮原子之6元芳香環。
Claims (9)
- 一種組合物之用途，其係用於製備治療哺乳動物骨質低下之病症之藥物，該組合物包括結構式I所示3,5-二羥基戊酸(3,5-dihydroxypentanoic acid)衍生物：
- 如申請專利範圍第1項所述組合物之用途，其中Ra為(a2)取代之(C1-C10)烷基，該取代基係選自下列取代基其中之一：氫基、(C1-C10)烷基、(C1-C10)烷氧基、(C1-C5)烷氧羰基(alkoxycarbonyl)、(C1-C5)醯氧基(acyloxyl)、(C3-C8)環烷基(cycloalkyl)、苯基、取代之苯基。
- 如申請專利範圍第1項所述組合物之用途，其中Ra為(a4) 取代之(C3-C8)環烷基、(a6)取代之苯胺基、(a8)取代之苯基(C1-C10)烷胺基之一，該取代基係各自選自下列取代基其中之一：(C1-C5)烷基、氟原子、氯原子、溴原子、碘原子、含氧原子之5元芳香環、含氧原子之6元芳香環、含氮原子之5元芳香環、含氮原子之6元芳香環。
- 如申請專利範圍第1項所述組合物之用途，其中Ra為(a12)酸性寡胜肽，其係選自下列取代基其中之一：-Lys-(Asp)m-Lys-PEG、D/L-Aspm、D/L-Glun，而m與n均為1至10之正整數。
- 如申請專利範圍第1項所述組合物之用途，其中Ra為(a13)骨標靶胜肽，其係選自下列取代基其中之一：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。
- 如申請專利範圍第1項所述組合物之用途，其中組合物係選自醫藥組合物與/或食品組合物其中之一。
- 一種組合物之用途，其係用於製備改善生物個體內骨質低下所介導病症或疾病之藥物，該組合物包含結構式II所示化合物，其中Rt選自下列取代基其中之一：(C1-C10)烷基、羥基、(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選自下列取代基其中之一：(C1-C10)不飽和烷基、羥基、胺基、含氧原子之5元芳香環、含氧原子之6元芳香環、含氮原子之5元芳香環、含氮原子之6元芳香環
- 一種化合物，其係如結構式I所示3,5-二羥基戊酸(3,5-dihydroxypentanoic acid)衍生物，
- 一種化合物，其係如結構式II所示，其中Rt選自下列取代基其中之一：(C1-C10)烷基、羥基、(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；
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