TWI716733B - 環胜肽、包含其之醫藥或化妝品組成物及其製備方法 - Google Patents
環胜肽、包含其之醫藥或化妝品組成物及其製備方法 Download PDFInfo
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- TWI716733B TWI716733B TW107131898A TW107131898A TWI716733B TW I716733 B TWI716733 B TW I716733B TW 107131898 A TW107131898 A TW 107131898A TW 107131898 A TW107131898 A TW 107131898A TW I716733 B TWI716733 B TW I716733B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- A—HUMAN NECESSITIES
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Abstract
Description
本發明係關於一種環胜肽、包含其之醫藥或化妝品組成物及其製備方法。更具體地,本發明係關於一種局部的或化妝品的皮膚護理之環胜肽、包含其之醫藥或化妝品組成物及其製備方法。
已經發現胜肽可廣泛應用於各種領域,例如局部或化妝品皮膚護理。在已知的胜肽中,發現具有精胺酸(R)-甘胺酸(G)-天門冬胺酸(D)模體(arginine (R)-glycine(G)-aspartate(D)motif)的胜肽作為細胞辨識中常見的元件。
已知含有RGD模體的胜肽可以結合於整合素(intergrin)RGD結合位,且可用於組織工程中塗佈合成的支架以通過模擬體內條件來增加細胞的附著。
在用於製備含有RGD模體的胜肽的常規方法中,必須使用耦合劑來催化胜肽的合成。然而,耦合劑的使用量並不小,且耦合劑本身的成本很高。因此,胜肽的生產成本不低,且所獲得的胜肽並非全部可用。
因此,期望能提供一種含有RGD模體的新胜肽,以及製備該胜肽的新方法,因此所獲得的胜肽可廣泛應用於各種領域。
本發明之目的在於提供一種新的環胜肽及包含其之醫藥或化妝品組成物。
其中,
R1為;
X為O、S、或N-R2,其中,R2為H、C1-6之烷基、(CH2CH2O)nH、-C(=O)-C1-10之烷基、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3;以及G’為H或OH。
本發明之醫藥或化妝品組成物包含:一賦形劑或金屬(II)硫酸鹽或氧金屬(II)硫酸鹽;以及上述本發明之環胜肽。在本發明之環胜肽及醫藥或化妝品組成物中,X優選為O、S或N-R2,其中,R2為H、C1-6之烷基、-C(=O)-C4-10之烷基、(CH2CH2O)nH、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3。在本發明之一例示性實施例中,X為O。
本發明之環胜肽包含精胺酸(R)、甘胺酸(G)及天門冬胺酸(D)之胺基酸,其可結合於整合素的RGD結合位。當本發明之環胜肽結合於皮膚的整合素RGD結合位時,可以恢復真皮層(dermis)和表皮層(epidermis)之間的傳遞過程,且可刺激基底膜(basement membrane)的重要蛋白質的產生。因此,可以達到改善疤痕、傷口、發炎過程、老化和/或皺紋形成之目的。因此,本發明之環胜肽及醫藥或化妝品組成物可以應用於局部或化妝品皮膚護理組成物。
在本發明之醫藥或化妝品組成物之一態樣中,用於本發明之合適的賦形劑可以是任何用於本領域之賦形劑,例如黏合劑、乳化劑、防沾黏劑(anti-adhesive agent)、分散劑、和潤滑劑。
在本發明之醫藥或化妝品組成物之另一態樣中,該金屬(II)硫酸鹽或氧金屬(II)硫酸鹽可以是Cu2+硫酸鹽或V(O)2+硫酸鹽。
在本發明之醫藥或化妝品組成物之又一態樣中,可以結合使用該賦形劑和該金屬(II)硫酸鹽和該氧金屬(II)硫酸鹽。
除了上述本發明之環胜肽和醫藥或化妝品組成物外,本發明之另一目的為提供一種用於製備本發明之環胜肽之新的生物相容性催化方法。
本發明之方法包含下列(A)至(D)之步驟。
在步驟(A)中,由商業來源或由我們的催化方法製備,提供下列式(II-1)或式(II’-1)及式(II-2)所表示之化合物。
Rc-NH-R1’-COOH (II-2)在此,Ra和Rb各自獨立為烷基、環烷基、芳基、或雜芳基;Rc和Rd各自為一保護基團;R1’為,其中,A1和A2各自獨立為H、C1-6之烷基或酯基,或A1、A2和與A1及A2連接的碳原子一起形成C5-8之環烷基;X為O、S、或N-R2,其中,R2為H、C1-6之烷基、(CH2CH2O)nH、-C(=O)-C1-10之烷基、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3;以及G為H或O-t-Bu。
在步驟(C)中,進行式(II-3)或式(II’-3)分別與由下列式(II-4)或式(II’-4)所表示之化合物之間的反應,以分別得到由下列式(II-5)或式(II’-5)所表示之化合物。
在步驟(D)中,將式(II-5)或式(II’-5)與一式(III)之催化劑進行環化反應,以分別得到一由下列式(I)或式(I’)所表示之化合物。
M(O)mL1 yL2 z (III)在此,M為一金屬,選自由IVB、VB、VIB、和錒系族所組成之群組;L1和L2分別為一配位基;m和y分別為大於或等於1之整數;以及z為大於或等於0之整數。
在本發明之方法中,Rc和Rd可為茀基甲氧基羰基(Fluorenylmethoxycarbonyl,Fmoc);以及Re可為4-甲氧基-2,3,6,-三甲基苯磺醯基(4-methoxy-2,3,6-trimethylbenzenesulphonyl,Mtr)。然而,本發明並不局限於此。
在本發明之方法中,進行式(II-1)或式(II’-1)與式(II-2)之化合物之間的反應,或者進行式(II-3)與式(II-4)或式(II’-3)與式(II’-4)之化合物之間的反應,可以與式(III)之催化劑或耦合劑一起進行。
在本發明之方法中,當以式(III)之催化劑進行步驟(B)至(D)之反應時,步驟(B)至(D)中使用的催化劑可以相同或不相同。
在式(III)之催化劑中,L1為一配位基,其優選為選自由Cl、OTf、OTs、NTf2、鹵素、RC(O)CHC(O)R、OAc、OC(O)CF3、OEt、O-iPr和丁基所組成之群組,其中,R為烷基(優選為C1-6之烷基;更優選為C1-3之烷基)。此外,L2
也為一配位基,其優選為選自由Cl、H2O、CH3OH、EtOH、THF、CH3CN和
所組成之群組。
此外,在式(III)之催化劑中,M可以是一金屬,選自由IVB、VB、VIB、和錒系族所組成之群組。在一態樣中,M為IVB族過渡元素,m為1且y為2;其中,M可為Ti、Zr、或Hf。在另一態樣中,M為VB族過渡元素,m為1且y為2或3;其中,M可為V、或Nb。在另一態樣中,M為VIB族過渡元素,m為1且y為4;其中,M為Mo、W、或Cr。在另一態樣中,M為VIB族過渡元素,m為2且y為2;其中,M為Mo、W、或Cr。在又另一態樣中,M選自錒系族,m為2且y為2;其中,M為U。式(III)之催化劑的具體實施例可為MoO2Cl2、V(O)OCl2、V(O)(OAc)2、V(O)(O2CCF3)2、Ti(O)(acac)2、Zr(O)Cl2、Hf(O)Cl2、Nb(O)Cl2、MoO2(acac)2、V(O)(OTs)2、V(O)(NTf2)2、或VO(OTf)2,但本發明並不局限於此。
再者,在式(III)之催化劑中,z可為大於或等於0之整數,且優選為z為0。
在用於製備該環胜肽的常規方法中,使用3-5當量的耦合劑,例如羥基苯並三唑(hydroxybenzotriazole,HOBt)、1-羥基-7-氮雜苯並三唑(1-hydroxy-7-azabenzotriazole,HOAt)、2-(1H-苯並三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸鹽(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,HBTU)、和苯並三唑-1-基-氧基三吡咯烷基磷六氟磷酸鹽(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,PyBOP)。由於這些耦合劑很貴,因此所獲得的環胜肽不容易商業化並應用於各種領域。
在製備本發明之環胜肽之方法中,式(III)之催化劑為水溶性的,且用於促進反應進行。因此,在本發明之製備方法中不須使用昂貴的耦合劑,因此,可以以更便宜的方法生產環胜肽,且所獲得的環胜肽可應用於各種領域。
在本發明中,除非另有說明,化合物中存在的烷基、環烷基、芳基、及雜芳基包含取代和未取代基團兩者。烷基、環烷基、芳基、及雜芳基上可能的取代基包含但不局限於烷基、烯基、鹵素、烷氧基、酮、醇、硫醚、胺甲酸酯(carbamate)、胺基、雜環基、或芳基;但烷基不能被烷基取代。
在本發明中,術語「鹵素」包含F、Cl、Br、和I,且優選為Cl或I。術語「烷基」是指直鏈或支鏈之烷基;優選為包含直鏈和支鏈的C1-20之烷基;更優選為包含直鏈和支鏈的C1-12之烷基;最優選為包含直鏈和支鏈的C1-6之烷基。烷基的具體例子包含但不局限於甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、叔丁基、戊基、新戊基、或己基。術語「烷氧基」是指本發明中定義的烷基與氧原子耦合的基團(moiety);優選為包含直鏈和支鏈的C1-20之烷氧基;更優選為包含直鏈和支鏈的C1-12之烷氧基;最優選為包含直鏈和支鏈的C1-6之烷氧基。烷氧基的具體例子包含但不局限於甲氧基、乙氧基、正丙氧基、
異丙氧基、正丁氧基、異丁氧基、第二丁氧基、叔丁氧基、戊氧基、新戊氧基、或己氧基。術語「烯基」是指包含至少一個雙鍵的直鏈或支鏈的碳氫基團;優選為包含含有至少一個雙鍵的直鏈和支鏈的C2-20之碳氫基團;更優選為包含含有至少一個雙鍵的直鏈和支鏈的C2-12之碳氫基團;最優選為包含含有至少一個雙鍵的直鏈和支鏈的C2-6之碳氫基團。烯基的具體例子包含但不局限於乙烯基、丙烯基、烯丙基、或1,4-丁二烯。術語「芳基」是指單價6-碳單環、10-碳雙環、或14-碳三環之芳香環系統。芳基的具體例子包含但不局限於苯基、萘基、芘基(pyrenyl)、蒽基(anthracenyl)、或菲基(phenanthryl);且該芳基優選為苯基。術語「雜環基」是指具有至少一雜原子之5-8員單環、8-12員雙環、或11-14員三環之雜芳基或雜環烷基,其中該雜原子選自由O、S、和N所組成之群組。雜環基的具體例子包含但不局限於吡啶基(pyridyl)、嘧啶基(pyrimidinyl)、呋喃基(furyl)、噻唑基(thiazolyl)、咪唑基(imidazolyl)、或噻吩基(thienyl)。術語「酯」是指由羧酸衍生的基團(moiety);優選為包含直鏈或支鏈的C1-12之酯;最優選為包含直鏈或支鏈的C1-6之酯。酯的具體例子包含但不局限於甲酸酯、乙酸酯、丙酸酯、丁酸酯、戊酸酯、或己酸酯。
由下列結合附圖的詳細描述中,本發明之其他目的、優點、和新穎特徵將變得更明顯。
已經以例示性的方式描述本發明,且應當理解,所使用的術語是在描述性質並非限制性質。鑒於上述教導,本發明的許多修飾和變化是可能的。
因此,應當理解在所附的權利範圍內,本發明可以以不同於具體描述的方式實施。
本發明之一優選實施例之環胜肽可以由下列方法製備。
在流程I’及II’中,也可以使用耦合劑,且該耦合劑可為例如羥基苯並三唑(HOBt)、1-羥基-7-氮雜苯並三唑(HOAt)、2-(1H-苯並三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸鹽(HBTU)、和苯並三唑-1-基-氧基三吡咯烷基磷六氟磷酸鹽(PyBOP)。
在下文中,本發明提供用於製備本發明之環胜肽的實施例,但本發明並不局限於此。
製備例1:
1H NMR(400MHz,CDCl3):δ=4.42(d,J=11.8Hz,1 H),4.16(d,J=12.0Hz,1 H),3.79(s,3 H),3.56-3.60(m,2 H),2.72-2.74(m,1 H),2.42-2.48(m,1 H),1.99(br.s,2 H),1.70-1.75(m,1 H),1.41-1.54(m,3 H),1.24-1.31(m,1 H),0.84-0.95(m,10 H),0.71(t,J=12.0Hz,1 H)ppm.MS(EI):m/z=286[M+H]+
製備例2:(茀基甲氧基羰基-胺基)-2,2-二甲基-1,3-二噁烷-5-羧酸((Fmoc-amino)-2,2-dimethyl-1,3-dioxane-5-carboxylic acid,Fmoc-ADMDOA)
依照文獻步驟(J.Pept.Sci. 2008,14,1163)製備此化合物Fmoc-2-6。1H NMR(400MHz,CDCl3)δ 7.77-7.30(m,8H,aromatic),5.81(bs,1H,NH),4.42(d,J=7.2Hz,2H,CH2),4.27(t,J=7.2Hz,1H,CH),4.20(d,J=12.0Hz,2H,CH2O),4.14(d,J=12.0Hz,2H,CH2O),3.02(b,1H,COOH),1.51(s,6H,C(CH3)2).
製備例3:5-((苄氧基)羰基)-2,2-二甲基-1,3-二噁烷-5-甲苯磺酸銨(5-((Benzyloxy)carbonyl)-2,2-dimethyl-1,3-dioxan-5-aminium tosylate)
依照文獻步驟(J.Pept.Sci. 2008,14,1163)製備此化合物2-6-OBn-TsOH。1H NMR(400MHz,CDCl3)δ 8.76(b,H3N+),7.72(d,J=6.1Hz,2H,aromatic in TolSO2OH),7.29(bs,5H,Ph),7.07(d,J=8.0Hz,2H,aromatic in TolSO2OH),5.19
(s,2H,CH2Ph),4.24(s,4H,2×CH2O),2.31(s,3H,CH3 in TolSO2OH),1.44(s,3H,CH3),1.40(s,3H,CH3).
製備例4:二胜肽Fmoc-Asp(O t Bu)-D-Phe-OH之合成
在N2氣下於室溫取Fmoc-Asp(O t Bu)-OH(2.06g,5mmol,1.0當量)於1,2-二氯乙烷(DCE,10mL),加入苯甲酸酐(1.14g,5.05mmol,1.01當量)和MoO2Cl2(100mg,0.5mmol,10mol%),並藉由TLC分析監測反應,反應在室溫下攪拌2小時,直到起始胺基酸完全消耗並冷卻至0℃。藉由注射器(syringe)將溶於1,2-二氯乙烷(5mL)的D-苯丙胺酸苯甲基酯(D-phenylalanine benzyl ester,1.275g,5.0mmol,1.0當量)加入上述溶液中,接著在0℃下加入胺鹼(5.0mmol,1.0當量),將反應混合物在室溫下攪拌30分鐘後,蒸發溶劑並將殘餘物以乙酸乙酯(100mL)溶解,以飽和碳酸氫鈉水溶液(30mL)、水(30mL)、食鹽水(30mL)洗,並以硫酸鈉乾燥,待溶劑蒸發後,殘餘物以矽膠急速層析法純化,得到白色固體的Fmoc-Asp(O t Bu)-D-Phe-OBn(2.68g,產率81%)。TLC Rf=0.5(乙酸乙酯/己烷=1/5);1H NMR(400MHz,CDCl3):δ 7.77(d,J=7.6,2H),7.57(q,J=3.6,2H),7.41(t,J=7.6,2H),7.35-7.32(m,4H),7.30-7.27(m,4H),7.17(t,J=6.0,3H),7.02(t,J=6.4,3H),5.83(br,1H),5.13(q,J=12.0,2H),4.87(q,J=7.2,1H),4.58-4.49(m,1H),4.36(d,J=7.2,2H),4.20(t,J=7.2,1H),3.10(dd,J=16.4,5.6,2H),1.43(s,9H);13C NMR(100MHz,CDCl3)δ 170.8,170.0,156.0,143.8,143.6,141.3,135.5,135.0,129.2,128.6,128.5,127.7,127.1,125.1,120.0,81.9,67.3,67.2,53.4,51.1,47.0,37.8,
37.3,28.0;HRMS(ESI),C40H42N2NaO7理論值([M+Na]+):685.2889,實際值:685.2887.
在室溫下取Fmoc-Asp(O t Bu)-D-Phe-OBn(2.0g,3.0mmol,1當量)溶於乙酸乙酯/甲醇(v/v=1/1,150mL),加入10%Pd/C(383mg,10mol%),反應在氫氣(氣球)下攪拌1.5小時,接著以矽藻土過濾,以甲醇(30mL)、乙酸乙酯(30mL)多次清洗矽藻土,並合併濾液以真空濃縮,得到白色固體的二胜肽Fmoc-Asp(O t Bu)-D-Phe-OH(1.699g,99%)。TLC R f =0.23(乙酸乙酯/己烷=2/1)。
1H NMR(300MHz,CDCl3):δ 7.75(d,J=7.5,2H),7.54(d,J=7.2,2H),7.39(t,J=7.5,2H),7.29(d,J=7.2,2H),7.23-7.16(m,5H),7.06(d,J=7.5,1H),6.12(d,J=8.7,1H),3.21(dd,J=9.6,6.3,1H),3.06(dd,J=9.6,6.6,1H),2.72(dd,J=16.8,6.3,1H),2.57(dd,J=16.2,5.7,1H),1.43(s,9H);13C NMR(100MHz,CDCl3)δ 171.4,170.8,170.0,156.0,143.7,143.6,141.2,135.7,129.2,128.5,127.7,127.1,125.1,120.0,81.9,67.3,53.4,52.3,51.0,47.0,37.9,37.4,29.7,28.0;HRMS(ESI),C33H36N2NaO7理論值([M+Na]+):595.2420,實際值:595.2423.
製備例5:二胜肽Fmoc-Arg(Mtr)-Gly-OCH3之合成(藉由EDC-HOBt耦合)
1H NMR(400MHz,CDCl3):δ 7.72(d,J=7.6,2H),7.63-7.54(m,3H),7.25(t,J=7.6,2H),7.24-7.22(m,1H),6.49(br,1H),6.40(br,1H),6.07(d,J=8.01H),4.32(q,J=6.8,3H),4.14(t,J=7.2,1H),4.02(dd,J=17.6,5.2,1H),3.89(dd,J=17.6,5.2,1H),3.78(s,3H),3.66(s,3H),3.34-3.23(m,2H),2.66(s,3H),2.60(s,3H),2.16(s,
3H),2.05(s,3H),1.93(t,J=6.0,1H),1.72-1.60(m,3H),1.27(t,J=6.8,1H);13C NMR(100MHz,CDCl3)172.8,170.6,158.6,156.5,143.8,143.7,141.2,138.5,136.6,134.7,134.1,133.0,129.1,127.7,125.1,124.9,124.3,120.3,120.0,111.7,67.1,60.4,55.4,52.3,47.0,41.0,40.2,31.9,30.0,29.7,25.1,24.0,21.0,18.3;HRMS(ESI),C34H41N5NaO8S理論值([M+Na]+):702.2573,實際值:702.2575.
實施例1
將溶於甲醇(5mL)之2-6-OBn-TsOH(1.23g,2.8mmol)冷卻至0℃,加入碳酸氫鈉(1.5當量)並在室溫下攪拌1小時,將甲醇蒸發並以乙醚(10mL)回溶生成的殘餘物,以硫酸鈉乾燥並過濾。將溶劑移除並在真空下乾燥,以得到2-6-OBn。
取Fmoc-Asp(O t Bu)-D-Phe-OH(1.6g,2.8mmol,1.0eq)溶於1,2-二氯乙烷(DCE,5mL),在氮氣氣氛於室溫下加入2,6-二硝基苯甲酸酐(2,6-dinitrobenzoic anhydride,974mg,2.82mmol,1.01eq)和MoO2Cl2(56mg,0.28mmol,10mol%),並逐漸加熱至40℃,且藉由TLC分析監測反應。反應在40℃下攪拌2小時直到起始二胜肽完全耗盡,接著冷卻至0℃,藉由注射器(syringe)將溶於1,2-二氯乙烷(4mL)之2-6-OBn苯甲基酯(743mg,2.8mmol)加入上述溶液中,接著在0℃下加入胺類(2.8mmol,1.0當量)。將反應混合物在室溫下攪拌10-12小時後,蒸發溶劑並將剩餘的殘餘物以乙酸乙酯回溶,有機層以飽和碳酸氫鈉水溶液(2mL)、水(2mL)、食鹽水(2mL)洗,並以硫酸鈉乾燥,待溶劑蒸發後,剩餘的殘餘物以矽膠急速層析法純化,得到白色固體的
Fmoc-Asp(O t Bu)-D-Phe-ADMDOA-OBn(1.85g,產率:82%)。接著以乙酸乙酯/甲醇(v/v=1/1,80mL)回溶,並在環境溫度下加入10%Pd/C(242mg,10mol%),反應在氫氣(氣球)下攪拌3小時,接著通過矽藻土短塞(short plug)過濾,將矽藻土以甲醇(15mL)、乙酸乙酯(15mL)清洗3次,並合併濾液以真空濃縮,以得到白色固體的二胜肽Fmoc-Asp(O t Bu)-D-Phe-ADMDOA-OH(Fmoc-3-6)(1.62g,98%)。1H NMR(400MHz,CDCl3):δ 12.18(b,1H,COOH),7.85(d,J=7.2,2H),7.73-7.72(m,6H),7.38-7.28(m,5H),7.31-7.14(m,6H),6.86(d,J=16.0,1H),6.42(d,J=5.4,1H),6.08(br,1H),4.80(q,J=7.4,1H),4.46-4.42(m,1H),4.28(d,J=12.0,2H),4.13(d,J=12.0,2H),3.14-3.04(m,2H),2.89-2.69(m,2H),1.44(s,9H,C(CH3)3),1.34(s,6H,CMe2);TLC R f =0.31(EtOAc/Hex,2/1);HRMS(ESI),C39H45N3NaO10理論值([M+Na]+):738.3003,實際值:738.3008.
取H-D-Phe-Asp(O t Bu)-OMe.HCl(1-HCl)(490mg,1.3mmol,1.01當量)溶於甲醇(8mL)並冷卻至0℃,在室溫下加入碳酸氫鈉(1.5當量)並攪拌1小時,蒸發甲醇後將生成的殘餘物以四氫呋喃(15mL)回溶,以硫酸鈉乾燥並過濾,移除溶劑並在真空下乾燥,以獲得D-Phe-Asp(O t Bu)-OMe(1)。
在乾燥的50-mL雙頸圓底瓶中加入溶於無水二氯甲烷(12mL)之MoO2Cl2(50mg,0.25mmol,20mol%),在環境溫度下將Fmoc-2-6(497.1mg,
1.25mmol)加入上述溶液中,接著加入苯甲酸酐(342mg,1.28mmol),並加熱至40℃反應6小時候冷卻至0℃。
在0℃下,將容於二氯甲烷(5mL)之D-Phe-Asp(O t Bu)-OMe(441.8mg,1.26mmol)加入上述溶液中,並將反應混合物逐漸回溫至環境溫度且攪拌2.5小時,之後加入2,6-二甲吡啶(2,6-lutidine,145μL),並將混合物繼續攪拌4.5小時。以水(16mL)終止反應並將有機層分離,水溶液層以二氯甲烷(50mL×2)萃取,合併有機層以無水硫酸鈉乾燥、過濾並濃縮。粗殘餘物藉由矽膠管柱層析法純化(乙酸乙酯/己烷=2/3),以得到Fmoc-保護的三胜肽(Fmoc-3’-6)(695mg,76%)。TLC R f 0.2(乙酸乙酯/己烷=3:7);1H NMR(400MHz,CDCl3)δ 8.15(bs,NH,1H),7.88(d,J=7.2Hz,2H),7.57(d,J=7.2Hz,2H),7.41-7.28(m,4H),7.16-7.13(m,5H),7.10(bs,NH,1H),4.82(d,J=6.6Hz,1H),4.76(d,J=5.8Hz,1H),4.61-4.57(m,2H),4.30(d,J=11.8Hz,2H,CH2O),4.17(t,J=6.4Hz,1H),3.57(s,3H),4.05(d,J=12.0Hz,2H,CH2O),3.33(dd,J=14.0,6.8Hz,1H),3.09(dd,J=14.0,8.0Hz,1H),2.88-2.62(m,2H),1.38(s,9H),1.35(s,3H,CH3),1.31(s,3H,CH3);HRMS(ESI)C40H47N3NaO10理論值(M+Na+):752.3159;實際值:752.3166.
在環境溫度下,取Fmoc-保護的三胜肽(Fmoc-3’-6)(910mg,1.25mmol)溶液,以溶於二氯甲烷(5mL)之20%哌啶處理1小時,藉由與甲醇(5mL)共蒸發後移除哌
啶,粗產物在真空下乾燥,接著藉由矽膠管柱層析法純化,以獲得三胜肽(3’-6)(534.2mg,84%)。TLC R f 0.31(乙酸乙酯/己烷=9:1);1H NMR(400MHz,CDCl3)δ 8.26(d,J=8.0Hz,1H,NH),7.20-7.14(m,5H),7.00(d,J=8.2Hz,1H,NH),4.77-4.74(m,1H),4.60-4.56(m,1H),4.10(d,J=12.0Hz,2H,CH2O),3.90(d,J=12.0Hz,2H,CH2O),3.64(s,3H,OCH3),3.12(dd,J=14.0,6.4Hz,1H),2.96(dd,J=14.0,8.2Hz,1H),2.80(dd,J=16.0,4.0Hz,1H),2.46(dd,J=16.0,4.6Hz,1H),1.35(s,9H,C(CH3)3),1.37(s,3H,CH3),1.35(s,3H,CH3);HRMS(ESI)C25H37N3O8理論值(M+H+):508.2659;實際值:508.2654.
實施例2
在環境溫度下,取Fmoc-Asp(O t Bu)-D-Phe-ADMDOA-OH(Fmoc-3-6)(715.0mg,1mmol,1.0當量)溶於1,2-二氯乙烷(DCE,7mL),加入2,6-二硝基苯甲酸酐(414.3mg,1.01mmol,1.01當量)和VO(OTf)2(55mg,0.15mmol,15mol%),在氮氣氣氛下,將反應混合物加熱至40℃,並藉由TLC分析監測反應。反應在40℃下攪拌4小時直到起始Fmoc-3-6完全耗盡後冷卻至0℃,藉由注射器將溶於1,2-二氯乙烷之NH2-Arg(Mtr)-Gly-OCH3(457.8mg,1.0mmol)溶液加入上述溶液中,接著在0℃下加入胺鹼(1.0mmol,1.0當量),反應混合物在環境溫度下攪拌10-12小時,蒸發反
應溶劑,並將剩餘的殘餘以乙酸乙酯(85mL)回溶,有機層以飽和碳酸氫鈉水溶液(16mL)、水(16mL)、和食鹽水(10mL)洗,並以硫酸鈉乾燥。待溶劑蒸發後,剩餘的殘餘物藉由急速矽膠管柱層析法純化,以提供Fmoc-Asp(O t Bu)-D-Phe-ADMDOA-Arg(Mtr)-Gly-OCH3(Fmoc-5-6)(866.0mg,產率:75%)。TLC R f 0.42(乙酸乙酯);δ 7.77(d,2H,J=7.4Hz),7.55(m,2 H),7.36(t,2 H,J=7.6Hz),7.30-7.18(m,8 H),6.65(br,1 H),6.59(br,1 H),4.77(br,1 H),4.64-4.56(m,1H),4.39(t,1 H,J=6.8Hz),4.35-4.23(m,1H),4.19(d,J=12.0Hz,2H,CH2O),4.15(t,1 H,J=7.2Hz),4.18-4.07(m,3H),3.78(s,3H,OCH3),3.66-3.56(m,1H),3.53(s,3H,CO2CH3),3.43-3.39(m,1H),3.19-3.10(m,2H),3.06-2.94(m,1H),2.64(s,3H),2.50(s,3H),2.26-2.08(m,2H),2.07(s,3H),1.41(s,9 H,C(CH3)3),1.38(s,3H,CH3),1.36(s,3H,CH3);HRMS(ESI),C58H74N8NaO15S理論值([M+Na]+):1177.4892,實際值:1177.4890.
在乾燥的25-mL雙頸圓底瓶中,加入溶於二氯甲烷(5mL/mmol)之催化劑(10-15mol%)和耦合劑(1.5當量),在0℃下以DIEA(4.0當量)攪拌處理5分鐘,在0℃下加入Fmoc-Gly-Arg(Mtr)-OH(4)(748.2mg,1.1mmol)反應20分鐘,接著加入三胜肽(3’-6)(558.0mg,1.1mmol),20分鐘後移除冰浴並在環境溫度下繼續攪拌6天。粗產物在真空下乾燥,並藉由矽膠管柱層析法純化,以獲得Fmoc-保護的五胜肽(Fmoc-5’-6)(890.2mg)(70%;藉由MoO2Cl2/4-硝基苯甲酸酐)。TLC R f 0.66(乙
酸乙酯/甲醇=9.5:0.5);1H NMR(400MHz,CDCl3)δ 7.73(d,J=8.0,1H,NH),7.73(d,J=8.2,2H),7.51(d,J=6.4,1H,NH),7.55(d,J=7.2,2H),7.40(bd,1H,NH),7.33(d,J=8.0,2H),7.34-7.12(m,2H),7.13-7.04(m,6H),6.82(d,J=7.6Hz,1H,NH),6.55(s,1H),6.40(bs,2H),4.85(dd,J=14.2,6.4Hz,1H),4.69(dd,J=14.0,8.4Hz,1H),4.43-4.22(m,3H),4.12(d,J=12.0Hz,2H,CH2O),4.17-4.13(m,1H),3.87-3.86(m,1H),3.76(s,3H,OCH3),3.73-3.71(m,1H),3.63(s,3H,CO2CH3),3.54-3.46(m,1H),3.43-3.36(m,2H),3.20-3.16(m,1H),3.08(dd,J=14.0,9.3Hz,1H),2.71(m,1H),2.66(t,J=8.0Hz,1H,NH),2.64(s,3H,CH3),2.61(s,3H,CH3),2.12(bs,1H,NH),2.08(s,3H,CH3),1.74-1.66(m,2H),1.47-1.45(m,2H),1.38(s,9H,C(CH3)3),1.41(s,3H,CH3),1.39(s,3H,CH3);HRMS(ESI)C58H75N8O15S理論值(M+H+):1155.5073;實際值:1155.5079.
實施例3
在Fmoc-5-6的Fmoc去保護和環化後,獲得以下化合物 t-Boc-6-6-MTr。
在環境溫度下,取Fmoc-保護的五胜肽(Fmoc-5-6)(57.8mg,0.05mmol),以溶於二氯甲烷(3mL)之20%哌啶處理1小時,藉由與甲醇(3mL)共蒸發後移除哌啶,粗產物在真空下乾燥,生成的粗產物藉由在回流的甲苯中與10mol%的V(O)Cl2、Zr(O)Cl2、V(O)(acac)2、或Ti(O)(acac)2處理10小時,以形成分子內的醯胺鍵。將生成的粗混合物冷卻至環境溫度並濃縮,粗殘物( t-Boc-6-6-MTr)以三氟乙酸(7mL)和水(1.5mL)回溶,接著以苯基甲基硫醚(thioanisole,1.5mL)處理。混合物以二異丙醚(7mL)誘導沉澱,並將生成的固體以二異丙醚洗,且在真空下乾燥,以獲得環胜肽(6-6)。該環五胜肽可以進一步藉由HPLC純化(逆相(reverse phase)C-18管柱(梯度:95/5至80/20,水/乙腈),以得到純的6-6(22.3mg,產率:75%)。
t-Boc-6-6-MTr數據:TLC:R f 0.39(乙酸乙酯/甲醇=3/1);1H NMR(400MHz,CDCl3):δ 8.02(s,1H,C=NH),7.84(bs,1H,NH),7.59(bs,1H,NH),7.39-7.19(m,6H),6.99(br,1H),6.62(br,1H,NH),6.30(br,1H,NH),4.80-4.72(m,1H),4.72-4.63(m,1H),4.30-4.25(m,1H),4.24(d,J=11.8,2H,CH2O),4.16(d,J=11.8,2H,CH2O),4.10-4.07(m,2H),3.61-3.56(m,2H),3.54-3.25 3.34(m,2H,CH2-quanidine),3.45(s,3H,OCH3),3.19-3.06(m,1H),3.01-2.82(m,2H),2.70(s,3H,CH3),2.61(s,
3H,CH3),2.14(s,3H,CH3),1.78-1.63(m,2H),1.48-1.33(m,2H),1.50(s,9H,C(CH3)3),1.37(s,3H,CH3),1.34(s,3H,CH3);HRMS(ESI),C42H61N8O12S理論值([M+H]+):901.4130,實際值:901.4133.
同時進行 t-Boc-6-6-MTr的MTR、tert-Boc和縮丙酮(acetonide)去保護後,獲得化合物6-6。
化合物6-6之數據:1H NMR(400MHz,CDCl3)δ 9.66(bs,2H,G-NH2 +),8.30(bs,1H,G-NH),7.81(bd,J=8.0,1H,amide NH),7.70(d,J=8.2,1H,amide NH),7.68(d,J=8.2,1H,amide NH),7.58(t,J=8.0,1H,amide NH),7.36(d,J=8.2,1H,amide NH),7.19-7.14(m,5H,Ph),6.90(bs,2H,G-NH2),4.69(dd,J=16.0,7.6,1H),4.57(bt,1H),4.32(bs,2H),4.20(s,2H,CH2O),4.19(dd,J=16.0,7.4,1H),4.03(s,2H,CH2O),3.39(t,J=14.8Hz,2H),3.19-3.11(m,4H),2.70(dd,J=16.2,7.4,1H),2.60(dd,J=16.2,10.2,1H),1.82-1.77(m,2H),1.53-1.51(m,2H);HRMS(ESI)C25H37N8O9理論值(M++H):593.2678;實際值:593.2680;HPLC分析條件:(C18,250×4.6mm,0.5(mL/min),λ=254nm).a.1%三氟乙酸溶於水/乙腈(95:5)30min;b.1%三氟乙酸溶於水/乙腈(5:95)31-60min;t R 31.5,39.6min.
在環境溫度下,取Fmoc-保護的五胜肽(Fmoc-5’-6)(58.0mg,0.05mmol),以溶於二氯甲烷(3mL)之20%哌啶處理1小時,藉由與甲醇(3mL)共蒸發後移除哌啶,粗產物在真空下乾燥,生成的粗產物藉由在回流的甲苯中與10mol%的V(O)Cl2、Zr(O)Cl2、V(O)(acac)2、或Ti(O)(acac)2處理10小時,以形成分子內的醯胺鍵。將生成的粗混合物冷卻至環境溫度並濃縮,粗殘物(MTr-6’-6-t-Boc)以三氟乙酸(7mL)和水(1.5mL)回溶,接著以苯基甲基硫醚(thioanisole,1.5mL)處理。混合物以二異丙醚(7mL)誘導沉澱,並將生成的固體以二異丙醚洗,且在真空下乾燥,以獲得環胜肽(6’-6)。該環五胜肽可以進一步藉由HPLC純化(逆相(reverse phase)C-18管柱)(梯度:95/5至80/20,水/乙腈),以得到純的6’-6(25.2mg,產率:86%)。
在5’-6-Fmoc的Fmoc去保護和環化後,獲得以下化合物MTr-6’-6-t-Boc。
Mtr-6’-6-t-Boc的數據:1H NMR(400MHz,CDCl3)δ 7.66 and 7.31(m,2H,imine and amide),7.21-7.15(m,5H,Ph group),6.46(s,1H,amide),6.30(br,2H,amide),4.82(dd,J=6.0,6.9Hz,1H),4.56-4.52(m,1H),4.42-4.31(m,1H),4.16(d,J=11.8Hz,2H,CH2O),3.96(d,J=12.0Hz,2H,CH2O),3.82-3.79(m,1H),3.78(s,3H,OCH3-Ph),3.35-3.18(m,3H),2.78-2.69(m,1H),2.73(t,J=8.4Hz,2H,CH2-quanidine),2.64(s,3H,CH3-Ph),2.62(s,3H,CH3-Ph),2.38(t,J=10.4Hz,1H),
2.05(s,3H,CH3-Ph),1.62-1.54(m,2H),1.40(m,2H),1.39(s,3H,CH3),1.37(s,9H,t-Bu),1.33(s,3H,CH3);R f 0.45(EtOAc/MeOH,9/1);HRMS(ESI)C42H61N8O12S理論值(M++H):901.4130;實際值:901.4132.
進行MTr-6’-6-t-Boc的MTR、tert-Boc和縮丙酮(acetonide)去保護後,獲得化合物6’-6。
化合物6’-6的數據:1H NMR(400MHz,CDCl3)δ 10.07(bs,2H,G-NH2 +),8.24(bs,1H,G-NH),7.79 7.50(bd,J=8.4,1H,amide NH),7.70(d,J=8.2,1H,amide NH),7.65(d,J=8.2,1H,amide NH),7.56(t,J=8.0,1H,amide NH),7.49(d,J=8.2,1H,amide NH),7.24-7.15(m,5H,Ph),4.71(dd,J=13.2,6.8,1H),4.51(bt,1H),4.28(bs,2H),4.24(dd,J=15.8,7.0,1H),3.88(s,2H),3.80(s,2H),3.28(t,J=13.8Hz,1H),3.20-3.05(m,3H),2.72(dd,J=16.0,7.6Hz,1H),2.63(dd,J=16.0,10.4,1H),1.74(m,2H),1.41(m,2H);HRMS(ESI)C25H37N8O9理論值(M++H):593.2678;實際值:593.2681;HPLC分析條件:(C18,250×4.6mm,0.5(mL/min),λ=254nm).a.1%三氟乙酸溶於水/乙腈(90:10)30min;b.1%三氟乙酸溶於水/乙腈(10:90)31-60min;t R 32.1,40.0min.
在前述實施例中,該環-五胜肽之製備可以與賦形劑或金屬(II)硫酸鹽或氧金屬(II)硫酸鹽共同使用,以形成醫藥或化妝品組成物,其中,該金屬(II)硫酸鹽或氧金屬(II)硫酸鹽可以為Cu2+硫酸鹽或V(O)2+硫酸鹽。
雖然已經以優選實施例說明了本發明,但應當理解的是,在不背離如下文所要求保護之本發明之精神及範圍下,可以進行許多其他可能的修飾和變化。
Claims (19)
- 如申請專利範圍第1項所述之環胜肽,其中,R2為H、C1-6之烷基、-C(=O)-C4-10之烷基、(CH2CH2O)nH、或C(=O)(C2H4)2C(=O)O(C2H4O)nH。
- 如申請專利範圍第1項所述之環胜肽,其中,X為O。
- 一種製備如申請專利範圍第1項所述之環胜肽之方法,包含以下步驟:(A)提供由下列式(II-1)或式(II’-1)及式(II-2)所表示之化合物:
- 如申請專利範圍第7項所述之方法,其中,L1為選自由Cl、OTf、OTs、NTf2、鹵素、RC(O)CHC(O)R、OAc、OC(O)CF3、OEt、O-iPr和丁基所組成之群組,其中,R為烷基。
- 如申請專利範圍第7項所述之方法,其中,Rc和Rd為茀基甲氧基羰基;以及Re為4-甲氧基-2,3,6,-三甲基苯磺醯基。
- 如申請專利範圍第7項所述之方法,其中,以該式(III)之催化劑進行該式(II-1)或該式(II’-1)與該式(II-2)之化合物之間的反應,或以該式(III)之催化劑進行該式(II-3)與該式(II-4)或該式(II’-3)與該式(II’-4)之化合物之間的反應。
- 如申請專利範圍第7項所述之方法,其中,M為IVB族過渡元素,m為1且y為2。
- 如申請專利範圍第7項所述之方法,其中,M為VB族過渡元素,m為1且y為2或3。
- 如申請專利範圍第7項所述之方法,其中,M為VIB族過渡元素,m為1且y為4。
- 如申請專利範圍第7項所述之方法,其中,M為VIB族過渡元素,m為2且y為2。
- 如申請專利範圍第7項所述之方法,其中,M選自錒系族,m為2且y為2。
- 如申請專利範圍第7項所述之方法,其中,該式(III)之催化劑為MoO2Cl2、V(O)OCl2、V(O)(OAc)2、V(O)(O2CCF3)2、Ti(O)(acac)2、Zr(O)Cl2、Hf(O)Cl2、Nb(O)Cl2、MoO2(acac)2、V(O)(OTs)2、VO(OTf)2、或V(O)(NTf2)2。
- 如申請專利範圍第7項所述之方法,其中,z為0。
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