CN115043879A - 双氢青蒿素衍生物及其制备方法 - Google Patents
双氢青蒿素衍生物及其制备方法 Download PDFInfo
- Publication number
- CN115043879A CN115043879A CN202110252345.6A CN202110252345A CN115043879A CN 115043879 A CN115043879 A CN 115043879A CN 202110252345 A CN202110252345 A CN 202110252345A CN 115043879 A CN115043879 A CN 115043879A
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- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- alkyl
- group
- compound
- dihydroartemisinin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000000138 dihydroartemisinin derivatives Chemical class 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 201000004792 malaria Diseases 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
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- 229910052805 deuterium Inorganic materials 0.000 description 6
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 238000012453 sprague-dawley rat model Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
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- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 3
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
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Abstract
本发明涉及一种双氢青蒿素衍生物、其制备方法及其应用。具体而言,本发明涉及一种通式(I)所示的双氢青蒿素衍生物、其立体异构体或药学上可以接受的盐、其制备方法以及含有它们的药物组合物以及在制备药物中的用途。通式(I)化合物的结构如下所示,其基团定义与说明书定义一致。
Description
技术领域
本发明涉及一种双氢青蒿素衍生物、其制备方法及其应用。具体而言,本发明涉及一种通式(I)所示的双氢青蒿素衍生物、其立体异构体或药学上可以接受的盐、其制备方法以及含有它们的药物组合物以及在制备药物中的用途。
背景技术
青蒿,别名草蒿,属菊科类一年生或二年生草本植物。青蒿素是我国药学人员于20世纪70年代从菊科植物黄花蒿叶中提取的一种含过氧化基团的倍半萜内酯化合物。青蒿素类药物作为世界卫生组织推荐的抗疟一线用药,具有高效、速效、安全、剂量小、服用方便、制备简廉等优点。青蒿素衍生物主要包括青蒿琥酯、双氢青蒿素、蒿甲醚、蒿乙醚等。双氢青蒿素作为第一种被开发的青蒿素衍生物,具有高效抗疟、低毒和起效迅速等优点,在抗肿瘤免疫领域具有良好的双向调节作用,既能降低B细胞高反应性以减少免疫复合物沉积所致的自身免疫疾病,又可提高T细胞的免疫功能。而由于双氢青蒿素稳定性差、水溶性低,口服生物利用度,容易导致耐药问题。因此,提高双氢青蒿素的水溶性和稳定性具有重要意义。
发明内容
为解决现有技术中存在的缺点和不足,本发明提供了一种新的双氢青蒿素衍生物,可提高其稳定性和水溶性,进而改善药物在体内吸收代谢分布的特征,提高药物口服生物利用度、减少给药剂量和频率、提高病人使用顺应性、提高安全性、延长作用时间。
具体而言,本发明涉及一种通式(I)所示的化合物及其立体异构体或其药学上可接受的盐,其中:
Ra选自氢原子或者C1-6烷基;
Rb和Rb’各自独立地选自氢原子、C1-6烷基或者天然或可药用的氨基酸侧链;
Rc选自C1-6烷基或苄基;
X1选自C1-4亚烷基,所述的烷基任选进一步被0至4个选自卤素或者C1-4烷氧基的取代基所所取代;
X2选自键、-C(=O)O-或者-OC(=O)-;
X3选自键或者C1-4亚烷基,所述的烷基任选进一步被0至4个选自卤素或者C1-4烷氧基的取代基所所取代;
X4选自键、-OC(=O)-或者-C(=O)-。
本发明优先方案,一种通式(I)所述的化合物,其立体异构体或其药学上可接受的盐,
其中:
Ra选自氢原子;
Rb和Rb’各自独立地选自氢原子或甲基;
Rc选自甲基、乙基、丙基、异丙基或苄基;
L选自-CH2-OC(=O)-或者-CH2-OC(=O)-C2H4-C(=O)-。
本发明优先方案,一种通式(I)所示的化合物,其立体异构体或其药学上可接受的盐,所述的化合物包括但不限于以下结构之一:
本发明还提供一种药物组合物,所述药物组合物含有治疗有效剂量的本发明所述的化合物及其立体异构体或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
本发明还提供通式(I)所述的化合物、其立体异构体或其药学上可以接受的盐,或其药物组合物在制备药物中的应用,包括但不限于用于治疗疟疾、炎症、自身免疫疾病或肿瘤。
详细说明
本发明所述基团和化合物中所涉及的元素碳、氢、氧、氮或卤素均包括它们的同位素情形,本发明所述基团和化合物中所涉及的元素碳、氢、氧或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“天然或可药用氨基酸”:蛋白质分子的基本骨架是氨基酸序列,组成蛋白质的基本氨基酸有20种,此20种基本氨基酸是生物进行蛋白后期修饰的基础,此外,在这些基本氨基酸的基础上,还生物合成羟脯氨酸、羟赖氨酸等衍生出来的氨基酸类型,这些由生物合成的氨基酸统称为“天然氨基酸”;用人工方法合成的氨基酸为“非天然氨基酸”。“可药用氨基酸”是指在药学上可接受的天然或非天然氨基酸。
“氨基酸的侧链”是指共价连接至D或L-氨基酸结构并且可表示为-CH(COOH)(NH2)-R的部分。例如,在丙氨酸-CH(COOH)(NH2)(CH3)的情况下,氨基酸(R)的侧链是-CH3。
本发明的“=O”为本领域通常习惯用法,是指以双键相连的氧原子,譬如羰基中与碳原子相连的双键氧原子。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”当作一基团或一基团的一部分时是指包括1至20个碳原子的直链或者带有支链的脂肪烃基团。优选为1至10个烷基,更优选为1至6个烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的,当被取代时,取代基优选为一个或多个以下的基团:烷基、烷氧基、卤素、羟基、硝基、氰基、环烷基、环烷基氧基或氨基。
“亚烷基”是二价烷基。优选为C1-C10亚烷基,更优选为C1-C6亚烷基,特别优选为C1-C4亚烷基。亚烷基基团的实施例包括但不限于亚甲基、亚乙基、亚正丙基等。亚烷基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环,但没有一个环具有完全共轭的π电子的芳香环系统。优选为3至12元环烷基,更优选为3至8元环烷基,最优选为3至6元环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。
“稠环基”指5至18元,系统含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香环系统,优选为6至12元,更优选为7至10元。根据组成环的数目可以分双环、三环、吡啶酮或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:
“桥环基”指5至18元,系统含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香环系统,优选为6至12元,更优选为7至10元。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环桥环烷基,优选为双环、三环或吡啶酮,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:
“螺环烷基”指5至18元的单环之间公用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目,将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基。优选为单螺环烷基。螺环烷基的非限制性实施例包括但不限于:
环烷基可以是任选取代的或未取代的。当被取代时,取代基优选为一个或多个以下的基团:烷基、烷氧基、卤素、羟基、硝基、氰基、环烷基、环烷基氧基或氨基。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“环烷基氧基”是指(环烷基-O-)的基团。其中,环烷基见本文有关定义。C3-C8的环烷氧基为优先选择。其实例包括,但不限于:环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。
“羟基”指-OH。
“氨基”指-NH2。
“卤素”是指氟、氯、溴和碘。
“苄基”是指-CH2-苯基。
“DMAP”指4-二甲氨基吡啶。
“BTC”指三光气。
“Et”指乙基。
“Bn”指苄基。
“DIPEA”指N,N-二异丙基乙胺。
“TMS”指三甲基硅基。
“BOP”指苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的药物。本发明的前药通过修饰雌二醇中的功能基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到雌二醇。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“有效剂量”指引起组织、系统或受试者生理或医学反应的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐,包括无机酸和碱、有机酸和碱的盐。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。
1H NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm),测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,q=四重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100x4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
在下列实施例中,除非另有指明,所有温度为摄氏温度。
除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于AldrichChemical Company,ABCR GmbH&Co.KG,Acros Organics,韶远化学科技(上海)有限公司,国药集团药业股份有限公司,百灵威科技有限公司等公司等处购买。
对化合物进行纯化,采用硅胶柱层析和薄层色谱法,其中洗脱剂体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷:乙酸乙酯;D:石油醚:二氯甲烷体系;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行调节,如醋酸或三乙胺等。
实施例中无特殊说明,反应在氮气氛下进行。实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。室温为最适宜的反应温度,为20℃~30℃。
实施例1
(双(((S)-1-异丙氧基-1-氧代丙烷-2-基)氨基)磷酰基)甲基((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧基肾上腺素[4,3-i]异色烯-10-基)丁二酸酯
第一步
1a采用公知的方法“Journal of Organic Chemistry,2014,79(6),2666-2681”制备而得。
第二步
1b采用公知的方法“Journal of Medicinal Chemistry,2017,60(20),8580-8590”制备而得。
第三步
1c采用公知的方法“Journal of Medicinal Chemistry,2017,60(20),8580-8590”制备而得。
第四步
(2S,2’S)-2,2’-((((苄氧基)甲基)磷酰)双(氮杂二酰)二丙酸二异丙酯
将苄氧甲基磷酰二氯1c(4.2g,0.018mol)溶解于200mL二氯甲烷中,氩气保护下,降温至-60℃。加入L-丙氨酸异丙酯盐酸盐(6.5g,0.039mol)。加毕,滴加三乙胺(8.87g,0.088mol)。滴毕,保温反应30分钟,自然升温至室温反应3小时。反应液依次用1M盐酸及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:1)纯化,得到标题产物1d(2.5g黄色油状物),产率:33.2%。
MS m/z(ESI):429.5[M+1]
第五步
(2S,2’S)-2,2’-(((羟甲基)磷酰)双(氮杂二酰)二丙酸二异丙酯
将(2S,2’S)-2,2’-((((苄氧基)甲基)磷酰)双(氮杂二酰)二丙酸二异丙酯1d(2.5g,5.8mmol)溶解于50mL甲醇中,加氢反应3天。过滤,浓缩得到标题产物1e(1.2g黄色油状物),产率:61.5%。
MS m/z(ESI):339.3[M+1]
第六步
4-氧代-4-((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧肾上腺素[4,3-i]等色素-10-基)氧基)丁酸
1h采用公知的方法“专利CN104418864”制备而得。
第七步
(双(((S)-1-异丙氧基-1-氧代丙烷-2-基)氨基)磷酰基)甲基((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧基肾上腺素[4,3-i]异色烯-10-基)丁二酸酯
将(2S,2’S)-2,2’-(((羟甲基)磷酰)双(氮杂二酰)二丙酸二异丙酯1e(0.5g,1.48mmol),4-氧代-4-((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧肾上腺素[4,3-i]等色素-10-基)氧基)丁酸1h(0.57g,1.48mmol),N,N-二异丙基乙胺乙酸乙酯(0.29g,2.22mmol)以及苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(0.8g,1.78mmol)依次加入到10ml四氢呋喃中搅拌反应过夜。加入50ml乙酸乙酯,反应液依次用1M盐酸,碳酸钠溶液以及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:1)纯化,得到标题产物1(0.55g无色油状物),产率:55.2%。
MS m/z(ESI):727.3[M+23]
1H NMR(400MHz,DMSO-d6):δ5.67(d,1H),5.57(s,1H),4.65-4.92(m,4H),4.11-4.25(m,2H),3.72-3.87(m,2H),2.61-2.71(m,4H),2.11-2.32(m,2H),1.95-2.05(m,1H),1.75-1.85(m,1H),1.35-1.65(m,5H),1.15-1.35(m,22H),0.85(d,3H),0.75(d,3H)
实施例2
(2S,2'S)-二异丙基2,2'-(((((((((((((((((((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧树脂)[1,2]二氧肾上腺素[4,3-i]等色胺-10-基)氧基)羰基)氧基)甲基)磷酰)双(氮杂二酰)碳酸酯
将双氢青蒿素(0.2g,0.7mmol)和DMAP(0.2g,1.62mmol)溶于5mL四氢呋喃中。氩气保护下,降温至0℃。滴加1mL三光气(71mg,0.24mmol)的二氯甲烷溶液。后升至室温反应30分钟。冰浴下加入5mL(2S,2’S)-2,2’-(((羟甲基)磷酰)双(氮杂二酰)二丙酸二异丙酯1e(0.36g,1.07mmol)。室温反应过夜。加入50ml乙酸乙酯,反应液依次用1M盐酸及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:1-乙酸乙酯)纯化,得到标题产物2(0.1g无色油状物),产率:21.9%。
1H NMR(400MHz,CDCl3):δ5.53(s,1H),4.96-5.06(m,3H),4.82(d,1H),3.95-4.12(m,3H),3.61-3.68(m,1H),3.28-3.38(m,2H),2.62-2.72(m,1H),2.35(t,1H),1.95-2.05(m,1H),1.61-1.91(m,4H),1.15-1.47(m,34H),0.89-0.97(m,6H)
实施例3
(双(((S)-1-乙氧基-1-氧代丙烷-2-基)氨基)磷酰基)甲基((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧基肾上腺素[4,3-i]异色烯-10-基)丁二酸酯
将(2S,2’S)-2,2’-(((羟甲基)磷酰)双(氮杂二酰)二丙酸二乙酯3a(0.97g,3.12mmol)(3a合成方法同实施例1中合成1e,将第四步中的L-丙氨酸异丙酯盐酸盐换成L-丙氨酸乙酯盐酸盐),4-氧代-4-((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧肾上腺素[4,3-i]等色素-10-基)氧基)丁酸1h(1.2g,3.12mmol),DIPEA(0.6g,4.7mmol)以及苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(1.66g,3.75mmol)依次加入到20ml四氢呋喃中搅拌反应过夜。加入50ml乙酸乙酯,反应液依次用1M盐酸,碳酸钠溶液以及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:1)纯化,得到标题产物3(1.2g无色油状物),产率:57.1%。MS m/z(ESI):699.4[M+23]
1H NMR(400MHz,CDCl3):δ5.80(d,1H),5.44(s,1H),4.41(d,2H),4.11-4.22(m,4H),3.95-4.05(m,2H),3.37-3.48(m,2H),2.71-2.82(m,4H),2.51-2.61(m,1H),2.31-2.42(m,1H),2.01-2.08(m,1H),1.85-1.95(m,1H),1.65-1.75(d,2H),1.58-1.65(m,1H),1.21-1.52(m,21H),0.96(d,3H),0.85(d,3H)
实施例4
(2S,2'S)-二乙基2,2'-(((((((((((((((((((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧树脂)[1,2]二氧肾上腺素[4,3-i]等色胺-10-基)氧基)羰基)氧基)甲基)磷酰)双(氮杂二酰)碳酸酯
将双氢青蒿素(1g,3.52mmol)和DMAP(1g,8.2mmol)溶于20mL四氢呋喃中。氩气保护下,降温至0℃。滴加4mL三光气(71mg,0.24mmol)的二氯甲烷溶液。后升至室温反应30分钟。冰浴下加入15mL(2S,2’S)-2,2’-(((羟甲基)磷酰)双(氮杂二酰)二丙酸二异丙酯3a(1.3g,4.22mmol)。室温反应过夜。加入50ml乙酸乙酯,反应液依次用1M盐酸及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:1-乙酸乙酯)纯化,得到标题产物4(0.3g无色油状物),产率:14.2%。
1H NMR(400MHz,CDCl3):δ5.53(s,1H),4.82(d,1H),4.11-4.21(m,4H),3.97-4.11(m,3H),3.65(m,1H),3.25-3.43(m,2H),2.62-2.72(m,1H),2.35(t,1H),1.95-2.05(m,1H),1.61-1.91(m,4H),1.35-1.48(m,12H),1.21-1.31(m,6H),0.85-0.97(m,7H)
实施例5
(双(((S)-1-苄氧基-1-氧代丙烷-2-基)氨基)磷酰基)甲基((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧基肾上腺素[4,3-i]异色烯-10-基)丁二酸酯
第一步
乙酰氧甲基磷酸二乙酯
将羟甲基磷酸二乙酯(30g,0.178mol)和三乙胺(27g,0.268mol)溶于300mL二氯甲烷中。降温至0℃,滴加乙酰氯(16.9g,0.214mol)。滴毕,室温反应过夜。补加400mL二氯甲烷,反应液依次用1M盐酸,10%碳酸钠溶液及饱和盐水洗,有机相用无水硫酸钠干燥,过滤,浓缩,得到标题产物5a(35g无色油状物),产率:93.3%。
第二步
乙酰氧甲基磷酰二氯
合成方法同实施例1中合成1c。得到标题产物5b(22g黄色油状物),产率:69.2%。
第三步
(2S,2'S)-2,2'-((乙酰氧基甲基)磷酰基)双(氮杂二酰)二丙酸二苄酯
合成方法同实施例1中合成1d。得到标题产物5c(16g油状物),产率:44.3%。
MS m/z(ESI):499.4[M+23]
第四步
(2S,2'S)-2,2'-((羟甲基)磷酰双(氮杂二酰)二丙酸二苄酯
将5c(15g,0.032mol)溶于120mL苄醇中搅拌,加入三乙胺(16g,0.16mol)。室温反应过夜。减压蒸馏除去苄醇,粗品用硅胶柱色谱法(乙酸乙酯/石油醚(V/V)=1:10-1:1-乙酸乙酯)纯化,得到标题产物5d(6g无色油状物),产率:44.2%。
MS m/z(ESI):424.4[M+1]
第五步
(双(((S)-1-苄氧基-1-氧代丙烷-2-基)氨基)磷酰基)甲基((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧[1,2]二氧基肾上腺素[4,3-i]异色烯-10-基)丁二酸酯
合成方法同实施例1中合成1(将1e换成5d)。得到标题产物5(0.3g白色固体),产率:41.2%。
MS m/z(ESI):823.5[M+23]
1H NMR(400MHz,CDCl3):δ7.32-7.37(m,10H),5.78(d,1H),5.43(s,1H),5.09-5.45(m,4H),4.39-4.45(m,2H),4.01-4.15(m,2H),3.35-3.55(m,2H),2.52-2.79(m,5H),2.31-2.41(m,1H),2.01-2.08(m,1H),1.85-1.95(m,1H),1.55-1.75(m,3H),1.21-1.51(m,13H),0.96(d,3H),0.85(d,3H)
实施例6
(2S,2'S)-二苄基2,2'-(((((((((((((((((((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-三甲基十氢-3H-3,12-环氧树脂)[1,2]二氧肾上腺素[4,3-i]等色胺-10-基)氧基)羰基)氧基)甲基)磷酰)双(氮杂二酰)碳酸酯
合成方法同实施例2中合成2(将2a换成5d)。得到标题产物6(0.25g无色油状物),产率:6.36%。
1H NMR(400MHz,CDCl3):δ7.29-7.37(m,10H),5.49(s,1H),5.09-5.25(m,4H),4.79(d,1H),3.98-4.18(m,3H),3.65(m,1H),3.25-3.43(m,2H),2.65(m,1H),2.35(t,1H),1.95-2.05(m,1H),1.71-1.91(m,4H),1.59-1.65(m,1H),1.37-1.48(m,9H),1.32(d,3H),1.21-1.31(m,1H),0.85-0.97(m,7H)
测试例1、Sprague Dawley(SD)大鼠体内药代动力学研究
健康成年SD大鼠,雄性,180-220g,购于成都达硕实验动物有限公司;适应性饲养3天后开始试验。受试化合物以DMSO溶解,再依次加入及Solutol HS-15及生理盐水,旋涡混合均匀,最终给药溶剂配比为DMSO:Solutol HS-15:生理盐水=5:5:90(v/v/v)。所有受试化合物均在临用前新鲜配制,均为透明澄清溶液。动物按体重随机分组,每组3只,给药前禁食不少于8小时,自由饮水,给药4小时后进食。各组大鼠分别静脉注射(IV)或灌胃(PO)给予受试化合物溶液,于给药前及给药后不同时刻采集静脉血约0.1ml,肝素抗凝,12000转/分,4℃离心10分钟后收集血浆,于-80℃保存待测。采用LC-MS/MS法分别测定血浆中的原形药物(前药)及代谢物(原药)浓度,以原药的血药浓度计算主要药动学参数,结果如表1所示:
表1 SD大鼠药代动力学测试结果
结论:实施例1大鼠灌胃给药后,在动物体内快速代谢,主要以双氢青蒿素形式存在,根据双氢青蒿素血浆中暴露水平计算口服绝对生物利用度分别为10.9%,表明具实施例1的前药设计有效提高了原药双氢青蒿素的口服生物利用度。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (5)
2.根据权利要求1所述的化合物,其立体异构体或其药学上可接受的盐,其中:
Ra选自氢原子;
Rb和Rb’各自独立地选自氢原子或甲基;
Rc选自甲基、乙基、丙基、异丙基或苄基;
L选自-CH2-OC(=O)-或者-CH2-OC(=O)-C2H4-C(=O)-。
4.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1-3中任一项所述的化合物及其立体异构体或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
5.根据权利要求1-3中任一项所述的化合物、其立体异构体或其药学上可以接受的盐,或根据权利要求4所述的药物组合物在制备药物中的应用,包括但不限于用于治疗疟疾、炎症、自身免疫疾病或肿瘤。
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