CN107286190A - 核苷之烃氧基苄基氨基磷酸/膦酸酯衍生物的制备及其医药用途 - Google Patents
核苷之烃氧基苄基氨基磷酸/膦酸酯衍生物的制备及其医药用途 Download PDFInfo
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- CN107286190A CN107286190A CN201710255252.2A CN201710255252A CN107286190A CN 107286190 A CN107286190 A CN 107286190A CN 201710255252 A CN201710255252 A CN 201710255252A CN 107286190 A CN107286190 A CN 107286190A
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- alkyl
- substitution
- oxyl
- base
- acid
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- -1 oxyl benzylamino phosphoric acid/phosphate derivatives Chemical class 0.000 title claims abstract description 133
- 239000002777 nucleoside Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title description 5
- 239000000651 prodrug Substances 0.000 claims abstract description 55
- 229940002612 prodrug Drugs 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- 201000011510 cancer Diseases 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 71
- 238000006467 substitution reaction Methods 0.000 claims description 70
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 57
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 20
- 229960004217 benzyl alcohol Drugs 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 18
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000003835 nucleoside group Chemical group 0.000 claims description 15
- 229910052698 phosphorus Inorganic materials 0.000 claims description 15
- 239000011574 phosphorus Substances 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- 125000003368 amide group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
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- 238000000034 method Methods 0.000 claims description 13
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims description 11
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 241000700605 Viruses Species 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
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- 238000002425 crystallisation Methods 0.000 claims description 7
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- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
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- 229910019213 POCl3 Inorganic materials 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
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- 239000000194 fatty acid Substances 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 230000002503 metabolic effect Effects 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001241 acetals Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 2
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 claims description 2
- 229960000846 camphor Drugs 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 125000005171 cycloalkylsulfanyl group Chemical group 0.000 claims description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical group 0.000 claims description 2
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 2
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 2
- 229960001340 histamine Drugs 0.000 claims description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N histamine Natural products NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 2
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 2
- 125000000405 phenylalanyl group Chemical group 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- 239000002574 poison Substances 0.000 claims description 2
- 231100000614 poison Toxicity 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims description 2
- 125000005454 tryptophanyl group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
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- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims 2
- 150000007524 organic acids Chemical class 0.000 claims 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims 1
- JNRLEMMIVRBKJE-UHFFFAOYSA-N 4,4'-Methylenebis(N,N-dimethylaniline) Chemical compound C1=CC(N(C)C)=CC=C1CC1=CC=C(N(C)C)C=C1 JNRLEMMIVRBKJE-UHFFFAOYSA-N 0.000 claims 1
- 208000001490 Dengue Diseases 0.000 claims 1
- 206010012310 Dengue fever Diseases 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 125000001980 alanyl group Chemical group 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical class BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
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- 125000003843 furanosyl group Chemical group 0.000 claims 1
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- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims 1
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- 125000002114 valyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- SNGARVZXPNQWEY-UHFFFAOYSA-N phenylmethanediol Chemical compound OC(O)C1=CC=CC=C1 SNGARVZXPNQWEY-UHFFFAOYSA-N 0.000 abstract description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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Abstract
本发明涉及一种由烃氧基苄醇和D或L‑氨基酸酯共同构成的新型核苷氨基磷酸/膦酸酯前药及其制备方法和用途。所述含有烃氧基苄基的新型核苷氨基磷酸/膦酸酯前药为式(I)所示的化合物或其异构体或可药用盐,它可用作各种核苷类似物,例如非环核苷、碳环核苷、呋喃环核苷等的前体药物,强化核苷类化合物的生物活性,从而优化这类化合物在病毒感染及癌症治疗领域的已有应有。
Description
技术领域
本发明属于医药技术领域,具体而言,涉及一种由D-或L-氨基酸酯和烃氧基取代苄醇共同构成的新型核苷氨基磷酸/膦酸酯前药及其制备方法和用途。
发明背景
核苷类化合物是脱氧核糖核酸和核糖核酸,也即生物遗传基因DNA与RNA的结构单体,在所有生命体中皆有重要功能,并被广泛用于病毒感染和癌症的治疗。1960年代以来,许多生物活性的核苷类似物被用于治疗各种病毒感染,如疱疹、艾滋病、乙型和丙型肝炎。这些人工合成的核苷类似物、能够通过阻断病毒核酸链的生长,破坏病毒基因的复制,成为抗病毒药物(图1)。
如图1所示,核苷必须首先分三步活化成三磷酸核苷,才能参与DNA或RNA的合成,进而表现出生理活性。当一个核苷类似物能够选择性打入病毒或癌细胞的遗传基因,阻止其核酸链复制繁殖,同时对宿主细胞基因无伤害(毒性)时,这个核苷类似物就可成为抗病毒或抗癌药物。
三磷酸核苷本身由于携带多个负电荷、极性非常高,难以通过细胞壁而进入细胞内部,所以不能直接作为抗病毒药物使用。早期核苷类抗病毒药物的形式就是极性适中的核苷本身,它在进入细胞后在宿主细胞激酶(kinase)作用下分三步磷酰化,最终成为三磷酸核苷而发挥药效。近来随着核苷磷酸酯类前药技术的进步,用化学的方法直接将单磷酸的低极性等价结构单元引入核苷分子中,使核苷磷酸酯前药在进入细胞内部后再释放出单磷酸核苷,而不必受核苷激酶的选择性限制。由此,核苷磷酸酯前药就成为了升级核苷类药物性能的流行方式。
核苷前药的研究是当前一个热点,尤其磷酸酯类前药是一种最有效的升级核苷药物的方式,也能够使得一些由于核苷激酶限制不能磷酰化的核苷表现出生物活性,文献报道的核苷的磷酸酯类前药之结构类型主要有七类(J.Am.Chem.Soc.,2004,126,5154-5163;WO2012094248,CN 102532199,CN 103980318,CN 103435672,图2),其杰出代表为McGuigan等发明的芳基氨基磷酸酯(2-5),是目前在核苷类化合物前药中应用最为广泛和成功的一个;核苷前药(2-6)和(2-7)含有取代苄基,它们只能在氧化酶(如细胞色素P450酶)的帮助下,氧化裂解脱去,释放出单磷酸核苷。由于P450酶系主要分布于肝脏,所以这些核苷前药主要在肝细胞内裂解释放,被称为肝靶向(HepDirect)前药。
McGuigan型核苷前药是已故英国科学家Christopher McGuigan于1990年代最先发明、并被不断完善了的芳基氨基磷酸酯结构单元(3-1,图3),结构特点是它含有一个氨基酸酯的氨基磷酰胺化生成的磷酰胺键P(O)-N,以及一个芳基酚参与形成的磷酯键P(O)-O-Ar。已证实McGuigan前药(3-1)的氨基酸酯键首先断裂释放出游离羧酸衍生物(3-2),产生的羧基官能团能够催化酚基氧磷键裂解,形成五元环磷酸酯衍生物(3-3),随后释放出单核苷酸(3-4),最终代谢生成能够参与核酸链聚合、具有生理活性的三核苷酸(3-6)。所以核苷前药(3-1)乃是其单核苷酸(3-4)的等价物,它能够用化学方式绕开选择性高、效率差的单核苷酸激酶催化下的单磷酸酯化反应,直接输送核苷的5′-单磷酯进入细胞并产生生物活性。其结果是McGuigan前药能使那些因无法单磷酰化而失去生物活性的核苷重新具有生物活性,或者提高已知核苷药物的生物活性。
众所周知,McGuigan前药(3-1)分子中氨基酸酯的酶水解反应引发了其后一系列生成单核苷酸(3-4)的代谢过程,而由于酯水解酶广泛分布于肠胃消化道内,所以化合物(3-1)的水解代谢始自于肠胃道,大量的氨基酸酯基常常在到达肝细胞之前就会被酶水解代谢。当核苷与含取代苄基的磷酸酯结合后,生成的前药对肠胃道酯水解酶更加稳定,能够提高核苷单磷酸酯前药富集于肝细胞内的水平,从而使得这类核苷前药具有较好的肝靶向作用,特别适合于开发治疗肝病,如肝癌和肝炎等的药物。
综合McGuigan前药和HepDirect前药的结构特点,以Hepdirect前药结构中的取代苄基置换掉McGuigan前药中的芳基,本申请人曾首次发明了由短链烷基取代苄醇与氨基酸酯构成的苄基氨基磷酸酯前药(CN102532199)。通过后续的深入研究、系统筛选甄别苄基苯环上取代基的不同位置和种类的药理效应,本人又发现了当苄基苯环上带有酚羟基、或者是可以代谢解离出酚羟基的烃氧基时,该烃氧基苄基与氨基酸酯构成的氨基磷酸酯前药在体外细胞中代谢释放出核苷单磷酸酯的能力,远远大于相应的短链烷基取代苄醇构成的苄基氨基磷酸酯前药。作为代谢释放单核苷酸能力最强的取代苄基氨基磷酸/膦酸酯,本发明所描述的烃氧基苄基氨基磷酸/膦酸酯衍生物输送核苷单磷酸酯的能力甚至优于或者至少相当于McGuigan前药,可以大大优化核苷类化合物的生物活性,可以成为升级核苷固有的抗病毒或抗癌活性的一种全新选择。本文在此首次公开含有烃氧基之苄醇与氨基酸酯共同构成的核苷氨基磷酸/膦酸酯衍生物的制备、及其在医药领域的应用。
发明内容
综合McGuigan前药(图2,2-5)和HepDirect前药(2-6)的结构特点,用HepDirect前药结构中的取代苄基置换掉McGuigan前药中的芳环,本发明人曾首次合成出了可以成为核苷前药的短链烷基取代苄基氨基磷酸/膦酸酯前药(CN102532199),在此基础上通过后续的深入研究、系统筛选甄别苄基苯环上取代基的不同位置和种类的药学效应,本申请人进一步发现当苄基苯环上带有酚羟基(例如水杨醇)、或者是可以代谢解离出酚羟基的烃氧基时,该取代苄基与氨基酸酯构成的烃氧基苄基氨基磷酸酯前药在体外细胞中代谢释放出核苷单磷酸酯的能力,远远大于相应的短链烷基取代苄醇构成的苄基氨基磷酸酯前药,并且丝毫不亚于McGuigan类芳基氨基磷酸酯前药。所以本发明所描述的烃氧基苄基氨基磷酸/膦酸酯前药可以强化核苷类化合物的生物活性,优化核苷固有的抗病毒或抗癌活性。
另一方面,水杨醇氧化代谢产物为水杨酸,所以邻位烃氧苄基氨基磷酸酯前药能够克服McGuigan前药释放出有毒代谢产物苯酚的弱点。还有一点优势是,由于苄基磷酸酯相对于酚基磷酸酯有更高的水解稳定性,所以烃氧苄基氨基磷酸酯前药相对于McGuigan前药在消化道内的损耗会减少许多,肝靶向性更强因而特别适合于开发治疗肝病,如肝癌和肝炎等的药物。
本发明是通过以下技术方案来实现的。
一种式(I)所示的烃氧基苄基氨基磷酸酯/膦酸酯化合物,其立体异构体、或其药学可接受的盐、水合物、溶剂化物或结晶,分子结构中的任何一个氢原子都可以被氘原子置换。
如式(I)所示,本发明的烃氧基苄基氨基磷酸/膦酸酯前药结构中含有一个由烃氧基苄醇参与形成的磷酯键和一个由L-或D-氨基酸酯参与形成的磷酰胺键。
其中,
R1为各种天然或非天然氨基酸侧链,氨基酸构型可以是D-型、L-型或者其消旋混合物;
R2可以选自C1-12饱和或不饱和烷基、卤素(F、Cl、Br、I)取代的C1-12烷基、羟基取代的C1-12烷基、C1-6烷氧基羰基取代的C1-12烷基、羧基取代的C1-12烷基、氰基取代的C1-12烷基、C3-7环烷基取代的C1-6烷基、苯基取代的C1-6烷基、C1-6烷基砜基取代的C1-6烷基、C1-6烷基亚砜基取代的C1-6烷基、胺基取代的C1-12烷基、C1-6烷基酰胺基取代的C1-6烷基、C1-6烷基磺酰胺基C1-6烷基、胺基羰基C1-6烷基、单环杂环烷基C1-6烷基、C3-C8的饱和或不饱和环烷基;
R2’可以是氢、羟基、卤素(F、Cl、Br、I)、氰基、硝基、C1-6烷基、C1-6烷氧基、杂原子(O、S、N)取代C1-6烷基、杂原子取代C1-6烷氧基、C3-7环烷基、C3-7环烷基取代的C1-4烷基、C3-7杂环烷基取代C1-4烷基,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基可以被卤素、羟基、氰基、胺基或者硝基取代;
PG-可以是各种酚羟基的保护基,它与氧原子构成烃氧基PG-O-。式(I)苄醇结构中烃氧基PG-O-可以位于苄醇羟甲基HOCH2-的邻位、间位或者对位,优选邻位取代。
PG-可选自各类酰基:C1-C22碳链的直链或带支链的脂肪酸酰基R0-21CO-、C3-C22碳链的不饱和的脂肪酸酰基R2-21CO-、芳基甲酰基ArCO-、杂环芳基甲酰基、芳基烷基脂肪酸酰基、碳酸酯酰基(如Boc-、-CO-或Cbz-)、氨基碳酸酯酰基(-NHCOO-)、丙氨酰基、甘氨酰基、脯氨酰基、赖氨酰基、苯丙氨酰基、亮氨酰基、异亮氨酰基、缬氨酰基、色氨酰基、酪胺酰基、天冬氨酰基、天冬酰胺酰基、谷氨酰基、谷氨酰胺酰基、甲硫氨酰基、苏氨酰基、组胺酰基、丝氨酰基、半胱氨酰基、精氨酰基或β-丙氨酰基;
PG-也可选自各类醚类保护基:C1-12饱和或不饱和烷基,杂原子(O、S、N)取代的C1-12烷基、C3-7环烷基、C3-7环烷基取代的C1-4烷基、C3-7杂环烷基取代C1-4烷基、取代或未取代苄基(如Bn-或PMB-)、取代或未取代烯丙基、硅基R’R”R”’Si-,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基可以被卤素、羟基、氰基、胺基或者硝基取代;
PG-还可以是缩醛类保护基:甲氧基亚甲基MOM-、四氢吡喃基THP-、特戊酰氧基亚甲基tBuCO2CH2-、异丙氧基羰基氧亚甲基iPrOCO2CH2-、亚甲基二氧基-OCH2O-等等。
X1可以不存在、或者是-OCH2-或-OCH(CH3)-。
X2选自O、CH2、C=CH2、CHCH3或环丙烷基
X3可以不存在、或者是亚甲基CH2。
T1、T2相互独立,可以是H或者CH2R3,而R3为H、OH或F;T1、T2也可以互相键合在一起构成如下五元呋喃糖环:
其中,X1、X2、X3定义如前所述;R4、R5、R6、R7、R8、R9相互独立,可以是氢、羟基、氟、氯、溴、氰基、叠氮、氨基或C1-4的烷基、C2-4的烯基、C2-4的炔基或者C1-4的烷氧基。
Base是嘌呤或者嘧啶类碱基,或者其化学和代谢衍生物,其具有以下结构通式:
其中,X4可以选自氢、卤素(F、Cl、Br、I)、C1-8短链烷基如甲基、乙烯基、2-溴代乙烯基、(取代)乙炔基;
X5、X6和X7各自独立,可以选自氢、卤素(F、Cl、Br、I)、羟基、氨基、C1-4烷氧基、苄氧基、C3-6环烷基氧基、C1-4烷硫基、苄硫基、C3-6环烷基硫基、C1-4烷氨基或者C3-6环烷基氨基,这里所述烷基、环烷基、苄基可以被卤素、羟基、氰基、胺基或者硝基取代。
Z为氮、CH或者CX4,X4定义如前所述。
(I)式所描述的烃氧基苄基氨基磷酸/膦酸酯化合物结构中,烃氧基可以是RCOO-或者R’O-,位于苄醇羟甲基的邻位、间位或者对位,优选邻位取代,具有下式(II)-(VII)的结构:
其中,R1、R2、R2’、T1、T2、X1、X2、X3、Base的定义如前所述;
R选自C0-21饱和或不饱和烷基、C3-7的饱和或不饱和环烷基、杂原子(O、S、N)取代的C1-12烷基、C3-7环烷基取代的C1-4烷基、C3-7杂环烷基取代C1-4烷基、芳基、杂环芳基、芳基烷基、杂环芳基烷基、C1-C12烷氧基、芳基烷氧基、杂环芳基烷氧基,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基、芳基、杂环芳基可以被卤素、羟基、氰基、氨基、胺基或者硝基取代。
R’选自C1-12饱和或不饱和烷基,杂原子(O、S、N)取代的C1-12烷基、C3-8环烷基、C3-8环烷基取代的C1-4烷基、C3-8杂环烷基取代C1-4烷基、芳基C1-4烷基、杂环芳基C1-4烷基、硅基R’R”R”’Si-、甲氧基亚甲基MOM-、亚甲二氧基-OCH2O-、特戊酰氧基亚甲基tBuCO2CH2-、异丙氧基羰基氧亚甲基iPrOCO2CH2-,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基、芳基、杂环芳基可以被卤素、羟基、氰基、氨基、胺基或者硝基取代。
上述结构式(I)-(VII)中,
代表各种核苷类似物,包括常见的呋喃环核苷、碳环核苷以及非环核苷它可以选自以下核苷,但不仅限于以下核苷化合物:
并且,通式(I)-(VII)结构中的磷原子手性中心,可以是差向异构体富集的如(Ib)、(Ic)、(Ie)、(If);也可以是外消旋的如(Ia)和(Id):
对于通式(I)-(VII)所描述的烃氧基苄基氨基磷酸/膦酸酯化合物,可以通过一些具体的实例来解释,它们优先选择以下的化合物,但不仅仅局限于以下的化合物:
其中,R1为D-或L-氨基酸的侧链;T2为氢、甲基或者亚甲基羟基(-CH2OH)。
上述化合物分为氨基磷酸酯和氨基膦酸酯两大类,均可以通过本领域的技术人员知晓的任何方法制备。
关于氨基磷酸酯(尤其是手性氨基磷酸酯)的合成方法,最为常见的是专利WO2010081082、WO2011123668和文献J.Org.Chem.,2011,76(20),8311-19中描述的方法:在四氢呋喃、二氧六环等适当溶剂中,将核苷母体化合物(VIII)与强碱(如叔丁基氯化镁或N-甲基吡啶)混合后,慢慢加入手性或者消旋的氨基磷酸酯中间体磷试剂(IX)或者(X)的溶液,通过缩合反应偶联而得产物(I)。反应分子式如下:
上述制备烃氧基苄基氨基磷酸酯(I)的缩合偶联方法,关键之处乃是合成含有烃氧基苄基的氨基磷酸酯中间体磷试剂(IX)和(X)。具体地,本发明的烃氧基苄基氨基磷酸酯中间体磷试剂的结构如下式(IXa)、(IXb)、(Xa)或(Xb)所示。
结构式(IX)和(X)中LG为离去集团,常为苯环上带有强吸电子基团EWG的酚氧基,而吸电子基常见的有卤素(F、Cl、Br)、砜基、磺基和硝基,可以是一个或者多达五个。优选地,LG离去集团为五氟苯酚氧基或者对硝基苯酚氧基;R1为氨基酸的侧链;R2’可以是氢、羟基、卤素(F、Cl、Br、I)、氰基、硝基、C1-6烷基、C1-6烷氧基、杂原子(O、S、N)取代C1-6烷基、杂原子取代C1-6烷氧基、C3-7环烷基、C3-7环烷基取代的C1-4烷基、C3-7杂环烷基取代C1-4烷基,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基可以被卤素、羟基、氰基、胺基或者硝基取代;PG-可以是各种酚羟基的保护基,它与氧原子构成烃氧基PG-O-,烃氧基可以位于苄醇羟甲基HOCH2-的邻位、间位或者对位,优选邻位取代的烃氧基。
另一方面,本发明提供了一种氨基磷酸酯中间体磷试剂(IX)和(X)的通用制备方法。反应分子式如下:
含烃氧基苄基的氨基磷酸酯中间体(IX)和(X)可以由三氯氧磷依次分步与等当量的烃氧基取代的苄醇、氨基酸酯和带强吸电子基的苯酚反应,在适当碱性缚酸剂存在下、在适当的有机溶剂中制备而得。三氯氧磷与烃氧基取代的苄醇的反应产物可不必分离而直接用于下一步反应,即与氨基酸酯或其盐酸盐以及取代苯酚分步缩合、生成含烃氧基苄基的氨基磷酸酯中间体磷试剂(IX)和(X)。多步反应可以一锅处理,合成方法简单,产率很高,可以工业化生产。烃氧基苄基氨基磷酸酯中间体(IX)和(X)的稳定性高,可以柱层析纯化处理,也可以用叔丁基甲基醚、乙醚、乙酸乙酯、石油醚或者它们的混合溶剂重结晶纯化。
优选地,碱性缚酸剂是三乙基胺。
优选地,有机溶剂可以是苯、甲苯、氯仿、二氯甲烷、乙醚、二异丙基醚、叔丁基甲基醚、四氢呋喃、二氧六环、乙酸乙酯、乙腈等中的一种或多种,推荐为二氯甲烷、乙醚、二异丙基醚。
优选地,反应温度为-78℃到溶剂同流温度,推荐为-78℃到室温。
优选地,反应时间为3-72小时,推荐以TLC监测反应终点。
优选地,重结晶溶剂为叔丁基甲基醚、二异丙基醚、乙醚、乙酸乙酯、石油醚或者它们适当比例混合的溶剂。
另一类烃氧基苄基氨基膦酸酯的制备,可以采用专利CN201410168286.4公开的方法,以非环核苷单膦酸(XI)为原料,在适当酰化缩合剂存在下、在适当的有机溶剂中,分步与氨基酸酯、烃氧基苄醇酰化反应可以制得。反应分子式如下:
在一定条件下,非环核苷单膦酸(XI)与氨基酸酯的反应产物(XII)可不必分离而直接用于下一步反应,即与氨基酸酯或其盐酸盐以及烃氧基苄醇分步酰化、生成含烃氧基苄基的氨基膦酸酯(Ig)和(Ih)。两步反应可以一锅处理,合成方法简单,产率很高,可以工业化生产。反应粗产物(Ig)和(Ih)为磷手性中心未被拆分的差向异构体混合物,少量产物可以柱层析纯化处理,大量的可以用L-或者D-酒石酸进行拆分来纯化分离,也即用乙腈、丙酮、乙酸乙酯、水或者它们的混合溶剂来重结晶分离(Ig)或者(Ih)与酒石酸形成的盐;也可以利用两种差向异构体的溶解度差异来动力学拆分;或者利用超临界色谱进行分离纯化。
优选地,酰化缩合剂是N,N′-二环己基碳二亚胺(DCC)、1-乙基-(3-二甲基氨基丙基)碳化二胺基盐酸盐(EDC)、1-羟基苯并三唑(HOBt)、2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)、PyBOP等常见氨基酸缩合试剂。
优选地,碱性缚酸剂是三乙基胺或者二异丙基乙基胺。
优选地,有机溶剂可以是N,N-二甲基甲酰胺、N,N-二甲基乙酰胺甲苯、N-甲基吡咯烷酮、二甲亚砜、乙腈等中的一种或多种,推荐为N,N-二甲基甲酰胺、N-甲基吡咯烷酮。
优选地,反应温度为0℃到溶剂回流温度,推荐为室温到20-60℃。
优选地,反应时间为3-72小时,推荐以TLC监测反应终点。
又一方面,本发明提供一种药物组合物,该药物组合物包含前述的化合物或其异构体或可药用盐。
再一方面,本发明的前述核苷类似物的、含有烃氧基苄基的氨基磷酸酯前药或其异构体或可药用盐,可以用于升级各种核苷类抗病毒药物或抗癌药物。即本发明提供前述的化合物或其异构体或可药用盐在制备预防和/或治疗由病毒,例如HIV、HBV和HCV等病毒感染引起的疾病的药物;或者在制备预防和/或治疗癌症的药物中的用途。
附图说明
附图图1为核苷、核苷酸与核酸的聚合过程;
附图图2为常见核苷前药;
附图图3为McGuigan型芳基胺基磷酸酯(3-1)及其代谢作用机理。
具体实施方式
以下实施例中,所有水敏感反应均在干燥条件下进行。苯、四氢呋喃在金属钠存在下回流、干燥、蒸馏后保存待用,二氯甲烷用五氧化二磷干燥处理后使用。核苷类似物由市场上购买或者参照文献方法合成(J.Org.Chem.2011,76,8311;Org.Proc.Res.Dev.,2010,14,1194;J.Org.Chem.,2003,68,6799;WO 2010075549A2),核苷类似物使用前最好在真空下50℃左右干燥。核苷化合物的含烃氧基苄基的氨基磷酸酯衍生物可以利用硅胶柱层析方法分离,得到的是烃氧基苄基氨基磷酸酯(I)的差向异构体混合物,可以进一步通过手性拆分或重结晶或手性柱柱层析等方式分离。
通过下述实施例有助于理解本发明,但并不限制本发明的内容。
实施例1
将化合物1(12.8g,50mmol)溶于二氯甲烷(100mL)中并冷却至-78℃下,20分钟内缓慢滴加2-乙酰氧基苄醇(8.3g,50mmol)和三乙胺(7.7mL,55mmol)的二氯甲烷(100mL)溶液。反应液在-78℃下搅拌30分钟,然后升温到0℃,慢慢加入干燥D-丙氨酸异丙酯盐酸盐(7.68g,50mmol)的二氯甲烷(100mL)溶液,随后向上述反应液中缓慢滴加三乙胺(14.7mL,105mmol),90分钟滴加完毕,并使反应液零度下继续搅拌3小时。旋转蒸发除去溶剂,加入乙酸乙酯研粉,过滤,滤液浓缩,残余物用硅胶柱层析分离纯化(石油醚∶乙酸乙酯=7∶3)得到无色油状产物3(17.7g,84%)、久置能缓慢固化。1H NMR(CDCl3,400MHz)δ8.22(dd,J1=9.0Hz,J2=1.8Hz,2H),7.23-7.42(m,4H),7.10(dd,J1=9.0Hz,J2=1.8Hz,2H),5.10-5.17(m,2H),4.99-5.05(m,1H),3.95-4.01(m,1H),3.65-3.73(m,1H),2.38(s,3H),1.35-1.45(m,3H),1.10-1.30(m,6H);31P NMR(CDCl3)δ1.92,1.99;MS(m/z)481(M+H)。
实施例2
将苄醇4(152mg,1mmol)和POCl3(95μL,1mmol)的无水乙醚(5mL)溶液冷却到-78℃,缓慢滴加三乙胺(140μL,1mmol),滴加完毕继续搅拌2小时。再于-78℃下向反应液中滴加L-丙氨酸异丙酯盐酸盐(168mg,1mmol)、三乙胺(280μL,2mmol)的二氯甲烷(1mL)溶液,反应60分钟后使反应液在1.5小时内慢慢升温到0℃。
向反应瓶中加入五氟苯酚(184mg,1mmol)的二氯甲烷(1mL)溶液,随后在1小时内慢慢滴加三乙胺(140μL,1mmol),反应液缓慢升至室温搅拌过夜。过滤除去三乙胺盐酸盐,滤饼用少量二氯甲烷洗涤,合并的有机相用水洗后干燥(Na2SO4),浓缩后残余物柱层析可以得到两个差向异构体5a和5b的等比混合物5,两个差向异构体5a和5b可以利用乙酸乙酯-石油醚混合溶剂重结晶而分离。
5:1H NMR(CDCl3)δ6.98-6.67(m,3H),5.99(s,2H),5.63-5.79(m,2H),4.72-4.84(m,1H),4.34(m,1H),3.84-3.91(m,1H),1.40-1.48(m,3H),1.20-1.36(m,6H);31P NMR(CDCl3)δ9.93,9.82;MS(m/z)512(M+H)。
5a:1H NMR(CDCl3,400MHz)δ6.67-6.98(m,3H),5.99(s,2H),5.67(s,2H),4.74-4.84(m,2H),4.32-4.38(m,1H),3.84-3.90(m,1H),1.46(d,3H),1.21-1.37(m,6H);31P NMR(CDCl3)δ9.93;MS(m/z)512(M+H)。
实施例3
采用与实施例2同样的合成方法,由苄醇6制得化合物7、7a和7b。混合产物7:1HNMR(CDCl3,400MHz)δ7.01-7.31(m,3H),5.03-5.09(m,1H),4.72(s,1H),4.64(s,1H),4.02-4.08(m,1H),3.84-3.91(m,1H),2.33(s,1.5H),2.30(s,1.5H),1.36-1.46(m,3H),1.22-1.34(m,6H);MS(m/z)516(M+H)。
7a:1H NMR(CDCl3,400MHz)δ7.01-7.28(m,3H),5.03-5.09(m,1H),4.64(s,2H),4.02-4.08(m,1H),3.84-3.90(m,1H),2.30(s,3H),1.41-1.46(m,3H),1.24-1.28(m,6H);MS(m/z)516(M+H)。
7b:1H NMR(CDCl3,400MHz)δ7.10-7.32(m,3H),5.06-5.12(m,1H),4.71(s,2H),4.07-4.11(m,1H),3.77-3.81(M,1H),2.33(s,3H),1.45-1.49(m,3H),1.24-1.30(m,6H);MS(m/z)516(M+H)。
实施例4
将化合物1(1.28g,5mmol)溶于二氯甲烷(10mL)中并冷却至-78℃下,20分钟内缓慢滴加苄醇(0.76g,5mmol)和三乙胺(0.8mL,5.5mmol)的二氯甲烷(10mL)溶液。反应液在-78℃下搅拌30分钟,然后升温到0℃,慢慢加入干燥L-丙氨酸异丙酯盐酸盐(0.77g,5mmol)的二氯甲烷(10mL)溶液,随后向上述反应液中缓慢滴加三乙胺(1.5mL,10.5mmol),90分钟滴加完毕,并使反应液零度下继续搅拌3小时。旋转蒸发除去溶剂,加入乙酸乙酯研粉,过滤,滤液浓缩,残余物用硅胶柱层析分离纯化(石油醚∶乙酸乙酯=7∶3)得到无色膏状产物8(77%)。1H NMR(CDCl3,400MHz)δ8.24(d,2H),7.46(d,2H),6.66-6.88(m,3H),5.97(s,2H),5.29-5.33(m,2H),5.01-5.07(m,1H),4.00-4.06(m,1H),3.78-3.83(m,1H),3.10-3.13(m,1H),1.47-1.40(m,3H),1.20-1.33(m,6H);MS(m/z)467(M+H)。
实施例5
采用与化合物8同样的合成方法,制得化合物9。1H NMR(CDCl3,400MHz)δ8.21-8.26(m,2H),7.28-7.42(m,3H),7.09-7.12(m,2H),5.32(s,1H),5.13-5.17(m,1H),4.99-5.04(m,1H),3.95-4.01(m,1H),3.83(s,3H),3.67-3.75(m,1H),1.35-1.45(m,3H),1.10-1.30(m,6H);31P NMR(CDCl3)δ1.95,1.99;MS(m/z)480(M+H)。
实施例6
在-78℃下向三氯氧磷(1.39g,9.1mmol)的无水二氯甲烷(15mL)溶液中滴加2-甲氧基苄醇(1.26g,9.1mmol)和三乙胺(1.26mL,9.1mmol)的无水CH2Cl2(2mL)溶液。在相同温度下搅拌3小时后,向反应混合物一次性加入D-丙氨酸异丙酯盐酸盐(1.52g,9.1mmol),然后15分钟内滴加三乙胺(2.64mL,18.5mmol)的无水CH2Cl2(2mL)溶液。在-78℃下再搅拌1小时,然后在1小时内升温至室温。向反应液中滴加五氟苯酚(1.0g,9.1mmol)和三乙胺(1.5mL,10.9mol)在无水二氯甲烷(2mL)中的混合溶液,并在室温下搅拌过夜。过滤收集固体,浓缩滤液。将所得残余物和收集的固体合并,并在EtOAc(20mL)和H2O(10mL)之间分配。分离有机层,水层用EtOAc(2×10mL)萃取。将合并的有机层用盐水(10mL)洗涤,用无水Na2SO4干燥,然后浓缩。给出的残余物用二异丙基醚和石油醚(1∶2,40mL)的混合物处理并加热至回流。将整个固体溶解后,将其冷却并在室温下保持3天后析出白色固体纯品10a(0.97g)。1H NMR(400MHz,Chloroform-d)δ7.81-7.00(m,3H),7.00-6.77(m,1H),5.37-5.21(m,2H),5.07(m,1H),4.16-4.00(m,1H),3.88(s,3H),1.47(d,J=4.0Hz,3H),1.40-1.21(m,6H);31P NMR(400MHz,Chloroform-d)δ3.5;MS(m/z)498(M+H)。
实施例7
在-78℃下向三氯氧磷(1.39g,9.1mmol)的无水二氯甲烷(15mL)溶液中滴加5-氯-2-甲氧基苄醇(1.74g,9.1mmol)和三乙胺(1.26mL,9.1mmol)的无水CH2Cl2(2mL)溶液。在相同温度下搅拌3小时后,向反应混合物一次性加入D-丙氨酸异丙酯盐酸盐(1.52g,9.1mmol),然后15分钟内滴加三乙胺(2.64mL,18.5mmol)的无水CH2Cl2(2mL)溶液。在-78℃下再搅拌1小时,然后在1小时内升温至室温。向反应液中滴加五氟苯酚(1.0g,9.1mmol)和三乙胺(1.5mL,10.9mol)在无水二氯甲烷(2mL)中的混合溶液,并在室温下搅拌过夜。过滤收集固体,浓缩滤液,将所得残余物和收集的固体合并,并在EtOAc(20mL)和H2O(10mL)之间分配。分离有机层,水层用EtOAc(2×10mL)萃取。将合并的有机层用盐水(10mL)洗涤,用无水Na2SO4干燥,然后浓缩。给出的残余物用二异丙基醚和石油醚(1∶2,40mL)的混合物处理并加热至回流。将整个固体溶解后,将其冷却并在室温下保持3天后析出白色固体纯品11a(1.17g)。1H NMR(400MHz,CDCl3)δ7.42-7.34(m,1H),7.03-6.94(m,1H),6.95-6.88(m,1H),5.37-5.21(m,2H),5.07(m,1H),4.16-4.00(m,1H),3.88(s,3H),1.47(d,3H),1.40-1.21(m,6H);31P NMR(400MHz,CDCl3)δ3.7;MS(m/z)532(M+H)。
实施例8
化合物12(260mg,1mmol)溶于20mL无水四氢呋喃中,0℃下加入叔丁基氯化镁格氏试剂(1.0M,2mL,2mmol),室温搅拌反应30分钟。缓慢滴加入化合物10a(1.0g,2mmol)的四氢呋喃溶液(4mL),反应混合物室温下搅拌过夜,加入饱和氯化铵溶液(20mL)淬灭反应,乙酸乙酯萃取(20mL x 3),有机相合并,干燥,浓缩,残余物以硅胶柱层析纯化(二氯甲烷∶甲醇=20∶1)进而得到白色泡沫状产物13。1H NMR(CD3OD,400MHz)δ7.54-7.57(m,1H),7.22-7.44(m,4H),6.00(s,1H),5.75-5.60(m,1H),4.97-5.13(m,3H),4.04-4.42(m,4H),3.88(s,3H),3.71-3.85(m,2H),1.71-1.77(m,2H),1.11-1.38(m,12H);31P NMR(CD3OD)δ7.89;MS(m/z)572(M+H)。
实施例9
采用实施例8的合成方法,将化合物14与磷试剂9在叔丁基氯化镁的催化下SN2取代反应,可以得到产物15。1H NMR(CD3OD,400MHz)δ7.59(d,J=7.5Hz,1H),6.88-7.33(m,3H),6.25(t,J=7.5Hz,1H),5.85(d,J=7.5Hz,1H),4.95-5.01(m,2H),4.32-4.45(m,2H),4.20-4.25(m,1H),4.00-4.08(m,1H),2.32(s,3H),1.16-1.37(m,9H);31P NMR(CD3OD,400MHz)δ3.67,4.89;MS(m/z)604(M+H)。
实施例10
采用实施例8的合成方法,将化合物16与磷试剂8在叔丁基氯化镁的催化下SN2取代反应,可以得到产物17。1H NMR(CD3OD,400MHz)δ7.86(d,J=6.4Hz,1H)7.16-7.39(m,4H),6.22-6.30(m,1H),5.77(s,2H),4.96-4.99(m,1H),3.90-4.50(m,5H),2.57(t,J=7.6Hz,2H),1.74-1.79(m,2H),2.00-2.35(m,2H),1.20-1.53(m,29H),0.90(t,J=6.4Hz,3H);31P NMR(CD3OD,400MHz)δ3.91,4.22;MS(m/z)574(M+H)。
实施例11
采用实施例8的合成方法,将化合物18与磷试剂3在叔丁基氯化镁的催化下SN2取代反应,可以得到产物19。1H NMR(CD3OD,400MHz)δ7.94(d,J=8.4Hz,1H),7.22-7.45(m,4H),5.13-5.19(m,1H),4.67(s,2H),4.52-4.57(m,2H),3.77-3.82(m,1H),3.45-3.48(m,1H),3.13-3.17(m,2H),2.57-2.60(m,1H),2.35(s,3H),1.12-1.4(m,9H);31P NMR(CD3OD,400MHz)δ5.5,3.9;MS(m/z)589(M+H)。
实施例12
采用实施例8的合成方法,将化合物20与手性磷试剂5a在叔丁基氯化镁的催化下SN2取代反应,可以得到产物21,为SP单一差向异构体富集的化合物。1H NMR(CD3OD)δ7.49(d,J=8.2Hz,1H),6.67-6.98(m,3H),6.20(d,J=18.4Hz,1H),5.99(s,2H),5.73(d,J=8.2Hz,1H),5.47(m,2H),5.01-5.06(m,1H),3.50-4.40(m,5H),1.19-1.39(m,12H);31P NMR(CD3OD,400MHz)δ5.2;MS(m/z)588(M+H)。
实施例13
在80mL DMF的溶剂中,加入(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤22(3.5g,8.9mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC,1.9g,10mmol)、三乙胺(3.8mL,27mmol)、4-(N,N-二甲氨基)吡啶(320mg,2.6mmol)和苄醇23(2.23g,14.7mmol),室温搅拌30分钟后,于100度加热反应24小时,反应完毕,减压浓缩除去溶剂,残余物溶于水中,经反相C-18柱层析(甲醇∶水=1∶9)纯化,得到黄色膏状产物24;MS(m/z)422(M+H)。
实施例14
将化合物24(47mg,0.11mmol)悬浮于乙腈(1mL)中,50℃搅拌下加入二氯亚砜(33μL,0.25mmol),然后在75-80℃反应两小时。随后氮气保护下蒸除溶剂,残余物溶于干燥的二氯甲烷(2mL)中并冷却至-30℃。一小时内慢慢加L-丙氨酸异丙酯盐酸盐(30mg,0.2mmol)和三乙胺(30μL,0.22mmol)的二氯甲烷溶液(0.5mL),反应液慢慢升至室温过夜。待反应结束,加入10%磷酸二氢钠溶液淬灭反应,加入二氯甲烷(10mL)稀释、萃取,有机相用饱和食盐溶液洗涤、干燥(硫酸钠)、过滤然后浓缩,残余物以柱层析纯化,得到白色固体产物25(30mg,52%)。1HNMR(CDCl3)δ8.32(s,1H),7.92(s,1H),6.68-6.96(m,3H),6.02(s,2H),5.80(m,2H),4.94-5.07(m,3H),4.29-4.42(m,1H),3.08-4.14(m,4H),1.16-1.30(m,12H);31P NMR(CDCl3)δ23.92,24.89;MS(m/z)535(M+H)。
实施例15
在氮气保护下,将化合物22(287mg,1mmol)溶于10mL乙腈中,随后加入TMSBr(0.66mL,5mmol)并使反应液在室温下搅拌过夜。减压蒸除溶剂,残余物溶于无水三乙胺(2mL)和吡啶(8mL)混合溶剂中,随后加入D-丙氨酸异丙酯盐酸盐(250mg,1.5mmol)和对-乙酰氧基苄醇(250mg,1.5mmol)搅拌溶解。在另外一个反应瓶中将化合物26(1.1g,5mmol)和三苯基膦(1.31g,5mmol)于无水吡啶(50mL)中混合,生成的亮黄色溶液立即用双头针转移到化合物22的反应瓶中,反应液于50-60℃加热5小时。反应结束后减压浓缩,残余物在乙酸乙酯和碳酸氢钠水溶液间分配,有机相用无水硫酸钠干燥、过滤、浓缩,残余物用手性制备色谱(Diacel’s Chiralpak AS)分离,用含25%甲醇的乙腈流动相层析,得到产物(27a)和(27b)。
27a:1H NMR(CDCl3)δ8.32(s,1H),7.92(s,1H),7.35(d,J=8.5Hz,2H),7.08(d,J=8.5Hz,2H),5.99(s,2H),4,87-5.06(m,3H),4.55-4.68(m,1H),3.78-4.07(m,4H),3.52-3.63(m,1H),3.32-3.37(m,1H),2.31(s,3H),1,14-1.35(m,12H);31P NMR(CDCl3)δ23.96;MS(m/z)549(M+H)。
27b:1H NMR(CDCl3)δ8.34(s,1H),7.92(s,1H),7.31(d,J=8.5Hz,2H),7.05(d,J=8.5Hz,2H),5.99(s,2H),4,87-5.06(m,3H),4.61-4.71(m,1H),3.78-4.07(m,5H),3.52-3.63(m,1H),2.30(s,3H),1,14-1.35(m,12H))HHHH;31P NMR(CDCl3)δ24.93;MS(m/z)549(M+H)。
实施例16
采用实施例15的合成方法,将化合物22与D-丙氨酸异丙酯盐酸盐和5-氯-2-甲氧基苄醇缩合,得到浅黄色泡沫状固体产物28(48%)。1H NMR(400MHz,Methanol-d4)δ8.19(s,,1H),8.18(s,1H),7.27(dt,J=5.0,2.6Hz,2H),6.95(d,J=9.4Hz,1H),5.51(s,1H),5.07-4.93(m,2H),4.37(d,J=3.1Hz,1H),4.25(dd,J=14.6,7.2Hz,2H),4.07-3.89(m,2H),3.38(s,3H),1.45-1.31(m,3H),1.24(dt,J=6.2,4.0Hz,9H);31P NMR(MeOH-d4)δ26.92,26.39;MS(m/z)555(M+H)。
实施例17
采用实施例15的合成方法,将化合物22与L-丙氨酸异丙酯盐酸盐和5-氯-2-甲氧基苄醇缩合,得到无色泡沫状固体产物29(58%)。1H NMR(400MHz,Chloroform-d)δ8.23(s,1H),7.91(s,0.5H),7.90(s,0.5H),7.26(dd,1H),7.18-7.09(m,1H),6.70(dd,1H),6.62(s,2H),5.07-4.79(m,3H),4.43-4.14(m,2H),4.09(m,1H),4.01-3.78(m,2H),3.73(d,J=4.7Hz,3H),3.71-3.57(m,2H),1.34-1.00(m,12H).;31P NMR(MeOH-d4)δ25.04,24.20;MS(m/z)555(M+H)。
实施例18
采用实施例15的合成方法,将化合物22与L-丙氨酸异丙酯盐酸盐和2-甲氧基苄醇缩合,得到淡黄色泡沫状固体产物30(58%)。1H NMR(400MHz,Chloroform-d)δ8.34(s,1H),7.98(s,0.5H),7.93(s,0.5H),7.38-7.24(m,3H),7.05-6.80(m,2H),5.78(s,2H),5.17-4.88(m,3H),4.35(m,1H),4.22-3.75(m,6H),3.62(m,1H),1.36(d,J=7.0Hz,3H),1.32-1.11(m,9H);31P NMR(CDCl3)δ24.56,23.78;MS(m/z)521(M+H)。
实施例19
采用实施例15的合成方法,将化合物22与D-丙氨酸异丙酯盐酸盐和2-甲氧基苄醇缩合,可以得到淡黄色泡沫状固体产物31,采用硅胶柱层析、DCM-MeOH(25∶1)为流动相缓慢洗脱,可以纯化得到两个差向异构体31a与31b,其磷手性中心的构型未确定,31a为先洗脱下来的产物。
31a:1H NMR(400MHz,Methanol-d4)δ8.20(s,1H),8.16(s,1H),7.28-7.12(m,4H),5.03-4.96(m,1H),4.36(dd,1H),4.23(dd,1H),4.11(q,1H),4.03-3.68(m,4H),2.29(s,3H),1.34(dd,3H),1.29-1.16(m,9H);31P NMR(CDCl3)δ26.56;MS(m/z)521(M+H)。
31b:1H NMR(400MHz,Methanol-d4)δ8.21(s,1H),8.15(s,1H),7.35-7.10(m,4H),5.17-4.95(m,3H),4.37(dd,1H),4.22(dd,1H),4.11(q,1H),4.00-3.84(m,2H),3.70(dd,1H),2.33(s,3H),1.47-1.11(m,12H);31P NMR(CDCl3)δ26.04;MS(m/z)521(M+H)。
实施例20
采用实施例15的合成方法,将化合物22与L-丙氨酸异丙酯盐酸盐和4-甲氧基苄醇缩合,柱层析方法纯化得到无色泡沫状固体产物32a和32b的混合物32。产物32a和32b两种差向异构体可以使用D-酒石酸拆分的方法分离,其具体方法如下:
将柱层析得到的32a和32b两种异构体的混合物10g溶于100mL乙腈中,加入3.78gD-酒石酸,加热反应液至60-65℃保持3小时,冷却后过滤收集得到的白色沉淀,为产物32与D-酒石酸的混合物盐。
将1.2g上述32的酒石酸盐悬浮于10mL水-乙腈(10∶1)溶剂中,加热到60-65℃保持1小时,得到的沉淀为PR构型的32a的酒石酸盐。
取0.6g化合物32a的酒石酸盐悬浮于2mL二氯甲烷和1mL水之间,加入氨水调节pH8-9之间,萃取分层,有机相浓缩,加水1mL并在55-60℃之间搅拌一小时,冷却后过滤即使游离的化合物32a。
使用L-酒石酸对混合物32拆分则得到纯的PS构型的32b。
32a:1H NMR(CDCl3)δ8.35(s,1H),7.96(s,1H),7.29(d,J=8.6Hz,2H),6.90(d,J=8.6Hz,2H),5.75(s,2H),4.86-5.06(m,3H),4.37-4.41(m,1H),3.14-4.15(m,6H),3.82(s,3H),1.14-1.34(m,12H);31P NMR(CDCl3)δ23.74;MS(m/z)521(M+H)。
32b:1H NMR(CDCl3)δ8.36(s,1H),7.94(s,1H),7.28(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),5.76(s,2H),4.86-5.06(m,3H),4.30-4.34(m,1H),3.14-4.15(m,6H),3.81(s,3H),1.14-1.34(m,12H);31P NMR(CDCl3)δ24.57;MS(m/z)521(M+H)。
实施例21
采用实施例15的合成方法,将化合物22与D-丙氨酸异丙酯盐酸盐和苄醇33缩合,得到无色泡沫状固体产物34(48%)。1H NMR(CDCl3)δ8.36(s,0.5H),8.35(s,0.5H),7.95(s,0.5H),7.94(s,0.5H),7.16-7.40(m,4H),5.89(s,2H),4.90-5.05(m,4),3.45-4.40(m,8H),1.42(s,9H),1.12-1.26(m,15H);MS(m/z)678(M+H)。
实施例22
化合物34(70mg,0.1mmol)于0℃下溶于4毫升二氯甲烷中,慢慢加入1毫升三氟乙酸,搅拌反应2小时,蒸除溶剂后得到的残余物在饱和NaHCO3水溶液和氯仿/异丙醇(4∶1)之间分配萃取,有机相用食盐水洗涤后干燥,浓缩,残余物用二异丙基醚洗涤后得到白色的产物35。1H NMR(MeOH-d4)8.37(s,0.5H),8.36(s,0.5H),7.95(s,0.5H),7.93(s,0.5H),7.16-7.44(m,4H),4.90-5.05(m,4),3.45-4.40(m,6H),1.12-1.26(m,15H);MS(m/z)578(M+H)。
实施例23
采用实施例15的合成方法,将化合物22与L-丙氨酸异丙酯盐酸盐和苄醇36缩合,得到淡黄色泡沫状固体产物37(48%)。1H NMR(CDCl3)δ8.22(s,1H),7.95(s,1H),6.88-6.92(m,3H),6.08(s,2H),4.94-5.00(m,2H),4.20-4.25(m,1H),4.05-4.11(m,1H),3.78-4.01(m,3H),3.74(s,1.5H),3.72(s,1.5H),3.57-3.65(m,2H),1.28-1.31(m,3H),1.10-1.20(m,9H);MS(m/z)535(M+H)。
实施例24
采用实施例15的合成方法,将化合物22与L-丙氨酸异丙酯盐酸盐和苄醇38缩合,得到淡黄色泡沫状固体产物39(45%)。1H NMR(CDCl3)δ8.22(s,1H),7.95(s,0.5H),7.94(s,0.5H),7.15-7.90(m,3H),6.02(s,2H),4.94-5.00(m,2H),4.20-4.25(m,1H),4.05-4.11(m,1H),3.78-4.01(m,3H),3.74(s,1.5H),3.72(s,1.5H),3.57-3.65(m,2H),1.28-1.31(m,3H),1.10-1.20(m,9H);MS(m/z)548(M+H)。
实施例25
将化合物31(50mg,0.1mmol)溶于1mL乙腈中,加入富马酸(10mg,0.9eq),加热回流30分钟得到澄清溶液,降温至45-50℃之间后趁热过滤,滤液冷却至室温后析出白色固体,滤除溶剂,滤饼以冷乙腈洗涤,得到白色固体产物40。
实施例26
将化合物31a(50mg,0.1mmol)溶于无水乙腈(2mL)中,加入富马酸(10mg,0.09mmol)后加热回流1小时,冷却至室温慢慢析出固体,过滤,用0-5℃冷乙腈洗涤滤饼,得到白色粉末固体40a。
实施例27
将化合物31b(50mg,0.1mmol)溶于无水乙腈(2mL)中,加入富马酸(10mg,0.09mmol)后加热回流4小时,冷却至室温慢慢析出固体,过滤,用0-5℃冷乙腈洗涤滤饼,得到白色粉末固体40b。
实施例28(HCV活性)
化合物的抗HCV活性的测试方法参考文献报道(WO2007/027248)在人肝细胞Huh-7中进行,待测化合物的活性通过带有萤光素酶基因的HCV基因型1b复制子的复制情况来评估。萤光素酶的信号强度直接对应于病毒RNA的复制量。核苷磷酸酯前药配置成从0.1到30μM等不同浓度的DMSO溶液,索菲布韦41为参照,然后施加到96-孔板上,随后加入复制子细胞(每孔6000个细胞)。细胞在核苷前药的存在下孵化48小时,然后测量萤光素酶强度。萤光素酶信号的减弱标志着细胞中HCV复制子RNA的减弱,它可以进而用以计算抗病毒活性指标EC50。
经测试,化合物13和21表现出较好的抗丙肝病毒活性,具体结果见下表,在100μM下对PBM、CEM等细胞均无任何毒性。
对比化合物13和42的HCV体外活性,可知苄基苯环上邻位甲氧基取代明显比甲基取代使得氨基磷酸酯前药活性提升更大;而对比化合物21和41,可见烃氧基苄基与酚基相比具有更强的释放出核苷单磷酸的能力,表现为化合物21相对于丙肝药物索菲布韦具有更佳的体外活性。
实施例29(HIV活性)
化合物的抗HIV-1活性的测试方法参考文献报道(Antimicrob.AgentsChemother.,1992,36,2423)在PBM淋巴细胞中进行。核苷磷酸酯前药配置成(20-40mM)的DMSO溶液,然后稀释成一系列不同的浓度后与HIV-1LAI病毒感染了的PBM细胞共同培养。HIV-1LAI病毒与PBM细胞数量比MOI=0.01,DMSO溶剂本身对病毒繁殖没有影响,AZT为参照,抗病毒活性指标EC50根据抑制率-浓度曲线计算而得(Adv.Enzyme Regul.,1984,22,27)。
经测试证实,化合物25、28、29、30、31a、31b、32a、32b、35及37均表现出非常好的抗艾滋病毒活性,结果见下表1。
实施例30大鼠灌胃替诺福韦衍生物后药代动力学实验
取大鼠三组共12只,按10mg/kg剂量灌胃给予替诺福韦二吡呋酯43、化合物31和44(每组四只大鼠,雌雄各二),分别于给药前0.5h和给药后0.25,0.5,1.0,1.5,2.0,4.0,6.0,8.0,12,24h取血约150μL至肝素化试管中,于8000rpm离心5min,分离出血浆。取40.0μL大鼠血浆样品,加入20.0μL内标工作液(含Labetalol 500ng/mL)甲醇∶水(1∶1,v∶v)溶液,加入320μL0.1%甲酸乙腈沉淀蛋白,涡旋混合5分钟,样品于4℃的离心机中以17000x g离心10分钟。取上清液10μL用LC-MS测定替诺福韦22的浓度。利用DAS 2.0药代动力学专业软件,以统计矩方法进行运算,求得每只动物相应的药动学参数(表2)。
表2大鼠灌胃三种替诺福韦衍生物后大鼠体内替诺福韦22的药代动力学参数
由表2可以看出,三个替诺福韦前药衍生物灌胃给药后的达峰时间相当,主要差别在AUC0-24h。2-甲氧基苄基氨基膦酸酯前药31组的AUC较43与44组有较大幅度提升,达到后者AUC的2.5倍以上,而相应的前药44与替诺福韦二吡呋酯43的药代参数接近,体现出烃氧基苄醇参与构成的氨基膦酸酯前药在生物体内代谢、传送替诺福韦过程中的优越性。
Claims (10)
1.一种式(I)所示的烃氧基苄基氨基磷酸酯/膦酸酯化合物,其立体异构体、或其药学可接受的盐、水合物、溶剂化物或结晶,分子结构中的任何一个氢原子都可以被氘原子置换:
如式(I)所示,本发明的烃氧基苄基氨基磷酸/膦酸酯前药结构中含有一个由烃氧基苄醇参与形成的磷酯键和一个由L-或D-氨基酸酯参与形成的磷酰胺键。
其中,
R1为各种天然或非天然氨基酸侧链,氨基酸构型可以是D-型、L-型或者其消旋混合物;
R2可以选自C1-12饱和或不饱和烷基、卤素(F、Cl、Br、I)取代的C1-12烷基、羟基取代的C1-12烷基、C1-6烷氧基羰基取代的C1-12烷基、羧基取代的C1-12烷基、氰基取代的C1-12烷基、C3-7环烷基取代的C1-6烷基、苯基取代的C1-6烷基、C1-6烷基砜基取代的C1-6烷基、C1-6烷基亚砜基取代的C1-6烷基、胺基取代的C1-12烷基、C1-6烷基酰胺基取代的C1-6烷基、C1-6烷基磺酰胺基C1-6烷基、胺基羰基C1-6烷基、单环杂环烷基C1-6烷基、C3-C8的饱和或不饱和环烷基;
R2’可以是氢、羟基、卤素(F、Cl、Br、I)、氰基、硝基、C1-6烷基、C1-6烷氧基、杂原子(O、S、N)取代C1-6烷基、杂原子取代C1-6烷氧基、C3-7环烷基、C3-7环烷基取代的C1-4烷基、C3-7杂环烷基取代C1-4烷基,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基可以被卤素、羟基、氰基、胺基或者硝基取代;
PG-可以是各种酚羟基的保护基,它与氧原子构成烃氧基PG-O-。式(I)苄醇结构中烃氧基PG-O-可以位于苄醇羟甲基HOCH2-的邻位、间位或者对位,优选邻位取代的烃氧基:
PG-可选自各类酰基保护基:C1-C22碳链的直链或带支链的脂肪酸酰基R0-21CO-、C3-C22碳链的不饱和的脂肪酸酰基R2-21CO-、芳基甲酰基ArCO-、杂环芳基甲酰基、芳基烷基脂肪酸酰基、碳酸酯酰基(如Boc-、-CO-或Cbz-)、氨基碳酸酯酰基(-NHCOO-)、丙氨酰基、甘氨酰基、脯氨酰基、赖氨酰基、苯丙氨酰基、亮氨酰基、异亮氨酰基、缬氨酰基、色氨酰基、酪胺酰基、天冬氨酰基、天冬酰胺酰基、谷氨酰基、谷氨酰胺酰基、甲硫氨酰基、苏氨酰基、组胺酰基、丝氨酰基、半胱氨酰基、精氨酰基或β-丙氨酰基;
PG-也可选自各类醚类保护基:C1-12饱和或不饱和烷基,杂原子(O、S、N)取代的C1-12烷基、C3-7环烷基、C3-7环烷基取代的C1-4烷基、C3-7杂环烷基取代C1-4烷基、芳基取代C1-6烷基(如Bn-或PMB-)、杂环芳基取代C1-6烷基、硅基R’R”R”’Si-,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基、芳基、杂环芳基可以被卤素、羟基、氰基、氨基、胺基或者硝基取代;
PG-还可以是缩醛类保护基:甲氧基亚甲基MOM-、四氢吡喃基THP-、特戊酰氧基亚甲基tBuCO2CH2-、异丙氧基羰基氧亚甲基iPrOCO2CH2-、亚甲基二氧基-OCH2O-等等。
X1可以不存在、或者是-OCH2-或-OCH(CH3)-。
X2选自O、S、CH2、C=CH2、CHCH3或环丙烷基
X3可以不存在、或者是亚甲基CH2。
T1、T2相互独立,可以是H或者CH2R3,而R3为H、OH或F;T1、T2也可以互相键合在一起构成如下五元呋喃糖环:
其中,X1、X2、X3定义如前所述;R4、R5、R6、R7、R8、R9相互独立,可以是氢、羟基、氟、氯、溴、氰基、叠氮、氨基或C1-4的烷基、C2-4的烯基、C2-4的炔基或者C1-4的烷氧基。
Base是嘌呤或者嘧啶类碱基,或者其化学和代谢衍生物,其具有以下结构通式:
其中,X4可以选自氢、卤素(F、Cl、Br、I)、C1-8短链烷基如甲基、乙烯基、2-溴代乙烯基、(取代)乙炔基;
X5、X6和X7各自独立,可以选自氢、卤素(F、Cl、Br、I)、羟基、氨基、C1-4烷氧基、苄氧基、C3-6环烷基氧基、C1-4烷硫基、苄硫基、C3-6环烷基硫基、C1-4烷氨基或者C3-6环烷基氨基,这里所述烷基、环烷基、苄基可以被卤素、羟基、氰基、胺基或者硝基取代。
Z为氮、CH或者CX4,X4定义如前所述。
2.根据权利要求1所述的烃氧基苄基氨基磷酸/膦酸酯化合物,其立体异构体、或其药学可接受的盐、水合物、溶剂化物或结晶,烃氧基为RCOO-且位于苄基的邻位、间位或者对位,优选邻位取代,具有下式(II)、(III)或(IV)的结构:
其中,R1、R2、R2’、T1、T2、X1、X2、X3、Base的定义如权利要求1所述;
R选自C0-21饱和或不饱和烷基、C3-7的饱和或不饱和环烷基、杂原子(O、S、N)取代的C1-12烷基、C3-7环烷基取代的C1-4烷基、C3-7杂环烷基取代C1-4烷基、芳基、杂环芳基、芳基C1-6烷基、杂环芳基C1-6烷基、C1-C12烷氧基、芳基C1-6烷氧基、杂环芳基C1-6烷氧基,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基、芳基、杂环芳基可以被卤素、羟基、氰基、氨基、胺基或者硝基取代。
3.根据权利要求1所述的烃氧基苄基氨基磷酸/膦酸酯化合物,其立体异构体、或其药学可接受的盐、水合物、溶剂化物或结晶,烃氧基为R’O-且位于苄基的邻位、间位或者对位,优选邻位取代,其具有下式(V)、(VI)或(VII)的结构:
其中,R1、R2、R2’、T1、T2、X1、X2、X3、Base的定义如权利要求1所述;
R’选自C1-12饱和或不饱和烷基,杂原子(O、S、N)取代的C1-12烷基、C3-8环烷基、C3-8杂环烷基、C3-8环烷基取代的C1-4烷基、C3-8杂环烷基取代C1-4烷基、芳基C1-6烷基、杂环芳基C1-6烷基、硅基R’R”R”’Si-、甲氧基亚甲基MOM-、亚甲二氧基-OCH2O-、特戊酰氧基亚甲基tBuCO2CH2-、异丙氧基羰基氧亚甲基iPrOCO2CH2-,这里所述烷基、杂原子取代烷基、环烷基、杂环烷基、芳基、杂环芳基可以被卤素、羟基、氰基、氨基、胺基或者硝基取代。
4.根据权利要求1至3中任一项所述的烃氧基苄基氨基磷酸/膦酸酯化合物,其立体异构体、或其药学可接受的盐、水合物、溶剂化物或结晶,其特征在于结构式中
代表各种核苷类似物,包括常见的呋喃环核苷、碳环核苷以及非环核苷,它可以选自以下核苷,但不仅限于以下核苷化合物:
5.根据权利要求1-4任一项所述的烃氧基苄基氨基磷酸/膦酸酯化合物、其立体异构体、或其药学可接受的盐、水合物、溶剂化物或结晶,通式(I)-(VII)结构中的磷原子手性中心,可以是差向异构体富集的如(Ib)、(Ic)、(Ie)、(If);也可以是外消旋的如(Ia)和(Id):
6.根据权利要求1-5任一项所述的烃氧基苄基氨基磷酸/膦酸酯化合物、其立体异构体、或其药学可接受的盐、水合物、溶剂化物或结晶,通式(I)-(VII)优先选择以下的化合物,但不仅仅局限于以下的化合物:
其中,R1为D-或L-氨基酸的侧链;T2为氢、甲基或者亚甲基羟基(-CH2OH)。
7.一种适用于制备手性烃氧基苄基氨基磷酸酯前药的中间体磷试剂,选自下式(IXa)、(IXb)、(Xa)或(Xb):
其中LG为离去集团,为氯或者苯环上带有强吸电子基团EWG的酚氧基,而吸电子基常见的有卤素(氟、氯、溴)、砜基、磺基和硝基,至少有含一个或者多达五个吸电子基。优选地,LG离去集团为五氟苯酚氧基或者对硝基苯酚氧基;PG-O-为烃氧基,R1和R2’的定义如权利要求1所述。
8.一种制备氨基磷酸酯中间体磷试剂(IX)和(X)的通用方法:
三氯氧磷依次分别与等当量的烃氧基取代的苄醇、L-或D-氨基酸酯以及带强吸电子基的苯酚反应,在适当碱性缚酸剂(如三乙基胺)存在下、在适当的有机溶剂(如二氯甲烷)中一步法制备而得,磷试剂可以柱层析纯化,也可以重结晶纯化。
9.权利要求1至6中任一项所述的化合物或其异构体或可药用盐。其特征在于,所述异构体包括互变异构体、顺反异构体、构象异构体和光学异构体;所述可药用盐为式(I)-(VII)的化合物与无机酸或有机酸形成的盐,优选地,所述有机酸为富马酸。
10.一种药物组合物,该药物组合物包含权利要求1至6中任一项所述的化合物或其异构体或可药用盐,在制备预防和/或治疗由病毒,例如HIV、HBV、HCV、HSV、登革热、伊波拉病毒等感染引起的疾病的药物;或者在制备预防和/或治疗癌症的药物中的用途。
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