CN1291994C - 核苷酸膦酸酯类似物前药及其筛选和制备方法 - Google Patents
核苷酸膦酸酯类似物前药及其筛选和制备方法 Download PDFInfo
- Publication number
- CN1291994C CN1291994C CNB018131611A CN01813161A CN1291994C CN 1291994 C CN1291994 C CN 1291994C CN B018131611 A CNB018131611 A CN B018131611A CN 01813161 A CN01813161 A CN 01813161A CN 1291994 C CN1291994 C CN 1291994C
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- Prior art keywords
- methyl
- amino
- tautomer
- salt
- alkyl
- Prior art date
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- Expired - Lifetime
Links
- 229940002612 prodrug Drugs 0.000 title abstract description 108
- 239000000651 prodrug Substances 0.000 title abstract description 108
- 238000000034 method Methods 0.000 title abstract description 55
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 2
- -1 magnesium alkoxide Chemical class 0.000 claims abstract description 59
- 239000000203 mixture Substances 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims description 31
- 239000002585 base Substances 0.000 claims description 28
- 239000011782 vitamin Substances 0.000 claims description 28
- 235000013343 vitamin Nutrition 0.000 claims description 28
- 229940088594 vitamin Drugs 0.000 claims description 28
- 229930003231 vitamin Natural products 0.000 claims description 28
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 27
- 239000003513 alkali Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000003729 nucleotide group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 150000001413 amino acids Chemical class 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
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- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 2
- 125000005335 azido alkyl group Chemical group 0.000 claims description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 abstract description 79
- 230000000840 anti-viral effect Effects 0.000 abstract description 23
- 238000012216 screening Methods 0.000 abstract description 20
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 239000011777 magnesium Substances 0.000 abstract description 8
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- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract 2
- 238000002560 therapeutic procedure Methods 0.000 abstract 2
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical class COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 abstract 1
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 55
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 49
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 30
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- 230000000694 effects Effects 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
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- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
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- 125000000623 heterocyclic group Chemical group 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 241000725303 Human immunodeficiency virus Species 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
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- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 6
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- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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Abstract
本发明提供了一种新方法,该方法用于筛选核苷酸甲氧基膦酸酯类似物前药以鉴定能选择性靶向所需组织具有抗病毒或抗肿瘤活性的前药。该方法鉴定了用于逆转录病毒治疗或肝DNA病毒治疗的PMPA的新型混合的酯-酰胺化物,包括具有本发明所定义的取代基的结构式(5a)化合物。本发明还提供了上述新化合物在可药用赋形剂中的组合物及其在治疗和预防中的用途。还提供了一种用烃氧基镁制备本发明使用的原料和化合物的改进方法。
Description
本申请涉及核苷酸甲氧基膦酸酯类似物前药。尤其涉及制备和鉴定上述前药的改进方法。
许多核苷酸甲氧基膦酸酯类似物是已知的。一般,这些化合物具有A-OCH2P(O)(OR)2结构,其中,A是核苷类似物残基,R独立地是氢或各种保护基团或前药官能团。参见US5663159、5977061和5798340,Oliyai等人;″Pharmaceutical Research″16(11):1687-1693(1999),Stella等人;″J.Med.Chem.″23(12):1275-1282(1980);Aarons,L.,Boddy,A.和Petrak,K.(1989)NovelDrug Delivery and Its Therapeutic Application(Prescott,L.F.和Nimmo,W.S.,ed.),pp.121-126;Bundgaard,H.(1985)Design of Prodrugs(Bundgaard,H.,ed.)pp.70-74和79-92;Banerjee,P.K.和Amidon,G.L.(1985)Design of Prodrugs(Bundgaard,H.,ed.)pp.118-121;Notari,R.E.(1985)Design of Prodrugs(Bundgaard,H.,ed.)pp.135-156;Stella,V.J.和Himmelstein,K.J.(1985)Design of Prodrugs(Bundgaard,H.,ed.)pp.177-198;Jones,G.(1985)Design ofProdrugs(Bundgaard,H.,ed.)pp.199-241;Connors,T.A.(1985)Design of Prodrugs(Bundgaard,H.,ed.)pp.291-316。上文引用的所有文献和专利引入本发明作为参考。
发明慨述
已知,用于抗病毒或抗肿瘤治疗的核苷酸甲氧基膦酸酯类似物前药通常是由于其具有全身效应而被选用。例如,上述前药由于具有增强生物利用度而被选用,即,上述前药具有经胃肠道吸收并迅速转变成母体药物以确保母体药物到达所有组织的能力。然而,申请人现已发现,可以选用在治疗部位富集的前药,正如本发明公开的研究中所述,类似物富集在HIV(人免疫缺陷病毒)感染的局限病灶部位。本发明的目的是提供一种对周围组织毒性较低而对母体核苷酸甲氧基膦酸酯类似物治疗的靶组织具有较强效力的母体药物,这也是本发明的其它优点之一。
相应地,根据上述研究结果,本发明提供了一种用于鉴定能在靶组织中带来增强活性的核苷酸甲氧基膦酸酯类似物前药的筛选方法,该方法包括:
(a)提供至少一种上述前药;
(b)选择至少一种治疗靶组织和至少一种非靶组织;
(c)向靶组织和所述的至少一种非靶组织施用前药;和
(d)测定步骤(c)中由前药在组织中带来的相对抗病毒活性。
在优选的实施方案中,靶组织是HIV被活泼复制的部位和/或是作为HIV贮主的部位,非靶组织是完整动物。出乎意料的是,我们发现,选择淋巴组织作为针对HIV靶组织来实施本发明方法,可以鉴定出能够提高活性药物向上述组织送递的前药。
已被本方法鉴定的本发明优选化合物具有式(1)结构,
其中Ra是H或甲基,
其手性富集组合物、盐、其游离碱和其溶剂化物也是优选的。
本发明的优选化合物具有式(2)结构,
其富集非对映异构体、盐、游离碱和溶剂化物也是优选的。
另外,我们出乎意料地发现,磷原子上的取代基和/或酰胺化取代基的手性对实施本发明监测到的富集有影响。因此,在本发明另一实施方案中,我们提供了具有式(3)结构的本发明非对映体富集化合物和其盐、游离碱和溶剂化物,
该化合物基本上不含有非对映异构体(4),
其中,
R1是在体内可水解的氧酯基或是羟基;
B是杂环碱基;
R2是羟基或是氨基酸残基,所述氨基酸通过氨基酸的氨基与P原子连接且氨基酸的每个羧基取代基任选被酯化,但R1和R2不同时为羟基;
E是-(CH2)2-、-CH(CH3)CH2-、-CH(CH2F)CH2-、-CH(CH2OH)CH2-、-CH(CH=CH2)CH2-、-CH(C≡CH)CH2-、-CH(CH2N3)CH2-、
-CH(R6)OCH(R6’)-、-CH(R9)CH2O-或-CH(R8)O-,其中右侧键连接杂环碱基;
虚线表示任选的双键;
R4和R5独立地是氢、羟基、卤素、氨基或具有1-5个碳原子的选自酰氧基、烷氧基、烷硫基、烷基氨基和二烷基氨基的取代基;
R6和R6’独立地是H、C1-C6烷基、C1-C6羟烷基或C2-C7烷酰基基;
R7独立地是H、C1-C6烷基或一起形成-O-或-CH2-;
R8是H、C1-C6烷基、C1-C6羟烷基或C1-C6卤代烷基;和
R9是H、羟甲基或酰氧基甲基。
结构(3)非对映异构体是指在磷原子手性中心上的(S)异构体。
本发明优选的实施方案是具有结构(5a)的非对映异构体富集化合物及其盐、互变异构体、游离碱和溶剂化物,
该化合物基本上不含有非对映异构体(5b),
其中,
R5是甲基或氢;
R6独立地是H、烷基、烯基、炔基、芳基或芳烷基,或R6独立地是被1-3个选自烷基氨基、烷基氨基烷基、二烷基氨基烷基、二烷基氨基、羟基、氧代、卤素、氨基、烷硫基、烷氧基、烷氧基烷基、芳氧基、芳氧基烷基、芳基烷氧基、芳基烷氧基烷基、卤代烷基、硝基、硝基烷基、叠氮基、叠氮基烷基、烷酰基、烷酰基烷基、羧基或烷酰基氨基的取代基取代的烷基、烯基、炔基、芳基或芳烷基;
R7是任一天然或可药用氨基酸的侧链,并且,如果该侧链含有羧基,则该羧基任选被烷基或芳基酯化;
R11是氨基、烷基氨基、氧代或二烷基氨基;和
R12是氨基或H。
本发明优选的实施方案是结构(6)的化合物9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤,在本发明中也称作GS-7340。
本发明另一优选的实施方案是结构(5)的富马酸盐(结构(7))9-[(R)-2-[[(S)-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(1∶1),
本发明中也称作GS-7340-2。
任选将结构(1)-(7)化合物配制成含有可药用赋形剂的组合物。有效剂量的上述组合物被用于治疗或预防病毒(特别是HIV或肝DNA病毒)感染。
在其它实施方案中,本发明提供了一种用烃氧基镁制备9-[2-(膦酰基甲氧基)丙基]腺嘌呤(下文称作″PMPA″)或9-[2-(膦酰基甲氧基)乙基]腺嘌呤(下文称″PMEA″)的简便方法,该方法包括将9-(2-羟基丙基)腺嘌呤或9-(2-羟基乙基)腺嘌呤、被保护的p-甲苯磺酰氧基甲基膦酸酯和烃氧基镁混合,并分别回收PMPA或PMEA。
发明详述
本发明筛选方法中使用的核苷酸甲氧基膦酸酯类似物母体药物是具有A-OCH2P(O)(OH)2结构的化合物,其中,A是核苷类似物残基。这些化合物本身是已知的,不是本发明的组成部分。尤其是,母体化合物含有一个杂环碱基B和一个糖苷配基E,一般具有下式结构:
其中,B定义如下,E定义如上。在US4,659,825、4,808,716、4,724,233、5,142,051、5,130,427、5,650,510、5,663,159、5,302,585、5,476,938、5,696,263、5,744,600、5,688,778、5,386,030、5,733,896、5,352,786和5,798,340以及EP 821,690和654,037中公开了母体化合物的实例。
在本发明筛选方法中使用的前药是上一段描述的母体核苷酸甲氧基膦酸酯类似物的共价修饰类似物。一般,母体药物的磷原子是进行前药修饰的优选位置,但在杂环碱基B或糖苷配基E上发现了进行前药修饰的其它位置。许多上述前药是已知的。它们主要是磷原子的酯或酰胺化物,也包括在碱基和糖苷配基上的取代物。这些修饰物本身不是本发明的组成部分,且不影响本发明范围。
核苷酸甲氧基膦酸酯类似物的磷原子含有2个可进行诸如酰胺化或酯化共价修饰的化合价(除非一个磷酰基羟基被酯化成糖苷配基E羟基取代基,使得仅有一个磷化合价可被自由取代)。所述酯通常是芳氧基酯。酰胺化物通常是具有被烷基或芳基(一般是苯基、环烷基或叔、正或仲烷基)酯化的游离羧基的天然单氨基酸。在例如US5,798,340中公开了本发明筛选方法中使用的合适前药。然而,任何被认为在体内靶组织细胞内可能被转化成游离的核苷酸甲氧基膦酸酯类似物母体药物(例如,通过水解、氧化或因暴露于生物组织而发生其它共价转化)的前药都适用于本发明方法。这些前药目前也许不为人知,但将来会被鉴定,因此,这些前药成为能在本发明方法中鉴定的合适候选前药。由于这些前药在本发明方法中只是用于筛选的候选前药,因此,它们的结构不适用于实施或实现筛选方法,不过当然,无论这些前药在鉴定中是否被证明具有选择性,它们的结构最终是不确定的。
与母体药物结合的前一部分基团可以相同或不同。然而,在筛选鉴定中使用的每种前药在结构上与其它待测前药不同。通常,根据其立体化学或其共价结构来选择不同(即,结构不同)的前药,或者,上述两个特征都发生变化。然而,最好每种检测的前药都有几乎纯的结构和立体化学,否则筛选试验的结果不太有用。自然,在本发明的范围内,在本发明方法的每个实施方案中仅检定单一一种前药,然后,通常将试验结果与用其它前药的在先研究结果进行比较。
我们发现,前药的立体化学能够影响其在靶组织中的富集能力。手性部位在磷原子上,也发现在其取代基上。例如,用来制备酰胺化物的氨基酸可以是D或L形,且膦酸酯或氨基酸酯也可含有手性中心。在分子的核甙类似物部分也发现有手性部位,但这些手性部位一般都已被母体药物的立体化学决定,并且其作为筛选的一部分不会有变化。例如,由于较其相应的S异构体更具有活性,因此优选PMPA的R异构体。如果各个手性部位不纯,则通常要将这些非对映异构体或旋光对映体进行手性富集,从而使得筛选的结果更有意义。正如所指出的那样,通过富集或提纯在上述手性中心上不含其它立体异构的立体异构体(就大多数核苷酸甲氧基膦酸酯类似物而言,该立体异构体一般是非对映异构体而不是对映异构体),使各立体异构体完全不同,进而使得每个试验化合物基本上是单一化合物。形成基本上单一的化合物或手性富集,意味着所需的立体异构体构成了超过化合物重量的约60%,通常超过约80%,优选超过约95%。
新筛选方法
一旦选择了至少一种候选前药,就可用本发明筛选方法的其余步骤来鉴定对靶组织具有预期选择性的前药。为了便于随后在组织或细胞中进行检测,最适宜用可检测基团标记前药,例如,放射性标记。然而,对于前药或其代谢物(包括母体药物)也可用其它合适的检测方法,因此标记并非是必需的。例如,所述检测方法包括质谱、HPLC、生物测定或免疫测定。上述检测方法可测定前药和其一种或多种代谢产物,但优选仅测定母体药物的产生。这是基于前药在所有试验组织体内转化成抗病毒活性母体二磷酸酯的程度和速率都相同的假设(不保证在所有情况下)。换句话说,可以测定二磷酸酯。
如果筛选用于治疗HIV感染的前药,优选的靶组织是淋巴组织。淋巴组织是本领域技术熟练人员所熟知的,包括CD4细胞、淋巴细胞、淋巴结、巨噬细胞和包括诸如外周血单核细胞(PBMCs)和神经胶质细胞的单核细胞的巨噬细胞样细胞。淋巴组织还包括在诸如肺、皮肤和脾的淋巴组织或细胞内富集的非淋巴组织。对于其它抗病毒药物,其它靶当然是特定病毒涉及的复制或潜伏的主要部位,例如,肝炎病毒的靶是肝和HSV病毒的靶是外周神经。类似地,肿瘤的靶组织事实上就是肿瘤本身。上述组织是本领域技术熟练人员熟知的且无需用过多实验来进行选择。当筛选抗病毒化合物时,用病毒感染靶组织。
作为本发明方法的组成部分,对非靶组织或细胞也进行筛选。关于这一点,可以使用任何数量或种类的上述组织或细胞。一般,预计母体药物对其有毒的组织被用作非靶组织。非靶组织的选择完全依赖于前药性质和母体药物活性。例如,选择非肝组织用于抗肝炎前药筛选,与肿瘤一样的组织的未转染细胞足以满足抗肿瘤选择性前药的筛选。
需要说明的是,本发明方法与通常进行的确定前药的口服生物可利用率的研究不同。在口服生物利用率的研究中,其目的是鉴定基本上转化成母体药物进入体循环的前药。在本发明中,其目的是发现在胃肠道或循环中没有被代谢的前药。因此,在本发明方法中,待评估的靶组织一般不包括小肠,或者,如果包括肠,则耙组织还包括除小肠之外的其它组织。
本发明筛选方法中使用的靶和非靶组织一般是在完整活动物中。含有酯的前药更适宜在狗、猴子或其它非啮齿动物体内进行检测;小鼠和大鼠血浆中含有高循环浓度的酯酶,如果希望治疗的对象是人类或高级哺乳动物,则会产生使人误解的结果。
并非必需用完整动物来进行本发明方法。在本发明的范围内也可使用灌注器官、体外培养器官(例如,皮肤移植物)或保持在各种细胞培养装置,例如,滚瓶或零重力悬浮液体系中的细胞系。例如,MT-2细胞可用作选择性HIV前药的靶组织。因此,术语″组织″不能理解为那样必须是活体细胞状结构或如同在自然界中可发现的组织结构,虽然这些组织是优选的。更准确地说,术语″组织″应理解为是具有特定来源、起源或分化期的细胞的同义词。
事实上,靶和非靶组织可以是相同组织,但它们处于不同的生物状态。例如,本发明方法可用来选择在病毒感染组织(靶组织)中带来活性而在未被病毒感染的细胞(相应的非靶组织)中基本上保持非活性的前药。可用同样策略来选择预防性前药,即,对于病毒性感染,预防性前药易被代谢成具有抗病毒活性的代谢物,而在未感染细胞中基本上不代谢。类似地,可在转化细胞和未转化的相应组织中进行前药筛选。这在选择用于治疗诸如白血病的血液恶性肿瘤的前药的比较试验中是特别有用的。
不受任何特定操作理论的限制,与其它组织或细胞相比,可以认为组织选择性前药被靶细胞选择性吸收和/或在细胞内被选择性地代谢。本发明甲氧基膦酸酯前药的独特优点是它们在生理pH下被代谢成双阴离子,从而确保它们不会逆扩散到细胞之外。因此,本发明前药能长期保持疗效,并保持高细胞内浓度,从而具有增强效力。相信在靶组织中活性增加的机理包括增加了靶细胞的吸收、增强了细胞内存留或是这两种机制共同作用的结果。然而,在靶组织中选择能力或增强送递的存在方式并不重要。而且,前药在靶组织中向母体化合物的代谢转化也不全都重要。在靶组织中只需要存在能带来最终药物活性的转化;在其它组织中的代谢可以提供中间体,该中间体在靶组织中最终转化成抗病毒药物。
所需的选择程度或增强送递程度随母体化合物和其测量方法而改变(%剂量分布或母体药物浓度)。一般,如果母体药物已占有大量治疗窗口,那么,对于目标前药,低选择度可能就足够了。另一方面,对有毒化合物可能需要进行更广泛的筛选来鉴定选择性前药。仅在靶组织中和在人们公知抗母体化合物对其相对有毒的组织中进行筛选能降低本发明方法的相对费用,例如,对于PMEA(高剂量PMEA会引起肾脏中毒),其主要病灶将在肾和淋巴组织上。
前药在所选择组织中的相对抗病毒活性的检测步骤通常是通过分析靶和非靶组织中前药代谢产物的相对存在量或活性来完成,所述代谢产物已知具有抗病毒或抗肿瘤活性,或被转化成具有抗病毒或抗肿瘤活性的代谢产物。因此,一般来讲,为了鉴定在靶组织中被优先代谢成抗病毒或抗肿瘤活性代谢产物或前体的前药,我们在基本上相同的时间内测定组织中母体药物的相对存在量,所述前体在靶组织中终会产生活性代谢产物。至于抗病毒化合物,活性代谢产物是膦酸酯母体化合物的二磷酸酯。正是由于该代谢产物被引入到病毒核酸中,从而切断了延长的核酸链,并终止了病毒复制。前药的代谢产物可以是合成代谢产物、分解代谢产物或是合成代谢和分解代谢的共同产物。在本发明方法的实施中,产生代谢产物的方式并不重要。
本发明方法不限于分析本身具有抗病毒或抗肿瘤活性的代谢产物。相反,我们能够分析活性代谢产物的非活性前体。抗病毒活性二磷酸酯代谢产物的前体包括母体药物的一磷酸酯、母体药物的其它代谢产物的一磷酸酯(例如,杂环碱基上取代基的中间体修饰)、母体本身和在磷酸化作用之前在将前药转化成母体过程中由细胞产生的代谢产物。因为前体是细胞代谢的产物,因此前体结构可能变化相当大。然而,这种情况是已知的,或者,本领域技术人员很容易确定。
如果所分析的前药本身没有抗肿瘤或抗病毒活性,则可能需要调整原始分析结果。例如,在试验组织中,如果细胞内非活性代谢产物向活性代谢产物的转化以不同速率进行,就必须调整非活性代谢产物的原始分析结果以考虑到细胞类型的差异,这是因为,相关参数是指靶组织中活性的产生,而不是指非活性代谢产物的积累。然而,进行适当的调整应属于本领域的一般技术。因此,当本发明方法的步骤(d)要求测定活性时,可以直接测定活性或用外推法测定活性。这并不意味本发明方法仅限于分析本身具有活性的中间体。例如,也可测定前药在试验组织中的缺乏或下降。步骤(d)仅要求评估当前药与有关组织互相影响时由前药带来的活性,这可以以外推法或其它间接测定方法为基础。
本发明方法的步骤(d)要求测定前药的″相对″活性。可理解的是,不要求每次鉴定或每次系列鉴定都必须还包括用选择的非靶组织进行操作。相反,采用非靶组织的原始对照或采用能代表由所述非靶组织得到的预期结果的算法以提供基准非靶活性也在本发明的范围内。
然后将步骤(d)中得到的结果最恰当地用于选择或鉴定能在靶组织中产生比在非靶组织中更高的抗病毒活性的前药。正是该前药被选择用于进行进一步的研究。
可以理解的是,在进行本发明方法前,可以对候选前药进行一些预先评估。例如,前药必须能在不被代谢的情况下大量地穿过胃肠道,其在血液中必须基本上稳定,并且前药应当能在一定程度上渗透细胞。在大多数情况下,还要求前药在基本上不被代谢的前提下完成第一个肝循环。上述预先研究是任选的,并是本领域技术熟练人员熟知的。
上述关于抗病毒活性的论述也适用于核苷酸甲氧基膦酸酯类似物的抗肿瘤前药。例如,所述前药包括PMEG的前药和PMEA的脒基类似物。在这种情况下,诸如PMEG的细胞毒素膦酸酯是值得应用的候选前药,这是因为,它们的细胞毒性事实上带来了其抗肿瘤活性。
然后,由本发明的新筛选方法鉴定的化合物可进入传统的临床前或临床程序,以确定是否达到了所需目的。一般,如果靶组织中母体药物活性或浓度(%剂量分布)是母体化合物在非靶组织中活性或浓度的2x,优选5x,则认为前药具有选择性。或者,可将候选前药与基准前药进行比照。在这种情况下,选择性是相对的而不是绝对的。虽然选择程度是随意的,但与原型相比,选择性前药是那些在靶组织中产生大约10x浓度或活性的前药。
制备原料和中间体的新方法
本发明还包括制备本发明优选原料(母体药物)、PMEA和(R)-PMPA的改进方法。一般,所述方法包括将9-(2-羟基丙基)腺嘌呤(HPA)或9-(2-羟基乙基)腺嘌呤(HEA)与烃氧基镁反应,然后向反应混合物中进入保护的糖苷配基合成子对甲苯磺酰基氧基甲基膦酸酯(甲苯磺酸酯),并分别回收PMPA或PMEA。
优选,HPA是富集或分离的R对映异构体。如果使用手性HPA混合物,则可在完成合成后从手性PMPA混合物中分离出R-PMPA。
甲苯磺酸酯一般用低级烷基保护,但其它合适的保护基对于本领域技术熟练人员而言是显而易见的。适宜使用被前药膦酸酯取代基预取代的甲苯磺酸酯(前药膦酸酯取代基在甲苯磺酰化反应中能充当保护基),借此可省略脱保护步骤并直接回收前药或中间体。
对烃氧基镁的烷基的要求不严格,可以是任何C1-C6支链或直链烷基,但优选叔丁基(对于PMPA)或异丙基(对于PMEA)。反应条件也不是严格的,但优选包括在搅拌或其它适度搅拌条件下在约70-75℃加热反应混合物。
如果对保留膦酸酯取代基没有兴趣,则可将产物脱保护(当甲苯磺酸酯保护基是烷基时,通常用三甲基溴硅烷进行脱保护),然后用本领域技术人员熟知的重结晶法或其它常规方法回收产物。
杂环碱基
在结构(3)和(4)所描述的本发明化合物中,杂环碱基B选自下述结构:
其中,
R15是H、OH、F、Cl、Br、I、OR16、SH、SR16、NH2或NHR17;
R16是C1-C6烷基或C2-C6烯基,包括CH3、CH2CH3、CH2CCH、CH2CHCH2和C3H7;
R17是C1-C6烷基或C2-C6烯基,包括CH3、CH2CH3、CH2CCH、CH2CHCH2和C3H7;
R18是N、CF、CCl、CBr、Cl、CR19、CSR19或COR19;
R19是H、C1-C9烷基、C2-C9烯基、C2-C9炔基、C1-C9烷基-C1-C9烷氧基或未取代的或被OH、F、Cl、Br或I取代的C7-C9芳烷基,因此,R19包括-CH3、-CH2CH3、-CHCH2、-CHCHBr、-CH2CH2C1、-CH2CH2F、-CH2CCH、-CH2CHCH2、-C3H7、-CH2OH、-CH2OCH3、-CH2OC2H5、-CH2OCCH、-CH2OCH2CHCH2、-CH2C3H7、-CH2CH2OH、-CH2CH2OCH3、-CH2CH2OC2H5、-CH2CH2OCCH、-CH2CH2OCH2CHCH2和-CH2CH2OC3H7;
R20是N或CH;
R21是N、CH、CCN、CCF3、CC≡CH或CC(O)NH2;
R22是H、OH、NH2、SH、SCH3、SCH2CH3、SCH2CCH、SCH2CHCH2、SC3H7、NH(CH3)、N(CH3)2、NH(CH2CH3)、N(CH2CH3)2、NH(CH2CCH)、NH(CH2CHCH2)、NH(C3H7)、卤素(F、Cl、Br或I)或X,其中X是-(CH2)m(O)n(CH2)mN(R10)2,其中,m独立地是0-2,n是0-1,和
R10独立地是
H;
C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6烷基氨基-C1-C6烷基、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
C2-C15烷基、C3-C15烯基、C6-C15芳烯基、C3-C15炔基、C7-C15芳炔基、C1-C6烷基氨基-C1-C6烷基、C5-C15芳烷基、C6-C15杂烷基或C3-C6杂环烷基,其中,烷基中不与N6连接的亚甲基被-O-代替;
任选两个R10相连和N一起形成饱和或不饱和的C2-C5杂环,该杂环含有1或2个N杂原子和任选还含有1个O或S杂原子;
或上述R10之一被1-3个卤素、CN或N3取代;但任选至少一个R10不是H;
R23是H、OH、F、Cl、Br、I、SCH3、SCH2CH3、SCH2CCH、SCH2CHCH2、SC3H7、OR16、NH2、NHR17或R22;和
R24是O、S或Se。
B还包括保护的或不保护的杂环碱基,尤其是嘌呤和嘧啶碱基。用于保护环外胺和其它不稳定基团的保护基是已知的(Greene等人,″Protective Groups in Organic Synthesis″),包括N-苯甲酰基、异丁酰基、4,4’-二甲氧基三苯甲基(DMT)等等。保护基的选择对本领域普通技术人员而言是显而易见的,其取决于不稳定基团的性质和保护基预计将遭遇的化学条件,如酸性、碱性、氧化、还原或其它条件。具有代表性的被保护杂环碱是N4-苯甲酰基胞嘧啶、N6-苯甲酰基腺嘌呤和N2-异丁酰基鸟嘌呤等等。
被保护的碱基具有式Xa.1、XIa.1、XIb.1、XIIa.1或XIIIa.1,
其中,R18、R20、R21和R24定义同上;R22A是R39或R22,条件是R22不是NH2;R23A是R39或R23,条件是R23不是NH2;R39是NHR40、NHC(O)R36或CR41N(R38)2,其中R36是C1-C19烷基、C1-C19烯基、C3-C10芳基、金刚烷基(adamantoyl)、烷基芳基(alkylanyl)、或被1或2个下述原子或基团取代的C3-C10芳基:卤素、甲基、乙基、甲氧基、乙氧基、羟基和氰基;R38是C1-C10烷基,或两个R38一起形成1-吗啉代、1-哌啶或1-吡咯烷;R40是C1-C1a烷基,包括甲基、乙基、丙基、异丙基、丁基、异丁基,叔丁基、戊基、己基、辛基和癸基;和R41是氢或CH3。
至于XIa.1和XIb.1结构的碱基,如果在R22A或R23A位置上存在R39,则在同一碱基上的两个R39一般相同。具有代表性的R36的实例是苯基、被上述R36芳基取代基之一取代的苯基、-C10H15(C10H15是2-金刚烷基)、-CH2-C6H5、-C6H5、-CH(CH3)2、-CH2CH3、甲基、丁基、叔丁基、庚基、壬基、十一烷基或十一碳烯基。
碱的实例包括次黄嘌呤;鸟嘌呤;腺嘌呤;胞嘧啶;肌苷;胸腺嘧啶;尿嘧啶;黄嘌呤;2-氨基嘌呤、2,6-二氨基嘌呤、2-氨基-6-氯嘌呤、次黄嘌呤、肌苷和黄嘌呤的8-氮杂衍生物;腺嘌呤、鸟嘌呤、2-氨基嘌呤、2,6-二氨基嘌呤、2-氨基-6-氯嘌呤、次黄嘌呤、肌苷和黄嘌呤的7-去氮杂-8-氮杂衍生物;2-氨基嘌呤、2,6-二氨基嘌呤、2-氨基-6-氯嘌呤、次黄嘌呤、肌苷和黄嘌呤的1-去氮杂衍生物;2-氨基嘌呤、2,6-二氨基嘌呤、2-氨基-6-氯嘌呤、次黄嘌呤、肌苷和黄嘌呤的7-去氮杂衍生物;2-氨基嘌呤、2,6-二氨基嘌呤、2-氨基-6-氯嘌呤、次黄嘌呤、肌苷和黄嘌呤的3-去氮杂衍生物;6-氮杂胞嘧啶;5-氟胞嘧啶;5-氯胞嘧啶;5-碘胞嘧啶;5-溴胞嘧啶;5-甲基胞嘧啶;5-溴乙烯基尿嘧啶;5-氟尿嘧啶;5-氯尿嘧啶;5-碘尿嘧啶;5-溴尿嘧啶;5-三氟甲基尿嘧啶;5-甲氧基甲基尿嘧啶;5-乙炔基尿嘧啶和5-丙炔基尿嘧啶。
优选的B是选自脒基、3-去氮杂脒基、1-去氮杂脒基、8-氮杂脒基、7-去氮杂脒基、腺嘌呤基、3-去氮杂腺嘌呤基、1-去氮杂腺嘌呤基、8-氮杂腺嘌呤基、7-去氮杂腺嘌呤基、2,6-二氨基嘌呤基、2-氨基嘌呤基、6-氯-2-氨基嘌呤基、和6-硫代-2-氨基嘌呤基的9-嘌呤残基,或B’是选自胞嘧啶基、5-卤代胞嘧啶基和5-(C1-C3-烷基)胞嘧啶基的1-嘧啶基残基。
优选具有下式结构的B基团
其中,
R22独立地是卤素、氧、NH2、X或H,但任选至少一个R22是X;
X是-(CH2)m(O)n(CH2)mN(R10)2,其中m=0-2,n=0-1,且R10独立地是
H,
C1-C15烷基、C2-C15烯基、C6-C15芳烯基、C6-C15芳炔基、C2-C15炔基、C1-C6-烷基氨基-C1-C6烷基、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基,
C2-C15烷基、C3-C15烷基、C6-C15芳烯基、C3-C15炔基、C7-C15芳炔基、C1-C6-烷基氨基-C1-C6烷基、C5-C15芳烷基、C6-C15杂烷基或C3-C6杂环烷基,其中,烷基中不与N6连接的亚甲基被-O-代替,
任选两个R10相连与N一起形成饱和或不饱和的C2-C5杂环,该杂环含有1或2个N杂原子和任选还含有O或S杂原子,
或上述R10之一被1-3个卤素、CN或N3取代,但任选至少一个R10不是H;和
Z是N或CH,条件是,杂环核与尿环的差别不多于一个Z。
E基团表示在核苷酸甲氧基膦酸酯类似物中使用的糖苷配基。优选,E是-CH(CH3)CH2-或-CH2CH2-。还优选,糖苷配基中的手性中心上的侧基基本上仅是(R)构型(羟甲基除外,其为富集的(S)对映异构体)。
R1是可在体内水解的结构为-OR35或-OR6的氧基酯,其中,R35的定义见US5,798,340第64栏第49行,在本发明中引作参考,R6的定义同上。优选R1是芳氧基,一般是未取代的或对位取代的(与R6的定义相同)苯氧基。
R2是氨基酸残基,任选其条件是,通过少于约5个原子与酰胺化物的N原子连接的任一羧基被酯化。R2一般具有下式结构:
其中,
n=1或2;
R11是R6或H;优选R6=C3-C9烷基,独立地被OH、卤素、O或N取代的C3-C9烷基,C3-C6芳基,独立地被OH、卤素、O或N取代的C3-C6芳基或独立地被OH、卤素、O或N取代的C3-C6芳烷基;
R12独立地是H或未取代的或被选自OH、O、N、COOR11和卤素的取代基取代的C1-C9烷基,未取代的或被选自OH、O、N、COOR11和卤素的取代基取代的C3-C6芳基,或未取代的或被选自OH、O、N、COOR11和卤素的取代基取代的C3-C9芳烷基;
R13独立地是C(O)-OR11,氨基,酰胺,胍基(guanidinyl),咪唑基,吲哚基,亚砜,磷酰基,C1-C3烷基氨基,C1-C3烷基二氨基,C1-C6烯基氨基,羟基,巯基,C1-C3烷氧基,C1-C3烷硫基,(CH2)nCOOR11,未取代的或被OH、卤素、SH、NH2、苯基、羟基苯基或C7-C10烷氧基苯基取代的C1-C6烷基,未取代的或被OH、卤素、SH、NH2、苯基、羟基苯基或C7-C10烷氧基苯基取代的C2-C6烯基和未取代的或被OH、卤素、SH、NH2、苯基、羟基苯基或C7-C10烷氧基苯基取代的C6-C12芳基;和
R14是H或C1-C9烷基或独立地被OH、卤素、COOR11、O或N取代的C1-C9烷基,C3-C6芳基,独立地被OH、卤素、COOR11、O或N取代的C3-C6芳基或独立地被OH、卤素、COOR11、O或N取代的C3-C6芳烷基。
优选,R11是C1-C6烷基,最优选是异丙基,R13是天然氨基酸侧链,n=1,R12是H和R14是H。在结构(2)的化合物中,本发明包括苯氧基和异丙基酯已被水解成-OH的代谢产物。类似地,本发明还包括化合物(5a)、5(b)和(6)的脱酯富集的代谢产物膦酰基酰胺化物。
芳基和″O″或″N″取代基的定义见US 5,798,340第16栏第42-58行。
氨基酸一般是天然或1型氨基酸。合适的具体实例参见US5,798,340,例如,见表4和第8-10栏。
本发明中的烷基,除非另作说明,是指伯、仲、叔或环烷基。除非另作说明,烷基是C1-C12烷基。其实例是-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3)、-CH2CH(CH3)2、-CH(CH3)CH2CH3、-C(CH3)3、-CH2CH2CH2CH2CH3、-CH(CH3)CH2CH2CH3、-CH(CH2CH3)2、-C(CH3)2CH2CH3)、-CH(CH3)CH(CH3)2、-CH2CH2CH(CH3)2、-CH2CH(CH3)CH2CH3、-CH2CH2CH2CH2CH2CH3、-CH(CH3)CH2CH2CH2CH3、-CH(CH2CH3(CH2CH2CH3)、-C(CH3)2CH2CH2CH3、-CH(CH3)CH(CH3)CH2CH3、-CH(CH3)CH2CH(CH3)2、-C(CH3)(CH2CH3)2、-CH(CH2CH3)CH(CH3)2、-C(CH3)2CH(CH3)2和-CH(CH3)C(CH3)3。烯基和炔基以相同方式定义,但分别含有至少一个双键或三键。
当公开了烯醇或酮式基团基团时,也认为本发明教导了其相应的互变异构体。
本发明前药化合物可以其游离碱形式或以US5,798,340中列举的各种盐的形式提供,并且,还可以如US5,798,340所公开的那样,将本发明前药化合物与可药用赋形剂或溶剂化稀释剂一起配制成药剂。这些前药具有抗病毒效用并已为母体药物确认(参见US5,798,340和其它涉及核苷酸甲氧基膦酸酯类似物的引证文献)。可以理解的是,不考虑本发明公开的结构(4)非对映异构体的相对非选择特性,至少作为一种在通过体外水解化学生产母体药物的过程中的中间体,结构(4)非对映异构体是有用的。
参照下述实施例,可更充分地理解本发明:
实施例1a
使用异丙醇镁由腺嘌呤来制备PMEA。向腺嘌呤(16.8g,0.124mol)的DMF(41.9ml)悬浮液中加入碳酸亚乙酯(12.1g,0.137mol)和氢氧化钠(.100g,0.0025mol)。在130℃加热该混合物过夜。将反应冷却至低于50℃,并加入甲苯(62.1ml)。将所得淤浆进一步冷却至5℃,并保持2小时,过滤并用甲苯(2x)冲洗。在65℃真空干燥所得的湿固体,得到20.0g(90%)灰白色固体9-(2-羟基乙基)腺嘌呤。Mp:238-240℃。
将9-(2-羟基乙基)腺嘌呤(HEA)(20.0g,0.112mol)悬浮在DMF(125ml)中并加热至80℃。向混合物中加入异丙醇镁(11.2g,0.0784mol),或叔丁醇镁,然后在1小时内加入对甲苯磺酰基氧基甲基膦酸二乙酯(66.0g,0.162mol)。在80℃搅拌混合物7小时。真空蒸馏除去30ml挥发物,并向反应中补加30ml新鲜DMF。冷却反应至室温后,加入三甲基溴硅烷(69.6g,0.450mol)并在80℃加热反应混合物6小时。浓缩反应得到浓稠胶状物。将该胶状物溶解在360ml水中,用120ml二氯甲烷萃取,用氢氧化钠调节pH至3.2,将所得淤浆在室温搅拌过夜。冷却淤浆至4℃,并保持1小时。过滤分离出固体,用水(2x)洗涤,并在56℃真空干燥,得到20g(65.4%)灰白色固体9-[2-(膦酰基甲氧基)乙基]腺嘌呤(PMEA)。Mp:>200℃(分解)。1H NMR(D2O)·3.49(t,2H);3.94(t,2H);4.39(t,2H);8.13(s,1H);8.22(s,1H)。
实施例1b
使用叔丁醇镁由腺嘌呤来制备PMPA。向腺嘌呤(40g,0.296mol)的DMF(41.9ml)悬浮液中加入(R)-碳酸亚丙酯(34.5g,0.338mol)和氢氧化钠(.480g,0.012mol)。在130℃加热混合物过夜。冷却反应至100℃,加入甲苯(138ml),然后,保持反应温度为100-110℃,加入甲磺酸(4.7g,0.049mol)。再加入甲苯(114ml)以形成均匀溶液。在7小时内冷却该溶液至3℃,并在3℃保持1小时。过滤分离出所得的固体,用丙酮(2x)冲洗。在80℃真空干燥固体,得到42.6g(75%)灰白色固体(R)-9-[2-(羟基)丙基]腺嘌呤(HPA)。Mp:188-190℃。
将(R)-9-[2-(羟基)丙基]腺嘌呤(HPA)(20.0g,0.104mol)悬浮在DMF(44.5ml)中,并加热至65℃。在1小时内向混合物中加入叔丁醇镁(14.2g,0.083mol)或异丙醇镁,然后,保持温度为78℃,在2小时内加入对甲苯磺酰基氧基甲基膦酸二乙酯(66.0g,0.205mol)。在75℃搅拌混合物4小时。冷却反应至低于50℃后,加入三甲基溴硅烷(73.9g,0.478mol),并在77℃加热反应混合物3小时。然后,加热反应至80℃,常压蒸馏除去挥发物。将残余物溶解在50℃水(120ml)中,然后用乙酸乙酯(101ml)萃取。用氢氧化钠调节水相pH至1.1,放入纯(R)-PMPA晶种,并用氢氧化钠再调节水层pH至2.1。在室温搅拌所得淤浆过夜。冷却该淤浆至4℃并保持3小时。过滤分离出固体,用水(60ml)洗涤,并在50℃真空干燥,得到18.9g(63.5%)灰白色固体粗产物(R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤(PMPA)。
将(R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤粗产物在水(255ml)中加热回流直至固体全部溶解。在4小时内冷却溶液至室温。将所得淤浆在4℃冷却3小时。过滤分离出固体,用水(56ml)和丙酮(56ml)洗涤,并在50℃真空干燥,得到15.0g(50.4%)白色固体(R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤(PMPA)。Mp:278-280℃。
实施例2
GS-7171(II)的制备
反应图解1
将无水PMPA(I)(14.6kg,50.8mol)、苯酚(9.6kg,102mol)和1-甲基-2-吡咯烷酮(39kg)加入到搪瓷反应器中。加热混合物至85℃并加入三乙胺(6.3kg,62.3mol)。然后在6小时内在100℃加入1,3-二环己基碳化二亚胺(17.1kg,82.9mol)的1-甲基-2-吡咯烷酮(1.6kg)溶液。持续加热16小时。冷却反应至45℃,加入水(29kg),并冷却反应至25℃。从反应中滤除固体,用水(15.3kg)冲洗。将合并的滤液和冲洗液减压浓缩得到褐色淤浆,加入水(24.6kg),用NaOH(25%水溶液)调节pH至11。通过硅藻土(2kg)过滤除去细小沉淀,然后用水(4.4kg)冲洗。用乙酸乙酯(28kg)萃取合并的滤液和冲洗液。用HCl(37%水溶液)(4kg)调节水溶液PH至3.1。过滤分离出粗产物II并用甲醇(12.7kg)洗涤。使粗产物II的湿饼在甲醇(58kg)中形成淤浆。过滤分离出固体,用甲醇(8.5kg)洗涤,并减压干燥得到9.33kg白色粉末II:1H NMR(D2O)δ1.2(d,3H),3.45(q,2H),3.7(q,2H),4(m,2H),4.2(q,2H),4.35(dd,2H),6.6(d,2H),7(t,1H),7.15(t,2H),8.15(s,1H),8.2(s,1H);31P NMR(D2O)δ15.0(去耦)。GS-7171(III)。(反应图解1)将一苯基PMPA(II)(9.12kg,25.1mol)和乙腈(30.7kg)加入到搪瓷反应器中。在低于50℃的条件下加入亚硫酰氯(6.57kg,56.7mol)。在75℃加热反应混合物直至固体溶解。将反应温度升至80℃,在氮气气氛下通过常压蒸馏收集挥发物(11.4kg)。将罐残余物冷却至25℃,加入二氯甲烷(41kg),并冷却至-29℃。在-18℃,在60分钟内加入(L)-丙氨酸异丙酯(7.1kg,54.4mol)的二氯甲烷(36kg)溶液,然后在-18至-11℃,在30分钟内加入三乙胺(7.66kg,75.7mol)。加热反应混合物至室温,并用磷酸二氢钠溶液洗涤5次(每次洗涤用10%水溶液15.7kg)。用无水硫酸钠(18.2kg)干燥有机溶液,过滤,用二氯甲烷(28kg)冲洗,并减压浓缩得到油状物。将丙酮(20kg)加入到油状物中,并减压浓缩混合物。向得到的油状物中加入丙酮(18.8kg)。用色谱法(22kg硅胶60,230~400目,38×38cm硅胶柱床)提纯一半产物溶液,柱用480kg丙酮洗脱。对于另一半油状物,可用新鲜硅胶和丙酮重复上述提纯步骤。减压浓缩含纯产物的馏分得到油状物。将乙腈(19.6kg)加入到油状物中,并减压浓缩混合物。加入乙腈(66.4kg)并冷却溶液至0至-5℃,保持16小时。滤除固体,减压浓缩滤液,得到5.6kg黑色油状物III:1H NMR(CDCl3)δ1.1(m 12H),3.7(m,1H),4.0(m,5H),4.2(m,1H),5.0(m,1H),6.2(s,2H),7.05(m,5H),8.0(s,1H),8.25(d,1H);31P NMR(CDCl3)δ21.0,22.5(分解)。
GS-7171(III)的另一种制备方法
反应图解2
一苯基PMPA(II)。将带有回流冷凝器和氮气入口的圆底烧瓶置于70℃油浴中。向圆底烧瓶中加入无水PMPA(I)(19.2g,67mmol),N,N-二甲基甲酰胺(0.29g,3.3mmol)和环丁砜(40mL)。在4小时内加入亚硫酰氯(14.2g,119mmol)。在该时间内加热升温至100℃,得到均匀溶液。在5分钟内向溶液中加入苯氧基三甲基硅烷(11.7g,70mmol)。然后在100℃油浴中持续加热2小时或2小时以上。将反应倾入快速搅拌的在0℃冷却的丙酮(400mL)中。滤出固体,减压干燥,并溶解在甲醇(75mL)中。用冰/水浴冷却,将溶液pH用氢氧化钾溶液(45%水溶液)调节至3.0。过滤分离出固体,用甲醇冲洗并减压干燥,得到20.4g白色粉末II(反应图解2)。GS-7171(III)。在40℃油浴中,将一苯基PMPA(II)(3g,8.3mmol)、环丁砜(5mL)和N,N-二甲基甲酰胺(1滴)在圆底烧瓶中混合。加入亚硫酰氯(1.96g,16.5mmol)。20分钟后,从油浴中移开澄清溶液,用二氯甲烷(10ml)稀释,并将其加入到(L)-丙氨酸异丙酯(5g,33mmol)和二异丙基乙胺(5.33g,41mmol)的-10℃二氯甲烷(20mL)溶液中。加热反应混合物至室温,并用磷酸二氢钠溶液洗涤三次(10%水溶液,每次用10mL)。用无水硫酸钠干燥有机溶液,减压浓缩得到油状物。将油状物与富马酸(0.77g,6.6mmol)和乙腈(40mL)混合,并加热回流得到均匀溶液。将该溶液用冰浴冷却,滤出固体。将GS-7171富马酸盐固体减压干燥得3.7g。将该盐(3.16g,5.3mmol)悬浮于二氯甲烷(30mL)中并与碳酸钾溶液(5mL,2.5M水溶液)一起搅拌直至固体溶解。分离出有机层,然后用水(5mL)洗涤,无水硫酸钠干燥,并减压浓缩得到2.4g褐色泡沫III。
实施例3
A.通过间歇洗脱色谱法分离非对映异构体
使用市售的带有Chiralpak AS、20μm、21×50mm保护柱的Chiralpak AS、20μm、21×250mm半制备HPLC柱,通过间歇洗脱色谱法拆分GS-7171(III)的非对映异构体。ChiralpakAS是由Diacel制造并由Chiral Teehnologies,Inc.在北美销售的专利填充材料(US5,202,433、RE 35,919、5,434,298、5,434,299和5,498,752)。Chiralpak AS是由涂布在硅胶载体上的直链淀粉三[(S)-α-甲基苄酯氨基甲酸酯]组成的手性固定相(CSP)。
将GS-7171非对映体混合物溶解在流动相中,并将大约1g GS-7171等分试样泵入色谱系统。不需要的非对映异构体GS-7339是第一个从柱中洗脱出的主宽峰(持续时间约15分钟)。当完成GS-7339峰的洗脱时,将流动相立即变换为100%甲醇,使目标非对映异构体GS-7340(IV)与上述甲醇溶剂一起以锐峰从柱中洗脱。甲醇用来减少总循环时间。完成第一对注射后,以单一主馏分形式收集两种非对映体,所述单一主馏分含有纯化的非对映体中的一种(非对映异构体之一的含量>99.0%)。真空除去流动相溶剂,得到纯化的非对映异构体松散泡沫。
在两种非对映异构体馏分中回收了约95%原料GS-7171。GS-7340馏分约占总回收质量的50%。
色谱条件如下:
流动相(最初):GS-7171-乙腈∶异丙醇(90∶10)
(最后): 100%甲醇
流速: 10ml/分钟
操作时间: 约45分钟
检测: UV 275nm
温度: 室温
洗脱曲线: GS-7339(非对映异构体B)
: GS-7340(非对映异构体A;(IV))
B.用SMB色谱法分离GS-7171的非对映异构体
关于模拟移动床色谱法(SMB)的一般说明参见Strube等人的″Organic Process Research and Development″2:305-319(1998)。
GS-7340(IV)。在10cm×5cm填充床上(Chiral TechnologiesInc.,涂布在硅胶上的20微米Chiralpak AS)(1.2kg)通过模拟移动床色谱法提纯2.8kg S-7171(III)。用在乙腈中的30%甲醇洗脱柱。将含有产物的馏分浓缩,得到IV的乙腈溶液(2.48kg)。将溶液静置固化,得到含有乙腈的湿晶状物。减压干燥晶状物,得到1.301kg褐色晶体粉末IV,非对映体纯度为98.7%:mp 117-120℃;1H NMR(CDCl3)δ1.15(m 12H),3.7(t,1H),4.0(m,5H),4.2(dd,1H),5.0(m,1H),6.05(s,2H),7.1(m,5H),8.0(s,1H),8.2(s,1H);31P NMR(CDCl3)δ21.0(去耦)。
C.用C18 RP-HPLC进行非对映异构体分离
使用下列简述条件,通过反相HPLC将GS-7171(III)进行色谱分离,以分离非对映异构体。
色谱柱:Phenomenex LunaTM C18(2),5μm,孔径大小100,
(Phenomenex,Torrance,CA),或等效色谱柱
保护柱:Pellicular C18(Alltech,Deerfield,IL),或等效保
护柱
流动相:A-0.02%(85%)H3PO4,在水和乙腈(95:5)中
B-0.02%(85%)H3PO4,在水和乙腈(50∶50)中
流动相梯度:
时间 | %流动相A | %流动相B |
0 | 100 | 0 |
5 | 100 | 0 |
7 | 70 | 30 |
32 | 70 | 30 |
40 | 0 | 100 |
50 | 0 | 100 |
操作时间:50分钟
平衡延迟:在100%流动相A的条件下为10分钟
流速:1.2ml/分钟
温度: 室温
检测: UV 260nm
样品溶液: 20mM磷酸钠缓冲液,pH6
保留时间: GS-7339,约25分钟
GS-7340,约27分钟
D.结晶法分离非对映异构体GS-7340(IV)。将GS-7171(III)的乙腈溶液减压浓缩成琥珀色泡沫(14.9g)。将该泡沫溶解在乙腈中(20mL)并加入IV的晶体作为晶种。混合物搅拌过夜,冷却至5℃,并过滤分离出固体。干燥固体,得到2.3g白色晶体IV,非对映体纯度为98%(31P NMR):1H NMR(CDCl3)δ1.15(m 12H),3.7(t,1H),3.95(m,2H),4.05(m,2H),4.2(m,2H),5.0(m,1H),6.4(s,2H),7.1(m,5H),8.0(s,1H),8.2(s,1H);31P NMR(CDCl3)δ19.5(去耦)。对选自该产物的单晶进行X-射线晶体分析,得到如下数据:
晶体颜色和晶型: 无色,柱状
晶体大小: 0.25×0.12×0.08mm
晶系: 正交晶系
晶格: 简单点格
晶格参数: a=8.352(1)
b=15.574(2)
c=18.253(2)
V=2374.2(5)
空间群: p212121(#19)
Z值 4
理论密度: 1.333g/cm3
F000: 1008.00
μ(MoKα): 1.60cm-1
实施例4
GS-7340富马酸盐的制备
GS-7340-02(V)。(反应图解1)将GS-7340(IV)(1.294kg,2.71mol)、富马酸(284g,2.44mol)和乙腈(24.6kg)加入到搪瓷反应器中。加热回流混合物使固体溶解,趁热过滤,冷却至5℃并保持16小时。过滤分离出产物,用乙腈(9.2kg)冲洗,干燥得到1329g白色粉末(V):mp 119.7-121.1℃;[αD]20-41.7°(c1.0,乙酸)。
实施例5
GS-7120(VI)的制备
反应图解3
将一苯基PMPA(II)(200g,0.55mol)和乙腈(0.629kg)加入到5L圆低烧瓶中。在低于27℃加入亚硫酰氯(0.144kg,1.21mol)。在70℃加热反应混合物直至固体溶解。在氮气气氛下,常压蒸馏除去挥发物(0.45L)。将罐残余物冷却至25℃,加入二氯甲烷(1.6kg),并将混合物冷却至-20℃。在-20至-10℃,在18分钟内加入(L)-α-氨基丁酸乙酯(0.144kg,1.1mol)的二氯甲烷(1.33kg)溶液,然后,在-8至-15℃,在15分钟内加入三乙胺(0.17kg,1.65mol)。加热反应混合物至室温,用磷酸二氢钠溶液洗涤4次(10%水溶液,每次洗涤用0.3L)。有机溶液用无水硫酸钠(0.5kg)干燥,并过滤。所得的固体用二氯甲烷(0.6kg)冲洗,将合并的滤液和冲洗液减压浓缩成油状物。在15×13cm硅胶床柱(1.2kg,230~400目硅胶60)上通过色谱法提纯该油状物。柱用二氯甲烷和甲醇梯度洗脱。减压浓缩含有产物的馏分,得到211g褐色泡沫VI(反应图解3)。
实施例5a
通过间歇洗脱色谱法对GS-7120进行非对映异构体分离
除下述条件之外,采用实施例3A中针对GS-7171的非对映体分离条件来提纯非对映体混合物:
流动相(最初): GS-7120-乙腈∶异丙醇(98∶2)
(最后): 100%甲醇
洗脱曲线: GS-7341(非对映异构体B)
: GS-7342(非对映异构体A)
实施例6
用结晶法对GS-7120进行非对映异构体分离
将一苯基PMPA(II)(50g,0.137mol)和乙腈(0.2L)加入到1L圆低烧瓶中。加入亚硫酰氯(0.036kg,0.303mol),引起升温10℃。加热回流混合物直至固体溶解。在氮气气氛下常压蒸馏除去挥发物(0.1L)。将罐残余物冷却至25℃,加入二氯甲烷(0.2kg),并将混合物冷却至-20℃。在-20至-8℃,在30分钟内加入(L)-α-氨基丁酸乙酯(0.036kg,0.275mol)的二氯甲烷(0.67kg)溶液,然后,在不超过-6℃,在10分钟内加入三乙胺(0.042kg,0.41mol)。加热反应混合物至室温,用磷酸二氢钠溶液洗涤4次(10%水溶液,每次0.075L)。有机溶液用无水硫酸钠(0.1kg)干燥,并过滤。所得的固体用乙酸乙酯(0.25L)冲洗,并将合并的滤液和冲洗液减压浓缩成油状物。将油状物用乙酸乙酯(0.25L)稀释,放入晶种,搅拌过夜并冷却至-15℃。过滤分离出固体,减压干燥得到17.g褐色粉末GS-7342(表5):1H NMR(CDCl3)δ0.95(t,3H),1.3(m,6H),1.7,(m,2H),3.7(m,2H),4.1(m,6H),4.4(dd,1H),5.8(s,2H),7.1(m,5H),8.0(s,1H),8.4(s,1H);31P NMR(CDCl3)δ21(去耦)。
实施例7
GS-7097的非对映异构体分离
除了下述条件之外,采用用于GS-7171(实施例3A)的分离条件来提纯非对映体混合物:
流动相(开始):GS-7120-乙腈∶异丙醇(95∶5)
(最后):100%甲醇
洗脱曲线:GS-7115(非对映异构体B)
:GS-7114(非对映异构体A)
实施例8
GS-7097的另一种制备方法
GS-7097:苯基PMPA、乙基L-丙氨酰酰胺化物。在干燥N2下,将PMPA(15.0g,41.3mmol)、L-丙氨酸乙酯盐酸盐(12.6g,83mmol)和三乙胺(11.5mL,83mmol)与500mL吡啶一起形成淤浆。将该悬浮液与三苯基膦(37.9g,145mmol)、Aldrithiol 2(2,2’-二吡啶基二硫化物)(31.8g,145mmol)和120mL吡啶的溶液混合。在内部温度为57℃的条件下,加热该混合物15小时。将完成的反应真空浓缩得到黄色糊状物100g。在25×11cm硅胶柱床(230~400目硅胶60,1.1kg)上,用柱色谱法提纯该糊状物。柱用8L 2%甲醇的二氯甲烷溶液洗脱,然后用26L洗脱液进行线性梯度洗脱,洗脱液的最终组成为最高含有13%甲醇。浓缩含有纯化产物的馏分,得到12.4g粗产物(5),理论收率为65%。根据1H NMR,该产物含有约15%(重量)三乙胺盐酸盐杂质。将该产物溶解在350mL乙酸乙酯中,用20mL水萃取,有机溶液用无水硫酸钠干燥并浓缩,以除去杂质,得到11.1g纯的白色GS-7097,收率为58%。上述方法也可用来合成GS-7003a和GS-7003b(苯基丙氨酰酰胺化物)的非对映体混合物以及GS-7119和GS-7335(甘氨酰基酰胺化物)的混合物。使用诸如实施例3A、6和7中描述的间歇洗脱方法可分离上述非对映异构体。
实施例9
前药非对映异构体的体外研究
GS-7340(游离碱)和tenofovir disoproxil富马酸盐(TDF)的体外抗-HIV-1活性和它们在MT-2细胞中的细胞毒性以及它们在人类血浆和MT-2细胞提取液中的稳定性列于下表1。相对于TDF,GS-7340的抗病毒活性增加到10倍并且在血浆中的稳定性增加到200-倍。可以预计,口服给药后,更高的血浆稳定性将导致GS-7340循环浓度高于TDF循环浓度。
表1.体外活性和稳定性
HIV-1活性 | 细胞毒性 | 稳定性T1/2(分钟) | |||
IC50μM | CC50μM | 人类血浆 | MT-2细胞提取液 | P/MT-2 | |
GS-7340 | 0.005 | >40 | 90.0 | 28.3 | 3.2 |
TDF | 0.05 | 70 | 0.41 | 70.7 | 0.006 |
tenofovir | 5 | 6000 | - | - | - |
与GS-7340细胞内代谢得到的相对细胞内PMPA作比较,评价TDF细胞内代谢得到的相对细胞内PMPA,为此,将前药和PMPA进行放射标记,并用针以等克分子浓度输入到无损伤人类的全部血液中。1小时后,分离出血浆、红细胞(RBCs)和外周血单核细胞(PBMCs)并用带有放射检测的HPLC分析。结果见表2。
1小时后,分别与TDF和PMPA相比较,GS-7340在PBMCs中产生的PMPA类细胞内总浓度为10x和30x。1小时后,血浆中84%的放射活性来自未代谢的GS7340,而在1小时后却检测不到TDF。由于在血浆中检测不到未代谢的TDF,因此,可以预计,在1小时后,10x差额是TDF和GS-7340在体内的最小差额。表示全部三种化合物在PBMCs中的HPLC色谱分析结果见附图1。
表2.PMPA前药或PMPA在人类血液中温育1小时后,在
血浆、PBMCs和RBCs中的PMPA代谢产物
化合物 | 基质 | 回收的总C-14μg-eq | 代谢物(%总峰面积) | |||||
PMPA% | PMPAp,% | PMPApp,% | Met.X,% | Met.Y,% | GS7340,% | |||
GS-7340(60μg-eq) | 血浆/FPPBMCRBC/FP | 43.01.2512.6 | 1458 | -16- | -21- | 21824 | 13-11 | 84-57 |
PMPA | PMPAp | PMPApp | 单-POC | GS-4331 | ||||
GS-4331(TDF)(60μg-eq) | 血浆/FPPBMCRBC/FP | 48.10.13310.5 | 115093 | -257.0 | -18- | 897- | --- | |
PMPA | PMPAp | PMPApp | ||||||
PMPA(60μg-eq) | 血浆/FPPBMCRBC/FP | 55.70.0333.72 | 1008674 | -1410 | --16 |
附图1.TDF、GS-7340或PMPA在37℃人类血液中温育1小时后,
人类血液PBMC提取液的HPLC/C-14示踪分析结果
Met.X和MetY(代谢产物X和Y)见表5。下标″p″表示磷酸化作用。上述结果是1小时后从人类血液中得到的结果。由于1小时后血浆中仍有84%GS-7340未发生代谢,因此,随着时间的延长,预计体外差额会增加。由于口服给药后血浆中存在未代谢的GS-7340,因此,相对临床效力与体外观察到的IC50值有关。
在下表3中,列举了tenofovir、TDF、GS-7340、几种核苷和蛋白酶抑制剂nelfinivir的IC50值。如表所示,nelfinavir和GS-7340的效力较所有其它核苷酸或核苷大2-3数量级。
表3.抗转录病毒化合物的体外抗-HIV-1活性
1.A.S.Mulato and J.M.Cherrington,Antiviral Research36,91(1997)
化合物 | IC50(μM) |
Adefovir(PMEA) | 13.4±4.21 |
Tenofovir(PMPA) | 6.3±3.31 |
AZT | 0.17±0.081 |
3TC | 1.8±0.251 |
d4T | 8±2.51 |
Nelfinavir | 0.006±0.0021 |
TDF | 0.05 |
GS 7340 | 0.005 |
本发明分离的非对映异构体的体外细胞培养抗-HIV-1活性和CC50的其它研究结果列于下表。
表4.非对映异构体的效果
化合物 | 非对映异构体 | IC50(μM) | 改变倍数 | A/B活性 | CC50(μM) |
PMPA | - | 5 | 1x | - | 6000 |
丙氨酸甲酯 | 1∶1混合物 | 0.025 | 200x | 20x | 80 |
GS-69 57a | A | 0.0075 | 670x | ||
GS-6957b | 0.15 | 33x | |||
苯丙氨酸甲酯 | 1∶1混合物 | 0.03 | 170x | 10x | 60 |
GS-7003a | A | 0.01 | 500x | ||
GS-7003b | B | 0.1 | 50x | ||
甘氨酸乙酯 | 1∶1混合物 | 0.5 | 10x | 20x | |
GS-7119 | A | 0.05 | 100x | >100 | |
GS-7335 | B | 1.0 | 5x | ||
丙氨酸异丙酯 | 1∶1混合物 | 0.01 | 500x | 12x | |
GS-7340 | A | 0.005 | 1.000x | 40 | |
GS-7339 | B | 0.06 | 83x | >100 | |
ABA乙酯 | 1∶1混合物 | 0.008 | 625x | 7.5x | >100 |
GS-7342 | A | 0.004 | 1,250x | ||
GS-7341 | B | 0.03 | 170x | ||
丙氨酸乙酯 | 1∶1混合物 | 0.02 | 250x | 10x | 60 |
GS-7114 | A | 0.005 | 1,000x | ||
GS-7115 | B | 0.05 | 100x |
分析方法参考:Arimilli,MN,等人(1997)9-[2-(膦酰基甲氧基)丙基]腺嘌呤(PMPA)前药的合成、体外生物学评估和口服生物可利用度。Antiviral Chemistry and Chemotherapy 8(6):557-564。
“苯丙氨酸甲酯”是tenofovir的甲基苯丙氨酰单酰胺化单苯酯;“甘氨酸甲基酯”是tenofovir的甲基甘氨酰单酰胺化单苯酯。
在上述每一实例中,相信异构体A具有与GS-7340(S)相同的绝对立体化学,异构体B具有与GS-7339相同的绝对立体化学。
可在PLCE、MT-2提取液和人类血浆中测定已分离的非对映异构体的体外代谢和稳定性。将下文列举的生物样品80μl转移至用螺旋盖密封的离心管中并在37℃温育5分钟。将在适当缓冲剂中含有0.2mg/mL试验化合物的溶液20μ1加入到生物样品中并混合。立即抽样20μl反应混合物并与60μl含有0.015mg/mL 2-羟甲基萘作为HPLC分析内标的甲醇混合。将该样品作为计时起点样品。然后,在特定时间抽样20uL反应混合物并与60uL含有内标的甲醇混合。将得到的混合物在15,000GG离心5分钟,并在下述条件下用HPLC分析上清液。
生物样品评估如下:
(1)用PBS(含磷酸盐的缓冲盐水)将PLCE(猪肝羧酸酯酶,购自Sigma,160u/mg蛋白质,21mg蛋白质/mL)稀释20倍。
(2)除了改用下述HEPES缓冲液作为培养基外,根据公开的方法[A.Pompon,I.Lefebvre,J.-L.Imbach,S.Kahn和D.Farquhar,″Antiviral Chemistry & Chemotherapy″,5:91-98(1994)]由MT-2细胞制备MT-2细胞提取液。
(3)人类血浆(混合的正常人类血浆,购自George King BiomedicalSystems,Inc.)。
本发明研究中使用的缓冲体系如下。
在针对PLCE的研究中,将试验化合物溶解在PBS中。PBS(含磷酸盐的缓冲盐水,Sigma)含有0.01M磷酸盐、0.0027M氯化钾和0.137M氯化钠。37℃时pH为7.4。
在针对MT-2细胞提取液的研究中,将试验化合物溶解在HEPES缓冲液中。HEPES缓冲液含有0.010M HEPES、0.05M氯化钾、0.005M氯化镁和0.005M dl-二硫苏糖醇。37℃时pH为7.4。
在针对人类血浆的研究中,将试验化合物溶解在TBS中。TBS(tris缓冲盐水,Sigma)含有0.05M Tris、0.0027M氯化钾和0.138M氯化钠。37℃时pH为7.5。
在下述条件下进行HPLC分析。
柱: Zorbax Rx-C8,4.6×250mm,5μ
(MAC-MOD Analytical,Inc.Chadds Ford,PA)
检测: UV 260nm
流速: 1.0ml/分钟
操作时间: 30分钟
注射进样体积:20μL
柱温: 室温
流动相A: 50mM磷酸钾(pH6.0)/CH3CN=95/5(v/v)
流动相B: 50mM磷酸钾(pH6.0)/CH3CN=50/50(v/v)
梯度操作: 0分钟 100%流动相A
25分钟 100%流动相B
30分钟 100%流动相B
结果列于表5(还包括选自表4的IC50值)。
表5.PMPA单酰胺化物的异构体A和B在37℃的体外代谢
实施例10
用前药非对映异构体给长耳短腿小猎犬
口服给药后血浆和PBMC的暴露
在以10mg-当量/kg剂量口服给药后,研究猎犬体内GS7340的药代动力学。
制剂。在给药前0.5小时内,将前药配制成在50mM柠檬酸中的溶液,研究中使用的所有化合物由Gilead Sciences合成。所使用的化合物如下表:
GSI | 氨基酸酰胺化物 | AA酯 | 非对映异构体 | 批号 |
GS-7340-2 | 丙氨酸 | 异丙基 | 异构体A | 1504-187-19 |
GS-7339 | 丙氨酸 | 异丙基 | 异构体B | 1509-185-31 |
GS7114 | 丙氨酸 | 乙基 | 异构体A | 1509-181-26 |
GS7115 | 丙氨酸 | 乙基 | 异构体B | 1509-181-22 |
GS7119 | 甘氨酸 | 乙基 | 异构体A | 1428-163-28 |
GS7342 | α-氨基丁酸 | 乙基 | 异构体A | 1509-191-12 |
GS7341 | α-氨基丁酸 | 乙基 | 异构体B | 1509-191-7 |
给药方法和样品采集。体内阶段的研究根据“Guide for the Careand Use of Laboratory Animals”(National Institutes ofHealthpublication 86-23)的介绍进行并被Institutional AnimalCare and Use Committee许可。研究中使用禁食的雄性长耳短腿小猎犬(10±2kg)。通过管饲法以单次量(1.5-2ml/kg)口服每种药物。剂量为10mg-当量PMPA/kg。对于PBMCs,在给药后0(给药前)、2、8和24小时采集血样。对于血浆,在给药后0(给药前)、5、15和30分钟和1、2、3、4、6、8、12和24小时采集血样。立即在2,000rpm下离心处理血样(1.0ml)10分钟,得到血浆。冷冻血浆样品并在70℃保存以备用于分析。
外周血单核细胞(PBMC)的制备。将在特定时间抽采的全部血液(8ml)与等量的含磷酸盐的缓冲盐水(PBS)混合,在15ml Ficoll-Paque溶液(Pharmaeia Bioteeh)上分层,并在400xg离心40分钟。除去PBMC层并用PBS洗涤一次。将形成的PMBC小丸在0.5ml PBS中重组,使细胞重新悬浮,用血细胞计数器计数并在70℃保存以备用于分析。细胞数与平均单个细胞体积的乘积用于计算细胞内浓度。已报道的数值200飞升/细胞用作静止PBMC体积(B.L.Robins、R.V.Srinivas、C.Kim、N.Bischofberger和A.Fridland,Antimicrob.Agents Chemother.42,612(1998)。测定血浆和PBMCs中的PMPA和前药。通过用氯乙醛将PMPA衍生为易发萤光的N1,N6-亚乙烯基腺嘌呤衍生物来测定狗血浆样品中PMPA浓度(L.Naesens、J.Balzarini和E.De Clercq,Clin.Chem.38,480(1992)。简而言之,将血浆(100μl)与200μl乙腈混合使蛋白质沉淀。然后在室温下将样品减压蒸发至干。将干燥的样品在200μl衍生化鸡尾酒(0.34%氯乙醛于100mM乙酸钠中的溶液,pH4.5)中重组,涡旋,并离心。将上清液转移至干净的用螺帽密封的试管中,并在95℃温育40分钟。然后将衍生化样品蒸发至干燥并在100μl水中重组以用于HPLC分析。
在用HPLC测定细胞内PMPA之前,必须通过选择性氧化除去PBMC提取液中存在的大量与腺嘌呤有关的核糖核甙酸。我们使用了Tanaka等人的改进方法(K.Tanaka,A.Yoshioka,S.Tanaka和Y.Wataya,Anal.Biochem.,139,35(1984))。简而言之,将PBMC样品按1∶2比例与甲醇混合并减压蒸发至干。将干燥样品按血浆分析中所述的方法衍生化。将衍生化的样品与20μl 1M鼠李糖和30μl0.1M过碘酸钠混合并在37℃温育5分钟。温育后,加入40μl4M甲胺和20μl 0.5M肌苷。在37℃温育30分钟后,减压蒸发样品至干并在水中重组以进行HPLC分析。
在任何PBMC样品中没有测定到未发生改变的前药。对于可能含有完整前药的血浆样品,实验证明在衍生化反应过程中没有发生向PMPA的进一步转化。将前药标样加入到不合有药物的血浆中并按上述方法进行衍生化。在任何血浆样品中没有检测到PMPA的存在,并且预计的转化百分数小于1%。
HPLC体系由带有AS3000自动注射进样器的P4000溶剂递送体系和F2000荧光检测器(Thermo Separation,San Jose,CA)组成。色谱柱是Inertsil ODS-2柱(4.6×150mm)。使用的流动相是:A,5%乙腈在含5mM溴化四丁基铵(TBABr)的25mM磷酸钾缓冲液中的溶液,pH6.0;B,60%乙腈在含有5mM TBABr的25mM磷酸钾缓冲液中的溶液,pH6.0。流速为2ml/分钟和柱温用柱加热炉保温在35℃。对于PMPA,梯度曲线是90%A/10%B 10分钟,对于前药,梯度曲线是65%A/35%B 10分钟。进行荧光检测,激发波长为236nm,发射波长为420nm,注射进样体积为10μl。用实验室数据获取系统(PeakPro,Beckman,Allendale,NJ)采集和存储数据。药代动力学计算。PMPA和前药暴露量用0-24小时内血浆或PBMC中的浓度曲线的面积(AUC)表示。
用梯形规则计算AUC值。
血浆和PBMC浓度。本发明研究结果见附图2和3。附图2表示在口服PMPA前药的纯非对映异构体后,血浆和PBMC暴露的GS7340-2代谢时间过程。
附图2. 以10mg-当量/kg剂量用GS 7340-2给猎犬口服给药后
血浆和PBMCs中的PMPA和前药浓度
附图2中的柱状图表示在服用PMPA s.c.、TDF和酰胺化酯前药后,在犬PBMCs和血浆中tenofovir的AUC(0-24小时)。所有酰胺化前药在PBMC暴露中增加。例如,与PMPAs.c.和TDF相比,GS7340在PBMC暴露中增加到~21倍;在血浆暴露中分别降低为1/6.25和1/1.29。
附图3.以10mg-当量/kg剂量对犬给药后,
描绘PBMCs和血浆中的Tenofovir暴露
用PMPA前药以10mg-当量/kg剂量给犬给药后
在PBMC和血浆中PMPA的AUC(0-24小时)
上述体内数据表明,GS7340可以经口送递体内,使对PMPA的全身暴露降到最低,并大大提高了PMPA在主要引起HIV复制的细胞中的细胞内浓度。
表6
在犬口服PMPA前药后,PBMC和血浆中的PMPA暴露
GS# | 基团 | 血浆中PMPA AUC | PBMC中PMPA AUC | 血浆中前药 | PBMC/血浆暴露比例 | ||||
平均值 | StDev | N | 平均值 | StDev | N | ||||
GS-7114GS-7115 | 单丙氨酸乙酯-A单丙氨酸乙酯-B | 5.86.6 | 0.91.5 | 22 | 706284 | 33194 | 55 | 是是 | 12243 |
GS-7340-2GS-7339 | 单丙氨酸异丙酯-A单丙氨酸异丙酯-A | 5.06.4 | 1.11.3 | 52 | 805200 | 22257 | 55 | 是是 | 16131 |
GS-7119 | 单甘氨酸乙酯-A | 6.11 | 1.86 | 2 | 530 | 304 | 5 | 是 | 87 |
GS-7342GS7341 | 单ABA乙酯-A单ABA乙酯-B | 4.65.8 | 1.21.4 | 22 | 1060199 | 51186 | 55 | 是是 | 23034 |
实施例11
GS-7340的生物分布
作为GS-7340临床前特性描述的一部分,测定其在犬体内生物分布。在对长耳短腿小猎犬口服给药后,测定GS-7340(tenofovir的异丙基丙氨酰单酰胺化单苯酯)的组织分布。给两只雄性动物口服14C=GS-7340(8.85mg-当量PMPA/kg,33.2μCi/kg;腺嘌呤的8-碳原子被标记)的含水溶液(50mM柠檬酸,pH2.2)。在24-小时期间内得到血浆和外周血单核细胞(PBMCs)。关笼收集24小时内的尿和粪便。给药24小时后,将动物杀死提取组织进行分析。通过氧化和液体闪烁计数测定总放射活性。
将单次剂量放射标记的GS7340口服24小时后,PMPA的生物分布以及以前使用TDF(GS-4331)得到的数据列于表4中。在TDF情况下,血浆中的前药浓度低于分析检测浓度,并且在血浆中观察到的主要化合物是母体药物。在用GS-7340给药后,在淋巴组织、骨髓和骨骼肌肉中PMPA浓度增加到10倍。
在淋巴组织中的积蓄与从PBMC分析得到的数据一致,这是因为,这些组织主要由淋巴细胞组成。同样,在骨髓中的蓄积大概应归于淋巴细胞在该组织中的高百分比(70%)。
表7.以10mg-当量PMPA/kg剂量口服后,犬体内放射标记的
GS-7340在分泌物和组织中的分布(平均值,N=2)
组织/组织液 | GS-4331 | GS-7340 | 组织浓度GS 7340对GS-4331的比例 | ||
%剂量 | 浓度(μg当量/g) | %剂量 | 浓度(μg当量/g) | ||
肝肾肺 | 12.404.580.03 | 38.3087.900.53 | 16.453.780.34 | 52.9480.214.33 | 1.40.98.2 |
髂淋巴结腋淋巴结腹股沟淋巴结肠系膜淋巴结 | 0.000.000.000.00 | 0.510.370.281.20 | 1.010.010.000.04 | 5.425.544.126.88 | 10.614.815.05.7 |
甲状腺脑下垂体唾腺(L+R)肾上腺 | 0.000.000.000.00 | 0.300.230.451.90 | 0.000.000.030.00 | 4.781.805.543.47 | 15.87.812.31.8 |
脾脏胰腺 | 0.000.00 | 0.630.57 | 0.170.01 | 8.133.51 | 12.86.2 |
前列腺睾丸(L+R)骨骼肌心脏 | 0.000.020.000.03 | 0.231.950.110.46 | 0.000.020.010.15 | 2.142.011.121.97 | 9.11.010.14.3 |
股骨骨髓 | 0.000.00 | 0.080.20 | 0.000.00 | 0.282.05 | 3.510.2 |
皮腹部脂肪眼(L+R) | 0.000.000.00 | 0.130.160.06 | 0.000.000.00 | 0.950.900.23 | 7.25.83.7 |
脑脑脊髓液脊髓 | 0.000.000.00 | <LOD<LOD<LOD | 0.000.000.00 | <LOD0.000.04 | n.d.n.d.n.d. |
胃空肠十二指肠回肠大肠胆囊胆汁 | 0.111.340.490.011.630.000.00 | 1.923.014.960.505.973.589.63 | 0.260.790.440.162.650.040.22 | 2.684.168.774.6147.2025.0240.48 | 1.41.41.89.27.97.04.2 |
粪便总胃肠道内容物尿 | 40.965.6123.72 | n.d.n.d.n.d. | 0.1921.6414.73 | n.d.n.d.n.d. | n.a.n.a.n.a. |
血浆(24小时)血浆(0.25小时)PBMC*全部血液 | 0.00n.a.0.000.00 | 0.203.68n.d.0.85 | 0.00n.a.0.000.16 | 0.203.4863.200.20 | 1.00.9n.d.0.2 |
总回收率 | 81.10 | 68.96 |
*计算时采用标准的15×106细胞总回收率和每个细胞的平均PBMC体积=0.2飞升。
n.s.=没有样品,n.a.=不适用,n.d.=未检测到。
Claims (18)
1.具有结构(Ia)的核苷酸类似物化合物
其盐、互变异构体或游离碱,其富集在下面结构(Ib)的非对映异构体,
其中,
R5是甲基或氢;
R6a和R6b独立地是H、烷基、烯基、炔基、芳基或芳烷基,它们各自可任选地被1-3个选自烷基氨基、烷基氨基烷基、二烷基氨基烷基、二烷基氨基、羟基、氧代、卤素、氨基、烷硫基、烷氧基、烷氧基烷基、芳氧基、芳氧基烷基、芳基烷氧基、芳基烷氧基烷基、卤代烷基、硝基、硝基烷基、叠氮基、叠氮基烷基、烷酰基、烷酰基烷基、羧基或烷酰基氨基的取代基取代;
R7是任一天然或可药用氨基酸的侧链,并且,条件是当该侧链含有羧基时,则任选该羧基选用烷基或芳基酯化;
R11是氨基、烷基氨基、氧基或二烷基氨基;和
R12是氨基或H。
2.权利要求1的核苷酸类似物化合物,其盐、互变异构体或游离碱,其包括至少大约80重量%的结构(Ib)的非对映异构体。
3.权利要求1的核苷酸类似物化合物,其盐、互变异构体或游离碱,其包括至少大约95重量%的结构(Ib)的非对映异构体。
5.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其中R5为甲基,R6a为苯基,R6b为甲基,R7为甲基,R11为氨基,和R12为氢。
6.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其中R5为甲基,R6a为苯基,R6b为甲基,R7为苄基,R11为氨基,和R12为氢。
7.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其中R5为甲基,R6a为苯基,R6b为乙基,R7为氢,R11为氨基,和R12为氢。
8.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其中R5为甲基,R6a为苯基,R6b为异丙基,R7为甲基,R11为氨基,和R12为氢。
9.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其中R5为甲基,R6a为苯基,R6b为乙基,R7为乙基,R11为氨基,和R12为氢。
10.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其中R5为甲基,R6a为苯基,R6b为乙基,R7为甲基,R11为氨基,和R12为氢。
11.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其为基本上纯的9-[(R)-2-[[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤。
12.权利要求4的核苷酸类似物化合物,其盐、互变异构体或游离碱,其为基本上纯的9-[(R)-2-[(S)-1-(异丙氧基羰基)乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐。
13.一种药物组合物,其包含权利要求1-12中任一项的核苷酸类似物化合物,其盐、互变异构体或游离碱及可药用赋形剂。
14.权利要求13的组合物,其中赋形剂为凝胶。
15.权利要求13的组合物,其适合局部给药。
16.权利要求1-12中任一项的化合物在制备用于预防或治疗肿瘤或病毒疾病的药物的用途。
17.权利要求16的用途,其中病毒疾病为HIV感染。
18.权利要求16的用途,其中病毒疾病为嗜肝脱氧核糖核酸病毒感染。
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Cited By (2)
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US10065958B2 (en) | 2010-07-22 | 2018-09-04 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
CN104558036A (zh) * | 2014-12-11 | 2015-04-29 | 杭州和泽医药科技有限公司 | 一种替诺福韦艾拉酚胺半反丁烯二酸盐晶型及其制备方法 |
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