CN102504001A - 3,5-二取代的和3,5,7-三取代的-3H-噁唑并以及3H-噻唑并[4,5-d]嘧啶-2-酮化合物及其前药 - Google Patents
3,5-二取代的和3,5,7-三取代的-3H-噁唑并以及3H-噻唑并[4,5-d]嘧啶-2-酮化合物及其前药 Download PDFInfo
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- PNYKGCPSFKLFKA-UHFFFAOYSA-N tofenacin Chemical compound C=1C=CC=C(C)C=1C(OCCNC)C1=CC=CC=C1 PNYKGCPSFKLFKA-UHFFFAOYSA-N 0.000 description 1
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- 150000004684 trihydrates Chemical class 0.000 description 1
- FEZBIKUBAYAZIU-UHFFFAOYSA-N trimethobenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NCC=2C=CC(OCCN(C)C)=CC=2)=C1 FEZBIKUBAYAZIU-UHFFFAOYSA-N 0.000 description 1
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- 229960004799 tryptophan Drugs 0.000 description 1
- SZCZSKMCTGEJKI-UHFFFAOYSA-N tuberin Natural products COC1=CC=C(C=CNC=O)C=C1 SZCZSKMCTGEJKI-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000002498 viral encephalitis Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 description 1
- 229960002791 zimeldine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Images
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Abstract
本发明涉及具有免疫调节活性的3,5-二取代的和3,5,7-三取代的-3H-噁唑并和3H-噻唑并[4,5-d]嘧啶-2-酮化合物及其前药。本发明还涉及该化合物和含有该化合物的药物组合物的治疗和预防疾病的用途,涉及通过给予有效量的该化合物和前药来治疗本发明所述的疾病和失调的方法。
Description
本发明专利申请是国际申请号为PCT/US2005/045589,国际申请日为2005年12月16日,进入中国国家阶段的申请号为200580043101.6,名称为“3,5-二取代的和3,5,7-三取代的-3H-噁唑并以及3H-噻唑并[4,5-d]嘧啶-2-酮化合物及其前药”的发明专利申请的分案申请。
发明领域
本发明涉及具有免疫调节活性的3,5-二取代的和3,5,7-三取代的-3H-噁唑并以及3H-噻唑并[4,5-d]嘧啶-2-酮化合物及其前药。本发明还涉及这种化合物及含这种化合物的药物组合物的治疗或预防疾病的用途,涉及通过给予有效量的该化合物和前药治疗本文所述的疾病和失调的方法。
发明背景
在过去的几十年中,人们致力于开发鸟嘌呤类似物及其核苷可能的治疗用途。目前,许多核苷类似物目前已作为抗病毒药物市场化了,这些类似物包括HIV逆转转录酶抑制剂,例如AZT,ddI,ddC,d4T和3TC,以及鸟苷核苷类似物阿巴卡韦。虽然并不遵照某一具体的理论,核苷类似物可通过直接抑制病原体或肿瘤、通过激发宿主的免疫功能或通过这些或其它机制的一些组合来发挥优势。
所研究的显示出免疫调节活性的鸟苷类似物中的一种是5-氨基-3-(β-D-呋喃核糖基噻唑并[4,5-d]嘧啶-2,7(3H,6H)二酮(7-硫-8-氧代鸟苷)。例如,在授予Robins等人的美国专利5,041,542中揭示了某些嘧啶并[4,5-d]嘧啶核苷在治疗BDF1小鼠抗L1210中是有效的。另外,授予Robins等的美国专利5,041,426和4,880,784揭示了3-β-D-呋喃核糖基噻唑并[4,5-d]嘧啶显示出明显的免疫活性,包括鼠科脾细胞增殖和对SemlikiForest病毒的体内活性。许多出版物也对噻唑并[4,5-d]嘧啶部分的非糖基化衍生物进行了描述,参见例如,美国专利5,994,321和5,446,045,Revankar等人,J.Het.Chem.,30,1341-49(1993);Lewis等人,J.Het.Chem.,32,547-56(1995)。
发明概述
本发明描述了新颖的3,5-二取代的和3,5,7-三取代的-3H-噁唑并和3H-噻唑并[4,5-d]嘧啶-2-酮化合物,及其药物活性前药,药物活性代谢产物,药学上可接受的盐和药学上可接受的溶剂合物,它们被用作免疫调节剂。
在另一个实施方式中,本发明包括一种对需要治疗或预防丙型肝炎病毒感染的患者进行丙型肝炎病毒感染治疗或预防的方法,该方法包括给予患者治疗或预防有效量的3,5-二取代的和3,5,7-三取代的-3H-噁唑并和3H-噻唑并[4,5-d]嘧啶-2-酮化合物或其前药。
在一个总体方面,本发明涉及的前药是式I的3,5-二取代的和3,5,7-三取代的-3H-噁唑并和3H-噻唑并[4,5-d]嘧啶-2-酮化合物,或其药学上可接受的盐,水合物,或立体异构体:
式中,
X是O或S,
Y是O或S,
R1是H、烷基、芳基、环烷基或杂环基,
R2是NH2、-NHC(O)R4、-NHR5、-N=CHNR6R7,
R3是H、Cl、Br或OR8,
R4是-C1-C7-烷基或-O(C1-C7-烷基),
R5是-C1-C7-烷基,
R6和R7独立地是-C1-C7-烷基,或者与氮一起形成五元或六元杂环,
R8是-CHR9R10,
R9是H、-C1-C7-烷基、环烷基、芳基、杂环基、-NR11R12或OR5,
R10是-C1-C7-烷基、环烷基、芳基、杂环基、-NR11R12或OR5,
R11和R12独立地是H、-C1-C7-烷基或-C(O)R4,
其中,当X是O,Y是S,且R3是H、Cl、Br或OR8时,R1不是H或β-D-核糖或其酯,
其中,上述的烷基、芳基、环烷基或杂环基部分任选被1-4个选自下组的取代基取代:
氢,
烷酰基,
烷基胺,
氨基,
芳基、环烷基、杂环基,
叠氮基,
C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6烷基胺、C1-C6二烷基胺、C2-C6烯基或C2-C6炔基,其中,各取代基可插有一个或多个杂原子,
羧基,
氰基,
卤素,
羟基,
巯基,
硝基,
硫代烷基,
-N=N-NH2,
-C(O)2-(C1-C6烷基)、-C(O)2-(芳基)、-C(O)2-(环烷基)、-C(O)2-(杂环基)、-O-(C1-C6卤代烷基)、-O-(C1-C6烷基)芳基、-O-(C1-C6烷基)环烷基、-O-(C1-C6烷基)杂环基、-O-(C1-C6烷基)氨基、-O-(C1-C6烷基)烷基氨基、-O-(C1-C6烷基)二烷基氨基、-O-(C1-C6烷基)-C(O)-氨基、-O-(C1-C6烷基)-C(O)-烷基氨基、-O-(C1-C6烷基)-S(O)2-氨基、-O-(C1-C6烷基)-S(O)2-烷基氨基、-O-(C1-C6烷基)-S(O)2-二烷基氨基、-O-(C1-C6烷基)-C(O)-二烷基氨基、-O-芳基、-O-杂环基、-NHC(O)-(C1-C6烷基)、-NHC(O)-(C1-C6烯基)、-NHC(O)-(芳基)、-NHC(O)-(环烷基)、-NHC(O)-(杂环基)、-NHC(O)-(C1-C6烷基)芳基、-NHC(O)-(C1-C6烷基)环烷基、-NHC(O)-(C1-C6烷基)杂环基、-NHC(O)-(C1-C6烷基)氨基、-NHC(O)-(C1-C6烷基)烷基胺、-NHC(O)-(C1-C6烷基)二烷基胺、-NHC(O)-(C1-C6烷基)C(O)氨基、-NHC(O)-(C1-C6烷基)C(O)烷基胺、-NHC(O)-(C1-C6烷基)C(O)二烷基胺、-NHC(O)-(C1-C6烷基)N(H)-(C1-C6烷基)C(O)2-(C1-C6烷基)、-NH-(C1-C6烷基)-C(O)-氨基、-NH-(C1-C6烷基)-C(O)-烷基氨基、-NH-(C1-C6烷基)-C(O)-二烷基氨基、-NHC(O)-(C1-C6烷基)S(O)2(C1-C6烷基)、-NHC(O)-(C1-C6烷基)-S-(杂环基)、-NHS(O)2-(C1-C6烷基)、-NHS(O)2-(芳基)、-NH-(C1-C6烷基)-S(O)2-氨基、-NH-(C1-C6烷基)-S(O)2-烷基氨基、-NH-(C1-C6烷基)-S(O)2-二烷基氨基、-NHS(O)2-(环烷基)、-NHS(O)2-(杂环基)、-NHS(O)(C1-C6烷基)、-NHS(O)(芳基)、-NHS(O)(环烷基)、-NHS(O)(杂环基)、-NHS(C1-C6烷基)、-NHS(芳基)、-NHS(环烷基)和-NH-S-(杂环基),
其中,上述各取代基还可以任选被1-5个选自下组的取代基取代:
氨基,
C1-C6烷基胺,C1-C6二烷基胺,
C1-C6烷基、C1-C6烷氧基、C1-C6烯基、C1-C6羟基和C1-C6羟基烷基,
它们各自任选被选自下组的基团取代:
氰基,
卤素,和
硝基。
在一个实施方式中,本发明涉及式I的化合物,其中的R2是NH2。
在另一个实施方式中,本发明涉及式I的化合物,其中的R3是H。
在另一个实施方式中,本发明涉及式I的化合物,其中x是O,Y是S。
在另一个实施方式中,本发明涉及式I的化合物,其中,R1选自以下:
在另一个实施方式中,本发明涉及式I化合物,选自以下:
在另一个总体方面,本发明涉及式II的3,5-二取代的和3,5,7-三取代的-3H-噁唑并以及3H-噻唑并[4,5-d]嘧啶-2-酮的化合物,或其药学上可接受的盐,水合物或立体异构体:
式中,
X是O或S,
Y是O或S,
Z是O或CH2,
R2是-NH2、-NHC(O)R4、-NHR5、-N=CHNR6R7,
R4是-C1-C7-烷基或-O(C1-C7-烷基),
R5是-C1-C7-烷基,
R6和R7独立地是-C1-C7-烷基,或者与氮一起形成五元或六元杂环,
R13是OH或SH,
R14是H、-CH2OH或-CH2-O-C(O)C1-18烷基,
R15是OH、烯基、-OC(O)C1-18烷基、-OC(O)芳基或-OC(O)杂环基,
R16、R17、R18和R19独立地是H、卤素、N3、烷基、-(CH2)mOR20、-(CH2)mOC(O)C1-18烷基、-OC(O)芳基、-OS(O)2芳基,或者R16和R17是烯基,或者R17和R19结合在一起形成间二氧杂环戊烯环,
R20是H或烷基,
m是0或1,
n是01或2,
其中,如果R2是NH2,则必须存在以下中的一个:
Z是CH2
或n是2或m是1;
R16、R17、R18和R19中至少一个是卤素、N3、烷基或-(CH2)mOR20,其中m是1,如果R17是N3,则R18和R19不是H,而如果R17是OH,以及R16和R19是H,则R18不是F;或者
R16和R17是烯基,
上述的烷基、芳基、环烷基或杂环基部分任选被1-4个选自以下组的取代基取代:
氢,
烷酰基,
烷基胺,
氨基,
芳基、环烷基、杂环基,
叠氮基,
C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6烷基胺,C1-C6二烷基胺,C2-C6烯基或C2-C6炔基,其中,各取代基可插有一个或多个杂原子,
羧基,
氰基,
卤素,
羟基,
巯基,
硝基,
硫代烷基,
-N=N-NH2,
-C(O)2-(C1-C6烷基)、-C(O)2-(芳基)、-C(O)2-(环烷基)、-C(O)2-(杂环基)、-O-(C1-C6卤代烷基)、-O-(C1-C6烷基)芳基、-O-(C1-C6烷基)环烷基、-O-(C1-C6烷基)杂环基、-O-(C1-C6烷基)氨基、-O-(C1-C6烷基)烷基氨基、-O-(C1-C6烷基)二烷基氨基、-O-(C1-C6烷基)-C(O)-氨基、-O-(C1-C6烷基)-C(O)-烷基氨基、-O-(C1-C6烷基)-S(O)2-氨基、-O-(C1-C6烷基)-S(O)2-烷基氨基、-O-(C1-C6烷基)-S(O)2-二烷基氨基、-O-(C1-C6烷基)-C(O)-二烷基氨基、-O-芳基、-O-杂环基、-NHC(O)-(C1-C6烷基)、-NHC(O)-(C1-C6烯基)、-NHC(O)-(芳基)、-NHC(O)-(环烷基)、-NHC(O)-(杂环基)、-NHC(O)-(C1-C6烷基)芳基、-NHC(O)-(C1-C6烷基)环烷基、-NHC(O)-(C1-C6烷基)杂环基、-NHC(O)-(C1-C6烷基)氨基、-NHC(O)-(C1-C6烷基)烷基胺、-NHC(O)-(C1-C6烷基)二烷基胺、-NHC(O)-(C1-C6烷基)C(O)氨基、-NHC(O)-(C1-C6烷基)C(O)烷基胺、-NHC(O)-(C1-C6烷基)C(O)二烷基胺、-NHC(O)-(C1-C6烷基)N(H)-(C1-C6烷基)C(O)2-(C1-C6烷基)、-NH-(C1-C6烷基)-C(O)-氨基、-NH-(C1-C6烷基)-C(O)-烷基氨基、-NH-(C1-C6烷基)-C(O)-二烷基氨基、-NHC(O)-(C1-C6烷基)S(O)2(C1-C6烷基)、-NHC(O)-(C1-C6烷基)-S-(杂环基)、-NHS(O)2-(C1-C6烷基)、-NHS(O)2-(芳基)、-NH-(C1-C6烷基)-S(O)2-氨基、-NH-(C1-C6烷基)-S(O)2-烷基氨基、-NH-(C1-C6烷基)-S(O)2-二烷基氨基、-NHS(O)2-(环烷基)、-NHS(O)2-(杂环基)、-NHS(O)(C1-C6烷基)、-NHS(O)(芳基)、-NHS(O)(环烷基)、-NHS(O)(杂环基)、-NHS(C1-C6烷基)、-NHS(芳基)、-NHS(环烷基)和-NH-S-(杂环基),
其中,上述各取代基还可以任选被1-5选自以下的取代基取代:
氨基,
C1-C6烷基胺、C1-C6二烷基胺,
C1-C6烷基、C1-C6烷氧基、C1-C6烯基、C1-C6羟基和C1-C6羟基烷基,
它们各自任选被选自下组的基团取代:
氰基,
卤素,和
硝基。
在另一个实施方式中,本发明涉及式II的化合物,其中R2是NH2。
在另一个实施方式中,本发明涉及式II的化合物,其中R13是OH。
在另一个实施方式中,本发明涉及式II的化合物,其中X是O,Y是S。
在另一个实施方式中,本发明涉及式II的化合物,选自以下:
在另一个总体方面,本发明涉及选自以下的3,5-二取代的和3,5,7-三取代的-3H-噁唑并以及3H-噻唑并[4,5-d]嘧啶-2-酮化合物:
本发明还涉及式I所示的前药、式II所示的化合物和本发明的其它化合物或代谢物的药学活性代谢物、药学上可接受的盐和药学上可接受的溶剂合物。本发明还描述了制备本发明的化合物的有利方法。
本发明的式I的前药、式II的化合物和本发明的其它化合物可以用作免疫系统的增强剂,并具有某些免疫系统的特性,包括调节、促有丝分裂、增大和/或增强,或者是具有这些性能的化合物的中间体。预期这种化合物对寄主的免疫系统的自然杀伤细胞、巨噬细胞、树突细胞或淋巴细胞中至少一种显示作用。因为这种化合物的这些性能而可有效用作抗病毒剂和抗肿瘤剂或者用于抗病毒和抗肿瘤剂的中间体。它们可以作为合适的药物组合物的活性成分,用于治疗被感染的宿主。
本发明的一个方面,式I的前药、式II的化合物和本发明的其它化合物被用于治疗哺乳动物(包括,人)中全部病毒性疾病,该治疗是通过给予该哺乳动物治疗有效量的该化合物来进行的。预期可用本发明的化合物治疗的病毒性疾病包括由RNA和DNA病毒所引起的急性和慢性感染。在不以任何形式限制可被治疗的病毒性感染的范围,式I所示的前药、式II所示的化合物和本发明的其它化合物在由以下病毒感染引起的疾病的治疗中尤其有效:腺病毒、巨细胞病毒、甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、包括黄热病毒的黄热病病毒和丙肝病毒(HCV)的黄热病病毒类(vlaviviruses)、1型和2型单纯性疱疹病毒、带状疱疹、人疱疹病毒6、人免疫缺陷病毒(HIV)、人乳头状瘤病毒(HPV)、甲型流感病毒、乙型流感病毒、麻疹、副流感病毒、脊髓灰质炎病毒、痘病毒(包括天花和猴痘病毒)、鼻病毒、呼吸道合胞体病毒(RSV)、引起出血热的多种病毒家族:包括沙粒病毒家族(Arenaviruses、LCM,胡宁病毒、Machup病毒、Guanarito病毒和Lassa热)、Bunya病毒类(Hanta病毒和里夫特裂谷热)和Filo病毒家族(埃博拉和马堡病毒);各种病毒性脑炎:包括西尼罗病毒、LaCrosse病毒、加里福尼亚脑炎病毒、委内瑞拉马脑炎病毒、东部马脑炎病毒、西部马脑炎病毒、日本马脑炎病毒、Kysanur森林病毒;和扁虱传播的病毒(tickborneViruses):如Chrimean-Congo出血热病毒。
在本发明的另一个方面,式I的前药、式II的化合物和本发明的其它化合物可用来治疗哺乳动物的细菌、真菌和原生动物感染,该治疗是通过给予该哺乳动物治疗有效量的化合物。通过给予本发明的化合物预期可治疗的全部范围的病原微生物,包括但不限于那些对抗生素有耐药性的生物体。一般发现化合物激活免疫系统旁路耐受性机制多个组成部分的能力降低对抗生素的易感性,因此通过给予式I的前药、式II的化合物和本发明的其它化合物来治疗哺乳动物中由这类耐药性微生物引起的感染是本发明的一个具体应用。
在本发明的另一个方面,通过给予哺乳动物治疗有效量的式I的前药、式II的化合物和本发明的其它化合物可用来治疗哺乳动物的肿瘤。预期可治疗的肿瘤或癌症包括但不限于那些由病毒引起的肿瘤或癌症,这些化合物的作用涉及抑制感染了病毒的细胞转化为新生物态,抑制病毒从被转化的细胞扩散到其它正常细胞和/或阻止病毒转化的细胞的生长。预期本发明的化合物可用于抵抗广谱的肿瘤,包括但不限于:癌、肉瘤和白血病。这类肿瘤包括:乳房癌、结肠癌、膀胱癌、肺癌、前列腺癌、胃癌和胰腺癌以及成淋巴细胞白血病和粒细胞性白血病。
在本发明另一个方面,治疗哺乳动物的方法包括给予治疗和/或预防有效量的含本发明化合物的药物。这一方面,其作用涉及调节哺乳动物免疫系统的某些部分,具体是调节Th1和TH2的细胞因子活性,包括但不限于:白介素家族,如IL-I至IL-12,以及其它细胞因子,如TNFα,和干扰素,包括干扰素α、干扰素β和干扰素γ,以及它们的下游效应物。在对Th1和TH2细胞因子调节时,可预期该调节可包括:刺激Th1和Th2,抑制Th1和Th2,刺激Th1或Th2并抑制另一个,或双模式调节(在高浓度时对Th1/Th2水平产生一种效应(如,全身化的抑制),而在低浓度时对Th1或Th2产生另一种效应(如,刺激Th1或Th2,并抑制另一个)。
本发明另一个方面,以治疗有效量给予正在接受不包括本发明化合物的抗感染药物的哺乳动物含有式I的前药、式II的化合物或本发明的其它化合物的药物组合物。在本发明的优选方面,含有式I的前药、式II的化合物或本发明的其它化合物的药物组合物以治疗有效量与直接作用于感染媒介以抑制其生长或杀灭感染媒介的抗感染药物一起给予。
另一方面,本发明涵盖了对需要治疗或预防丙肝病毒感染的哺乳动物(优选的是对其需要的人)进行治疗或预防丙肝病毒感染的方法。
另一方面,本发明涵盖了对需要治疗或预防丙肝病毒感染的患者治疗或预防丙肝病毒感染的方法,所述方法包括给予该患者治疗有效量或预防有效量的式I的前药、式II的化合物或本发明的其它化合物和药学上可接受的赋形剂、载体或运载体。
另一方面,本发明涵盖了对需要治疗或预防丙肝病毒感染的患者治疗或预防丙肝病毒感染的方法,所述方法包括给予该患者治疗有效量或预防有效量的式I的前药、式II的化合物或本发明的其它化合物和其它治疗剂,所述的其它治疗剂优选适合于所要进行的应用的其它抗病毒剂或抗肿瘤剂。
在本发明的优选方面中,含有治疗有效量的式I所示的前药的药物组合物具有改进的口服利用度,并作为免疫调节剂给药。在本发明的另一个优选的方面,包含治疗有效量本发明的式I所示前药的药物组合物在药剂通过衬于胃部的淋巴组织时能掩盖活性结构,从而使该组织的活化最小,并使其具有提高的口服耐受性。
附图简述
图1示出由化合物134在人PBMC中诱导的pg/ml IFN-α对由相同浓度的艾沙托立宾(isatoribine)诱导的pg/ml IFN-α的曲线。
图2示出由化合物122在人PBMC中诱导的pg/ml IFN-α对由相同浓度的艾沙托立宾诱导的pg/ml IFN-α的曲线。
发明详述和优选的实施方式
在本说明书中使用以下术语时,它们有如下定义:
术语“包含”和“包括”指开放式、非限定性的形式。
术语“嘧啶”指含氮单杂环。
本文所用的术语“烷基”除非另有说明,包括具有直链、支链或环状部分(包括稠合和桥连的双环和螺环部分)或前述部分的组合的饱和单价烃基。对于具有环部分的烷基,该基团必须至少含有三个碳原子。
本文使用的术语“烯基”除非另作说明,包括含有至少一个碳-碳双键的烷基部分,其中烷基的定义同上,且包括所述链烯基部分的E型和Z型异构体。
本文使用的术语“炔基”除非另作说明,包括含有至少一个碳-碳三键的烷基部分,其中烷基的定义同上。
本文使用的术语“烷氧基”除非另作说明,包括O-烷基基团,其中烷基的定义同上。
术语“Me”表示甲基,“Et”表示乙基,“Ac”表示乙酰基,“Bz”表示苯甲酰基,和“Tol”表示甲苯酰基。
本文使用的术语“环烷基”除非另作说明,指非芳族、饱和或部分饱和、单环或稠合、螺或非稠合双环或三环烃,如本文所用它总共含有3-10个碳原子,优选的是5-8个环碳原子。环烷基的例子包括含有3-7个碳原子,优选是3-6个碳原子的单环,如环丙基、环丁基、环戊基、环己基、环庚基等。环烷基的示例性例子非限定性地来自下列:
本文使用的术语“芳基”除非另作说明,包括通过除去芳烃中的一个氢得到的有机基团,如苯基或萘基。
本文使用的术语“杂环基”或“杂环”除非另作说明,包括含有1-4个各自选自O、S和N的杂原子的芳族(例如,杂芳基)和非芳族杂环基团,其中每个杂环基团的环系统中有4-10个原子,条件是,所述基团的环不含有两个相邻的O或S原子。非芳杂环基团包括环系统中仅有4个原子的基团,但芳杂环基团在其环系统中必须有至少5个原子。杂环基团包括苯并稠合环系统。4元杂环基团的例子是氮杂环丁基(衍生自氮杂环丁烷)。5元杂环基团的例子是噻唑基,10元杂环基团的例子是喹啉基。非芳族杂环基团的例子是吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢硫代吡喃基、哌啶子基、吗啉代、硫代吗啉代、噻噁烷基、哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、氧杂环庚基、硫杂环庚基、氧杂吖庚因基(oxazepinyl)、二氮杂基、硫杂吖庚因基(thiazepinyl)、1,2,3,6-四氢吡啶基、2-吡咯烷基、3-吡咯烷基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二噁唑基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫杂戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、3H-吲哚基和喹嗪基。芳杂环基团的例子是吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁烷基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、肉啉基、吲唑基、中氮茚基、2,3-二氮杂萘基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基(benzofurazanyl)、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、1,5-二氮杂萘基和呋喃并吡啶基(furopyridinyl)。衍生自上列基团的前述基团可为C-连接的或N-连接的。例如,衍生自吡咯的基团可为吡咯-1-基(N-连接的)或吡咯-3-基(C-连接的)。进一步的是,衍生自咪唑的基团可为咪唑-1-基(N-连接的)或咪唑-3-基(C-连接的)。4-10元杂环可任选地在任何环中碳、硫或氮原子上被1-2个氧代/环所取代。2个环中碳原子被氧代取代的杂环基团的例子是1,1-二氧代-硫代吗啉基。其它示例性的4-10元杂环来自,但不限于,下列分子:
术语“免疫调节剂”指能通过刺激或抑制来改变正常或异常的免疫系统的天然或合成产品。
术语“预防”指本发明的化合物或组合物防止被诊断出患有疾病或具有患病危险的患者的疾病的能力。该术语也涵盖了预防已患有或具有这类疾病症状的患者疾病的进一步发展。
术语“患者”或“对象”表示动物(如牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔、豚鼠等)或哺乳动物,包括杂交和转基因动物和哺乳动物。在治疗或预防HCV感染中,术语“患者”或“对象”优选地表示猴子或人,更佳为人。在某一具体的实施方式中,患者或对象是丙肝病毒感染的或暴露于丙肝病毒中的。在某一实施方式中,患者是婴孩(0-2岁)、儿童(2-17岁)、青少年(12-17岁)、成人(18岁及以上)或老人(70岁以上)患者。另外,患者包括免疫受损的(immunocompromised)患者,如HIV阳性患者、癌症患者、经受免疫疗法或化疗的患者。在某一具体的实施方式中,患者是健康个体,即没有显示出其它病毒感染症状的患者。
术语“治疗有效量”指足以治疗或预防病毒疾病、延缓或最小化与病毒感染或病毒引起的疾病有关的症状或者治愈或缓解疾病或感染或其病因的本发明化合物的用量。具体而言,治疗有效量表示足以使体内产生治疗效果的用量。与一定量本发明化合物的使用有关,该术语优选地涵盖改进总的疗效、减少或避免疾病的症状或病因,或者增加另一种治疗剂的治疗效应或与另一种治疗剂产生协同作用的无毒性的用量。
术语“预防有效量”指足以预防感染、病毒感染的复发或传播的本发明的化合物或其它活性组分的用量。预防有效量可指足以预防原发性感染或感染的复发或传播或与感染有关的疾病的量。与一定量的本发明化合物的使用有关,该术语优选地涵盖改进总的预防或者增加另一种预防剂或治疗剂的预防效应或与另一种预防剂或治疗剂产生协同作用的无毒性的用量。
术语“组合”指同时或相继使用一种以上的预防剂和/或治疗剂,并使其各自产生的作用加合或协同。
术语“治疗”指:
(i)预防疾病、失调或病情在倾向于发生该疾病、失调或病情、但尚未诊断出已罹患的动物中的发生;
(ii)抑制疾病、失调或病情,即阻止其发展;和
(iii)缓解疾病、失调或病情,即使疾病、失调和/或病情消退。
术语“α”和“β”指所画的化学结构中手性碳原子上取代基的特定立体化学构型。
本发明化合物可显示出互变现象。虽然式不能显示出所有可能的互变形式,应当明白的是它们趋向于代表所显示化合物的所有互变形式,不仅仅限于所画出的式。例如,应当明白,不论式II中显示的取代基为其烯醇形式或酮形式,它们代表相同的化合物(如下例所示):
某些本发明的化合物可能存在单一的立体异构体(即基本上不含其它立体异构体)、消旋体和/或对映异构体和/或非对映异构体的混合物。所有的这类单一立体异构体、消旋体和其混合物都在本发明的范围里。优选的是,光学活性的本发明化合物以光学纯形式使用。
本技术领域的技术人员都知道,具有一个手性中心(即,一个不对称碳原子)的光学纯化合物是基本上由两种可能的对映异构体中的一种构成的(即为对映异构体纯),具有一个以上手性中心的光学纯的化合物同时为非对映体纯的和对映体纯的化合物。优选的是,本发明化合物使用时的形式为至少90%光学纯,即它含有至少90%的单一异构体(80%对映体过量(“e.e.”)或非对映体过量(“d.e.”)),更好的是至少95%单一异构体(90%e.e.或d.e.),进一步的是至少97.5%单一异构体(95%e.e.或d.e.)),最好是至少99%的单一异构体(98%e.e.或d.e.)。
另外,式I的前药、式II的化合物或本发明的其它化合物趋向于覆盖所示结构的溶剂合物形式和非溶剂合物形式。例如,式I包括水合和非水合形式的所示结构的化合物。溶剂合物的其它例子包括与异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸或乙醇胺组合的结构。
除了式I的前药、式II的化合物和本发明的其它化合物外,本发明包括这类化合物和代谢物的药学上的活性代谢物和药学上可接受的盐。
“药学上可接受的前药”是指一种在展示其生理效应前,在生理条件下可被转化或被溶剂分解为特定化合物或这类化合物的药学上可接受的盐的化合物。典型的是,前药制剂的目的是针对改善化学稳定性、改善患者接受性和顺应性、改善生物利用度、延长作用时间、改善器官选择性、改善配制(如,提高水溶性)和/或降低副作用(如,毒性)。前药的制备可运用现有技术中已知的方法,例如Burger′s Medicinal Chemistry and Drug Chemistry,1,172-178,949-982(1995);也可参见Bertolini等,J.Med.Chem.,40,2011-2016(1997);Shan等,J.Pharm.Sci.,86(7),765-767;Bagshawe,Drug Dev.Res.,34,220-230(1995);Bodor,Advances in Drug Res.,13,224-331(1984);Bundgaard,Design of Prodrugs(Elsevier Press 1985);Larsen,Design and Application ofProdrugs,Drug Design and Development(Krogsgaard-Larsen等编,HarwoodAcademic Publishers,1991);Dear等,J.Chromatogr.B,748,281-293(2000);Spraul等,J.Pharmaceutical&Biomedical Analysis,10,601-605(1992);以及Prox等,Xenobiol.,3,103-112(1992)中所描述的方法。
“药学上的活性代谢物”表示特定化合物或其盐经体内代谢而产生的药理活性产物。大多数药物进入体内后,成为化学反应的底物,其物理性质和生物效应会发生改变。这些代谢转变常常会影响本发明化合物的极性、改变药物在体内的分布和排泄出体外的方式。但是,在一些情况下,药物的代谢是治疗效应所需的。例如,抗代谢类的抗癌药在其转运入癌细胞后必须转化成它们的活性形式。
由于大多数药物进行某些种类的代谢转化,在药物代谢中起作用的生化反应可能很多且是不同的。虽然其它器官也会参与药物代谢,但是药物代谢的主要部位是肝脏。
这些转化中的许多所具有一个特征是代谢产物或“代谢物”比母体药物的极性更大,但极性药物有时也会得到极性更小的产物。具有高脂/水分配系数的物质很容易通过膜,也能很容易地从管状尿道通过肾小管细胞扩散返回血浆。因此,这类物质趋向于有低的肾清除率和长的体内持续时间。若药物代谢成极性更大、分配系数更低的化合物,它的管内重吸收会大大减少。此外,在近肾小管和在肝实质细胞中对阳离子和阴离子的特定分泌机制对高极性物质起作用。
作为具体的例子,非那西丁(乙酰氧乙苯胺,acetophenetidin)和乙酰苯胺(acetanilide)都是温和的止痛剂和解热剂,但是它们在体内转化为极性更大且更为有效的代谢物,即对-羟基乙酰苯胺(对乙酰氨基酚,acetaminophen),其在当今被广泛使用。当给予人一剂乙酰苯胺时,血浆中连续出现相继的代谢物峰和衰退。第一小时中,乙酰苯胺为主要的血浆成份。第二小时中,随着乙酰苯胺水平的降低,代谢物乙酰氨基酚浓度达到峰值。最终在数小时后,主要的血浆组分是进一步的代谢物,它是惰性的且可从体内排泄出去。因此,一种或多种代谢物的血药浓度、以及药物本身的血药水平在药理学上可以是很重要的。
“药学上可接受的盐”指保留了特定化合物的游离酸和碱的生物效应、且不是生物学上的或不利的盐。本发明的化合物可具有有效的酸性、足够的碱性或两种官能团,因此,可与许多无机碱或有机碱、无机酸或有机酸分别进行反应,以形成药学上可接受的盐。例举的药学上可接受的盐包括通过将本发明化合物与无机酸或有机酸或无机碱反应制备的盐,如硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐(bisulfites)、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。
若本发明的化合物是碱,所需的药学上可接受的盐可通过现有技术中任何合适的方法制备,例如,用下述物质处理游离碱基:用无机酸,如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或用有机酸,如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸(pyranosidyl acid),如葡糖醛酸或半乳糖醛酸、α-羟基酸,如柠檬酸或酒石酸;氨基酸,如天门冬氨酸或谷氨酸;芳族酸,如苯甲酸或肉桂酸;磺酸,如对甲苯磺酸或乙磺酸等。
若本发明化合物是一种酸,所需的药学上可接受的盐可通过任何合适的方法制备,例如,用无机或有机碱处理游离酸,所述的碱为例如,胺(伯、仲或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等。合适盐的例子包括:衍生自氨基酸(如甘氨酸和精氨酸)、氨、伯胺、仲胺或叔胺以及环胺(如哌啶、吗啉和哌嗪)的有机盐;和衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
对于固体试剂,本技术领域的技术人员都知道本发明的化合物和盐可以不同的晶体或多晶态形式存在,所有这些都在本发明和特定式的范围内。
治疗和预防丙型肝炎病毒感染的方法
本发明提供了在需要治疗或预防丙肝病毒感染的患者中治疗或预防丙肝病毒感染的方法。
本发明进一步提供了将治疗有效量的式I的前药、式II的化合物或本发明的其它化合物或这些化合物的组合在治疗和/或预防丙肝病毒感染过程中引入患者的血流中。
本发明的式I的前药、式II的化合物或本发明的其它化合物或其药学上可接受的盐、溶剂合物或水合物在急性或慢性治疗或预防感染时的预防或治疗剂量的大小(magnitude),将随感染的性质和严重程度、给予活性组分的途径而不同。剂量,以及某些情况下给药频度,也会根据要治疗的感染、个体患者的年龄、体重和反应而不同。合适的剂量方案可由本领域的技术人员根据这些因素很容易地确定。
本发明的方法特别适合于人类患者。具体而言,本发明的方法和剂量可用于免疫损伤患者,包括但不限于:癌症患者、HIV感染患者和患有免疫退化疾病的患者。此外,这些方法可用于目前处于好转状态的免疫损伤患者。本发明的方法和剂量也可用于经受其它抗病毒治疗的患者。本发明的预防方法具体可用于有被病毒感染危险的患者。这些患者包括但不限于:健康护理工作人员,如,医生、护士、收容所护理人员;军事人员;教师;育儿工作者;旅行或居住在国外,特别是居住在第三世界的患者,包括社会救助工作者,传教士和外交使节。最后,这些方法和组合物包括对难以控制的患者或对治疗产生耐药性(如对逆转转录酶抑制剂、蛋白酶抑制剂等产生耐药性)的患者。
剂量
本发明化合物的毒性和药效可通过在细胞培养或试验动物中的标准药物过程来测定,如测定LD50(致使50%种群死亡的剂量)和ED50(对50%种群治疗有效的剂量)。毒性和治疗效应的剂量比为治疗指数,其可表示为LD50/ED50。
从细胞培养分析和动物研究中得到的资料可用来确定用于人体的化合物的剂量。这类化合物的剂量优选在包括几乎没有或没有毒性的ED50的外周浓度范围里。可在此范围内,根据所用剂型和给药途径改变剂量。对于用于本发明方法中的任何化合物,治疗有效剂量可从细胞培养分析中最初估算。可在动物模型中配制剂量以得到包括细胞试验中测定的IC50(即,达到症状最大抑制的一半的试验化合物的浓度)的循环血药浓度(circulating plasma concertration)范围;或者,在动物模型中调配化合物的剂量,以得到化合物的循环血药浓度范围,使其与得到固定反应量级所需的浓度一一对应。这类信息可以用来更准确地确定对人体有用的剂量。血药水平可通过,例如高效液相色谱进行测定。
本发明的方案和组合物在用于人体前,优选先对所需的治疗或预防活性进行体外试验,然后再进行体内试验。例如,体外分析可用来确定是否需要给予特定的治疗方案,体外分析包括体外细胞培养分析,其中对式I的前药、式II的化合物和本发明的其它化合物应答的细胞被暴露于配体,并通过合适的技术测量应答的强度。然后就化合物的效能和式I的前药与式II的化合物间的转化程度来评估该化合物。用于本发明方法的化合物可在给人体试验前用合适的动物模型进行试验,所述的动物模型包括但不限于:大鼠、小鼠、鸡、牛、猴子、兔子、仓鼠等。然后化合物可用于合适的临床试验。
本发明的式I的前药、式II的化合物或本发明的其它化合物或其药学上可接受的盐、溶剂合物或水合物,在急性或慢性治疗或预防感染或疾病的预防剂量或治疗剂量的量值会随感染的性质和严重程度、活性组分的给药途径而不同。剂量,以及可能的给药频度也会随要治疗的感染、患者的年龄、体重和反应而不同。本领域的人员可根据对这些因素的考虑很容易地选择合适的剂量方案。在某一个实施方式中,给药剂量根据使用的特定化合物和患者的体重和病情而定。剂量也可根据不同的本发明的具体化合物而不同;合适的剂量可根据前述的体外测试和动物研究来预测,从而使得在所述的系统或参照本文所述的内容测量时显示出使用浓度低于其它化合物却有效的那些化合物适用较小的剂量。一般来说,每天的剂量范围为约0.001-100mg/kg,优选的是约1-25mg/kg,更好的是约5-15mg/kg。对于治疗被丙肝病毒感染的人,在一日内分1-4次给予约0.1mg-约15g/天的剂量,优选的是100mg/天到12克/天,更好是100-8000mg/天。
另外,推荐的日剂量可在一段时间里以单一制剂或与其它治疗剂联合循环给药。在一个实施方式中,日剂量为单剂或等分剂量。在一个相关的实施方式中,推荐的日剂量可每周给予一次、每周给予两次、每周给予三次、每周给予四次或每周给予五次。
在优选的实施方式中,本发明的化合物经给药可在患者体内全身分布。在相关的实施方式中,本发明的化合物经给药可在体内产生全身作用。
在另一个实施方式中,本发明的化合物通过口服、粘膜(包括舌下、颊部、直肠、鼻或阴道)给药、非胃肠道(包括皮下、肌内、推注(bolus injection)、动脉内或静脉内)给药、透皮给药或局部给药。在某一具体的实施方式中,本发明的化合物通过粘膜(包括舌下、颊部、直肠、鼻或阴道)给药、非胃肠道(包括皮下、肌内、静脉推注、动脉内或静脉内)给药、透皮给药或局部给药。在另一具体实施方式中,本发明的化合物通过口服给药。在另一具体实施方式中,本发明的化合物不是通过口服给药的。
正如本领域的普通技术人员所了解的那样,对于不同的感染可用不同的治疗有效量。相似的是,足以治疗或预防这类感染、但不足以引起或足以减少与常规治疗有关的副作用的量也涵盖在上述的剂量范围和给药频度方案里。
联合治疗
本发明的具体方法还包括给予其它的治疗剂(即,非本发明化合物的治疗剂)。在本发明特定的实施方式中,本发明化合物可与至少一种其它治疗剂联合使用。所述治疗剂包括但不限于:抗生素、止吐药、抗抑郁剂和抗真菌剂、抗炎剂、抗病毒剂、抗癌药、免疫调节剂、β-干扰素、烷基化剂、激素或细胞因子。本发明优选的实施方式涵盖给予HCV特异性活性或显示出抗-HCV活性的其它治疗剂。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与抗生素联合给药或配制。例如,它们可与大环内酯类(如,妥布霉素)、头孢菌素(如,头孢氨苄头孢拉定头孢呋辛头孢丙烯头孢克洛头孢克肟或头孢羟氨苄)、克红霉素(如克拉霉素)、红霉素(如,红霉素)、青霉素(如,青霉素V(V-或))或是喹喏酮(如,氧氟沙星环丙沙星或诺氟沙星)、氨基糖苷类抗生素(如,安普霉素、阿贝卡星、班贝霉素、布替罗星、地贝卡星、新霉素、十一烯酸酯(盐)、奈替米星、巴龙霉素、核糖霉素、西索米星和大观霉素)、酰胺醇(amphenicol)抗生素(如,叠氮氯霉素、氯霉素、氟苯尼考和甲砜霉素)、安莎霉素抗生素(如,利福米特和利福平)、碳头孢烯(如,氯碳头孢)、碳青霉烯(如,比阿培南和亚胺培南)、头孢菌素(如,头孢克洛、头孢羟氨苄、头孢孟多、头孢曲秦、头孢西酮、头孢唑兰、头孢咪唑、头孢匹胺和头孢匹罗)、头霉素类(如,头孢拉宗、头孢美唑和头孢米诺)、单菌霉素类(如,氨曲南、卡芦莫南和替吉莫南)、氧头孢烯类(如,氟氧头孢和拉氧头孢)、青霉素类(如,氮脒青霉素、匹伏氮脒青霉素(amdinocillinpivoxil)、阿莫西林、巴氨西林、苄基青霉素酸、苄基青霉素钠、依匹西林、芬贝西林、氟氯西林、培那西林、喷沙西林氢碘化物、苄胺青霉素(penicillino-benethamine)、青霉素O、青霉素V、苄星青霉素V、哈胺青霉素V、青四环素和phencihicillin potassium)、林可酰胺(如,克林霉素和林可霉素)、安福霉素、杆菌肽、卷曲霉素、多粘菌素E、持久霉素、恩维霉素、四环素类(如,阿哌环素、金霉素、氯莫环素和地美环素)、2,4-二氨基吡啶类(如,溴莫普林)、硝基呋喃类(如,左呋喃他酮和呋唑氯铵)、喹诺酮类和其类似物(如,西诺沙星、克林沙星、氟甲喹和格帕沙星)、磺胺类(如,乙酰磺胺甲氧吡嗪,苄磺胺,诺丙磺胺、酞磺醋胺、磺胺柯定和磺胺西汀)、砜类(如,地百里砜、葡砜钠和苯丙砜)、环丝氨酸、莫匹罗星和马铃薯球蛋白。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与止吐剂联合给药或配制。合适的止吐剂包括但不限于:甲氧氯普胺、多潘立酮、丙氯拉嗪、异丙嗪、盐酸氯丙嗪、曲美苄胺、昂丹司琼、格拉司琼、羟嗪、乙酰亮氨酸单乙醇胺、阿立必利、阿扎司琼、苯喹胺、氨醇醋茶碱、溴必利、布克力嗪、氯波必利、赛克力嗪、茶苯海明、地芬尼多、多拉司琼、美克洛嗪、美沙拉妥、美托哌丙嗪、大麻隆、氮羟哌丙嗪、匹哌马嗪、东莨菪碱、舒必利、四氢大麻酚、硫乙拉嗪、氨砜拉嗪、托烷司琼和它们的混合物。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与抗抑郁药联合给药或配制。合适的抗抑郁药包括但不限于:苯奈达林、卡罗沙酮、西酞普兰、二甲沙生、芬咖明、吲达品、盐酸茚洛秦、奈福泮、诺米芬辛、羟色氨酸、奥昔哌汀、帕罗西汀、舍曲林、硫西新、三唑酮、苯酰甲苄肼、异丙氯肼、异丙烟肼、异卡波肼、尼亚拉胺、奥他莫辛、苯乙肼、可替宁、罗利普令、咯利普兰、马普替林、美曲吲哚、米安色林、米氮平(mirtazepine)、阿地唑仑、阿米替林、氧阿米替林、阿莫沙平、布替林、氯米帕明、地美替林、地昔帕明、二苯西平、二甲他林、度琉平、多塞平、三氟丙嗪、丙米嗪、丙米嗪N-氧化物、伊普吲哚、洛非帕明、美利曲辛、美他帕明、去甲替林、诺昔替林、奥匹哌醇、苯噻啶、丙吡西平、普罗替林、奎纽帕明、噻奈普汀、曲米帕明、阿屈非尼、贝那替秦、安非他酮、布他西丁、地奥沙屈、度洛西汀、依托哌酮、非巴氨酯、非莫西汀、芬戊二醇、氟西汀、氟伏沙明、血卟啉、金丝桃素、左法哌酯、美地沙明、米那普仑、苯哒吗啉、吗氯贝胺、奈法唑酮、奥沙氟生、吡贝拉林、普罗林坦、吡琥胺酯、利坦色林、罗克吲哚、氯化铷、舒必利、坦度螺酮、托扎啉酮、托芬那辛、甲苯噁酮、反苯环丙胺、L-色氨酸、文拉法辛、维洛沙秦和齐美定。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与抗真菌剂联合给药或配制。合适的抗真菌剂包括但不限于:两性霉素B、伊曲康唑、酮康唑、氟康唑、intrathecal、氟胞嘧啶、咪康唑、布康唑、克霉唑、制霉菌素、特康唑、噻康唑、环吡酮、益康唑、碘氯苯炔醚、萘替芬、特比萘芬、十一烯酸酯(盐)和灰黄霉素。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与抗炎剂联合给药或配制。有用的抗炎剂包括但不限于:非甾体类抗炎药,如水杨酸、乙酰水杨酸、水杨酸甲酯、二氟尼柳、双水杨酯、奥沙拉秦、柳氮磺吡啶、对乙酰氨基酚、吲哚美辛、舒林酸、依托度酸、甲芬那酸、甲氯灭酸钠、托美丁、酮咯酸、双氯酚酸(dichlofenac)、布洛芬、萘普生、萘普生钠,非诺洛芬、酮洛芬、氟吡洛芬(flurbinprofen)、奥沙普秦、吡罗昔康、美洛昔康、安吡昔康、屈恶昔康、pivoxicam、替诺昔康、萘丁美酮、保泰松、羟布宗、安替比林、氨基比林、阿扎丙宗和尼美舒利;白三烯拮抗剂,包括但不限于:齐留通、金硫葡糖、金硫丁二钠和金诺芬;甾体类,包括但不限于:阿氯米松二丙酸酯、安西奈德、倍氯米松二丙酸酯、倍他米松、倍他米松苯甲酸酯、倍他米松二丙酸酯、倍他米松磷酸钠、倍他米松戊酸酯、氯倍他索二丙酸酯、氯可托龙三甲基乙酸酯、氢化可的松、氢化可的松衍生物、地奈德、去羟米松、地塞米松、氟尼缩松、flucoxinolide、氟氢缩松、氯氟松、甲羟松、甲泼尼龙、乙酸甲泼尼龙、甲泼尼龙琥珀酸钠、莫米松糠酸酯、帕拉米松乙酸酯、泼尼松龙、泼尼松龙乙酸酯、泼尼松龙磷酸钠、泼尼松龙tebuatate、泼尼松、曲安西龙、曲安奈德、曲安西龙二乙酸酯和己曲安奈德;以及其它的抗炎药,包括但不限于:甲氨蝶呤、秋水仙碱、别嘌醇、丙磺舒、磺吡酮和苯溴马隆。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与其它抗病毒剂联合给药或配制。有用的抗病毒剂包括但不限于:蛋白酶抑制剂、核苷逆转录酶抑制剂、非核苷逆转录酶抑制剂和核苷类似物。抗病毒剂包括但不限于:齐多夫定、无环鸟苷、更昔洛韦、阿糖腺苷、碘苷、曲氟尿苷、左旋韦林(levovirin)、三氮唑核苷(viramidine)和利巴韦林、以及膦甲酸、金刚烷胺、金刚乙胺、沙奎那韦、茚地那韦、安泼那韦、洛匹那韦、利托那韦、α-干扰素、β-干扰素、阿德福韦、抗来呋定、思替卡韦(entecavir)、普来可那立(pleconaril)。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与免疫调节剂联合给药或配制。免疫调节剂包括但不限于:甲氨蝶呤、来氟米特、环磷酰胺、环孢素A、霉酚酸酯(mycophenolatemofetil)、雷伯霉素(西罗莫司)、咪唑立宾、抗氧禁胍菌素(deoxyspergualin)、布喹那、malononitriloamindes(如leflunamide)、T细胞受体调节剂和细胞因子受体调节剂、肽模拟物和抗体(如,人的、人化的、嵌合、单克隆、多克隆、Fvs、ScFvs、Fab或F(ab)2片段或表位结合片段)、核酸分子(如,反义核酸分子和三螺旋体)、小分子、有机化合物和无机化合物。T细胞受体调节剂的例子包括但不限于:抗-T细胞受体抗体(如,抗-CD4抗体(如cM-T412(Boeringer)、IDEC-(IDEC和SKB)、mAB4162W94、Orthoclone和OKTcdR4a(Janssen-Cilag))、抗-CD3抗体(如,Nuvion(ProductDesignLabs)、OKT3(Johnson&Johnson)或Rituxan(IDEC))、抗-CD5抗体(如,抗-CD5蓖麻蛋白连接的免疫结合物)、抗-CD7抗体(如,CHH-380(Novartis))、抗-CD8抗体、抗-CD40配合物单克隆抗体(如,IDEC-131(IDEC))、抗-CD52抗体(如,CAMPATH1H(Ilex))、抗-CD2抗体、抗-CD11a抗体(如,Xanelim(Genentech))和抗-B7抗体(如,IDEC-114(IDEC))和CTLA4-免疫球蛋白。细胞因子受体调节剂的例子包括但不限于:可溶的细胞因子受体(如,细胞外域的TNF α受体或其片段、细胞外域IL-1β受体或其片段和细胞外域IL-6受体或其片段)、细胞因子或其片段、(如,白介素(IL)-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-15、TNF-α、干扰素(IFN)-α、IFN-β、IFN-γ和GM-CSF)、抗细胞因子受体抗体(如,抗-IFN受体抗体、抗-IL-2受体抗体(如,Zenapax(ProteinDesignLabs))、抗-IL-4受体抗体、抗-IL-6受体抗体、抗-IL-10受体抗体和抗-IL-12受体抗体)、抗-细胞因子抗体(如,抗-IFN抗体、抗-TNF α抗体、抗-IL-1β抗体、抗-IL-6抗体、抗-IL-8抗体(如,ABX-IL-8(Abgenix))和抗-IL-12抗体)。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与抑制病毒酶的药剂联合给药或配制。所述的药剂包括,但不限于,HCV蛋白酶的抑制剂,如BILN 2061和NS5b聚合酶的抑制剂,如NM107和其前体药物NM283(IdenixPharmaceuticals公司,美国马里兰州Cambridge)。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与如Wu在Curr Drug Targets Infect Disord(2003;3(3):207-19)中所述的抑制HCV聚合酶的药剂或与如Bretner M等人,在Nucleosides Nucleotides Nucleic Acids(2003;22(5-8):1531)中所述的抑制病毒螺旋化功能的药剂或与如Zhang X在Drugs(2002;5(2):154-8)中所述的HCV特定靶向物的抑制剂联合给药或配制。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与抑制病毒复制的药剂联合给药或配制。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与细胞因子联合给药或配制。细胞因子的例子包括但不限于:白介素-2(IL-2)、白介素-3(IL-3)、白介素-4(IL-4)、白介素-5(IL-5)、白介素-6(IL-6)、白介素-7(IL-7)、白介素-9(IL-9)、白介素-10(IL-10)、白介素-12(IL-12)、白介素15(IL-15)、白介素18(IL-18)、来自血小板的生长因子(PDGF)、促红细胞生成素(Epo)、表皮细胞生长因子(EGF)、成纤维细胞生长因子(FGF)、粒细胞巨噬细胞刺激因子(GM-CSF)、粒细胞集群刺激因子(G-CSF)、巨噬细胞集群刺激因子,(M-CSF)、泌乳刺激素和干扰素(IFN)(例如,IFN-α和IFN-γ)。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与激素联合给药或配制。激素的例子包括但不限于:黄体化激素释放激素(LHRH)、生长激素(GH)、生长激素释放激素、ACTH、生长激素抑制素、生长激素、生长调节素、甲状旁腺素、下丘脑释放因子、胰岛素、胰高血糖素、脑啡肽、抗利尿激素、降血钙素、肝素、低分子量肝素、类肝素、合成和天然的阿片、胰岛素甲状腺刺激激素和内啡肽。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与β-干扰素联合给药或配制,β-干扰素包括但不限于:干扰素β-1a、干扰素β-1b。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与α-干扰素联合给药或配制,α-干扰素包括但不限于:干扰素α-1、干扰素α-2a(roferon)、干扰素α-2b、内含子、Peg-内含子、Pegasys、同义干扰素(ingergen)和albuferon。
本发明的式I的前药、式II的化合物和本发明的其它化合物可与吸收促进剂联合给药或配制,尤其是以淋巴系统为靶向的吸收促进剂,其包括但不限于:甘胆酸钠;癸酸钠;N-月桂酰基-β-D-麦芽吡喃糖苷;EDTA;混合的胶束;和Muranishi在Crit.Rev.Ther.Drug Carrier Syst,7-1-33中所报告的物质,该文献全文纳入本文供参考。也可使用其它已知的吸收促进剂。因此,本发明也涵盖了包含一种或多种式I的前药、式II的化合物和本发明的其它化合物与一种或多种吸收促进剂的药物组合物。
本发明的式I所前药、式II的化合物和本发明的其它化合物可与烷基化剂联合给药或配制。烷基化剂的例子包括但不限于:氮芥、吖丙啶、甲基蜜胺、磺酸烷酯、亚硝基脲、三氮烯、二氯甲基二乙胺(mechlorethamine)、环磷酰胺、异环磷酰胺、美法仑(melphalan)、苯丁酸氮芥、四氮六甲圜(hexa甲基melaine)、三胺硫磷、白消安、卡氯芥、链脲菌素、氮烯唑胺和替莫唑胺。
本发明的式I的前药、式II的化合物和本发明的其它化合物以及其它治疗剂可具有加合作用,或更佳的是具有协同作用。在优选的实施方式中,含有本发明化合物的组合物可与另一种治疗剂同时给予,所述的另一种治疗剂可为与含有本发明化合物的组合物一部分相同或不同的组合物。在另一个实施方式中,在给予另一种治疗剂之前或之后给予本发明的化合物。在一个独立的实施方式中,对以前曾使用另一种治疗剂(特别是抗病毒剂)治疗或是目前不再接受使用另一种治疗剂治疗的患者,给予本发明的化合物。
在一个实施方式中,本发明的方法包括给予一种或多种本发明的式I所示的前药、式II所示的化合物和本发明的其它化合物而不再给予其它的治疗剂。
药物组合物和剂型
包含本发明的式I的前药、式II的化合物和本发明的其它化合物或其药学上可接受的盐、水合物的药物组合物和单剂剂型也在本发明的范围内。本发明的个体剂型适合于口服、粘膜给药(包括舌下、颊部、直肠、鼻或阴道给药)、非胃肠道(包括舌下、肌内、推注、动脉内或静脉内给药)透皮给药或局部给药。本发明的药物组合物和剂型典型地还包含一种或多种药学上可接受的赋形剂。无菌制剂也在本发明的范围内。
在一个可选的实施方式中,其中的药物组合物包括本发明式I的前药、式II的化合物或本发明的其它化合物或其药学上可接受的盐或水合物,以及至少一种其它的治疗剂。其它治疗剂的例子包括但不限于上述所列的物质。
本发明的组合物、形状和剂型类型典型地随其应用而改变。例如,用于一种疾病或相关疾病的急性治疗的剂型可含有比慢性治疗相同疾病所用量更大的一种或多种活性组份。相似的是,非胃肠道剂型可含有比用于治疗相同疾病或失调的口服剂型更少量的一种或多种活性组份。本领域的技术人员可以很容易地了解涵盖于本发明中的特定剂型的这些和其它方式可以是相互不同的。参见,例如,Remington’s Pharmaceutical Science,第18版,Mack Publishing,美国宾夕法尼亚Eston(1990)。剂型的例子包括但不限于:片剂;囊片(caplet);胶囊,例如软弹性明胶胶囊的胶囊;扁胶囊(cachet);糖锭(troche);锭剂;分散剂;栓剂;软膏剂;泥敷剂(poutice);糊剂;粉剂;敷料;霜剂;膏药;溶液剂;贴剂;气雾剂(如鼻喷雾剂或吸入剂);凝胶;适合对患者进行口服或粘膜给药的液体剂型,包括悬浮剂(如,水性或非水性液体悬浮剂、水包油乳剂或油包水液体乳剂)、溶液和酏剂;适合对患者非胃肠道给药的液体剂型;和可用来重构(reconstitute)以适合对患者非胃肠道给药液体剂型的无菌固体(如,结晶或无定形固体)。
典型的药物组合物和剂型包括一种或多种载体、赋形剂或稀释剂。合适的赋形剂是药学领域中公知的,本文提供了合适的赋形剂的非限定性例子。一种特定的赋形剂是否适合掺入药物组合物或剂型取决于该技术领域公知的各种因素,包括但不限于要对病人给药的途径。例如,诸如片剂的口服剂型可含有不适合非胃肠道剂型的赋形剂。特定赋形剂的适合度也根据剂型中的特定活性成分而定。
本发明还涵盖包含活性组份的无水药物组合物和剂型,因为水会加速某些化合物的降解。例如,加入水(如5%的水)是药学领域中是普遍接受的,它可作为模拟长期存放的手段来测定诸如制剂在一段时间里的保存期限或稳定性等性质。参见,如Jens T.Carstensen,Drug Stability:Principles&Practice,第2版,Marcel Dekker,美国纽约州纽约,1995,第379-80页。实际上,水和热量会加速一些化合物的分解。因此,由于在制造、处理、包装、贮存、运输和使用制剂时一般会遇到潮气和/或湿度,水对制剂的影响是极为巨大的。
本发明的无水药物组合物和剂型可使用无水或低湿度的组份和低湿度或低潮湿的条件进行制备。
无水药物组合物应在制备和贮存中使其无水性质得以维持。因此,无水组合物优选地使用防水的材料进行包装,使它们能包含在合适的配方药盒中。合适包装的例子包括但不限于:密封箔、塑料、单位剂型容器(如小瓶)、浮泡包装和带包装。
本发明还涵盖包含一种或多种减少活性组份分解速率的化合物的药物组合物和剂型。这类化合物(下面称为稳定剂)包括但不限于:抗氧化剂,如抗坏血酸、pH缓冲剂或盐缓冲剂。
如同赋形剂的量和类型,剂型中活性组份的量和特定的类型会根据各种因素而不同,例如,但不限于,因给予病人的途径不同而不同。但是,包含本发明化合物或其药学上可接受的盐或水合物的本发明的典型剂型包含0.1mg到1500mg/单位,以提供每天约0.01到200mg/kg的剂量。
口服剂型
适合口服给药的本发明的药物组合物可为不连续的剂型,例如,但不限于:片剂(如咀嚼片)、囊片、胶囊和液体(如矫味的糖浆剂)。这类剂型含有预定量的活性组份,可用药学领域技术人员公知的方法制备。一般参见Remington’sPharmaceutical Sciences,第18版,Mack Publishing,美国宾夕法尼亚州Easton(1990)。
典型的本发明口服剂型的制备是通过使活性组份与至少一种赋形剂根据常规药物复合技术密切混合。赋形剂可根据所需给药的制备形式具备各种赋形剂形式。例如,适合用于口服液体或气雾剂剂型的赋形剂包括但不限于:水、多元醇、油、醇、调味剂、防腐剂和着色剂。适合用于固体口服剂型(如粉末、片剂、胶囊和囊片)的赋形剂例子包括但不限于:淀粉、糖、微晶纤维素、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
由于片剂和胶囊剂易于给药,它们代表了口服剂型中最佳的剂型,在此情况下使用了固体赋形剂。若需要,片剂可用标准的水性或非水性技术进行包衣。此类剂型可用药学中的任何方法进行制备。一般来说,药物组合物和剂型的制备是通过使活性组份与液体载体、细分散固体载体或两者均匀密切地混合,必要时再使产品形成所需的形状。
例如,片剂可通过压制或模压来制备。压制的片剂可通过在合适的机器中压制任选地与赋形剂混合的、自由流动形式(如粉末或颗粒)的活性组份来制备。模压片剂的制备可通过在合适的机器中模压用惰性液体赋形剂湿润的粉末化的化合物。可用于本发明口服剂型的赋形剂例子包括但不限于:粘合剂、填充剂、崩解剂和润滑剂。适合用于药物组合物和剂型的粘合剂包括但不限于:玉米淀粉、土豆淀粉或其它淀粉、明胶、诸如阿拉伯胶、藻酸钠、藻酸、其它藻酸盐、粉末化黄芪胶、瓜耳胶的天然和合成的胶、纤维素和它的衍生物(如乙基纤维素、乙酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠)、聚乙烯基吡咯烷酮、甲基纤维素、预明胶化的淀粉、羟丙基甲基纤维素(如,第2208、2906、2910号)、微晶纤维素和其混合物。
适合用于本文的药物组合物和剂型中的填充剂包括但不限于:滑石粉、碳酸钙(如颗粒或粉末)、微晶纤维素、粉末化的纤维素、糊精、高岭土、甘露醇、硅酸、山梨醇、淀粉、预胶化淀粉和它们的混合物。本发明药物组合物中粘合剂或填充剂典型地占药物组合物或剂型的约50-99重量%。
微晶纤维素的合适类型包括但不限于:商品名为AVICEL-PH-101、AVICEL-PH-103AVICEL RC-581、AVICEL-PH-105(购自FMC Corporation美国纤维胶分支,Avicel销售部,美国宾夕法尼亚Marcus Hook),和它们的混合物。特定的粘合剂是微晶纤维素和羧甲基纤维素的混合物,商品名为AVICELRC-581。合适的无水或低潮的赋形剂或添加剂包括AVICEL-PH-103TM和Starch1500LM。
用于本发明组合物的崩解剂使片剂暴露于水环境时崩解。含有太多崩解剂的片剂会在贮存时崩解,而含有太少崩解剂的片剂不能以所需的速率崩解或在所需的条件下不能崩解。因此,既不太多也不太少的足量崩解剂而决定性地改变活性组份释放的崩解剂可用来形成本发明的固体口服剂型。崩解剂的用量可随制剂的类型而不同,这对于所述领域的普通技术人员来说是很容易辨别的。典型的药物组合物包含约0.5-约15重量%的崩解剂,特别是约1-5重量%的崩解剂。
可用于本发明药物组合物和剂型的崩解剂包括但不限于:琼脂-琼脂、藻酸、碳酸钙、微晶纤维素、交联羧甲基纤维素钠(croscarmellose sodium)、交联聚维酮(crospovidone)、polacrillin potassium、淀粉乙醇酸钠、土豆淀粉或木薯淀粉、预胶化淀粉、其它淀粉、粘土、其它藻胶、其它纤维素、胶和它们的混合物。
可用于本发明的药物组合物和剂型的润滑剂包括但不限于:硬脂酸钙、硬脂酸镁、矿物油、轻质矿物油、甘油、山梨醇、甘露醇、聚乙二醇、其它多元醇、硬脂酸、月桂基硫酸钠、滑石粉、氢化植物油(如花生油、棉籽油、葵花油、芝麻油、橄榄油、玉米油和豆油)、硬脂酸锌、油酸乙酯、月桂酸乙酯、琼脂和它们的混合物。其它的润滑剂包括,例如,硅酸盐硅胶(AEROSIL 200,由W.R.Grace Co.制造,美国马里兰州Baltimore)、合成二氧化硅的凝结气雾胶(由美国得克萨斯州,Plano的Degussa Co出售.)、CAB-O-SIL(pyrogenic二氧化硅产品,由美国马塞诸塞州,波士顿的Cabot Co.出售)和它们的混合物。若需要使用时,润滑剂以占低于药物组合物或剂型的约1重量%的用量合用。
缓释剂型
可通过控释方式或采用本领域普通人员公知的递药设备来给予本发明的活性组份。例子包括但不限于:美国专利3,845,770;3,916,899;3,536,809;3,598,123;和4,008,719;5,674,533;5,059,595;5,591,767;5,120,548;5,073,543;5,639,476;5,354,556和5,733,566中所描述的那些,所有这些专利都纳入本文供参考。这类剂型通过使用各种比例的下列物质而慢释放或控释一种或多种活性组份以得到所需的释放曲线,所述的物质是例如,羟丙基甲基纤维素、其它的聚合物基质、凝胶、可渗透膜、渗透系统、多层包衣、微颗粒、脂质体、微球或其组合。为本领域普通技术人员所公知的合适的控释制剂(包括本文所述的)可很容易地选来与本发明的活性组份共同使用。因此本发明涵盖了适合口服的单一单位剂型,例如,但不限于:适合控释的片剂、胶囊、凝胶胶囊(gelcap)和囊片(caplet)。
所有的控释药品所具有的一般目的是通过其非控制的配对物来促进药物疗效。理想的是,在药物治疗中使用最佳设计的控释制剂的特征在于在最短的时间里使用来治愈或控制病情的药物最小化。控释制剂的优点包括药物活性的延长、给药频度的降低、病人顺应性的增加。另外,控释制剂可用来影响开始作用的时间或其它特性,如药物的血药水平,并因此影响共同发生的副作用(例如,不利反应)。
大多数控释制剂被设计成开始释放一定量的药物(活性组份)以迅速产生所需的治疗作用,然后逐渐和持续地释放其它量的药物以在一段延长的时间里维持治疗或预防作用的水平。为了在体内维持该稳定的血药水平,药物必须以代替代谢和排泄的药物的速率从剂型中释放。通过各种条件可刺激活性组份的控制释放,这些条件包括但不限于:pH、温度、酶、水或其它生理条件或化合物。
非胃肠道剂型
非胃肠道剂型可通过各种途径给予病人,包括但不限于:皮下、静脉内(包括推注)、肌内和动脉内给药。由于它们的给药典型地绕过病人对污染物的天然防御,非胃肠道剂型优选的是无菌的,或在给予病人前能消毒。非胃肠道剂型的例子包括但不限于:备用的注射液、准备溶于或悬浮于供注射的药学上可接受的赋形剂的无水和/或冻干产品(可重构的粉末)、注射用悬浮液和乳剂。
用于本发明非胃肠道剂型的合适的运载体是为本领域技术人员所公知的。例子包括但不限于:注射用水USP;水性赋形剂,例如但不限于,氯化钠注射液、Ringer注射液、右旋糖注射液、右旋糖和氯化钠注射液、以及乳酸化的Ringer注射液;水混溶赋形剂,例如但不限于:乙醇、聚乙二醇和聚丙二醇;非水性赋形剂,例如但不限于:玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苄酯。能增加本文揭示的一种或多种活性组分的溶解度的化合物也可掺入本发明的非胃肠道剂型。
透皮剂型
透皮剂型包括“贮库型”或“基质型”贴剂,它可用于皮肤并佩带一段时间以使所需量的活性组分渗透。
可用来提供本发明的透皮和局部剂型的合适的赋形剂(如载体和稀释剂)和其它材料是药学领域中的技术人员所公知的,可根据给予药物组合物或剂型的特定组织而定。出于这一考虑,典型的赋形剂包括但不限于:水、丙酮、乙醇、乙二醇、丙二醇、丁-1,3-二醇、肉豆蔻酸异丙酯、棕榈酸异丙酯、矿物油和它们的混合物。根据要处理的特定组织,在用本发明的活性组分处理前、处理中或处理后可使用其它的化合物。例如,可使用渗透促进剂帮助活性组分向组织渗透。合适的渗透促进剂包括但不限于:丙酮;各种醇,如乙醇、油醇和四氢呋喃;烷基亚砜,如二甲亚砜;二甲基乙酰胺;二甲基甲酰胺;聚乙二醇;吡咯烷酮类,如聚乙烯吡咯烷酮:科利当(Kollidon)级(吡维酮、聚维酮);脲和各种水溶或水不溶的糖酯,如吐温80(聚山梨醇酯80)和司盘60(山梨糖单硬脂酸酯)。
也可调节药物组合物或剂型的pH或药物组合物或剂型给予的组织的pH来改善一种或多种活性组分的递送。相似的是,可调节溶剂载体的极性、它的离子强度或张力来改善递送。诸如硬脂酸的化合物也可加到药物组合物或剂型中以有利地改变一种或多种活性组分的亲水性或亲脂性从而改进递送。就此而言,硬脂酸酯可作为制剂的脂质载体、作为乳化剂或表面活性剂、并可作为递送促进剂或渗透促进剂。活性组分的不同的盐、水合物或溶剂合物可用来进一步调节所得组合物的性质。
局部给药剂型
本发明的局部剂型包括但不限于:霜剂、洗液、膏剂、凝胶剂、溶液剂、乳剂、悬浮剂或为本领域技术人员所公知的其它剂型。参见,如Remington′sPharmaceutical Sciences,第18版,Mack Publishing,美国宾夕法尼亚Easton(1990);和Introduction to Pharmaceutical Dosage Forms,第4版,Lea&Febiger,美国Philadelphia(1985)。
本发明所涵盖的可用来提供透皮和局部剂型的合适的赋形剂(例如,载体和稀释剂)和其它材料是为药学领域技术人员所公知的,根据药物组合物或剂型给予的特定组织而定。出于这一考虑,典型的赋形剂包括但不限于:水、丙酮、乙醇、乙二醇、丙二醇、丁-1,3-二醇、肉豆蔻酸异丙酯、棕榈酸异丙酯、矿物油和其它的混合物。
本发明所涵盖的可用来提供透皮和局部剂型的合适的赋形剂(例如,载体和稀释剂)和其它材料是为药学领域技术人员所公知的,根据药物组合物或剂型给予的特定组织而定。出于这一考虑,典型的赋形剂包括但不限于:水、丙酮、乙醇、乙二醇、丙二醇、丁-1,3-二醇、肉豆蔻酸异丙酯、棕榈酸异丙酯、矿物油和其它的混合物。
根据要处理的特定组织,可在用本发明活性组分处理前、处理中或处理后使用其它的组分。例如,可使用渗透促进剂帮助活性组分向组织渗透。合适的渗透促进剂包括但不限于:丙酮;各种醇,如乙醇、油醇和四氢呋喃;烷基亚砜,如二甲亚砜;二甲基乙酰胺;二甲基甲酰胺;聚乙二醇;吡咯烷酮类,如聚乙烯吡咯烷酮:科利当(Kollidon)级(吡维酮、聚维酮);脲和各种水溶或水不溶的糖酯,如吐温80(聚山梨醇酯80)和司盘60(山梨糖单硬脂酸酯)。
粘膜给药剂型
本发明的粘膜剂型包括但不限于:眼溶液、喷雾剂和气溶胶或本技术领域技术人员已知的其它形式。参见,如Remington′s Pharmaceutical Sciences,第18版,Mack Publishing,美国宾夕法尼亚Easton(1990);和Introduction toPharmaceutical Dosage Forms,第4版,Lea&Febiger,美国Philadelphia(1985)。适合用来治疗口腔内粘膜组织的剂型可配制成口腔洗液或口腔凝胶。在某一实施方式中,气溶胶包含载体。在另一个实施方式中,气溶胶不含载体。
本发明的化合物也可通过吸入直接对肺部给药。对于吸入给药,本发明的化合物可通过许多不同的设备对肺部进行常规的递送。例如,定量剂量吸入器(“MDI”)使用含有合适的低沸点抛射剂的小罐直接将化合物递送到肺部,所述的抛射剂是如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。MDI设备可从许多供应商处购得,如3M Corporation、Aventis、Boehringer Ingleheim、Forest Laboratories、Glaxo-Wellcome、Schering Plough和Vectura。
或者,可使用干粉吸入器(DPI)设备对肺部给予本发明的化合物(参见,如Raleigh等,Proc.Amer.Assoc.Cancer Research Annual Meeting,1999,40,397,在此全文纳入供参考)。DPI设备典型地使用诸如气体爆发机制在容器中产生干粉烟雾,然后被病人吸入。DPI设备在该领域中也是公知的,可从许多供应商处购得,包括,如,Fisons、Glaxo-Wellcome、Inhale Therapeutic Systems、MLLaboratories、Qdose和Vectura。普及的变体是多剂量DPI(“MDDPI”)系统,它可递送一种以上的治疗剂量。MDDPI设备可购自,如AstraZeneca、GlaxoWellcome、IVAX、Schering Plough、SkyePharma和Vectura。例如,用于吸入器或吹药器的明胶胶囊和弹药筒可配制成含有化合物与用于这些系统的合适的粉末基质(如乳糖或淀粉)的粉末混合物。
用来将本发明化合物递送到肺部的另一种设备是液体喷雾设备,如,Aradigm Corporation出产的设备。液体喷雾设备使用极小的喷嘴使液体药物制剂气溶胶化,然后可直接吸入肺部。
在优选的实施方式中,喷雾装置被用来将本发明的化合物递送到肺部。喷雾器通过使用,例如超声波能量形成易于吸入的细小颗粒,而从液体药物制剂中制造气溶胶(参见,如Verschoyle等,British J.Cancer,1999,80,Suppl 2,96,在此纳入本文供参考)。喷雾器的例子包括Sheffield/Systemic PulmonaryDelivery Ltd.(参见,Armer等,美国专利No.5,954,047;van der Linden等,美国专利No.5,950,619;van der Linden等,美国专利No.5,970,974,在此纳入本文供参考);Aventis和Batelle Pulmonary Therapeutics提供的设备。
在特别优选的实施方式中,电流体力学(EHD)气溶胶设备被用来向肺部递送本发明的化合物。EHD气溶胶设备使用电能使气溶胶液体药物溶液或悬浮液气溶胶化(参见,如Noakes等,美国专利No.4,765,539;Coffee,美国专利No.4,962,885;Coffee,PCT申请,WO94/12285;Coffee,PCT申请,WO94/14543;Coffee,PCT申请,WO95/26234;Coffee,PCT申请,WO95/26235;Coffee,PCT申请,WO95/32807,在此纳入本文供参考)。当使用EHD气溶胶设备向肺部递送药物时,制剂的电化学性质可能是需要最优化的重要参数,这类最优化可由本领域的技术人员常规地进行。EHD气溶胶设备可比现存的肺部递送技术更有效地向肺部递送药物。其它的肺内递送本发明化合物的方法是为本领域熟练技术人员所公知的,且也在本发明的范围内。
适合用喷雾器和液体喷雾设备和EHD气溶胶设备使用的液体药物制剂典型地包括本发明的化合物和药学上可接受的载体。优选的是,药学上可接受的载体是诸如醇、水、聚乙二醇或全氟碳的液体。任选的是,可加入另一种材料来改变化合物溶液或悬浮液的气溶胶性质。优选的是,该材料是诸如醇、多元醇、聚多元醇或脂肪酸的液体。配制适合用于气溶胶设备的液体药物溶液或悬浮液的其它方法是本领域技术人员所公知的(参见,如Biesalski,美国专利No.5,112,598;Biesalski,5,556,611,在此纳入本文供参考)。化合物也可配制成直肠组合物或阴道组合物,如栓剂或滞留灌肠剂,例如含有诸如可可豆酯或其它甘油酯的常规栓剂基质。
除了前述的制剂外,化合物也可配制成贮库制剂。这类长期作用的制剂可通过(例如皮下或肌内)植入给予或通过肌内注射给予。由此,化合物可用合适的聚合物材料或疏水材料(例如,在可接受的油中的乳剂)或离子交换树脂配制,或者作为微溶的衍生物,例如作为微溶的盐。
或者,可使用其它的药物递送系统。脂质体和乳剂是可用来递送本发明化合物的公知的递送载体的例子。可使用诸如二甲亚砜的某些有机溶剂,虽然通常会有较大的毒性。本发明的化合物也可在控释系统中递送。在一个实施方式中可使用泵(Sefton,CRC Crit.RefBiomed Eng,1987,14,201;Buchwald等,Surgery,1980,88,507;Saudek等,N.Engl.J.Med.,1989,321,574)。在另一个实施方式中可使用聚合物材料(参见Medical Applications of ControlledRelease,Langer和Wise编,CRC Pres.,Boca Raton,Fla.(1974);Controlled DrugBioavailability,Drug Product Design and Performance,Smolen和Ball编辑,Wiley,N.Y.(1984);Ranger和Peppas,J.Macromol.Sci.Rev.Macromol.Chem.,1983,23,61;也可参见Levy等,Science,1985,228,190;During等,Ann.Neurol.,1989,25,351;Howard等,1989,J.Neurosurg.71,105)。在另一个实施方式中,控释系统可位于本发明化合物的靶向物的周围,如肺部,这样只需要部分全身剂量(参见,如,Goodson,in Medical Applications of ControlledRelease,同上,第2卷,115页(1984))。其它的控释系统也可使用(参见,如Langer,Science,1990,249,1527)。
可用来提供本发明的粘膜给药剂型的合适的赋形剂(如载体和稀释剂)和其它材料的是药学领域中技术人员所公知的,可以根据组合物或剂型给予的特定部位或方法而定。出于这点考虑,典型的赋形剂包括但不限于:水、乙醇、乙二醇、丙二醇、丁-1,3-二醇、肉豆蔻酸异丙酯、棕榈酸异丙酯、矿物油和它们的混合物,所述的赋形剂是无毒的且药学上可接受的。这类附加组分的例子是本技术领域公知的。参见,如,Remington′s Pharmaceutical Sciences,第18版,Mack Publishing,美国宾夕法尼亚Easton(1990)。
也可调节药物组合物或剂型的pH或施用药物组合物或剂型的组织的pH来改善一种或多种活性组分的递送。相似的是,可以调节溶剂载体的极性、溶剂载体的离子强度或张力以改善递送。诸如硬脂酸酯的化合物也可加到药物组合物或剂型中以有利地改变一种或多种活性组分的亲水性或亲脂性,从而改善递送。就此而言,硬脂酸酯可作为制剂的液体运载体、作为乳化剂或表面活性剂,并作为递送促进剂或渗透促进剂。活性成分的不同的盐、水合物或溶剂合物可用来进一步调节所得组合物的性质。
药盒
本发明提供了包括一个或多个容器的药物包装或药盒,所述容器包含用于治疗或预防丙肝病毒感染的式I的前药、式II的化合物或本发明的其它化合物。在其它实施方式中,本发明提供了包括含有用于治疗或预防丙肝病毒感染的式I所示的前药、式II所示的化合物或本发明的其它化合物的一个或多个容器的药物包装或药盒,和含有其它治疗剂一个或多个容器,所述的其它治疗剂包括但不限于那些上述所列的药物,特别是抗病毒剂、干扰素、抑制病毒酶的药剂或抑制病毒复制的药剂,优选的其它的治疗剂为HCV特异性或显示出抗HCV活性。
本发明还提供了包括一个或多个容器的药物包装或药盒,其中包含一种或多种本发明的药物组合物的成分。与这类容器任选地关联的是一个由政府机构规定的药品或生物制品生产、使用或销售所需形式的说明书,该说明书显示对人体给予所述药品或生物制品的制造、使用或销售已获得政府机构许可。
本发明的试剂可用下述反应途径和合成流程,使用易于获得的起始材料通过本技术领域已知的一般技术进行制备。本发明的未经公证的化合物的合成可通过对本领域技术人员而言显而易见的修饰,如通过合适的保护干扰基团、通过改变成该技术领域公知的其它合适的试剂或通过对反应条件进行常规的改变可以成功地进行。或者,本文所述的或本领域一般了解的其它反应也可用于制备本发明的其它化合物。
化合物的制备
在下述合成流程中,除非特别指出,所有的温度为摄氏度,所有的份数和百分数是以重量为基础的。试剂均购自商业化供应商,例如Aldrich ChemicalCompany或Lancaster Synthesis Ltd.,除非特别指出,所述的试剂不经纯化直接使用。四氢呋喃(THF)和N,N-二甲基甲酰胺(DMF)购自Aldrich,它们在安全密闭的瓶子中并可直接使用。除非特别指出,下列溶剂和试剂在干燥氮气下蒸馏。在Na-二苯甲酮羰游基(Na-benzophenone ketyl)中蒸馏THF和Et2O;在CaH2中蒸馏CH2Cl2、二异丙胺、吡啶和Et3N;在P2O5,然后是CaH2中蒸馏MeCN;从Mg中蒸馏MeOH;从CaH2中蒸馏PhMe、EtOAc和i-PrOAc;在干燥氩气下通过简单的常压蒸馏纯化TFAA。
在氩气正压和室温下(除非特定指出)、于无水溶剂中进行下列反应,且将反应烧瓶用橡胶隔片固定以便于通过注射器引入底物和试剂。烘箱干燥和/或加热干燥玻璃器皿。反应用TLC分析,通过起始材料的消耗来判断反应的终止。分析用的薄层层析(TLC)是在铝背衬的硅胶60F2540.2毫米板(EM Science)上进行的,用UV光(254nm)显象,然后与市售的醇制磷钼酸一起加热。制备薄层层析(TLC)是在铝背衬硅胶60F2541.0mm板(EM Science)上进行的,用UV光(254nm)显象。
除非特别指出,一般的是这样进行后处理:用反应溶剂或萃取溶剂使反应体积加倍,然后用萃取体积的25体积%的指定水性溶液洗涤。用无水Na2SO4和/或Mg2SO4干燥产物溶液,然后过滤并在旋转蒸发仪上减压蒸发溶剂,并注明“真空去除溶剂”。使用230-400目硅胶或50-200目中性氧化铝在正压下进行柱层析。在实施例指定的压力或环境压力下进行氢解。
1H-NMR谱是在Varian Mercury-VX400仪上,在400MHz操作下记录的,而13C-NMR谱则在75MHz操作下记录的。NMR谱从CDCl3溶液(单位ppm)中得到,用氯仿作为参比的标准物(7.27ppm和77.00ppm),适当时为CD3OD(3.4和4.8ppm和49.3ppm),DMSO-d6,或内标的四甲基甲硅烷(0.00ppm)。其它的NMR溶剂可按需使用。若报道峰多重性时,使用下列缩写:s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(加宽的峰)、dd(成对的双峰)、dt(成对的三重峰)。偶合常数记录为赫兹(Hz)。
以干燥油、KBr晶片或CDCl3溶液形式,在FT-IR光谱仪上记录红外(IR)光谱,当报告所得结果时以波数(cm-1)记录。质谱记录为(+)-ES LC/MS,由Anadys药品股份有限公司的分析化学部进行。元素分析由Atlantic Microlab,Inc.(Norcross,GA)进行。熔点(mp)的测定是在开口的毛细管装置中进行的,未经校正。
所述的合成途径和实验过程中使用了许多常见的化学缩写:THF(四氢呋喃)、DMF(N,N-二甲基甲酰胺)、EtOAc(乙酸乙酯)、DMSO(二甲亚砜)、DMAP(4-二甲氨基吡啶)、DBU(1,8-二偶氮环[5.4.0]十一-7-烯)、DCM(4-(二氰基亚甲基)-2-甲基-6-(4-二甲氨基-苯乙烯基)-4H-吡喃)、MCPBA(3-氯过氧苯甲酸)、EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)、HATU(O-(7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸酯)、HOBT(1-羟基苯并三唑水合物)、TFAA(三氟乙酸酐)、pyBOP(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸酯)、DIEA(二异丙基乙胺)、BOC(叔丁氧基羰基)、2,2-DMP(2,2-二甲氧基丙烷)、IPA(异丙醇)、TEA(三乙胺)、DCE(1,2-二氯乙烷)、PPTS(对甲苯磺酸吡啶)、DEAD(偶氮羧酸二乙酯)、PS(支撑的聚合物polymer supported)、HF(氟化氢)、MeCN(乙腈)、MeOH(甲醇)、Val(缬氨酸)、Phe(苯丙氨酸)、HPLC(高压液相色谱)、TLC(薄层层析)、TLC(薄层层析)、Bz(苯甲酰基)、Ac(乙酰基)、Tol(甲苯酰基)、Me(甲基)等。
实施例1
5-氨基-3-(2’-C-甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(4)
步骤1)制备5-氨基-3-(2’-C-甲基2’,3’,5’-三-O-苯甲酰基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(3)
a.BSA,MeCN,室温;TMSORTf,80℃,67%
向杂环1(168mg,1.00mmol)和过苯甲酰基核糖2[根据Wolfe等人J.Org.Chem.1997,62,1754-1759中所述的方法制备](522mg,0.90mmol)在无水MeCN(10mL)中的非均相混合物中加入BSA(742μL,3.00mmol)。将所得混合物搅拌15分钟,并随之加入TMSOTf(333μL,1.50mmol)。将反应混合物在65℃下搅拌4小时(h),然后在90℃下搅拌3小时。然后将混合物冷却到室温(rt),以DCM(150mL)稀释,并以pH7缓冲液(100mL)分配。水相以DCM(3×50mL)进一步萃取,合并的有机相通过Na2SO4干燥并过滤。将澄清滤液以EtOAc(200mL)稀释,通过SiO2薄垫过滤,浓缩并经快速色谱纯化(10-40%EtOAc-DCM),制得380mg(67%)核苷3,其为白色固体:1H(400MHz,OMSO-d6)δ8.43(s,1H),7.85-8.02(m,6H),7.46-7.97(m,7H),7.35(t,J=8.06,2H),6.96(br s,2H),6.77(br s,1H),4.54-4.82(m,4H),1.77(s,3H);[MH-H]+m/z 627。
步骤2)制备5-氨基-3-(2’-C-甲基-β-D-呋喃核糖基-3H-噻唑并[4,5-d]嘧啶-2-酮(4)
b.K2CO3,MeOH,10%
室温下向核苷3(380mg,0.606mmol)在MeOH(20mL)的悬液中加入K2CO3(17mg,0.12mmol)。室温下搅拌所得的混合物18小时,并以HOAc(15μL,0.25mmol)处理,浓缩并且经HPLC纯化(MeCN-H2O),制得20mg(10%)标题化合物4,经冻干后为白色固体:1H(400MHz,DMSO-d6)δ8.33(s,1H),6.86(brs,2H),6.09(br s,1H),5.19(br s,1H),4.88(br s,1H),4.55(t,J=5.87,1H),3.97(br s,1H),3.76-3.81(m,1H),3.61(br s,2H),1.04(s,3H);[M+H]+m/z315。对C11H14N4O5S·H2O的分析计算值:C,39.75;H,4.85;N,16.86;S,9.65。测量值:C,40.23;H,4.76;N,16.64;S,9.45。
实施例2
5-氨基-3-(2’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(10)
步骤1)制备N’-(7-氯-2-氧代-2,3-二氢-噻唑并[4,5-d]嘧啶-5-基)-N,N-二甲基-甲脒(7)
d.SOCl2,DMF.
于0℃,向5-氨基-7-羟基-3H-噻唑并[4,5-d]嘧啶-2-酮(10.0g,53.7mmol)在MeCN(200mL)的悬液中,通过加液漏斗于20分钟内滴加SOCl2(20.0mL,274mmol)。所得的混合物缓慢加热至室温,然后浸入60℃的油浴,并搅拌48小时。将反应混合物冷却至室温,缓慢倒入在300mL含NaHCO3(46g,548mmol)的水中的300g碎冰。该含水混合物用20%IPA-DCM(3×500mL)萃取,合并的有机相用Na2SO4干燥,浓缩至残余物,该残余物用EtOAc研碎后得6.33g(46%)氯脒7,其为棕褐色固体:1H(400MHz,DMSO-d6)δ12.60(s,1H),8.69(s,1H),3.25(s,3H),3.11(s,3H);[M+H]+m/z 258。
步骤2)制备N’-(7-氯-2-氧代-3-[2’-脱氧-3’,5’-二-O-(p-甲苯酰基)-β-D-呋喃核糖基]-2,3-二氢-噻唑并[4,5-d]嘧啶-5-基)-N,N-二甲基-甲脒(8)
a.6NaH,MeCN,90%.
室温下,向杂环7(1.79g,6.94mmol)在无水MeCN的悬液中加入95%NaH(183mg,7.63mmol)。搅拌所得的混合物30分钟,并加入氯代糖5(2.70g,6.94mmol)[购自Berry&Associates,Inc.,Dexter,MI]。反应混合物加热至55℃,搅拌1小时,冷却,浓缩后,经快速色谱纯化(SiO2,5-10%EtOAc-DCM),获得3.8g(90%)核苷8,为固体物质,通过在MeOH中研碎进一步纯化:1H(400MHz,DMSO-d6)δ8.64(s,1H),7.83(Abq,JAB=8.19,ΔVAB=38.53,4H),7.28(ABq,JAB=8.19,ΔVAB=36.13,4H),6.56(dd,J=8.19,5.07,1H),5.76-5.80(m,1H),4.56-4.60(m,1H),4.45-4.50(m,2H),3.27-3.34(m,1H),3.15(s,3H),3.03(s,3H),2.57-2.64(m,1H),2.35(s,3H),2.39(s,3H)。
步骤3)制备5-氨基-3-(2’,3’-二-O-(对-甲苯酰基)-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(9)
b.Zn-Cu,HOAc,67%.
室温下,向氯代芳基核苷8(924mg,1.47mmol)在乙酸(10.4mL)的溶液中加入Zn-Cu对(1.54g,11.9mmol)。所得悬液于环境温度下剧烈搅拌3.5小时,通过硅藻土过滤,然后浓缩为固体物,该固体物经过快速色谱(SiO2,0-10%EtOAc-CHCl3)纯化,获得520mg(67%)化合物9,为棕褐色固体:1H NMR(400MHz,d6-DMSO)δ8.34(s,1H),7.85(ABq,JAB=8.4,ΔVAB=17.6,4H),7.30(ABq,JAB=8,4,ΔVAB=27.1,4H),6.87(s,2H),6.47(m,1H),5.78(m,1H),4.62(m,1H),4.47(m,2H),3.35(m,2H),2.38(s,3H),2.35(s,3H)。
步骤4)制备5-氨基-3-(2’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(10)
c,K2CO3,MeOH,46%.
室温下,向上面步骤3)获得的二酯9(300mg,0.577mmol)在MeOH(20mL)的悬液中加入K2CO3(188mg,1.36mmol)。所得的混合物搅拌8小时,并以HOAc(164μL,2.86mmol)骤冷,然后浓缩,并经HPLC纯化(MeCN-H2O,TFA),获得75mg(46%)标题化合物10,冻干后为为白色固体(TFA盐):1H(400MHz,DMSO-d6)δ8.34(s,1H),7.15(br s,2H),6.33(t,J=7.0,1H),4.33(br s,1H),3.72-3.73(m,1H),3.39-3.56(m,2H),2.89-2.96(m,1H),1.99-2.05(m,1H);[M+H]+m/z 285。对C10H12N4O4S-C2HF3O2的分析计算值:C,36.18;H,3.29;N,14.31;S,8.05。测量值:C,36.28;H,3.35;N,13.96;S,8.05。
实施例3
5-氨基-3-{2’-O-乙酰基-3’-脱氧-β-D-呋喃核糖基}-3H-噻唑并[4,5-d]嘧啶-2-酮(15)
步骤1)制备5-氨基-3-(2’,5’-二-O-苯甲酰基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(12)
a.11a,BSA,MeCN,室温;TMSOTf,80℃,78%.
室温下,向杂环1(25.0g,0.149mol)和脱氧呋喃核糖11a(47.0g,0.122mol)[可从相应的甲基呋喃核糖(Walton等,J.Med Chem.1965,8,659-663),通过Valdivia等Tetrahedron Lett.2005,46,6511-6514所述的方法制备]在无水MeCN(640mL)的非均相混合物中,通过加液漏斗于20分钟内逐滴加入BSA(113mL,0.458mol)。室温下在20分钟内,在所得悬液中滴加TMSOTf(41.5mL,0.229mol)进行处理,该悬液变为几乎均相。混合物加热至回流(内T 83℃)并搅拌8小时,然后冷却至室温,通过旋转蒸发浓缩为油状残余物。将残余物溶于EtOAc(500mL)中,冷却至10℃,用1M PH7磷酸盐缓冲液(400mL)缓慢处理,保持内部温度低于35℃。完成添加缓冲液后,用固体K2HPO4调节该混合物pH至7.0,并持续剧烈搅拌1小时。加入硅藻土(25g),混合物再搅拌30分钟。该三相混合物通过硅藻土薄垫过滤,获得澄清的两相。含水相用固体NaCl饱和,然后用EtOAc(4×250mL)萃取。合并的有机相用盐水洗涤(400mL),用Na2SO4和活性炭(1g)干燥,然后通过SiO2薄垫过滤。将萃取的琥珀色滤液浓缩至干,沉淀出固体杂环。将残余物溶于DCM,用少量MgSO4处理,然后通过硅藻土过滤。萃取的滤液浓缩并在高真空下35℃干燥,获得棕褐色易碎的泡沫体(69.5g)。将该固体泡沫体通过快速色谱纯化(SiO2,5-40% EtOAc-己烷),获得46.3g(77%)核苷12,为浅米色固体泡沫:1H NMR(DMSO-d6)δ8.35(s,1H),7.93-8.01(m,4H),7.61-7.69(m,2H),7.47-7.56(m,4H),6.94(s,2H),6.09(d,J=1.9,1H),6.00(d,J=7.4,1H),4.64-4.69(m,1H),4.57(dd,J=2.1,2.7,1H),4.36(dd,J=12.1,5.8,1H),2.92-3.00(m,1H),2.32(dd,J=14.0,5.8,1H);[M+H]+m/z 493。
步骤2)制备5-氨基-3-(3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(13)
b.K2CO3,MeOH,78%.
室温下,向二苯甲酸酯12(46.3g,94.0mmol)和无水MeOH(1.0L)的非均相混合物中加入K2CO3(2.59g,18.8mmol)。该混合物30分钟内成为均相,然后在3小时内再次为非均相。加入另外的MeOH(100mL)以提高流动性,搅拌该反应混合物总共24小时。该悬液用HOAc(2.26mL,39.5mmol)处理,然后在45℃下浓缩,随后冷却,然后用EtOH(200mL)和醚(1800mL)研碎1小时。滤出固体物,用醚洗涤(3×250mL),空气干燥,然后用水洗涤(2×250mL),获得19.47g(78%)二醇13,为白色固体,该固体真空干燥并在水中重结晶:1HNMR(DMSO-d6)δ8.31(s,1H),6.82(s,2H),5.82(d,1H),5.41(d,1H),4.79-4.83(m,1H),4.65(t,J=5.8,1H),4.13-4.20(m,1H),3.40-3.49(m,2H),2.31(ddd,J=16.0,9.4,7.0,1H),1.81(ddd,J=12.5,5.8,2.3,1H);[M+H]+m/z285。对C10H12N4O4S的分析计算值:C,42.25;H,4.25;N,19.71;S,11.28.测量值:C,42.36;H,4.32;N,19.72;S,11.23。
步骤3)制备5-氨基-3-(2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(14)
c.Ac2O,Et3N,DMAP,MeCN.f.1,BSA,MeCN,室温;TMSOTf,80℃。
于0℃,向二醇13(8.00g,28.1mmol)、Et3N(11.8mL,84.4mmol)和DMAP(344mg,2.81mmol)在无水MeCN(190mL)的悬液中滴加Ac20(5.44mL,57.7mmol)。所得混合物在1.5小时内成为均相,将该混合物缓慢加热至室温,搅拌18小时,随后浓缩为残余物,该残余物经快速色谱纯化(SiO2,0-100%EtOAc-DCM),获得8.34g(80%)二乙酸酯14,为白色固体泡沫,该固体泡沫可以通过用醚-己烷研碎进一步纯化:1H(400MHz,DMSO-d6)δ8.34(s,1H),6.91(s,2H),5.90(d,J=1.9,1H),5.65(d,J=7.4,1H),4.33-4.39(m,1H),4.25(dd,J=12.1,3.1,1H),4.01(dd,J=11.7,6.6,1H),2.65-2.73(m,1H),2.06(dd,J=13.6,6.2,1H),2.05(s,3H),1.98(s,3H);[M+H]+m/z 369。对C14H16N4O6S的分析计算值:C,45.65;H,4.38;N,15.21;S,8.70。测量值:C,45.69;H,4.52;N,15.02;S,8.64。
或者,按照与上面步骤1类似的方式,二乙酸酯14可以由杂环1和脱氧呋喃核糖11b[可以通过Valdivia等人,Tetrahedron Lett.2005,46,659-663中所述方法制备]制备,产率为63%。
步骤4)制备5-氨基-3-(2’-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(15)
d.北极洲念珠菌(Candida Arctica),丙酮,pH 7缓冲液91%
室温下,向缓慢搅拌的二乙酸酯14(5.08g,13.8mmol)和北极洲念珠菌(Candida Arctica)脂肪酶丙烯酸树脂(2.50g)[购自Sigma]在丙酮(50mL)的悬液中加入50mM pH 7的磷酸盐缓冲液(250mL)。所得的混合物慢慢搅拌18小时,并进行过滤,浓缩和用EtOAc萃取(4×250mL)。合并的有机相用Na2SO4干燥,浓缩,然后经快速色谱纯化(SiO2,0-15%EPA-DCM),获得4.11g(91%)标题化合物15,为白色固体,该固体通过用醚-己烷研碎进一步纯化:1H(400MHz,DMSO-d6)δ8.33(s,1H),6.87(s,2H),5.88(d,J=2.3,1H),5.66(d,J=7.8,1H),4.76(t,J=5.8,1H),4.11-4.18(m,1H),3.43-3.53(m,2H),2.50-2.57(m,1H),2.05(s,3H),1.98(dd,J=13.6,5.8,1H);[MH+H]+m/z 327。对C12H14N4O5S分析计算值:C,44.17;H,4.32;N,17.17;S,9.83。测量值:C,44.12;H,4.45;N,16.88;S,9.69。
实施例4
5-氨基-3-(2’-O-乙酰基-5’-O-苯甲酰基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(16)
f.11c,BSA,MeCN,室温;80℃.
室温下,向杂环1(106mg,0.633mmol)和脱氧呋喃核糖11c[购自Berry&Associates,Inc.,Dexter,MI]183mg,0.57mmol)在无水MeCN(8mL)的非均相混合物中加入BSA(464μL,1.89mmol)。所得混合物浸入60℃油浴并搅拌4小时。该混合物通过旋转蒸发浓缩,并分配在EtOAc(100mL)和饱和NaHCO3(50mL)之间。有机相用Na2SO4干燥,然后浓缩。粗产物用Et2O-EtOAc研碎,获得132mg(54%)米色固体,该固体经HPLC纯化(MeCN-H2O),提供分析样品:1H(400MHz,DMSO-d6)δ8.33(s,1H),7.91-7.94(m,2H),7.60-7.65(m,1H),7.47-7.50(m,2H),6.94(s,2H),5.93(d,J=1.8,1H),5.72(dd,J=5.9,1.5,1H),4.50-4.53(m,2H),4.31(q,J=7.0,1H),2.80-2.88(m,1H),2.14(dd,J=13.2,5.1,1H),2.07(s,3H);[M+H]+m/z 431。
实施例5
5-氨基-3-苄基-3H-噻唑并[4,5-d]嘧啶-2-酮(18)
a.POCl3,DMF,90℃。b.胍盐酸盐,NaOMe,MeOH,19%,经两步
于0℃,向POCl3(8.09mL,86.8mmol)中连续加入固体3-苄基-噻唑烷-2,4-二酮[按照Lo等人,J.Org.Chem.1957,999-1001中所述方法制备]和DMF。反应混合物搅拌5分钟,然后转移到90℃油浴中搅拌3小时。将该深色混合物倒入冰(100g)和水(100mL)中,然后用EtOAc萃取(3×100mL)。合并的有机相用MgSO4干燥,然后通过硅藻土过滤,浓缩,溶于DCM中,通过SiO2薄垫过滤,最后浓缩为深色油状物,该油状物不需进一步纯化即可使用。
于-5℃,将胍盐酸盐固体(8.87g,92.8mmol)加入25%NaOMe-MeOH(18mL,79.6mmol)的MeOH(48mL)溶液。所得的混合物搅拌5分钟,然后用粗氯乙醛[上面制得的]的MeOH(20mL)溶液进行处理。将该反应混合物置于90℃油浴,在2小时内,蒸馏所有MeOH进行浓缩,然后再加热30分钟。残余物溶于EtOAc(200mL)中,并用1N HCl(100mL)分配。含水相用固体NaHCO3处理并且用EtOAc(3×100mL)分配。由碱萃取的合并的有机相用Na2SO4干燥,然后浓缩为残余物,该残余物经色谱纯化(SiO2,50-70%EA-DCM),获得1.4g(19%)标题化合物18,为白色固体:1H(400MHz,DMSO-d6)δ8.32(s,1H),7.24-7.34(m,5H),6.83(s,2H),5.01(s,2H);[M+H]+m/z 259。
实施例6
5-氨基-3-(3’,3’-C,O-二甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(23)
步骤1)制备1,2-O-异亚丙基-3-甲基-3-O-甲基-5-O-三苯甲基-α-D-呋喃核糖(20)
a.KH(xs),二噁烷,DMF(3∶1);MeI,室温,72小时,87%
室温下,向叔醇19(716mg,1.60mmol)[按照Just等人,Tetrahedron Lett.2000,41,9223-9227中所述方法制备]在无水二噁烷(6mL)的混合物中加入过量的KH(30%矿物油中分散液)。所得的混合物搅拌1小时,然后用MeI处理(2mL,32mmol),得到大量沉淀。加入DMF(2mL)以保持该反应混合物足以液体搅拌72小时。该混合物用EtOAc(100mL)稀释,用饱和NaHCO3水溶液分配(50mL)。有机相用Na2SO4干燥,浓缩并经快速色谱纯化(SiO2,10-60%EtOAc-己烷),获得640mg甲醚20,为白色固体:1H(400MHz,DMSO-d6)δ7.22-7.35(m,15H),5.72(d,J=2.9,1H),4.30(d,J=2.9,1H),4.07(dd,J=7.7,2.6,1H),3.14(s,3H),2.92-3.05(m,2H),1.51(s,3H),1.28(s,3H),0.82(s,3H)。
步骤2)制备1,2,5-四-O-乙酰基-3,3-C,O-二甲基-β-D-呋喃核糖(21)
b.HOAc,Ac2O,H2SO4,室温,33%.
向HOAc(5O.0mL)和Ac2O(3.83mL,40.6mmol)的溶液中加入呋喃糖20(3.62g,8.11mmol)。在该无色溶液中加入1M H2SO4的HOAc(0.41mL,0.41mmol)溶液,形成深黄色溶液。该溶液室温搅拌16小时,然后通过旋转蒸发浓缩。过量的HOAc通过一定调节甲苯共沸几次。将残余物溶于DCM(100mL),用饱和NaHCO3(30mL)洗涤。有机层用Na2SO4干燥,滗析,浓缩为油状非均相混合物。该混合物均相快速色谱纯化(SiO2,5-35%EtOAc-己烷),获得0.78g(33%)三乙酸酯21,为淡黄色油状物:1H(400MHz,DMSO-d6)δ5.91(d,J=2.0,1H),5.07(d,J=2.4,1H),4.29(dd,J=3.2,12.0,1H),4.15(dd,J=3.2,7.2,1H),3.96(dd,J=6.8,12.0,1H),3.17(s,3H),2.10(s,3H),2.04(s,6H),1.33(s,3H)。
步骤3)制备5-氨基-3-(2’,5’-二-O-乙酰基-3’,3’-C,O-二甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(22)
c.BSA,MeCN,室温;TMSOTf,80℃,65%.
室温下,向杂环1的无水MeCN(5.0mL)混合物中滴加BSA(0.52mL,2.11mmol)。所得的混合物浸入40℃油浴中,搅拌90分钟,成为均相。加入呋喃糖21(0.20g,0.73mmol),然后加入TMSOTf(158.4μL,0.88mmol)。然后,将反应混合物浸在80℃油浴中加热2小时。反应物冷却至室温,分配在1M pH 7的磷酸盐缓冲液(15mL)和EtOAc(30mL)之间。所得乳液通过硅藻土过滤,产生两个独立的层。分离有机层,用Na2SO4干燥,过滤,真空浓缩为深橙棕色残余物。该残余物经快速色谱纯化(SiO2,5-50%EtOAc-己烷),获得0.30g(59%)核苷22,为极细的淡黄色固体:1H(400MHz,DMSO-d6)δ8.34(s,1H),6.90(brs,2H),6.11(dd,J=8.0,27.6,2H),4.3-4.17(m,3H),2.75(s,3H),2.02(s,3H),2.01(s,3H),1.35(s,3H);[M+H]+m/z 413。
步骤4)制备5-氨基-3-(3’,3’-C,O-二甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(23)
d.K2CO3,MeOH,室温.
将核苷22(230mg,0.56mmol)溶解在5.6mL MeOH中。加入固体K2CO3(15.4mg,0.11mmol),反应物室温搅拌16小时。加入HOAc(16.0μl,0.28mmol),搅拌反应物30分钟,然后真空浓缩该混合物至干。残余的黄色固体用Et2O研碎(3×10mL),通过滴管小心滗析滤液。然后,固体物质用H2O洗涤(3×5mL),用Et2O漂洗(2×5mL),并在真空室干燥24小时,获得76.4mg(42%)细粉碎的白色固体:1H(400MHz,DMSO-d6)δ8.35(s,1H),6.83(br s,2H),5.93(d,J=8.58,1H),5.24(d,J=7.02,1H),4.95(t,J=7.4,1H),4.57(t,J=5.46,1H),3.95(t,J=5.07,1H),3.46-3.58(m,2H),3.26(s,3H),1.29(s,3H);[M+H]+m/z329。
实施例7
5-氨基-3-(5’-O-乙酰基-2’-O-[2”-O-乙酰基丙基]-3-甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(27)
1)制备1,2-O-异亚丙基-3-甲基-5-O-三苯甲基-α-D-呋喃核糖(25)
a.H2,5%Pd/C,EtOAc,室温,48小时,6∶1(α/β),78%.
在氮气保护下,向化合物24(2.40g,5.60mmol)[按照Bera等人,Helvetica Chimica Acta 2000,83(7),1398-1407所述方法制备]溶于EtOAc(50mL)的溶液中加入5%Pd/C(240mg)。烧瓶中充有1个大气压的H2,室温搅拌72小时。反应混合物通过硅藻土过滤,真空浓缩为澄清的无色油状物。经快速色谱纯化(SiO2,0-40%EtOAc-己烷),获得1.88g的混合物25(78%),为6∶1(α/β)异构体混合物:1H(400MHz,DMSO-d6)δ7.22-7.38(m,15H),7.63(d,J=3.2,1H),4.53(t,J=4.0,1H),3.67(dq,J=2.8,1.6,1H),3.18(dd,J=3.2,10.4,1H),2.99(dd,J=5.2,10.8,1H),1.89-1.98(m,1H),1.38(s,3H),1.24(s,3H),0.81(d,J=6.8,3H)。
步骤2)制备1,5-二-O-乙酰基-2-O-(2’-O-乙酰基丙基)-3-甲基-β-D-呋喃核糖(26)
b.HOAc,Ac2O,H2SO4,室温,19%.
按照与实施例6的步骤3类似的方式,将化合物25转化为化合物26,产率为19%。粗残余物经快速色谱纯化(SiO2,2-30%EtOAc-己烷),通过1HNMR(DMSO-d6)产生5∶1(β/α)的端基异构体(anomer)的混合物(被三苯甲烷污染),该混合物无需进一步纯化即可用于下一步骤:1H(400MHz,DMSO-d6)δ6.07(d,J=2.8,1H),5.02(ddd,J=6.8,6.8,2.8,1H),4.25(dd,J=12.0,3.2,1H),4.06-4.21(m,2H),2.14-2.23(m,1H),2.03(s,3H),2.00(s,3H),1.99(s,3H),1.41(s,3H),1.39(s,3H),0.91(d,J=6.8,3H)。
步骤3)制备5-氨基-3-(5’-O-乙酰基-2’-O-[2”-O-乙酰基丙基]-3-甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(27)
c.BSA,MeCN,室温;TMSOTf,60℃,11%.
室温下,向杂环1在无水MeCN(5.0mL)的混合物中滴加BSA(0.52mL,2.11mmol)。搅拌所得的混合物30分钟,然后加入呋喃糖26(0.20g,0.73mmol),再加入TMSOTf(158.4μL,0.88mmol)。将反应混合物浸在60℃油浴中,成为均相溶液。继续搅拌2.5小时。冷却反应混合物至室温,然后分配在1M pH 7磷酸盐缓冲液和EtOAc之间。混合物通过硅藻土垫过滤,分成独立的层。有机相用Na2SO4干燥,过滤,浓缩,经快速色谱纯化(SiO2,5-50%EtOAc-己烷),获得30.0mg标题化合物27,为白色固体:1H(400MHz,DMSO-d6)δ.8.36(s,1H),6.90(s,2H),6.09(d,J=7.2,1H),5.16(t,J=7.2,1H),4.88(dt,J=6.4,3.2 1H),4.20(dd,J=3.2,12.0,1H),4.08(dd,J=6.4,12.0,1H),2.28(dq,J=6.8,14,1H),1.97(s,3H),1.87(s,3H),1.54(s,3H),1.41(s,3H),0.86(d,J=6.8,3H);[M+H]+m/z 441。
实施例8
5-氨基-3-(3’-甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(30)
1)制备5-氨基-3-(3’-O-乙酰基-2’,5’-二-O-苯甲酰基-3’-甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(29)
a.杂环1,BSA,TMSOTf,CH3CN,88%.
将5-氨基-3H-噻唑并[4,5-d]嘧啶-2-酮(123mg,0.733mmol)、3’-C-甲基-呋喃核糖28[按照Wang等人,J.Med.Chem.2000,43,3704-3713中所述方法制备](302mg,0.66mmol)、BSA(447mg,2.2mmol)和MeCN(8mL)剧烈混合30分钟,直到获得均相溶液。然后,在该反应物中加入TMSOTf(0.186mL,1.1mmol),置于预热至65℃的油浴中。3小时后,反应物冷却至室温,旋转蒸发除去溶剂。将所得固体溶解在EtOAc(200mL)中,用饱和NaHCO3水溶液萃取(2×100mL)。有机相用Na2SO4干燥,浓缩。粗产物经快速色谱纯化(SiO2,0-40%EtOAc-CHCl3),获得365mg(88%)棕褐色固体:1H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.92(d,J=6.4,4H),7.69(m,2H),7.53(m,4H),6.93(br s,2H),6.90(s,1H),6.43(d,J=7.2,1H),6.10(t,J=9.2,1H),4.80(br s,1H),4.59(br,s,1H),2.09(s,3H),1.97(s,3H);[M+H]+m/z 565。
步骤2)制备5-氨基-3-(3’-甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(30)
b.K2CO3,MeOH,66%.
将5-氨基-3-(2’,5’-二-O-苯甲酰基-3’-O-乙酰基-3’-C-甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(365mg,0.647mmol)溶解在MeOH(10mL)。加入K2CO3(17.9mg,0.129mmol),室温搅拌反应物16小时。加入乙酸(15.5mg,0.258mmol),反应物通过旋转蒸发浓缩。然后,粗产物经HPLC纯化(MeCN-H2O),获得135mg(66%)固体物质:1H NMR(400MHz,d6-DMSO)δ8.35(s,1H),6.82(brs,2H),5.91(d,J=8.0,1H),5.38(d,J=6.4,1H),4.81(t,J=6.0,1H),4.68(s,1H),4.51(t,J=5.6,1H),3.78(t,J=5.6,1H),3.48-3.53(m,2H),1.21(s,3H);[MH+H]+m/z 315。对C11H14N4O5S·0.5H2O的分析计算值:C,40.86;H,4.68;N,17.33;S,9.92。测量值:C,40.78;H,4.90;N,16.94;S,9.87。
实施例9
制备5-氨基-2,3-二氢-2-硫代-3-β-D-呋喃核糖基-噻唑并[4,5-d]嘧啶-7(6H)-酮(33)
1)制备5-氨基-2,3-二氢-2-硫代-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃核糖基)噻唑并[4,5-d]嘧啶-7(6H)-酮(32)
a.BSA,TAR,MeCN,60℃;TMSOTf,60℃,80%.
混合杂环31[按照Robins等,J.Med.Chem.1990,33,407-415所述方法制备](150mg,0.75mmol)、TAR(214mg,0.675mmol)、MeCN(10mL)和BSA(0.55mL,2.25mmol),并于60℃加热1小时。然后,在反应物中加入TMSOTf(250mg,1.13mmol),并于60℃搅拌16小时。混合物通过旋转蒸发浓缩,将粗固体溶解在EtOAc(20mL)中。该有机相用饱和NaHCO3水溶液萃取(2×10mL),通过旋转蒸发浓缩至干。残余物用Et2O研碎(10mL),获得200mg(80%)固体物质,该固体物质通过HPLC进一步纯化(MeCN-H2O),产生分析纯的样品:1H NMR(400MHz,d6-DMSO)δ11.54(s,1H),7.04(br s,2H),6.59(m,1H),6.10(m,1H),5.70(t,J=12,1H),4.42(dd,J=12.0,3.2,1H),4.27(m,1H),4.18(m,1H),2.08(s,3H),2.05(s,3H),1.99(s,3H);[M+H]+m/z 459。对C16H18N4O8S2的分析计算值:C,41.92;H,3.96;N,12.22;S,13.99。测量值:C,41.78;H,3.99;N,12.02;S,13.72。
步骤2)制备5-氨基-2,3-二氢-2-硫代-3-β-D-呋喃核糖基-噻唑并[4,5-d]嘧啶-7(6H)-酮(33)
b.K2CO3,MeOH,室温,66%.
将核苷三酯32(100mg,0.21mmol)和K2CO3(42.7mg,0.31mmol)溶于MeOH(5mL),并在环境温度下搅拌16小时。在该混合物中加入HOAc(37mg,0.62mmol),通过旋转蒸发除去溶剂。然后,残余物经HPLC纯化(MeCN-H2O),获得47mg(66%)固体:1H NMR(400MHz,d6-DMSO)δ11.66(s,1H),6.91(br s,2H),6.47(s,1H),5.31(d,J=5.2,1H),4.94(s,1H),4.78(s,2H),4.27(d,J=8.0,1H),3.78(m,1H),3.69(m,1H),3.52(m,1H);[M+H]+m/z 333。对C10H12N4O5S2·0.5TFA·0.75H2O·0.25MeCN的分析计算值:C,33.43;H,3.60;N,14.41。测量值:C,33.11;H,3.73;N,14.80。
实施例10
5-氨基-2,3-二氢-2-硫代-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)噻唑并[4,5-d]嘧啶-7-(6H)-酮(34)
制备5-氨基-2,3-二氢-2-硫代-3-(2’,3’,5’)-三-O-乙酰基-β-D-呋喃木糖基)噻唑并[4,5-d]嘧啶-7-(6H)-酮(34)
a.BSA,四乙酰基呋喃木糖,MeCN,60℃,30分钟;TMSOtf,4小时,15%.
将杂环31(265.3mg,1.33mmol)、四乙酰基呋喃木糖(380mg,1.19mmol)、BSA(1.26mL,5.32mmol)和MeCN(10ml)加热至60℃保持30分钟。然后,在反应物中加入TMSOTf(0.36mL,2.0mmol)。4小时后,反应进行后处理:通过旋转蒸发除去溶剂,将粗固体溶解在乙酸乙酯(15mL)中。然后,该有机相用饱和碳酸氢钠萃取(2×10mL)。有机相浓缩,粗固体在1∶1EtOAc-己烷中研碎。收集固体并经HPLC纯化(MeCN-H2O),获得40mg(15%):1H NMR(400MHz,d6-DMSO)δ11.45(s,1H),6.90(br s,2H),6.49-6.58(m,1H),6.35-6.49(m,1H),5.58(d,J=5.6,1H),4.55(s,1H),4.31(m,2H),2.11(m,3H),1.99(m,3H),1.98(m,3H);[M+H]+m/z 459。对C16H18N4O8S2的分析计算值:C,41.92;H,3.96;N,12.22;S,13.99。测量值:C,42.14;H,3.99;N,12.11;S,14.01。
实施例11
5-氨基-3-β-D-呋喃核糖基-3H-噻唑并-[4,5-d]嘧啶-2-硫酮(39)
步骤1)制备5-氨基-3H-噻唑并[4,5-d]嘧啶-2-硫酮(37)
b.O-乙基黄原酸钾盐,DMF,30%.
5-溴-嘧啶-2,4-二胺(2.0g,10.58mmol)[按照类似于English et等,J.Am.Chem.Soc.1946,68,453-458中所述的方法制备]和O-乙基黄原酸钾盐(3.39g,21.16mmol)在DMF(25mL)中加热至140℃。5小时后,反应冷却至环境温度,加入25m水。然后,用1N HCl调节pH至5.0。形成红色沉淀,过滤收集该沉淀,获得900mg(30%)固体:1H NMR(400MHz,d6-DMSO)δ13.85(s,1H),8.33(br s,1H),6.90(s 2H)。
步骤2)制备5-氨基-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-硫酮(38)
c.TAR,BSA,CH3CN,TMSOTf,57%.
将5-氨基-3H-噻唑并[4,5-d]嘧啶-2-硫酮(250mg,1.36mmol)、TAR(389mg,1.22mmol)和BSA(1.0mL,4.08mmol)在乙腈(10mL)中加热至60℃。30分钟后,在反应中加入TMSOTf(0.37mL,2.04mmol),使反应进行16小时。溶剂通过旋转蒸发除去,将粗产物再溶于EtOAc(15mL)。有机相用浓NaHCO3水溶液萃取(2×10mL)。然后,有机相再次浓缩,并经过快速色谱纯化(SiO2,5%MeOH-EtOAc),获得301mg(57%)白色固体:1H NMR(400MHz,d6-DMSO)δ8.49(s,1H),7.08(br s,2H),6.65(s,1H),6.12(m,1H),5.79(t,J=8.0,1H),4.43(dd,J=12.0,3.6,1H),4.28-4.34(m,1H),4.17(dd,J=11.6,6.8,1H),2.09(s,3H),2.05(s,3H),1.97(s,3H);[M+H]+m/z 443。
步骤3)制备5-氨基-3-β-D-呋喃核糖基-3H-噻唑并-[4,5-d]嘧啶-2-硫酮(39)
d.K2CO3,MeOH,74%.
将5-氨基-3-(2’,3’,5’-三-O-乙酰基-^D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-硫酮(202mg,0.46mmol)溶解在MeOH(5mL),加入K2CO3(18.9mg,0.14mmol)。1小时后,加入乙酸(21mg,0.28mmol),反应物通过旋转蒸发浓缩。粗固体经HPLC纯化(MeCN-H2O),产生108mg(74%)白色固体:1H NMR(400MHz,d6-DMSO)δ8.45(s,1H),6.96(br s,2H),6.53(d,J=4.4,1H),5.33(d,J=6.0,1H),5.03(m,1H),4.86(d,J=6.4,1H),4.67(t,J=6.0,1H),4.33(m,1H),3.79(m,1H),3.70(m,1H),3.53(m,1H)。对C10H12N4O4S2·O.35H2O的分析计算值:C,37.22;H,3.97;N,17.36;S,19.87。测量值:C,37.64;H,3.87;N,17.02;S,19.39。
实施例12
5-氨基-3-β-D-呋喃木糖基-3H-噻唑并-[4,5-d]嘧啶-2-硫酮(41)
步骤1)制备5-氨基-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-硫酮(40)
e.四乙酰基呋喃木糖,BSA,MeCN,TMSOTf,13%.
将5-氨基-3H-噻唑并[4,5-d]嘧啶-2-硫酮(237mg,1.28mmol)、四乙酰基木糖(370mg,1.16mmol)和BSA(1.25mL,5.12mmol)在MeCN(10mL)中加热至60℃,持续30分钟。在该混合物中加入TMSOTf(347μL,1.92mmol),于60℃搅拌反应混合物16小时,然后通过旋转蒸发除去溶剂,粗固体再溶于EtOAc(15mL)。然后,该有机相用浓NaHCO3萃取(2×10mL),然后浓缩为固体残余物,该残余物经快速色谱纯化(0-100%EtOAc-CHCl3),获得67mg(13%)棕褐色固体:1H NMR(400MHz,d6-DMSO)δ8.51(s,1H),6.90(br s,2H),6.67(d,J=4.O,1H),6.49(t,J=2.0,1H),5.62(m,1H),5.63(m,1H),4.37(m,1H),4.21(br m,1H),2.18(s,3H),1.97(s,3H),1.94(s,3H);[MH+H]+m/z 443。
步骤2)制备5-氨基-3-β-D-呋喃木糖基-3H-噻唑并-[4,5-d]嘧啶2-硫酮(41)
f.K2CO3,MeOH,62%.
将5-氨基-2,3-二氢-2-硫代-3-(2,3,5-三-O-乙酰基-β-D-呋喃木糖基)噻唑并[4,5-d]嘧啶-7-硫酮(65mg,0.14mmol)溶于MeOH(5mL)。在该溶液中加入K2CO3(19mg,O.137mmol),搅拌所得混合物3小时,并用HOAc(140μL,2.4mmol)骤冷,通过旋转蒸发除去溶剂。粗产物经HOLC纯化(MeCN-H2O),获得30mg(62%)白色固体:1H NMR(400MHz,d6-DMSO)δ8.50(s,1H),6.90(br s,2H),6.45(d,J=5.2,1H),5.67(d,J=8.0,1H),5.49(d,J=8.4,1H),5.03(m,1H),4.49(t,J=5.2,1H),4.02(m,2H),3.72(m,2H)。对C10H12N4O4S2·O.4H2O的分析计算值:C,37.12;H,3.99;N,17.32;S,19.82。测量值:C,37.53;H,3.80;N,17.04;S,19.42。
实施例13
5-氨基-7-乙氧基-3-(2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(43)
步骤1)制备5-氨基-7-羟基-3-(2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(42)
a.1,2,5-三-O-乙酰基-β-D-呋喃核糖,BSA,MeCN,40℃;TMSOTf,80℃.
向杂环6(4.60g,25.00mmol)在无水MeCN(83.0mL)的混合物中滴加BSA(15.28mL,62.49mmol)。然后,将反应物浸在40℃油浴中,搅拌90分钟,加入1,2,5-三-O-乙酰基-β-D-呋喃核糖(5.42g,20.80mmol),再加入TMSOTf(5.65mL,31.24mmol)。将所得稠混合物浸在80℃油浴中,该混合物在15分钟后澄清为均相溶液。反应物于80℃搅拌2小时,冷却至室温,然后分配1M pH 7磷酸盐缓冲液(50mL)和EtOAc(100mL)之间。所得乳液通过硅藻土垫过滤,获得分离的两个独立层。有机层用Na2SO4干燥,过滤,真空浓缩为残余物。该残余物经快速色谱纯化(SiO2,0-6%MeOH-DCM),获得3.41g(43%)核苷42,为极细的淡黄色固体:1H(400MHz,DMSO-d6)δ11.22(s,1H),6.95(brs,2H),5.79(d,J=2.0,1H),5.59(d,J=7.2,1H),4.20-4.34(m,1H),4.22(dd,J=3.2,12.0,1H),3.99(dd,J=6.4,11.6,1H),2.57-2.67(m,1H),2.05(s,3H),1.99(s,3H),1.97-2.03(m,1H);[M+H]+m/z 385。对C14H16N4O7S的分析计算值:C,43.75;H,4.20;N,14.58;S,8.34。测量值:C,43.64;H,4.31;N,14.37;S,8.19。
步骤2)制备5-氨基-7-乙氧基-3-(2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(43)
b.EtOH,S-TPP,DEAD,THF,室温,20%.
向化合物42(99mg,0.26mmol)溶于无水THF(5.5mL)的溶液中加入S-TPPPPH3树脂(0.36g,0.77mmol,2.15mmol/g)。该化合物冷却至0℃,加入EtOH(30.1μL,0.52mmol),再加入DEAD(176.0μL,0.39mmol)。从冰浴中取出反应混合物,加热至室温,并搅拌16小时。反应混合物真空浓缩为残余物,该残余物经几次快速色谱后纯化(SiO2,用2%MeOH/0-40%EtOAc的己烷溶液洗脱),获得0.22mg化合物43(20%):1H(400MHz,DMSO-d6)δ6.95(br s,2H),5.87(d,J=2.4,1H),5.64(d,J=7.2,1H),4.39(q,J=6.8,2H),4.32-4.4(m,1H),4.25(dd,J=3.2,11.6,1H),3.96-4.03(m,1H),2.63-2.71(m,1H),2.05(s,3H),2.03-2.08(m,1H),1.99(s,3H),1.30(t,J=6.8,3H);[M+H]+m/z 413。
实施例14
5-氨基-7-乙氧基-3-(β-D-呋喃核糖基)-2,3-二氢-2-硫代-噻唑并[4,5-d]嘧啶-7(6H)-酮(45)
步骤1)制备5-氨基-7-乙氧基-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃核糖基)-2,3-二氢-2-硫代-噻唑并[4,5-d]嘧啶-7(6H)-酮(44)
c.S-TPP,乙醇,DEAD,THF,65%.
将5-氨基-2,3-二氢-2-硫代-3-(2,3,5-三-(9-乙酰基-β-D-呋喃核糖基)噻唑并[4,5-d]嘧啶-7(6H)-酮(250mg,0.54mmol)和S-TPP PH3P树脂(753mg,1.62mmol)悬液于THF(15mL)中,冷却至0℃。顺序加入乙醇(50μL,1.08mmol)和DEAD(148μL,0.82mmol)。1小时后,加热反应混合物至环境温度并搅拌16小时。然后过滤反应混合物,浓缩经快速色谱纯化(SiO2,15%EtOAc-CHCl3),获得200mg(65%)白色泡沫体:1H NMR(400MHz,d6-DMSO)δ6.91(s,1H),6.47(brs,2H),6.29(m,1H),6.18(s,1H),4.62-4.31(m,5H),1.42(t,J=4.2,3H),1.38(s,3H),1.35(s,3H),1.32(s,3H);[M+H]+m/z 487。
步骤2)制备5-氨基-7-乙氧基-3-β-D-呋喃核糖基-2,3-二氢-2-硫代-噻唑并[4,5-d]嘧啶-7(6H)-酮(45)
d.K2CO3,MeOH,83%.
将5-氨基-2,3-二氢-2-硫代-3-(2,3,5-三-O-乙酰基-β-D-呋喃核糖基)噻唑并-[4,5-d]嘧啶-7(6H)-乙醚(180mg,0.37mmol)和K2CO3(12.8mg,0.01mmol)悬浮于MeOH(5mL)。1小时后,加入乙酸,旋转蒸发除去溶剂。然后,粗产物经过HPLC纯化(MeCN-H2O),获得105mg(83%)固体:1H NMR(400MHz,d6-DMSO)δ6.98(s,2H),6.50(d,J=4.8,1H),5.32(d,J=5.2,1H),5.01(s,1H),4.85(d,J=5.6,1H),4.68(t,J=5.6,1H),4.43(dd,J=13.6,6.8,2H),4.30(m,1H),3.80(m,1H),3.71(m,1H),3.66(m,1H),1.31(t,J=6.8,3H);[M+H]+m/z 361。
制备5-氨基-3H-噁唑并[4,5-d]嘧啶-2-酮(50)
d.NaH,Im2C=O,DMF.
将2,4-二氨基-嘧啶-5-醇(500mg,3.97mmol)[按照Hull.J.Chem.Soc.1956,2033-2035中所述的方法制备]悬浮于DMF(10mL)。在该悬液连续加入NaH(86.7mg,3.77mmol)和CDI(707mg,4.36mmol),剧烈搅拌下在60℃加热反应混合物持续3小时。将化合物冷却至环境温度,然后用水骤冷(25mL)。通过旋转蒸发除去溶剂和水,然后,残余物在水(5mL)中研碎。固体通过过滤收集并干燥,获得230mg(38%):1H NMR(400MHz,d6-DMSO)δ11.90(br s,1H),7.72(br s,1H),6.72(s,2H);对C5H4N4O2·0.2H2O的分析计算值:C,38.56;H,2.85;N,35.98。测量值:C,39.01;H,2.71;N,35.58;[M+H]+m/z 153。
a.NaH,Im2C=S,DMF。b.BSA,适当β-D-呋喃核糖,MeCN,室温;TMSOTf,80℃。
c.K2CO3,MeOH,室温。d.NaH,Im2C=O,DMF.
二氨基羟基嘧啶46与NaH和CDI在DMF中反应,形成杂环50,或与NaH和TCDI在DMF中反应形成杂环47。两种氨基嘧啶47和50可以独立地与适当选择的β-D-呋喃核糖(其中,R1、R2和R3可以独立地是乙酰基或苯甲酰基)经BSA-TMSOTf参与的偶合反应,分别获得核苷48和51。核苷48和51经碱甲醇分解可分别制得脱保护的核苷49和52。
方案1
a)NaH,DMF,4小时,75℃
实施例15
制备5-氨基-3-吡啶-3-基甲基-3H-噻唑并[4,5-d]嘧啶-2-酮(54)
步骤1:制备5-氨基-3-吡啶-3-基甲基-3H-噻唑并[4,5-d]嘧啶-2-酮(54)
环境温度下,将5-氨基-3H-噻唑并[4,5-d]嘧啶-2-酮(107mg,0.64mmol)溶解在DMF(4mL)。加入氢化钠(30mg,1.32mmol),混合物加热至30℃。持续搅拌0.5小时后,加入3-溴甲基-吡啶溴化氢盐(179mg,0.71mmol)。然后,混合物加热至75℃,搅拌4小时。完成后,使反应物冷却至室温,然后浓缩。加入水(12mL)。所得的混合物用H2O(12mL)稀释,然后用乙酸乙酯萃取(3×5mL)。合并的有机层用盐水洗涤,用Na2SO4干燥,过滤和浓缩。粗产物通过柱色谱纯化(SiO2,20-50%EtOAc-CH2Cl2),产生90mg(54%)化合物54,为白色固体:1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.48(d,J=3.6,1H),8.32(s,1H),7.71(d,J=8.4,1H),7.36(m,1H),6.86(s,2H),5.04(s,2H);[M+H]+260.1。
实施例16
制备5-氨基-3-(6-氯-吡啶-3-基甲基)-3H-噻唑并[4,5-d]嘧啶-2-酮(55)
步骤1:制备5-氨基-3-(6-氯-吡啶-3-基甲基)-3H-噻唑并[4,5-d]嘧啶-2-酮(55)
按照类似于实施例15的步骤1的方式,获得111mg标题化合物55,产率为54%,为橙色固体:1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.30(s,1H),7.77(d,J=8.8,1H),7.47(d,J=8.0,1H),6.85(s,2H),5.11(s,2H);[M+H]+294.1。
实施例17
制备(Z)-5-氨基-3-(4-氯-2-丁烯-1-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(56)
步骤1:制备(Z)-5-氨基-3-(4-氯-2-丁烯-1-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(56)
按照类似于实施例15,步骤1的方式,获得74mg标题化合物56,产率为46%,为黄色固体:1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),6.80(s,2H),5.81(m,1H),5.66(m,1H),4.53(d,J=6.0,2H),4.27(d,J=8.0,2H);[M+H]+257.2。
实施例18
制备5-氨基-3-己基-3H-噻唑并[4,5-d]嘧啶-2-酮(57)
步骤1:制备5-氨基-3-己基-3H-噻唑并[4,5-d]嘧啶-2-酮(57)
按照类似于实施例15,步骤1的方式,制备51mg标题化合物57,产率为15%,为米色固体:1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),6.78(s,1H),3.82(t,J=7.2,2H),1.64(m,2H),1.27(m,6H),0.85(t,J=6.8,3H);[M+H]+]253.1。
实施例19
制备(±)-5-氨基-3-环戊基-3H-噻唑并[4,5-d]嘧啶-2-酮(58)
步骤1:制备(±)-5-氨基-3-环戊基-3H-噻唑并[4,5-d]嘧啶-2-酮(58)
按照类似于实施例15,步骤1的方式,制备21mg标题化合物58,产率为5%,为淡黄色固体:1H NMR(400MHz,CDCl3)δ8.09(s,1H),5.23(s,2H),2.24(m,1H),2.00(m,4H),1.66(m,4H);[M+H]+237.0。
实施例20
制备5-氨基-3-(4-硝基苯基)-3H-噻唑并[4,5-d]嘧啶-2-酮(59)
步骤1:制备5-氨基-3-(4-硝基苯基)-3H-噻唑并[4,5-d]嘧啶-2-酮(59)
按照类似于实施例15,步骤1的方式,制备45mg标题化合物59,产率为10%,为橙色固体:1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.18(d,J=9.2,2H),7.99(d,J=9.2,2H),5.74(s,2H);[M+H]+290.2。
实施例21
5-氨基-3-(2,3,5,6-四氟-吡啶-4-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(60)
步骤1:制备5-氨基-3-(2,3,5,6-四氟-吡啶-4-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(60)
按照实施例15,步骤1的方式,制备35mg标题化合物60,产率为5%,为橙色固体:1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),4.01(s,2H);[M+H]+318.4。
方案2
a)(E)-1,4-二氯-2-丁烯,NaH,DMF
b)0.1M HCI
实施例22
制备(E)-5-氨基-3-(4-氯-2-丁烯-1-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(62)
步骤1:制备(E)-5-氨基-3-(4-氯-2-丁烯-1-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(61)。
标题化合物61可以采用以下方法合成,5-氨基-3H-噻唑并[4,5-b]嘧啶-2-酮(1)在DMF中用氢化钠和(E)-1,4-二氯-2-丁烯在不同的条件下处理制得。
步骤2:制备(E)-5-氨基-3-(4-羟基-2-丁烯-1-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(62)
不同化合物62可以采用以下方法合成,(E)-5-氨基-3-(4-氯-2-丁烯-1-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(61)用0.1M HCl在不同条件下处理制得。
方案3
a)BSA,TMSOTf,CH3CN,80℃,3-4小时
b)K2CO3,DMF,室温,过夜
实施例23
制备(3’S)-5-氨基-3-(3’-脱氧-3’-羟基甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(65)
步骤1:制备(3’S)-5基-3-(3’-乙酰氧基甲基-2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(64)
环境温度下,将(3S)-3-O-乙酰氧基甲基-1,2,5-三-O-乙酰基-3-脱氧-α,β-D-呋喃核糖(63)[按照Cooperwood等人.Nucleotides,and Nucleic Acids2000,19,219-236中所述的方法制备,其中,制得相同化合物的对映体](176mg,0.53mmol)溶解在乙腈(7mL)。加入5-氨基-3H-噻唑并[4,5-d]嘧啶-2-酮(1)(89mg,0.53mmol),然后搅拌该混合物0.5小时,然后加热至40℃。5分钟后,于40℃,加入BSA(0.39mL,1.59mmol),再搅拌混合物0.5小时。然后加热该混合物至80℃。加入TMSOTf(0.14mL,0.80mmol),于80℃搅拌反应物3-4小时。完成后,将反应冷却至室温,然后用pH 7.0的缓冲液(1.0MK2HPO4和1.0M NaH2PO4,2ml)猝灭。混合物用CH2Cl2萃取(3×10mL)。合并的有机层用盐水洗涤,用Na2SO4干燥,真空浓缩。粗产物通过柱色谱纯化(SiO2,0-10%MeOH-CH2Cl2),获得77mg(33%)化合物64,为淡黄色的粉末固体:1HNMR(400MHz,CDCl3)δ8.14(s,1H),6.04(d,J=1.6,1H),5.90(dd,J=6.8,1.6,1H),5.24(s,2H),4.52(dd,J=12.0,2.8,1H),4.36(m,2H),4.17(m,2H),3.54(m,1H),2.18(s,9H);[M+H]+441.2;对C17H2ON4O8S·0.6H2O的元素分析:计算值:C,45.25;H,4.74;N,12.42;S,7.11;测量值:C,45.24;H,4.66;N,12.02;S,7.24。
步骤2:制备(3’S)-5-氨基-3-(3’-脱氧-3’-羟基甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(65)
环境温度下,将(3’S)-5-氨基-3-(3’-乙酰氧基甲基-2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮64(114mg,0.28mmol)溶解在甲醇(2mL)。加入碳酸钾(2mg,催化剂),室温下搅拌该混合物过夜。完成之后,加入乙酸(2μL),室温下再搅拌混合物30分钟。混合物浓缩,经HPLC纯化,然后用EtOAc研碎,获得79mg(90%)化合物65,为白色固体:1H NMR(400MHz,D2O)δ8.28(s,1H),6.10(m,1H),5.18(m,1H),4.20(m,1H),3.95(m,2H),3.78(m,2H),3.00(m,1H);[M+H]+315.2;对C11H14N4O5SO·0.3H2O·0.15iPrOH的元素分析:计算值:C,41.83;H,4.84;N,17.04;S,9.75;测量值:C,41.92;H,4.61;N,16.89;S,9.78。
实施例24
制备5-氨基-3-(5’-脱氧-5’-羟基甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(68)
步骤1:制备5-氨基-3-(5’-O-乙酰氧基甲基-2’,3’-二-O-乙酰基-5’-脱氧-β-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(67)
按照类似于实施例23,步骤1的方式,由5-O-乙酰氧基甲基-1,2,3-三-O-乙酰基-5-脱氧-α,β-D-呋喃核糖(66)[按照Pakulski等,Polish J.Chem.1995,69,912-917中所述的方法制备],制备113mg标题化合物67,产率为53%,为粘性黄色固体:1H NMR(400MHz,CDCl3)δ8.15(s,1H),6.34(m,1H),6.25(d,J=6.0,1H),6.11(d,J=4.0,1H),6.04(m,1H),5.76(t,J=6.0,1H),5.42(s,1H),4.93(m,1H),4.35(m,1H),4.21(q,J=5.6,1H),2.20(s,9H);[M+H]+441.2。
步骤2:制备5-氨基-3-(5’-脱氧-5’-羟基甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(68)
按照类似于实施例23,步骤2的方式,制备43mg标题化合物68,产率为71%,为白色固体:1H NMR(400MHz,d6-DMSO)δ8.33(s,1H),6.84(s,2H),5.86(d,J=4.4,1H),5.26(d,J=5.2,1H),4.93(m,1H),4.74(q,J=10.0,4.4,2H),4.40(m,1H),3.82(m,2H),1.76(m,3H);[M+H]+315.2;对C11H14N4O5S·0.4H2O·0.2iPrOH的元素分析:计算值:C,41.77;H,4.96;N,16.80;S,9.61;测量值:C,41.61;H,4.85;N,16.68;S,9.58。
实施例25
制备5-氨基-3-(3’-脱氧-3’-O-对-甲苯磺酰基-β-D-呋喃木糖基)-3H-噻唑并-[4,5-d]嘧啶-2-酮(73)
方案4
a)TsCl,py,室温,24小时
b)Ac2O,AcOH,H2SO4,室温,24小时
步骤1:制备1,2-O-异亚丙基-3-O-对-甲苯磺酰基-5-O-三苯甲基-β-D-呋喃木糖(70)
环境温度下,将1,2-O-异亚丙基-5-O-三苯甲基-β-D-呋喃木糖(69)[按照Johnston等,Tetrahedron Lett.1995,36,4341-4344中所述的方法制备](4.25g,9.83mmol)溶解在吡啶(60mL)中。在该溶液中加入对-甲苯磺酰基氯(2.81g,14.74mmol)。24小时之后,反应完全,粗混合物浓缩。残余物溶解在EtOAc(50niL)中,用饱和NH4Cl水溶液(25mL)、饱和NaHCO3水溶液(25mL)和盐水(25mL)洗涤。有机相用MgSO4干燥,过滤,然后浓缩。混合物通过ISCO色谱纯化(SiO2,2-15%EtOAc-己烷),获得5.20g(90%)化合物70,为白色固体:1H(400MHz,CDCl3)δ7.61(m,2H),7.32-7.34(m,6H),7.23-7.32(m,9H),5.92(d,J=4.4,1H),4.74(dd,J=11.2,3.6,2H),4.19-4.22(m,1H),3.45(dd,J=10.4,6.4,1H),3.05(q,J=5.2,1H),2.40(s,3H),1.49(s,3H),1.31(s,3H)。
步骤2:制备1,2,5-三-O-乙酰基-3-O-对-甲苯磺酰基-α,β-D-呋喃木糖(71)
环境温度下将1,2-O-异亚丙基-3-O-对-甲苯磺酰基-5-O-三苯甲基-β-D-呋喃木糖(70)(5.20g,8.86mmol)溶解在AcOH(60mL)。在该溶液中滴加乙酸酐(4.23mL,44.71mmol)。所得的混合物冷却至0℃,然后缓慢加入1MH2SO4(9.75mL,9.75mmol)。24小时后,反应完全,粗混合物浓缩,然后与甲苯共沸(2×20mL)。残余物溶解在CH2Cl2(50mL)中,用饱和NaHCO3水溶液洗涤(20mL)。有机相用MgSO4干燥,过滤,然后浓缩。该混合物然后通过ISCO色谱纯化(SiO2,2-40%EtOAc-己烷),获得3.09g(81%)化合物71,为无色油状物:1H(400MHz,CDl3)δ(α和β异构体的混合物)7.80-7.85(m),7.37-7.39(m),6.36(d,J=4.4),6.06(s),5.20-5.30(m),4.56-4.62(m),4.26-4.29(m),2.50(s),2.06-2.08(m)。
步骤3:制备5-氨基-3-[2’,5’-二-O-乙酰基-3’-脱氧-3’-O-p-甲苯磺酰基-β-D-呋喃木糖基]-3H-噻唑并-[4,5-d]嘧啶-2-酮(72)
按照类似于实施例23,步骤1的方式,制备161mg标题化合物72,产率为54%,为松散的黄色固体:1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.85(d,J=8.8,2H),7.39(d,J=8.8,2H),6.18(d,J=2.8,1H),5.90(br s,2H),5.77(d,J=4.4,1H),5.01(dd,J=6.4,5.2,1H),4.34(m,1H),4.27(m,2H),2.48(s,3H),2.04(s,6H);[M+H]+539.3。
步骤4:制备5-氨基-3-[3’-脱氧-3’-O-对-甲苯磺酰基-β-D-呋喃木糖基]-3H-噻唑并-[4,5-d]嘧啶-2-酮(73)
按照类似于实施例23,步骤2的方式,制备68mg标题化合物73,产率为61%,为白色固体:1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.83(d,J=8.0,2H),7.48(d,J=8.0,2H),6.80(s,2H),5.92(d,J=6.0,1H),5.71(d,J=6.4,1H),5.20(m,1H),4.89(q,J=5.6,3.6,1H),4.73(s,2H),4.10(m,2H),2.43(s,3H);[M+H]+455.2;对(C17H18N4O7S2·0.4H2O)的元素分析:计算值:C,44.22;H,4.10;N,12.14;S,13.89;测量值:C,44.45;H,4.15;N,12.07;S.13.71。
实施例26
制备5-氨基-3-(3’-脱氧-3’-亚甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(76)
步骤1:制备5-氨基-3-(2’-O-乙酰基-5’-O-苯甲酰基-3’-脱氧-3’-亚甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(75)
按照类似于实施例23,步骤1的方式,由1,2-二-O-乙酰基-5-O-苯甲酰基-3-脱氧-3-亚甲基-α,β-D-呋喃核糖(74)[按照Girardet等在J.Med.Chem.2000,43,3704-3713所述的方法制备],制备107mg标题化合物75,产率为85%,为黄色固体:1H NMR(400MHz,CDCl3)δ8.13(s,1H),8.05(dd,J=8.4,1.2,2H),7.57(tt,J=7.2,1.2,1H),7.44(t,J=7.2,2H),6.51(m,1H),6.17(d,J=4.4,1H),5.30(s,2H),5.11(m,2H),4.82(dd,J=11.6,4.8,2H),4.52(dd,J=11.6,6.8,1H),2.14(s,3H);[M+H]+443.2。
步骤2:制备5-氨基-3-(3’-脱氧-3’-亚甲基-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(76)
按照类似于实施例23,步骤2的方式,制备35mg标题化合物76,产率为35%,为灰白色固体:1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),5.83(d,J=5.6,1H),5.74(d,J=7.6,1H),5.51(m,2H),5.19(d,J=11.2,2H),4.72(t,J=6.0,1H),4.54(br s,2H),3.85(s,2H);[MH+H]+297,2;对(C11H12N4O4S·0.2H2O·0.25iPrOH)的元素分析:计算值:C,44.81;H,4.61;N,17.79;S,10.18;测量值:C,44.84;H,4.33;N,17.76;S,10.22。
实施例27
制备(3’R)-5-氨基-3-(3’-脱氧-3’-氟-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(79)
步骤1:制备(3’R)-5-氨基-3-(2’-O-乙酰基-5’-O-苯甲酰基-3’-脱氧-3’-氟-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(78)
按照类似于实施例23,步骤1的方式,由1,2-二-O-乙酰基-5-O-苯甲酰基-3-脱氧-3-(R)-氟-α,β-D-呋喃木糖(77)[按照Gosselin等在CarbohydrateResearch 1993,249,1-17中所述的方法制备],制备148mg标题化合物78,产率为56%,为淡黄色固体:1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.05(d,J=8.8,2H),7.57(t,J=7.6,1H),7.44(t,J=8.0,2H),6.29(ddd,J=21.2,4.8,1.2,1H),5.98(d,J=4.8,1H),5.32(ddd,J=52.0,4.0,1.2,1H),5.20(s,1H),4.83(dd,J=11.2,4.8,1H),4.61(m,1H),2.00(s,3H);[M+H]+449.3。
步骤2:(3’R)-5-氨基-3-(3’-脱氧-3’-氟-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(79)
按照类似于实施例23,步骤2的方式,制备43mg标题化合物79,产率为56%,为黄色固体:1H NMR(400MHz,DMSO-d6)δ·8.36(s,1H),6.87(s,2H),5.97(d,J=4.8,1H),5.73(d,J=5.6,1H),5.22(dtd,J=24.4,5.6,2.0,1H),5.02(ddd,J=52.8,4.4,1.6,1H),4.07(m,2H),3.62(m,2H);[M+H]+303.6。
实施例28
制备(3’S)-5-氨基-3-(2’,5’-二-O-乙酰基-3’-叠氮基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(83)
方案5
a)Tf2O,py,CH2Cl2,-10℃,0.5小时
b)NaN3,py,DMF,室温,5d
c)Ac2O,AcOH,H2SO4,室温,24小时
步骤1:制备(3R)-3-叠氮基-3-脱氧-1,2-O-异亚丙基-5-O-三苯甲基-β-D-呋喃核糖(81)
环境温度下,将1,2-O-异亚丙基-5-O-三苯甲基-β-D-呋喃木糖(69)[按照Johnston等在Tetrahedron Lett.1995,36,4341-4344中所述的方法制备](3.28g,7.58mmol)溶解在CH2Cl2(75mL),然后冷却至-10℃。在该溶液中加入吡啶(0.86mL,10.61mmol),再缓慢加入三氟甲磺酸酐(1.53mL,9.10mmol)。于-10℃搅拌1小时后,通过缓慢添加5%NaHSO3(150mL)使反应猝灭,然后加热至室温。然后分离各层,含水相再用CH2Cl2萃取(2×75mL)。有机层合并,用MgSO4干燥,然后过滤和浓缩。残余物与甲苯共沸(2×10mL),然后高真空干燥,获得三氟甲磺酸酯(triflate)80。
环境温度下,将三氟甲磺酸酯80溶解在DMF(100mL)中。在该溶液中加入吡啶(0.92mL,11.37mmol),再加入叠氮化钠(1.97g,30.32mmol)。5小时后,反应完全,粗混合物浓缩。残余物溶解在EtOAc(60mL),用饱和NH4Cl水溶液洗涤(40mL)。有机层用MgSO4干燥,过滤和浓缩。然后,混合物通过ISCO色谱纯化(SiO2,2-15%EtOAc-己烷),获得1.80g(52%,对第二步骤)化合物81,为白色固体:1H(400MHz,CDCl3)δ7.44-7.47(m,6H),7.26-7.32(m,6H),7.24-7.25(m,3H),5.90(d,J=3.6,1H),4.77(t,J=4.4,1H),4.18-4.22(m,1H),3.66(q,J=6.0,1H),3.52(dd,J=10.4,3.2,1H),3.20(dd,J=10.8,4.0,1H),1.59(s,3H),1.40(s,3H)。
步骤2:制备(3R)-1,2,5-三-O-乙酰基-3-叠氮基-3-脱氧-α,β-D-呋喃核糖(82)
环境温度下,将(3R)-3-叠氮基-3-脱氧-1,2-O-异亚丙基-5-O-三苯甲基-β-D-呋喃核糖(81)(1.20g,2.62mmol)溶解在AcOH(30mL)中。在该溶液中滴加乙酸酐(1.24mL,13.10mmol)。所得的混合物冷却至0℃,再加入1MH2SO4(2.88mL,2.88mmol)。24小时后,反应完成,粗混合物浓缩,然后与甲苯共沸(2×10mL)。残余物溶解在CH2Cl2(30mL)中,用饱和NaHCO3水溶液洗涤(20mL)。有机相用MgSO4干燥,过滤和浓缩。然后,混合物通过ISCO色谱纯化(SiO2,2-40%EtOAc-己烷),获得0.66g(83%)化合物82,为无色油状物:1H(400MHz,CDCl3)δ(α,β异构体的混合物)6.43(d,J=4.4),6.14(s),5.34(d,J=4.8),5.21(dd,J=7.6),4.20-4.37(m),4.04-4.10(m),2.10-2.20(m)。
步骤3:制备(3’R)-5-氨基-3-(2’,5’-二-O-乙酰基-3’-叠氮基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(83)
按照类似于实施例23,步骤1的方式,制备288mg标题化合物83,产率为85%,为橙色固体:1H NMR(400MHz,CDCl3)δ8.17(s,1H),6.18(d,J=2.4,1H),5.95(dd,J=6.4,2.8,1H),5.14(s,2H),4.61(m,1H),4.24(dd,J=12.0,5.2,1H),4.17(m,2H),2.12(s,6H);[M+H]+410.4。
方案6
a)Tf2O,py,CH2Cl2,0℃,0.5小时;氯脒碱,NaH,CH3CN,室温,50℃,12小时
b)NaIO4,OsO4,CH3OH/H2O;NaBH4,CH3OH
c)Zn-Cu,AcOH
d)2M HCl,CH3OH
实施例29
制备(1’R,2’S,3’R,4’R)-N’-[7-氯-2-氧代-3-(2’,3’-O-异亚丙基-4’-乙烯基-环戊烷-1’-基)-2,3-二氢-噻唑并[4,5-d]嘧啶-5-基]-N,N-二甲基-甲脒(88)
步骤1:制备(1’R,2’S,3’R,4’R)-N’-[7-氯-2-氧代-3-(2’,3’-O-异亚丙基-4’-乙烯基-环戊烷-1’-基)-2,3-二氢-噻唑并[4,5-d]嘧啶-5-基]-N,N-二甲基-甲脒(85)
环境温度下,将(1R,2S,3R,4R)-2,3-O-异亚丙基-4-乙烯基-环戊烷-1-醇(84)[按照Yang等在J.Org.Chem.2004,69,3993-3996中所述的方法制备](96mg,0.52mmol)溶解在CH2Cl2(2mL)和吡啶(10mL)。将该溶液冷却至0℃,再缓慢加入三氟甲磺酸酐(115μL,0.68mmol)。0.5小时后,反应完成,该反应用H2O(10mL)猝灭,然后用CH2Cl2(10mL)稀释。分离各层后,含水相用CH2Cl2(2×10mL)进一步洗涤。合并有机部分,用MgSO4干燥,过滤然后浓缩。所得的黄色油状物可以直接用于下一步骤。
环境温度下,将上面的三氟甲磺酸酯(131mg,0.51mmol)悬浮于CH3CN(10mL)。在该悬液中加入氢化钠(15mg,0.62mmol),再加入N’-[7-氯-2-氧代-2,3-二氢-噻唑并[4,5-d]嘧啶-5-基]N,N-二甲基-甲脒(氯脒碱,160mg,0.62mmol)的CH3CN(8mL)溶液。于50℃搅拌反应物12小时,然后添加H2O(5mL)进行猝灭。所得的混合物用EtOAc萃取(3×20mL)。有机部分合并,用MgSO4干燥,过滤然后浓缩。然后,混合物通过柱色谱纯化(SiO2,2-20%EtOAc-己烷),获得94.8mg(43%)化合物85,为白色固体:1H(400MHz,CDCl3)δ8.63(s,1H),5.92(m,1H),5.09-5.29(m,4H),4.55-4.61(m,1H),3.23(s,3H),3.21(s,3H),2.65-2.77(m,1H),2.42-2.51(m,1H),2.18-2.22(m,1H),1.56(s,3H),1.29(s,3H);[M+H]+424.1。
步骤2:制备(1’R,2’S,3’R,4’R)-5-氨基-7-氯-3-(2’,3’-O-异亚丙基-4’-羟基甲基-环戊烷-1’-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(86)
标题化合物86可采用以下方法制备,首先(1’R,2’S,3’R,4’R)-N’-[7-氯-2-氧代-3-(2’,3’-O-异亚丙基-4’-乙烯基-环戊烷-5-基)-2,3-二氢-噻唑并[4,5-d]嘧啶-5-基]-N,N-二甲基-甲脒(85)在CH3OH和H2O中用高碘酸钠和四氧化锇处理。然后,粗产物用硼氢化钠在CH3OH中处理,获得化合物86。
步骤3:制备(1’R,2’S,3’R,4’R)-5-氨基-3-(2’,3’-O-异亚丙基-4’-羟基甲基-环戊烷-1’-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(87)
标题化合物可以采用以下方法制备,(1’R,2’S,3’R,4’R)-5-氨基-7-氯-3-(2’,3’-O-异亚丙基-4’-羟基甲基-环戊烷-1’-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(86)在AcOH中用锌铜对在不同条件下处理制备。
步骤4:制备(1’R,2’S,3’R,4’R)-5-氨基-3-(2’,3’-二氧-4’-羟基甲基-环戊烷-1’-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(88)
标题化合物88可以采用以下方法制备,(1’R,2’S,3’R,4’R)-5-氨基-3-(2’,3’-O-异亚丙基-4’-羟基甲基-环戊烷-1’-基)-3H-噻唑并[4,5-d]嘧啶-2-酮(87)在CH3OH中用2M HCl在不同条件进行处理制备。
实施例30
制备5-氨基-3-(3’-(R)-甲氧基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(89)
如下制备所需的糖,即乙酸1,2,5-三-O-乙酰基-3)-甲氧基-D-呋喃木糖α和β的混合物(91):
a.NaH,THF,CH3I
b.H2SO4,AcOH-Ac2O
步骤1:制备1,2-O-异亚丙基-3-甲氧基-5-O-三苯甲基-D-呋喃木糖(90)
三苯甲醇69(5g,11.57mmol)与碘甲烷(2.5ml;34.7mmol)在THF(40ml)中混合。加入碘化四丁铵(427mg),混合物在冰浴中冷却。在缓慢氮气流中,分成小份加入固体氢化钠-油混合物(1.33g,60%NaH,34.7mmol)。在缓慢升温至环境温度的同时搅拌反应物过夜。将反应物小心倒入饱和氯化铵和冰中,用乙醚萃取三次。合并醚部分,用盐水洗涤,干燥(MgSO4),过滤并蒸发溶剂,获得化合物90,为混浊的油状物。1H NMR(400MHz,CDCl3)δ7.42 7.42(m,6H),7.26(m,9H),5.85(d,J=3.6Hz,1H),4.54(d,J=3.6Hz,1H),4.38(m,1H),3.785(d,J=3.2Hz,1H),3.42(m,1H),3.35(m,4H),1.53(s,3H),1.336(s,3H)。
步骤2:1,2,5-三-O-乙酰基-3-甲氧基-D-呋喃木糖α和β混合物(91)
将三苯甲基化合物90(6.1g,11.57mmol)溶解在乙酸(20ml)和乙酸酐(10ml)的混合物中并且在冰水浴中冷却。加入硫酸在乙酸酐和乙酸中的混合物(0.5ml硫酸,2.5ml乙酸,2.5ml乙酸酐,在添加之前在冰浴中过冷),环境温度下搅拌该混合物过夜。将反应物倒入400g冰水中,用乙酸乙酯萃取三次。合并有机部分,用饱和碳酸氢钠洗涤,干燥(MgSO4),过滤和组分,获得半固体。该半固体采用快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(10-100%)纯化,获得化合物91(1.26g,4.34mmol,38%),为端基异构体的油状混合物。1H NMR(400MHz,CSCl3)δ6.39(d,J=4.4Hz),6.17(s),4.4-4.52(m),4.3-4.39(m),4.1-4.24(m),3.86(d,J=5.6Hz),3.45(s),3.41(s),2.07-2.16(m)。
步骤3:制备5-氨基-3-(3’-甲氧基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(89)
按照类似于实施例23,步骤1的方式,使用1,2,5-三-O-乙酰基-3-甲氧基-D-呋喃木糖α和β混合物(91),获得43mg(6%)化合物89,为白色固体:1HNMR(DMSO-d6)δ2.01(d,J=9.2Hz,6H),3.36(s,3H),4.17-4.24(m,2H),4.31-4.37(m,2H),5.86(d,J=6Hz,1H),6.14(dd,J=4.4,1.6Hz,1H),6.85(br s,2H),8.35(s,1H);MS(ESI)[(M+H)+]399.96,对(C15H18N4O7S·0.5H2O)的元素分析:计算值:C,44.22;H,4.70;N,13.75。测量值:C,44.27;H,4.54;N,13.60。
实施例31
制备5-氨基-3-(3’-辛氧基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶2-酮(92)
如下制备所需糖,即乙酸1,2,5-三-O-乙酰基-3(S)-辛氧基-D-呋喃木糖α和β的混合物(94):
a.NaH,THF,辛基溴
b.H2SO4,AcOH-Ac2O
步骤1:制备1,2-O-异亚丙基-3-辛氧基-S-O-三苯甲基-D-呋喃木糖(5)
三苯甲醇69(5g,11.57mmol)与辛基溴(3.99ml,23.14mmol)在THF(40ml)中混合。加入碘化四丁铵(427mg),混合物在冰浴中冷却。在缓慢氮气流下,分批加入固体氢化钠-油混合物(1.33g,60%NaH,34.7mmol)。缓慢加热至环境温度的同时搅拌反应混合物过夜。将反应物小心倒入饱和氯化铵和冰的混合物中,用乙醚萃取三次。合并醚部分,用盐水洗涤,干燥(MgSO4),过滤并蒸发溶剂,获得混浊油状物。该油状物通过快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(10-30%)纯化,获得化合物93,为清澈的油状物(2.37g,4.72mmol,41%)。1H NMR(400MHz,CDCl3)δ7.427.42(m,6H),7.26(m,9H),5.85(d,J=3.6Hz,1H),4.50(d,J=3.6Hz,1H),4.343(m,1H),3.86(d,J=3.6Hz,1H),3.45(m,2H),3.32(m,2H),1.54(m,3H),1.41(m,2H),1.33(s,3H),1.22(m,10H),0.889(t,J=6.8Hz,3H)。
步骤2:乙酸1,2,5-三-O-乙酰基-3-辛氧基-D-呋喃木糖α和β的混合物(94)
三苯甲基化合物93(4.12g,7.57mmol)溶解在乙酸(35ml)和乙酸酐(15ml)的混合物中,在冰水浴中冷却。加入硫酸在乙酸酐和乙酸中的混合物(0.5ml硫酸,2ml乙酸,2ml乙酸酐,添加之前在冰浴中预冷却),在环境温度搅拌混合物过夜。将反应物倒入400g冰水中,用乙酸乙酯萃取三次。合并有机部分,用饱和碳酸氢钠洗涤,干燥(MgSO4),过滤并蒸发,获得半固体。该半固体采用快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(5-60%)纯化,获得混合物94(1.12grams,2.88mmol,38%),为端基异构体的油状混合物。1H NMR(400MHz,CDCl3)δ6.39(d,J=3.6Hz),6.1(s),5.19(m),4.46-4.52(m),4.31-4.43(m),4.11-4.25(m),3.93(m),3.45-3.68(m),3.4-3.46(m),2.07-2.1(m),1.540(m),1.27(m),0.882(t,J=6.8Hz)。
步骤3:制备5-氨基-3-(3’-辛氧基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(92)
按照类似于实施例23,步骤1的方式,使用乙酸1,2,5-三-O-乙酰基-3-辛氧基-D-呋喃木糖α和β的混合物(94)制备,获得80mg(11%)化合物92,为松散白色固体:1H NMR(400MHz DMSO-d6)δ0.84-0.88(m,3H),1.23-1.30(m,10H),1.49-1.52(m,2H),2.00(s,3H),2.02(s,3H),3.41-3.44(m,1H),3.57-3.59(m,1H),4.16-4.21(m,1H),4.30-4.37(m,3H),5.87(d,J=5.6,1H),6.12(dd,J=4.4,1.2Hz,1H),6.85(br s,2H),8.35(s,1H);MS(ESI)[(M+H)+]测量值497.40。对(C22H32N4O7S)的元素分析:C,53.21;H,6.50;N,11.28。测量值:C,53.52;H,6.49;N,11.21。
实施例32
制备5-氨基-3-(3’-(R)-(2-甲氧基-乙氧基),2’,5’-二-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(95)
如下制备所需糖,即乙酸1,2,5-三-O-乙酰基-3-(2-甲氧基-乙氧基)-D-呋喃木糖α和β的混合物(98):
a.NaH,THF,2-溴乙基甲醚
b.乙酰基溴,Ac2O,
c.H2SO4,AcOH-Ac2O
步骤1:1,2-O-异亚丙基-3-(2-甲氧基-乙氧基)-5-O-三苯甲基-D-呋喃木糖(96)
三苯甲醇69(5g,11.57mmol)和2-溴乙基甲醚(2.17ml,23.14mmol)在THF(40ml)中混合。加入碘化四丁铵(427mg),混合物在冰浴中冷却。在缓慢氮气流下,分批加入固体氢化钠-油混合物(1.33g,60%NaH,34.7mmol)。缓慢加热至环境温度的同时搅拌反应物过夜。将反应物小心倒入饱和氯化铵和冰的混合物中,用乙醚萃取三次。合并醚部分,用盐水洗涤,干燥(MgSO4),过滤并蒸发溶剂,获得混浊油状物。该油状物通过快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(3-30%)纯化。分离醚产物96为稠的油状物(4.54g,9.26mmol,80%)。1H NMR(400MHz,CDCl3)δ7.42(m,6H),7.26(m,9H),5.86(d,J=3.6Hz,1H),4.54(d,J=4Hz,1H),4.37(m,1H),4.35(m,1H),3.95(d,J=2.8Hz,1H),3.64-3.68(m,1H),3.47-3.52(m,2H),3.29-3.33(m,2H),3.24(s,3H)1.53(s,3H),1.326(s,3H).
步骤2:1,2-O-异亚丙基-3-(2-甲氧基-乙氧基)-5-O-乙酰基-D-呋喃木糖(97)
将三苯甲醚96(5.5g,11.22mmol)溶解在乙酸酐(30ml)中,加入乙酰基溴(2.0ml,22.4mmol)。1小时后,过滤反应物,滤液蒸发至干。残余物采用快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(10-100%)纯化,获得1.54g(5.31mmol,47%)乙酸酯97。1H NMR(400MHz,CDCl3)δ5.925(d,J=3.6Hz,1H),4.58(d,J=3.6Hz,1H),4.38(m,2H),4.23(m,1H),3.92(d,J=3.6Hz,1H),3.72(m,1H),3.60(m,1H),3.50(m,2H),3.35(s,3H),2.08(s,3H),1.49(s,3H),1.32(s,3H)。
步骤3:乙酸1,2,5-三-O-乙酰基-3-(2-甲氧基-乙氧基)-D-呋喃木糖α和β的混合物(98)
将乙酸酯97(1.71克,5.89mmol)溶解在乙酸酐和乙酸的混合物(1∶4,30ml)中,并在冰浴中冷却。加入硫酸乙酸的溶液(125μL H2SO4在1.0ml乙酸酐中),将混合物维持在-10℃过夜。将该冷溶液倒入80g冰中,静置20分钟,用乙酸乙酯萃取三次。合并有机部分,用盐水洗涤,干燥(MgSO4),过滤并除去溶剂,获得1.94g粗产物。粗产物采用快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(10-75%)纯化,获得760mg(2.27mmol,38%)混合物98,为端基异构体的混合物。1H NMR(400MHz,CDCl3)δ6.40(d,J=4.4Hz),6.10(s),5.21(m),4.47-4.54(m),4.33-4.45(m),4.16-4.27(m),4.03(m),3.72-3.85(m),3.6-3.7(m),3.48-3.54(m),3.35-3.48(m),2.06-2.11(m)。
步骤4:制备5-氨基-3-(3’-(2-甲氧基-乙氧基),2’,5’-二-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(95)
按照类似于实施例23,步骤1的方式,使用乙酸1,2,5-三-O-乙酰基-3-(2-甲氧基-乙氧基)-D-呋喃木糖α和β的混合物(98),获得220mg(42%)化合物95,为松散白色固体:1H NMR(400MHz DMSO-d6)δ2.04(d,J=8.4Hz,6H),3.29(s,3H),3.49-3.52(m,2H),3.58-3.63(m,1H),3.76-3.81(m,1H),4.19-4.24(m,1H),4.36-4.43(m,3H),5.88(d,J=6Hz,1H),6.18(dd,J=3.6,2Hz,1H),6.87(brs,2H),8.38(s,1H);MS(ESI)[(M+H)+]测量值443.31。对(C17H22N4O85·0.1H2O·0.2EtOAc)的元素分析:C,46.29;H,5.19;N,12.13。测量值:C,46.09;H,5.25;N,11.72。
实施例33
制备5-氨基-3-(3’-丁氧基-α-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶2-酮(99)
如下制备所需糖,即乙酸1,2,5-三-O-乙酰基-3-丁氧基-D-呋喃木糖α和β的混合物(101):
a.NaH,THF,正丁基碘b.H2SO4,AcOH-Ac2O
步骤1:制备1,2-O-异亚丙基-3-丁氧基-5-O-乙酰基-D-呋喃木糖(100)
三苯甲醇69(5g,11.57mmol)与正丁基碘(2.6ml,23.14mmol)在THF(40ml)中混合。加入碘化四丁铵(427mg),混合物在冰浴中冷却。在缓慢氮气流体下,分批加入固体氢化钠-油混合物(1.33g,60%NaH,34.7mmol)。缓慢加热至环境温度的同时搅拌反应物过夜。将反应物小心倒入饱和氯化铵和冰的混合物中,用乙醚除去三次。合并醚部分,用盐水洗涤,干燥(MgSO4),过滤并且蒸发溶剂,获得一混浊油状物。该油状物通过快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(1-30%)纯化,获得化合物100,为清澈油状物(2.32g,4.75mmol,41%)。1H NMR(400MHz,CDCl3)δ7.42(m,6H),7.26(m,9H),5.86(d,J=3.6Hz,1H),4.51(d,J=3.6Hz,1H),4.35(m,1H),3.86(d,J=3.6Hz,1H),3.46(m,2H),3.29(m,2H),1.54(m,3H),1.38(m,2H),1.33(s,3H),1.23(m,2H),0.83(t,J=7.6Hz,3H)。
步骤2:制备乙酸1,2,5-三-O-乙酰基-3-丁氧基-D-呋喃木糖α和β的混合物(101)
将三苯甲基化合物100(2.32g,4.75mmol)溶解在5%乙酸酐的乙酸(50ml)溶液,在冰水浴中冷却,加入0.02ml硫酸,在环境温度搅拌混合物过夜。将该反应混合物倒在150g冰上,用二氯甲烷萃取三次。有机部分干燥(MgSO4)、过滤,并与甲苯干燥,获得3.19g半固体。该半固体采用快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(5-75%)纯化,获得混合物101(0.760g,2.29mmol,48%),为端基异构体的油状混合物。1H NMR(400MHz,CDCl3)66.38(d,J=3.6Hz),6.11(s),5.2(m),4.50(m),4.31-4.42(m),4.13-4.25(m),3.93(d,J=3.6Hz),3.5-3.7(m),3.4-3.47(m),2.06-2.15(m),1.51-1.55(m),1.3-1.4(m),0.89-0.94(m)。
步骤3:制备5-氨基-3-(3’)-丁氧基-2’,5’-二-O-乙酰基-α-D-呋喃木糖基]-3H-噻唑并[4,5-d]嘧啶-2-酮(102)
按照类似于实施例23,步骤1的方式,使用乙酸1,2,5-三-O-乙酰基-3-丁氧基-D-呋喃木糖α和β的混合物(101),获得40mg(8%)化合物102,为白色固体。不经纯化用于步骤2。
步骤2:制备5-氨基-3-(3’-丁氧基-α-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(99)
按照类似于实施例23,步骤2的方式,使用102,获得5mg(15%)化合物99,为白色固体:1H NMR(400MHz,(CDCl3)δ0.84(t,J=7.2Hz,3H),1.27-1.32(m,2H),1.51-1.54(m,2H),3.20(t,J=9.2Hz,1H),3.35(t,J=10.8Hz,1H),3.72-3.84(m,3H),3.97-4.01(m,1H),4.74(t,J=9.2Hz,1H),5.17(br s,2H),5.38(d,J=9.2Hz,1H),7.96(s,1H);MS(ESI)[(M+H)+]测量值356.80。
实施例34
制备5-氨基-3-(3’-甲基2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(103)
如下制备所需糖,即1,2,3,5-四-O-乙酰基-3(S)-甲基-D-呋喃木糖α和β的混合物(105):
a.i.Ac2O,吡啶,ii.H2SO4,Ac2O-AcOH
步骤1:1,2,3,5-四-O-乙酰基-3-甲基D-呋喃木糖α和β的混合物(105)
将二醇104[按照Lu和Just在Tetrahedron Letters 41(2000)9223-9227中所述方法制备](1.69g,8.28mmol)溶解在二氯甲烷(25ml)中,加入吡啶(4.7ml)。乙酸酐(3.9ml,41mmol)与DMAP(50mg)一起加入,该混合物于环境温度搅拌过夜。反应物用二氯甲烷稀释,用饱和氯化铵洗涤。含水相用二氯甲烷萃取两次以上,合并有机部分,干燥(MgSO4),干燥并蒸发,获得无色油状物。将该油状物溶解在5%乙酸酐的乙酸(68ml)溶液中,加入硫酸(0.02ml),于环境温度搅拌过夜。将反应物倒在冰上,用饱和碳酸氢钠萃取两次,干燥(MgSO4),过滤并蒸发,获得2.84g油状物。残余物采用快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(5-75%)纯化,获得1.2g(3.61mmol,44%)化合物105,为清澈的油状物,其谱图与端基混合物一致。1H NMR(400MHz,CDCl3)δ6.41(d,J=4.8Hz),6.03(d,J=1.2Hz),5.75(d,J=0.8Hz),5.49(d,J=5.2Hz),4.37-4.45(m),4.2-4.29(m),2.03-2.135(m),1.637S),1.624(s)。
步骤2:制备5-氨基-3-(3’-甲基,2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(103)
按照类似于实施例23,步骤1的方式,使用1,2,3,5四-O-乙酰基-3-甲基D-呋喃木糖α和β的混合物(105),获得170mg(28%)化合物103,为白色固体:1H NMR(400MHz DMSO-d6)δ1.57(s,3H),2.03(s,6H),2.07(s,3H),4.04(dd,J=8.0,2.8Hz,1H),4.24(m,1H),4.41(dd,J=12.0,2.8Hz,1H),5.73(d,J=4.8Hz,1H),6.24(d,J=4.4Hz,1H),6.89(br s,2H),8.36(s,1H);MS(ESI)[(M+H)+]测量值441.08。对(C17H2ON4O8S·0.3H2O)的元素分析:C,45.80;H,4.66;N,12.57。测量值:C,45.84;H,4.50;N,12.47。
实施例35
制备5-氨基-3-(5’-(1,2-二乙酰氧基-乙基),2’,3’-二-O-乙酰基-β-D-呋喃葡糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(106)
如下制备所需糖,即五-O-乙酰基呋喃葡糖(108)。
a.H2SO4,Ac2O-AcOH
步骤1:五-O-乙酰基呋喃葡糖(108)
将1,2-O-异亚丙基-α-D-呋喃葡糖(107)(5g,22.7mmol)溶解在乙酸(180ml)和乙酸酐(21.5ml)中,在冰水浴中冷却,加入硫酸(0.02ml,98%),环境温度下搅拌混合物24小时。将混合物倒在冰上,加入水,该混合物用二氯甲烷萃取两次。合并有机部分,用饱和碳酸氢钠洗涤两次,干燥(MgSO4),过滤,获得油状残余物。该残余物在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(20-100%)纯化,获得5.33g(13.66mmol,60%)化合物18,为油状物,其谱图与端基异构体混合物一致。1H NMR(400MHz,CDCl3)δ6.41(d,J=3.6Hz),6.12(s),5.58(m),5.41(d,J=3.6Hz),5.20-5.37(m),4.56-4.62(m),4.02-4.18(m),2.00-2.13(m)。
步骤2:制备5-氨基-3-(5’-(1,2-二乙酰氧基-乙基),2’,3’-二-O-乙酰基-β-D-呋喃葡糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(106)。
按照类似于实施例23,步骤1的方式,使用五-O-乙酰基呋喃葡糖(108)制备,获得80mg(9%)化合物106,为白色固体:1H NMR(400MHz CDCl3)δ2.07(s,6H),2.09(s,3H),2.14(s,3H),4.03-4.07(m,1H),4.47(dd,J=6.4,2Hz,1H),4.67(dd,J=12.4,2.0Hz,1H),5.31(br s,2H),5.58-5.6(m,1H),5.68(m,1H),5.97(d,J=5.6Hz,1H),6.10(dd,J=3.6,2Hz,1H),8.16(s,1H);MS(ESI)[(M+H)+]测量值499.40。对(C19H22N4O10S·0.1IPA)元素分析:C,45.95;H,4.56;N,11.11。测量值:C,45.92;H,4.76;N,10.80。
实施例36
制备5-氨基-3-(3’-乙酰氧基甲基-,2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(109)
如下制备所需的糖,即四-O-乙酰基-S-乙酰氧基甲基-D-呋喃木糖α和β的混合物(113):
a.NaOH,二噁烷 b.乙酸酐,吡啶,c.H2SO4,Ac2O-AcOH
步骤1:1,2-O-异亚丙基-3(S)-(羟基-羟基甲基)-D-呋喃木糖(111)
环氧化物110[按照Lu和Just在Tetrahedron Letters 41(2000)9223-9227中所述方法制备](1.68g,8.3mmol)溶解在二噁烷(9ml),加入1.0M NaOH(16.6ml,16.6mmol),加热反应至50℃持续30分钟。将反应冷却至环境温度,加入16.6ml 1.0M HCl和100ml无水乙醇,搅拌5分钟,该混合物真空蒸发为固体。将该固体悬浮于200ml CH2Cl2,进行超声处理,获得极细固体的悬液。该悬液干燥(MgSO4),通过硅藻土过滤并蒸发,获得化合物111,为稠油状物(1.81g,8.22mmol,99%)。1H NMR(400MHz,CDC13)δ5.94(d,J=3.6Hz,1H),4.4(d,J=4Hz,2H),4.03(m,2H),3.83(d,J=11.6,1H),3.78(d,J=12Hz,1H),2.66(bs,2H,OH),1.7(bs,1H,OH),1.52(s,3H),1.33(s,3H)。
步骤2:1,2-O-异亚丙基-3-(乙酰氧基-甲基乙酰氧基)-5-O-乙酰基-D-呋喃木糖(112)
将三醇111(1.81g,8.22mmol)溶解在吡啶(30ml)中,加入乙酸酐(7.75ml,82mmol),再加入DMAP(50mg),搅拌该混合物72小时。真空蒸发挥发组分,将残余物分配在二氯甲烷和饱和氯化铵之间。含水相用二氯甲烷萃取两次,合并有机部分,干燥(MgSO4),过滤并蒸发溶剂,获得2-83g油状物。残余物采用快速色谱在120g硅胶柱上以乙酸乙酯的己烷溶液的梯度液洗脱(10-80%)纯化,获得1.82g(5.26mmol,64%)化合物112,为清澈的油状物。1H NMR(400MHz,CDCl3)55.92(d,J=3.6Hz,1H),5.02(m,2H),4.51-4.58(m,2H),4.35(dd,J=8.4Hz,J=2.8Hz,1H),4.16-4.22(m,1H),2.10(s,3H),2.09(s,3H),2.08(s,3H),1.53(s,3H),1.32(s,3H)。
步骤3:四-O-乙酰基-3-(乙酰氧基甲基)D-呋喃木糖,α和β的混合物(113)
将三乙酸酯112(1.74g,5.01mmol)溶解在乙酸(45ml),加入乙酸酐(2.37ml,25mmol),再加入硫酸的乙酸溶液(0.5ml的1.0M溶液,0.5mmol),在环境温度搅拌该混合物过夜。反应物用二氯甲烷(70ml)稀释,用水洗涤。水层用二氯甲烷萃取两次。合并有机部分,转移到大的烧杯中,加入饱和碳酸氢钠。在烧杯中加入固体碳酸氢钠,直到观察不到气泡。分离有机相,用二氯甲烷萃取含水相,合并有机相并干燥(MgSO4),过滤并蒸发,获得油状物,该油状物用甲苯进一步干燥,获得化合物113,为清澈的油状物(1.91g,3.89mmol,97%),其NMR与端基异构体的化合物一致。1H NMR(400MHz,CDCl3)δ6.42(d,J=4.4Hz),6.05(d,J=1.6Hz),5.79(d,J=I.6Hz),5.5(d,J=4.4Hz),4.89-4.93(m),4.12-4.58(m),2.04-2.2(许多单峰)。
步骤4:制备5-氨基-3-(3’-乙酰氧基甲基-,2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(109)
按照类似于实施例23,步骤1的方式,使用四-O-乙酰基-3-乙酰氧基甲基-D-呋喃木糖α和β的混合物(113),获得272mg(37%)化合物109,为白色固体:1H NMR(400MHz(DMSO-d6)δ2.03(s,3H),2.05(s,3H),2.07(s,3H),2.09(s,3H),4.20(m,1H),4.44-4.57(m,3H),4.79(d,J=12.4Hz,1H),5.84(d,J=5.6Hz,1H),6.38(d,J=6Hz,1H),6.87(br s,2H),8.37(s,1H);MS(ESI)[(M+H)+]测量值499.12。对(C19H22N4O10S·0.1H2O)元素分析:C,45.61;H,4.47;N,11.20。测量值:C,45.93;H,4.44;N,10.83。
实施例37
制备5-氨基-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(114)
步骤1:制备5-氨基-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮(114)
按照类似于实施例23,步骤1的方式,使用市售的四-O-乙酰基呋喃木糖制备,获得110mg(14%)化合物114,为白色固体:1H NMR(400MHz(CDCl3)δ2.08(s,3H),2.10(s,3H),2.18(s,3H),4.42-4.45(m,2H),4.52-4.56(m,1H),5.13(br s,2H),5.49(dd,J=3.6,2.4Hz,1H),6.00(d,J=5.2Hz,1H),6.22(dd,J=4,1.6Hz,1H),8.15(s,1H);MS(ESI)[(M+H)+]测量值426.93。对(C16H18N4O8S)元素分析:C,45.07;H,4.25;N,13.14。测量值:C,44.86;H,4.17;N,13.05。
实施例38
5-氨基-3-(3’-C-甲基-β-D-呋喃核糖基)噻唑并[4,5-d]嘧啶-2,7(3H,6H)-二酮(117)
步骤1)制备5-氨基-3-(3’-O-乙酰基-2’,5’-二-O-苯甲酰基-3’-C-甲基-β-D-呋喃核糖基)噻唑并[4,5-d]嘧啶-2,7(3H,6H)-二酮(116)
a.BSA,MeCN,室温,1小时;+糖,TMSOTf,60℃,1小时,45%.
在环境温度下,将5-氨基-3H,6H-噻唑并[4,5-d]嘧啶(116mg,0.631mmol)、3’-C-甲基-呋喃核糖11(272mg,0.598mmol)[按照Giradet等在Med.Chem.2000,43,3704-3713中所述的方法制备]、BSA(0.462ml,1.89mmol)和乙腈(5mL)剧烈混合40分钟。获得均相溶液后,在反应物中加入TMSOTf(0.171mL,210mg)。然后,加入反应至60℃。1小时后,通过旋转蒸发除去溶剂。将所得固体溶解在乙酸乙酯(10mL)中,用饱和碳酸氢钠萃取(2×5mL)。然后,含水相用乙酸乙酯(5mL)反萃取,有机层合并。固体杂质迅速从有机相沉淀,滤出沉淀物丢弃。有机相浓缩,然后将所得固体在醚(5mL)中研碎,获得167mg(45%)棕褐色固体:1H NMR(400MHz,d6-DMSO)δ12.2(br s,1H),8.01(m,4H),7.83(m,2H),7.53(m,4H),7.28(br s,2H),6.4(m,1H),6.02(m,1H),4.82-4.67(m,2H),3.38(s,1H),2.01(s,3H),1.98(s,3H);[M+H]+m/z581。
步骤2)制备5-氨基-3-(3’-C-甲基-β-D-呋喃核糖基)噻唑并[4,5-d]嘧啶-2,7(3H,6H)-二酮(117)
b.K2CO3,MeOH,室温,74%.
将核苷三酯116(100mg,0.172mmol)溶解在甲醇(5mL),加入K2CO3(28.6mg,0.207mmol)。反应进行16小时。该反应物用乙酸(24.8mg,0.412mmol)中和。然后,旋转真空除去溶剂,固体经HPLC纯化(MeCN-H2O),获得42mg(74%)白色固体:1H NMR(400MHz,d6-DMSO)δ11.20(s,1H),6.89(br s,2H),5.80(d,J=8.0,1H),5.36(d,J=6.0,1H),4.77(t,J=8.0,1H),4.62(s,1H),4.48(m,1H),3.75(m,1H),3.58-3.44(m,2H),1.19(s,3H);对C14H14N4O6S·0.125H2O·0.125HCO2H分析计算值:C,39.33;H,4.34;N,16.43;S,9.40。测量值:C,39.77;H,4.81;N,15.02;S,9.69;[M+H]+m/z 331。
实施例39
5-氨基-3-(2’-C-甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(120)
步骤1)制备5-氨基-3-(2’,3’,5’-三-O-苯甲酰基-2’-C-甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(1119)
a.BSA,MeCN,80℃,2.5小时;+糖,SnCl4,80℃,1.5小时,42%.
室温下,向杂环4(268mg,1.44mmol)在无水MeCN(8mL)的悬液中加入BSA(971μL,3.93mmol)。加热所得混合物至80℃持续2.5小时,并加入2-C-甲基-β-D-呋喃核糖118[按照Wolfe等在J,Org.Chem.1997,62,1754-1759中所述的方法制备](760mg,1.31mmol)在MeCN(6mL)的溶液。在该混合物中加入SnCl4(276μL,2.35mmol),于80℃再持续搅拌1.5小时。用10%MeOH-CHCl3的TLC分析表明反应完成。混合物冷却至室温,用EtOAc稀释(150mL),用1∶1的盐水-NaHCO3混合物分配。含水相再用EtOAc(50mL)萃取,合并的有机相用Na2SO4干燥,过滤并浓缩。残余物经HPLC纯化(SiO2,0-4%MeOH-DCM),获得353mg(42%)白色固本:1H(400MHz,DMSO-d6)δ11.3(br s,1H),7.93-8.08(brm,3H),7.85-7.87(m,2H),7.33-7.66(m,10H),6.97(br s,2H),6.64(s,1H),6.16-6.26(br m,1H),4.56-4.79(br m,3H),1.79(s,3H);M+m/z 642。
步骤2)制备5-氨基-3-(2’-C-甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(120)
b.NH3(g),MeOH,室温,34%.
在一个密封管中,于-30℃,用NH3(气体)饱和的核苷三酯119(209mg,0.325mmol)和MeOH(10mL)的混合物搅拌48小时。将混合物升温至室温,减压,浓缩,然后经HPLC纯化(MeCN-H2O),获得36mg(34%)标题化合物,冻干后为白色固体:1H(400MHz,DMSO-d6)δ11.18(s,1H),6.92(br s,2H),5.95(s,1H),5.18-5.28(br m,1H),4.75(br s,1H),4.53(dd,J=11.3,5.46,1H),3.95(br s,1H),3.73-3.78(m,1H),3.29(br s,2H),1.04(s,3H);[M+H]+m/z 331。
实施例40
5-氨基-3-(3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(122)
步骤1)制备5-氨基-3-(2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(121)
a.BSA,MeCN,室温,1小时;+糖,TMSOTf,60℃,1小时,45%.
室温下,向杂环6(4.60g,25.0mmol)和脱氧呋喃核糖HB(5.42g,20.8mmol)在MeCN(83mL)的悬液中加入BSA(15.3mL,62.5mmol)。将所得混合物浸在40℃油浴中1.5小时,并滴加TMSOTf(5.65mL,31.2mmol)。将该稠反应混合物浸入80℃油浴中,搅拌2.5小时,然后通过旋转蒸发浓缩为残余物,该残余物分配在EtOAc(300mL)和pH 7缓冲液(100mL)之间。有机相用Na2SO4干燥并浓缩为残余物,该残余物用EtOAc研碎,然后过滤,获得2.31g(29%)白色细固体。滤液浓缩为残余物,该残余物经快速色谱纯化(SiO2,0-6%MeOH-DCM),获得1.12g(14%)极细的淡黄色固体。总之,核苷121的合并产率为43%:1H(400MHz,DMSO-d6)δ11.23(s,1H),6.95(br s,2H),5.79(d,J=2.0,1H),5.59(d,J=7.2,1H),4.28-4.34(m,1H),4.22(dd,J=3.2,12.0,1H),3.99(dd,J=6.4,11.6,1H),2.56-2.65(m,1H),2.04(s,3H),1.98(s,3H),1.97-2.04(m,1H);[M+H]+m/z 384.8。对C14H16N4O7S·0.5H2O的分析计算值:C,42.74;H,4.36;N,14.24;S,8.15。测量值:C,42.72;H,4.22;N,14.15;S,8.19。
步骤2)制备5-氨基-3-(3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(122)
b.K2CO3,MeOH,室温,74%.
室温下,向核苷二酯121(1.91g,4.97mmol)在MeOH(50mL)的悬液中加入K2CO3(820mg,5.97mmol)。搅拌反应混合物18小时,然后用HOAc(0.68mL,12mmol)猝灭,搅拌30分钟,最后通过旋转蒸发浓缩。残余物与甲苯(3×50mL)共沸,然后用水研碎(250mL)。过滤该固体物质,用水洗涤(2×250mL),空气干燥,用醚研碎(250mL),过滤后提供1.17g(62%)核苷122,为米色固体:1H(400MHz,DMSO-d6)6 11.26(br s,1H),6.93(br s,1H)7.14(d,J=2.4,1H),5.39(d,J=4.4,1H),4.74-4.79(m,1H),4.65(t,J=5.6,1H),4.09-4.16(m,1H),3.41-3.43(m,2H),2.23-2.30(m,1H),1.78(ddd,J=2.4,6.4,8.4,1H)1.76-1.81(m,1H);[M+H]+m/z 301.5。对C10H12N4O5S·1.25H2O的分析计算值:C,37.20;H,4.53;N,17.36;S,9.93。测量值:C,37.06;H,4.27;N,17.14;S,9.84。
实施例41
5-氨基-3-(2’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(130)
步骤1)制备5-N-乙酰基-氨基-3-(β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮
向四乙酸艾沙托立宾(isatoribine tetraacetate)123[CAS#533897-42-6,按照Webber等在美国专利6,924,271中所述制备](12.3g,25.4mmol)在MeOH(180mL)的悬液中加入浓NH4OH(180mL)。搅拌所得混合物1小时,并浓缩,经快速色谱纯化(SiO2,15-30%IPA-CHCl3),获得2.50g(27%)乙酰氨124,为白色固体:[M+H]+m/z 359。
步骤2)制备5-N-乙酰基-氨基-3-(5’-O-叔丁基二甲基甲硅烷基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮
室温下,向三醇124(2.48g,6.93mmol)的DMF(15mL)溶液中顺序加入咪唑(943mg,13.9mmol)和TBSCl(1.04g,6.93mmol)。搅拌所得混合物1小时,然后用EtOAc稀释(300mL),用水(2×100mL)然后是盐水(100mL)萃取。有机相用Na2SO4干燥,浓缩,并用醚研碎,获得2.18g(67%)硅氧烷125,为米色固体:1H(400MHz,DMSO-d6)δ12.16(br s,1H),11.81(br s,1H),5.81(d,J=4.77,1H),5.34(d,J=5.13,1H),5.03(d,J=5.50,1H),4.79(dd,J=10.3,5.13,1H),4.13(dd,J=10.6,5.5,1H),3.71-3.78(m,2H),3.40-3.64(m,1H),2.18(s,3H),0.84(s,9H),0.00(s,6H);[M+H]+m/z 473。
步骤3)制备5-N-乙酰基-氨基-3-(5’-O-叔丁基二甲基甲硅烷基-2’,3’-硫代-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮
室温下,向二醇125(1.00g,2.12mmol)的MeCN(50mL)溶液中加入TCDI(754mg,4.23mmol)。搅拌所得混合物18小时,然后浓缩,经快速色谱纯化(SiO2,40%EtOAc-CHCl3),用醚研碎,获得730mg(67%)白色固体:1H(400MHz,DMSO-d6)δ12.18(br s,1H),11.75(br s,1H),6.21-6.24(m,2H),5.79(brs,1H),4.35(br s,1H),3.72(br d,J=6.6,2H),2.21(s,3H),0.84(s,9H),0.01(s,6H);[M+H]+m/z 515。
步骤4)制备5-N-乙酰基-氨基-3-(5’-O-叔丁基二甲基甲硅烷基-2’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮
室温下,向硫代碳酸酯126(712mg,1.38mmol)和Bu3SnH(2.66mL,10.0mmol)在无水甲苯(140mL)的悬液中加入AIBN(30mg,0.18mmol)。将混合物浸在130℃油浴中15分钟,然后取出,冷却,浓缩并经快速色谱纯化(SiO2,80-100%EtOAc-CHCl3),获得450mg(71%)2’-脱氧和3’-脱氧区域异构体(regioisomer)的混合物(2∶1)(报告主要的异构体):1H(400MHz,DMSO-d6)δ12.12(br s,1H),11.82(br s,1H),6.26(t,J=7.0,1H),5.22(d,J=4.0,1H),4.31-4.34(m,1H),3.69-3.75(m,2H),3.57-3.62(m,1H),2.93-2.99(m,1H),2.18(s,3H),2.00-2.18(m,1H),0.84(s,9H),0.00(s,6H);[M+H]+m/z 457。
步骤5)制备5-N-乙酰基-氨基-3-(2’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮
室温下,向上面步骤4获得的区域异构体(744mg,1.60mmol)在MeCN(30mL)的悬液中加入48%HF水溶液(1.67mL)。搅拌反应混合物1小时,然后浓缩为紫色残余物,该残余物经快速色谱纯化(SiO2,1.5-15%MeOH-DCM),获得503mg(92%)区域异构体的混合物,该混合物可通过HPLC纯化(MeCN-H2O),获得169mg(31%)核苷129,经冻干后为白色固体:1H(400MHz,DMSO-d6)612.14(s,1H),11.85(s,1H),6.26(t,J=7.0,1H),4.30-4.32(m,1H),3.69-3.71(m,1H),3.38-3.53(m,4H),2.92-2.98(m,1H),2.19(s,3H),1.97-2.03(s,1H);[M+H]+m/z343。
步骤6)制备5-氨基-3-(2’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮
室温下,向乙酰氨129(169mg,0.494mmol)在MeOH(10mL)的悬液中加入K2CO3(158mg,1.14mmol)。搅拌所得的混合物8小时,然后用HOAc猝灭(137μL,2.40mmol),浓缩并经HPLC纯化(MeCN-H2O),获得125mg(84%)标题化合物130,经冻干后为白色固体:1H(400MHz,DMSO-d6)δ11.16(s,1H),6.90(br s,2H),6.22(t,J=7.0,1H),4.27-4.31(m,1H),3.67-3.71(m,1H),3.52(dd,J=11.3,5.5,1H),3.40(dd,J=11.7,6.2,1H),2.86-2.93(m,1H),1.97(ddd,J=12.9,7.0,3.5,1H);[M+H]+m/z 301。对C10H12N4O5S·H2O分析计算值:C,37.73;H,4.43;N,17.60;S,10.07。测量值:C,38.13;H,4.27;N,17.40;S,9.89。
方案7
a)BSA,TMSOTf,CH3CN,80℃,3-4小时
b)K2CO3,DMF,室温,过夜
实施例42
制备5-氨基-3-(3’-脱氧-3’-亚甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(132)
步骤1:制备5-氨基-3-(2’-O-乙酰基-5’-O-苯甲酰基-3’-脱氧-3’-亚甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(131)
环境温度下,将1,2-二-O-乙酰基-5-O-苯甲酰基-3-脱氧-3-亚甲基(methylidene)-α,β-D-呋喃核糖(127)(132mg,0.39mmol)[按照Girardet等在J.Med.Chem.2000,43,3704-3713中所述的方法制备]溶解在乙腈(5mL)中。加入5-氨基-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(1)(73mg,0.39mmol),然后搅拌混合物0.5小时,之后加热至40℃。5分钟后,于40℃,加入BSA(0.29mL,1.18mmol),再搅拌混合物0.5小时。然后,加热混合物至80℃。加入TMSOTf(0.107mL,0.59mmol),于80℃搅拌反应物3-4小时。完成后,使反应冷却至室温,然后用pH 7.0的缓冲液猝灭(1.0M K2HPO4和1.0M NaH2PO4,2ml)。混合物用CH2Cl2萃取(3×10mL)。合并的有机层用盐水洗涤,用Na2SO4干燥,真空浓缩。粗产物通过柱色谱纯化(SiO2,0-10%MeOH-CH2Cl2),获得23mg(13%)化合物131,为淡黄色固体:1H NMR(400MHz,CDCl3)69.85(s,1H),8.03(d,7=8,2H),7.54(m,1H),7.417(t,J=8,2H),6.50(s,2H),6.07(d,J=4.8,1H),5.73(m,1H),5.37(d,J=32,2H),4.83(m,2H),4.46(m,1H),2.00(s,3H);[M+H]+459.3;对C20H18N4O7S·O.7EtOAc的元素分析:计算值:C,52.65;H,4.57;N,10.77;S,6.16;测量值:C,53.59;H,4.57;N,10.83;S,6.17。
步骤2:制备(3’S)-5-氨基-3-(3’-脱氧-3’-亚甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(132)
环境温度下,将(3’S)-5-氨基-3-(3’-乙酰氧基甲基-2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H-噻唑并[4,5-d]嘧啶-2-酮131(113mg,0.25mmol)溶解在甲醇(5mL)中。加入碳酸钾(38mg,0.27mmol),室温搅拌混合物过夜。完成后,加入乙酸(34μL),室温下再搅拌混合物30分钟。混合物浓缩,通过HPLC纯化,然后用EtOAc研碎,获得49mg(64%)化合物132,为白色固体:1H NMR(400MHz,DMSO-d6)δ11.563(s,1H),6.82(s,2H),5.80(m,1H),5.62(m,1H),5.16(d,J=14.4,2H),4.51(m,1H),3.53(m,2H),1.89(s,2H);[M+H]+313.07。
实施例43
制备5-氨基-3-(2’,3’,5’-三-羟基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(134)
步骤1:制备5-氨基-3-(2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(133)
按照类似于实施例42,步骤1的方式,所有市售四-O-乙酰基呋喃木糖,制得740mg标题化合物133,产率为20%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.32(s,1H),6.98(br s,2H),6.09(dd,J=8.6,2.3Hz,1H),5.76(d,J=5.5Hz,1H),5.38(dd,J=8.6,2.3Hz,1H),4.14(m,1H),4.26(m,1H),4.16(m,1H),2.08(s,3H),2.04(s,3H),2.00(s,3H);[M+H]+442.8;对C16H18N4O9S·1.0OH2O元素分析:计算值:C,41.74;H,4.38;N,12.17;测量值:C,41.92;H,4.23;N,11.71。
步骤2:制备5-氨基-3-(2’,3’,5’-三-羟基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(134)
按照类似于实施例42,步骤2的方式,制得43mg标题化合物134,产率为67%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.24(br s,1H),6.86(br s,2H),5.60(d,J=4.68Hz,1H),5.57(d,J=4.68Hz,1H),5.04(d,J=7.8Hz,1H),4.64(m,1H),4.41(m,1H),3.87(m,2H),3.54(m,2H);[M+H]+316.9;对C11H14N4O5S·1.3H2O的元素分析:计算值:C,35.35;H,4.33;N,16.49;测量值:C,35.73;H,4.21;N,16.15。
实施例44
制备5-氨基-3-(3’-(R)-辛氧基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(135)
按照实施例31所述,制备所需糖,即乙酸1,2,5-三-O-乙酰基-3(S)-辛氧基-D-呋喃木糖α和β的混合物(94)。
步骤1:制备5-氨基-3-(3’-(R)-辛氧基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶2-酮(135)
按照类似于实施例42,步骤1的方式,由乙酸1,2,5-三-O-乙酰基-3(S)-辛氧基-D-呋喃木糖α和β的混合物(94),制备18.8mg标题化合物135,产率为2%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.21(s,1H),6.94(br s,2H),6.12(m,1H),5.74(d,J=6.2Hz,1H),4.30(m,3H),4.16(m,1H),3.57(m,1H),3.41(m,1H),2.02(d,J=8.6Hz,6H),1.50(m,2H),1.26(m,10H),0.86(m,3H);[M+H]+512.9;对C22H32N4O8S的元素分析:计算值:C,51.55;H,6.29;N,10.93;测量值:C,51.47;H,6.37;N,10.77。
实施例45
制备5-氨基-3-(3’-(R)-甲氧基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(137)
按照实施例30所述,制备所需糖,即乙酸1,2,5-三-O-乙酰基-3)-甲氧基-D-呋喃木糖α和β的混合物(91)。
步骤1:制备5-氨基-3-(3’-(R)-甲氧基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(136)
按照类似于实施例42,步骤1的方式,由乙酸1,2,5-三-O-乙酰基-3)-甲氧基-D-呋喃木糖α和β的混合物(91),制得230mg标题化合物136,产率为31%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.21(s,1H),6.94(br s,2H),6.14(m,1H),5.74(d,J=6.2Hz,1H),4.33(m,2H),4.18(m,2H),3.35(s,3H),3.30(s,3H),2.04(s,3H),2.01(s,3H);[M+H]+414.8;对C15H18N4O8S的元素分析:计算值:C,43.48;H,4.38;N,13.52;测量值:C,43.12;H,4.36;N,13.17。
步骤2:制备5-氨基-3-(3’-(R)-甲氧基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(137)
按照类似于实施例42,步骤2的方式,制得43mg标题化合物137,产率为29%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.50(br s,1H),6.98(br s,2H),5.68(d,J=5.5Hz,1H),5.60(d,J=7.8Hz,1H),5.10(m,1H),4.48(m,1H),4.08(m,1H),3.84(m,1H),3.57(m,2H),3.35(s,3H);[M+H]+330.9;对C11H14N4O6S·0.7H2O·0.1iPrOH的元素分析:计算值:C,38.89;H,4.68;N,16.06;测量值:C,38.78;H,4.30;N,15.84。
实施例46
制备5-氨基-3-(3’-(R)-(2-甲氧基-乙氧基),2’,5’-二-羟基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(139)
按照实施例32所述,制备所需的糖,即乙酸1,2,5-三-O-乙酰基-3-(2-甲氧基-乙氧基)-D-呋喃木糖α和β的混合物(98)。
步骤1:制备5-氨基-3-(3’-(R)-(2-甲氧基-乙氧基),2’,5’-二-O-乙酰基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(138)
按照类似于实施例42,步骤1的方式,由乙酸1,2,5-三-O-乙酰基-3-(2-甲氧基-乙氧基)-D-呋喃木糖α和β的混合物(98),制得118mg标题化合物138,产率为21%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.23(s,1H),6.90(brs,2H),6.13(m,1H),5.74(d,J=6.24Hz,1H),4.33(m,3H),4.17(m,1H),3.73(m,1H),3.57(m,1H),3.46(m,2H),3.25(s,3H),2.03(s,3H),2.01(s,3H);[M+H]+459.3;对C17H22N4O9S·0.3H2O·0.5EtOAc的元素分析:计算值:C,44.93;H,5.28;N,11.03;测量值:C,44.93;H,5.01;N,11.14。
步骤2:制备5-氨基-3-(3’-(R)-(2-甲氧基-乙氧基),2’,5’-二-羟基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(139)
按照类似于实施例42,步骤2的方式,制得43mg标题化合物139,产率为36%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.44(br s,1H),6.97(br s,2H),5.67(d,J=5.46Hz,1H),5.60(d,J=7.8Hz,1H),5.10(m,1H),4.39(m,1H),4.08(m,1H),3.98(m,1H),3.71(m,1H),3.59(m,3H),3.45(m,2H),3.27(s,3H);[M+H]+374.9;对C13H18N4O7S·1.OH2O·0.25EtOAc的元素分析:计算值:C,40.57;H,5.35;N,13.52测量值:C,40.81;H,4.96;N,13.40。
实施例47
制备5-氨基-3-(3’-(S)-甲基,2’,3’,5’-三-羟基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(141)
按照实施例34所述,制备所需的糖,即1,2,3,5四-O-乙酰基-3(S)-甲基D-呋喃木糖α和β的混合物(105)。
步骤1:制备5-氨基-3-(3’-(S)-甲基,2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(140)
按照类似于实施例42,步骤1的方式,由1,2,3,5四-O-乙酰基-3(S)-甲基D-呋喃木糖α和3的混合物(105),制得110mg标题化合物140,产率为15%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.27(br s,1H),6.98(br s,2H),6.25(d,J=4.68Hz,1H),5.77(d,J=4.68Hz,1H),4.40(dd,J=9.4,3.1Hz,1H),4.22(m,1H),3.68(dd,J=4.7,3.1Hz,1H),2.08(s,3H),2.04(s,3H),2.02(s,3H),1.56(s,3H);[M+H]+456.8;对C17H2ON4O9S·0.5H2O·0.2iPrOH的元素分析:计算值:C,44.27;H,4.77;N,11.73;测量值:C,44.45;H,4.55;N,11.62。
步骤2:制备5-氨基-3-(3’-(S)-甲基,2’,3’,5’-三-羟基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(141)
按照类似于实施例42,步骤2的方式,制得31mg标题化合物141,产率为54%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.36(br s,1H),6.94(br s,2H),5.70(d,J=5.46Hz,1H),5.58(d,J=4.7Hz,1H),5.09(br s,1H),4.48(m,2H),3.59(m,3H),1.17(s,3H);[M+H]+330.9;对C11H14N4O6S·1.1H2O的元素分析:计算值:C,37.73;H,4.66;N,16.00;测量值:C,37.66;H,4.22;N,15.60。
实施例48
制备5-氨基-3-(5’-(1,2-二乙酰氧基-乙基),2’,3’-二-羟基-β-D-呋喃葡糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(143)
按照实施例35中所述,制备所需的糖,即五-O-乙酰基呋喃葡糖(108)。
步骤1:制备5-氨基-3-(5’-(1,2-二乙酰氧基-乙基),2’,3’-二-O-乙酰基-β-D-呋喃葡糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(142)
按照类似于实施例42,步骤1的方式,由五-O-乙酰基呋喃葡糖(108)制备100mg标题化合物142,产率为10%,为白色固体:1H NMR(400MHz,CDCl3)δ5.91(m,1H),5.81(br s,2H),5.73(d,J=6.2Hz,1H),5.51(m,1H),5.41(m,1H),4.55(dd,J=12.5,2.3Hz,1H),4.29(t,J=7.02Hz,1H),3.90(m,1H),1.96(s,3H),1.93(s,3H),1.90(s,3H),1.55(br s,1H);[M+H]+515.3;对C19H22N4O11S·0.15MeOH元素分析:计算值:C,44.29;H,4.39;N,10.79;测量值:C,44.69;H,4.44;N,10.41。
步骤2:制备5-氨基-3-(5’-(1,2-二乙酰氧基-乙基),2’,3’-二-羟基-β-D-呋喃葡糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(143)
按照类似于实施例42,步骤2的方式,制得45mg标题化合物143,产率为83%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.34(br s,1H),6.96(br s,2H),5.72(d,J=4.7Hz,1H),5.63(d,J=3.12Hz,1H),5.11(d,J=9.4Hz,1H),4.56(m,2H),4.39(t,J=5.46Hz,1H),3.96(m,1H),3.74(m,2H),3.51(m,1H),3.36(m,1H);[M+H]+346.9;对C11H14N4O7S·1.0H2O元素分析:计算值:C,36.26;H,4.43;N,15.38;测量值:C,36.20;H,4.37;N,15.01。
实施例49
制备5-氨基-3-(3’-(S)-乙酰氧基甲基-,2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(144)
按照实施例36所述,制备所需的糖,即四-O-乙酰基-3-乙酰氧基-D-呋喃木糖α和β的混合物(113)。
步骤1:制备5-氨基-3-(3’-(S)-乙酰氧基甲基-,2’,3’,5’-三-O-乙酰基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶2-酮(144)
按照类似于实施例42,步骤1的方式,由四-O-乙酰基-3-乙酰氧基甲基-D-呋喃木糖α和β的混合物(113),制得80mg标题化合物144,产率为13%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.23(s,1H),6.93(br s,2H),6.37(d,J=5.46Hz,1H),5.69(d,J=5.46Hz,1H),4.77(d,J=11.7Hz,1H),4.52(m,3H),4.39(dd,J=7.8,1.6Hz,1H),4.17(dd J=7.8,3.9Hz,1H),2.08(s,3H),2.06(s,3H),2.05(s,3H),2.03(s,3H);[M+H]+514.8;对C19H22N4O11S元素分析:计算值:C,44.36;H,4.31;N,10.89;测量值:C,44.16;H,4.37;N,10.69。
实施例50
制备5-氨基-3-(3’-(R)-丁氧基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(146)
按照实施例33中所述的方法,制备所需的糖,即乙酸1,2,5-三-O-乙酰基-3-丁氧基-D-呋喃木糖α和β的混合物(101)。
步骤1:制备5-氨基-3-(3’-(R)-丁氧基-2’,5’-二-O-乙酰基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(145)
按照类似于实施例42,步骤1的方式,由乙酸1,2,5-三-O-乙酰基-3-丁氧基-D-呋喃木糖α和β的混合物(101),制得标题化合物145,无需纯化可用于步骤2。
步骤2:制备5-氨基-3-(3’-(R)-丁氧基-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2-酮(146)
按照类似于实施例42,步骤2的方式,制得5.3mg标题化合物146,产率为16%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.22(br s,1H),6.92(brs,2H),5.64(d,J=5.46Hz,1H),5.60(d,J=7.8Hz,1H),5.08(m,1H),4.39(t,J=6.24Hz,1H),4.07(m,1H),3.92(t,J=7.02Hz,1H),3.57(m,3H),3.42(m,1H),1.48(m,2H),1.33(m,2H),0.88(t,J=7.02Hz,3H);[M+H]+372.9;对C14H2ON4O6S·1.OH2O·0.4MeOH元素分析:计算值:C,42.89;H,5.90;N,13.89;测量值:C,43.18;H,5.68;N,13.65。
实施例51
制备(3’S)-5-氨基-3-(3’-脱氧-3’-羟基甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(148)
步骤1:制备(3’S)-5-氨基-3-(3’-乙酰氧基甲基-2’,5’-二-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(147)
按照类似于实施例42,步骤1的方式,由(3’S)-3-O-乙酰氧基甲基-1,2,5-三-O-乙酰基-3-脱氧-α,β-D-呋喃核糖[按照Cooperwood等在Nucleosides,Nucleotides,and Nucleic Acids 2000,19,219-236中所述的方法制备,其中,制得同一化合物的对映体],制得224mg标题化合物147,产率为49%,为米色固体:1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),7.00(s,2H),5.77(m,1H),4.35(dd,J=11.7,2.3,1H),4.26(m,1H),4.15(m,2H),4.07(m,3H),2.013(s,9H);[M+H]+457.3。
步骤2:制备(3’S)-5-氨基-3-(3’-脱氧-3’-羟基甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(148)
按照类似于实施例42,步骤2的方式,制得34mg标题化合物148,产率为58%,为米色固体:1H NMR(400MHz,D2O)δ5.99(m,1H),5.13(m,1H),4.17(m,1H),3.90(m,2H),3.76(m,2H),2.93(m,1H);[M+H]+331.2;对C11H14N4O6S元素分析:计算值:C,35.20;H,5.10;N,14.93;S,8.54;测量值:C,35.17;H,4.35;N,14.73;S,8.46。
实施例52
制备5-氨基-3-(5’-脱氧-5’-羟基甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(150)
步骤1:制备5-氨基-3-(5’-O-乙酰氧基甲基-2’,3’-二-O-乙酰基-5’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(149)
按照类似于实施例42,步骤1的方式,由5-O-乙酰氧基甲基-1,2,3-三-O-乙酰基-5-脱氧-α,β-D-呋喃核糖[按照Pakulski等在Polish J.Chem.1995,69,912-917中所述的方法制备],制得96mg标题化合物149,产率为34%,为白色固体:1H NMR(400MHz,CDCl3)δ11.92(s,1H),6.15(d,J=6.4,1H),5.94(s,2H),5.71(m,1H),4.91(m,1H),4.40(m,1H),4.16(m,2H),2.09(s,9H),2.00(m,2H);[M+H]+457.0;对(C17H2ON4O9S·0.25H2O):计算值:C,44.30;H,4.48;N,12.16;S,6.96;测量值:C,44.79;H,4.62;N,11.55;S,6.59。
步骤2:制备5-氨基-3-(5’-脱氧-5’-羟基甲基-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(150)
按照类似于实施例42,步骤2的方式,制得28mg标题化合物150,产率为56%,为白色固体:1H NMR(400MHz,d6-DMSO)δ11.23(s,1H),6.94(s,2H),5.74(m,1H),5.22(m,1H),4.87(m,1H),4.40(m,1H),4.00(m,2H),3.44(s,3H),1.72(m,2H);[M+H]+330.9。
实施例53
制备5-氨基-3-[3’-脱氧-3’-O-对-甲苯磺酰基-β-D-呋喃木糖基]-3H,6H-噻唑并-[4,5-d]嘧啶-2,7-二酮(151)
步骤1:制备5-氨基-3-[2’,5’-二-O-乙酰基-3’-脱氧-3’-O-对-甲苯磺酰基-β-D-呋喃木糖基]-3H,6H-噻唑并-[4,5-d]嘧啶-2,7-二酮(151)
按照类似于实施例42,步骤1的方式,制得24.6mg标题化合物151,产率为12%,为米色固体:1H NMR(400MHz,CDCl3)δ11.89(s,1H),7.84(d,J=8.4,2H),7.40(d,J=8.4,2H),6.22(d,J=4.4,1H),5.92(br s,2H),5.75(d,J=4.8,1H),4.95(d,J=4.8,1H),4.30(m,1H),4.25(d,J=6,2H),2.48(s,3H),2.05(s,6H);[M+H]+555.3。
实施例54
制备(3’R)-5-氨基-3-(3’-脱氧-3’-氟-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(153)
步骤1:制备(3’R)-5-氨基-3-(2’-O-乙酰基-5’-O-苯甲酰基-3’-脱氧-3’-氟-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(152)
按照类似于实施例42,步骤1的方式,由1,2-二-O-乙酰基-5-O-苯甲酰基-3-脱氧-3-(R)-氟-α,β-D-呋喃木糖[按照Gosselin等在CarbohydrateResearch 1993,249,1-17中所述的方法制备],制得149mg标题化合物152,产率为24%,为黄色固体:1H NMR(400MHz,CDCl3)δ11.57(s,1H),8.04(d,J=6.8,2H),7.56(t,J=7.6,1H),7.43(t,J=7.6,2H),6.35(dd,J=22.4,4.8,1H),5.92(s,2H),5.32(dd,J=51.6,4.8,1H),5.20(s,1H),4.79(dd,J=11.2,4,1H),4.59(m,2H),4.5(m,1H),2.06(s,3H);[M+H]+465.3。
步骤2:(3’R)-5-氨基-3-(3’-脱氧-3’-氟-β-D-呋喃木糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(153)
按照类似于实施例42,步骤2的方式,制得14.3mg标题化合物153,产率为45%,为白色固体:1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),6.97(s,2H),5.77(m,1H),5.19(m,1H),4.98(m,1H),4.01(m,1H),3.60(m,2H),2.09(s,2H);[M+H]+318.9;对(C10H11FN4O5S·0.4EA·2H2O)元素分析:计算值:C,35.76;H,4.71;N,14.3;测量值:C,35.71;H,3.68;N,14.15。
实施例55
制备3-烯丙基-5-氨基-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(154)
步骤1:制备3-烯丙基-5-氨基-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(154)
按照类似于实施例15,步骤1的方案1的方式,制得178mg标题化合物154,产率为35%,为淡黄色固体:1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),6.09(s,2H),5.06-5.01(m,1H),4.32(dd,J=10.3,1.5,1H),4.196(dd,J=16.9,1.5,1H),3.55(d,J=4.4,2H);[M+H]+225.1。
实施例56
制备5-氨基-3-吡啶-3-基甲基-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(155)
步骤1:制备5-氨基-3-吡啶-3-基甲基-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(155)
按照类似于实施例15,步骤1的方式,制得143mg标题化合物155,产率为24%,为白色固体:1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),7.76(d,J=2.2,1H),7.68(dd,J=2.2,1.5,1H),6.88(m,1H),6.55(s,2H),6.15(s,2H),4.17(s,2H);[M+H]+276.1。
实施例57
制备5-氨基-3-(4-氯-丁-2-烯基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(156)
步骤1:制备5-氨基-3-(4-氯-丁-2-烯基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(156)
按照类似于实施例15,步骤1的方式,制得440mg标题化合物156,产率为63%,为淡黄色固体:1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),6.90(s,2H),5.82-5.74(m,1H),5.65-5.59(m,1H),4.45(d,J=7.0,2H),4.39(d,J=7.8,2H);[M+H]+273.1。
实施例58
制备5-氨基-3-己基-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(157)
步骤1:制备5-氨基-3-己基-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(157)
按照类似于实施例15,步骤1的方式,制得154mg标题化合物157,产率为35%,为米色固体:1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),6.88(s,2H),3.74(t,J=6.8,2H),1.61(m,4H),1.26(m,4H),0.85(t,J=6.8,3H);[M+H]+269.31。
方案X
a)Tf2O,py,CH2Cl2,0℃,0.5小时;氯脒碱,NaH,CH3CN,室温,50℃,12小时
b)NaIO4,OsO4,CH3OH/H2O,0℃,1小时-室温,2小时;NaBH4,CH3OH,室温,1小时;2MHCl,CH3OH,回流,5小时
实施例59
制备(1’R,2’S,3’R,4’R)-5-氨基-3-(2’,3’-二氧-4’-羟基甲基-环戊烷-1’-基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(158)
环境温度下,将(1’R,2’S,3’R,4’R)-N’-[7-氯-2-氧代-3-(2’,3’-O-异亚丙基-4’-乙烯基-环戊烷-1’-基)-2,3-二氢-噻唑并[4,5-d]嘧啶-5-基]-N,N-二甲基-甲脒(85)(85mg,0.20mmol)溶解在CH3OH(3.0mL)和H2O(1.5mL)中。溶液冷却至0℃。然后,在该溶液中加入高碘酸钠(90mg,0.42mmol)和四氧化锇(2mg,催化剂)。于0℃搅拌反应1小时,室温搅拌2小时,之后过滤并浓缩。将所得的混合物溶于CH2Cl2(10mL),然后用H2O洗涤(2×10mL)。有机层用MgSO4干燥,过滤,然后浓缩。
环境温度下,将上述产物溶解在CH3OH(3mL)。然后,在该溶液中加入硼氢化钠(12mg,0.32mmol)。搅拌反应1小时,然后浓缩。将所得的混合物溶解在CH2Cl2,用H2O洗涤(2×10mL)。有机层用MgSO4干燥,过滤,然后浓缩。
环境温度下,将上述产物溶于CH3OH(1mL)和2M HCl(5mL)。回流条件下搅拌反应5小时,然后浓缩。所得的混合物经反相HPLC纯化,获得9.1mg(13%)化合物158,为白色固体:1H(400MHz,CD3OD)δ4.95(m,1H),4.69(dd,J=7.2,5.6,1H),4.03(t,J=5.2,1H),3.71(dd,J=11.2,6.4,1H),3.60(dd,J=11.2,6.4,1H),3.35(s,1H),1.93-2.14(m,3H)。
实施例60
5-氨基-3-(2’-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(160)
a.北极洲念珠菌,丙酮,pH 7磷酸盐缓冲液,97%.
制备5-氨基-3-(2’-O-乙酰基-3’-脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(160)
向核苷二乙酸酯121(200.0mg,0.52mmol)在丙酮(5.0mL)、pH 7磷酸盐缓冲液(2.5mL)和H2O(22.5mL)的悬液中加入固定在丙烯酸类树脂中的北极洲念珠菌(0.10g)。加入酶后5分钟内混合物发生脱色。室温搅拌反应16小时。加入硅藻土(1.0g),搅拌10分钟后,混合物通过硅藻土垫过滤。滤饼用丙酮漂洗(3×10mL),真空减少丙酮量。用固体NaCl使残余的含水层重盐化(heavily salted)。加入乙酸乙酯,剧烈搅拌两相混合物30分钟后,进行分离。有机层用Na2SO4干燥,滗析,浓缩,并通过快速色谱纯化(SiO2,50-100%EtOAc-己烷+2%MeOH)。获得155.0mg单乙酸酯160(97%):1H(400MHz,DMSO-d6)δ11.20(s,1H),6.94(br s,2H),5.79(d,J=2.4,1H),5.63(d,J=8.0,1H),4.76(t,J=6.0,1H),4.11(dt,J=5.2,10.4,1H),3.43-3.52(m,2H),2.44-2.5(m,1H),2.05(s,3H),1.95(dd,J=6.0,13.6,1H);[M+H]+m/z 342。对C12H14N4O6S·0.5H2O的分析计算值:C,42.10;H.4.12;N,16.37;S,9.37。测量值:C,42.30;H,4.26;N,16.37;S,9.23。
实施例61
5-氨基-3-(2’,3’-二脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(165)
步骤1)制备5-N-乙酰氨基-3-(5’-叔丁基二甲基甲硅烷基-2’-脱氧-2’-O-硫代羰基咪唑-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(161)
室温下,向醇127和醇128(247mg,0.541mmol)在MeCN(8mL)的混合物中加入TCDI(193mg,1.08mmol)。搅拌反应混合物18小时,然后浓缩,并经快速色谱纯化(SiO2,EtOAc),获得150mg(49%)硫代氨基甲酸酯161和162的混合物,为固体物质:1H NMR(400MHz,d6-DMSO)δ12.18(br s,1H),11.72(brs,1H),8.54(s,1H),7.86(s,1H),7.10(s,1H),6.36(m,1H),6.04(s,1H),4.38-4.43(m,1H),3.68-3.80(m,2H),2.63-2.69(br m,1H),2.36-2.41(m,1H),2.17(s,3H),0.84(s,9H),0.00(s,6H);[M+H]+m/z 567。
步骤2):制备5-N-乙酰基氨基-3-(5’-叔丁基二甲基甲硅烷基-2’,3’-二脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(163)
室温下,向硫代氨基甲酸酯161和162(57mg,0.10mmol)与Bu3SnH(187μL,0.705mmol)在PhMe(10mL)的混合物中加入AIBN(1.6mg,0.010mmol)。将反应混合物浸入130℃油浴,搅拌20分钟,浓缩并经快速色谱纯化(SiO2,60-80%EtOAc-CHCl3),获得28mg(64%)化合物163,为白色固体:1H NMR(400MHz,d6-DMSO)δ12.13(br s,1H),11.80(br s,1H),6.11(dd,J=8.4,3.7,1H),3.95-4.02(m,1H),3.64(d,J=5.1,2H),2.54-2.59(m,1H),2.23-2.33(m,1H),2.19(s,3H),2.04-2.13(m,1H),1.94-1.97(m,1H),0.82(s,9H),-0.01(6H);[M+H]+m/z 441。
步骤3)制备5-N-乙酰基氨基-3-(2’,3’-二脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(164)
硅氧烷163(84mg,0.19mmol)在2M HF-MeCN(20mL)的溶液搅拌10分钟,然后浓缩并经快速色谱纯化(SiO2,5-10%MeOH-CHCl3),获得10mg(16%)醇164,为白色固体:1H NMR(400MHz,d6-DMSO)δ12.15(br s,1H),11.78(br s,1H),6.10(dd,J=8.4,4.0,1H),4.66(t,J=5.9,1H),3.91-3.97(m,1H),3.46(t,J=5.9,2H),2.51-2.58(m,1H),2.21-2.32(m,1H),2.19(s,3H),2.01-2.18(m,1H),1.89-1.97(m,1H);[M+H]+m/z 327。
步骤4)制备5-氨基-3-(2’,3’-二脱氧-β-D-呋喃核糖基)-3H,6H-噻唑并[4,5-d]嘧啶-2,7-二酮(165)
室温下,向乙酰胺164(19mg,0.058mmol)的MeOH(3mL)溶液中加入K2CO3(64mg,0.46mmol)。搅拌反应混合物18小时,然后用HOAc(53μL)猝灭,浓缩并用MeOH-H2O研碎,获得6mg(36%)标题化合物165,为白色固体:1HNMR(400MHz,d6-DMSO)δ11.15(s,1H),6.85(br s,2H),6.07(dd,J=8.4,4.4,1H),4.63(t,J=5.9,1H),3.89-3.95(m,1H),3.46(t,J=5.5,2H),2.44-2.48(m,1H),2.17-2.27(m,1H),2.01-2.11(m,1H),1.86-1.93(m,1H);[M+H]+m/z 285。
化合物的抗病毒活性
根据本发明可使用许多测试方法以测定本发明化合物的抗病毒活性程度,如细胞培养、动物模式和对人体给药。本文所述的测试可用来分析一段时间里的病毒生长以测定在本发明化合物的存在下病毒的生长特征。
在另一个实施方式中,对易受病毒感染的动物对象给予病毒和本发明的化合物。将受感染且给予本发明化合物的对象的感染易发程度、严重性、长度、病毒负载、死亡率等与只给予病毒(不给予本发明化合物)对象的感染易发程度、严重性、长度、病毒负载、死亡率等进行比较。本发明化合物的抗病毒活性可在本发明化合物的存在下,通过其对感染的易发程度、严重性、长度、病毒负载、死亡率的降低来显示。在一个特定的实施方式中,对动物对象同时给予病毒和本发明的化合物。在另一个特定实施方式中,在给予本发明化合物前对动物给予病毒。在另一个特定的实施方式中,在给予病毒前对动物给予本发明的化合物。
在另一个实施方式中,病毒生长率的测定可如下进行:在存在或不存在本发明化合物条件下,于感染后的多个时间点从人体或动物对象取出生物液体/临床样品(如,鼻呼出物、咽喉处的擦拭物、痰、支气管-齿槽灌洗物、尿液、唾液、血液或血清)并检测病毒的水平。在特定的实施方式中,病毒生长率的分析可如下进行:在样品中的病毒经细胞培养生长后、在生长培养基上生长后或在对象中生长后,运用本技术领域公知的任何方法分析样品中病毒的存在,所述方法为例如但不限于,免疫分析(如ELISA;关于ELISA的讨论可参见,例如Ausubel等编,1994,Current Protocols in Molecular Biology,第I卷,JohnWiley&Sons,Inc.,纽约,11.2.1)、免疫荧光染色法或免疫斑点法分析,利用免疫特异性识别要被分析的病毒的抗体或检测病毒特异性的核酸(如,通过南方染污(Southern blot)或RT-PCR分析等)。
在特定的实施方式中,病毒滴度的测定如下进行:从感染的细胞或感染的对象中得到生物液体/临床样品,制备该样品的一系列稀释物,并用可使对病毒易感的单层细胞(如原代细胞、转化细胞系、病人组织样品等)产生单个空斑(plagues)的病毒稀释度感染该单层细胞。然后计算空斑数,病毒滴度表示为斑点形成单位/毫升样品。
在一个特定的实施方式中,对象中的病毒生长率可通过抗体抗对象中的病毒的滴度进行评估。抗体血清滴度可通过本领域中周知的任何方法进行测定,例如但不限于,血清样品中抗体或抗体片段的量可通过如,ELISA进行定量。另外,式I化合物的体内活性可如下测定:直接给予试验动物以该化合物,收集生物液体(如鼻呼出物、咽喉处的擦拭物、痰、支气管-齿槽灌洗物、尿液、唾液、血液或血清)并测试液体的抗病毒活性。
在要被分析病毒水平的样品是生物流体/临床样品(如鼻呼出物、咽喉处的擦拭物、痰、支气管-齿槽灌洗物、尿液、唾液、血液或血清)的实施方式中,样品可包含在或不包含在应答的细胞中。来自含有完整细胞的对象的样品可直接进行处理,而不含完整细胞的分离物可经过或不经过首先在易感细胞系(如原代细胞、转化细胞系、病人组织样品等)或生长培养基(如,LB肉汤/琼脂、YT肉汤/琼脂、血液琼脂等)上进行培养。可通过离心(如,室温下300×g,5分钟),然后在相同的条件下用pH 7.4的PBS(无Ca++和Mg++)洗涤使得细胞悬液变澄清。细胞团(cell pellet)可再悬浮于小体积PBS中供分析。含有完整细胞的原发性临床分离物可与PBS混合,并在室温下以300×g离心5分钟。用消毒滴管尖从交界面上除去粘液,并可将细胞团在相同条件下以PBS再次洗涤。然后将细胞团再悬浮于小体积的PBS中供分析。
在另一个实施方式中,将本发明的化合物给予被病毒感染的人。被病毒感染且给予本发明化合物的人的易感率、严重程度、长度、病毒负载、死亡率等可与受到病毒感染但未给予本发明化合物或给予安慰剂的人体观察到的易感率、严重程度、长度、病毒负载、死亡率等进行比较。本发明化合物的抗病毒活性可通过本发明化合物的存在对感染的易感率、严重程度、长度、病毒负载、死亡率的降低来显示。本技术领域公知的任何方法都可用来测定在对象(例如,那些前述的对象)中的抗病毒活性。
此外,式I的前药的体内活性可如下测定:直接给予动物或人体对象该化合物,收集生物液体/临床样品(如,鼻呼出物、咽喉处的擦拭物、痰、支气管-齿槽灌洗物、尿液、唾液、血液或血清),并测试生物液体/临床样品中的抗病毒活性(如,在病毒的存在下向培养中的细胞中加入本发明的化合物)。
式I的前药的代谢
本发明式I的前药若要作为有效的前药使用,则必须在体内代谢为式II化合物和本发明的其它化合物。常用肝细胞(hepatocyes)来测试化合物在动物体内的转化程度,且已知这种转化在来自不同物种的肝细胞间可不同,这种不同表现在影响到整个动物体的代谢。参见Seddon T.等人,Biochem Pharmacol.,38(10),1657-65(1989)。
在新鲜猕猴肝细胞的存在下,对式I的化合物14、15、13、114、30、103、67、65和76的代谢稳定性进行了研究,并监测了6-氧代谢产物的形成(即式II所示的化合物和本发明的其它化合物)。为了比较,还对泛西洛维的代谢稳定性进行了评估。
新鲜肝细胞悬液的制备
新鲜猕猴肝细胞悬液(批号#:Cy141),购自CellzDirect(Tucson,AZ)。肝细胞培养基(无血清,无菌)购自In Vitro Technologies(Baltimore,MD)。
以1.25百万个细胞/mL的浓度从肝细胞培养基中的新鲜猕猴肝细胞制得猕猴肝细胞悬液。最终培养浓度(测试品加入后)为1.0百万个细胞/mL。
储备液的制备
使用了原有的100mM的DMSO储备液。使用紫外-观光微孔板读数装置检测了测试品的浓度。使用新鲜配制的化合物122的DMSO储备液的吸光度来确定校正系数。
孵化(incubation)
在可移除的96-孔管中配制反应悬液,每孔含有320μL密度为1.25百万个细胞/mL的新鲜猕猴肝细胞悬液和40μL肝细胞培养基。将上述混合物在37℃、95%湿度和5%CO2条件下,开口预孵化30分钟。在每管中加入10×浓度的40μL测试品使反应开始,以获得终浓度为50μM的测试品和1百万个细胞/mL的细胞密度。翻转各管数次以混合各管中的反应悬液。在六个其它的可移除的96-孔管中加入等量的50μL各反应悬液(于15、30、45、60、90和120分钟,每时间点取出一管)。将开口管在37℃、95%湿度和5%CO2条件下孵育。
分析样品的制备
在预设的时间点向含有50μL反应悬液的各管中加入150μL终止液以终止反应。终止液的组成如下:15mL乙腈(含1μg/mL水粉蕈素作为内标和0.1%甲酸)加1mL水。
标准曲线的获得方法如下。向80μL细胞悬液(细胞密度为1.25百万个/mL)中,加入10μL肝细胞培养基和10μL适当浓度的化合物的肝细胞培养基溶液。然后立即加入化合物,并加入300μL终止液(见上)。
将所有猝灭的样品置于湿冰上,直至进行分析。然后用台式顶置多管涡旋混合器(bench top Multi-Tube Vortexer,VWR Scientific Products)将它们混合约30秒,并在4℃下以4,000转/分钟(3,220rcf)离心10分钟。将澄清的上清液(100μL)移入洁净的深孔96-孔板中,在氮气下蒸发至干,在100μL90∶10的水∶乙腈中重构,并用适当的LC/MS/MS方法,分析测试品的母体(parent)形式和代谢产物。
生物分析
化合物在API3000LC/MS/MS仪上以ESI-Positive MRM(多反应控制)模式进行定量。式I的前药的降解和产物产生的结果示于表1。
表1
以50μM式1所示的前药培养2小时后,在猕猴肝细胞中形成的代谢产物的浓度
在新鲜猕猴肝细胞中,化合物14、15、13、114、30、103、67、65和76以及泛西洛维均代谢产生了相应的6-氧代谢物:化合物122产生于前三种式I所示的前药,以及分别产生了134、117、141、157、148和132。泛西洛维产生了喷西洛维。
从外周血单核细胞(PBMC)中诱导产生的IFN-α
使用标准方法从人血液中制备了外周血单核细胞(PBMC),它主要含有单核细胞、NK细胞、外周树突状细胞以及T细胞和B细胞。简要来说,它们是通过密度梯度离心从白细胞层纯化得到的,白细胞层为全血中含有白血细胞和血小板的组分。或者,白细胞层的制备是通过全血离心,并将分离的混合物中的上层血浆层和下层红细胞间的奶油色薄层分离出而进行的。
PBMC的钝化
新鲜收集的捐献白细胞层获自圣地亚哥血库(San Diego Blood Bank)。使用histopaque-1077梯度(gradient)(Sigma),基本按照产品说明书所述从白细胞层分离出PBMC。将白细胞层移入50ml离心管中,并加入PBS至总体积为35ml。然后将10 ml histopaque-1077置于各管底部,并将各管于室温下,在5804R离心机(Eppendorf)中,以259×g不间断离心30分钟。移去各管中的顶部PBS层并丢弃,并将白细胞层移入新管内。用PBS将总体积调整到50ml,然后将各管在室温下以259×g离心10分钟。以此方式将细胞再用PBS洗涤3次。
然后将细胞(PBMC)团在30-40ml完全(RPMI 1640)培养基中重悬浮。以2.5或7.5×106个细胞/ml完全培养基接种PBMC(分别为1×和3×接种),并静养过夜,然后暴露于化合物下24小时。然后收集细胞和培养基,室温下用5415C微离心机(Eppendorf)以735×g离心5分钟,并将上清液以IFN-αELISA分析。
式I的前药、式II的化合物和本发明的其它化合物在通过经选择的途径给药时显示降低的免疫应答以及良好口服给药特性的能力不亚于采用文献中所描述的化合物进行的类似试验的结果。全文纳入本文作为参考的文献是:美国专利5,041,426和4,880,784,和美国专利申请10/861,430(美国专利申请公开号为US2005/0070556),其揭示了艾沙托立宾对IFN-α的诱导。
因此,本发明化合物的相对活性表示为相对于32或100μM艾沙托立宾所诱导产生的IFN-α的百分比
ELISA方案
按照Biosource中所记叙的方案进行人IFN-αELISA(#KHC4012)。但是,为了确保读数在检测的线性范围中,通常将PBMC上清液样品1∶3(2.5×106个细胞/ml接种)或1∶15(7.5×106个细胞/ml接种)稀释,然后与未经稀释的上清液样品一起进行分析。各样品的浓度通过O.D.值对照标准曲线计算得出。
本发明的化合物所显示出的相对于艾沙托立宾的从PBMC中诱导IFN-α的范围如下:
0-10%:化合物142、157、141、148和33
11-50%:化合物152和165
51-100%:化合物32、160、130和137
>100%:化合物133、34、147、121、122、134、117、132和153。
与艾沙托立宾的比较
结果显示,化合物134和122对体外诱导人PBMC产生IFN-α的提高显著优于艾沙托立宾。图1和图2为化合物A诱导人PBMC产生皮克/ml IFN-α与等浓度的艾沙托立宾诱导产生的皮克/ml IFN-的比较。结果总结如下。
当以1×PBMC接种时,化合物134和122的100μM测试化合物显著和基本上诱导了比艾沙托立宾所诱导的更多的IFN-α产物,尤其是相对于艾沙托立宾的弱应答物(图1和图2的左侧)。当接种提高到3×时,100μM测试剂所产生的IFN-α量的区别虽然看来很明显且统计学上是显著的,但清晰度稍弱(图1和图2的右侧)。然而,当化合物134和122的浓度均为32μM并以3×接种时,化合物134和122显著并出乎意料地超过艾沙托立宾(图1和图2的右侧和插入部分)。
应当明白,前述内容是例举和解释性的,它仅供阐述本发明和其优选的实施方式用。通过常规的实验,所述领域的技术人员能容易地了解可不背离本发明精神的做出明显的修饰和改变。因此,本发明不为上述阐述所限定,本发明由下列权利要求书和它们的等同物所限定。
Claims (8)
6.一种药物组合物,其包含药学上可接受的载体和如权利要求1-5中任一项所述的化合物;或其药学上可接受的盐或互变异构体。
7.一种治疗或预防有效量的如权利要求1-5中任一项所述的化合物或其药学上可接受的盐或互变异构体在制备用于在患者中调节免疫细胞因子活性的药物中的应用。
8.一种治疗或预防有效量的如权利要求1-5中任一项所述的化合物或其药学上可接受的盐或互变异构体在制备用于在患者中治疗丙型肝炎病毒感染的药物中的应用。
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CN201110291130.1A Active CN102504001B (zh) | 2004-12-17 | 2005-12-16 | 3,5-二取代的和3,5,7-三取代的-3H-噁唑并以及3H-噻唑并[4,5-d]嘧啶-2-酮化合物及其前药 |
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