JP4980059B2 - 抗ウイルスヌクレオシド類似体およびウイルス感染特にhiv感染の処置方法 - Google Patents
抗ウイルスヌクレオシド類似体およびウイルス感染特にhiv感染の処置方法 Download PDFInfo
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- JP4980059B2 JP4980059B2 JP2006532288A JP2006532288A JP4980059B2 JP 4980059 B2 JP4980059 B2 JP 4980059B2 JP 2006532288 A JP2006532288 A JP 2006532288A JP 2006532288 A JP2006532288 A JP 2006532288A JP 4980059 B2 JP4980059 B2 JP 4980059B2
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- 230000000840 anti-viral effect Effects 0.000 title claims description 45
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- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 6
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 6
- QBEIABZPRBJOFU-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)CC1 QBEIABZPRBJOFU-VDTYLAMSSA-N 0.000 claims description 5
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- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 claims description 3
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- PUSXDQXVJDGIBK-NKWVEPMBSA-N [(2s,5r)-5-(6-aminopurin-9-yl)oxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](COP(O)(O)=O)O1 PUSXDQXVJDGIBK-NKWVEPMBSA-N 0.000 claims description 2
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- 239000012258 stirred mixture Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009044 synergistic interaction Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XJJBXZIKXFOMLP-ZETCQYMHSA-N tert-butyl (2s)-pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN1 XJJBXZIKXFOMLP-ZETCQYMHSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ZJGSQAUGHPGIQF-UHFFFAOYSA-N triethynylalumane Chemical compound C#C[Al](C#C)C#C ZJGSQAUGHPGIQF-UHFFFAOYSA-N 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
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Description
RはH、F、Cl、Br、I、C1−C4アルキル(好ましくはCH3)、−C≡N、−C≡C−Ra、
XはH、C1−C4アルキル(好ましくはCH3)、F、Cl、BrまたはIであり、
化合物が構造式IIであるときにZがCH2でOではないという条件付きでZはOまたはCH2であり、
R3は−C≡C−Hであり、
R2はHまたはリン酸、二リン酸、三リン酸またはホスホトリエステル基であり、
R1はH、アシル基、C1−C20アルキルまたはエーテル基であり、
R2はH、アシル基、C1−C20アルキルまたはエーテル基、リン酸、二リン酸、三リン酸、ホスホジエステル基または
Nuは生物学的に活性な抗ウイルス化合物の遊離基であって、該化合物からのアミノ基またはヒドロキシル基がリン酸、ホスホラミデート、炭酸塩または隣接部分を具えたウレタン基を形成し、
R8はH、またはC1−C20アルキルまたはエーテル基、好ましくはC1−C12アルキル基であり、
kは0〜12、好ましくは0〜2であり、
R3はC1−C4アルキル(好ましくはCH3)、−(CH2)n−C≡C−Ra、
R3aとR3bは独立にH、F、Cl、BrまたはIから選ばれ、
R4とR5がともにHではないとの条件付きで、R4とR5とはH、F、Cl、Br、I、OH、C1−C4アルキル(好ましくはCH3)、−(CH2)n−C≡C−Ra、
RaはH、F、Cl、Br、Iまたは−C1−C4アルキル、好ましくはHまたはCH3であり、
YはH、F、Cl、Br、Iまたは−C1−C4アルキル、好ましくはHまたはCH3であり、
nは0、1、2、3、4または5、好ましくは0、1、または2であり、
およびそれらのアノマー、薬学的に受容可能な塩、溶媒和物またはその多形体である。
Nomura他、J.Med.Chem.42、2901−2908(1999年)
J.P.H.VerheydenおよびJ.G.Moffatt,J.Org.Chem.,39,3573−3579(1974年)
1(11.9g、30.19mmol)のCH3CN(150mL)溶液にAr大気圧下で0℃でDBN(11.2mL、90.57mmol)を添加し、全体を室温で終夜攪拌した。AcOHでの中和後、反応混合物を乾燥状態に蒸発させて、残留物をCHCl3/飽和水性NaHCO3(200mL、x2/50mL)間で区分した。
Hz, H−3’), 5.04−5.13 (2H, m, CH2CH=CH 2), 5.88−5.98 (1H, m, CH2CH=CH2), 6.23 (1H, t, J1',2'a=J1',2'b= 6.5 Hz, H−1’), 7.89 (1H, d, J6,Me= 1.2 Hz, H−6); FAB−MS m/z 283 (M++H), 321 (M++K). Anal. Calcd for C13H18N2O5・1/2H2O : C, 54.16 ; H, 6.57 ; N, 9.62. Found: C, 53.87 ; H, 6.49 ; N, 9.28.
B.V.JoshiおよびC.B.Reese,Tetrahedron Lett.,32、2371−2374(1992年)
Kato他Chem.Pharm.Bull.,47,1256−1264(1999年)
P.Callant、L.D’HaenesおよびM.Vandewalle、Synth.Commun.、14、155−161(1984年) I.Gillaizeau、I.M.Lagoja、S.P.Nolan、V.Aucagne、J.Rozenski、P.HerdewijnおよびL.A.Agrofoglio、Eur.J.Org.Chem.666−671(2003年)
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21. Lee, L. S. , and Y. C. Cheng. 1976. Human deoxythymidine kinase. I. Purification and general properties of the cytoplasmic and mitochondrial isozymes derived from blast cells of acute myelocytic leukemia. J Biol Chem 251: 2600−2604.
22. Lewis, W. , and M. C. Dalakas. 1995. Mitochondrial toxicity of antiviral drugs. Nat Med 1: 417−22.
23. Lin, T. S. , M. Z. Luo, M. C. Liu, S. B. Pai, G. E. Dutschman, and Y. C. Cheng. 1994. Antiviral activity of 2’, 3’−dideoxy−beta−L−5−fluorocytidine (beta−L−FddC) and 2’, 3’− dideoxy−beta−L−cytidine (beta−L−ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro. Biochem Pharmacol 47: 171−4.
24. Lin, T. S. , M. Z. Luo, M. C. Liu, S. B. Pai, G. E. Dutschman, and Y. C. Cheng. 1994. Synthesis and biological evaluation of 2’, 3’−dideoxy−L−pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). J Med Chem 37: 798−803.
25. Lin, T. S. , M. Z. Luo, M. C. Liu, Y. L. Zhu, E. Gullen, G. E. Dutschman, and Y. C. Cheng. 1996. Design and synthesis of 2’, 3’−dideoxy−2’, 3’−didehydro−beta−L−cytidine (beta−L−d4C) and 2’, 3’−dideoxy 2’, 3’−didehydro−beta−L−5−fluorocytidine (beta−L−Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human immunodeficiency virus (HIV) in vitro. J Med Chem 39: 1757−9.
26. Lin, T. S. , R. F. Schinazi, M. S. Chen, E. Kinney−Thomas, and W. H. Prusoff. 1987. Antiviral activity of 2’, 3’−dideoxycytidin−2’−ene (2’, 3’−dideoxy−2’, 3’−didehydrocytidine) against human immunodeficiency virus in vitro. Biochem Pharmacol 36 : 311−6.
27. Lin, T. S. , R. F. Schinazi, and W. H. Prusoff. 1987. Potent and selective in vitro activity of 3’−deoxythymidin−2’−ene (3’−deoxy−2’, 3’−didehydrothymidine) against human immunodeficiency virus. Biochem Pharmacol 36: 2713−8.
28. Lu, Z. H. , R. Zhang, and R. B. Diasio. 1993. Comparison of dihydropyrimidine dehydrogenase from human, rat, pig and cow liver. Biochemical and immunological properties. Biochem Pharmacol 46: 945−52.
29. Maag, H. , R. M. Rydzewski, M. J. McRoberts, D. Crawford−Ruth, J. P. Verheyden, and E. J. Prisbe. 1992. Synthesis and anti−HIV activity of 4’−azido−and 4’− methoxynucleosides. J Med Chem 35: 1440−51.
30. Medina, D. J. , C. H. Tsai, G. D. Hsiung, and Y. C. Cheng. 1994. Comparison of Mitochondrial Morphology, Mitochondrial DNA Content, and Cell Viability in Cultured Cells Treated with Three Anti−Human Immunodeficiency Virus Dideoxynucleosides. Antimicrob Agents Chemother 38 : 1824−1828.
31. Mellors, J. W. , G. E. Dutschman, G. J. Im, E. Tramontano, S. R. Winkler, and Y. C. Cheng. 1992. In vitro selection and molecular characterization of human immunodeficiency virus−1 resistant to non−nucleoside inhibitors of reverse transcriptase. Mol Pharmacol 41: 446−51.
32. O−Yang, C. , H. Y. Wu, B. Fraser−Smith, and K. A. M. Walker. 1992. Synthesis of 4’− Cyanothymidine and Analogs as Potent Inhibitors of HIV. Tetrahedron Letters 33 : 37− 40.
33. Parker, W. B. , and Y. C. Cheng. 1995. ≡Disruption of Energy Metabolism and Mitochondrial Function≡, p. 483−490, Neurotoxicology : Approaches and Methods. Academic Press Inc. , New York.
34. Parker, W. B. , and Y. C. Cheng. 1994. Mitochondrial Toxicity of Antiviral Nucleoside Analogs. The Journal of HIH Reasearch 6 : 57−61.
35. Richman, D. D. 1993. Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents. Antimicrob Agents Chemother 37: 1207−13.
36. Richman, D. D. , M. A. Fischl, M. H. Grieco, M. S. Gottlieb, P. A. Volberding, O. L. Laskin, J. M. Leedom, J. E. Groopman, D. Mildvan, M. S. Hirsch, and et al. 1987. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS−related complex. A double−blind, placebo−controlled trial. N Engl J Med 317: 192−7.
37. Schinazi, R. F. , C. K. Chu, A. Peck, A. McMillan, R. Mathis, D. Cannon, L. S. Jeong, J. W. Beach, W. B. Choi, S. Yeola, and et al. 1992. Activities of the four optical isomers of 2’, 3’−dideoxy−3’−thiacytidine (BCH−189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob Agents Chemother 36: 672−6.
38. Sommadossi, J. P. , Z. Zhou, M. J. Hitchcock, H. M. McClure, M. el Kouni, and E. Cretton. 1992. Catabolism of 2’, 3’−Didehydro−2’, 3−DideoxyThymidine (D4T) in Isolated Hepatocytes and in Rhesus Monkeys. Proc. Annu. Meeting American Cancer Research 33: A3253. Univ. of Alabama.
39. Yarchoan, R. , J. M. Pluda, R. V. Thomas, H. Mitsuya, P. Brouwers, K. M. Wyvill, N. Hartman, D. G. Johns, and S. Broder. 1990. Long−term toxicity/activity profile of 2’,3’−dideoxyinosine in AIDS or AIDS−related complex. Lancet 336: 526−9
August, E. M. , M. E. Marongiu, T. S. Lin, and W. H. Prusoff. 1988. Initial studies on the cellular pharmacology of 3’−deoxythymidin−2’−ene (d4T): a potent and selective inhibitor of human immunodeficiency virus. Biochenm Pharmacol 37 : 4419−22. Bridges, E. G. , G. E. Dutschman, E. A. Gullen, and Y. C. Cheng. 1996. Favorable interaction of beta−L (−) nucleoside analogues with clinically approved anti−HIV nucleoside analogues for the treatment of human immunodeficiency virus. Biochem Pharmacol 51: 731−6. Brinkman, K., H. J. ter Hofstede, D. M. Burger, J. A. Smeitink, and P. P. Koopmans. 1998. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. Aids 12: 1735−44. Browne, M. J. , K. H. Mayer, S. B. Chafee, M. N. Dudley, M. R. Posner, S. M. Steinberg, K. K. Graham, S. M. Geletko, S. H. Zinner, S. L. Denman, and et al. 1993. 2’, 3’−didehydro−3’−deoxythymidine (d4T) in patients with AIDS or AIDS−related complex: a phase I trial. J lnfect Dis 167: 21−9. Chen, C. H. , and Y. C. Cheng. 1989. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti−human immunodeficiency virus compound 2’, 3’−dideoxycytidine. J Biol Chem 264: 11934−7. Chen, C. H. , M. Vazquez−Padua, and Y. C. Cheng. 1991. Effect of anti−human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 39 : 625−8. Cheng, Y. C. 1978. Thymidine Kinase from Blast Cells of Myelocytic Leukemia, p. 365−371, Methods in Enzymology, vol. LI. Academic Press, New York. Coates, J. A. , N. Cammack, H. J. Jenkinson, A. J. Jowett, M. I. Jowett, B. A. Pearson, C. R. Penn, P. L. Rouse, K. C. Viner, and J. M. Cameron. 1992. (−)−2’−deoxy−3’− thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob Agents Chemother 36: 733−9. Coates, J. A. , N. Cammack, H. J. Jenkinson, I. M. Mutton, B. A. 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Takeda, H. Tanaka, T. Nitanda, M. Baba, G. E. Dutschman, and Y. C. Cheng. 2003. Synthesis of a Highly Active New Anti−HIV Agent 2’, 3’−Didehydro− 3’deoxy−4’−ethynylthymidine. Bioorg Med Chem Setter 13: 3775−3777. Johnson, A. A. , A. S. Ray, J. Hanes, Z. Suo, J. M. Colacino, K. S. Anderson, and K. A. Johnson. 2001. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 276 : 40847−57. Larder, B. A. 1995. Viral resistance and the selection of antiretroviral combinations. J Acquir Immune Defic Syndr Hum Retrovirol 10 Suppl 1 : S28−33. Larder, B. A. , B. Chesebro, and D. D. Richman. 1990. Susceptibilities of zidovudine−susceptible and−resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay. Antimicrob Agents Chmother 34: 436−41. Lee, L. S. , and Y. C. Cheng. 1976. Human deoxythymidine kinase. I. Purification and general properties of the cytoplasmic and mitochondrial isozymes derived from blast cells of acute myelocytic leukemia. J Biol Chem 251: 2600−2604. Lewis, W. , and M. C. Dalakas. 1995. Mitochondrial toxicity of antiviral drugs. Nat Med 1: 417−22. Lin, T. S. , M. Z. Luo, M. C. Liu, S. B. Pai, G. E. Dutschman, and Y. C. Cheng. 1994. Antiviral activity of 2’, 3’−dideoxy−beta−L−5−fluorocytidine (beta−L−FddC) and 2’, 3’− dideoxy−beta−L−cytidine (beta−L−ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro. Biochem Pharmacol 47: 171−4. Lin, T. S. , M. Z. Luo, M. C. Liu, S. B. Pai, G. E. Dutschman, and Y. C. Cheng. 1994. Synthesis and biological evaluation of 2’, 3’−dideoxy−L−pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). J Med Chem 37: 798−803. Lin, T. S. , M. Z. Luo, M. C. Liu, Y. L. Zhu, E. Gullen, G. E. Dutschman, and Y. C. Cheng. 1996. Design and synthesis of 2’, 3’−dideoxy−2’, 3’−didehydro−beta−L−cytidine (beta−L−d4C) and 2’, 3’−dideoxy 2’, 3’−didehydro−beta−L−5−fluorocytidine (beta−L−Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human immunodeficiency virus (HIV) in vitro. J Med Chem 39: 1757−9. Lin, T. S. , R. F. Schinazi, M. S. Chen, E. Kinney−Thomas, and W. H. Prusoff. 1987. Antiviral activity of 2’, 3’−dideoxycytidin−2’−ene (2’, 3’−dideoxy−2’, 3’−didehydrocytidine) against human immunodeficiency virus in vitro. Biochem Pharmacol 36 : 311−6. Lin, T. S. , R. F. Schinazi, and W. H. Prusoff. 1987. Potent and selective in vitro activity of 3’−deoxythymidin−2’−ene (3’−deoxy−2’, 3’−didehydrothymidine) against human immunodeficiency virus. Biochem Pharmacol 36: 2713−8. Lu, Z. H. , R. Zhang, and R. B. Diasio. 1993. Comparison of dihydropyrimidine dehydrogenase from human, rat, pig and cow liver. Biochemical and immunological properties. Biochem Pharmacol 46: 945−52. Maag, H. , R. M. Rydzewski, M. J. McRoberts, D. Crawford−Ruth, J. P. Verheyden, and E. J. Prisbe. 1992. Synthesis and anti−HIV activity of 4’−azido−and 4’− methoxynucleosides. J Med Chem 35: 1440−51. Medina, D. J. , C. H. Tsai, G. D. Hsiung, and Y. C. Cheng. 1994. Comparison of Mitochondrial Morphology, Mitochondrial DNA Content, and Cell Viability in Cultured Cells Treated with Three Anti−Human Immunodeficiency Virus Dideoxynucleosides. Antimicrob Agents Chemother 38 : 1824−1828. Mellors, J. W. , G. E. Dutschman, G. J. Im, E. Tramontano, S. R. Winkler, and Y. C. Cheng. 1992. In vitro selection and molecular characterization of human immunodeficiency virus−1 resistant to non−nucleoside inhibitors of reverse transcriptase. Mol Pharmacol 41: 446−51. O−Yang, C. , H. Y. Wu, B. Fraser−Smith, and K. A. M. Walker. 1992. Synthesis of 4’− Cyanothymidine and Analogs as Potent Inhibitors of HIV. Tetrahedron Letters 33 : 37− 40. Parker, W. B. , and Y. C. Cheng. 1995. ≡Disruption of Energy Metabolism and Mitochondrial Function≡, p. 483−490, Neurotoxicology : Approaches and Methods. Academic Press Inc. , New York. Parker, W. B. , and Y. C. Cheng. 1994. Mitochondrial Toxicity of Antiviral Nucleoside Analogs. The Journal of HIH Reasearch 6 : 57−61. Richman, D. D. 1993. Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents. Antimicrob Agents Chemother 37: 1207−13. Richman, D. D. , M. A. Fischl, M. H. Grieco, M. S. Gottlieb, P. A. Volberding, O. L. Laskin, J. M. Leedom, J. E. Groopman, D. Mildvan, M. S. Hirsch, and et al. 1987. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS−related complex. A double−blind, placebo−controlled trial. N Engl J Med 317: 192−7. Schinazi, R. F. , C. K. Chu, A. Peck, A. McMillan, R. Mathis, D. Cannon, L. S. Jeong, J. W. Beach, W. B. Choi, S. Yeola, and et al. 1992. Activities of the four optical isomers of 2’, 3’−dideoxy−3’−thiacytidine (BCH−189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob Agents Chemother 36: 672−6. Sommadossi, J. P. , Z. Zhou, M. J. Hitchcock, H. M. McClure, M. el Kouni, and E. Cretton. 1992. Catabolism of 2’, 3’−Didehydro−2’, 3−DideoxyThymidine (D4T) in Isolated Hepatocytes and in Rhesus Monkeys. Proc. Annu. Meeting American Cancer Research 33: A3253. Univ. of Alabama. Yarchoan, R. , J. M. Pluda, R. V. Thomas, H. Mitsuya, P. Brouwers, K. M. Wyvill, N. Hartman, D. G. Johns, and S. Broder. 1990. Long−term toxicity/activity profile of 2’,3’−dideoxyinosine in AIDS or AIDS−related complex. Lancet 336: 526−9
4: 4’、5’−オキシランブロック化ヌクレオシド
8: 4’、5’−ビニル化合物
9: 中間体
Claims (21)
- 以下の構造式を有し、
XはH、C1−C4アルキル、F、Cl、BrまたはIであり、
R1はH、アシル基、C1−C20アルキルまたはエーテル基であり、
R2はH、アシル基、C1−C20アルキル若しくはエーテル基、リン酸、二リン酸、三リン酸、ホスホジエステル基または
Nuは、リン酸、ホスホラミデート、炭酸塩または隣接部分を具えたウレタン基を形成する生物活性抗ウイルス化合物の遊離基であり、
R8はH、またはC1−C20アルキル若しくはエーテル基であり、
R3は−(CH 2 ) n −C≡C−R a であり、
R3aおよびR3bはそれぞれ独立にH、F、Cl、BrまたはIであり、
RaはHまたは−C1−C4アルキルであり、
kは0、1、または2であり、
nは0、1、2、3、4または5であり、
またはこれらのアノマー、薬学的に受容可能な塩、多形体若しくは溶媒和物であることを特徴とする化合物。 - R3が−(CH2)n−C≡C−Raであり、nが0または1である請求項1〜3のいずれかひとつに記載の化合物。
- RがCH3であり、R3が−(CH2)n−C≡C−Raであり、nが0であり、RaがHである請求項1〜5のいずれかひとつに記載の化合物。
- R3aおよびR3bがともにHである請求項1〜6のいずれかひとつに記載の化合物。
- R2がH、アシル基、リン酸、二リン酸、三リン酸またはホスホジエステル基である請求項1〜8のいずれかひとつに記載の化合物。
- R2がHである請求項8に記載の化合物。
- 請求項1〜10のいずれかに記載の化合物の有効量を含む、ウイルス病気症状、不全またはウイルス病気に伴う症状の治療において使用するための薬学的組成物。
- 少なくとも1種の付加された抗HIV剤を更に含む請求項11に記載の薬学的組成物。
- 前記付加された抗HIV剤が、ヌクレオシド逆転写酵素阻害剤(NRTI)、非ヌクレオシド逆転写酵素阻害剤、プロテアーゼ阻害剤、融合阻害剤およびこれらの混合物からなる群から選ばれる請求項12に記載の薬学的組成物。
- 前記付加された抗HIV剤が、ddC、アバカビル、ddI、ddA、3TC、AZT、D4T、FTC、FddC、Fd4C、アタザナビル、アデフォビル ジピボキシル、テノフォビル ジソプロキシル、エテカビル(Etecavir)、インジナビル、KHI−227.2−[3−[3−(S)−[[(テトラヒドロ・フラニルオキシ)カルボニル]アミノ]−4−フェニル−2(R)−ヒドロキシブチル]]−N−(1,1−ジメチルエチル)デカヒドロ−3−イソキノリン・カルボキシアミド、VB−11,328、KNI−174、Val−Val−Sta、CPG53820、ビス−ValHOEt−N2 アザ−ペプチド 等電子体、C2−Sym ホスフィニクアミド誘導体、2,5−ジアミノ−N,N’−ビス(N−ベンジルオキシ・カルボニルエリル)−1,6−ジフェニル−3(S)、4(S)−ヘキサンジオル BzOCValPhe[ジCHOH(SS)PheValBzOC、2,5−ジアミノ−N,N’−ビス(N−ベンジルオキシ・カルボニルエリル)−1,6−ジフェニル−3(R)、4(R)−ヘキサンジオルBzOCValPhe[ジCHOH(RR)PheValBzOC、[ビス(SATE)ddAMP]、BILA 2186BS、エイジネラーゼ、A−98881、A−83962、A−80987、(2−ナフタルカルボニル)Asn[脱カルボニルPhe−ヒドロキシエチル]ProOtertブチル、2−アミノベンジルスタチンValylCbz誘導体、10H−2(Cbz−ValNH)3PhPr[14]パラシクロフェイン誘導体、10H−2(Cbz−ValNH)3PhPr[13]パラシクロフェイン誘導体、10H−2(Cbz−ValNH)3PhPr[13]メタシクロフェイン誘導体、10H−2(Cbz−Tle)3PhPr[14]パラシクロフェイン誘導体、1−(20HPr)−4−置換−ピペラジン(シクロプロピル)、チエニルカルバメート誘導体、1−(20HPr)−4−置換―ピペラジン(シクロブチル)、チエニルカルバメート誘導体、1−(20HPr)−4−置換―ピペラジン(3−ペンチル)、チエニルカルバメート誘導体、10H−2(Cbz−ValNH)3PhPr[17]パラシクロフェイン誘導体、A−81525、XM323、チプラナビル、チエノピリド(Thienopyrid)CONチエニルウレタン誘導体、SDZPRI053、SD146、テリナビル(Telinavir)、(R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu、サキナビル サキナビル/メルフィナビル(Melfinavir)誘導体、イソクインCON Thf−Thfウレタン類似体、イソクインCONチエニルウレタン類似体、R−87366、DMP460、L685,434、L685,434−6−ヒドロキシル誘導体、L685,434−OEtNMe2、L685,434−OPrMorph誘導体、L689,502、ラシナビル(Lasinavir)、アルヴィラン、ネルフィナビル−オクタヒドロ−チエノピリジン類似体、P9941、パリナビル(Palinavir)、ペニシリン、2イソクイン−OHPrNH2類似体からなる群から選ばれることを特徴とする請求項12に記載の薬学的組成物。
- 原因病原体がHIV−1またはHIV−2である感染の治療のための医薬の製造における請求項1〜10のいずれかひとつに記載の化合物の使用。
- 少なくとも1種の付加された抗HIV剤を更に含む前記医薬の製造における請求項15に記載の化合物の使用。
- 前記少なくとも1種の付加された抗HIV剤が、ヌクレオシド逆転写酵素阻害剤(NRTI)、非ヌクレオシド逆転写酵素阻害剤、プロテアーゼ阻害剤、融合阻害剤およびこれらの混合物からなる群から選ばれる請求項16に記載の化合物の使用。
- 併用療法でのHIV感染の治療のための医薬の製造における請求項1〜10のいずれかに記載の化合物の使用であって、前記化合物が、ヌクレオシド逆転写酵素阻害剤(NRTI)、非ヌクレオシド逆転写酵素阻害剤、プロテアーゼ阻害剤、融合阻害剤およびこれらの混合物からなる群から選ばれた少なくとも1種の付加された化合物と組み合わされることを特徴とする化合物の使用。
- 前記付加された化合物が、3TC(ラミブジン)、AZT(ジドブジン)、(−)−FTC,ddI(ジダノシン),ddC(ザルシタビン(Zalcitabine))、アバカビル(ABC)、テノフォビル(PMPA)、D−D4FC(リバーセット)、D4T(スタブジン)、ラシビル(Racivir)、L−FddC、L−D4FC(エルブシタビン)、NVP(ネビラピン)、DLV(デラビルジン)、EFV(エファビレンズ)、SQVM(サキナビルメシレート),RTV(リトナビル)、IDV(インジナビル)、SQV(サキナビル)、NFV(ネルフィナビル)、APV(アンプレナビル)、LPV(ロピナビル)、T20(フセオン(fuseon)、エンツビリデ(entuviride))およびこれらの混合物からなる群から選ばれる請求項18に記載の使用。
- 症状が進展する危険にある患者のウイルス感染による二次的な症状の発症の可能性を低減しまたは発症を遅延させるための医薬の製造における請求項1〜10のいずれかに記載の化合物の使用であって、前記化合物が、あるいはさらに、ヌクレオシド逆転写酵素阻害剤(NRTI)、非ヌクレオシド逆転写酵素阻害剤、プロテアーゼ阻害剤、融合阻害剤およびこれらの混合物からなる群から選ばれた少なくとも1種の付加された化合物と組み合わされることを特徴とする化合物の使用。
- 前記症状が後天性免疫不全症候群(AIDS)である請求項20に記載の使用。
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PCT/US2004/004713 WO2005011709A1 (en) | 2003-02-19 | 2004-02-18 | Anti-viral nucleoside analogs and methods for treating viral infections, especially hiv infections |
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MXPA05008736A (es) | 2005-10-05 |
US20100048500A1 (en) | 2010-02-25 |
US7589078B2 (en) | 2009-09-15 |
EP1653976A4 (en) | 2009-07-29 |
EP1653976A1 (en) | 2006-05-10 |
PL378354A1 (pl) | 2006-03-20 |
US20120252751A1 (en) | 2012-10-04 |
PL219609B1 (pl) | 2015-06-30 |
BRPI0407374A (pt) | 2006-01-10 |
EA200501325A1 (ru) | 2006-02-24 |
CA2514466C (en) | 2015-05-26 |
HK1087341A1 (en) | 2006-10-13 |
EA012844B1 (ru) | 2009-12-30 |
PL398295A1 (pl) | 2012-05-21 |
WO2005011709A1 (en) | 2005-02-10 |
CN1777432A (zh) | 2006-05-24 |
US8193165B2 (en) | 2012-06-05 |
JP2006528972A (ja) | 2006-12-28 |
KR101228503B1 (ko) | 2013-01-31 |
ZA200506630B (en) | 2006-06-28 |
KR20060026402A (ko) | 2006-03-23 |
EP2298783B1 (en) | 2017-12-06 |
CN1777432B (zh) | 2011-06-08 |
US9126971B2 (en) | 2015-09-08 |
KR20110079783A (ko) | 2011-07-07 |
CA2514466A1 (en) | 2005-02-10 |
US20040167096A1 (en) | 2004-08-26 |
CN102174038A (zh) | 2011-09-07 |
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