CN102015739A - 新的化合物以及用于治疗的方法 - Google Patents
新的化合物以及用于治疗的方法 Download PDFInfo
- Publication number
- CN102015739A CN102015739A CN2009801139076A CN200980113907A CN102015739A CN 102015739 A CN102015739 A CN 102015739A CN 2009801139076 A CN2009801139076 A CN 2009801139076A CN 200980113907 A CN200980113907 A CN 200980113907A CN 102015739 A CN102015739 A CN 102015739A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- bases
- compound
- alkenyl
- alkynyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 191
- 238000000034 method Methods 0.000 title claims description 48
- 238000002560 therapeutic procedure Methods 0.000 title 1
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 85
- 238000011282 treatment Methods 0.000 claims abstract description 62
- -1 amino-acid ester Chemical class 0.000 claims description 130
- 210000004027 cell Anatomy 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 58
- 201000011510 cancer Diseases 0.000 claims description 50
- 239000003814 drug Substances 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 230000003287 optical effect Effects 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 26
- 150000001413 amino acids Chemical class 0.000 claims description 25
- 230000003902 lesion Effects 0.000 claims description 24
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 23
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 19
- 238000006467 substitution reaction Methods 0.000 claims description 19
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 18
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 18
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 229920001021 polysulfide Polymers 0.000 claims description 15
- 239000005077 polysulfide Substances 0.000 claims description 15
- 150000008117 polysulfides Polymers 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000004641 (C1-C12) haloalkyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 230000012010 growth Effects 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 150000007970 thio esters Chemical group 0.000 claims description 9
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 230000000259 anti-tumor effect Effects 0.000 claims description 8
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 claims description 8
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 7
- 150000007942 carboxylates Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 6
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229940009456 adriamycin Drugs 0.000 claims description 6
- 230000001093 anti-cancer Effects 0.000 claims description 6
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 5
- 108010069236 Goserelin Proteins 0.000 claims description 5
- 238000009395 breeding Methods 0.000 claims description 5
- 230000001488 breeding effect Effects 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 229960003171 plicamycin Drugs 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 4
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical group C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 claims description 4
- 108010023617 abarelix Proteins 0.000 claims description 4
- 229960002184 abarelix Drugs 0.000 claims description 4
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 4
- 229960005102 foscarnet Drugs 0.000 claims description 4
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 claims description 4
- 108700020746 histrelin Proteins 0.000 claims description 4
- 229960002193 histrelin Drugs 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 239000002502 liposome Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 108010027841 pegademase bovine Proteins 0.000 claims description 4
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 3
- 102100040018 Interferon alpha-2 Human genes 0.000 claims description 3
- 108010079944 Interferon-alpha2b Proteins 0.000 claims description 3
- 108010050904 Interferons Proteins 0.000 claims description 3
- 102000014150 Interferons Human genes 0.000 claims description 3
- 108010063738 Interleukins Proteins 0.000 claims description 3
- 102000015696 Interleukins Human genes 0.000 claims description 3
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 3
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 229910001573 adamantine Inorganic materials 0.000 claims description 3
- 230000002155 anti-virotic effect Effects 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 229940079322 interferon Drugs 0.000 claims description 3
- 239000002777 nucleoside Substances 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 3
- 229960004276 zoledronic acid Drugs 0.000 claims description 3
- XSSYCIGJYCVRRK-RQJHMYQMSA-N (-)-carbovir Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1C[C@H](CO)C=C1 XSSYCIGJYCVRRK-RQJHMYQMSA-N 0.000 claims description 2
- UQQHOWKTDKKTHO-ICQCTTRCSA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-5-(6-methoxypurin-9-yl)oxolane-3,4-diol Chemical compound C1=NC=2C(OC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O UQQHOWKTDKKTHO-ICQCTTRCSA-N 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- ZSNNBSPEFVIUDS-SHYZEUOFSA-N 1-[(2r,4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](N=[N+]=[N-])[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 ZSNNBSPEFVIUDS-SHYZEUOFSA-N 0.000 claims description 2
- HBOMLICNUCNMMY-UHFFFAOYSA-N 1-[4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1OC(CO)C(N=[N+]=[N-])C1 HBOMLICNUCNMMY-UHFFFAOYSA-N 0.000 claims description 2
- JVYNJRBSXBYXQB-UHFFFAOYSA-N 4-[3-(4-carboxyphenoxy)propoxy]benzoic acid;decanedioic acid Chemical compound OC(=O)CCCCCCCCC(O)=O.C1=CC(C(=O)O)=CC=C1OCCCOC1=CC=C(C(O)=O)C=C1 JVYNJRBSXBYXQB-UHFFFAOYSA-N 0.000 claims description 2
- GIMSJJHKKXRFGV-BYPJNBLXSA-N 4-amino-1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidin-2-one Chemical compound C1=C(I)C(N)=NC(=O)N1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 GIMSJJHKKXRFGV-BYPJNBLXSA-N 0.000 claims description 2
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 claims description 2
- NHFYSWLWSKSKFU-PLDAJOQYSA-N 5-fluoro-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-1,3-diazinane-2,4-dione Chemical class O=C1NC(=O)C(C)(F)CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 NHFYSWLWSKSKFU-PLDAJOQYSA-N 0.000 claims description 2
- SEHFUALWMUWDKS-UHFFFAOYSA-N 5-fluoroorotic acid Chemical class OC(=O)C=1NC(=O)NC(=O)C=1F SEHFUALWMUWDKS-UHFFFAOYSA-N 0.000 claims description 2
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- FYEHYMARPSSOBO-UHFFFAOYSA-N Aurin Chemical compound C1=CC(O)=CC=C1C(C=1C=CC(O)=CC=1)=C1C=CC(=O)C=C1 FYEHYMARPSSOBO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 241001060848 Carapidae Species 0.000 claims description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 claims description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 claims description 2
- 108010092160 Dactinomycin Proteins 0.000 claims description 2
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 2
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 claims description 2
- NRGONRDRXCPMIC-GDKBPFBDSA-N N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 NRGONRDRXCPMIC-GDKBPFBDSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 102000003923 Protein Kinase C Human genes 0.000 claims description 2
- 108090000315 Protein Kinase C Proteins 0.000 claims description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 2
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 claims description 2
- 229930183665 actinomycin Natural products 0.000 claims description 2
- 125000002015 acyclic group Chemical group 0.000 claims description 2
- 229940060205 adagen Drugs 0.000 claims description 2
- 150000003838 adenosines Chemical class 0.000 claims description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 239000000430 cytokine receptor antagonist Substances 0.000 claims description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 claims description 2
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- 229940084910 gliadel Drugs 0.000 claims description 2
- 229960002913 goserelin Drugs 0.000 claims description 2
- 229940029575 guanosine Drugs 0.000 claims description 2
- 239000007943 implant Substances 0.000 claims description 2
- 102000002467 interleukin receptors Human genes 0.000 claims description 2
- 108010093036 interleukin receptors Proteins 0.000 claims description 2
- 229940047122 interleukins Drugs 0.000 claims description 2
- 238000001361 intraarterial administration Methods 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 210000002540 macrophage Anatomy 0.000 claims description 2
- 229940101533 mesnex Drugs 0.000 claims description 2
- FBOZXECLQNJBKD-UHFFFAOYSA-N methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-UHFFFAOYSA-N 0.000 claims description 2
- 229940048111 pegademase bovine Drugs 0.000 claims description 2
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 229940098901 polifeprosan 20 Drugs 0.000 claims description 2
- WTTIBCHOELPGFK-LBPRGKRZSA-N r82150 Chemical compound C1N(CC=C(C)C)[C@@H](C)CN2C(=S)NC3=CC=CC1=C32 WTTIBCHOELPGFK-LBPRGKRZSA-N 0.000 claims description 2
- 229960000329 ribavirin Drugs 0.000 claims description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 claims description 2
- 229960001055 uracil mustard Drugs 0.000 claims description 2
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 claims description 2
- 239000011719 vitamin A Substances 0.000 claims description 2
- 229940033942 zoladex Drugs 0.000 claims description 2
- 230000004663 cell proliferation Effects 0.000 claims 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
- 230000009385 viral infection Effects 0.000 abstract description 9
- 208000036142 Viral infection Diseases 0.000 abstract description 2
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 239000002585 base Substances 0.000 description 411
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 264
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 171
- 239000007787 solid Substances 0.000 description 72
- 238000004679 31P NMR spectroscopy Methods 0.000 description 66
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 66
- 238000005160 1H NMR spectroscopy Methods 0.000 description 65
- 230000014759 maintenance of location Effects 0.000 description 65
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 52
- 238000004440 column chromatography Methods 0.000 description 49
- 229940024606 amino acid Drugs 0.000 description 33
- 235000001014 amino acid Nutrition 0.000 description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 20
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 18
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 18
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 18
- 239000000376 reactant Substances 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 150000001854 cinnolines Chemical class 0.000 description 13
- 150000002240 furans Chemical class 0.000 description 13
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000008585 benzisoquinolines Chemical class 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 10
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 150000002475 indoles Chemical class 0.000 description 10
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 9
- 125000005605 benzo group Chemical group 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 150000005053 phenanthridines Chemical class 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 238000004007 reversed phase HPLC Methods 0.000 description 9
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 8
- AAQTWLBJPNLKHT-UHFFFAOYSA-N 1H-perimidine Chemical compound N1C=NC2=CC=CC3=CC=CC1=C32 AAQTWLBJPNLKHT-UHFFFAOYSA-N 0.000 description 8
- CYBHWCLUGRHMCK-UHFFFAOYSA-N 4aH-carbazole Chemical compound C1=CC=C2C3C=CC=CC3=NC2=C1 CYBHWCLUGRHMCK-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 7
- 125000001188 haloalkyl group Chemical group 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000006072 paste Substances 0.000 description 7
- 150000003250 quinolizines Chemical class 0.000 description 7
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 6
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Chemical group 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000004519 grease Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 125000000904 isoindolyl group Chemical class C=1(NC=C2C=CC=CC12)* 0.000 description 6
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 210000001165 lymph node Anatomy 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 150000003009 phosphonic acids Chemical class 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 230000010261 cell growth Effects 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- NMIQOOQCPBIZQI-UHFFFAOYSA-N C(CC)OC1=NC=C2NC=NC2=N1 Chemical compound C(CC)OC1=NC=C2NC=NC2=N1 NMIQOOQCPBIZQI-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000012054 celltiter-glo Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- SYLTXFOKMOCILU-UHFFFAOYSA-N imidazo[1,2-b][1,2,4]triazine Chemical compound N1=CC=NC2=NC=CN21 SYLTXFOKMOCILU-UHFFFAOYSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- JBMBVWROWJGFMG-UHFFFAOYSA-N 2-chloro-7h-purine Chemical compound ClC1=NC=C2NC=NC2=N1 JBMBVWROWJGFMG-UHFFFAOYSA-N 0.000 description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 241000282465 Canis Species 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000725643 Respiratory syncytial virus Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 125000005018 aryl alkenyl group Chemical group 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 230000005907 cancer growth Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052681 coesite Inorganic materials 0.000 description 3
- 229910052906 cristobalite Inorganic materials 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 210000001508 eye Anatomy 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- SXQCTESRRZBPHJ-UHFFFAOYSA-M lissamine rhodamine Chemical compound [Na+].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O SXQCTESRRZBPHJ-UHFFFAOYSA-M 0.000 description 3
- 159000000003 magnesium salts Chemical class 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 210000003739 neck Anatomy 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 150000003217 pyrazoles Chemical class 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 229910052682 stishovite Inorganic materials 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 3
- 229910052905 tridymite Inorganic materials 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 2
- 0 *c1c2nc[n](CC*CC(C(C3O)O)C3=O)c2nc(*)n1 Chemical compound *c1c2nc[n](CC*CC(C(C3O)O)C3=O)c2nc(*)n1 0.000 description 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 2
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 241001466953 Echovirus Species 0.000 description 2
- 241000709661 Enterovirus Species 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 241000150562 Hantaan orthohantavirus Species 0.000 description 2
- 241000701027 Human herpesvirus 6 Species 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 241000714209 Norwalk virus Species 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 208000002774 Paraproteinemias Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000003070 absorption delaying agent Substances 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- FZICDBOJOMQACG-UHFFFAOYSA-N benzo[h]isoquinoline Chemical compound C1=NC=C2C3=CC=CC=C3C=CC2=C1 FZICDBOJOMQACG-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- IMHDGJOMLMDPJN-UHFFFAOYSA-N biphenyl-2,2'-diol Chemical group OC1=CC=CC=C1C1=CC=CC=C1O IMHDGJOMLMDPJN-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- WDQPAMHFFCXSNU-BGABXYSRSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=N/C(C)C)/C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-BGABXYSRSA-N 0.000 description 2
- 229960004287 clofazimine Drugs 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000012050 conventional carrier Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000004982 dihaloalkyl group Chemical group 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 2
- 229960003727 granisetron Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- UFBBWLWUIISIPW-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazole Chemical compound C1=CSC2=NC=CN21 UFBBWLWUIISIPW-UHFFFAOYSA-N 0.000 description 2
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000000867 larynx Anatomy 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 101150029755 park gene Proteins 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229960001218 pegademase Drugs 0.000 description 2
- 229960001744 pegaspargase Drugs 0.000 description 2
- 108010001564 pegaspargase Proteins 0.000 description 2
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 2
- 229960004448 pentamidine Drugs 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000000505 pernicious effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000007639 printing Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Chemical class 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 229960005137 succinic acid Drugs 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 210000002105 tongue Anatomy 0.000 description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical class O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- LGEZTMRIZWCDLW-UHFFFAOYSA-N 14-methylpentadecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC(C)C LGEZTMRIZWCDLW-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- HIYWOHBEPVGIQN-UHFFFAOYSA-N 1h-benzo[g]indole Chemical compound C1=CC=CC2=C(NC=C3)C3=CC=C21 HIYWOHBEPVGIQN-UHFFFAOYSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical class C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- FNSNICXJJMJFKQ-UHFFFAOYSA-N 2-(1,3-thiazol-2-yl)imidazo[2,1-b][1,3]thiazole Chemical compound S1C(=NC=C1)C1=CN2C(S1)=NC=C2 FNSNICXJJMJFKQ-UHFFFAOYSA-N 0.000 description 1
- XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- PDHWTDJKKJYOGD-UHFFFAOYSA-N 2-[2-amino-6-(cyclopropylamino)purin-9-yl]ethoxymethylphosphonic acid Chemical compound C=12N=CN(CCOCP(O)(O)=O)C2=NC(N)=NC=1NC1CC1 PDHWTDJKKJYOGD-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- 125000004610 3,4-dihydro-4-oxo-quinazolinyl group Chemical group O=C1NC(=NC2=CC=CC=C12)* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- WREGKURFCTUGRC-UHFFFAOYSA-N 4-Amino-1-[5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1OC(CO)CC1 WREGKURFCTUGRC-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- XZLIYCQRASOFQM-UHFFFAOYSA-N 5h-imidazo[4,5-d]triazine Chemical group N1=NC=C2NC=NC2=N1 XZLIYCQRASOFQM-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- SPHOZXNZJHRHSL-UHFFFAOYSA-N 6-butoxy-7h-purin-2-amine Chemical compound CCCCOC1=NC(N)=NC2=C1NC=N2 SPHOZXNZJHRHSL-UHFFFAOYSA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- NZVORGQIEFTOQZ-UHFFFAOYSA-N 9-[2-(phosphonomethoxy)ethyl]guanine Chemical compound N1C(N)=NC(=O)C2=C1N(CCOCP(O)(O)=O)C=N2 NZVORGQIEFTOQZ-UHFFFAOYSA-N 0.000 description 1
- IRWJFLXBMUWAQM-UHFFFAOYSA-N 9h-xanthen-1-amine Chemical compound O1C2=CC=CC=C2CC2=C1C=CC=C2N IRWJFLXBMUWAQM-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 241000701386 African swine fever virus Species 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- IMMRDRYCKTVKPJ-UHFFFAOYSA-N CC(C)OC(OCOP(COCC[n]1c2nc(N)nc(OC)c2nc1)(OCOC(OC(C)C)=O)=O)=O Chemical compound CC(C)OC(OCOP(COCC[n]1c2nc(N)nc(OC)c2nc1)(OCOC(OC(C)C)=O)=O)=O IMMRDRYCKTVKPJ-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- 241000694440 Colpidium aqueous Species 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 206010061079 Congenital uterine anomaly Diseases 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 description 1
- 102100021906 Cyclin-O Human genes 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical compound OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- NTURVSFTOYPGON-UHFFFAOYSA-N Dihydroquinazoline Chemical compound C1=CC=C2C=NCNC2=C1 NTURVSFTOYPGON-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Chemical group 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 241000175212 Herpesvirales Species 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 206010020460 Human T-cell lymphotropic virus type I infection Diseases 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 101710091977 Hydrophobin Proteins 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229940127048 Metastron Drugs 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- BYEIJZFKOAXBBV-ATZCPNFKSA-N N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine Chemical compound CC(C)[C@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)CCC[C@H](N)C(O)=O BYEIJZFKOAXBBV-ATZCPNFKSA-N 0.000 description 1
- IZVGPDXGCRNKKL-UHFFFAOYSA-N N1CCCCC1.CC1=CC(=NN1)C Chemical compound N1CCCCC1.CC1=CC(=NN1)C IZVGPDXGCRNKKL-UHFFFAOYSA-N 0.000 description 1
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000150452 Orthohantavirus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- LUSZGTFNYDARNI-UHFFFAOYSA-N Sesamol Natural products OC1=CC=C2OCOC2=C1 LUSZGTFNYDARNI-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- XGTJCNSZEASLLL-YFKPBYRVSA-N [(2s)-1-(2,6-diaminopurin-9-yl)-3-hydroxypropan-2-yl]oxymethylphosphonic acid Chemical compound NC1=NC(N)=C2N=CN(C[C@@H](CO)OCP(O)(O)=O)C2=N1 XGTJCNSZEASLLL-YFKPBYRVSA-N 0.000 description 1
- FRPXSOOHWNMLPH-LURJTMIESA-N [(2s)-1-(6-aminopurin-9-yl)-3-hydroxypropan-2-yl]oxymethylphosphonic acid Chemical compound NC1=NC=NC2=C1N=CN2C[C@@H](CO)OCP(O)(O)=O FRPXSOOHWNMLPH-LURJTMIESA-N 0.000 description 1
- BFZJTDBFUROXJA-UHFFFAOYSA-N [1-(6-aminopurin-9-yl)-3-fluoropropan-2-yl]oxymethylphosphonic acid Chemical compound NC1=NC=NC2=C1N=CN2CC(CF)OCP(O)(O)=O BFZJTDBFUROXJA-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- 231100000230 acceptable toxicity Toxicity 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005024 alkenyl aryl group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004848 alkoxyethyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 125000004647 alkyl sulfenyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000005025 alkynylaryl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- ZXKINMCYCKHYFR-UHFFFAOYSA-N aminooxidanide Chemical compound [O-]N ZXKINMCYCKHYFR-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000005015 aryl alkynyl group Chemical group 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical class O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- MIURHJCJPVLLHQ-UHFFFAOYSA-N carbonic acid;chloromethane Chemical compound ClC.OC(O)=O MIURHJCJPVLLHQ-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 208000025046 carcinoma of lip Diseases 0.000 description 1
- 208000025188 carcinoma of pharynx Diseases 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000012321 colectomy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 201000010918 connective tissue cancer Diseases 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- NLORYLAYLIXTID-ISLYRVAYSA-N diethylstilbestrol diphosphate Chemical compound C=1C=C(OP(O)(O)=O)C=CC=1C(/CC)=C(\CC)C1=CC=C(OP(O)(O)=O)C=C1 NLORYLAYLIXTID-ISLYRVAYSA-N 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical class C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229960001766 estramustine phosphate sodium Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- LIYGYAHYXQDGEP-UHFFFAOYSA-N firefly oxyluciferin Natural products Oc1csc(n1)-c1nc2ccc(O)cc2s1 LIYGYAHYXQDGEP-UHFFFAOYSA-N 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 229960000297 fosfestrol Drugs 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical class CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940078545 isocetyl stearate Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 201000004962 larynx cancer Diseases 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 description 1
- 229910000022 magnesium bicarbonate Inorganic materials 0.000 description 1
- 239000002370 magnesium bicarbonate Substances 0.000 description 1
- 235000014824 magnesium bicarbonate Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000029559 malignant endocrine neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- BKBBTCORRZMASO-ZOWNYOTGSA-M methotrexate monosodium Chemical compound [Na+].C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C([O-])=O)C=C1 BKBBTCORRZMASO-ZOWNYOTGSA-M 0.000 description 1
- 229960003058 methotrexate sodium Drugs 0.000 description 1
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- FYFFGSSZFBZTAH-UHFFFAOYSA-N methylaminomethanetriol Chemical class CNC(O)(O)O FYFFGSSZFBZTAH-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical group 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 208000020717 oral cavity carcinoma Diseases 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- JJVOROULKOMTKG-UHFFFAOYSA-N oxidized Photinus luciferin Chemical compound S1C2=CC(O)=CC=C2N=C1C1=NC(=O)CS1 JJVOROULKOMTKG-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940090668 parachlorophenol Drugs 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- YWFGPFUURZNKDW-UHFFFAOYSA-M sodium 2-amino-9-[(2-oxido-2-oxo-1,3,2lambda5-dioxaphosphinan-5-yl)oxymethyl]-1H-purin-6-one Chemical compound [Na+].Nc1nc(=O)c2ncn(COC3COP([O-])(=O)OC3)c2[nH]1 YWFGPFUURZNKDW-UHFFFAOYSA-M 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- VYFPSYVVFFFYBF-UHFFFAOYSA-N sodium;triphenylphosphane Chemical compound [Na].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VYFPSYVVFFFYBF-UHFFFAOYSA-N 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- AHBGXTDRMVNFER-FCHARDOESA-L strontium-89(2+);dichloride Chemical compound [Cl-].[Cl-].[89Sr+2] AHBGXTDRMVNFER-FCHARDOESA-L 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 1
- 229960003454 tamoxifen citrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- IWVMCIAPBOORJL-UHFFFAOYSA-N thieno[2,3-b]furan Chemical class C1=CSC2=C1C=CO2 IWVMCIAPBOORJL-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 208000025358 tongue carcinoma Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- MYAJTCUQMQREFZ-UHFFFAOYSA-K tppts Chemical compound [Na+].[Na+].[Na+].[O-]S(=O)(=O)C1=CC=CC(P(C=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=C(C=CC=2)S([O-])(=O)=O)=C1 MYAJTCUQMQREFZ-UHFFFAOYSA-K 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000001701 trimethoxybenzyl group Chemical group 0.000 description 1
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001018 xanthene dye Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/76—Chemiluminescence; Bioluminescence
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Oncology (AREA)
- Physics & Mathematics (AREA)
- Communicable Diseases (AREA)
- Biotechnology (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Plasma & Fusion (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了用于治疗肿瘤并预防或者治疗病毒感染的具有结构(1)的新的化合物,其中Z、Y、R1、R2′和R2在说明书中定义。
Description
背景技术
含有膦酸酯基团的核苷酸类似物在例如下述文件中披露:美国专利4,659,825、4,808,716、4,724,233、5,142,051、5,302,585、5,208,221、5,352,786、5,356,886、5,663,159、5,977,061和05459256,欧洲公开号EP421,819、434,450、481,214、468,119、269,947、481,214、630,381、369,409、454,427、618,214和398,231以及WO 95/07920、27002808A1、09526734A1、94/03467、94/03467、95/07920、07/002912、05/066189、02/08241和94/03467,CN 101066981,Daluge等(34th Interscience Conference onAntimicrobial Agents and Chemotherapy,Oct.4-7,1994),Cihlar等″Antimicrobial Agents and Chemotherapy″39(1):117-124(1995)和Holy等″ACS Symp.Ser.″401:57-71(1989)and Holy,″Kem.Ind.″38(10):457-462(1989),Naessens等“Biochem.Pharmacol.”1999 Jul 15;58(2):311-23,Valerianova等“Anticancer Res.”2001May-Jun;21(3B):2057-64,Parker WB,Shaddix SC,Rose LM,Pham PT,Hua M,Vince R.Nucleosides NucleotidesNucleic Acids.2000 Apr;19(4):795-804,Daluge SM,Good SS,Faletto MB,Miller WH,St Clair MH,Boone LR,Tisdale M,Parry NR,Reardon JE,Dornsife RE,Averett DR,KrenitskyTA.Antimicrob Agents Chemother.1997May;41(5):1082-1093,和WO2007/136650。
发明内容
本发明的一种实施方案为具有结构(1)的化合物和其治疗用盐(therapeutically acceptable salt)和/或富集的旋光异构体(enriched opticalisomer),所述的结构(1)如下所示:
其中
Y独立为-OR3;氨基酸、氨基酸酰胺或者氨基酸酯或者经氨基酸的氨基连接的氨基酸硫酯;
R1为CH3或者H;
R2′和R2独立为H、卤素、NH2、NH(R10)、N(R10)2或者X,但至少一个R2或者R2′为X;
R3独立为H;未取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基;或者被下述基团取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基:C1-C12烷氧基、卤素、羧基、羧酸酯基团、羟基、氨基、CN、NO2、OH、巯基、硫羟酸酯基团(thiolester)、叠氮基、芳基氨基、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基;
X为-OR10,
R10为未取代的以下基团:C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
或者R10为C2-C15烷基、C3-C15烯基、C6-C15芳基烯基、C3-C15炔基、C7-C15芳基炔基、C1-C6烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂烷基或者C3-C6杂环烷基,其中在烷基部分中与-OR10的氧不相邻的1至2个亚甲基已被-O-、-S-或者N(R3)替代;
或者前述的R10基团中的一个取代有卤素、R3、CN或者N3中的1至3个;
Z为N或者CH,条件是杂环的核与嘌呤的不同之处在于:它们中的Z最多有一个是不同的。
在另一种实施方案中,本发明为具有结构(1)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(1)如下所示:
其中
其中Y独立为-OR3;氨基酸、氨基酸酰胺或者氨基酸酯或者经氨基酸的氨基连接的氨基酸硫酯,或者结构(2)的基团:
条件是至少一个Y为结构(2)的基团;
R1为CH3或者H;
R2′和R2独立为H、卤素、NH2、NH(R10)、N(R10)2或者X;
R3独立为H;未取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基;或者被下述基团取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基:C1-C12烷氧基、卤素、羧基、羧酸酯基团、羟基、氨基、CN、NO2、OH、巯基、硫羟酸酯基团、叠氮基、芳基氨基、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基;
R4为R3,或者OR4为NH2、NH(R10)或者N(R10)2;
X为-OR10,
R10为未取代的以下基团:C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
或者R10为C2-C15烷基、C3-C15烯基、C6-C15芳基烯基、C3-C15炔基、C7-C15芳基炔基、C1-C6烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂烷基或者C3-C6杂环烷基,其中在烷基部分中与-OR10的氧不相邻的1至2个亚甲基已被-O-、-S-或者N(R3)替代;
或者前述的R10基团中的一个取代有卤素、R3、CN或者N3中的1至3个;
Z为N或者CH,条件是杂环的核与嘌呤的不同之处在于:它们中的Z最多有一个是不同的。
在另一种实施方案中,本发明提供了具有结构(3)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(3)如下所示:
其中
Y独立为-OR3;氨基酸、氨基酸酰胺或者氨基酸酯或者经氨基酸的氨基连接的氨基酸硫酯;
R1为CH3或者H;
R2′为-OR10;
R3独立为H;未取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基;或者被下述基团取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基:C1-C12烷氧基、卤素、羧基、羧酸酯基团、羟基、氨基、CN、NO2、OH、巯基、硫羟酸酯基团、叠氮基、芳基氨基、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基;其中当R3为未取代的C1-C12烷基时,在R3上与-OR3的氧不相邻的1至4个亚甲基任选被-O-或者-S-或者-C(O)-替代;
R10为未取代的以下基团:C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
或者R10为C1-C15烷基、C3-C15烯基、C6-C15芳基烯基、C3-C15炔基、C6-C15芳基炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂烷基或者C3-C6杂环烷基,其中在烷基部分中与-OR10的氧不相邻的1至2个亚甲基已被-O-、-S-或者N(R3)替代;
或者前述的R10基团中的一个取代有卤素、R3、CN或者N3中的1至3个。
在另一种实施方案中,本发明提供了具有结构(3)的化合物和其治疗用盐和/或富集的旋光异构体,其中Y独立为-OR3;氨基酸、氨基酸酰胺或者氨基酸酯或者经氨基酸的氨基连接的氨基酸硫酯,或者结构(2)的基团:
条件是至少一个Y为结构(2)的基团;
R1为CH3或者H;
R2′为-OR10;
R3独立为H;未取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基;或者被下述基团取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基:C1-C12烷氧基、卤素、羧基、羧酸酯基团、羟基、氨基、CN、NO2、OH、巯基、硫羟酸酯基团、叠氮基、芳基氨基、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基;其中当R3为未取代的C1-C12烷基时,在R3上与-OR3的氧不相邻的1至4个亚甲基任选被-O-或者-S-或者-C(O)-替代;
R10为未取代的以下基团:C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
或者R10为C2-C15烷基、C3-C15烯基、C6-C15芳基烯基、C3-C15炔基、C6-C15芳基炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂烷基或者C3-C6杂环烷基,其中在烷基部分中与-OR10的氧不相邻的1至2个亚甲基已被-O-、-S-或者N(R3)替代;
或者前述的R10基团中的一个取代有卤素、R3、CN或者N3中的1至3个。
在另一种实施方案中,本发明提供了具有结构(4)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(4)如下所示:
其中每个Ra独立为C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基-C1-C4烷基-,其中Ra和-NH-上的氮任选形成(5-7)元环;
每个Rb独立为C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基-C1-C4烷基-;
R10为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,其中C1-C8烷基任选被一个C1-C4烷氧基取代。
优选地,本发明提供了结构(4)的化合物和其治疗用盐和/或富集的旋光异构体,其中每个Ra独立为C1-C4烷基,或者苄基,每个Rb独立为C1-C4烷基,R10为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,其中C1-C8烷基任选被一个C1-C4烷氧基取代。
在另一种实施方案中,本发明提供了具有结构(5)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(5)如下所示:
其中每个Rb独立为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,或者C6-C10芳基-C1-C4烷基-;
R10为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,其中C1-C8烷基任选被一个C1-C4烷氧基取代。
优选地,本发明提供了结构(5)的化合物和其治疗用盐和/或富集的旋光异构体,其中每个Rb独立为C1-C4烷基,或者苄基,R10为C1-C4烷基。
在另一种实施方案中,本发明提供了具有结构(6)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(6)如下所示:
其中
Ra为C1-C4烷基、C2-C4烯基、C2-C4炔基、C6-C10芳基-C1-C4烷基-,其中Ra和-NH-上的氮任选形成(5-7)元环;
Rb为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,或者C6-C10芳基-C1-C4烷基-;
Rc为C6-C10芳基,其任选被一个或者两个选自卤素、氰基或者C1-C4烷基的取代基取代;
R10为C1-C4烷基。
优选地,本发明提供了结构(6)的化合物和其治疗用盐和/或富集的旋光异构体,其中Ra为C1-C4烷基或者苄基,Rb为C1-C4烷基,Rc为苯基。
在另一种实施方案中,本发明提供了具有结构(7)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(7)如下所示:
其中
每个Rc独立为C1-C4烷基,其被一个C1-C4烷基-O-C(O)-O-基团取代;R10为C1-C4烷基。
在另一种实施方案中,本发明提供了具有结构(8)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(8)如下所示:
其中R2′为C4-C7环烷基-NH-;每个Ra独立为C1-C4烷基、C2-C4烯基、C2-C4炔基,其中Ra和-NH-上的氮任选形成(5-7)元环;每个Rb独立为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,或者C6-C10芳基C1-C4烷基-。
在另一种实施方案中,本发明提供了具有结构(9)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(9)如下所示:
其中R2′为C4-C7环烷基-NH-;每个Ra独立为C1-C4烷基、C2-C4烯基、C2-C4炔基,其中Ra和-NH-上的氮任选形成(5-7)元环;Rb为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,或者C6-C10芳基-C1-C4烷基-;Rc为C6-C10芳基,其任选被一个或者两个选自卤素、氰基或者C1-C4烷基的取代基取代。
在另一种实施方案中,本发明提供了具有结构(10)的化合物和其治疗用盐和/或富集的旋光异构体,所述的结构(10)如下所示:
其中Rb独立为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,或者C6-C10芳基-C1-C4烷基-。优选地,Rb为C1-C4烷基。
本发明的其它实施方案包括与药用载体组合的化合物(1),所述的化合物在治疗恶性肿瘤或者预防或者治疗病毒感染中的用途,以及化合物(1)与其它抗病毒剂或者抗肿瘤剂的组合。
本发明提供了式I的化合物,使用所述化合物的药物组合物以及使用所述化合物的方法。为了解释本说明,将应用下述定义,且只要是适当的,以单数使用的术语也将包括复数形式,且反之亦然。
如本申请使用的那样,且除非被随后的上下文修改:
烷基表示C1-C15支链的、正链的或者环状的饱和烃。优选地,烷基包含1至8个碳原子,或者1至6个碳原子,或者1至4个碳原子。烷基的代表性的实例包括但不限于甲基、乙基、丙基、环丙基、环丁基、异丙基、正丁基、仲丁基、异丁基和叔丁基、戊基、异戊基、1-甲基丁基、1-乙基丙基、新戊基、以及叔戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。
烯基表示C2-C15支链的、正链的或者环状的烃,其含有至少1个(通常1-3个)顺式或者反式取向的共轭或者非共轭的双键,包括烯丙基、乙烯基、丙烯基、异丙烯基、1-丁烯基、2-丁烯基和3-丁烯基、1-异丁烯基和2-异丁烯基等。
炔基表示C2-C15支链的、正链的或者环状的烃,其含有至少1个(通常1-3个)三键,例如2-丙炔基。
烷氧基表示烷基-O-,其中烷基在上面定义。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊基氧基、己基氧基、环丙基氧基-、环己基氧基-等。本申请使用的术语“低级烷氧基”是指具有1-7个碳且优选为1-4个碳的烷氧基。
本申请使用的术语“卤代(halo)”或者“卤素(halogen)”是指氟、氯、溴和碘。
卤代烷基是指被一个或者多个如本申请梭定义的卤素取代的如本申请所定义的烷基。优选地,卤代烷基可为单卤代烷基、二卤代烷基或者多卤代烷基,所述的多卤代烷基包括全卤代烷基。单卤代烷基可在烷基中具有一个碘、溴、氯或者氟。二卤代烷基和多卤代烷基可在烷基中具有两个或者多个相同的卤素原子或者不同卤素原子的组合。优选地,多卤代烷基含有多达12、10、或者8或者6或者4或者3或者2个卤素。卤代烷基的非限制性实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。全卤代烷基是指全部氢原子都被卤素原子替代的烷基。
烷基氨基是指烷基-NH-,其中烷基在本申请中定义。
杂烷基是指包含一定数目的碳原子和选自O、N、Si和S的一至三个杂原子的直链或者支链烃基或者它们的组合,其中氮原子和硫原子可任选被氧化且氮杂原子可任选被季铵化。一个或者多个杂原子O、N和S可位于杂烷基的任意内部位置。
术语″芳基″是指单环或者二环芳烃基,其在环的部分具有6-14个碳原子。优选地,芳基为(C6-C10)芳基。非限制性实例包括苯基、联苯基、萘基或者四氢萘基,每个基团可任选被1-4个取代基取代,所述的取代基诸如任选取代的烷基、三氟甲基、环烷基、卤素、羟基、烷氧基、酰基、烷基-C(O)-O-、芳基-O-、杂芳基-O-、任选取代的氨基、巯基、烷基硫基、芳基硫基、硝基、氰基、羧基、烷基-O-C(O)-、氨甲酰基、烷基硫羰基(alkylthiono)、磺酰基、磺酰氨基、杂环烷基等。
此外,芳基表示仅含有碳环原子的芳香取代基,其可为单芳环或者多芳环,所述的多芳环稠合在一起、共价连接或者与共有的基团诸如亚甲基或者亚乙基部分连接。共有的连接基团也可为如在二苯甲酮中的羰基或者如在二苯基醚中的氧或者如在二苯胺中的氮。芳基氨基表示芳基-NH2-。
芳烷基表示芳基-烷基-,其中芳基和烷基在本申请中定义。
芳烯基表示芳基-烯基-,其中芳基和烯基在本申请中定义。
芳炔基表示芳基-炔基-,其中芳基和炔基在本申请中定义。
环烷基表示饱和的、单环或者二环烃环,通常具有构成所述环的特定数目的碳原子(即C3-C7环烷基是指具有3、4、5、6或者7个作为环原子的碳原子的环烷基)。环烷基可在任何环原子处与基团或底物连接,除非该连接不符合化合价要求。
杂芳基表示5-14元的单环或者二环或者稠合的多环系统,其为芳香性的,且具有选自N、O或者S的1至8个杂原子。优选地,杂芳基为5-10或者5-7元环系统。典型的杂芳基包括噻吩-2-基或者噻吩-3-基、呋喃-2-基或者呋喃-3-基、吡咯烷-2-基或者吡咯烷-3-基、咪唑-2-基、咪唑-4-基或者咪唑-5-基、吡唑-3-基、吡唑-4-基或者吡唑-5-基、噻唑-2-基、噻唑-4-基或者噻唑-5-基、异噻唑-3-基、异噻唑-4-基或者异噻唑-5-基、噁唑-2-基、噁唑-4-基或者噁唑-5-基、异噁唑-3-基、异噁唑-4-基或者异噁唑-5-基、1,2,4-三唑-3-基或者1,2,4-三唑-5-基、1,2,3-三唑-4-基或者1,2,3-三唑-5-基、四唑基、吡啶-2-基、吡啶-3-基或者吡啶-4-基、哒嗪-3-基或者哒嗪-4-基、吡嗪-3-基、吡嗪-4-基或者吡嗪-5-基、吡嗪-2-基、嘧啶-2-基、嘧啶-4-基或者嘧啶-5-基。术语“杂芳基”也指这样的基团,其中的杂芳环与一个或者多个芳环、环脂肪族环或者杂环基环稠合,其中所述的连接基团或者连接点位于所述的杂芳环上。非限制性的实例包括但不限于吲嗪-1-基、吲嗪-2-基、吲嗪-3-基、吲嗪-5-基、吲嗪-6-基、吲嗪-7-基或者吲嗪-8-基、异吲哚-1-基、异吲哚-3-基、异吲哚-4-基、异吲哚-5-基、异吲哚-6-基或者异吲哚-7-基、吲哚-2-基、吲哚-3-基、吲哚-4-基、吲哚-5-基、吲哚-6-基或者吲哚-7-基、吲唑-2-基、吲唑-3-基、吲唑-4-基、吲唑-5-基、吲唑-6-基或者吲唑-7-基、嘌呤-2-基、嘌呤-4-基、嘌呤-5-基、嘌呤-6-基、嘌呤-7-基或者嘌呤-8-基、喹嗪-1-基、喹嗪-2-基、喹嗪-3-基、喹嗪-4-基、喹嗪-6-基、喹嗪-7-基、喹嗪-8-基或者喹嗪-9-基、喹啉-2-基、喹啉-3-基、喹啉-4-基、喹啉-5-基、喹啉-6-基、喹啉-7-基或者喹啉-8-基、异喹啉-1-基、异喹啉-3-基、异喹啉-4-基、异喹啉-5-基、异喹啉-6-基、异喹啉-7-基或者异喹啉-8-基、酞嗪-1-基、酞嗪-4-基、酞嗪-5-基、酞嗪-6-基、酞嗪-7-基或者酞嗪-8-基、二氮杂萘-2-基、二氮杂萘-3-基、二氮杂萘-4-基、二氮杂萘-5-基或者二氮杂萘-6-基、喹唑啉-2-基、喹唑啉-3-基、喹唑啉-5-基、喹唑啉-6-基、喹唑啉-7-基或者喹唑啉-8-基、噌啉-3-基、噌啉-4-基、噌啉-5-基、噌啉-6-基、噌啉-7-基或者噌啉-8-基、蝶啶-2-基、蝶啶-4-基、蝶啶-6-基或者蝶啶-7-基、4aH-咔唑-1-基、4aH-咔唑-2-基、4aH-咔唑-3-基、4aH-咔唑-4-基、4aH-咔唑-5-基、4aH-咔唑-6-基、4aH-咔唑-7-基或者4aH-咔唑-8-基、咔唑-1-基、咔唑-2-基、咔唑-3-基、咔唑-4-基、咔唑-5-基、咔唑-6-基、咔唑-7-基或者咔唑-8-基、咔啉-1-基、咔啉-3-基、咔啉-4-基、咔啉-5-基、咔啉-6-基、咔啉-7-基、咔啉-8-基或者咔啉-9-基、菲啶-1-基、菲啶-2-基、菲啶-3-基、菲啶-4-基、菲啶-6-基、菲啶-7-基、菲啶-8-基、菲啶-9-基或者菲啶-10-基、吖啶-1-基、吖啶-2-基、吖啶-3-基、吖啶-4-基、吖啶-5-基、吖啶-6-基、吖啶-7-基、吖啶-8-基或者吖啶-9-基、萘嵌间二氮杂苯-1-基、萘嵌间二氮杂苯-2-基、萘嵌间二氮杂苯-4-基、萘嵌间二氮杂苯-5-基、萘嵌间二氮杂苯-6-基、萘嵌间二氮杂苯-7-基、萘嵌间二氮杂苯-8-基或者萘嵌间二氮杂苯-9-基、菲咯啉-2-基、菲咯啉-3-基、菲咯啉-4-基、菲咯啉-5-基、菲咯啉-6-基、菲咯啉-8-基、菲咯啉-9-基或者菲咯啉-10-基、吩嗪-1-基、吩嗪-2-基、吩嗪-3-基、吩嗪-4-基、吩嗪-6-基、吩嗪-7-基、吩嗪-8-基或者吩嗪-9-基、吩噻嗪-1-基、吩噻嗪-2-基、吩噻嗪-3-基、吩噻嗪-4-基、吩噻嗪-6-基、吩噻嗪-7-基、吩噻嗪-8-基、吩噻嗪-9-基或者吩噻嗪-10-基、吩噁嗪-1-基、吩噁嗪-2-基、吩噁嗪-3-基、吩噁嗪-4-基、吩噁嗪-6-基、吩噁嗪-7-基、吩噁嗪-8-基、吩噁嗪-9-基或者吩噁嗪-10-基、苯并异喹啉-2-基、苯并异喹啉-3-基、苯并异喹啉-4-基、苯并异喹啉-5-基、苯并异喹啉-6-基或者苯并异喹啉-1-基、苯并异喹啉-3-基、苯并异喹啉-4-基、苯并异喹啉-5-基、苯并异喹啉-6-基、苯并异喹啉-7-基、苯并异喹啉-8-基、苯并异喹啉-9-基或者苯并异喹啉-10-基、噻吩并[2,3-b]呋喃-2-基、噻吩并[2,3-b]呋喃-3-基或者噻吩并[2,3-b]呋喃-4-基、7H-吡嗪并[2,3-c]咔唑-2-基、7H-吡嗪并[2,3-c]咔唑-3-基、7H-吡嗪并[2,3-c]咔唑-5-基、7H-吡嗪并[2,3-c]咔唑-6-基、7H-吡嗪并[2,3-c]咔唑-7-基、7H-吡嗪并[2,3-c]咔唑-8-基、7H-吡嗪并[2,3-c]咔唑-9-基、7H-吡嗪并[2,3-c]咔唑-10-基或者7H-吡嗪并[2,3-c]咔唑-11-基、2H-呋喃并[3,2-b]-吡喃-2-基、2H-呋喃并[3,2-b]-吡喃-3-基、2H-呋喃并[3,2-b]-吡喃-5-基、2H-呋喃并[3,2-b]-吡喃-6-基或者2H-呋喃并[3,2-b]-吡喃-7-基、5H-吡啶并[2,3-d]-o-噁嗪-2-基、5H-吡啶并[2,3-d]-o-噁嗪-3-基、5H-吡啶并[2,3-d]-o-噁嗪-4-基、5H-吡啶并[2,3-d]-o-噁嗪-5-基、5H-吡啶并[2,3-d]-o-噁嗪-7-基或者5H-吡啶并[2,3-d]-o-噁嗪-8-基、1H-吡唑并[4,3-d]-噁唑-1-基、1H-吡唑并[4,3-d]-噁唑-3-基或者1H-吡唑并[4,3-d]-噁唑-5-基、4H-咪唑并[4,5-d]噻唑-2-基、4H-咪唑并[4,5-d]噻唑-4-基或者4H-咪唑并[4,5-d]噻唑-5-基、吡嗪并[2,3-d]哒嗪-3-基、吡嗪并[2,3-d]哒嗪-5-基或者吡嗪并[2,3-d]哒嗪-8-基、咪唑并[2,1-b]噻唑-2-基、咪唑并[2,1-b]噻唑-3-基、咪唑并[2,1-b]噻唑-5-基或者咪唑并[2,1-b]噻唑-6-基、呋喃并[3,4-c]噌啉-1-基、呋喃并[3,4-c]噌啉-3-基、呋喃并[3,4-c]噌啉-6-基、呋喃并[3,4-c]噌啉-7-基、呋喃并[3,4-c]噌啉-8-基或者呋喃并[3,4-c]噌啉-9-基、4H-吡啶并[2,3-c]咔唑-1-基、4H-吡啶并[2,3-c]咔唑-2-基、4H-吡啶并[2,3-c]咔唑-3-基、4H-吡啶并[2,3-c]咔唑-4-基、4H-吡啶并[2,3-c]咔唑-5-基、4H-吡啶并[2,3-c]咔唑-6-基、4H-吡啶并[2,3-c]咔唑-8-基、4H-吡啶并[2,3-c]咔唑-9-基、4H-吡啶并[2,3-c]咔唑-10-基或者4H-吡啶并[2,3-c]咔唑-11-基、咪唑并[1,2-b][1,2,4]三嗪-2-基、咪唑并[1,2-b][1,2,4]三嗪-3-基、咪唑并[1,2-b][1,2,4]三嗪-6-基或者咪唑并[1,2-b][1,2,4]三嗪-7-基、苯并[b]噻吩-7-基、苯并噁唑-2-基、苯并噁唑-4-基、苯并噁唑-5-基、苯并噁唑-6-基或者苯并噁唑-7-基、苯并咪唑-2-基、苯并咪唑-4-基、苯并咪唑-5-基、苯并咪唑-6-基或者苯并咪唑-7-基、苯并噻唑-2-基、苯并噻唑-4-基、苯并噻唑-4-基、苯并噻唑-5-基、苯并噻唑-6-基或者苯并噻唑-7-基、苯并氧杂-1-基(1-benzoxapinyl)、苯并氧杂-2-基、苯并氧杂-4-基、苯并氧杂-5-基、苯并氧杂-6-基、苯并氧杂-7-基、苯并氧杂-8-基或者苯并氧杂-9-基、苯并噁嗪-2-基、苯并噁嗪-4-基、苯并噁嗪-5-基、苯并噁嗪-6-基、苯并噁嗪-7-基或者苯并噁嗪-8-基、1H-吡咯并[1,2-b][2]苯并氮杂-1-基、1H-吡咯并[1,2-b][2]苯并氮杂-2-基、1H-吡咯并[1,2-b][2]苯并氮杂-3-基、1H-吡咯并[1,2-b][2]苯并氮杂-5-基、1H-吡咯并[1,2-b][2]苯并氮杂-6-基、1H-吡咯并[1,2-b][2]苯并氮杂-7-基、1H-吡咯并[1,2-b][2]苯并氮杂-8-基、1H-吡咯并[1,2-b][2]苯并氮杂-9-基、1H-吡咯并[1,2-b][2]苯并氮杂-10-基或者1H-吡咯并[1,2-b][2]苯并氮杂-11-基。典型的稠合的杂芳基包括但不限于喹啉-2-基、喹啉-3-基、喹啉-4-基、喹啉-5-基、喹啉-6-基、喹啉-7-基或者喹啉-8-基、异喹啉-1-基、异喹啉-3-基、异喹啉-4-基、异喹啉-5-基、异喹啉-6-基、异喹啉-7-基或者异喹啉-8-基、吲哚-2-基、吲哚-3-基、吲哚-4-基、吲哚-5-基、吲哚-6-基或者吲哚-7-基、苯并[b]噻吩-2-基、苯并[b]噻吩-3-基、苯并[b]噻吩-4-基、苯并[b]噻吩-5-基、苯并[b]噻吩-6-基或者苯并[b]噻吩-7-基、苯并噁唑-2-基、苯并噁唑-4-基、苯并噁唑-5-基、苯并噁唑-6-基或者苯并噁唑-7-基、苯并咪唑-2-基、苯并咪唑-4-基、苯并咪唑-5-基、苯并咪唑-6-基或者苯并咪唑-7-基、苯并噻唑-2-基、苯并噻唑-4-基、苯并噻唑-5-基、苯并噻唑-6-基或者苯并噻唑-7-基。杂芳基可为单环、二环、三环或者多环基团,优选地为单环、二环或者三环基团,更优选地为单环或者二环。
杂芳烷基表示杂芳基-烷基-,其中杂芳基和烷基均在本申请中定义。
杂环基团(heterocycle)或者杂环基(heterocyclo)表示任选取代的、全部饱和的或者不饱和的、芳香的或者非芳香的环基,例如其为4-至7-元单环,7-至12-元二环或者10-至15-元三环系统,其在至少一个含有碳原子的环中具有至少一个杂原子。含有杂原子的杂环基团的每个环可具有选自氮原子、氧原子和硫原子的1、2或者3个杂原子,其中氮原子和硫原子也可任选被氧化。杂环基团可在杂原子或者碳原子处连接。
代表性的单环杂环基团包括吡咯烷基、吡咯基、吡唑基、氧杂环丁烷基、吡唑啉基、咪唑基、咪唑啉基、咪唑烷基、三唑基、噁唑基、噁唑烷基、异噁唑啉基、异噁唑基、噻唑基、噻二唑基、噻唑烷基、异噻唑基、异噻唑烷基、呋喃基、四氢呋喃基、噻吩基、噁二唑基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、4-哌啶酮基、吡啶基、吡嗪基、嘧啶基、哒嗪基、四氢吡喃基、吗啉基、硫吗啉基、S-氧代硫吗啉基(thiamorpholinyl sulfoxide)、S,S-二氧代硫吗啉基(thiamorpholinyl sulfone)、1,3-二氧戊环基和四氢-1,1-二氧代噻吩基、1,1,4-三氧代-1,2,5-噻二唑烷-2-基等。
代表性的二环杂环基团包括吲哚基、二氢吲哚基、苯并噻唑基、苯丙噁嗪基、苯并噁唑基、苯并噻吩基、苯并噻嗪基、奎宁环基、喹啉基、四氢喹啉基、十氢喹啉基、异喹啉基、四氢异喹啉基、十氢异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基(诸如呋喃并[2,3-c]吡啶基、呋喃并[3,2-b]-吡啶基]或者呋喃并[2,3-b]吡啶基)、二氢异吲哚基、1,3-二氧代-1,3-二氢异吲哚-2-基、二氢喹唑啉基(诸如3,4-二氢-4-氧代-喹唑啉基)、酞嗪基(phthalazinyl)等。
杂环烷基表示任意的全饱和的烷基形成的具有C3-C7的环基,其中1至3个CH2基团取代有N(R)、O或者S。杂环烷基包括杂芳基的相应的饱基团,且非限制性的实例包括例如哌嗪基、吗啉代、氮丙啶基、吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、四氢呋喃基。
异构体是指具有相同分子式的不同化合物。本申请使用的术语“旋光异构体”是指任意的各种立体异构构型,其可以本发明给定的化合物存在并包括几何异构体。可理解的是取代基可连接在碳原子的手性中心上。因此,本发明包括化合物的对映异构体、非对映异构体或者外消旋化合物。″对映异构体”是一对立体异构体,其彼此为非重叠的镜像。一对对映异构体的1∶1的混合物为″外消旋”混合物。适当时,该术语用于指定外消旋混合物。″非对映异构体”为具有至少两个不对称原子的立体异构体,但其彼此不为镜像。根据Cahn-lngold-Prelog R-S系统对绝对立体化学进行指定。当化合物为纯对映异构体时,在每个手性中心的立体化学可通过R或者S指定。绝对构型不明的经拆分的化合物可依照它们在钠旋光性测量(sodium Dline)的波长下旋转平面偏振光的方向(右旋或者左旋)来命名为(+)或者(-)。本申请描述的某些化合物含有一个或者多个不对称中心且可因此产生对映异构体、非对映异构体和其它可以如(R)-或者(S)-的绝对立体化学的形式定义的立体异构形式。本发明意在包括所有那些可能的异构体,包括外消旋混合物、旋光纯的形式和中间体混合物。旋光性(R)-和(S)-异构体可使用手性合成子或者手性试剂来制备,或者使用常规技术来拆分。如果化合物含有双键,则取代基可为E或者Z构型。如果化合物含有二取代的环烷基,则所述环烷基取代基可具有顺-或者反-构型。所有的互变异构形式也意在包括在本发明中。
本申请使用的术语“药用盐”是指保留本发明化合物的生物有效性和特性的盐,且其不是在生物学上或者其它方面不期望的。在许多实例中,本发明的化合物能够由于氨基和/或者羧基或者其类似基团(例如苯酚或者羟基酰胺基酸(hydroxyamic acid))的存在而形成酸盐和/或者碱盐。用无机酸和有机酸可形成药用酸加成盐。可从中衍生为盐的无机酸可包括,例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可从中衍生为盐的有机酸可包括,例如乙酸、丙酸、羟乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、枸橼酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。用无机碱和有机碱可形成药用碱加成盐。可从中衍生为盐的无机碱可包括,例如钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等;特别优选的是铵盐、钾盐、钠盐、钙盐和镁盐。可从中衍生为盐的有机碱可包括,例如伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代的胺)、环胺、碱离子交换树脂等,特别的诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。本发明的药用盐可由母体化合物、碱部分或者酸部分通过常规化学方法来合成。通常,所述的盐可通过使这些化合物的酸形式与化学量的适当的碱(诸如氢氧化钠、氢氧化钙、氢氧化镁、氢氧化钾、碳酸钠、碳酸钙、碳酸镁、碳酸钾、碳酸氢钠、碳酸氢钙、碳酸氢镁或者碳酸氢钾等)反应来制备,或者通过使这些化合物的游离碱的形式与化学量的适当的酸反应来制备。该反应典型地在水中或者在有机溶剂中或者在两者的混合物中进行。通常,如果可行,优选的非水介质为醚、乙酸乙酯、乙醇、异丙醇或者乙腈。所列的额外的适当的盐可见于下述文献:例如Remington′s Pharmaceutical Sciences,20th ed.,MackPublishing Company,Easton,Pa.,(1985),将其引入本申请作为参考。
药用载体包括任意的和所有的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料、类似的材料和它们的组合,其被本领域的普通的技术人员所知(参见,例如Remington′s Pharmaceutical Sciences,18th Ed.Mack PrintingCompany,1990,pp.1289-1329,引入本申请作为参考)。除了任意的常规载体与活性成分不相容的情况之外,也预期了所述的载体在治疗组合物或者药物组合物中的用途。
本申请使用的术语“药用载体/辅料″包括任意的和所有的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料、类似的材料和它们的组合,其被本领域的普通的技术人员所知(参见,例如Remington′s PharmaceuticalSciences,18th Ed.Mack Printing Company,1990,pp.1289-1329,引入本申请作为参考)。除了任意的常规载体与活性成分不相容的情况之外,也预期了所述的载体在治疗组合物或者药物组合物中的用途。
术语″治疗有效量″的本发明的化合物是指这样的本发明的化合物的量,其能够产生患者的生物或者药物响应、或者缓解症状、减慢或者延缓疾病进展、或者预防疾病等。在一种优选的实施方案中,“有效量”是指这样的量,其可抑制或者减少癌细胞的增殖、或者抑制或者减少体外或者体内的肿瘤/癌症生长、或者抑制或者减少在患者诸如哺乳动物中的肿瘤性疾病。在另一种优选的实施方案中,“有效量”也指这样的量,其可减少原发的肿瘤/癌症大小、抑制癌细胞浸润外周器官、减慢或者终止肿瘤转移、或者在某种程度上减轻与肿瘤或者癌症相关的至少一种或者多种症状等。
本申请使用的术语“患者”是指动物。优选地,动物为哺乳动物。患者也指例如灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、小鼠、鱼、鸟等。在一种优选的实施方案中,所述受试者为人类。
本申请使用的术语“紊乱(disorder)”或者“疾病(disease)”是指任意的功能紊乱(derangement)或者异常;病态的身体或者精神状态。参见Dorland′sIllustrated Medical Dictionary,(W.B.Saunders Co.27th ed.1988)。
本申请使用的术语″抑制(inhibition)″或者“抑制(inhibiting)”是指减少或者抑制特定的病症、症状或者疾病,或者显著地减少生物活性或者病变的基线活性(baseline activity)。在一种实施方案中,所述的术语是指引起肿瘤或者癌症生长减少的能力,或者引起肿瘤或者癌症大小减少的能力。
本申请使用的术语,在一种实施方案中,“治疗(treating)″或者″处置(treatment)″任意疾病或者障碍是指缓解疾病或者障碍(即终止或者减少疾病或者至少一种其临床症状的发展)。在另一种实施方案中,“治疗″或者“处置”是指缓解至少一种身体参数,其可能不被患者辨别。在另一种实施方案中,“治疗″或者“处置”是指在身体上(例如可辨别症状的稳定)、生理上(例如身体参数的稳定)或者在身体和生理上调节疾病或者障碍。在另一种实施方案中,“治疗″或者“处置”是指预防或者延缓疾病或者障碍的发作或者发展。
除非本申请另有说明或上下文明显矛盾,本申请使用的术语“一个(a)”、“一个(an)”和“那个(the)”用在本发明的上下文(尤其是权利要求的上下文)中时应该解释为包括单数和复数形式。对在本申请的值的范围的描述仅用来作为快速描述的方法,其单独涉及落入本范围内的各个单独的值。除非本申请另作说明,将每个单独的值引入说明书,就如同其单独地在本申请描述一样。除非本申请另有说明或上下文明显矛盾,所有在本申请描述的方法可按照任意的顺序进行。本申请提供的任意的和所有的实例的用途,或者示例性的语言(例如″诸如”)仅用来更好地阐明本发明且不作为对另外要求的本发明范围的限制。在本说明书中的语言不应解释为用来说明对实践本发明而言是关键的任何非要求保护的要素。
烷芳基、烯基芳基、炔基芳基、芳基烷基、芳基炔基或者芳烯基表示取代有至少1个(通常为1-3个)芳基的烷基、炔基或者烯基,或者取代有至少1个(通常为1-3个)烷基、炔基或者烯基的芳基。
在本发明化合物上的任意不对称碳原子可以(R)-、(S)-或者(R,S)-构型存在,优选地以(R)-或者(S)-构型存在。如果可能,在原子上有不饱和键的取代基可以顺式(Z)-或者反式(E)-的形式存在。因此,本发明的化合物可为其一种可能的异构体或者混合物的形式,例如基本上为纯的几何(顺式或者反式)异构体、非对映异构体、旋光异构体(对映体)、外消旋化合物或者它们的混合物。
任意所得的异构体的混合物可根据组分的物理化学差异分离为纯的几何异构体或者旋光异构体、非对映异构体、外消旋化合物,其通过例如色谱法和/或者分步结晶来分离。
任意所得的最终产物或者中间体的外消旋化合物可通过已知方法拆分为旋光对映体,例如通过对用光学活性的酸或者碱获得的其非对映异构体盐进行分离,然后释放光学活性的酸性化合物或者碱性化合物。特别地,可因此使用羟酰胺或者磺酰胺部分将本发明的化合物拆分为它们的旋光对映体,例如,通过对用旋光性共配体(co-ligand)例如L-组氨酸或者D-组氨酸形成的金属(例如Zn2+)复合物的分步结晶来分离。外消旋产物也可经手性色谱法分离,例如使用手性吸附剂的高效液相色谱(HPLC)。
最后,本发明的化合物也可以游离的形式或作为其盐得到。
当碱性基团存在于本发明的化合物中时(诸如在取代基中),化合物可转化为其酸加成盐,优选地为其药用盐。这些盐可用无机酸或者有机酸形成。适当的无机酸包括但不限于盐酸、硫酸、磷酸或者氢卤酸。适当的有机酸包括但不限于羧酸,诸如(C1-C4)烷烃羧酸,其例如未被取代或者被卤素取代,例如乙酸;诸如饱和的或者不饱和的二羧酸,例如草酸、琥珀酸、马来酸或者富马酸;诸如羟基羧酸,例如羟乙酸、乳酸、苹果酸、酒石酸或者枸橼酸;诸如氨基酸,例如天冬氨酸或者谷氨酸;适当的有机酸还包括有机磺酸,诸如(C1-C4)烷基磺酸,例如甲磺酸;或者芳基磺酸,其例如未被取代或者被例如卤素取代。优选的为用盐酸、甲磺酸和马来酸形成的盐。
当酸性基团存在于本发明的化合物中时,化合物可转化为其与药用碱形成的盐。该盐包括碱金属盐,例如钠盐、锂盐和钾盐;碱土金属盐,诸如钙盐和镁盐;与有机碱形成的铵盐,例如三甲胺盐、二乙胺盐、三(羟甲基)甲胺盐、二环己胺盐和N-甲基-D-葡萄糖胺盐;与氨基酸诸如精氨酸盐、赖氨酸盐等形成的盐。盐可使用常规方法在含醚溶剂或者含醇溶剂中方便地形成,所述的溶剂诸如低级链烷醇。在后者的溶液中,盐可用二乙醚类(例如乙醚)沉淀来形成。所得的盐可通过用酸处理转化为游离化合物。这些或者其它的盐也可用于纯化得到的化合物。
当碱性基团和酸性基团两者存在于相同分子中时,本发明的化合物也可形成内盐。
此外,本发明的化合物包括它们的盐也可以它们的水合物或者包括其它用于其结晶的溶剂的形式来获得。
R1典型地为H,当R1不为H时,R1典型地为(R)构型。
R2和R2′通常为X、H或者NH2,但典型地R2′或者R2中至少一个为X。在某些实施方案中,R2′和R2均为X,且可相同或者不同,但通常仅R2或者R2′中的一个为X。通常,X出现在6位且2-位取代有NH2或者H。R2或者R2′也为卤素诸如氯或者溴,由此在某些实施方案中其它的R2或者R2′为X。特别地,卤素化合物用作中间体。
优选地,R2为氨基。
本申请的酯形成基团包括R3可广泛地改变。它们包括C3-C6芳基(包括苯基、吡咯烷-2-基和吡咯烷-3-基、噻吩-2-基和噻吩-3-基、咪唑-2-基和咪唑-4-基、噁唑-2-基、噁唑-4-基和噁唑-5-基、异噁唑-3-基和异噁唑-4-基、噻唑-2-基、噻唑-4-基和噻唑-5-基、异噻唑-3-基、异噻唑-4-基和异噻唑-5-基、吡唑-3-基和吡唑-4-基、吡啶-1-基、吡啶-2-基、吡啶-3-基和吡啶-4-基以及嘧啶-1-基、嘧啶-2-基、嘧啶-4-基和嘧啶-5-基)、取代有以下基团的C3-C6芳基:卤素、烷基C1-C12烷氧基、CN、NO2、OH、羧基、羧基酯基团、巯基、硫酯基团、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基[包括2-烷氧基苯基(C1-C12烷基)、3-烷氧基苯基(C1-C12烷基)和4-烷氧基苯基(C1-C12烷基)、2-甲氧基苯基、3-甲氧基苯基和4-甲氧基苯基、2-乙氧基苯基、3-乙氧基苯基和4-乙氧基苯基、2,3-二乙氧基苯基、2,4-二乙氧基苯基、2,5-二乙氧基苯基、2,6-二乙氧基苯基、3,4-二乙氧基苯基和3,5-二乙氧基苯基、2-乙氧羰基-4-羟基苯基和3-乙氧羰基-4-羟基苯基、2-乙氧基-4-羟基苯基和3-乙氧基-4-羟基苯基、2-乙氧基-5-羟基苯基和3-乙氧基-5-羟基苯基、2-乙氧基-6-羟基苯基和3-乙氧基-6-羟基苯基、2-O-乙酰基苯基、3-O-乙酰基苯基和4-O-乙酰基苯基、2-二甲基氨基苯基、3-二甲基氨基苯基和4-二甲基氨基苯基、2-甲基巯基苯基、3-甲基巯基苯基和4-甲基巯基苯基、2-卤代苯基、3-卤代苯基和4-卤代苯基(包括2-氟苯基、3-氟苯基和4-氟苯基以及2-氯苯基、3-氯苯基和4-氯苯基)、2,3-二甲基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2,6-二甲基苯基、3,4-二甲基苯基和3,5-二甲基苯基、2,3-二羧基乙基苯基、2,4-二羧基乙基苯基、2,5-二羧基乙基苯基、2,6-二羧基乙基苯基、3,4-二羧基乙基苯基和3,5-二羧基乙基苯基、2,3-二甲氧基苯基、2,4-二甲氧基苯基、2,5-二甲氧基苯基、2,6-二甲氧基苯基、3,4-二甲氧基苯基和3,5-二甲氧基苯基、2,3-二卤代苯基、2,4-二卤代苯基、2,5-二卤代苯基、2,6-二卤代苯基、3,4-二卤代苯基和3,5-二卤代苯基(包括2,4-二氟苯基和3,5-二氟苯基)、2-卤代烷基苯基、3-卤代烷基苯基和4-卤代烷基苯基(所述卤代烷基为含有1至5个卤素原子的C1-C12烷基,包括4-三氟甲基苯基)、2-氰基苯基、3-氰基苯基和4-氰基苯基、2-硝基苯基、3-硝基苯基和4-硝基苯基、2-卤代烷基苄基、3-卤代烷基苄基和4-卤代烷基苄基(所述卤代烷基为含有1至5个卤素原子的C1-C12烷基,包括4-三氟甲基苄基和2-三氯甲基苯基、3-三氯甲基苯基和4-三氯甲基苯基以及2-三氯甲基苯基、3-三氯甲基苯基和4-三氯甲基苯基)、N-甲基哌啶-4-基、N-甲基哌啶-3-基、1-乙基哌嗪基、苄基、-C6H4-C(O)-OC1-C5烷基(C1-C4烷基,包括2-乙基水杨酰基苯基、3-乙基水杨酰基苯基和4-乙基水杨酰基苯基)、2-乙酰基苯基、3-乙酰基苯基和4-乙酰基苯基、1,8-二羟基萘基(-O-C10H6-OH)和芳基氧基乙基[C6-C9芳基(包括苯氧基乙基)]、2,2′-二羟基联苯基、烷氧基乙基[C1-C6烷基,包括-CH2-CH2-O-CH3(2-甲氧基乙基)]、被OH取代或者被1至3个卤素原子取代的烷基(包括-CH3、-CH(CH3)2、-C(CH3)3、-CH2CH3、-(CH2)2CH3、-(CH2)3CH3、-(CH2)4CH3、-(CH2)5CH3、-CH2CH2F、-CH2CH2Cl、-CH2CF3和-CH2CCl3)、2-N,N-二烷基氨基苯基、3-N,N-二烷基氨基苯基和4-N,N-二烷基氨基苯基、-C6H4CH2-N(CH3)2、-N-2-丙基吗啉代、2,3-二氢-6-羟基茚、芝麻酚、儿茶酚单酯、-CH2-C(O)-N(R11)2(其中每个R11为相同的或者不同的H或者C1-C4烷基)、-CH2-S(O)(R11)、-CH2-S(O)2(R11)、-CH2-CH(OC(O)CH2R11)-CH2(OC(O)CH2R11)、胆甾醇基、5或者6碳单糖、二糖或者寡糖(3至9个单糖残基)、烯醇丙酮酸酯(HOOC-C(=CH2)O)、甘油、α-D-β-甘油二酯(其中构成甘油酯脂质的脂肪酸通常为天然存在的饱和或者不饱和的C6-26、C6-18或者C6-10脂肪酸,诸如亚油酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、棕榈油酸、亚麻酸等脂肪酸)、三甲氧基苄基、三乙氧基苄基、2-烷基吡啶基(C1-4烷基)、C1-C4烯基-C3-C6芳基(包括苄基、-CH2-吡咯基、-CH2-噻吩基、-CH2-咪唑基、-CH2-噁唑基、-CH2-异噁唑基、-CH2-噻唑基、-CH2-异噻唑基、-CH2-吡唑基、-CH2-吡啶基和-CH2-嘧啶基),所述的C1-C4烯基-C3-C6芳基在芳基部分被3至5个卤素原子或者1至2个选自下述的原子或者基团所取代:卤素、C1-C12烷氧基(包括甲氧基和乙氧基)、氰基、硝基、OH、C1-C12卤代烷基(1至6个卤素原子;包括-CH2-CCl3)、C1-C12烷基(包括甲基和乙基)、C2-C12烯基或者C2-C12炔基,以及其它在下面的表1a中所列的化合物。本申请的化合物的羟基任选取代有在WO94/21604中披露的基团III、IV或者V中的一个。
R4为R3,或者OR4为NH2、NH(R10)或者N(R10)2,但典型地在此位置上取代基为R3。氨基酸酰胺为其中其一个或者多个羧基被NH2、NH(R10)或者N(R10)2取代的氨基酸。一般而言,氨基酸为已知的天然存在的氨基酸,其以天然的蛋白成分出现。
典型地,R10为相对小的,由1至6个碳原子和0至1个N以及任选地S或者O原子构成。所述杂原子通常为O。通常,存在于R10的一个或者多个杂原子位于碳主链内,且不在分子远端的末端。R10通常不是羟基保护基团诸如苄基。通常,R10为C1-C6烷基;C3-C6环烷基或者C3-C4环烷基;C3-C4环烷基取代的C1-C2烷基;C3-C4环烷基,其被C1-C3烷基单取代、二取代或三取代;-CH(Phe)2;烯丙基;C1-C6烷基-O-C1-C6烷基或者C3-C6烷基-O-C3-C6烷基或者烯丙基,在每种情况任选地1或者2个H原子取代有C1-C3烷基。R10为正丙基、仲丙基或者环丙基、正丁基、仲丁基、叔丁基或者环丁基、正戊基、仲戊基、叔戊基或者环戊基、正己基、仲己基、叔己基或者环己基。
R10包括-CH2NHCH2CH2OCH2NH(CH3)2、
-CH2NHCH2OCH2N(CH3)2、
或者-CH2C≡CH.
R10基团特别是那些在前面两段中所述的,且特别是烷基或者烯烃的氢原子,,依次任选取代有1至3个任意的:卤素(特别是F)、氰基或者叠氮基或者它们的组合。典型的实施方案包括-CH2F、-CH2CN、-(CH2)2N3、-(CH2)2CH2F、-CH2N3、-CH2(氟环丙基)、-CHFCH3或者-(CH2)2NH(CH3)(CH2F)。
R10基团可带有手性N或者C原子。这些原子适于用作外消旋化混合物或者非对映异构混合物,或者它们可为手性纯的。一般而言,优选的是它们为手性纯的。
当R1为CH3时,化合物为(R)非对映异构体,与在本领域的理解一致的是本非对映异构体相比于(S)非对映异构体更具有抗病毒活性。(R)异构体典型地为手性富集的或者经分离的。对于结构(1)的抗肿瘤化合物,R1通常为H。
通常对Z进行选择以产生嘌呤核,尽管任选地对其进行选择是为了得到氮杂嘌呤核或者脱氮杂嘌呤核(单氮杂或者单脱氮杂)诸如1-脱氮杂、3-脱氮杂、8-氮杂或者7-脱氮杂。
Y典型地为结构II的基团。则其它的Y任选为OR3。其也任选为另一个非脯氨酰基氨基酸或者氨基酸酯或者氨基酸酰胺。当Y为氨基酸(包括结构II,其为脯氨酸残基)时,氨基酸羧基通常为酯化的。其也任选为酰胺(其中OR4为氨基或者R10取代的氨基)。氨基酸酯或者Y基团酯典型为R3。氨基酸酯典型为C1-C6烷基,而Y基团如酯通常为苯基。
本发明的化合物通常用于抑制肿瘤/癌细胞生长或者在肿瘤/癌细胞中的细胞增殖,减慢在肿瘤/癌细胞中的细胞周期进展。另外,本发明的化合物诱导凋亡。诱导凋亡已经用作治疗癌症/肿瘤的重要化疗方法。因此,本发明的化合物具有有价值的药物特性,且它们可用作抗增殖药物和抗肿瘤/抗癌症药物。
因此,在一方面,本发明的化合物可用于在体外和体内抑制细胞增殖。在一种实施方案,本发明的化合物可用于通过将肿瘤/癌细胞与有效量的所述化合物接触来抑制在肿瘤/癌细胞中的细胞增殖。在一种实施方案中,本发明的化合物可用于治疗细胞增殖疾病或者病症。所述的疾病可包括但不限于癌症、自身免疫性疾病、真菌疾病、关节炎、移植排斥、炎性肠病、在医疗操作后诱导的细胞增殖包括但不限于手术、血管成形术等诱导的细胞增殖。
在另一方面,本发明的化合物可用于在体外和体内抑制肿瘤/癌症生长。在一种实施方案中,化合物可用于通过将肿瘤/癌细胞与有效量的所述化合物接触来抑制肿瘤/癌细胞生长。在一种实施方案中,本发明提供了使用本发明的化合物来抑制肿瘤或者癌症生长的方法。根据所述方法可治疗的肿瘤或者癌症包括例如,血液性恶性肿瘤诸如白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性粒细胞性白血病、急性粒细胞性白血病、急性骨髓细胞性白血病、慢性骨髓细胞性白血病、毛细胞性白血病等;位于以下部位的肿瘤或者癌症:哺乳动物的胸、肺、甲状腺、淋巴结、生殖泌尿系统、肾、输尿管、膀胱、卵巢、睾丸、前列腺、肌骨骼系统、骨、骨骼肌、骨髓、胃肠道、胃、食道、小肠、结肠、直肠、胰腺、肝、平滑肌、中枢神经系统或者外周神经系统、脑、脊髓、神经、头、颈、耳朵、眼睛、鼻咽、口咽、唾液腺、心血管系统、口腔、舌、喉、下咽、软组织、皮肤、宫颈、肛门、视网膜和/或者心脏。
在一种实施方案中,本发明提供了使用本发明的化合物来治疗肿瘤性疾病或者肿瘤/癌症的方法。本申请使用的术语“肿瘤性疾病”是指任意异常的细胞或者组织的生长,其为良性的(非癌性的)或者恶性的(癌性的)。根据本发明的方法可治疗的肿瘤性疾病包括例如,源自下述疾病的瘤:急性骨髓细胞性白血病、慢性淋巴细胞性白血病、慢性骨髓细胞性白血病、皮肤T淋巴细胞瘤、毛细胞性白血病和非霍奇金淋巴瘤(non-Hodgkin’slymphoma)。
本发明的化合物用于治疗癌症或者肿瘤(包括发育异常诸如子宫发育异常)。这些包括血液性恶性肿瘤、口腔癌(例如唇部、舌部或者咽部口腔癌)、消化器官癌(例如食道、胃、小肠、结肠、大肠或者直肠癌)、肝和胆道癌、胰腺癌、呼吸系统癌诸如喉或者肺癌(小细胞和非小细胞癌)、骨癌、结缔组织癌、皮肤癌(例如黑素瘤)、胸癌、生殖器官癌(子宫、宫颈、睾丸、卵巢或者前列腺癌)、泌尿道癌(例如膀胱或者肾癌)、脑和内分泌腺癌诸如甲状腺癌。概括来说,本发明的化合物用于治疗任何瘤,不仅包括血液性恶性肿瘤,还有所有类型的实体瘤。
血液型恶性肿瘤广义地定义为血细胞和/或者它们的祖细胞(progenitors)的增殖疾病,其中这些细胞以不可控的方式增殖。在解剖学上,血液性恶性肿瘤分为两个原始的种类:淋巴瘤-淋巴样细胞的恶性团块,其主要但不仅仅在淋巴结上;以及白血病-典型地衍生自淋巴样细胞或者骨髓样细胞的瘤,且主要影响骨髓和外周血液。淋巴瘤可再分为霍奇金病和非霍奇金淋巴瘤(NHL)。后者包括几种不同的实体,其可在以下方面加以区别:临床上(例如进展的淋巴瘤(aggressive lymphoma)、缓慢进展的淋巴瘤(indolent lymphoma))、组织学上(例如滤泡性淋巴瘤、外套细胞淋巴瘤)或者基于恶性细胞起源(例如B淋巴细胞、T淋巴细胞)。白血病和相关的恶性肿瘤包括急性骨髓细胞性白血病(AML)、慢性骨髓细胞性白血病(CML)、急性淋巴细胞性白血病(ALL)和慢性淋巴细胞性白血病(CLL)。其它的血液性恶性肿瘤包括浆细胞不调症(plasma cell dyscrasias),其包括多发性骨髓瘤和骨髓增生异常综合征。
另外,本发明提供:
-用作药物的本发明的化合物;
-本发明的化合物在用于制备抑制在肿瘤/癌细胞中的细胞增殖或者减慢在肿瘤/癌细胞中的细胞周期进展的药物中的用途;
-本发明的化合物在用于制备治疗细胞增殖疾病或者病症的药物中的用途;
-本发明的化合物在用于制备抑制在体外和体内的肿瘤/癌症生长的药物中的用途;
-本发明的化合物在用于制备治疗肿瘤性疾病的药物中的用途;
-本发明的化合物在用于制备治疗肿瘤或者癌症的药物中的用途;
-本发明的化合物在用于制备治疗血液性恶性肿瘤的药物中的用途。
本发明的化合物也适于治疗或者预防病毒感染,所述的病毒包括DNA病毒和RNA病毒,特别是HSV和HIV。待治疗的病毒取决于潜在的母体药物的抗病毒活性。例如,PME系列的化合物用于对抗DNA病毒和逆转录病毒,而PMP化合物有效地对抗逆转录病毒。
代表性的病毒感染包括由DNA或者RNA病毒引起的感染,所述的病毒包括疱疹病毒(CMV、HSV 1、HSV 2、EBV、水痘-带状疱疹病毒[VZV]、1型牛疱疹病毒、1型马疱疹病毒、HHV-6、乳头瘤病毒(1-55型HPV,包括致癌HPV)、虫媒病毒(包括黄热病病毒、非洲猪瘟病毒和日本脑炎病毒)、披膜病毒(包括委内瑞拉马脑脊髓炎病毒)、流感病毒(A-C型)、逆转录病毒(HIV-1、HIV-2、HTLV-I、HTLV-II、SIV、FeLV、FIV、MoMSV)、腺病毒(1-8型)、痘病毒(痘苗病毒)、肠道病毒(1-3型脊髓灰质炎病毒、柯萨奇病毒、甲型肝炎病毒和埃可病毒(ECHO virus))、胃肠炎病毒(诺瓦克病毒(Norwalkviruses)、轮状病毒)、汉坦病毒属(汉坦病毒(Hantaan virus))、多瘤病毒、乳多泡病毒、鼻病毒、1-4型副流感病毒、狂犬病病毒和呼吸道合胞体病毒(RSV)。
因此,本发明提供了本发明的化合物在用于制备抗病毒感染的药物中的用途。
本发明的治疗有效的化合物用于口服或者持续释放形式。在这些用途中,酯或者其它基团在体内除去,例如经水解或者氧化除去,从而得到例如游离的氨基或者羟基。适当的保护性酯或者前体酯、或者保护性或前体酰胺化物基于酯酶和/或者肽酶的底物特异性来选择,预期所述的酯酶和/或者肽酶出现在其中预期有前体水解的细胞内。在这些酶的特异性未知的情况下,将筛选多种本发明的核苷酸类似物直到发现预期的底物特异性。这将在出现游离的膦酸盐或者抗肿瘤或者抗病毒活性后变得明显。通常选择下述的化合物,其为:(i)在肠上部不水解或者相对缓慢地水解,(ii)肠和细胞可渗透的以及(iii)在细胞浆和/或者体循环中水解。在特殊组织中的细胞筛选用于辨别在器官中释放的前体,所述的器官对靶标病毒或者微生物感染是敏感的,例如,对于肝,前体药物能够在肝中水解。其它的感染例如CMV或者HIV任选地用前体治疗,所述的前体在所有组织中以本质上相同的速率且相同的程度进行水解。在本领域已知的测定适于这些目的,包括肠内腔(intestinal lumen)稳定性、细胞渗透性、肝匀浆稳定性和血浆稳定性测定。这些测定也用于确定前体的生物利用度表征。然而,即使衍生物不在体内转化,它们作为化学中间体仍是有效的。
配制本申请的化合物和它们的生理上可接受的盐(下文统称为为活性成分),以便通过任何适于治疗所述病症的途径来给药。化合物和制剂优选地为无菌的。
将活性成分置于药物制剂中。这些制剂,既用于兽用,也用于人类使用,其包含至少一种如上定义的活性成分,与一种或者多种可接受载体一起以及任选的其它治疗成分。一种或者多种载体必须为″可接受的″,其意思为与制剂的其它成分相容且对受体不是有害的。
本制剂适宜地以单位剂型存在并可通过在药学领域任意已知的方法制备。一般而言,制剂经以下途径制备:将活性成分与液体载体或者精细分散的固体载体或者这两种载体均匀地和紧密地结合在一起,然后,如果必要,使产物成型。
适合于口服给药的本发明制剂被制成离散的单元,例如各自含有预定量活性成分的胶囊剂、扁囊剂或片剂;被制成粉末或颗粒;被制成水性液体或非水性液体中的溶液或悬浮液;或者被制成水包油型液体乳剂或者油包水型液体乳剂。活性成分还可以作为推注剂(bolus)、药糖剂或糊剂存在。
对于眼睛或其他外部组织例如嘴和皮肤的感染,该制剂优选作为局部软膏或乳膏涂用,所述软膏或乳膏含有的活性成分量例如,为0.075~20%w/w(包括0.1~20%的活性成分,0.1%w/w的增量,例如0.6%w/w、0.7%w/w等),优选为0.2~15%w/w,最优选为0.5~10%w/w。当配制为软膏时,活性成分可以与石蜡或水可混溶的软膏基质一起使用。或者,活性成分可以在含有水包油型乳膏基质的乳膏中进行配制。
如果希望,乳膏基质的水相可以包括例如至少30%w/w的多元醇,即具有两个或更多羟基的醇,例如丙二醇、丁-1,3-二醇、甘露醇、山梨糖醇、甘油和聚乙二醇(包括PEG 400)及其混合物。局部制剂理想地可以包括能增强活性成分通过皮肤或其他受影响部位的吸收性或渗透性的化合物。这样皮肤渗透增强剂的实例包括二甲亚砜和有关类似物。
本发明乳剂的油相可以从已知成分用已知方法形成。该相可以只含有乳化剂或至少一种乳化剂与脂肪或油或者与脂肪和油两者所形成的混合物。优选地,包括亲水性乳化剂和起稳定剂作用的亲脂性乳化剂。还优选包括油和脂肪两者。适用于本发明制剂的乳化剂稳定剂包括吐温60、司盘80、十八十六醇、苯甲醇、肉豆蔻醇、单硬脂酸甘油酯和十二烷基硫酸钠。适当的油或者脂肪直链或支链、单或二代烷基酯,例如二-异己二酸酯、硬脂酸异十六烷基酯、椰子油脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、棕榈酸2-乙基己基酯。这些酯根据所需要的性能可单独使用或组合使用。或者,使用高熔点的脂质,例如白色软石蜡和/或液体石蜡或其他矿物油。
适于向眼睛局部给药的制剂还包括滴眼液,其中活性成分溶解或悬浮于合适的载体中,对于活性成分而言优选水性溶剂。活性成分在这些制剂中的浓度为0.01~20%w/w。
适于鼻部给药的制剂(其中载体为固体)包括具有例如20至500微米(包括在20和500微米之间的范围的粒度,增量为5微米,诸如30微米、35微米等)范围的粒度的粗粉,其通过从含有粉末的容器中经鼻道快速吸入来给药。对于例如鼻腔喷雾或者鼻滴剂的适当的制剂(其中载体为液体)包括活性成分的水性或者油性溶液。适于气雾剂给药的制剂可根据常规方法来制备并可与其它治疗药物诸如喷他眯(pentamidine)一起递送以治疗肺孢子虫性肺炎。
适于阴道给药的制剂可如下存在:阴道栓剂、塞剂(tampons)、乳膏剂、凝胶剂、糊剂、泡沫剂或者喷雾制剂,所述的喷雾制剂含有除活性成分之外的在本领域中已知的适当的载体。
适于肠胃外给药的制剂包括水性和非水性无菌注射用溶液剂,其可含有抗氧化剂、缓冲液、抑菌剂和溶质,所述的溶质使制剂与预期的受体的血液等渗;以及可包括悬浮剂和增稠剂的水性和非水性无菌混悬剂。制剂可存在于单位剂量容器或者多剂量容器,例如密闭的安瓿瓶和管形瓶,且可保存在冷冻干燥(低压冻干的)的条件下,其在使用前仅需要加入无菌液体载体,例如注射用水。临时的注射用溶液和混悬液可由无菌的前述类型的粉末、颗粒和片剂来制备。优选的单位剂型为那些含有如上所述的活性成分的每日剂量或者每日单位亚剂量(sub-dose)或者它们的适当部分。
本发明还提供了兽用组合物,其含有至少一种以上所定义的活性成分和兽用的载体。兽用的载体是适用于对组合物进行给药目的的材料,可以是固体、液体或气体材料,此外其在兽医领域是惰性或可接受的,并且与活性成分相容。这些兽用组合物可以口服、肠胃外或者通过所希望的任何其他途径进行给药。
本申请的化合物任选地在控制释放药物制剂中使用,所述的制剂含有作为活性成分的一种或者多种活性化合物,其中活性成分是受控制的并受调节的以允许较少频率的给药或者改善给定化合物的药物代谢动力学或者毒性分布。一般而言,化合物从控制释放系统中给药,诸如玻璃体内的植入(参见WO 92/14450或者美国专利5,098,443)或者基体(matrices)(参见美国专利4,740,365或者美国专利5,141,752)。许多其它的给药系统为已知的且适于在本申请使用。
另外,本发明提供:
-用作药物的本发明的组合物;
-本发明的组合物在用于制备抑制在肿瘤/癌细胞中的细胞增殖或者减慢在肿瘤/癌细胞中的细胞周期进展的药物中的用途;
-本发明的组合物在用于制备治疗细胞增殖疾病或者病症的药物中的用途;
-本发明的组合物在用于制备抑制在体外和体内的肿瘤/癌症生长的药物中的用途;
-本发明的组合物在用于制备治疗肿瘤性疾病的药物中的用途;
-本发明的组合物在用于制备治疗肿瘤或者癌症的药物中的用途;
-本发明的组合物在用于制备治疗病毒感染的药物中的用途。
适当的给药途径包括口服给药、直肠给药、鼻部给药、局部给药(包括眼部给药、口腔含服给药和舌下给药)、阴道给药和肠胃外给药(包括皮下给药、肌内给药、玻璃体内给药、静脉内给药、皮内给药、鞘内给药和硬膜外给药)。优选的给药途径将取决于患者的状况、化合物的毒性和感染位点,以及临床医师已知的其它考虑因素。
对上面提及的每种治疗适应症,所需的活性成分(如上定义)的量将依照多种因素:包括所述的用途是抗肿瘤还是抗病毒、待治疗的病症的严重度、感染源、所述的用途是预防急性感染还是治疗急性感染、感染位点或者肿瘤位点(例如CMV视网膜炎为全身治疗或者经玻璃体内注射治疗,或者治疗在多发性硬化症患者中的HHV-6时,任选地经鞘内给药治疗)以及其它最终由主治医师或者兽医判断的因素。然而一般而言,经临床医师考虑的适当的剂量将在类似的膦酸甲氧酯(methoxyphosphonate)的范围内(参见前面),考虑到在效能上的区别,通常为每剂量0.1至250毫克每千克受体体重(包括在0.1和250毫克/千克/剂量之间的范围内的活性成分,增量为0.5毫克/千克/剂量,诸如2.5毫克/千克/剂量、3.0毫克/千克/剂量、3.5毫克/千克/剂量等),典型地在每剂量0.5至50毫克每千克受体体重的范围内且最通常地在每剂量1至15毫克每千克受体体重的范围内。
以适当的间隔以单位剂型给予预期的剂量,通常具有相对较高的诱导剂量和较低的、较少频率的维持剂量。在病毒感染的实例中,也预防性地使用化合物,例如在病毒感染之前的约从1至7天内给药。HPV肿瘤或者生长和疱疹损伤通常局部治疗,经局部注射或者经局部给予凝胶剂、软膏剂等。
本发明的化合物任选与一种、两种或者多种其它治疗药物合用,用于治疗或者预防上面提及的感染或者肿瘤。所述另外治疗药物的实例包括对于治疗或者预防病毒感染或者治疗肿瘤和相关病症有效的药物。
其它治疗药物包括3′-叠氮基-3′-脱氧胸苷(齐多夫定,AZT)、2′-脱氧-3′-硫胞苷(3TC)、2′,3′-二脱氧-2′,3′-二去氢腺苷(D4A)、2′,3′-二脱氧-2′,3′-二去氢胸苷(D4T)、卡波佛(碳环的2′,3′-二脱氧-2′,3′-二去氢鸟苷)、3′-叠氮基-2′,3′-二脱氧尿苷、5-氟胸苷、(E)-5-(2-溴乙烯基)-2′-脱氧尿苷(BVDU)、2-氯-2′-脱氧腺苷、2-脱氧柯福霉素(2-deoxycoformycin)、5-氟尿嘧啶、5-氟尿苷、5-氟-2′-脱氧尿苷、5-三氟甲基-2′-脱氧尿苷、6-氮杂尿苷、5-氟乳清酸、甲氨喋呤、三乙酰基尿苷、1-(2′-脱氧-2′-氟-1-β-D-阿糖基)-5-碘胞嘧啶(FIAC)、四氢咪唑(4,5,1-jk)-(1,4)-苯并二氮杂-2(1H)-硫酮(TIBO)、2′-去甲磷鸟苷(2’-nor-cyclic-GMP)、6-甲氧基嘌呤阿拉伯糖苷(ara-M)、6-甲氧基嘌呤阿拉伯糖苷′-O-戊酸酯、胞嘧啶阿糖胞苷(ara-C)、2′,3′-二脱氧核苷(诸如2′,3′-二脱氧胞啶(ddC)、2′,3′-二脱氧腺苷(ddA)和2′,3′-二脱氧肌酐(ddI))、无环核苷(诸如阿昔洛韦、伐昔洛韦、喷昔洛韦、泛昔洛韦、更昔洛韦)、无环核苷酸(诸如HPMPC、PMEA、PMEG、PMPA、PMPDAP、FPMPA、HPMPA和HPMPDAP)、(2R,5R)-9-[四氢-5-(膦酰甲氧基)-呋喃-2-基]腺嘌呤、(2R,5R)-1-[四氢-5-(膦酰甲氧基)-呋喃-2-基]胸腺嘧啶,以及其它的抗病毒药包括利巴韦林(腺嘌呤阿拉伯糖苷)、2-硫代-6-氮杂尿苷、杀结核菌素、金精三羧酸、3-deazaneoplanocin、neoplanocin、rimantidine、金刚化合物(adamantine)和膦甲酸(磷酸三钠甲酸盐)、细胞因子(包括TNF和TGF-β)、干扰素(包括IFN-α、IFN-β和IFN-γ)、白细胞介素(包括白细胞介素1、2、3、4、5、6、7、8、10、12、13)、巨噬细胞/粒细胞集落刺激因子(包括GM-CSF、G-CSF、M-CSF)、细胞因子拮抗剂(包括抗-TNF抗体、抗白细胞介素抗体)、可溶性白细胞介素受体、蛋白激酶C抑制剂,以及特别地治疗HIV、与IFN-α、IL-2或者IL-12的综合疗法。
另外,其它治疗药物为抗肿瘤/抗癌剂,其选自抗瘤剂,包括例如助剂(例如左旋咪唑、硝酸镓、格拉司琼(granisetron)、沙格司亭氯化锶-89、非格司亭、匹罗卡品、右丙亚胺和昂丹司琼);雄激素抑制剂(例如氟他胺和乙酸亮丙瑞林);抗生素衍生物(例如阿霉素、博来霉素硫酸盐、柔红霉素、更生霉素和伊达比星);抗雌激素药(例如他莫昔芬枸橼酸盐、其类似物和非类固醇类抗雌激素药诸如托瑞米芬、屈洛昔芬和雷洛昔芬);抗代谢物(例如氟达拉滨磷酸盐、干扰素α-2b重组体、甲氨喋呤钠、普卡霉素、6-巯基嘌呤和硫鸟嘌呤);细胞毒素剂(例如阿霉素、卡莫司汀[BCNU]、洛莫司汀[CCNU]、阿糖胞苷USP、环磷酰胺、雌莫司汀磷酸钠、六甲蜜胺、羟脲、异磷酰胺、丙卡巴肼、丝裂霉素、白消安、环磷酰胺、米托蒽醌、卡铂、顺铂、干扰素α-2a重组体、紫杉醇、替尼泊苷和链唑霉素);激素(例如乙酸甲羟孕酮、雌二醇、乙酸甲地孕酮、乙酸奥曲肽、二磷酸己烯雌酚、睾内酯和乙酸戈舍瑞林);免疫调节剂(例如阿地白介素);氮芥衍生物(例如苯丙氨酸氮芥、苯丁酸氮芥、氮芥和噻替派)以及类固醇(倍他米松磷酸酯钠和乙酸倍他米松)等。
其它治疗药物还包括下述抗癌剂:阿巴瑞克(Plenaxis);阿地白介素阿地白介素阿仑单抗阿利维A酸别嘌呤醇六甲蜜胺阿米斯丁阿那曲唑三氧化二砷天冬酰胺酶氮杂胞苷bevacuzimab贝沙罗汀胶囊贝沙罗汀凝胶博来霉素硼替佐米(bortezomib)白消安静脉注射剂白消安口服剂卡普睾酮卡培他滨卡铂卡莫司汀卡莫司汀含有聚苯丙生20的卡莫司汀植入剂(Gliadel);塞来考昔西妥昔单抗苯丁酸氮芥顺铂克拉屈滨氯苯吩嗪环磷酰胺环磷酰胺(Cytoxan);环磷酰胺(Cytoxan);阿糖胞苷阿糖胞苷脂质体达卡巴嗪更生霉素,放线菌素DDarbepoetinα柔红霉素脂质体(Danuo);柔红霉素,道诺霉素柔红霉素,道诺霉素地尼白介素2右丙亚胺多西他赛阿霉素(Adriamycin);阿霉素阿霉素(AdriamycinPFS);阿霉素脂质体丙酸甲雄烷酮丙酸甲雄烷酮(masterone);埃利奥特B溶液(Elliott′s B);表柔比星阿法依伯汀厄洛替尼雌莫司汀依托泊苷磷酸盐依托泊苷,VP-16依西美坦非格司亭氟尿苷(动脉内)氟达拉滨氟尿嘧啶,5-FU氟维斯群吉非替尼吉西他滨吉姆单抗奥佐米星乙酸戈舍瑞林(Zoladex);乙酸戈舍瑞林乙酸组氨瑞林(Histrelin);羟脲替伊莫单抗伊达比星异磷酰胺甲磺酸伊马替尼干扰素α-2a(Roferon);干扰素α-2b(Intron);依立替康lenalidomide来曲唑甲酰四氢叶酸乙酸亮丙瑞林左旋咪唑洛莫司汀-CCNUmeclorethamine,氮芥乙酸甲地孕酮苯丙氨酸氮芥,L-PAM6-巯基嘌呤,6-MP美司钠美司钠(Mesnex);甲氨喋呤甲氧沙林丝裂霉素C米托坦米托蒽醌苯丙酸诺龙奈拉滨诺非单抗奥普瑞白介素奥沙利铂紫杉醇紫杉醇紫杉醇蛋白结合颗粒palifermin氨羟二磷酸二钠(pamidronate)培加酶(pegademase)(Adagen(pegademase Bovine));培门冬酶(pegaspargase)Pegfilgrastim培美曲塞二钠喷司他丁哌泊溴烷普卡霉素(plicamycin,mithramycin)卟吩姆钠丙卡巴肼喹纳克林拉布立酶利妥昔单抗沙格司亭沙格司亭sorafenib链唑霉素sunitinib maleate滑石他莫昔芬替莫唑胺替尼泊苷,VM-26睾内酯硫鸟嘌呤,6-TG噻替派托泊替康托瑞米芬托西莫单抗托西莫单抗/I-131托西莫单抗曲妥单抗维甲酸,ATRA尿嘧啶氮芥(Uracil Mustard);戊柔比星长春碱长春新碱长春瑞滨以及唑来膦酸盐(zoledronate)
另外,如上所述的组合可经同时、分开或者先后给药(使用)给予患者。同时给药(使用)可发生在结合有两种或者多种活性成分的一种固定组合的形式,或者经同时给予两种或者多种独立配制的化合物。先后给药(使用)优选地表示在一个时间点给予组合的一种(或者多种)化合物或者活性成分,在不同时间点给予其它化合物或者活性成分,即以一种长期交叉方式,优选地是所述组合相对于独立给药单一化合物显示更加有效(特别地显示协同作用)。分开给药(使用)优选地表示在不同时间点各自独立地给予所述组合的化合物或者活性成分,优选地表示给予两种化合物,从而两种化合物所测量的无重叠血液水平以重叠的方式出现(在相同时间点)。
在本发明的任意化合物不能经与那些出现在下面实施例中的类似的方法来生产/合成的情况下,其它方法将对于技术人员来说是显而易见的。参见例如Liotta等″Compendium of Organic Synthesis Methods″(John Wiley&Sons,New York),Vol.1,Ian T.Harrison and Shuyen Harrison,1971;Vol.2,Ian T.Harrison and Shuyen Harrison,1974;Vol.3,Louis S.Hegedus and LeroyWade,1977;Vol.4,Leroy G.Wade,Jr.,1980;Vol.5,Leroy G.Wade,Jr.,1984;和Vol.6,Michael B.Smith;March,J.,″Advanced Organic Chemistry,ThirdEdition″,(John Wiley&Sons,New York,1985);以及″Comprehensive OrganicSynthesis.Selectivity,Strategy&Efficiency in Modern Organic Chemistry.In 9Volumes″,Barry M.Trost,主编(Pergamon Press,New York,1993印刷)。
本发明的6-烷氧基嘌呤衍生物的合成通过将在6位的离去基团用以适当方式保护的膦酸置换来方便地完成。
因此,将[2-(2-氨基-6-卤素-嘌呤-9-基)-乙氧基甲基]-膦酸二烷基酯(诸如在专利申请WO2005/066189中所述)与适当的醇一起在碱的存在下加热,所述碱通常用于形成醇盐,诸如氢化钠、六甲基二硅氨基钠、碳酸铯或者叔丁醇钾,所述的途径任选在溶剂诸如四氢呋喃、二甲氧基乙烷或者二甲基甲酰胺中进行,提供预期的6-烷氧基嘌呤中间体。本转化可在微波辐射下进行。除去膦酸的保护基团在如下情况下很方便地完成:通过用试剂(诸如溴代三甲基甲硅烷或者碘代三甲基甲硅烷)任选在酸和阳离子清除剂(诸如二甲基吡啶衍生物)和/或者非质子溶剂的存在下典型地在低于环境温度(但低于环境温度是不必要的)进行脱烷基化。对于技术人员显而易见的是其它膦酸保护基团诸如(但不限于)苄基酯或者对甲氧基苄基酯也可用于本目的,其通过典型的方法(诸如氢化作用或者用氧化剂或者强酸处理)除去。
本发明的膦酸二酰胺典型地通过如下途径产生:用偶联剂对相应的膦酸进行活化,接着与预期的胺亲核体进行缩合。
适当的偶联剂包括经常用于形成肽键的那些诸如二环己基碳二亚胺或者PyBOP,以及与三苯基膦组合的2,2’-二吡啶基二硫化物,在有机碱(诸如三烷基胺、吡啶或者二甲基吡啶)的存在下且任选在惰性溶剂(诸如DMF)中进行。在惰性气氛下加热可促进反应的进行。
这些方法也用于合成本发明的膦酸单芳基酯单胺。这些在相似的条件下方便地得到但在加入预期的醇下进行以形成酯键。可替换地,它们在对单酯通过用试剂(诸如碱金属氢氧化物)处理在醚溶剂(诸如THF)中进行皂化反应后,由所需的膦酸二酯得到;使单酯接受上述的偶联条件以形成预期的膦酰胺。
本发明的膦酸二酯可通过相应膦酸的烷基化来合成。
实施例
凝胶色谱法如下进行:使用Teledyne ISCO色谱系统和12g色谱柱,用二氯甲烷和50%在二氯甲烷中的甲醇分别作为溶剂A和B。典型的梯度洗脱为经历55倍柱体积从0%至30%B,但轻微改变以优化每个个体的分离。
分析性HPLC色谱法如下进行:使用Phenomenex Gemini 5μM C184.6×50mm色谱柱,用1%乙腈/0.05%在水中的甲酸作为溶剂A且用1%水/0.05%在乙腈中的甲酸作为溶剂B。梯度洗脱在2.5分钟内由5%至100%B,另外在100%B中洗脱1分钟,总共进行时间为3.5分钟。MS数据在ThermoFinnigan检测器中使用电喷射离子化作用(ESI)来收集。
制备性HPLC色谱法如下进行:使用Phenomenex Synergi 4μM HydroCombi-HTS 30×150mm色谱柱,用水作为溶剂A并用乙腈作为溶剂B。典型的梯度洗脱历时20分钟从2%至80%B,但轻微改变以优化每个个体的分离。
实施例1
[2-(2-氨基-6-丙氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(1)
(1)CAS#183194-25-4,[[2-(2-氨基-6-氯-9H-嘌呤-9-基)乙氧基]甲基]-膦酸、二(1-甲基乙基)酯如在专利WO2005/066189中所述制备。
将等份的正丙醇(7mL,93mmol)用氮气清洗然后在冰/水浴中冷却至0℃。逐滴加入六甲基二硅氨基钠(作为1.0M THF溶液,8mL,8mmol,5当量)然后将溶液搅拌30分钟。然后将该溶液加入至含有P-[[2-(2-氨基-6-氯-9H-嘌呤-9-基)乙氧基]甲基]-膦酸二(1-甲基乙基)酯I(625mg,1.6mmol,1当量)的20mL微波瓶中,并将混合物通过微波加热至140℃且保持20分钟。然后将混合物倒入至烧瓶中,蒸发为固体,且置于高真空过夜。然后将二氯甲烷和乙腈(各8mL)加入至烧瓶中,并再次将反应混合物在冰水浴中冷却至0℃。将2,6-二甲基吡啶(3.7mL,32mmol,20当量)加入至烧瓶中,然后逐滴加入溴代三甲基甲硅烷(3.1mL,24mmol,15当量)。在完成加入之后移去冰浴,并将反应混合物搅拌过夜。然后将反应混合物在1小时搅拌的同时经缓慢加入甲醇(30mL)进行淬灭。将溶液蒸发为固体并在水(8mL)中重新溶解。将(1)经反相HPLC从该溶液分离,其为白色固体(318mg,0.96mmol,60%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ16.47.
LC/MS:保留时间=1.48分钟(运行3.5分钟),质量=332(M+1).
实施例2&3
(2)-(3)通过如与(1)相同的方法使用适当的起始醇来制备。
[2-(2-氨基-6-甲氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(2)
反相HPLC得到(2),其为白色固体(376mg,1.24mmol,77%)。
1H NMR(300MHz,CD3OD)δ=8.05(s,1H),4.32(t,J=5.05Hz,2H),4.06(s,3H),3.90(t,J=5.05Hz,2H),3.64(d,J=8.9Hz,2H).
31P NMR(75MHz,CD3OD)δ15.43.
LC/MS:保留时间=1.21分钟(运行3.5分钟),质量=304(M+1).
[2-(2-氨基-6-异丙氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(3)
反相HPLC得到(3),其为白色固体(202mg,0.61mmol,38%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ16.47.
LC/MS=332(M++1).
实施例4
[2-(2-氨基-6-丁氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(4)
将P-[[2-(2-氨基-6-氯-9H-嘌呤-9-基)乙氧基]甲基]-膦酸、二(1-甲基乙基)酯(727mg,1.86mmol,1当量)和碳酸铯(1.21g,3.72mmol,2当量)称量置于小烧瓶中并用氮气清洗。然后加入1,2-二甲氧基乙烷(8mL)和正丁醇(0.68mL,7.44mmol,4当量),并将混合物搅拌10分钟。然后逐滴加入叔丁醇钾(作为在四氢呋喃中的1.0M溶液,2.05mL,2.05mmol,1.1当量)。
将反应混合物在室温搅拌2.5小时然后浓缩为固体。在二氯甲烷中混悬后,接着经滤过除去固体。浓缩滤液得到黄色油状物,其通过柱色谱分离产物得到(SiO2,12%在二氯甲烷中的MeOH),其为澄清的油状物(616mg,1.435mmol,77%)。然后将其在二氯甲烷(8mL)中在氮气气氛下溶解,并将反应烧瓶在冰水浴中冷却至0℃。加入2,6-二甲基吡啶(3.7mL,32mmol,20当量),然后逐滴加入溴代三甲基甲硅烷(3.1mL,24mmol,15当量)。在完成加入后将冰浴移去,并将反应混合物搅拌过夜。然后将反应混合物在1小时搅拌的同时经缓慢加入甲醇(30mL)进行淬灭。然后将溶液蒸发并将残留物在水(8mL)中重新溶解。将化合物(4)经反相HPLC由该溶液分离,其为白色固体(399mg,1.16mmol,62%)。
1H NMR(300MHz,CD3OD)δ=8.35(s,1H),4.55(t,J=6.0Hz,2H),4.40(宽单峰,2H),3.93(宽单峰,2H),3.73(d,J=9.1Hz,2H),1.83(m,2H),1.54(m,2H),1.01(t,J=7.35Hz,3H).
31P NMR(75MHz,CD3OD)δ17.19.
LC/MS:保留时间=1.67分钟(运行3.5分钟),质量=346(M+1).
实施例5-12
(5)-(12)通过如与(4)相同的方法使用适当的起始醇来制备。
[2-(2-氨基-6-乙氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(5)
反相HPLC得到(5),其为白色固体(306mg,0.965mmol,78%)。
1H NMR(300MHz,CD3OD)δ=7.98(s,1H),4.54(q,J=7.1Hz,2H),4.30(t,J=4.9Hz,2H),3.88(t,J=4.9Hz,2H),3.59(d,J=8.9Hz,2H),1.43(t,J=7.2Hz,3H).
31P NMR(75MHz,CD3OD)δ14.69.
LC/MS:保留时间=0.82分钟(运行3.5分钟),质量=318(M+1).
[2-(2-氨基-6-环己基氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(6)
反相HPLC得到(6),其为褐色固体(306mg,0.965mmol,78%)。
1H NMR(300MHz,CD3OD)δ=8.67(s,1H),5.38(m,1Hz),4.45(t,J=4.7Hz,2H),3.96(t,J=4.9Hz,2H),3.76(d,J=8.9Hz,2H),2.06(宽多重峰,2H),1.84(宽多重峰,2H),1.65(m,3H)1.45(m,3H).
31P NMR(75MHz,CD3OD)δ17.94.
LC/MS:保留时间=1.52分钟(运行3.5分钟),质量=372(M+1).
[2-(2-氨基-6-戊基氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(7)
反相HPLC得到(7),其为白色固体(164mg,0.457mmol,47%)。
1H NMR(300MHz,CD3OD)δ=8.17(s,1H),4.51(t,J=6.7Hz,2H),4.36(t,J=4.8Hz,2H),3.91(t,J=4.9Hz,2H),3.69(d,J=9.1Hz,2H),1.84(m,2H),1.45(m,4H),0.953(t,J=7.2Hz,3H).
31P NMR(75MHz,CD3OD)δ16.36.
LC/MS:保留时间=1.57分钟(运行3.5分钟),质量=360(M+1).
[2-(2-氨基-6-环丙氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(8)
反相HPLC得到(8),其为白色固体(315mg,0.957mmol,47%)。
1H NMR(300MHz,CD3OD)δ=8.02(s,1H),4.56(m,1H),4.31(t,J=4.9Hz,2H),3.89(t,J=5.0Hz,2H),3.62(d,J=8.9Hz,2H),0.84(s,4H).
31P NMR(75MHz,CD3OD)δ15.32.
LC/MS:保留时间=1.02分钟(运行3.5分钟),质量=330(M+1).
[2-(2-氨基-6-环丁氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(9)
反相HPLC得到实施例9的化合物,其为白色固体(253mg,0.738mmol,69%)。
1H NMR(300MHz,CD3OD)δ=8.14(s,1H),5.42(m,1H)4.34(t,J=4.9Hz,2H),3.90(t,J=5.0Hz,2H),3.68(d,J=8.9Hz,2H),2.52(m,2H),2.23(m,2H),1.80(m,2H).
31P NMR(75MHz,CD3OD)δ16.22.
LC/MS:保留时间=1.29分钟(运行3.5分钟),质量=344(M+1).
[2-(2-氨基-6-环戊基氧基-嘌呤-9-基)-乙氧基甲基]-膦酸(10)
反相HPLC得到(10),其为米色固体(319mg,0.738mmol,69%)。
1H NMR(300MHz,CD3OD)δ=8.11(s,1H),5.68(m,1H),4.34(t,J=4.9Hz,2H),3.90(t,J=4.9Hz,2H),3.67(d,J=8.8Hz,2H),1.85(宽多重峰,8H),
31P NMR(75MHz,CD3OD)δ15.85
LC/MS:保留时间=1.66分钟(运行3.5分钟),质量=358(M+1)
{2-[2-氨基-6-(2-甲氧基-乙氧基)-嘌呤-9-基]-乙氧基甲基}-膦酸(11)
反相HPLC得到实施例11的化合物,其为白色固体(450mg,1.3mmol,62%)。
1H NMR(300MHz,CD3OD)δ=8.11(s,1H),4.63(t,J=4.6Hz,2H),4.33(t,J=4.9Hz,2H),3.91(t,J=5.0Hz,2H),3.79(t,J=4.8Hz,2H),3.68(d,J=8.9Hz,2H),3.41(s,3H).
31P NMR(75MHz,CD3OD)δ16.01.
LC/MS:保留时间=1.03分钟(运行3.5分钟),质量=348(M+1).
[2-(2-氨基-6-环丙基氨基-嘌呤-9-基)-乙氧基甲基]-膦酸(12)
二酸(12),CAS#182798-83-0,如在专利WO2005/066189中所述制备。
实施例13
将(1)(52mg,0.159mmol,1当量)和L-丙氨酸正丁基酯盐酸盐(200mg,1.10mmol,7当量)称量置于小烧瓶中并用氮气清洗。加入吡啶(1mL),并将混合物在搅拌的同时升温至60℃。加入2,2′-二硫二吡啶(aldrithiol-2)(243mg,1.10mmol,7当量)、三苯基膦(289mg,1.10mmol,7当量)和三乙基胺(265μL,1.90mmol,12当量)在1mL吡啶中的溶液。将反应混合物在60℃在氮气下搅拌过夜。然后将反应混合物浓缩为固体并在高真空放置1小时以除去残留的吡啶。经柱色谱法纯化(SiO2,0-15%在二氯甲烷中的MeOH)提供预期的产物,其为黄色固体(25mg,0.042mmol,27%)。
1H NMR(300MHz,CD3OD)δ=7.93(s,1H),4.44(t,J=6.6Hz,2H),4.30(m,2H),4.10(m,4H),3.89(m,4H),3.76(d,J=8.3Hz,2H),1.85(m,2H),1.61(m,4H),1.40,(m,10H),1.07(t,J=7.5Hz,3H),0.92(m,6H).
31P NMR(75MHz,CD3OD)δ23.49.
LC/MS:保留时间=2.39分钟(运行3.5分钟),质量=586(M+1).
化合物(14)至(25)由(1)经与(13)相同的方法制备,除了在氨基酸试剂上的差异外。在本申请使用的“相同方法”表示相同的产生步骤,且对一种或者多种试剂进行适当调整。
实施例14
化合物(14)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH)其为灰白色固体(18mg,0.034mmol,21%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),4.44(t,J=6.7Hz,2H),4.32(m,2H),4.12(m,4H),3.91(m,4H),3.75(d,J=8.9Hz,2H),1.86(m,2H),1.51(m,2H),1.30(m,10H),1.07(t,J=7.4Hz,3H).
31P NMR(75MHz,CD3OD)δ23.56.
LC/MS:保留时间=2.00分钟(运行3.5分钟),质量=530(M+1).
实施例15
化合物(15)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为黄色固体(15mg,0.022mmol,7%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.03.
LC/MS:保留时间=2.51分钟(运行3.5分钟),质量=682(M+1).
实施例16
化合物(16)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为褐色固体(20mg,0.036mmol,22%).
1H NMR(300MHz,CD3OD)δ=8.01(s,1H),5.11(宽多重峰,2H),4.42(t,J=6.6Hz,2H),4.34(t,J=4.7Hz,2H),3.89(m,4H),3.76(d,J=8.2Hz,2H),1.85(m,2H),1.25(宽多重峰,18H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.495.
LC/MS:保留时间=2.19分钟(运行3.5分钟),质量=558(M+1).
实施例17
化合物(17)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(25mg,0.034mmol,20%).
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ22.99.
LC/MS:保留时间=2.86分钟(运行3.5分钟),质量=738(M+1).
实施例18
化合物(18)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(10mg,0.020mmol,10%).
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.51.
LC/MS:保留时间=1.81分钟(运行3.5分钟),质量=502(M+1).
实施例19
化合物(19)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(20mg,0.027mmol,15%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ22.93.
LC/MS:保留时间=2.78分钟(运行3.5分钟),质量=738(M+1).
实施例20
化合物(20)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为白色固体(80mg,0.113mmol,54%)。
1H NMR(300MHz,CD3OD)δ=7.82(s,1H),7.33(m,10H),5.09(m,4H),4.42(t,J=6.7Hz,2H),4.21(m,4H),3.6-3.9(宽多重峰,4H),2.9-3.2(宽多重峰,4H),2.05(m,2H),1.6-1.9(宽多重峰,8H),1.05(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.26.
LC/MS:保留时间=2.34分钟(运行3.5分钟),质量=706(M+1).
实施例21
化合物(21)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为无色、玻璃状固体(43mg,0.074mmol,36%)。
1H NMR(300MHz,CD3OD)δ=7.89(s,1H),4.45(t,J=6.6Hz,2H),4.31(m,2H),3.9-4.2(宽多重峰,8H),3.82(m,2H),3.0-3.3(宽多重峰,4H),2.11(宽多重峰,2H),1.7-1.95(宽多重峰,8H),1.25(m,6H),1.06(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.27.
LC/MS:保留时间=1.90分钟(运行3.5分钟),质量=582(M+1).
实施例22
化合物(22)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为白色固体(68mg,0.123mmol,59%)。
1H NMR(300MHz,CD3OD)δ=7.88(s,1H),4.45(t,J=6.5Hz,2H),4.32(m,2H),4.21(m,1H),4.18(m,1H),3.99(m,1H)3.76(宽多重峰,3H),3.66(m,6H),3.08-3.24(宽多重峰,4H),2.09,(m,2H),1.85(宽多重峰,8H),1.06(t,J=7.4Hz,3H).
31P NMR(75MHz,CD3OD)δ23.34.
LC/MS:保留时间=1.97分钟(运行3.5分钟),质量=554(M+1).
实施例23
化合物(23)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为褐色固体(52mg,0.085mmol,41%)。
1H NMR(300MHz,CD3OD)δ=7.88(s,1H),4.45(t,J=6.6Hz,2H),4.26(m,3H),4.10(m,6H),3.88(m,3H),3.19(m,4H),2.11(m,2H),1.85(宽多重峰,8H),1.68(m,4H),1.065(t,J=7.4Hz,3H),0.93(m,6H).
31P NMR(75MHz,CD3OD)δ23.28.
LC/MS:保留时间=2.43分钟(运行3.5分钟),质量=610(M+1).
实施例24
化合物(24)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为白色固体(47mg,0.077mmol,37%)。
1H NMR(300MHz,CD3OD)δ=7.89(s,1H),4.93(m,2H),4.45(t,J=6.7Hz,2H),4.33(宽多重峰,2H),4.17(宽多重峰,1H),4.02(m,2H),3.87(m,3H),3.25(宽多重峰,4H),2.11(m,2H),1.84(m,8H),1.21(m,12H),1.06(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.19.
LC/MS:保留时间=3.56分钟(运行6分钟),质量=610(M+1).
实施例25
化合物(25)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为淡褐色固体(75mg,0.118mmol,57%)。
1H NMR(300MHz,CD3OD)δ=7.88(s,1H),4.45(t,J=6.7Hz,2H),4.32(m,2H),4.21(m,1H),4.08(m,6H),3.87(m,3H),3.19(m,4H),2.07(m,2H),1.81(宽多重峰,9H),1.61(m,2H),1.38(m,5H),1.06(t,J=7.35Hz,3H),0.95(m,6H).
31P NMR(75MHz,CD3OD)δ23.31.
LC/MS:保留时间=4.03分钟(运行6分钟),质量=638(M+1).
实施例26
化合物(26)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为黄色油状物(8mg,0.012mmol,9%)。
1H NMR(300MHz,CD3OD)δ=7.88(s,1H),4.45(t,J=6.7Hz,2H),4.32(m,2H),4.21(m,1H),4.04(m,6H),3.90(m,3H),3.19(m,4H),2.11(m,2H),1.81(宽多重峰,8H),1.61(宽多重峰,4H),1.38(m,12H),1.07(t,J=7.35Hz,3H),0.91(m,6H).
31P NMR(75MHz,CD3OD)δ23.35.
LC/MS:保留时间=4.71分钟(运行6分钟),质量=694(M+1).
化合物27至32由(2)经与在实施例13中所述的相同方法制备。
实施例27
化合物(27)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(10mg,0.018mmol,14%)。
1H NMR(300MHz,CD3OD)δ=7.93(s,1H),4.32(m,2H),4.10(m,4H),4.05(s,3H),3.82(m,4H),3.75(d.J=8.3Hz,2H),1.61(m,4H),1.40(m,4H),1.33(m,6H),0.95(m,6H).
31P NMR(75MHz,CD3OD)δ23.49.
LC/MS:保留时间=2.23分钟(运行3.5分钟),质量=558(M+1).
实施例28
化合物(28)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(15mg,0.030mmol,17%)。
1H NMR(300MHz,CD3OD)δ=7.93(s,1H),4.32(m,2H),4.12(m,4H),4.05(s,3H),3.90(m,4H),3.75(d,J=8.6Hz,2H),1.30(宽多重峰,12H).
31P NMR(75MHz,CD3OD)δ23.51.
LC/MS:保留时间=1.74分钟(运行3.5分钟),质量=502(M+1).
实施例29
化合物(29)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为褐色固体(20mg,0.038mmol,22%)。
1H NMR(300MHz,CD3OD)δ=7.94(s,1H),4.98(m,2H),4.32(t,J=4.9Hz,2H),4.05(s,3H),3.90(m,4H),3.75(d,J=8.6Hz,2H),1.31(m,6H),1.23(m,12H).
31P NMR(75MHz,CD3OD)δ23.48.
LC/MS:保留时间=1.92分钟(运行3.5分钟),质量=530(M+1).
实施例30
化合物(30)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为白色固体(20mg,0.031mmol,17%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.01.
LC/MS:保留时间=2.29分钟(运行3.5分钟),质量=654(M+1).
实施例31
(31)
化合物(31)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(22mg,0.031mmol,17%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ22.99.
LC/MS:保留时间=2.65分钟(运行3.5分钟),质量=710(M+1).
实施例32
化合物(32)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(15mg,0.032mmol,17%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.50.
LC/MS:保留时间=1.63分钟(运行3.5分钟),质量=474(M+1).
化合物33和34由(3)经如在实施例13中所述的相同方法制备。
实施例33
化合物(33)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(47mg,0.089mmol,53%)。
1H NMR(300MHz,CD3OD)δ=7.91(s,1H),5.55(m,1H),4.31(m,2H),4.14(m,4H),3.89(m,4H),3.75(d,J=8.9Hz,2H),1.40(m,6H),1.25(m,12H).
31P NMR(75MHz,CD3OD)δ23.56.
LC/MS:保留时间=1.74分钟(运行3.5分钟),质量=530(M+1).
实施例34
化合物(34)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(42mg,0.073mmol,44%)。
1H NMR(300MHz,CD3OD)δ=7.91(s,1H),5.56(m,1H),4.31(m,2H),4.10(m,4H),3.89(m,4H),3.75(m,2H),1.62(m,4H),1.41(m,10H),1.33(m,6H),0.95(m,6H).
31PNMR(75MHz,CD3OD)δ23.51.
LC/MS:保留时间=2.17分钟(运行3.5分钟),质量=586(M+1).
化合物35和36由(4)经如在实施例13中所述的相同方法制备。
实施例35
化合物(35)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为褐色玻璃状固体(55mg,0.101mmol,56%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),4.49(t,J=6.7Hz,2H),4.32(t,J=4.9Hz,2H),4.18(m,4H),3.89(m,4H),3.75(d,J=8.6Hz,2H),1.80(m,2H),1.54(m,2H),1.32(m,6H),1.24(m,6H),1.00(t,J=7.4Hz,3H).
31P NMR(75MHz,CD3OD)δ23.52.
LC/MS:保留时间=1.88分钟(运行3.5分钟),质量=544(M+1).
实施例36
化合物(36)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(64mg,0.107mmol,45%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),4.49(t,J=6.6Hz,2H),4.31(t,J=4.8Hz,2H),4.09(m,4H),3.89(m,4H),3.75(d,J=8.9Hz,2H),1.82(m,2H),1.60(m,6H),1.39(m,4H),1.32(m,6H),0.94(m,9H).
31P NMR(75MHz,CD3OD)δ23.50.
LC/MS:保留时间=2.29分钟(运行3.5分钟),质量=600(M+1).
化合物37和38由(5)经如在实施例13中所述的相同方法制备。
实施例37
化合物(37)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为淡黄色固体(59mg,0.115mmol,49%)。
1H NMR(300MHz,CD3OD)δ=7.98(s,1H),4.51(m,2H),4.33(m,2H),4.14(m,4H),3.90(m,4H),3.75(d,J=8.8Hz,2H),1.41(m,3H),1.26(m,6H),1.23(m,6H).
31P NMR(75MHz,CD3OD)δ23.51.
LC/MS:保留时间=1.65分钟(运行3.5分钟),质量=516(M+1).
实施例38
化合物(38)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为玻璃状米色固体(60mg,0.105mmol,44%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),4.54(m,2H),4.31(t,J=4.9Hz,2H),4.09(m,4H),3.89(m,4H),3.75(d,J=8.6Hz,2H),1.60(m,4H),1.44(m,6H),1.33(m,8H),0.94(m,5H).
31P NMR(75MHz,CD3OD)δ23.50.
LC/MS:保留时间=2.10分钟(运行3.5分钟),质量=572(M+1).
化合物39和40由(6)经如在实施例13中所述的相同方法制备。
实施例39
化合物(39)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为白色固体(49mg,0.086mmol,47%)。
1H NMR(300MHz,CD3OD)δ=7.90(s,1H),5.31(m,1H),4.31(m,2H),4.12(m,4H),3.89(m,4H),3.74(d,J=8.8Hz,2H),2.04(宽多重峰,2H),1.85(宽多重峰,2H),1.62(m,3H),1.41(m,3H),1.32(m,6H),1.25(m,6H).
31P NMR(75MHz,CD3OD)δ23.53.
LC/MS:保留时间=1.97分钟(运行3.5分钟),质量=570(M+1).
实施例40
化合物(40)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(70mg,0.113mmol,63%)。
1H NMR(300MHz,CD3OD)δ=8.42(s,1H),5.37(m,1H),4.40(m,2H),4.12(m,6H),3.91(m,4H),3.23(m,2H),3.12(m,2H),2.11(m,4H),1.83(m,8H),1.65(m,3H),1.34(m,3H),1.24(m,6H).
31P NMR(75MHz,CD3OD)δ23.38.
LC/MS:保留时间=2.07分钟(运行3.5分钟),质量=622(M+1).
实施例41由(7)经如在实施例13中所述的相同方法制备。
实施例41
化合物(41)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为玻璃状淡黄色固体(54mg,0.097mmol,53%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),4.48(t,J=6.7Hz,2H),4.32(t,J=4.9Hz,2H),4.13(m,4H),3.89(m,4H),3.75(d,J=8.6Hz,2H),1.84(m,2H),1.44(m,4H),1.32(m,6H),1.27(m,6H),0.95(t,J=7.0Hz,3H).
31P NMR(75MHz,CD3OD)δ23.52.
LC/MS:保留时间=2.01分钟(运行3.5分钟),质量=558(M+1).
化合物42至44由(8)经如在实施例13中所述的相同方法制备。
实施例42
化合物(42)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为白色固体(57mg,0.108mmol,52%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),4.54(m,1H),4.32(t,J=4.8Hz,2H),4.14(m,4H),3.90(m,4H),3.75(d,J=9.2Hz,2H),1.32(m,6H),1.25(m,6H),0.83(m,4H).
31P NMR(75MHz,CD3OD)δ23.51.
LC/MS:保留时间=1.94分钟(运行3.5分钟),质量=528(M+1).
实施例43
化合物(43)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为玻璃状米色固体(89mg,0.152mmol,73%)。
1H NMR(300MHz,CD3OD)δ=7.93(s,1H),4.54(m,1H),4.32(t,J=5.0Hz,2H),4.10(m,4H),3.89(m,4H),3.75(d,J=8.9Hz,2H),1.60(m,4H),1.39(m,4H),1.33(m,6H),0.95(m,6H),0.83(m,4H).
31P NMR(75MHz,CD3OD)δ23.49.
LC/MS:保留时间=2.36分钟(运行3.5分钟),质量=584(M+1).
实施例44
化合物(44)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为淡黄色固体(61mg,0.105mmol,51%)。
1H NMR(300MHz,CD3OD)δ=8.60(s,1H),4.62(m,1H),4.43(m,2H),4.11(宽多重峰,6H),3.91(m,4H),3.21(m,3H),2.10(m,3H),1.80(m,6H),1.23(m,6H),0.87(s,4H).
31P NMR(75MHz,CD3OD)δ23.38,24.49.
LC/MS:保留时间=2.10分钟(运行3.5分钟),质量=572(M+1).
实施例45由(9)经如在实施例13中所述的相同方法制备。
实施例45
化合物(45)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为玻璃状淡黄色固体(41mg,0.097mmol,53%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),5.41(m,1H),4.31(t,J=4.9Hz,2H),4.12(m,4H),3.88(m,4H),3.75(d,J=8.8Hz,2H),2.50(m,2H),2.23(m,2H),1.88(m,1H),1.72(m,1H),1.31(m,6H),1.23(m,6H).
31P NMR(75MHz,CD3OD)δ23.52.
LC/MS:保留时间=1.82分钟(运行3.5分钟),质量=542(M+1).
化合物46和47由(10)经如在实施例13中所述的相同方法制备。
实施例46
化合物(46)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为淡黄色固体(56mg,0.101mmol,56%)。
1H NMR(300MHz,CD3OD)δ=7.90(s,1H),5.66(m,1H),4.31(t,J=4.8Hz,2H),4.12(m,4H),3.89(m,4H),3.75(d,J=9.1Hz,2H),2.01(m,2H),1.87(m,4H),1.68(m,2H),1.32(m,6H),1.23(m,6H).
31P NMR(75MHz,CD3OD)δ23.53.
LC/MS:保留时间=1.88分钟(运行3.5分钟),质量=556(M+1).
实施例47
化合物(47)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为黄色固体(105mg,0.171mmol,72%)。
1H NMR(300MHz,CD3OD)δ=7.91(s,1H),5.67(宽单峰,1H),4.31(t,J=4.9Hz,2H),4.08(m,4H),3.89(m,4H),3.75(d,J=8.3Hz,2H),3.22(m,4H),2.01(m,2H),1.88(m,3H),1.62(m,3H),1.39(m,4H),1.32(m,6H),0.96(m,6H).
31PNMR(75MHz,CD3OD)δ23.50.
LC/MS:保留时间=2.28分钟(运行3.5分钟),质量=612(M+1).
化合物48和49由(11)经如在实施例13中所述的相同方法制备。
实施例48
化合物(48)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为无色玻璃状固体(103mg,0.189mmol,69%)。
1H NMR(300MHz,CD3OD)δ=7.92(s,1H),4.62(t,J=4.7Hz,2H),4.32(t,J=4.7Hz,2H),4.14(m,4H),3.90(m,4H),3.81(m,2H),3.75(d,J=9.2Hz,2H),3.41(s,3H),1.32(m,6H),1.24(m,6H).
31P NMR(75MHz,CD3OD)δ23.52.
LC/MS:保留时间=1.67分钟(运行3.5分钟),质量=546(M+1).
实施例49
化合物(49)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为黄色固体(85mg,0.141mmol,52%)。
1H NMR(300MHz,CD3OD)δ=7.93(s,1H),4.61(t,J=4.7Hz,2H),4.32(t,J=4.8Hz,2H),4.09(m,4H),3.89(m,4H),3.80(m,2H),3.75(d,J=8.3Hz,2H),3.41(s,3H),1.60(m,4H),1.33(m,10H),0.94(m,6H).
31P NMR(75MHz,CD3OD)δ23.50.
LC/MS:保留时间=2.09分钟(运行3.5分钟),质量=602(M+1).
化合物50和51由(12)经如在实施例13中所述的相同方法制备。
实施例50
(50)
化合物(50)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(22mg,0.038mmol,18%)。
1H NMR(300MHz,CD3OD)δ=7.77(s,1H),4.27(m,2H),4.13(宽多重峰,6H),3.85(m,4H),3.18(m,4H),2.92(m,1H),2.10(m,2H),1.45-1.90(宽多重峰,6H),1.23(m,6H),0.85(m,2H),0.60(m,2H).
31P NMR(75MHz,CD3OD)δ23.38.
LC/MS:保留时间=2.09分钟(运行3.5分钟),质量=579(M+1).
实施例51
化合物(51)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为淡黄色固体(40mg,0.057mmol,27%)。
1H NMR(300MHz,CD3OD)δ=7.70(s,1H),7.34(m,10H),5.09(m,4H),4.16(m,4H),3.6-3.9(宽多重峰,4H),3.12(m,4H),2.92(m,1H),2.05(m,2H),1.89(m,2H),1.73(m,4H),0.84(m,2H),0.59(m,2H).
31P NMR(75MHz,CD3OD)δ23.36.
LC/MS:保留时间=2.04分钟(运行3.5分钟),质量=703(M+1).
实施例52
(52)
将[[2-(2-氨基-6-正丙氧基-9H-嘌呤-9-基)乙氧基]甲基]-膦酸(78mg,0.239mmol,1当量)、苯酚(112mg,1.193mmol,5当量)和L-丙氨酸正丁基酯盐酸盐(78mg,0.43mmol,1.8当量)称量置于小烧瓶中并用氮气清洗。加入吡啶(1mL)并将反应混合物在搅拌的同时升温至60℃。加入2,2′-二硫二吡啶(368mg,1.67mmol,7当量)、三苯基膦(438mg,1.67mmol,7当量)和三乙基胺(400μL,2.86mmol,12当量)在1.5mL吡啶中的溶液。将反应混合物在60℃在氮气下搅拌过夜。然后将反应混合物浓缩为固体并在高真空下放置1小时以除去残留的吡啶。经柱色谱法纯化(SiO2,0-15%在二氯甲烷中的MeOH)提供预期的产物,其为淡黄色固体(70mg,0.131mmol,55%)。
1H NMR(300MHz,CD3OD)δ=7.90(d,J=6.7Hz,1H),7.29(m,2H),7.16(m,1H),7.05(m,2H),4.44(m,2H),4.32(m,2H),4.04(m,3H),3.94(m,4H),1.86(m,2H),1.60(m,2H),1.35(宽多重峰,4H),1.23(m,2H),1.06(t,J=7.5Hz,3H),0.92(m,3H).
31P NMR(75MHz,CD3OD)δ22.885,24.02(非对映异构体).
LC/MS:保留时间=2.18分钟(运行3.5分钟),质量=535(M+1).
非对映异构体经制备性手性HPLC分离,使用Chiral-Pak AS柱和50∶50的甲醇∶乙醇流动相。
异构体B(52b)(从色谱柱上洗脱出的第一个异构体)在除去溶剂后分离得到,其为白色固体(70mg)。
1H NMR(300MHz,CD3OD)δ=7.88(s,1H),7.28(m,2H),7.15(m,1H),7.05(m,2H),4.44(t,J=6.7Hz,2H),4.32(t,J=5.0Hz,2H),4.05(m,3H),3.90(m,4H),1.86(m,2H),1.58(m,2H),1.35(m,4H),1.23(d,J=7.3Hz,3H),1.06(t,J=7.5Hz,3H),0.91(t,J=7.3Hz,3H).
31P NMR(75MHz,CD3OD)δ24.02.
LC/MS:保留时间=2.18分钟(运行3.5分钟),质量=535(M+1).
异构体A(52a)(从色谱柱上洗脱出的第二个异构体)在除去溶剂后分离得到,其为白色固体(65mg)。
1H NMR(300MHz,CD3OD)δ=7.90(s,1H),7.29(m,2H),7.16(m,1H),7.05(m,2H),4.44(t,J=6.7Hz,2H),4.33(t,J=5.0Hz,2H),4.05(m,3H),3.94(m,4H),1.86(m,2H),1.60(m,2H),1.35(m,2H),1.23(d,J=7.3Hz,3H),1.06(t,J=7.5Hz,3H),0.91(t,J=7.3Hz,3H).
31P NMR(75MHz,CD3OD)δ22.88.
LC/MS:保留时间=2.18分钟(运行3.5分钟),质量=535(M+1).
化合物53至57由实施例1经如在实施例52中所述的方法制备。
实施例53
化合物(53)按照类似于实施例52的方式合成并经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为灰白色固体(15mg,0.030mmol,10%)。
1H NMR(300MHz,CD3OD)δ=7.89(d,J=6.1Hz,1H),7.28(m,2H),7.15(m,1H),7.05(m,2H),4.45(m,2H),4.33(m,2H),4.08(m,2H),3.95(m,5H),1.87(m,2H),1.23(m,6H),1.06(t,J=7.5Hz,3H).
31PNMR(75MHz,CD3OD)δ22.895,24.04(非对映异构体).
LC/MS:保留时间=2.14分钟(运行3.5分钟),质量=507(M+1).
非对映异构体经制备性手性HPLC分离,使用Chiral-Pak OJ柱和70∶30的庚烷∶异丙醇流动相。
异构体B(53b)
手性制备性HPLC得到异构体B(从色谱柱上洗脱出的第一个异构体),其为白色固体,71mg。
1H NMR(300MHz,CD3OD)δ=7.88(s,1H),7.26(m,2H),7.15(m,1H),7.04(m,2H),4.45(t,J=6.6Hz,2H),4.31(t,J=5.1Hz,2H),4.09(m,2H),3.90(m,5H),1.86(m,2H),1.21(m,6H),1.06(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ22.89.
LC/MS:保留时间=2.14分钟(运行3.5分钟),质量=507(M+1).
异构体A(53a)
手性制备性HPLC得到异构体A(从色谱柱上洗脱出的第一个异构体),其为白色固体,51mg。
1H NMR(300MHz,CD3OD)δ=7.91(s,1H),7.28(m,2H),7.16(m,1H),7.06(m,2H),4.44(t,J=6.7Hz,2H),4.33(t,J=5.0Hz,2H),4.07(m,2H),3.94(m,5H),1.86(m,2H),1.21(m,6H),1.06(t,J=7.4Hz,3H).
31P NMR(75MHz,CD3OD)δ24.04.
LC/MS:保留时间=2.14分钟(运行3.5分钟),质量=507(M+1).
实施例54
化合物(54)按照类似于实施例52的方式合成并经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为褐色固体(15mg,0.029mmol,10%)。
1H NMR(300MHz,CD3OD)δ=7.89(d,J=5.9Hz,1H),7.27(m,2H),7.15(m,1H),7.05(m,2H),4.90(m,1H),4.43(m,2H),4.31(m,2H),3.95(m,5H),1.87(m,2H),1.22(m,9H),1.06(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ22.96,24.05(非对映异构体).
LC/MS:保留时间=2.24分钟(运行3.5分钟),质量=521(M+1).
实施例55
化合物(55)按照类似于实施例52的方式合成并经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为黄色固体(25mg,0.043mmol,14%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ23.21,23.71(非对映异构体).
LC/MS:保留时间=2.40分钟(运行3.5分钟),质量=583(M+1).
实施例56
化合物(56)按照类似于实施例52的方式合成并经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为无色玻璃状固体(11mg,0.0185mmol,4%)。
1H NMR(300MHz,CD3OD)δ=7.88(s=1H),7.33(宽多重峰,7H),7.16(m,1H),7.03(m,2H),5.10(m,2H),4.43(t,J=6.6Hz,2H),4.32(m,3H),4.05(m,1H),3.85(m,4H),3.07(m,2H),2.03(m,1H),1.5(m,4H),1.05(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ21.84,22.72(非对映异构体).
LC/MS:保留时间=2.23分钟(运行3.5分钟),质量=595(M+1).
实施例57
化合物(57)按照类似于实施例52的方式合成并经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为无色玻璃状固体(10mg,0.019mmol,6%)。
1H NMR(300MHz,CD3OD)δ=7.89(d,J=9Hz,1H),7.31(m,2H),7.17(m,1H),7.04(m,2H),4.44(m,2H),4.33(m,3H),4.12(m,3H),3.97(m,4H),3.10(m,2H),2.00(m,1H),1.85(m,6H),1.23(m,3H),1.06(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ21.83,22.79(非对映异构体).
LC/MS:保留时间=2.00分钟(运行3.5分钟),质量=533(M+1).
实施例58由(8)如在实施例52中所述的相同方法制备。
实施例58
化合物(58)按照类似于实施例52的方式合成并经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为白色固体(62mg,0.116mmol,56%)。
1H NMR(300MHz,CD3OD)δ=7.89(d,J=6.4Hz,1H),7.29(m,2H),7.15(m,1H),7.05(m,2H),4.55(m,1H),4.33(m,2H),4.08(m,2H),3.96(m,5H),1.58(m,2H),1.37(m,2H),1.23(d,J=7.1Hz,3H),0.93(m,3H),0.83(m,4H).
31P NMR(75MHz,CD3OD)δ22.87,24.004(非对映异构体).
LC/MS:保留时间=2.30分钟(运行3.5分钟),质量=533(M+1).
实施例59
将[[2-(2-氨基-6-正丙氧基-9H-嘌呤-9-基)乙氧基]甲基]-膦酸(140mg,0.423mmol,1当量)称量置于小烧瓶中并用氮气清洗。加入N-甲基吡咯烷酮(1mL)和三乙基胺(295μL,2.115mmol,5当量)并将反应混合物在搅拌的同时升温至60℃。一旦形成澄清的溶液,加入碳酸氯甲基酯·异丙酯(chloromethyl isopropyl carbonate)(324mg,2.115mmol,5当量)。将反应混合物在60℃在氮气下搅拌三小时然后在乙酸乙酯和水之间分配。将水层用乙酸乙酯洗涤三次,并将合并的有机层用盐水洗涤一次并浓缩为油状物,将其在高真空下放置1小时。经柱色谱法纯化(SiO2,0-15%在二氯甲烷中的MeOH)提供预期的产物(59),其为淡黄色油状物(12mg,0.021mmol,5%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ21.29.
LC/MS:保留时间=2.34分钟(运行3.5分钟),质量=564(M+1).
实施例60由(2)经如在实施例59中所述的相同方法制备。
实施例60
实施例60经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为无色粘稠的油状物(10mg,0.019mmol,10%)。
H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ21.28.
LC/MS:保留时间=2.07分钟(运行3.5分钟),质量=536(M+1).
实施例61由实施例3的化合物经如在实施例59中所述的相同方法制备。
实施例61
(61)经柱色谱法分离(SiO2,0-15%在二氯甲烷中的MeOH),其为无色粘稠的油状物(10mg,0.019mmol,10%)。
1H NMR(300MHz,CD3OD)δ=8.20(s,1H),4.48(t,J=6.7Hz,2H),4.36(t,J=4.9Hz,2H),3.91(t,J=4.9Hz,2H),3.70(d,J=8.9Hz,2H),1.87(m,2H),1.07(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ21.28.
LC/MS:保留时间=2.07分钟(运行3.5分钟),质量=536(M+1).
实施例62
将三苯基膦(60mg,0.23mmol,1.25当量)称量置于小烧瓶中并用氮气清洗,然后在2mL二氯甲烷中溶解。接着加入偶氮二羧酸二异丙酯(DIAD,46mg,0.23mmol,1.25当量)然后加入L-脯氨酸乙基酯盐酸盐(165mg,0.92mmol,5当量)。加入N,N-二异丙基乙基胺(200uL,约1.1mmol,约6当量)并将反应混合物搅拌15分钟。[[2-(2-氨基-6-正丙氧基-9H-嘌呤-9-基)乙氧基]甲基]-膦酸(61mg,0.184mmol,1当量)称量置于小烧瓶中并用氮气清洗。然后将试剂的混合物快速加入至含有[[2-(2-氨基-6-正丙氧基-9H-嘌呤-9-基)乙氧基]甲基]-膦酸的烧瓶中并将反应混合物在室温在氮气下搅拌2小时。然后将反应混合物浓缩为油状物,重新在甲醇中溶解,并将中间体由溶液经反相HPLC分离,其为白色固体(30mg,0.066mmol,36%)。将所有的对氯苯酚(17mg,0.132mmol,2当量)、DMAP(4mg,0.033mmol,0.5当量)和PyBroP(62mg,0.132mmol,2当量)称量置于含有中间体的烧瓶中。将该烧瓶用氮气清洗然后加入1mL二氯甲烷和N,N-二异丙基乙基胺(69uL,0.396mmol,6当量)。将反应混合物在室温搅拌过夜。然后将反应混合物浓缩为油状物,并在甲醇中重新溶解。将化合物62由该溶液经反相HPLC分离,其为白色固体(8mg,0.014mmol,8%)。
1H NMR(300MHz,CD3OD)δ=7.89(d,J=9Hz,1H),7.30(m,2H),7.11(m,2H),4.44(m,2H),4.33(m,2H),4.13(m,3H),3.96(m,3H),3.17(m,2H),2.01(m,1H),1.86(m,6H),1.23(m,3H),1.06(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ22.33,23.31(非对映异构体).
LC/MS:保留时间=2.98分钟(运行6分钟),质量=568(M+1).
实施例63
化合物(63)经如在实施例62中所述的相同方法制备,除了用对氰基苯酚取代对氯苯酚。化合物(63)经反相HPLC分离,其为白色固体(31mg,0.056mmol,18%)。
1H NMR(300MHz,CD3OD)δ=7.90(d,J=9Hz,1H),7.70(d,J=9Hz,2H),7.31(m,1H),7.20(m,1H),4.44(m,2H),4.33(m,2H),4.12(m,4H),4.00(m,2H),3.20(m,2H),2.02(m,1H),1.85(m,6H),1.23(m,3H),1.06(t,J=7.5Hz,3H).
31P NMR(75MHz,CD3OD)δ22.66,23.72(非对映异构体).
LC/MS:保留时间=2.98分钟(运行6分钟),质量=558(M+1).
实施例64
关于细胞生长抑制的细胞培养测定(GI
50
)
本测定是基于经比色法检测细胞相关蛋白对细胞计数进行定量。本测定依赖于磺酰罗丹明B(sulforhodamine B)(SRB)结合细胞蛋白成分的能力,所述的细胞已经通过三氟乙酸(TCA)固定在组织培养板上。SRB为具有两个磺基的亮粉色氨基呫吨染料,所述的磺基在弱酸性条件下结合碱性氨基酸残基并在碱性条件下解离。当SRB的结合为化学计量的时,从经染色的细胞提取的染料的量与细胞数量直接成比例。
细胞系:所有细胞系由ATCC(Manassas,VA)得到。含有Glutamax和胰蛋白酶的培养基购自Invitrogen(Carlsbad,CA)。阿霉素、氯苯吩嗪、TCA和SRB来自Sigma-Aldrich(St.Louis,MO)。吉西他滨由MoravekBiochemicals(Brea,CA)得到。
测定方案:
1.保持在培养基中的细胞系在表1中列出。对亚融合的(sub-confluent)细胞进行胰蛋白酶作用,对它们计数并根据在表1中所列的细胞计数调整细胞浓度。
2.将细胞在150μL培养基中分配到96孔板中。将板在潮湿的CO2培养箱中在37℃孵育过夜。
3.将每个细胞系的板用TCA固定。通过轻弹板将培养基从板中弃去并将100ul冷的10%(体积/体积)TCA加入至每孔。将板在4度冰箱中孵育1小时。通过轻弹板将TCA从板中弃去。在含有自来水的洗盆中冲洗板四次。将板在室温保存。这些板表示在第0天的细胞计数。
4.制备一组含有各种浓度的测试化合物的培养基溶液,其通过在96孔板中制备5倍连续稀释液来完成。每孔加入50μL稀释的化合物。将具有未处理的细胞和用阿霉素、氯苯吩嗪和吉西他滨处理的细胞的对照组包括在内。
5.在37℃孵育板5天。
6.用TCA固定板。通过轻弹板将培养基从板中弃去并于每孔加入100ul冷的10%(体积/体积)TCA。将板在4度冰箱孵育1小时。通过轻弹板将TCA从板中弃去。在含有自来水的洗盆中冲洗板四次。
7.通过在纸巾上轻拍板的下面来除去过量的水。允许板在室温风干。
8.于板的每孔中加入100ul 0.057%在1%(体积/体积)乙酸中的SRB溶液,所述的板在第0天和第5天用TCA固定。在室温放置30分钟。
9.轻弹板以弃去SRB。用1%(体积/体积)乙酸冲洗板四次。
10.将板在37度培养箱中保存以便于快速干燥。
11.一旦板完全干燥,于每孔中加入200ul 10mM Tris碱溶液(pH 10.5)。在室温放置30分钟以溶解SRB。
12.在微量培养板读数器(microplate reader)上在500nm测量OD。
13.使用下式计算细胞生长抑制作用的百分数:
占对照细胞生长的%=100*(OD样品-平均值OD第0天)/(OD阴性对照-平均值OD第0天)
对于GI50确定,绘制一条在化合物浓度和生长抑制作用百分数之间的剂量效应曲线。GI50值可通过使用S形剂量效应方程拟合剂量效应曲线来得到。
下表显示了本发明的化合物抑制癌细胞生长。
细胞毒性细胞培养测定(CC
50
):
本测定是基于通过测量细胞内ATP水平的细胞数的定量。在细胞内ATP的存在下Ultra-Glo重组体荧光素酶(Recombinant Luciferase)将甲虫荧光素转化为氧化荧光素(oxylucifer)和发光(luminescence),所述发光与细胞的数目成比例。
材料:MT4细胞系由ATCC(Manassas,VA)得到。培养基、HEPES和牛血清白蛋白购自Invitrogen(Carlsbad,CA)。Black 384孔Nunc细胞培养板来自VWR,且Cell Titer-Glo荧光细胞存活力测定剂(Luminescent CellViability assay)购自Promega。
确定CC50的测定方案:
1.将MT-4细胞保持在补充有10%胎牛血清、10mM Hepes和抗生素的RPMI-1640培养基中。
2.制备一组含有各种浓度的测试抑制剂的溶液,其通过在384孔板(20微升/孔)在培养基中制备5倍连续稀释液来完成。将细胞分配到384孔板(2000个细胞,浓度为20微升/孔)中。将作为对照组的具有未处理的细胞的样品包括在内。
3.将细胞在37℃、5%CO2在潮湿的培养箱中孵育5天。
4.通过将CellTiter-Glo底物与CellTiter-Glo缓冲液在黑暗中混合来制备CellTiter-Glo溶液。于每孔中加入40μL溶液。
5.在孵育3分钟后,读取化学发光(chemiluminescence)。
6.对关于未处理的对照组的荧光百分数进行绘图,并估算CC50值,其为导致抑制细胞生长50%的药物浓度。认为发光直接与细胞数目成比例。
测定化合物(1)-(60)并发现具有可接受毒性和抗肿瘤细胞的活性。
实施例65
将化合物(21)在具有天然存在的非霍奇金淋巴瘤(NHL)的狗中评价其效能。已证明犬NHL为用于临床前评价新治疗的相关模型,同时用于初期诱导和治疗耐药复发(参考Vail DM,Thamm DH.Spontaneously occurringtumors in companion animals as models for drug development.In:Teisher BA,ed.Anticancer Drug Development Guide.2nd ed.Totowa(NJ):Humana PressInc;2004;259-286.)。在有自发癌症的狗中对新治疗方法的评价提供了对犬类患者的潜在益处和治疗指数的快速评估。因为肿瘤自发地产生在免疫完整的宿主体内且具有相比于传代细胞系更强的异质性,所以不令人惊讶的是对于在犬类恶性肿瘤中的标准化疗药物的响应与那些在人类中的相应肿瘤的响应相似,并且得到的临床前结果在人类中为活性更可预测的(参考文献;Khanna C,Paoloni M.Translation of new cancer treatments from petdogs to humans.Nature Rev Cancer.2008;8:7-16.;Vail DM,Young KM.Canine lymphoma and lymphoid leukemia.In:Withrow SJ,Vail DM,eds.SmallAnimal Clinical Oncology.4th Ed.St.Louis(MO):Saunders;2007.p.699-733.)。在狗中的非霍奇金淋巴瘤代表关于组织学类型的同质种群,所述的组织学类型如被REAL/WHO或者NCI-Working Formulation schema所定义(即85%为中级至高级B细胞NHL),其中大多数为弥散大B细胞淋巴瘤(参考Jacobs RM,Messick JB,Valli VE.Tumors of the hemolymphaticsystem.In:Meuten DJ,editor.Tumors in Domestic Animals.4th Ed.Ames(IA):Iowa State Press;2002:119-198)。
在宠物狗中的癌症通过如下表征:在有完整免疫系统的背景中历时长期的肿瘤生长、个体间和瘤内的异质性、再发或者抗性疾病的发展以及病灶转移至相关远离的位点。在这些途径中,狗类癌症获得人类癌症的‘本质’问题,其以对于其它动物模型系统而言不可能的方式获得。对于这些癌症中的许多,发现了与人类癌症较强的相似处,包括组织学形态、肿瘤遗传学行为、生物学行为和对常规治疗的响应。在狗中发现的癌症进展的简洁的过程允许适时地对新的癌症治疗进行评估。
将化合物(21)以剂量为每千克体重0.3mg通过无菌盐水注射液(0.9%注射用氯化钠)的30分钟静脉内输注(总体积2ml/kg或者100ml)给予狗,每21天给药一次,所述的狗具有涉及多种淋巴结的非霍奇金淋巴瘤。诊断通过肿瘤的组织学评价被证实。使用在实体瘤中的响应评价标准(Response Evaluation Criteria in Solid Tumors,RECIST)指引(Therasse等,2000)来测量对肿瘤的治疗效果。肿瘤的大小和对治疗的响应通过在这些外周可进入的淋巴结中进行评价,其通过使用测径器测量最长的尺寸来测量并评价个体肿瘤测量中的改变和它们的总和。对治疗的响应通过肿瘤大小的显著减少来显示,起始于首次治疗后的第7天,持续改善直到第42天。肿瘤大小的减少、所有肿瘤的总和表征为部分响应(PR)(如果在目标损伤的LD的总和有至少30%的减少,则作为参考基线总和)以及完全向应(CR)(如果淋巴结恢复至在正常范围的大小)。通过吸气活组织检查(aspirated biopsy)的细胞学检查证实肿瘤细胞的缺失。
用化合物(21)治疗有非霍奇金淋巴瘤的狗在一次治疗后导致部分反应,且在持续治疗后导致具有完全消除肿瘤的完全反应。
用化合物(21)治疗的狗
**WNL是指当淋巴结减小至认为在该结节的正常范围内的大小时。
缩写
ATCC 美国模式培养结肠切除术
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
dt 双三重峰
Et 乙基
EDTA 乙二胺四乙酸
FAB 快原子轰击
gem 成对的
HR 高分辨
i 异
IR 红外光谱
m 多重峰
m 间位
Me 甲基
MeOH 甲醇
MeONa 甲醇钠
MS 质谱
v 波数
NMR 核磁共振
o 邻位
p 对位
Ph 苯基
PPh3 三苯基膦
Py 吡啶基
pyrr 吡咯基
q 四重峰
rel. 相关的
RT 室温
s 单峰
sat. 饱和的
sol. 溶液
t 三重峰
TBS 叔丁基二甲基甲硅烷基
td 三双重峰
TDA-1 三[2-(2-甲氧基乙氧基)乙基]胺
THF 四氢呋喃
TFA 三氟乙酸
TPPTS 三苯基膦三磺酸钠
Tr 三苯甲基,三苯基甲基
vic 连位的(vicinal)
HPLC 高效液相色谱
FBS 胎牛血清
RPMI 皇家公园纪念学会(Royal Park MemorialInstitute)
TCA 三氟乙酸
DIAD 偶氮二羧酸二异丙酯(di-isopropyl azodicarboxylate)
(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)
DME 二甲氧基乙烷
DCM 二氯甲烷
ACN 乙腈
NaHNDS 六甲基二硅氨基钠(Sodium hexamethyldisilazide)
SRB 磺酰罗丹明B(sulforhodamine B)
Claims (29)
1.具有结构(1)的化合物或其治疗用盐和/或富集的旋光异构体,所述的结构(1)如下所示:
其中
Y独立为-OR3;氨基酸、氨基酸酰胺或者氨基酸酯或者经氨基酸的氨基连接的氨基酸硫酯;
R1为CH3或者H;
R2′和R2独立为H、卤素、NH2、NH(R10)、N(R10)2或者X,但至少一个R2或者R2′为X;
R3独立为H;未取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基;或者被下述基团取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基:C1-C12烷氧基、卤素、羧基、羧酸酯基团、羟基、氨基、CN、NO2、OH、巯基、硫羟酸酯基团、叠氮基、芳基氨基、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基;
X为-OR10,
R10为未取代的以下基团:C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
或者下述的C2-C15烷基、C3-C15烯基、C6-C15芳基烯基、C3-C15炔基、C7-C15芳基炔基、C1-C6烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂烷基或者C3-C6杂环烷基,其中在烷基部分中与-OR10的氧不相邻的1至2个亚甲基已被-O-、-S-或者N(R3)替代;
或者前述的R10基团中的一个取代有卤素、R3、CN或者N3中的1至3个;
Z为N或者CH,条件是杂环的核与嘌呤的不同之处在于:它们中的Z最多有一个是不同的。
2.具有结构(3)的化合物或其治疗用盐和/或富集的旋光异构体,所述的结构(3)如下所示:
其中
Y独立为-OR3;氨基酸、氨基酸酰胺或者氨基酸酯或者经氨基酸的氨基连接的氨基酸硫酯;
R1为CH3或者H;
R2′为-OR10;
R3独立为H;未取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基;或者被下述基团取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基:C1-C12烷氧基、卤素、羧基、羧酸酯基团、羟基、氨基、CN、NO2、OH、巯基、硫羟酸酯基团、叠氮基、芳基氨基、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基;其中当R3为未取代的C1-C12烷基时,在R3上与-OR3的氧不相邻的1至4个亚甲基任选被-O-或者-S-或者-C(O)-替代;
R10为未取代的以下基团:C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
或者R10为C1-C15烷基、C3-C15烯基、C6-C15芳基烯基、C3-C15炔基、C6-C15芳基炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂烷基或者C3-C6杂环烷基,其中在烷基部分中与-OR10的氧不相邻的1至2个亚甲基已被-O-、-S-或者N(R3)替代;
或者前述的R10基团中的一个取代有卤素、R3、CN或者N3中的1至3个。
3.具有结构(3)的化合物或其治疗用盐和/或富集的旋光异构体,其中Y独立为-OR3;氨基酸、氨基酸酰胺或者氨基酸酯或者经氨基酸的氨基连接的氨基酸硫酯,或者结构(2)的基团:
条件是至少一个Y为结构(2)的基团;
R1为CH3或者H;
R2′为-OR10;
R3独立为H;未取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基;或者被下述基团取代的芳基、杂环基、C1-C12烷基、C2-C12烯基或者C2-C12炔基:C1-C12烷氧基、卤素、羧基、羧酸酯基团、羟基、氨基、CN、NO2、OH、巯基、硫羟酸酯基团、叠氮基、芳基氨基、C1-C12卤代烷基(1-6个卤素原子)、C2-C12烯基或者C2-C12炔基;其中当R3为未取代的C1-C12烷基时,在R3上与-OR3的氧不相邻的1至4个亚甲基任选被-O-或者-S-或者-C(O)-替代;
R10为未取代的以下基团:C1-C15烷基、C2-C15烯基、C6-C15芳基烯基、C6-C15芳基炔基、C2-C15炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂芳烷基、C5-C6芳基、C2-C6杂环烷基;
或者R10为C2-C15烷基、C3-C15烯基、C6-C15芳基烯基、C3-C15炔基、C6-C15芳基炔基、C1-C6-烷基氨基-C1-C6烷基-、C5-C15芳烷基、C6-C15杂烷基或者C3-C6杂环烷基,其中在烷基部分中与-OR10的氧不相邻的1至2个亚甲基已被-O-、-S-或者N(R3)替代;
或者前述的R10基团中的一个取代有卤素、R3、CN或者N3中的1至3个。
5.权利要求4的化合物或其治疗用盐和/或富集的旋光异构体,其中每个Ra独立为C1-C4烷基,或者苄基,每个Rb独立为C1-C4烷基,R10为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,其中C1-C8烷基任选被一个C1-C4烷氧基取代。
7.权利要求6的化合物或其治疗用盐和/或富集的旋光异构体,其中每个Rb独立为C1-C4烷基,或者苄基,R10为C1-C4烷基。
9.权利要求8的化合物或其治疗用盐和/或富集的旋光异构体,其中Ra为C1-C4烷基或者苄基,Rb为C1-C4烷基,以及Rc为苯基。
13.具有结构(10)的化合物或其治疗用盐和/或富集的旋光异构体,所述的结构(10)如下所示:
其中Rb独立为C1-C8烷基,或者C2-C8烯基,或者C2-C8炔基,或者C6-C10芳基-C1-C4烷基-。优选地,Rb为C1-C4烷基。
14.用于在受试者中抑制肿瘤/癌症生长的方法,其包括给予所述受试者治疗有效量的权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物。
15.用于在受试者中抑制肿瘤/癌细胞的细胞增殖的方法,其包括给予所述受试者治疗有效量的权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物。
16.用于在受试者中治疗细胞增殖疾病的方法,其包括给予所述受试者治疗有效量的权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物。
17.用于在受试者中治疗肿瘤性疾病的方法,其包括给予所述受试者治疗有效量的权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物。
18.用于在受试者中治疗非霍奇金淋巴瘤(NHL)的方法,其包括给予所述受试者治疗有效量的根据权利要求6的化合物。
19.药物组合物,其包含治疗有效量的权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物。
20.药物组合物,其包含治疗有效量的权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物和选自抗病毒剂或者抗肿瘤/抗癌剂的第二种治疗药物。
21.权利要求20的药物组合物,其中抗病毒剂选自:3′-叠氮基-3′-脱氧胸苷(齐多夫定,AZT)、2′-脱氧-3′-硫胞苷(3TC)、2′,3′-二脱氧-2′,3′-二去氢腺苷(D4A)、2′,3′-二脱氧-2′,3′-二去氢胸苷(D4T)、卡波佛(碳环的2′,3′-二脱氧-2′,3′-二去氢鸟苷)、3′-叠氮基-2′,3′-二脱氧尿苷、5-氟胸苷、(E)-5-(2-溴乙烯基)-2′-脱氧尿苷(BVDU)、2-氯-2′-脱氧腺苷、2-脱氧柯福霉素、5-氟尿嘧啶、5-氟尿苷、5-氟-2′-脱氧尿苷、5-三氟甲基-2′-脱氧尿苷、6-氮杂尿苷、5-氟乳清酸、甲氨喋呤、三乙酰基尿苷、1-(2′-脱氧-2′-氟-1-β-D-阿糖基)-5-碘胞嘧啶(FIAC)、四氢咪唑(4,5,1-jk)-(1,4)-苯并二氮杂-2(1H)-硫酮(TIBO)、2′-去甲磷鸟苷、6-甲氧基嘌呤阿拉伯糖苷(ara-M)、6-甲氧基嘌呤阿拉伯糖苷′-O-戊酸酯、胞嘧啶阿糖胞苷(ara-C)、2′,3′-二脱氧核苷、无环核苷、无环核苷酸、利巴韦林(腺嘌呤阿拉伯糖苷)、2-硫代-6-氮杂尿苷、杀结核菌素、金精三羧酸、3-deazaneoplanocin、neoplanocin、rimantidine、金刚化合物、膦甲酸(磷酸三钠甲酸盐)、细胞因子、干扰素,所述的干扰素包括白细胞介素、巨噬细胞/粒细胞集落刺激因子、细胞因子拮抗剂、可溶性白细胞介素受体,和蛋白激酶C抑制剂。
22.权利要求20的药物组合物,其中抗肿瘤/抗癌剂选自阿巴瑞克(Plenaxis);阿地白介素阿地白介素阿仑单抗阿利维A酸别嘌呤醇六甲蜜胺阿米斯丁阿那曲唑三氧化二砷天冬酰胺酶氮杂胞苷bevacuzimab贝沙罗汀胶囊贝沙罗汀凝胶博来霉素硼替佐米白消安静脉注射剂白消安口服剂卡普睾酮卡培他滨卡铂卡莫司汀卡莫司汀含有聚苯丙生20的卡莫司汀植入剂(Gliadel);塞来考昔西妥昔单抗苯丁酸氮芥顺铂克拉屈滨氯苯吩嗪环磷酰胺环磷酰胺(Cytoxan);环磷酰胺(Cytoxan);阿糖胞苷阿糖胞苷脂质体达卡巴嗪更生霉素,放线菌素DDarbepoetinalfa柔红霉素脂质体柔红霉素,道诺霉素柔红霉素,道诺霉素地尼白介素2右丙亚胺多西他赛阿霉素(Adriamycin);阿霉素阿霉素(AdriamycinPFS);阿霉素脂质体丙酸甲雄烷酮丙酸甲雄烷酮(masterone);埃利奥特B溶液(Elliott′s B);表柔比星阿法依伯汀厄洛替尼雌莫司汀依托泊苷磷酸盐依托泊苷,VP-16依西美坦非格司亭氟尿苷(动脉内)氟达拉滨氟尿嘧啶,5-FU氟维斯群吉非替尼吉西他滨吉姆单抗奥佐米星乙酸戈舍瑞林(Zoladex);乙酸戈舍瑞林乙酸组氨瑞林(Histrelin);羟脲替伊莫单抗伊达比星异磷酰胺甲磺酸伊马替尼干扰素α-2a (Roferon);干扰素α-2b(Intron);依立替康lenalidomide来曲唑甲酰四氢叶酸乙酸亮丙瑞林左旋咪唑洛莫司汀-CCNUmeclorethamine,氮芥乙酸甲地孕酮苯丙氨酸氮芥,L-PAM6-巯基嘌呤,6-MP美司钠美司钠(Mesnex);甲氨喋呤甲氧沙林丝裂霉素C米托坦米托蒽醌苯丙酸诺龙奈拉滨诺非单抗奥普瑞白介素奥沙利铂紫杉醇紫杉醇紫杉醇蛋白结合颗粒palifermin氨羟二磷酸二钠培加酶(Adagen(pegademase Bovine));培门冬酶Pegfilgrastim培美曲塞二钠喷司他丁哌泊溴烷普卡霉素(plicamycin,mithramycin)卟吩姆钠丙卡巴肼喹纳克林拉布立酶利妥昔单抗沙格司亭沙格司亭sorafenib链唑霉素sunitinib maleate滑石他莫昔芬替莫唑胺替尼泊苷,VM-26睾内酯硫鸟嘌呤,6-TG噻替派托泊替康托瑞米芬托西莫单抗托西莫单抗/I-131托西莫单抗曲妥单抗维甲酸,ATRA尿嘧啶氮芥(Uracil Mustard);戊柔比星长春碱长春新碱长春瑞滨以及唑来膦酸盐
23.权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物在制备用于在受试者中抑制肿瘤/癌症生长的药物中的用途。
24.权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物在制备用于在受试者中抑制肿瘤/癌细胞细胞增殖的药物中的用途。
25.权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物在制备用于在受试者中治疗细胞增殖疾病的药物中的用途。
26.权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物在制备用于在受试者中治疗肿瘤性疾病的药物中的用途。
27.权利要求1或者2或者3或者4或者6或者8或者10或者11或者12或者13的化合物在制备用于在受试者中治疗血液恶性肿瘤的药物中的用途。
28.根据权利要求6的化合物在制备用于治疗非霍奇金淋巴瘤(NHL)的药物中的用途。
29.权利要求19或者20的药物组合物在制备用于在受试者中抑制肿瘤/癌症生长的药物中的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3014808P | 2008-02-20 | 2008-02-20 | |
US61/030,148 | 2008-02-20 | ||
PCT/US2009/034471 WO2009105513A2 (en) | 2008-02-20 | 2009-02-19 | Novel compounds and methods for therapy |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610086843.7A Division CN105753905A (zh) | 2008-02-20 | 2009-02-19 | 新的化合物以及用于治疗的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102015739A true CN102015739A (zh) | 2011-04-13 |
CN102015739B CN102015739B (zh) | 2016-03-09 |
Family
ID=40532651
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610086843.7A Pending CN105753905A (zh) | 2008-02-20 | 2009-02-19 | 新的化合物以及用于治疗的方法 |
CN200980113907.6A Active CN102015739B (zh) | 2008-02-20 | 2009-02-19 | 化合物以及用于治疗的方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610086843.7A Pending CN105753905A (zh) | 2008-02-20 | 2009-02-19 | 新的化合物以及用于治疗的方法 |
Country Status (19)
Country | Link |
---|---|
US (1) | US8163718B2 (zh) |
EP (2) | EP2308885B1 (zh) |
JP (2) | JP5588356B2 (zh) |
KR (2) | KR101612138B1 (zh) |
CN (2) | CN105753905A (zh) |
AR (1) | AR071159A1 (zh) |
AU (3) | AU2009215547B2 (zh) |
CA (1) | CA2715885C (zh) |
CY (2) | CY1115571T1 (zh) |
DK (2) | DK2308885T3 (zh) |
ES (2) | ES2516715T3 (zh) |
HK (2) | HK1150313A1 (zh) |
HR (2) | HRP20140895T1 (zh) |
NZ (1) | NZ587464A (zh) |
PL (2) | PL2245037T4 (zh) |
PT (2) | PT2245037E (zh) |
SI (2) | SI2245037T1 (zh) |
TW (1) | TWI444384B (zh) |
WO (1) | WO2009105513A2 (zh) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104558035A (zh) * | 2013-10-22 | 2015-04-29 | 上海源力生物技术有限公司 | 一种替诺福韦前药的纯化方法 |
CN106795188A (zh) * | 2014-09-15 | 2017-05-31 | 加利福尼亚大学董事会 | 核苷酸类似物 |
CN107849071A (zh) * | 2015-08-10 | 2018-03-27 | 默沙东公司 | 抗病毒的β氨基酸酯膦酰二胺化合物 |
CN108096562A (zh) * | 2017-12-25 | 2018-06-01 | 武汉百药联科科技有限公司 | 20s蛋白酶体抑制剂在制备治疗日本乙型脑炎病毒感染的药物中的用途 |
CN108542913A (zh) * | 2012-12-13 | 2018-09-18 | 艾杜罗生物科技公司 | 包含具有确定立体化学的环嘌呤二核苷酸的组合物及其制备和使用方法 |
CN109311882A (zh) * | 2016-05-04 | 2019-02-05 | Bci制药公司 | 作为蛋白激酶抑制剂的腺嘌呤衍生物 |
CN112778363A (zh) * | 2019-11-05 | 2021-05-11 | 华创合成制药股份有限公司 | 一种硝基咪唑类唑衍生物及其制备方法和用途 |
Families Citing this family (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008520744A (ja) | 2004-11-19 | 2008-06-19 | ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア | 抗炎症性ピラゾロピリミジン |
DK2004654T3 (da) | 2006-04-04 | 2013-07-22 | Univ California | Pyrazolopyrimidin derivater til anvendelse som kinase antagonister |
GB2467670B (en) | 2007-10-04 | 2012-08-01 | Intellikine Inc | Chemical entities and therapeutic uses thereof |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
NZ587051A (en) | 2008-01-04 | 2012-12-21 | Intellikine Llc | Isoquinolinone derivatives, compositions and methods of inhibiting phosphatidyl inositol-3 kinase (pi3 kinase) |
US8993580B2 (en) | 2008-03-14 | 2015-03-31 | Intellikine Llc | Benzothiazole kinase inhibitors and methods of use |
JP5547099B2 (ja) | 2008-03-14 | 2014-07-09 | インテリカイン, エルエルシー | キナーゼ阻害剤および使用方法 |
US20110224223A1 (en) | 2008-07-08 | 2011-09-15 | The Regents Of The University Of California, A California Corporation | MTOR Modulators and Uses Thereof |
NZ590258A (en) | 2008-07-08 | 2013-10-25 | Intellikine Llc | Kinase inhibitors and methods of use |
CA2738429C (en) | 2008-09-26 | 2016-10-25 | Intellikine, Inc. | Heterocyclic kinase inhibitors |
US8697709B2 (en) | 2008-10-16 | 2014-04-15 | The Regents Of The University Of California | Fused ring heteroaryl kinase inhibitors |
US8476282B2 (en) | 2008-11-03 | 2013-07-02 | Intellikine Llc | Benzoxazole kinase inhibitors and methods of use |
ES2650337T3 (es) | 2009-01-08 | 2018-01-17 | International Institute Of Cancer Immunology, Inc. | Péptidos derivados de eEF2 para el tratamiento o prevención de cánceres |
CA2760791C (en) | 2009-05-07 | 2017-06-20 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
US8980899B2 (en) | 2009-10-16 | 2015-03-17 | The Regents Of The University Of California | Methods of inhibiting Ire1 |
CN102093422B (zh) | 2009-12-10 | 2015-02-25 | 中国人民解放军军事医学科学院毒物药物研究所 | 无环核苷膦酸酯衍生物及其医药用途 |
JP5951600B2 (ja) | 2010-05-21 | 2016-07-13 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | キナーゼ調節のための、化合物、組成物および方法 |
CN103298474B (zh) | 2010-11-10 | 2016-06-29 | 无限药品股份有限公司 | 杂环化合物及其用途 |
CA2824197C (en) | 2011-01-10 | 2020-02-25 | Michael Martin | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
TWI592411B (zh) | 2011-02-23 | 2017-07-21 | 英特爾立秦有限責任公司 | 激酶抑制劑之組合及其用途 |
JP6027610B2 (ja) | 2011-07-19 | 2016-11-16 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環式化合物及びその使用 |
CN103946226A (zh) | 2011-07-19 | 2014-07-23 | 无限药品股份有限公司 | 杂环化合物及其应用 |
TW201311663A (zh) | 2011-08-29 | 2013-03-16 | Infinity Pharmaceuticals Inc | 雜環化合物及其用途 |
CA2846496C (en) | 2011-09-02 | 2020-07-14 | The Regents Of The University Of California | Substituted pyrazolo[3,4-d]pyrimidines and uses thereof |
CA2752008A1 (en) | 2011-09-13 | 2013-03-13 | Universite De Montreal | Combination therapy using ribavirin as elf4e inhibitor |
WO2013095684A1 (en) | 2011-12-22 | 2013-06-27 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
AU2013202947B2 (en) * | 2012-06-13 | 2016-06-02 | Ipsen Biopharm Ltd. | Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
CN103665043B (zh) * | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药及其在医药上的应用 |
AU2013323426A1 (en) | 2012-09-26 | 2015-04-23 | The Regents Of The University Of California | Modulation of ire1 |
US9889180B2 (en) | 2012-11-19 | 2018-02-13 | Agency For Science, Technology And Research | Method of treating cancer |
JP6462659B2 (ja) | 2013-03-15 | 2019-01-30 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 非環式ヌクレオシドホスホン酸ジエステル |
US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
CA2925944C (en) | 2013-10-04 | 2023-01-10 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
SG10201808053XA (en) | 2014-03-19 | 2018-10-30 | Infinity Pharmaceuticals Inc | Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders |
WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
HUE056470T2 (hu) | 2014-12-26 | 2022-02-28 | Univ Emory | Vírusellenes N4-Hidroxicitidin származékok |
WO2017048702A1 (en) | 2015-09-14 | 2017-03-23 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same |
US10377782B2 (en) | 2015-09-15 | 2019-08-13 | The Regents Of The University Of California | Nucleotide analogs |
WO2017100108A1 (en) * | 2015-12-10 | 2017-06-15 | Merck Sharp & Dohme Corp. | Antiviral phosphodiamide prodrugs of tenofovir |
US10450335B2 (en) | 2015-12-15 | 2019-10-22 | Merck Sharp & Dohme Corp. | Antiviral oxime phosphoramide compounds |
US10759806B2 (en) | 2016-03-17 | 2020-09-01 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors |
WO2017197055A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Heterocyclic degronimers for target protein degradation |
CN109641874A (zh) | 2016-05-10 | 2019-04-16 | C4医药公司 | 用于靶蛋白降解的c3-碳连接的戊二酰亚胺降解决定子体 |
EP3454862A4 (en) | 2016-05-10 | 2020-02-12 | C4 Therapeutics, Inc. | SPIROCYCLIC DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
AU2017281797A1 (en) | 2016-06-24 | 2019-01-24 | Infinity Pharmaceuticals, Inc. | Combination therapies |
EP3532069A4 (en) | 2016-10-26 | 2020-05-13 | Merck Sharp & Dohme Corp. | ARYL-AMIDE PHOSPHODIAMIDE COMPOUNDS ANTIVIRALS |
CA3046029A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Antiviral benzyl-amine phosphodiamide compounds |
CA3047573A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Antiviral aliphatic ester prodrugs of tenofovir |
GB2590198B (en) | 2017-12-07 | 2022-02-23 | Univ Emory | N4-hydroxycytidine derivatives and anti-viral uses related thereto |
US11826375B2 (en) | 2018-07-19 | 2023-11-28 | Merck Sharp & Dohme Llc | Phosphinic amide prodrugs of tenofovir |
EP4337667A1 (en) * | 2022-07-21 | 2024-03-20 | Antiva Biosciences, Inc. | Compositions and dosage forms for treatment of hpv infection and hpv-induced neoplasia |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5854228A (en) * | 1986-11-18 | 1998-12-29 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiviral phosphonomethoxyalkylene purine and pyrimidine derivatives |
CN1950383A (zh) * | 2003-12-30 | 2007-04-18 | 吉里德科学公司 | 用于治疗病毒性疾病的膦酸酯、单膦酸酰胺化物、双膦酸酰胺化物 |
CN101066981A (zh) * | 2007-05-25 | 2007-11-07 | 中国科学院上海药物研究所 | 非环核苷膦酸酯类化合物及其组合物、制备方法和用途 |
WO2008005555A1 (en) * | 2006-07-07 | 2008-01-10 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
Family Cites Families (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1617457A1 (de) * | 1966-12-16 | 1972-04-20 | Erba Carlo Spa | Verfahren zur Stabilisierung von Zubereitungen interferierender Virusprodukte |
US3665838A (en) * | 1970-01-29 | 1972-05-30 | Wilson Lighting Ltd | Air chamber assembly |
CS233665B1 (en) | 1983-01-06 | 1985-03-14 | Antonin Holy | Processing of isomere o-phosphonylmethylderivative of anantiomere racemic vicinal diene |
US4740365A (en) | 1984-04-09 | 1988-04-26 | Toyo Boseki Kabushiki Kaisha | Sustained-release preparation applicable to mucous membrane in oral cavity |
CS263951B1 (en) | 1985-04-25 | 1989-05-12 | Antonin Holy | 9-(phosponylmethoxyalkyl)adenines and method of their preparation |
CS263952B1 (en) | 1985-04-25 | 1989-05-12 | Holy Antonin | Remedy with antiviral effect |
US5141752A (en) | 1986-05-09 | 1992-08-25 | Alza Corporation | Delayed drug delivery device |
CS264222B1 (en) | 1986-07-18 | 1989-06-13 | Holy Antonin | N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them |
AU613592B2 (en) | 1986-11-18 | 1991-08-08 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiviral phosophonomethoxy-alkyene purine and pyrimide derivatives |
US5459256A (en) | 1987-04-17 | 1995-10-17 | The Government Of The United States Of America As Represented By The Department Of Health And Human Services | Lipophilic, aminohydrolase-activated prodrugs |
GB8802142D0 (en) * | 1988-02-01 | 1988-03-02 | Air Prod & Chem | Method of freezing liquid & pasty products & freezer for carrying out said method |
CA2001715C (en) | 1988-11-14 | 1999-12-28 | Muzammil M. Mansuri | Carbocyclic nucleosides and nucleotides |
US5098443A (en) | 1989-03-23 | 1992-03-24 | University Of Miami | Method of implanting intraocular and intraorbital implantable devices for the controlled release of pharmacological agents |
CA2479846C (en) | 1989-05-15 | 2007-07-24 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Scienc Es Of The Czech Republic | Phosphonomethoxymethylpurine/pyrimidine derivatives |
PT95516A (pt) | 1989-10-06 | 1991-08-14 | Wellcome Found | Processo para a preparacao de derivados de 2',3'-didesoxi nucleosidos 6-substituidos |
MY104575A (en) | 1989-12-22 | 1994-04-30 | The Wellcome Foundation Ltd | Therapeutic nucleosides. |
US5302585A (en) | 1990-04-20 | 1994-04-12 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Use of chiral 2-(phosphonomethoxy)propyl guanines as antiviral agents |
SK280313B6 (sk) | 1990-04-24 | 1999-11-08 | �Stav Organick� Chemie A Biochemie Av �R | N-(3-fluór-2-fosfonylmetoxypropyl)deriváty purínov |
CA2087446A1 (en) | 1990-07-19 | 1992-01-20 | Michael R. Harnden | Antiviral phosphono-alken derivatives of purines |
EP0468119A1 (en) | 1990-07-24 | 1992-01-29 | Merrell Dow Pharmaceuticals Inc. | Novel carbocyclic analogs of certain nucleosides |
DE69129650T2 (de) | 1990-09-14 | 1999-03-25 | Acad Of Science Czech Republic | Wirkstoffvorläufer von Phosphonaten |
US5208221A (en) | 1990-11-29 | 1993-05-04 | Bristol-Myers Squibb Company | Antiviral (phosphonomethoxy) methoxy purine/pyrimidine derivatives |
US5378475A (en) | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
CZ284678B6 (cs) | 1991-05-20 | 1999-01-13 | Ústav Organické Chemie A Biochemie Avčr | Di(2-propyl)estery 1-fluor-2-fosfonomethoxy-3-p -toluensulfonyloxypropanů, způsob jejich přípravy a použití |
AU661347B2 (en) | 1991-10-11 | 1995-07-20 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiviral acyclic phosphonomethoxyalkyl substituted, alkenyl and alkynyl purine and pyrimidine derivatives |
US6057305A (en) | 1992-08-05 | 2000-05-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
DE4308096A1 (de) | 1993-03-13 | 1994-09-15 | Hoechst Ag | Prodrug-Derivate von Enzyminhibitoren mit Hydroxylgruppen, Verfahren zu deren Herstellung und ihre Verwendung |
EP0618214A1 (en) | 1993-04-01 | 1994-10-05 | Merrell Dow Pharmaceuticals Inc. | Unsaturated phosphonate derivatives of purines and pyrimidines |
DE69426904T2 (de) * | 1993-06-29 | 2001-10-11 | Mitsubishi Chem Corp | Phosphonat-Nukleotid Ester-Derivate |
EP0719273B1 (en) | 1993-09-17 | 2010-11-03 | Gilead Sciences, Inc. | Nucleotide analogs |
EP0754046A1 (en) | 1994-04-04 | 1997-01-22 | FREEMAN, William R. | Use of phosphonylmethoxyalkyl nucleosides for the treatment of raised intraocular pressure |
FR2723740B1 (fr) * | 1994-08-16 | 1996-11-08 | Pasteur Merieux Serums Vacc | Procede de preparation d'antigenes du virus grippal, antigenes obtenus et leurs applications |
US5977061A (en) * | 1995-04-21 | 1999-11-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | N6 - substituted nucleotide analagues and their use |
IL120202A (en) * | 1996-03-07 | 2001-03-19 | Akzo Nobel Nv | Container with freeze-dried vaccine components |
US20030072814A1 (en) * | 1999-12-16 | 2003-04-17 | Maibach Howard I. | Topical pharmaceutical composition for the treatment of warts |
ATE322494T1 (de) * | 2000-01-07 | 2006-04-15 | Universitaire Instelling Antwe | Purin derivate, ihre herstellung und verwendung |
SI2682397T1 (sl) | 2000-07-21 | 2017-08-31 | Gilead Sciences, Inc. | Predzdravila fosfonatnih nukleotidnih analogov in postopki za selekcijo in izdelavo le-teh |
FR2862306B1 (fr) * | 2003-11-17 | 2008-05-30 | Aventis Pasteur | Composition vaccinale |
DK1794524T3 (da) * | 2004-07-23 | 2012-04-16 | Bayer Technology Services Gmbh | Fremgangsmåde til frysning, tørring, lagring, analysering og fyldning (SFD-SAF-fremgangsmåde) (fremgangsmåde til frysetørring af piller til parenterale biologiske lægemidler) |
US20060165717A1 (en) * | 2005-01-25 | 2006-07-27 | Sanofi Pasteur | DCchol in newborns |
WO2007002912A2 (en) | 2005-06-29 | 2007-01-04 | Gilead Sciences, Inc. | Anti-proliferative compounds, compositions, and methods of use thereof |
WO2007002808A1 (en) | 2005-06-29 | 2007-01-04 | Gilead Sciences, Inc. | Anti-nonmelanoma carcinoma compounds, compositions, and methods of use thereof |
WO2007136650A2 (en) | 2006-05-16 | 2007-11-29 | Gilead Sciences, Inc. | Method and compositions for treating hematological malignancies |
US9521854B2 (en) * | 2006-05-31 | 2016-12-20 | Air Liquide Industrial U.S. Lp | Method and device for creating frozen pellets of a foodstuff |
-
2009
- 2009-02-16 TW TW098104834A patent/TWI444384B/zh active
- 2009-02-19 PL PL09712645T patent/PL2245037T4/pl unknown
- 2009-02-19 PT PT97126452T patent/PT2245037E/pt unknown
- 2009-02-19 KR KR1020107021189A patent/KR101612138B1/ko active IP Right Grant
- 2009-02-19 ES ES09712645.2T patent/ES2516715T3/es active Active
- 2009-02-19 NZ NZ587464A patent/NZ587464A/en unknown
- 2009-02-19 DK DK11151008.7T patent/DK2308885T3/da active
- 2009-02-19 CN CN201610086843.7A patent/CN105753905A/zh active Pending
- 2009-02-19 EP EP11151008.7A patent/EP2308885B1/en active Active
- 2009-02-19 US US12/388,789 patent/US8163718B2/en active Active
- 2009-02-19 SI SI200931021T patent/SI2245037T1/sl unknown
- 2009-02-19 CA CA2715885A patent/CA2715885C/en active Active
- 2009-02-19 ES ES11151008.7T patent/ES2529209T3/es active Active
- 2009-02-19 PT PT111510087T patent/PT2308885E/pt unknown
- 2009-02-19 PL PL11151008T patent/PL2308885T3/pl unknown
- 2009-02-19 JP JP2010547740A patent/JP5588356B2/ja active Active
- 2009-02-19 AU AU2009215547A patent/AU2009215547B2/en active Active
- 2009-02-19 EP EP09712645.2A patent/EP2245037B1/en active Active
- 2009-02-19 DK DK09712645.2T patent/DK2245037T3/da active
- 2009-02-19 CN CN200980113907.6A patent/CN102015739B/zh active Active
- 2009-02-19 KR KR1020167009014A patent/KR101728647B1/ko active IP Right Grant
- 2009-02-19 WO PCT/US2009/034471 patent/WO2009105513A2/en active Application Filing
- 2009-02-19 SI SI200931104T patent/SI2308885T1/sl unknown
- 2009-02-20 AR ARP090100607A patent/AR071159A1/es active IP Right Grant
-
2011
- 2011-05-03 HK HK11104417A patent/HK1150313A1/zh unknown
- 2011-10-12 HK HK11110815.9A patent/HK1156631A1/zh unknown
-
2014
- 2014-01-06 JP JP2014000324A patent/JP2014088416A/ja not_active Withdrawn
- 2014-07-10 AU AU2014203786A patent/AU2014203786B2/en active Active
- 2014-09-18 HR HRP20140895AT patent/HRP20140895T1/hr unknown
- 2014-09-18 CY CY20141100761T patent/CY1115571T1/el unknown
-
2015
- 2015-01-07 HR HRP20150005TT patent/HRP20150005T1/hr unknown
- 2015-01-30 CY CY20151100102T patent/CY1116015T1/el unknown
-
2016
- 2016-10-28 AU AU2016250468A patent/AU2016250468A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5854228A (en) * | 1986-11-18 | 1998-12-29 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiviral phosphonomethoxyalkylene purine and pyrimidine derivatives |
CN1950383A (zh) * | 2003-12-30 | 2007-04-18 | 吉里德科学公司 | 用于治疗病毒性疾病的膦酸酯、单膦酸酰胺化物、双膦酸酰胺化物 |
WO2008005555A1 (en) * | 2006-07-07 | 2008-01-10 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
CN101066981A (zh) * | 2007-05-25 | 2007-11-07 | 中国科学院上海药物研究所 | 非环核苷膦酸酯类化合物及其组合物、制备方法和用途 |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108542913A (zh) * | 2012-12-13 | 2018-09-18 | 艾杜罗生物科技公司 | 包含具有确定立体化学的环嘌呤二核苷酸的组合物及其制备和使用方法 |
CN104558035A (zh) * | 2013-10-22 | 2015-04-29 | 上海源力生物技术有限公司 | 一种替诺福韦前药的纯化方法 |
CN112898345A (zh) * | 2014-09-15 | 2021-06-04 | 加利福尼亚大学董事会 | 核苷酸类似物 |
CN106795188A (zh) * | 2014-09-15 | 2017-05-31 | 加利福尼亚大学董事会 | 核苷酸类似物 |
CN111808136A (zh) * | 2014-09-15 | 2020-10-23 | 加利福尼亚大学董事会 | 核苷酸类似物 |
CN106795188B (zh) * | 2014-09-15 | 2021-02-09 | 加利福尼亚大学董事会 | 核苷酸类似物 |
CN111808136B (zh) * | 2014-09-15 | 2024-06-11 | 加利福尼亚大学董事会 | 核苷酸类似物 |
CN107849071A (zh) * | 2015-08-10 | 2018-03-27 | 默沙东公司 | 抗病毒的β氨基酸酯膦酰二胺化合物 |
CN107849071B (zh) * | 2015-08-10 | 2021-03-09 | 默沙东公司 | 抗病毒的β氨基酸酯膦酰二胺化合物 |
CN109311882A (zh) * | 2016-05-04 | 2019-02-05 | Bci制药公司 | 作为蛋白激酶抑制剂的腺嘌呤衍生物 |
CN109311882B (zh) * | 2016-05-04 | 2022-02-11 | Bci制药公司 | 作为蛋白激酶抑制剂的腺嘌呤衍生物 |
CN108096562A (zh) * | 2017-12-25 | 2018-06-01 | 武汉百药联科科技有限公司 | 20s蛋白酶体抑制剂在制备治疗日本乙型脑炎病毒感染的药物中的用途 |
CN108096562B (zh) * | 2017-12-25 | 2021-05-11 | 武汉百药联科科技有限公司 | 20s蛋白酶体抑制剂在制备治疗日本乙型脑炎病毒感染的药物中的用途 |
CN112778363A (zh) * | 2019-11-05 | 2021-05-11 | 华创合成制药股份有限公司 | 一种硝基咪唑类唑衍生物及其制备方法和用途 |
CN112778363B (zh) * | 2019-11-05 | 2024-03-15 | 华创合成制药股份有限公司 | 一种硝基咪唑类唑衍生物及其制备方法和用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102015739B (zh) | 化合物以及用于治疗的方法 | |
EP3774791B1 (en) | Heterocyclic compounds as immunomodulators | |
ES2943028T3 (es) | Derivados de tetrahidro-imidazo[4,5-c]piridina como inmunomoduladores de PD-L1 | |
EP3802534B1 (en) | Tricyclic heterocyclic compounds as sting activators | |
ES2829914T3 (es) | Tratamiento de enfermedades malignas de células B mediante una combinación de inhibidor de JAK y PI3K | |
TW201726626A (zh) | 作為免疫調節劑之雜環化合物 | |
KR102057751B1 (ko) | 테노포비르 전구약물 및 그의 약학적 용도 | |
ES2655030T3 (es) | Compuestos y composiciones para el tratamiento de enfermedades parasitarias | |
TWI480282B (zh) | 稠合雜環衍生物及其用途 | |
US11008344B2 (en) | Tricyclic heteroaryl compounds as STING activators | |
TWI672304B (zh) | 作爲酪胺酸激酶抑制劑之經取代的乙炔基雜雙環化合物 | |
CN107417684A (zh) | 杂环丙烯酰胺 | |
CN102711470A (zh) | 新的三环化合物 | |
JP7384535B2 (ja) | キナゾリン化合物並びにその調製方法、使用及び医薬組成物 | |
TW201800403A (zh) | 二雜芳基化合物及其用途 | |
TW202010500A (zh) | 作為a2a受體拮抗劑的吡唑並三唑並嘧啶衍生物 | |
KR20210062668A (ko) | 고리형 디뉴클레오티드 유사체, 이의 약학 조성물 및 용도 | |
WO2022237747A1 (zh) | 小分子cd73拮抗剂及其用途 | |
TW202327601A (zh) | 芳胺類衍生物及其製備方法和醫藥用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee | ||
CP01 | Change in the name or title of a patent holder |
Address after: American California Patentee after: Gilead Sciences Inc. Address before: American California Patentee before: Gilead Sciences Inc. |