JP2017520545A - プロドラッグ化合物およびそれらの使用 - Google Patents
プロドラッグ化合物およびそれらの使用 Download PDFInfo
- Publication number
- JP2017520545A JP2017520545A JP2016572466A JP2016572466A JP2017520545A JP 2017520545 A JP2017520545 A JP 2017520545A JP 2016572466 A JP2016572466 A JP 2016572466A JP 2016572466 A JP2016572466 A JP 2016572466A JP 2017520545 A JP2017520545 A JP 2017520545A
- Authority
- JP
- Japan
- Prior art keywords
- optionally substituted
- group
- liver
- alkyl
- disease
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 123
- 239000000651 prodrug Substances 0.000 title claims abstract description 78
- 229940002612 prodrug Drugs 0.000 title claims abstract description 78
- 210000004185 liver Anatomy 0.000 claims abstract description 59
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- 201000010099 disease Diseases 0.000 claims abstract description 40
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 52
- 229940079593 drug Drugs 0.000 claims description 39
- 239000003124 biologic agent Substances 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 20
- 239000002777 nucleoside Substances 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 210000004027 cell Anatomy 0.000 claims description 12
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 8
- 230000003990 molecular pathway Effects 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 208000004930 Fatty Liver Diseases 0.000 claims description 6
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 208000010706 fatty liver disease Diseases 0.000 claims description 6
- 208000006454 hepatitis Diseases 0.000 claims description 6
- 231100000283 hepatitis Toxicity 0.000 claims description 6
- 229940075993 receptor modulator Drugs 0.000 claims description 6
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 208000030852 Parasitic disease Diseases 0.000 claims description 5
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 201000004792 malaria Diseases 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 230000009745 pathological pathway Effects 0.000 claims description 5
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 4
- 230000003054 hormonal effect Effects 0.000 claims description 4
- 201000001421 hyperglycemia Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 102000007399 Nuclear hormone receptor Human genes 0.000 claims description 3
- 108020005497 Nuclear hormone receptor Proteins 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 229940122029 DNA synthesis inhibitor Drugs 0.000 claims description 2
- 229940124683 HCV polymerase inhibitor Drugs 0.000 claims description 2
- 229940123752 RNA synthesis inhibitor Drugs 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims 3
- 230000009385 viral infection Effects 0.000 claims 3
- 239000005556 hormone Substances 0.000 claims 2
- 229940088597 hormone Drugs 0.000 claims 2
- 210000003494 hepatocyte Anatomy 0.000 claims 1
- 210000005260 human cell Anatomy 0.000 claims 1
- 210000004962 mammalian cell Anatomy 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 abstract description 21
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 10
- 239000011574 phosphorus Substances 0.000 abstract description 10
- 239000000203 mixture Substances 0.000 description 39
- -1 cyclic phosphates Chemical class 0.000 description 24
- 125000000217 alkyl group Chemical group 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 11
- 229910019142 PO4 Inorganic materials 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 9
- 235000021317 phosphate Nutrition 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000001226 triphosphate Substances 0.000 description 7
- 235000011178 triphosphate Nutrition 0.000 description 7
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 6
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
- 238000001994 activation Methods 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 6
- 229940122361 Bisphosphonate Drugs 0.000 description 5
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 239000002359 drug metabolite Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical class NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 150000008298 phosphoramidates Chemical class 0.000 description 4
- 230000002459 sustained effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 3
- KUFMXPZUZBPFCT-UHFFFAOYSA-N P(O)(OCOP(O)=O)=O Chemical compound P(O)(OCOP(O)=O)=O KUFMXPZUZBPFCT-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 238000007068 beta-elimination reaction Methods 0.000 description 3
- 239000012867 bioactive agent Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 150000004663 bisphosphonates Chemical class 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 150000004707 phenolate Chemical class 0.000 description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- LQPDKBWPSWLBHR-UHFFFAOYSA-N 2,4-dihydroxy-6-(2-phenylethyl)-1,3,5,2lambda5,4lambda5-trioxadiphosphinane 2,4-dioxide Chemical compound OP1(=O)OC(CCC2=CC=CC=C2)OP(O)(=O)O1 LQPDKBWPSWLBHR-UHFFFAOYSA-N 0.000 description 2
- NBGOGSINDRFTAR-UHFFFAOYSA-N 2,4-dihydroxy-6-phenyl-1,3,5,2lambda5,4lambda5-trioxadiphosphinane 2,4-dioxide Chemical compound OP1(OC(OP(O1)(O)=O)C1=CC=CC=C1)=O NBGOGSINDRFTAR-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- GQNXISSYRLLPHM-UHFFFAOYSA-N 3,7-diphenyl-2,4,6,8,9-pentaoxa-1lambda5,5lambda5-diphosphabicyclo[3.3.1]nonane 1,5-dioxide Chemical compound C1(=CC=CC=C1)C1OP2(OC(OP(O1)(O2)=O)C1=CC=CC=C1)=O GQNXISSYRLLPHM-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 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
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000001177 diphosphate Substances 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000009513 drug distribution Methods 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940102396 methyl bromide Drugs 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical compound COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 150000004712 monophosphates Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940005657 pyrophosphoric acid Drugs 0.000 description 2
- 239000012048 reactive intermediate Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AXEFIGHWTZPXOH-DLGLCQKISA-N (+-)-7,7-dimethyl-2-oxobicyclo(2.2.1)heptane-1-methanesulfonic acid Chemical compound C1N(C2)CN3CN1CN2C3.C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C AXEFIGHWTZPXOH-DLGLCQKISA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- 125000004890 (C1-C6) alkylamino 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
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- VNFSEMWWJUFZTG-UHFFFAOYSA-N 2,4-dihydroxy-6-(2-phenylethyl)-1,5,2lambda5,4lambda5-dioxadiphosphinane 2,4-dioxide Chemical compound OP1(OC(OP(C1)(O)=O)CCC1=CC=CC=C1)=O VNFSEMWWJUFZTG-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([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
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102000007592 Apolipoproteins Human genes 0.000 description 1
- 108010071619 Apolipoproteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 1
- QDXQAOGNBCOEQX-UHFFFAOYSA-N CC1=CCC=CC1 Chemical compound CC1=CCC=CC1 QDXQAOGNBCOEQX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- BYMMIQCVDHHYGG-UHFFFAOYSA-N Cl.OP(O)(O)=O Chemical compound Cl.OP(O)(O)=O BYMMIQCVDHHYGG-UHFFFAOYSA-N 0.000 description 1
- NJLHHACGWKAWKL-UHFFFAOYSA-N ClP(Cl)=O Chemical compound ClP(Cl)=O NJLHHACGWKAWKL-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 description 1
- 108050004099 Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101600111816 Homo sapiens Sex hormone-binding globulin (isoform 1) Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 235000005135 Micromeria juliana Nutrition 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010011356 Nucleoside phosphotransferase Proteins 0.000 description 1
- MDBVZFGSKMWJFD-UHFFFAOYSA-N OP(O)=O.OP(O)(O)=O Chemical class OP(O)=O.OP(O)(O)=O MDBVZFGSKMWJFD-UHFFFAOYSA-N 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
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 240000002114 Satureja hortensis Species 0.000 description 1
- 235000007315 Satureja hortensis Nutrition 0.000 description 1
- 108010089417 Sex Hormone-Binding Globulin Proteins 0.000 description 1
- 102100030758 Sex hormone-binding globulin Human genes 0.000 description 1
- 102300044179 Sex hormone-binding globulin isoform 1 Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 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 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005354 acylalkyl group Chemical group 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004647 alkyl sulfenyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000003609 aryl vinyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002244 furazanes Chemical class 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 125000005252 haloacyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000243 mutagenic effect Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 description 1
- 229960000761 pemoline Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003504 terephthalic acids Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
- A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
-
- 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
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65746—Esters of oxyacids of phosphorus the molecule containing more than one cyclic phosphorus atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
- Emergency Medicine (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Vascular Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本出願は、2014年7月2日提出の米国特許仮出願第62/020,044号および2015年4月24日提出の米国特許仮出願第62/152,341号の恩典を主張し、これらはどちらもその全体が参照により本明細書に組み入れられる。
医学および化学の分野における組成物および方法を開示する。開示する態様のいくつかは、薬用二重および三重リン含有プロドラッグ化合物、薬用組成物、ならびにそれらの調製工程およびそれらの使用法を目的とする。いくつかの態様は、酸/アルコール誘導体のプロドラッグ化合物、例えばホスフェート、ホスホネート、ホスホンアミデート、ホスホルアミデート、カルボキシレート、フェノレート、およびアルコキシル、それらの調製およびそれらの使用を含む。いくつかの態様において、そのようなプロドラッグ化合物は酸/アルコール誘導体を肝臓に選択的に送達するために有用である。
以下の背景の記載は、本発明の理解を助けるために提供するが、本発明に対する先行技術である、または先行技術を記載すると自認するものではない。
ホスフェート、ホスホネート、ホスホンアミデート、ホスホルアミデート、カルボキシレート、フェノレート、およびアルコキシレートなどの酸/アルコール誘導体の新規二重および三重リン含有プロドラッグ化合物、それらの調製ならびにそれらの使用を記載する。いくつかの態様は、活性化過程においてビニルケト反応性中間体を生成しない新規プロドラッグ化合物に関する。いくつかの態様は、経口薬物送達を増強するためのプロドラッグの使用を目的とする。いくつかの態様は、より高い三リン酸レベルを達成する効率を増強するためのプロドラッグの使用を目的とする。もう1つの局面は、肝炎、癌、肝線維症、脂肪肝、マラリア、他のウイルスおよび寄生虫感染症、ならびに肝臓が生化学的最終生成物、例えば、グルコース、コレステロール、トリグリセリド、リポタンパク質、アポリポタンパク質、および性ホルモン結合グロブリン(SHBG)の産生および/またはホメオスタシス制御に関与する代謝、心血管、および/またはホルモン疾患を含むが、それらに限定されるわけではない、肝臓および同様の組織および細胞への薬物分布増強から利益を得る疾患を処置するためのプロドラッグの使用を含む。そのような疾患の例には、糖尿病、高脂血症、アテローム性動脈硬化症、肥満などが含まれる。もう1つの局面において、プロドラッグを用いて、薬物の薬力学的半減期を延長する。いくつかの態様において、プロドラッグ法を用いて、親薬物の持続送達を達成することができる。もう1つの局面において、プロドラッグを用いて、薬物の治療指数を高める。いくつかの態様において、プロドラッグは診断用造影剤の肝臓への送達において有用である。いくつかのさらなる態様は、プロドラッグの作製法に関する。
式中、
R1およびR2は独立にH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
Yは結合、O、S、NR4、Si(R4)2、および置換されていてもよいC1-C6アルキルからなる群より選択され;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択され;
R4はH、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択される。
式中、
R1はH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R5はM、Cl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
Y'およびY''は独立にO、S、置換されていてもよいCH2、およびNR3からなる群より選択され;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択される。
式中、
R1はH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R6はCl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、置換されていてもよいアルキルアミノ、および-OP(O)(R7)2からなる群より選択され;
R7はOH、置換されていてもよいC1-C6アルキル、および置換されていてもよいC1-C6アルキルオキシからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
Y'はO、S、置換されていてもよいCH2、およびNR3からなる群より選択され;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択される。
式中、
R1はH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R8およびR9は独立にM、Cl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
R10はCl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択され;
Y'およびY''は独立にO、S、置換されていてもよいCH2、およびNR3からなる群より選択される。
本態様は、ホスフェート、ホスホネート、ホスホンアミデート、ホスホロアミデート、カルボキシレート、フェノレート、およびアルコキシレートなどの生物学的に活性な酸/アルコール誘導体の新規環式二重および三重リン含有プロドラッグ化合物、それらの調製ならびにそれらの使用に関する組成物および方法を目的とする。
式中、
R1およびR2は独立にH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択され;
R4はH、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R5はM、Cl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
R6はCl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、置換されていてもよいアルキルアミノ、および-OP(O)(R7)2からなる群より選択され;
R7はOH、置換されていてもよいC1-C6アルキル、および置換されていてもよいC1-C6アルキルオキシからなる群より選択され;
R8およびR9は独立にM、Cl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
R10はCl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
Yは結合、O、S、NR4、Si(R4)2、および置換されていてもよいC1-C6アルキルからなる群より選択され;
Y'およびY''は独立にO、S、置換されていてもよいCH2、およびNR3からなる群より選択される。
本開示に従い、また本明細書において用いられるとおり、以下の用語は、特に記載がないかぎり、以下の意味で定義される。前述の一般的記載および以下の詳細な記載はいずれも、例示および説明のためにすぎず、特許請求する主題を制限するものではないことが理解されるべきである。本出願において、単数形の使用は、特に記載がないかぎり、複数形を含む。本出願において、「または」の使用は、特に記載がないかぎり、「および/または」を意味する。さらに、「含む(including)」なる用語、ならびに「含む(includes)」、および「含まれる(included)」などの他の形態は、限定的ではない。
[肝組織中の薬物または薬物代謝物]/
[血液または別の組織中の薬物または薬物代謝物]
比は特定の時間に組織レベルを測定することによって求めることができ、または3つ以上の時点で測定した値に基づくAUC(曲線下面積)を表してもよい。
開示する化合物は、単独または他の処置との組み合わせで用いてもよい。これらの化合物は、他の薬剤との組み合わせで用いる場合、1日用量または1日用量の適切な分画(例えば、bid)として投与してもよい。化合物は、別の薬剤による処置クールの後に投与してもよく、別の薬剤による治療クール中に投与してもよく、治療法の一部として投与してもよく、または処置プログラム中の別の薬剤による治療前に投与してもよい。
環式プロドラッグ化合物を調製するための以下の手順は、プロドラッグ化合物を調製するために使用される一般的手順を示す。プロドラッグを薬物の合成の異なる段階で導入することができる。いくつかの態様において、これらの基の様々な反応条件に対する一般的感受性ゆえに、後期の段階で作製する。リン中心で単一の異性体を含む光学的に純粋なプロドラッグを、例えば、カラムクロマトグラフィおよび/もしくは結晶化の組み合わせによるジアステレオマーの分離により、またはキラル活性化ホスフェート(ホスホネート)中間体のエナンチオ選択的合成により、作製することができる。
スキームI
スキームII
スキームIII
スキームIV
2,4-ジヒドロキシ-6-フェニル-1,3,5,2,4-トリオキサジホスフィナン2,4-ジオキシド(化合物103)および3,7-ジフェニル-2,4,6,8,9-ペンタオキサ-1,5-ジホスファビシクロ[3.3.1]ノナン1,5-ジオキシド(化合物104)
Claims (26)
- 式Iの化合物、またはその立体異性体もしくは薬学的に許容される塩:
式中、
R1およびR2は独立にH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
Yは結合、O、S、NR4、Si(R4)2、および置換されていてもよいC1-C6アルキルからなる群より選択され;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択され;
R4はH、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択される。 - 式IIの化合物、またはその立体異性体もしくは薬学的に許容される塩:
式中、
R1はH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R5はM、Cl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
Y'およびY''は独立にO、S、置換されていてもよいCH2、およびNR3からなる群より選択され;R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択される。 - 式IIIの化合物、またはその立体異性体もしくは薬学的に許容される塩:
式中、
R1はH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R6はCl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、置換されていてもよいアルキルアミノ、および-OP(O)(R7)2からなる群より選択され;
R7はOH、置換されていてもよいC1-C6アルキル、および置換されていてもよいC1-C6アルキルオキシからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
Y'はO、S、置換されていてもよいCH2、およびNR3からなる群より選択され;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択される。 - 式IVの化合物、またはその立体異性体もしくは薬学的に許容される塩:
式中、
R1はH、M、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6ヘテロアルキル、置換されていてもよいC2-C6アルケニル、置換されていてもよいアリール、および置換されていてもよいヘテロアリールからなる群より選択され;
R8およびR9は独立にM、Cl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
R10はCl、OH、NH2、置換されていてもよいC1-C6アルキル、置換されていてもよいC1-C6アルキルオキシ、および置換されていてもよいアルキルアミノからなる群より選択され;
Mは生物学的作用物質または生物学的作用物質の一部または生物学的作用物質のプロドラッグであり;
XおよびX'は独立にOまたはNR3であり;
R3はH、C1-C6アルキル、およびC1-C6ヘテロアルキルからなる群より選択され;
Y'およびY''は独立にO、S、置換されていてもよいCH2、およびNR3からなる群より選択される。 - Mがヌクレオシド抗ウイルス薬または抗癌剤である、請求項1〜4のいずれか一項記載の化合物。
- Mが脂質モジュレーターである、請求項1〜4のいずれか一項記載の化合物。
- Mが核内ホルモン受容体モジュレーターである、請求項1〜4のいずれか一項記載の化合物。
- MがHCVポリメラーゼ阻害剤、逆転写酵素阻害剤、DNA合成阻害剤、RNA合成阻害剤、および代謝拮抗剤からなる群より選択される少なくとも1つの剤である、請求項1〜4のいずれか一項記載の化合物。
- 請求項1〜8記載の化合物のいずれかおよび薬学的に許容される賦形剤を含む薬学的組成物。
- 請求項1〜8記載の化合物のいずれかの有効量をその必要のある対象に投与する段階を含む、対象の肝臓における疾患、障害または状態を処置する方法。
- 請求項1〜8記載の化合物のいずれかの有効量をその必要のある対象に投与する段階を含む、対象において、肝臓における分子経路または標的に介入することによって疾患、障害または状態を処置する方法。
- 請求項1〜8記載の化合物のいずれかの有効量を対象に投与する段階を含む、対象において、肝臓における疾患、障害もしくは状態または生理的もしくは病原性経路が肝臓に関与する疾患、障害もしくは状態を処置する方法。
- 疾患、障害または状態が肝炎、肝臓癌、肝線維症、マラリア、ウイルス感染症、寄生虫感染症、癌、脂肪肝、糖尿病、高脂血症、アテローム性動脈硬化症、肥満、脂質異常症、高血糖症およびホルモン状態からなる群より選択される、請求項10〜12のいずれか一項記載の方法。
- さらなる治療薬の有効量をその必要のある対象に投与する段階をさらに含む、請求項10〜12のいずれか一項記載の方法。
- 対象が哺乳動物である、請求項10〜14のいずれか一項記載の方法。
- 対象がヒトである、請求項10〜14のいずれか一項記載の方法。
- 肝臓における疾患もしくは状態または生理的もしくは病原性経路が肝臓に関与する疾患もしくは状態を処置するための薬剤の調製において使用するための、請求項1〜8のいずれか一項記載の化合物。
- 肝臓における疾患もしくは状態または生理的もしくは病原性経路が肝臓に関与する疾患もしくは状態を処置するための薬剤の調製において使用するための、請求項1〜8のいずれか一項記載の化合物および有効量のさらなる治療薬。
- 肝炎、肝臓癌、肝線維症、マラリア、ウイルス感染症、寄生虫感染症、癌、脂肪肝、糖尿病、高脂血症、アテローム性動脈硬化症、肥満、脂質異常症、高血糖症およびホルモン状態からなる群より選択される疾患、障害または状態を処置するための薬剤の調製において使用するための、請求項1〜8のいずれか一項記載の化合物。
- 肝炎、肝臓癌、肝線維症、マラリア、ウイルス感染症、寄生虫感染症、癌、脂肪肝、糖尿病、高脂血症、アテローム性動脈硬化症、肥満、脂質異常症、高血糖症およびホルモン状態からなる群より選択される疾患、障害または状態を処置するための薬剤の調製において使用するための、請求項1〜8のいずれか一項記載の化合物および有効量のさらなる治療薬。
- 細胞を請求項1〜8記載の化合物のいずれか一つと接触させる段階を含む、細胞において分子経路に介入するまたは標的を調節する方法。
- 細胞がインビボである、請求項21記載の方法。
- 細胞がエクスビボである、請求項21記載の方法。
- 細胞が肝細胞である、請求項21記載の方法。
- 細胞が哺乳動物細胞である、請求項21記載の方法。
- 細胞がヒト細胞である、請求項21記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462020044P | 2014-07-02 | 2014-07-02 | |
US62/020,044 | 2014-07-02 | ||
US201562152341P | 2015-04-24 | 2015-04-24 | |
US62/152,341 | 2015-04-24 | ||
PCT/US2015/038044 WO2016003812A1 (en) | 2014-07-02 | 2015-06-26 | Prodrug compounds and uses therof |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2017520545A true JP2017520545A (ja) | 2017-07-27 |
Family
ID=55019855
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016572466A Pending JP2017520545A (ja) | 2014-07-02 | 2015-06-26 | プロドラッグ化合物およびそれらの使用 |
Country Status (5)
Country | Link |
---|---|
US (2) | US9994600B2 (ja) |
EP (1) | EP3164136A4 (ja) |
JP (1) | JP2017520545A (ja) |
CN (1) | CN106687118A (ja) |
WO (1) | WO2016003812A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2714207T3 (es) | 2008-08-13 | 2019-05-27 | Metabasis Therapeutics Inc | Antagonistas de glucagón |
CN114404427A (zh) | 2014-02-13 | 2022-04-29 | 配体药物公司 | 前药化合物及其用途 |
EP3154956A4 (en) | 2014-06-12 | 2018-01-17 | Ligand Pharmaceuticals, Inc. | Glucagon antagonists |
CN106687118A (zh) | 2014-07-02 | 2017-05-17 | 配体药物公司 | 前药化合物及其用途 |
EP3737676B1 (en) | 2018-01-09 | 2024-03-06 | Ligand Pharmaceuticals, Inc. | Acetal compounds and therapeutic uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08508245A (ja) * | 1993-03-08 | 1996-09-03 | エーザイ株式会社 | ホスホン酸誘導体 |
JP2013508459A (ja) * | 2009-10-26 | 2013-03-07 | ワーナー・チルコット・カンパニー・エルエルシー | 骨代謝疾患を治療するためのビスホスホネート化合物 |
JP2017512183A (ja) * | 2014-02-13 | 2017-05-18 | リガンド・ファーマシューティカルズ・インコーポレイテッド | プロドラッグ化合物およびそれらの使用 |
Family Cites Families (248)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE554888A (ja) | 1956-12-20 | |||
US3116282A (en) | 1960-04-27 | 1963-12-31 | Upjohn Co | Pyrimidine nucleosides and process |
BE633481A (ja) | 1962-06-12 | |||
CA777769A (en) | 1963-03-18 | 1968-02-06 | H. Roy Clarence | Substituted methylene diphosphonic acid compounds and detergent compositions |
US3328388A (en) | 1964-09-02 | 1967-06-27 | Merck & Co Inc | Arabinofuranosyl pyrimidines and methods of preparing same |
CH492738A (de) | 1967-09-13 | 1970-06-30 | Sandoz Ag | Verfahren zur Herstellung von 2-(Bis-(2-chloräthyl)aminophenyl-4- -amino)-2H-1,3,2-oxazaphosphorin-tetrahydro-2-oxid |
US3796700A (en) | 1970-06-30 | 1974-03-12 | Takedo Chem Ind Ltd | Adenosine derivatives and the production thereof |
DE2752125A1 (de) | 1977-11-22 | 1979-05-23 | Max Planck Gesellschaft | Neue phosphororganische ringverbindungen, ihre herstellung und verwendung |
US4376165A (en) | 1978-06-22 | 1983-03-08 | Miles Laboratories, Inc. | Method of preparing an enzyme-labeled ligand for use in specific binding assays and the labeled conjugate produced thereby |
US4340668A (en) | 1979-06-04 | 1982-07-20 | Miles Laboratories, Inc. | Heme-labeled specific binding assay |
US4318982A (en) | 1979-06-04 | 1982-03-09 | Miles Laboratories, Inc. | FMN-Labeled specific binding assay |
US4255566A (en) | 1980-02-19 | 1981-03-10 | Miles Laboratories | Flavin adenine dinucleotide derivatives and labeled conjugates prepared therefrom |
US4447529A (en) | 1981-07-06 | 1984-05-08 | Miles Laboratories, Inc. | Preparing homogeneous specific binding assay element to avoid premature reaction |
DE3132221A1 (de) | 1981-08-14 | 1983-05-19 | Behringwerke Ag, 3550 Marburg | Neue cyclophosphamid-derivate, verfahren zu ihrer herstellung und ihre verwendung |
DE3133077A1 (de) | 1981-08-21 | 1983-03-10 | Henkel KGaA, 4000 Düsseldorf | Neue cytostatisch wirksame epoxidgruppen tragende 1,3,2-oxazaphosphorin-verbindungen, verfahren zu ihrer herstellung sowie ihre verwendung in pharmazeutischen zubereitungen |
IT1201087B (it) | 1982-04-15 | 1989-01-27 | Gentili Ist Spa | Bifosfonati farmacologicamente attivi,procedimento per la loro preparazione e relative composizioni farmaceutiche |
US4440740A (en) | 1982-04-26 | 1984-04-03 | Merck & Co., Inc. | α-Keto aldehydes as enhancing agents of gastro-intestinal drug absorption |
CS233665B1 (en) | 1983-01-06 | 1985-03-14 | Antonin Holy | Processing of isomere o-phosphonylmethylderivative of anantiomere racemic vicinal diene |
US5047533A (en) | 1983-05-24 | 1991-09-10 | Sri International | Acyclic purine phosphonate nucleotide analogs |
DE3569737D1 (en) | 1984-03-01 | 1989-06-01 | Asta Pharma Ag | Salts of oxazaphosphorine derivatives |
US4579849A (en) | 1984-04-06 | 1986-04-01 | Merck & Co., Inc. | N-alkylguanine acyclonucleosides as antiviral agents |
FR2562543B1 (fr) | 1984-04-10 | 1987-09-25 | Elf Aquitaine | Nouveaux phosphonites cycliques, leur preparation et applications |
US4749694A (en) | 1984-04-26 | 1988-06-07 | Merck & Co., Inc. | Novel lysine esters used as absorption |
US4537772A (en) | 1984-05-02 | 1985-08-27 | Merck & Co., Inc. | Enhancing absorption of drugs from gastrointestinal tract using acylcarnitines |
US4898724A (en) | 1984-06-04 | 1990-02-06 | The Dow Chemical Company | Organis amine phosphonic acid complexes for the treatment of calcific tumors |
NL8403224A (nl) | 1984-10-24 | 1986-05-16 | Oce Andeno Bv | Dioxafosforinanen, de bereiding ervan en de toepassing voor het splitsen van optisch actieve verbindingen. |
IT1196315B (it) | 1984-10-29 | 1988-11-16 | Gentili Ist Spa | Procedimento per la preparazione di acidi difosfonici |
IL77243A (en) | 1984-12-21 | 1996-11-14 | Procter & Gamble | Pharmaceutical compositions containing geminal diphosphonic acid compounds and certain such novel compounds |
US4724232A (en) | 1985-03-16 | 1988-02-09 | Burroughs Wellcome Co. | Treatment of human viral infections |
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 |
US4822773A (en) | 1985-06-28 | 1989-04-18 | Merck & Co., Inc. | Enhancement of absorption of drugs from gastrointestinal tract using choline ester salts |
US4729989A (en) | 1985-06-28 | 1988-03-08 | Merck & Co., Inc. | Enhancement of absorption of drugs from gastrointestinal tract using choline ester salts |
US4973579A (en) | 1985-06-28 | 1990-11-27 | Merck & Co., Inc. | Enhancment of absorption of drugs from gastrointestinal tract using choline ester salts |
US4731360A (en) | 1985-08-16 | 1988-03-15 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
US4692441A (en) | 1985-08-16 | 1987-09-08 | Merck & Co., Inc. | Chorine esters as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal cavities |
US4963556A (en) | 1985-08-16 | 1990-10-16 | Merck & Co., Inc. | Choline esters as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal cavities |
US4847298A (en) | 1985-08-16 | 1989-07-11 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
US4963525A (en) | 1985-08-16 | 1990-10-16 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
US5258538A (en) | 1985-08-26 | 1993-11-02 | Applied Biosystems, Inc. | 2,3-disubstituted-1,3,2-oxazaphosphacycloalkanes as nucleic acid linking agents |
JPS62501712A (ja) | 1985-08-26 | 1987-07-09 | アメリカ合衆国 | 2′、3′―ジデオキシイノシン、2′,3′―ジデオキシグアノシンまたは2′,3′―ジデオキシアデノシンを含有する抗htlv―3/lav剤 |
US4757141A (en) | 1985-08-26 | 1988-07-12 | Applied Biosystems, Incorporated | Amino-derivatized phosphite and phosphate linking agents, phosphoramidite precursors, and useful conjugates thereof |
US4879277A (en) | 1985-08-26 | 1989-11-07 | The United States Of America As Represented By The Department Of Health And Human Services | Antiviral compositions and methods |
US5246937A (en) | 1985-09-18 | 1993-09-21 | Beecham Group P.L.C. | Purine derivatives |
DE3600289A1 (de) | 1986-01-08 | 1987-07-09 | Bayer Ag | Cyclische malonylphosphonsaeurediamide, verfahren zu ihrer herstellung und ihre verwendung als schaedlingsbekaempfungsmittel |
JPH0615553B2 (ja) | 1986-02-20 | 1994-03-02 | 日産化学工業株式会社 | ジヒドロピリジン−5−ホスホンアミド酸類 |
US4968788A (en) | 1986-04-04 | 1990-11-06 | Board Of Regents, The University Of Texas System | Biologically reversible phosphate and phosphonate protective gruops |
US4839466A (en) | 1986-04-11 | 1989-06-13 | The Rockefeller University | Insulin activity messengers |
JPS62249996A (ja) | 1986-04-23 | 1987-10-30 | Asahi Chem Ind Co Ltd | 新規なペンゾキサザホスホリン誘導体およびそれを有効成分とする殺虫剤組成物 |
US5091552A (en) | 1986-06-30 | 1992-02-25 | Board Of Regents, The University Of Texas System | Novel antitumor aldophosphamide analogs |
DE3722043A1 (de) | 1986-07-11 | 1988-01-14 | Asta Werke Ag Chem Fab | Loesungen von oxazaphosphorinen mit verbesserter stabilitaet und verfahren zu deren herstellung |
CS264222B1 (en) | 1986-07-18 | 1989-06-13 | Holy Antonin | N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them |
DE3626058A1 (de) | 1986-08-01 | 1988-02-11 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
DE10199052I1 (de) | 1986-11-21 | 2002-01-10 | Novartis Ag | Neue substituierte Alkandiphosphonsaeuren |
US5159067A (en) | 1987-01-28 | 1992-10-27 | University Of Georgia Research Foundation Inc. | 5'-Diphosphohexose nucleoside pharmaceutical compositions |
US5077280A (en) | 1988-04-12 | 1991-12-31 | Brown University Research Foundation | Treatment of viral infections |
EP0338372A3 (en) | 1988-04-22 | 1991-10-09 | American Cyanamid Company | Solubilized pro-drugs |
GB8815265D0 (en) | 1988-06-27 | 1988-08-03 | Wellcome Found | Therapeutic nucleosides |
EP0353692B1 (en) | 1988-08-02 | 1995-10-04 | Nissan Chemical Industries Ltd. | Drug effect-enhancing agent for antitumor drug |
US4882142A (en) | 1988-12-19 | 1989-11-21 | The Dow Chemical Company | Bone marrow suppressing agents |
US5658889A (en) | 1989-01-24 | 1997-08-19 | Gensia Pharmaceuticals, Inc. | Method and compounds for aica riboside delivery and for lowering blood glucose |
US5118672A (en) | 1989-07-10 | 1992-06-02 | University Of Georgia Research Foundation | 5'-diphosphohexose nucleoside pharmaceutical compositions |
JPH0377894A (ja) | 1989-08-18 | 1991-04-03 | Toray Ind Inc | メチレンジホスホン酸化合物 |
US6642245B1 (en) | 1990-02-01 | 2003-11-04 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
US5627165A (en) | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
CS276072B6 (en) | 1990-08-06 | 1992-03-18 | Ustav Organicke Chemie A Bioch | (2R)-2-/DI(2-PROPYL)PHOSPHONYLMETHOXY/-3-p-TOLUENESULFONYLOXY -1- TRIMETHYLACETOXYPROPANE AND PROCESS FOR PREPARING THEREOF |
ES2118069T3 (es) | 1990-09-14 | 1998-09-16 | Acad Of Science Czech Republic | Profarmacos de fosfonatos. |
HU206883B (en) | 1990-12-18 | 1993-01-28 | Richter Gedeon Vegyeszet | Process for producing new 15-nitro-2-beta-, 3-beta-dihydro- and 15-nitro-2-beta, 3-beta-, 6,7-tetrahydro-tabersonin derivatives and pharmaceutical compositions containing them |
US5168103A (en) | 1991-01-22 | 1992-12-01 | American Home Products Corporation | [[2-(amino-3,4-dioxo-1-cyclobuten-1-yl) amino]alkyl]-acid derivatives |
US5157027A (en) | 1991-05-13 | 1992-10-20 | E. R. Squibb & Sons, Inc. | Bisphosphonate squalene synthetase inhibitors and method |
WO1993016388A1 (en) | 1992-02-13 | 1993-08-19 | The Uab Research Foundation | Method of detecting and monitoring levels of 3'-amino-3'-deoxythymidine in body fluids and antibodies for same |
GB2266525A (en) | 1992-03-17 | 1993-11-03 | Merck & Co Inc | Substituted cephalosporin sulfone compositions useful in the treatment of leukemia |
GB2266527A (en) | 1992-03-17 | 1993-11-03 | Merck & Co Inc | Substituted azetidinones useful in the treatment of leukemia |
GB9205917D0 (en) | 1992-03-18 | 1992-04-29 | Smithkline Beecham Plc | Pharmaceuticals |
DE69322087T2 (de) | 1992-06-23 | 1999-04-08 | Yamanouchi Pharmaceutical Co., Ltd., Tokio/Tokyo | Neues kristall von heterozyclischen bis(phosphonsäure) monohydrat-derivat |
US5532225A (en) | 1992-07-31 | 1996-07-02 | Sri International | Acyclic purine phosphonate nucleotide analogs as antiviral agents, and related synthetic methods |
US5358941A (en) | 1992-12-02 | 1994-10-25 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids with lactose |
US5366965A (en) | 1993-01-29 | 1994-11-22 | Boehringer Mannheim Gmbh | Regimen for treatment or prophylaxis of osteoporosis |
ES2108425T3 (es) | 1993-02-10 | 1997-12-16 | Astra Pharma Prod | Analogos de atp sustituidos con n-alquilo-2. |
ATE273700T1 (de) | 1993-05-21 | 2004-09-15 | Us Gov Health & Human Serv | Neues verfahen zur hemmung der replication der virus - abhängigen reverse transciptase durch verwendung von dideoxydenucleotide-synthese inhibitoren |
US5514798A (en) | 1993-06-02 | 1996-05-07 | Gilead Sciences, Inc. | Method and cyclic carbonates for nucleotide analogues |
EP0632048B1 (en) | 1993-06-29 | 2001-03-21 | Mitsubishi Chemical Corporation | Phosphonate-nucleotide ester derivatives |
US5567689A (en) | 1993-08-13 | 1996-10-22 | The Uab Research Foundation | Methods for increasing uridine levels with L-nucleosides |
FR2709754B1 (fr) | 1993-09-10 | 1995-12-01 | Centre Nat Rech Scient | Composés 2' ou 3'-déoxy- et 2', 3'-didéoxy-beta-L-pentofuranonucléosides, procédé de préparation et application thérapeutique, notamment anti-virale. |
US20020120130A1 (en) | 1993-09-10 | 2002-08-29 | Gilles Gosselin | 2' or 3' -deoxy and 2', 3' -dideoxy-beta-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti- viral agents |
WO1995007086A1 (en) | 1993-09-10 | 1995-03-16 | Emory University | Nucleosides with anti-hepatitis b virus activity |
DE69435319D1 (de) | 1993-09-17 | 2010-12-16 | Gilead Sciences Inc | Nukleotidanaloge |
US5437772A (en) | 1993-11-01 | 1995-08-01 | The Electrosynthesis Co., Inc. | Portable lead detector |
US5567592A (en) | 1994-02-02 | 1996-10-22 | Regents Of The University Of California | Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal |
US5599686A (en) | 1994-06-28 | 1997-02-04 | Merck & Co., Inc. | Peptides |
US5866679A (en) | 1994-06-28 | 1999-02-02 | Merck & Co., Inc. | Peptides |
US6143864A (en) | 1994-06-28 | 2000-11-07 | Merck & Co., Inc. | Peptides |
AU2808495A (en) | 1994-07-04 | 1996-01-25 | Takeda Chemical Industries Ltd. | Phosphonic acid compounds, their production and use |
US5810856A (en) | 1995-03-09 | 1998-09-22 | Tveras; Rimvydas | Wiping element for an oral hygiene device, window wiper, or the like |
US5665713A (en) | 1995-04-12 | 1997-09-09 | Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
JP4413996B2 (ja) | 1995-06-07 | 2010-02-10 | エモリー・ユニバーシティ | 抗b型肝炎ウィルス活性を有するヌクレオシド |
US5665386A (en) | 1995-06-07 | 1997-09-09 | Avmax, Inc. | Use of essential oils to increase bioavailability of oral pharmaceutical compounds |
US5716928A (en) | 1995-06-07 | 1998-02-10 | Avmax, Inc. | Use of essential oils to increase bioavailability of oral pharmaceutical compounds |
US5627164A (en) | 1995-06-13 | 1997-05-06 | Exxon Research And Engineering Company | Pyrazolyl borates complexes-(LAW294) |
EP0871454B1 (en) | 1995-07-17 | 2003-11-12 | Cephalon, Inc. | Phosphorous-containing cysteine and serine protease inhibitors |
US5750493A (en) | 1995-08-30 | 1998-05-12 | Raymond F. Schinazi | Method to improve the biological and antiviral activity of protease inhibitors |
AU1164597A (en) | 1995-12-19 | 1997-07-14 | Darwin Discovery Limited | Ifosfamide, analogues thereof and their preparation |
TW369536B (en) | 1996-01-18 | 1999-09-11 | Mitsubishi Chem Corp | Phosphonate nucleotide compounds |
US5767097A (en) | 1996-01-23 | 1998-06-16 | Icn Pharmaceuticals, Inc. | Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes |
JPH09241284A (ja) | 1996-03-08 | 1997-09-16 | Koji Yamashita | 新規なオキシアザホスホリン誘導体 |
US6128582A (en) | 1996-04-30 | 2000-10-03 | Vertex Pharmaceuticals Incorporated | Molecules comprising an IMPDH-like binding pocket and encoded data storage medium capable of graphically displaying them |
US5962440A (en) | 1996-05-09 | 1999-10-05 | Bristol-Myers Squibb Company | Cyclic phosphonate ester inhibitors of microsomal triglyceride transfer protein and method |
RU2111970C1 (ru) | 1996-06-25 | 1998-05-27 | Иван Игоревич Федоров | 3'-оксимино-2',3'-дидезоксинуклеозиды |
GB9618634D0 (en) | 1996-09-06 | 1996-10-16 | Univ Southampton | Anti cancer drugs |
US6177404B1 (en) | 1996-10-15 | 2001-01-23 | Merck & Co., Inc. | Conjugates useful in the treatment of benign prostatic hyperplasia |
CZ120699A3 (cs) | 1996-10-16 | 1999-09-15 | Icn Pharmaceuticals, Inc. | Monocyklická L-nukleosidová analoga a jejich využití |
PL192286B1 (pl) | 1996-10-24 | 2006-09-29 | Novartis Ag | Podstawione kwasy aminoalkanofosfonowe, preparaty farmaceutyczne zawierające te związki oraz zastosowanie tych związków |
US5948750A (en) | 1996-10-30 | 1999-09-07 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
GB9623908D0 (en) | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
CA2271786A1 (en) | 1996-11-19 | 1998-05-28 | Kandasamy Ramasamy | Multivalent salts of pyridostigmine and related compounds |
HU0000769A (en) | 1996-12-27 | 2000-07-28 | G-rich oligo aptamers and methods of modulating an immune response | |
SE9700792L (sv) | 1997-03-06 | 1998-02-23 | Carlo Castro | Ryggsmörjare för insmörjning av hudkräm på en människokropp |
AU6452098A (en) | 1997-03-07 | 1998-09-22 | Metabasis Therapeutics, Inc. | Novel purine inhibitors of fructose-1,6-bisphosphatase |
WO1998039342A1 (en) | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
JP2001515482A (ja) | 1997-03-07 | 2001-09-18 | メタバシス・セラピューティクス・インコーポレイテッド | フルクトース−1,6−ビスホスファターゼの新規なベンズイミダゾールインヒビター |
GB9707659D0 (en) | 1997-04-16 | 1997-06-04 | Peptide Therapeutics Ltd | Hepatitis C NS3 Protease inhibitors |
IL132737A0 (en) | 1997-06-30 | 2001-03-19 | Icn Pharmaceuticals | Method of producing tiazofurin and other c-nucleosides |
US6130504A (en) | 1997-07-11 | 2000-10-10 | Sharp Kabushiki Kaisha | Plasma addressing display device and method for producing the same |
IL133461A (en) | 1997-07-25 | 2005-05-17 | Gilead Sciences Inc | Adefovir dipivoxil compositions |
IL121413A (en) | 1997-07-28 | 2000-10-31 | Green Cloud Ltd | Method for reducing the accumulation of precipitates and impurities on ultrasonic transducers |
US6143715A (en) | 1997-08-11 | 2000-11-07 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C inhibitor peptide analogues |
US6767991B1 (en) | 1997-08-11 | 2004-07-27 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C inhibitor peptides |
US5962522A (en) | 1997-09-05 | 1999-10-05 | Avmax, Inc. | Propyl gallate to increase bioavailability of orally administered pharmaceutical compounds |
US6180666B1 (en) | 1997-09-05 | 2001-01-30 | Anmax, Inc. | Use of gallic acid esters to increase bioavailability of orally administered pharmaceutical compounds |
US6391305B1 (en) | 1997-09-10 | 2002-05-21 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
US20020115596A1 (en) | 1997-10-27 | 2002-08-22 | Merk & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
US6423695B1 (en) | 1998-01-13 | 2002-07-23 | Ribapharm, Inc. | Cytokine related treatments of disease |
WO1999036074A1 (en) | 1998-01-15 | 1999-07-22 | Icn Pharmaceuticals, Inc. | Use of 8-cl-camp in prevention of restenosis of arterial walls |
CA2322008C (en) | 1998-02-25 | 2011-06-28 | Emory University | 2'-fluoronucleosides |
AU767599B2 (en) * | 1998-03-06 | 2003-11-20 | Metabasis Therapeutics, Inc. | Novel prodrugs for phosphorus-containing compounds |
US6312662B1 (en) | 1998-03-06 | 2001-11-06 | Metabasis Therapeutics, Inc. | Prodrugs phosphorus-containing compounds |
WO1999047549A1 (en) | 1998-03-16 | 1999-09-23 | Ontogen Corporation | PIPERAZINES AS INHIBITORS OF FRUCTOSE-1,6-BISPHOSPHATASE (FBPase) |
GB9806815D0 (en) | 1998-03-30 | 1998-05-27 | Hoffmann La Roche | Amino acid derivatives |
AU3376699A (en) | 1998-03-31 | 1999-10-18 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
HUP0102152A3 (en) | 1998-05-26 | 2002-04-29 | Icn Pharmaceuticals Inc Costa | Nucleosid and oligo nucleotid analogues having bicyclic sugar derivative |
GB9812523D0 (en) | 1998-06-10 | 1998-08-05 | Angeletti P Ist Richerche Bio | Peptide inhibitors of hepatitis c virus ns3 protease |
MXPA00012842A (es) | 1998-06-24 | 2004-06-22 | Univ Emory | Uso de 3'-azido-2',3'-didesoxiuridina en combinacion de drogas adicionales contra el vih para la manufactura de un medicamento para el tratamiento del vih. |
IT1305313B1 (it) | 1998-07-17 | 2001-05-04 | Colla Paolo | 3,4 - diidro- 6- benzil-4-oxopirimidine sostituite e relativo processodi produzione e impiego nella terapia delle infezioni da hiv-1. |
AU5475799A (en) | 1998-08-10 | 2000-03-06 | Centre National De La Recherche Scientifique | Beta-l-2'-deoxy-nucleosides for the treatment of hepatitis |
US6444652B1 (en) | 1998-08-10 | 2002-09-03 | Novirio Pharmaceuticals Limited | β-L-2'-deoxy-nucleosides for the treatment of hepatitis B |
DK1112275T3 (da) | 1998-09-09 | 2003-11-24 | Metabasis Therapeutics Inc | Hidtil ukendte heteroaromatiske inhibitorer for fructose-1,6-bisphosphatase |
US6045638A (en) | 1998-10-09 | 2000-04-04 | Atlantic Research Corporation | Monopropellant and propellant compositions including mono and polyaminoguanidine dinitrate |
JP2002528499A (ja) | 1998-10-29 | 2002-09-03 | ブリストル−マイヤーズ スクイブ カンパニー | Impdh酵素のインヒビターであるアミノ核誘導化合物 |
KR100618028B1 (ko) | 1998-11-05 | 2006-08-30 | 쌍트르 나쉬오날 드 라 르쉐르스 쉬앙티피끄 | 항-b형 간염 활성을 가진 뉴클레오시드 |
US6407077B1 (en) | 1998-11-05 | 2002-06-18 | Emory University | β-L nucleosides for the treatment of HIV infection |
US6756360B1 (en) | 1998-12-24 | 2004-06-29 | Metabasis Therapeutics, Inc. | Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes |
JP2003515523A (ja) | 1998-12-24 | 2003-05-07 | メタベイシス・セラピューティクス・インコーポレーテッド | 糖尿病治療のためのfbpアーゼ阻害物質とインスリンセンシタイザの組み合わせ |
US20020187945A1 (en) | 1999-01-29 | 2002-12-12 | Robert Tam | Modulation of immune response by ribavirin |
WO2000052015A2 (en) | 1999-03-05 | 2000-09-08 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing prodrugs |
US7205404B1 (en) | 1999-03-05 | 2007-04-17 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
US6608027B1 (en) | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
MXPA02000294A (es) | 1999-06-25 | 2002-06-21 | Vertex Pharma | Profarmacos de carbamatos inhibidores de impdh. |
CN1384834A (zh) | 1999-08-27 | 2002-12-11 | Icn药品公司 | 吡咯并[2,3-d]嘧啶核苷类似物 |
WO2001018013A1 (en) | 1999-09-08 | 2001-03-15 | Metabasis Therapeutics, Inc. | Prodrugs for liver specific drug delivery |
US6518253B1 (en) | 1999-11-19 | 2003-02-11 | Robert Tam | Treatment of viral infections using the L-isomer of ribavirin |
AU785355B2 (en) | 1999-12-03 | 2007-02-01 | Regents Of The University Of California At San Diego, The | Phosphonate compounds |
AU5076601A (en) | 1999-12-13 | 2001-07-03 | Icn Pharmaceuticals, Inc. | Pulmonary delivery of ribavirin or levovirinTM for systemic and quasi-systemic treatment of disease |
KR20030032908A (ko) | 1999-12-23 | 2003-04-26 | 아이씨엔 파마슈티컬스, 인코포레이티드 | L-누클레오시드, l-누클레오티드 및 이들의 유사체에대한 조성물 및 방법 |
US6770666B2 (en) | 1999-12-27 | 2004-08-03 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
CA2396593A1 (en) | 2000-01-28 | 2001-08-02 | Merck & Co., Inc. | Treatment or prevention of prostate cancer with a cox-2 selective inhibiting drug |
US6455508B1 (en) | 2000-02-15 | 2002-09-24 | Kanda S. Ramasamy | Methods for treating diseases with tirazole and pyrrolo-pyrimidine ribofuranosyl nucleosides |
US6495677B1 (en) | 2000-02-15 | 2002-12-17 | Kanda S. Ramasamy | Nucleoside compounds |
EP1259237A4 (en) | 2000-02-17 | 2004-07-28 | Merck & Co Inc | TREATMENT OR PREVENTION OF PROSTATE CANCER USING A SELECTIVE COX-2 INHIBITOR MEDICINE |
WO2001077091A2 (en) | 2000-04-05 | 2001-10-18 | Tularik Inc. | Ns5b hcv polymerase inhibitors |
CA2404639A1 (en) | 2000-04-13 | 2001-10-25 | Pharmasset, Ltd. | 3'-or 2'-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections |
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
NZ547204A (en) | 2000-05-26 | 2008-01-31 | Idenix Cayman Ltd | Methods and compositions for treating flaviviruses and pestiviruses |
WO2001093383A2 (en) | 2000-05-26 | 2001-12-06 | Versatile Optical Networks, Inc. | Wavelength locking system |
ES2227203T3 (es) | 2000-05-26 | 2005-04-01 | Idenix (Cayman) Limited | Metodos para tratar la infeccion por el virus de la hepatitis delta con beta-1-2'-desoxinucleosidos. |
US6875751B2 (en) | 2000-06-15 | 2005-04-05 | Idenix Pharmaceuticals, Inc. | 3′-prodrugs of 2′-deoxy-β-L-nucleosides |
GB0015627D0 (en) | 2000-06-26 | 2000-08-16 | Rademacher Group Limited | Phosphoglycan messengers and their medical uses |
US6448281B1 (en) | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
UA72612C2 (en) | 2000-07-06 | 2005-03-15 | Pyrido[2.3-d]pyrimidine and pyrimido[4.5-d]pyrimidine nucleoside analogues, prodrugs and method for inhibiting growth of neoplastic cells | |
GB0017676D0 (en) | 2000-07-19 | 2000-09-06 | Angeletti P Ist Richerche Bio | Inhibitors of viral polymerase |
ES2627903T3 (es) | 2000-07-21 | 2017-08-01 | Gilead Sciences, Inc. | Profármacos de análogos de nucleótidos de fosfonato y métodos para seleccionar y preparar los mismos |
AU2001292557A1 (en) | 2000-08-22 | 2002-03-04 | Ribapharm Inc. | Methods of drug delivery to hepatocytes and treatment of flaviviridae infections |
US20030008841A1 (en) | 2000-08-30 | 2003-01-09 | Rene Devos | Anti-HCV nucleoside derivatives |
AU2001282528A1 (en) | 2000-09-01 | 2002-03-22 | Shionogi And Co., Ltd. | Compounds having anti-hepatitis c virus effect |
DE60143672D1 (de) | 2000-10-18 | 2011-01-27 | Pharmasset Inc | Modifizierte nukleoside zur behandlung von virusinfektionen und abnormaler zellulärer proliferation |
WO2002040021A2 (en) | 2000-11-17 | 2002-05-23 | Idenix (Cayman) Limited | Methods for inhibiting the transmission of hiv using topically applied substituted 6-benzyl-4-oxopyrimidines |
US20040014696A1 (en) | 2000-12-07 | 2004-01-22 | Johnson Lau | Specificity in treatment of diseases |
AR031905A1 (es) | 2000-12-12 | 2003-10-08 | Schering Corp | Peptidos diarilicos como inhibidores de ns3-serina proteasa en hepatitis de virus c |
US6653295B2 (en) | 2000-12-13 | 2003-11-25 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus NS3 protease |
JP2005502580A (ja) | 2000-12-15 | 2005-01-27 | フアーマセツト・リミテツド | フラビウィルス感染治療用抗ウィルス薬 |
EP1346724A4 (en) | 2000-12-26 | 2004-11-17 | Mitsubishi Pharma Corp | REMEDIES FOR HEPATITIS C |
GEP20053601B (en) | 2001-01-22 | 2005-08-10 | Merck & Co Inc | Nucleoside Derivatives as Inhibitors of RNA-Dependent RNA Viral Polymerase |
AU2002254616B2 (en) | 2001-04-11 | 2007-09-06 | Idenix (Cayman) Limited | Phenylindoles for the treatment of HIV |
GB0114286D0 (en) | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
GB2378524A (en) | 2001-08-08 | 2003-02-12 | Bookham Technology Plc | Intergrated optic device |
GB0119369D0 (en) | 2001-08-08 | 2001-10-03 | Bookham Technology Plc | Optic system |
US20040077563A1 (en) | 2001-08-21 | 2004-04-22 | Johnson Lau | Methods of drug delivery to hepatocytes and treatment of flaviviridae infections |
US20030232760A1 (en) | 2001-09-21 | 2003-12-18 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
WO2003026675A1 (en) | 2001-09-28 | 2003-04-03 | Idenix (Cayman) Limited | Methods and compositions for treating flaviviruses and pestiviruses using 4'-modified nucleoside |
US7138376B2 (en) | 2001-09-28 | 2006-11-21 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides |
US20030072451A1 (en) | 2001-10-16 | 2003-04-17 | Pimentel Roberto J. | Method and apparatus for securely transferring wireless data |
JPWO2003034709A1 (ja) | 2001-10-17 | 2005-02-10 | ナルテック株式会社 | 伸長方法およびデータ処理装置 |
WO2003037908A1 (en) | 2001-10-31 | 2003-05-08 | Ribapharm Inc. | Antiviral combination therapy and compositions |
WO2003051896A1 (en) | 2001-12-17 | 2003-06-26 | Ribapharm Inc. | Cytidine libraries and compounds synthesized by solid-phase combinatorial strategies |
AU2002353164A1 (en) | 2001-12-17 | 2003-06-30 | Ribapharm Inc. | Unusual nucleoside libraries, compounds, and preferred uses as antiviral and anticancer agents |
WO2003051897A1 (en) | 2001-12-17 | 2003-06-26 | Ribapharm Inc. | Nucleoside analog libraries and compounds |
AU2002349905A1 (en) | 2001-12-17 | 2003-06-30 | Ribapharm Inc. | Nucleoside libraries and compounds by mcc combinatorial strategies on solid support |
WO2003051881A1 (en) | 2001-12-17 | 2003-06-26 | Ribapharm Inc. | Substituted purine nucleoside libraries and compounds by solid-phase combinatorial strategies |
AU2002353165A1 (en) | 2001-12-17 | 2003-06-30 | Ribapharm Inc. | Deazapurine nucleoside libraries and compounds |
US7261704B2 (en) | 2001-12-28 | 2007-08-28 | Terumo Kabushiki Kaisha | Syringe |
WO2003062255A2 (en) | 2002-01-17 | 2003-07-31 | Ribapharm Inc. | Sugar modified nucleosides as viral replication inhibitors |
EP1476169B1 (en) | 2002-02-13 | 2013-03-20 | Merck Sharp & Dohme Corp. | Inhibiting orthopoxvirus replication with nucleoside compounds |
AU2003232071A1 (en) | 2002-05-06 | 2003-11-17 | Genelabs Technologies, Inc. | Nucleoside derivatives for treating hepatitis c virus infection |
CA2485597C (en) | 2002-05-13 | 2013-07-02 | Metabasis Therapeutics, Inc. | Process for preparation of cyclic prodrugs of pmea and pmpa |
JP4476811B2 (ja) | 2002-05-13 | 2010-06-09 | メタバシス・セラピューティクス・インコーポレイテッド | Pmeaおよびそのアナログの新規ホスホン酸系プロドラッグ |
AU2003269892A1 (en) | 2002-06-27 | 2004-01-19 | Isis Pharmaceuticals, Inc. | Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
RS114104A (en) | 2002-06-28 | 2007-02-05 | Idenix (Cayman) Limited, | 2' and 3'-nucleoside prodrugs for treating flaviviridae infections |
US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
AU2003248748A1 (en) | 2002-06-28 | 2004-01-19 | Idenix (Cayman) Limited | 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
WO2004002999A2 (en) | 2002-06-28 | 2004-01-08 | Idenix (Cayman) Limited | Modified 2' and 3' -nucleoside produgs for treating flaviridae infections |
US20040067877A1 (en) | 2002-08-01 | 2004-04-08 | Schinazi Raymond F. | 2', 3'-Dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections |
US7094768B2 (en) | 2002-09-30 | 2006-08-22 | Genelabs Technologies, Inc. | Nucleoside derivatives for treating hepatitis C virus infection |
AU2003279797B2 (en) | 2002-09-30 | 2009-10-22 | Genelabs Technologies, Inc. | Nucleoside derivatives for treating hepatitis C virus infection |
KR101026294B1 (ko) | 2002-10-31 | 2011-03-31 | 메타베이시스 테라퓨틱스, 인크. | 1,3-프로판-1-아릴 디올의 신규 시클릭 포스페이트디에스테르 및 프로드럭 제조에서의 이들의 용도 |
SI1576138T1 (sl) | 2002-11-15 | 2017-07-31 | Idenix Pharmaceuticals Llc | 2'-metil nukleozidi v kombinaciji z interferon in flaviviridae mutacijo |
TWI332507B (en) | 2002-11-19 | 2010-11-01 | Hoffmann La Roche | Antiviral nucleoside derivatives |
TWI294882B (en) | 2002-12-09 | 2008-03-21 | Hoffmann La Roche | Anhydrous crystalline azido cytosine hemisulfate derivative |
ES2726998T3 (es) | 2003-05-30 | 2019-10-11 | Gilead Pharmasset Llc | Análogos de nucleósidos fluorados modificados |
PL1658302T3 (pl) | 2003-07-25 | 2011-03-31 | Idenix Pharmaceuticals Inc | Analogi nukleozydów purynowych do leczenia chorób spowodowanych przez Flaviviridae obejmujących zapalenie wątroby typu C |
TW200510425A (en) | 2003-08-13 | 2005-03-16 | Japan Tobacco Inc | Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor |
US7491794B2 (en) | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
US7144868B2 (en) | 2003-10-27 | 2006-12-05 | Genelabs Technologies, Inc. | Nucleoside compounds for treating viral infections |
KR20060096487A (ko) | 2003-10-27 | 2006-09-11 | 진랩스 테크놀러지스, 인크. | 바이러스 감염증들을 치료하기 위한 뉴클레오시드 화합물 |
ES2389602T3 (es) | 2003-12-30 | 2012-10-29 | Gilead Sciences, Inc. | Fosfonatos de nucleósidos y análogos de los mismos para el tratamiento de infecciones por el VPH |
WO2006033709A2 (en) | 2004-07-29 | 2006-03-30 | Metabasis Therapeutics, Inc. | Novel nucleoside derivatives |
US20050182252A1 (en) | 2004-02-13 | 2005-08-18 | Reddy K. R. | Novel 2'-C-methyl nucleoside derivatives |
WO2005123729A1 (en) | 2004-06-08 | 2005-12-29 | Metabasis Therapeutics, Inc. | Lewis acid mediated synthesis of cyclic esters |
US7206468B2 (en) | 2004-08-17 | 2007-04-17 | Huang Hung-Chia | Broad-band fiber-optic wave plates |
WO2007020193A2 (en) | 2005-08-15 | 2007-02-22 | F. Hoffmann-La Roche Ag | Antiviral phosphoramidates of 4 ' -substituted pronucleotides |
JP4954573B2 (ja) | 2006-02-28 | 2012-06-20 | オリンパス株式会社 | 内視鏡システム |
US7795291B2 (en) | 2006-07-07 | 2010-09-14 | Bristol-Myers Squibb Company | Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method |
CL2008003511A1 (es) | 2007-11-29 | 2010-02-19 | Metabasis Therapeutics Inc | Compuestos derivados nucleotidicos, inhibidores de polimerasa ns5b del virus de la hepatitis c; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento de la hepatitis c. |
BRPI0821106A2 (pt) | 2007-11-29 | 2015-06-16 | Ligand Pharm Inc | Pró-fármacos de nucleosídeo e usos dos mesmos |
BR112013029761A2 (pt) | 2011-05-19 | 2017-03-21 | Univ Emory | pró-drogas de monofosfato de purina para tratamento de infecções virais |
CU24265B1 (es) | 2012-05-15 | 2017-07-04 | Novartis Ag | Compuestos derivados de benzamida para inhibir la actividad de abl1, abl2 y bcr-abl1, útiles en el tratamiento del cáncer |
US20140142052A1 (en) * | 2012-05-17 | 2014-05-22 | Normoxys, Inc. | Phosphorylated polyols, pyrophosphates, and derivatives thereof having biological activity |
WO2014043380A1 (en) | 2012-09-14 | 2014-03-20 | Ligand Pharmaceuticals Incorporated | Novel nucleotide prodrug compounds and use |
CN106687118A (zh) | 2014-07-02 | 2017-05-17 | 配体药物公司 | 前药化合物及其用途 |
-
2015
- 2015-06-26 CN CN201580036167.6A patent/CN106687118A/zh active Pending
- 2015-06-26 JP JP2016572466A patent/JP2017520545A/ja active Pending
- 2015-06-26 EP EP15815591.1A patent/EP3164136A4/en not_active Withdrawn
- 2015-06-26 US US15/323,080 patent/US9994600B2/en active Active
- 2015-06-26 WO PCT/US2015/038044 patent/WO2016003812A1/en active Application Filing
-
2018
- 2018-06-11 US US16/005,601 patent/US10150788B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08508245A (ja) * | 1993-03-08 | 1996-09-03 | エーザイ株式会社 | ホスホン酸誘導体 |
JP2013508459A (ja) * | 2009-10-26 | 2013-03-07 | ワーナー・チルコット・カンパニー・エルエルシー | 骨代謝疾患を治療するためのビスホスホネート化合物 |
JP2017512183A (ja) * | 2014-02-13 | 2017-05-18 | リガンド・ファーマシューティカルズ・インコーポレイテッド | プロドラッグ化合物およびそれらの使用 |
Non-Patent Citations (7)
Title |
---|
CHINESE CHEMICAL LETTERS, vol. 7, no. 1, JPN6019005813, 1996, pages 29 - 32, ISSN: 0003981787 * |
CHINESE CHEMICAL LETTERS, vol. 7, no. 2, JPN6019005812, 1996, pages 153 - 156, ISSN: 0003981786 * |
DATABASE REGISTRY, JPN7019000456, 2008, ISSN: 0003981788 * |
DATABASE REGISTRY, JPN7019000457, 2008, ISSN: 0003981789 * |
ENDOCRINOLOGY, vol. 110, no. 3, JPN6019005810, 1982, pages 812 - 819, ISSN: 0003981785 * |
PUBCHEM[ONLINE], JPN7020000069, 2007, ISSN: 0004194114 * |
THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 274, no. 49, JPN6019005809, 1999, pages 34735 - 34741, ISSN: 0003981784 * |
Also Published As
Publication number | Publication date |
---|---|
EP3164136A1 (en) | 2017-05-10 |
CN106687118A (zh) | 2017-05-17 |
US20180291050A1 (en) | 2018-10-11 |
US9994600B2 (en) | 2018-06-12 |
WO2016003812A1 (en) | 2016-01-07 |
EP3164136A4 (en) | 2018-04-04 |
US20170158725A1 (en) | 2017-06-08 |
US10150788B2 (en) | 2018-12-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10150788B2 (en) | Prodrug compounds and uses thereof | |
US11278559B2 (en) | Prodrug compounds and their uses | |
WO2016138026A1 (en) | Gemcitabine derivatives | |
JP2022529321A (ja) | 環状リン酸エステル化合物 | |
JP2007500727A (ja) | 抗ウイルス処置のための核酸塩基ホスホネートアナログ | |
JP7181938B2 (ja) | ホスホロ(ン)アミダートアセタールおよびホスファ(ホナ)ートアルセタール化合物 | |
KR102369908B1 (ko) | 페난트롤린 포스폰산류 유도체 및 그의 제조방법과 응용 | |
CN115605492A (zh) | 核苷酸前药化合物 | |
RU2796403C2 (ru) | Фосфор(n)амидатацетальные и фосф(он)атацетальные соединения | |
KR102708995B1 (ko) | 포스포르(포스포론)아미다타세탈 및 포스프(온)아탈세탈 화합물 | |
TW202116329A (zh) | 環狀去氧核糖核苷酸化合物 | |
CN115768778A (zh) | 苄氧基磷酸(膦酸)酯化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170322 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180622 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190214 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190225 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190524 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190807 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20200120 |