WO2002008241A2 - Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same - Google Patents
Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same Download PDFInfo
- Publication number
- WO2002008241A2 WO2002008241A2 PCT/US2001/023104 US0123104W WO0208241A2 WO 2002008241 A2 WO2002008241 A2 WO 2002008241A2 US 0123104 W US0123104 W US 0123104W WO 0208241 A2 WO0208241 A2 WO 0208241A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- activity
- target tissue
- prodrug
- alkyl
- prodrugs
- Prior art date
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- 229940002612 prodrug Drugs 0.000 title claims abstract description 112
- 239000000651 prodrug Substances 0.000 title claims abstract description 112
- 238000000034 method Methods 0.000 title claims abstract description 68
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 5
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims abstract description 78
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- -1 magnesium alkoxide Chemical class 0.000 claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 37
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 19
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical class COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000012216 screening Methods 0.000 claims abstract description 16
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 239000011777 magnesium Substances 0.000 claims abstract description 7
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 5
- 238000011321 prophylaxis Methods 0.000 claims abstract description 4
- 210000001519 tissue Anatomy 0.000 claims description 101
- 230000000694 effects Effects 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 11
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 210000003563 lymphoid tissue Anatomy 0.000 claims description 10
- 239000012458 free base Substances 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 229940059260 amidate Drugs 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004437 phosphorous atom Chemical group 0.000 claims description 7
- VAQOTZQDXZDBJK-UHFFFAOYSA-N 2-(6-aminopurin-9-yl)ethanol Chemical compound NC1=NC=NC2=C1N=CN2CCO VAQOTZQDXZDBJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 239000001177 diphosphate Substances 0.000 claims description 5
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 5
- 235000011180 diphosphates Nutrition 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- LVOASXNJWPROPP-UHFFFAOYSA-N (4-methylphenyl)sulfonyloxymethylphosphonic acid Chemical compound CC1=CC=C(S(=O)(=O)OCP(O)(O)=O)C=C1 LVOASXNJWPROPP-UHFFFAOYSA-N 0.000 claims description 3
- MJZYTEBKXLVLMY-UHFFFAOYSA-N 1-(6-aminopurin-9-yl)propan-2-ol Chemical compound N1=CN=C2N(CC(O)C)C=NC2=C1N MJZYTEBKXLVLMY-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 2
- 125000005335 azido alkyl group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 2
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004971 nitroalkyl group Chemical group 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims 3
- 230000036436 anti-hiv Effects 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 150000007860 aryl ester derivatives Chemical group 0.000 claims 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 238000011200 topical administration Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000007858 starting material Substances 0.000 abstract description 4
- 230000001177 retroviral effect Effects 0.000 abstract 1
- 230000008685 targeting Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 36
- 210000002381 plasma Anatomy 0.000 description 33
- 239000000243 solution Substances 0.000 description 29
- 230000002829 reductive effect Effects 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- LDEKQSIMHVQZJK-AZFZMOAFSA-N propan-2-yl (2s)-2-[[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate Chemical compound O([C@H](C)CN1C2=NC=NC(N)=C2N=C1)CP(=O)(N[C@@H](C)C(=O)OC(C)C)OC1=CC=CC=C1 LDEKQSIMHVQZJK-AZFZMOAFSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000012071 phase Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 229910052736 halogen Inorganic materials 0.000 description 14
- 150000002367 halogens Chemical class 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 12
- 241000282472 Canis lupus familiaris Species 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 11
- 229930024421 Adenine Natural products 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 229960000643 adenine Drugs 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 11
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- 239000000047 product Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
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- 210000004369 blood Anatomy 0.000 description 9
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 8
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- 238000000926 separation method Methods 0.000 description 8
- 229930010555 Inosine Natural products 0.000 description 7
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 7
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- 238000004679 31P NMR spectroscopy Methods 0.000 description 6
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- 229910052698 phosphorus Inorganic materials 0.000 description 6
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 6
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- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 5
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- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
- C12Q1/18—Testing for antimicrobial activity of a material
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
Definitions
- R is an oxyester which is hydrolyzable in vivo, or hydroxyl;
- B is a heterocyclic base;
- Preferred embodiments of this invention are the diastereomerically enriched compounds having the structure (5a)
- any prodrug which is potentially believed to be capable of being converted in vivo within target tissue cells to the free methoxyphosphonate nucleotide analogue parent drug e.g., whether by hydrolysis, oxidation, or other covalent transformation resulting from exposure to biological tissues, is suitable for use in the method of this invention.
- Such prodrugs may not be known at this time but are identified in the future and thus become suitable candidates available for testing in the method of this invention. Since the prodrugs are simply candidates for screening in the methods their structures are not relevant to practicing or enabling the screening method, although of course their structures ultimately are dispositive of whether or not a prodrug will be shown to be selective in the assay.
- the pro-moieties bound to the parent drug may be the same or different.
- the target tissue preferably wiU be lymphoid tissue when screening for prodrugs useful in the treatment of HIV infection.
- Lymphoid tissue wiU be known to the artisan and includes CD4 ceUs, lymphocytes, lymph nodes, macrophages and macrophage-Uke ceUs including monocytes such as peripheral blood monocytic ceUs (PBMCs) and gUal ceUs.
- PBMCs peripheral blood monocytic ceUs
- the target and non-target tissue may in fact be the same tissue, but the tissues wiU be in different biological status.
- the method herein could be used to select for prodrugs that confer activity in viraUy-infected tissue (target tissue) but which remain substantiaUy inactive in vhaUy-uninfected ceUs (corresponding non-target tissue).
- the same strategy would be employed to select prophylactic prodrugs, i.e., prodrugs metabolized to antiviraUy active forms incidental to viral infection but which remain substantiaUy unmetaboUzed in uninfected cells.
- prodrugs could be screened in transformed ceUs and the untransformed counterpart tissue. This would be particularly useful in comparative testing to select prodrugs for the treatment of hematological maUgnancies, e.g. leukemias.
- the alkyl group of the magnesium alkoxide is not critical and can be any C x -
- R 23 is H, OH, F, Cl, Br, I, SCH3, SCH2CH3, SCH2CCH, SCH2CHCH2, SC3H7, OR 16 , NH2, NHR 17 or R 22 ; and R 24 is O, S or Se.
- B also includes both protected and unprotected heterocycUc bases, particularly purine and pyrimidine bases.
- Protecting groups for exocycUc amines and other labUe groups are known (Greene et al. "Protective Groups in Organic Synthesis") and include N-benzoyl, isobutyryl, 4,4'-dimethoxytrityl (DMT) and the like.
- Alkenyl and alkynyl are defined in the same fashion, but contain at least one double or triple bond, respectively.
- the combined filtrate and rinse was extracted with ethyl acetate (28 kg).
- Crude II was isolated by filtration and washed with methanol (12.7 kg). The crude II wet cake was slurried in methanol (58 kg).
- the GS-7171 diastereomeric mixture was dissolved in mobUe phase, and approximately 1 g aUquots of GS-7171 were pumped onto the chromatographic system.
- the undesired diastereomer, designated GS-7339 was the first major broad (approx. 15 min. duration) peak to elute from the column.
- the mobUe phase was immediately switched to 100% methyl alcohol, which caused the desired diastereomer, designated GS-7340 (IV), to elute as a sharp peak from the column with the methyl alcohol solvent front.
- the methyl alcohol was used to reduce the over-aU cycle time.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- Virology (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
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Abstract
Description
Claims
Priority Applications (41)
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AU8294101A AU8294101A (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
HU0301307A HU230960B1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and compositions thereof |
CA2416757A CA2416757C (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
APAP/P/2003/002724A AP1466A (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same. |
CNB018131611A CN1291994C (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
IL15365801A IL153658A0 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
UA2003021482A UA75889C2 (en) | 2000-07-21 | 2001-07-20 | Phosphonatnucleotide analogs prodrugs, a method for selection and preparation thereof |
DK01961695.2T DK1301519T4 (en) | 2000-07-21 | 2001-07-20 | PRODUCTS OF PHOSPHONATE NUCLEOTIDE ANALOGS AND METHODS OF SELECTION AND PREPARATION |
US10/333,107 US20040018150A1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
BR0112646A BRPI0112646B8 (en) | 2000-07-21 | 2001-07-20 | prodrugs of phosphonate nucleotide analogues and compositions comprising them |
MXPA03000587A MXPA03000587A (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same. |
ES01961695T ES2536972T5 (en) | 2000-07-21 | 2001-07-20 | Phosphonate nucleotide analog prodrugs and methods for selecting and preparing the same |
KR1020037000872A KR100767432B1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
NZ523438A NZ523438A (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
AU2001282941A AU2001282941C1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
EP01961695.2A EP1301519B2 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
KR1020067020061A KR100749160B1 (en) | 2000-07-21 | 2001-07-20 | Methods for making prodrugs of phosphonate nucleotide analogues |
SI200131040T SI1301519T1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
EA200300188A EA004926B1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues, method for method for screening to identify thereof, method for anti-viral therapy or prophylaxis |
EEP200300029A EE05366B1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs and Screening Methods for Phosphonate Nucleotide Analogs |
HRP20160074AA HRP20160074B1 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
JP2002514146A JP4651264B2 (en) | 2000-07-21 | 2001-07-20 | Prodrugs of phosphonate nucleotide analogs and methods for selecting and making them. |
ZA2002/10271A ZA200210271B (en) | 2000-07-21 | 2002-12-19 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
IS6689A IS2985B (en) | 2000-07-21 | 2003-01-17 | Phosphonate-nucleotide analogues and methods for selecting and generating them |
NO20030270A NO336718B1 (en) | 2000-07-21 | 2003-01-20 | Prodrugs of phosphonate nucleotide analogues, their preparation and its use in the therapeutic and prophylactic treatment of viral infections |
HRP20030047AA HRP20030047B1 (en) | 2000-07-21 | 2003-01-24 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
BG107572A BG66037B1 (en) | 2000-07-21 | 2003-02-19 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
HK03105871.0A HK1054238A1 (en) | 2000-07-21 | 2003-08-15 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
AU2005225039A AU2005225039B2 (en) | 2000-07-21 | 2005-10-18 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
NO20120466A NO20120466L (en) | 2000-07-21 | 2012-04-23 | Prodrugs of Phosphonate Nucleotide Analogs, and Methods for Selecting and Preparing Them |
NO20131717A NO20131717L (en) | 2000-07-21 | 2013-12-20 | Prodrugs of Phosphonate Nucleotide Analogs, and Methods for Selecting and Preparing Them |
NO20150909A NO20150909L (en) | 2000-07-21 | 2015-07-10 | Prodrugs of Phosphonate Nucleotide Analogs, and Methods for Selecting and Preparing Them |
LTPA2016009C LTC1301519I2 (en) | 2000-07-21 | 2016-04-05 | Prodrugs of nucleotide phosphonate analogues and methods for their selection and preparation |
BE2016C018C BE2016C018I2 (en) | 2000-07-21 | 2016-04-07 | |
FR16C0013C FR16C0013I2 (en) | 2000-07-21 | 2016-04-11 | PRODRUGS BASED ON NUCLEOTIDE ANALOGUES OF PHOSPHONATE AND METHODS FOR THE SELECTION AND PREPARATION THEREOF |
CY2016008C CY2016008I1 (en) | 2000-07-21 | 2016-04-12 | PRODRUGS OF NUCLEOTIDE PHOSPHONIC ANALOGUES AND METHODS FOR THEIR SELECTION AND PREPARATION |
LU93029C LU93029I2 (en) | 2000-07-21 | 2016-04-14 | ALAFENAMIDE TENOFOVIR OR SALT OR SOLVATE THEREOF, IN PARTICULAR ALFENAMIDE FUMARATE TENOFOVIR |
NO2016006C NO2016006I1 (en) | 2000-07-21 | 2016-04-19 | Prodrugs of phosphonate nucleotide analogues, their preparation and its use in the therapeutic and prophylactic treatment of viral infections |
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NO2023006C NO2023006I1 (en) | 2000-07-21 | 2023-02-03 | Tenofovir alafenamide or a salt or solvate thereof, especially tenofovir alafenamide fumarate - extension |
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EP (3) | EP3235823A1 (en) |
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IS (1) | IS2985B (en) |
LT (2) | LT2682397T (en) |
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US8735372B2 (en) | 2007-03-30 | 2014-05-27 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US8871271B2 (en) | 2005-06-13 | 2014-10-28 | Gilead Sciences, Inc. | Method and composition for pharmaceutical product |
WO2014195724A1 (en) | 2013-06-07 | 2014-12-11 | Cipla Limited | An efficient process for separation of diastereomers of 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy]propyl]adenine |
US8987437B2 (en) | 2011-05-19 | 2015-03-24 | Gilead Sciences, Inc. | Processes and intermediates for preparing anti-HIV Agents |
WO2015040640A3 (en) * | 2013-09-20 | 2015-06-04 | Laurus Labs Private Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
US9090642B2 (en) | 2010-07-19 | 2015-07-28 | Gilead Sciences, Inc. | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
WO2015079455A3 (en) * | 2013-11-27 | 2015-08-27 | Laurus Labs Private Limited | A recycling process for preparing tenofovir alafenamide diastereomers |
US9206217B2 (en) | 2009-05-20 | 2015-12-08 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
WO2015197006A1 (en) * | 2014-06-25 | 2015-12-30 | 四川海思科制药有限公司 | Substituted amino acid thioester compound, and composition and application thereof |
US9284342B2 (en) | 2009-05-20 | 2016-03-15 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
WO2016192692A1 (en) | 2015-06-05 | 2016-12-08 | Zentiva K.S. | Solid forms of tenofovir alafenamide |
AU2014271320B2 (en) * | 2011-08-16 | 2017-02-23 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
US9593137B2 (en) | 2011-12-22 | 2017-03-14 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
WO2017083304A1 (en) | 2015-11-09 | 2017-05-18 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
CN106800573A (en) * | 2015-11-25 | 2017-06-06 | 四川海思科制药有限公司 | A kind of phosphonate-nucleotide ester monohydrate and preparation method thereof and in application pharmaceutically |
CN106866737A (en) * | 2015-12-11 | 2017-06-20 | 南京圣和药业股份有限公司 | Phosphonate derivative and its application |
WO2017118928A1 (en) | 2016-01-06 | 2017-07-13 | Lupin Limited | Process for the separation of diastereomers of tenofovir alafenamide |
US9724360B2 (en) | 2014-10-29 | 2017-08-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
WO2017134089A1 (en) | 2016-02-02 | 2017-08-10 | Sandoz Ag | Crystalline forms of tenofovir alafenamide monofumarate |
WO2017157352A1 (en) | 2016-03-17 | 2017-09-21 | Zentiva, K.S. | A preparation method of diastereomerically pure tenofovir alafenamide or its salts |
US9783568B2 (en) | 2008-07-08 | 2017-10-10 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
JP2017535520A (en) * | 2014-09-30 | 2017-11-30 | ハンミ・ファイン・ケミカル・カンパニー・リミテッドHanmi Fine Chemical Co., Ltd. | Method for producing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine |
TWI616453B (en) * | 2015-08-27 | 2018-03-01 | Substituted amino acid thioester compounds, materials and uses thereof | |
TWI620754B (en) * | 2015-08-26 | 2018-04-11 | Method for preparing amino phosphate derivative and preparation method thereof | |
US9994600B2 (en) | 2014-07-02 | 2018-06-12 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
WO2018115046A1 (en) | 2016-12-23 | 2018-06-28 | Sandoz Ag | Crystalline solid forms of tenofovir alafenamide |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
WO2018144390A1 (en) | 2017-01-31 | 2018-08-09 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
WO2018153977A1 (en) | 2017-02-24 | 2018-08-30 | Hexal Ag | Stable composition of tenofovir alafenamide |
US10065958B2 (en) | 2010-07-22 | 2018-09-04 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
WO2018160088A1 (en) | 2017-02-28 | 2018-09-07 | Александр Васильевич ИВАЩЕНКО | Nucleotides containing an n-[(s)-1-cyclobutoxycarbonyl]phosphoramidate fragment, analogs thereof, and use thereof |
US10233202B2 (en) | 2015-05-29 | 2019-03-19 | Jiangsu Tasly Diyi Pharmaceutical Co., Ltd. | Tenofovir monobenzyl ester phosphamide prodrug, preparation method and use thereof |
US10251904B2 (en) | 2015-09-16 | 2019-04-09 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US10449210B2 (en) | 2014-02-13 | 2019-10-22 | Ligand Pharmaceuticals Inc. | Prodrug compounds and their uses |
US10456414B2 (en) | 2011-09-16 | 2019-10-29 | Gilead Pharmasset Llc | Methods for treating HCV |
EP3607939A1 (en) | 2015-06-30 | 2020-02-12 | Gilead Sciences, Inc. | Pharmaceutical formulations |
US10675296B2 (en) | 2017-07-11 | 2020-06-09 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US10682368B2 (en) | 2017-03-14 | 2020-06-16 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
US10836787B2 (en) | 2017-05-01 | 2020-11-17 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate |
US10851125B2 (en) | 2017-08-01 | 2020-12-01 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate |
WO2021011891A1 (en) | 2019-07-18 | 2021-01-21 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
WO2021035214A1 (en) * | 2019-08-22 | 2021-02-25 | Emory University | Nucleoside prodrugs and uses related thereto |
WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
US10988498B2 (en) | 2009-09-21 | 2021-04-27 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs |
WO2021165995A1 (en) | 2020-02-20 | 2021-08-26 | Cipla Limited | Novel salts and/or co-crystals of tenofovir alafenamide |
US11116783B2 (en) | 2013-08-27 | 2021-09-14 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
WO2021202669A2 (en) | 2020-04-01 | 2021-10-07 | Reyoung Corporation | Nucleoside and nucleotide conjugate compounds and uses thereof |
US11491169B2 (en) | 2020-05-29 | 2022-11-08 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11566041B2 (en) | 2020-04-21 | 2023-01-31 | Ligand Pharmaceuticals, Inc. | Nucleotide prodrug compounds |
US11613553B2 (en) | 2020-03-12 | 2023-03-28 | Gilead Sciences, Inc. | Methods of preparing 1′-cyano nucleosides |
US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
US11667656B2 (en) | 2021-01-27 | 2023-06-06 | Apotex Inc. | Crystalline forms of Tenofovir alafenamide |
US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
US11970482B2 (en) | 2018-01-09 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
Families Citing this family (135)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7388002B2 (en) * | 2001-11-14 | 2008-06-17 | Biocryst Pharmaceuticals, Inc. | Nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases |
IL161901A0 (en) * | 2001-11-14 | 2005-11-20 | Biocryst Pharmaceuticals Inc A | Nucleosides, preparation thereof and use as inhibiDevice for the reading and the signalling of environmental parameters tors of rna viral polymerases |
US20050239054A1 (en) * | 2002-04-26 | 2005-10-27 | Arimilli Murty N | Method and compositions for identifying anti-HIV therapeutic compounds |
US20090247488A1 (en) * | 2003-04-25 | 2009-10-01 | Carina Cannizzaro | Anti-inflammatory phosphonate compounds |
US20050261237A1 (en) * | 2003-04-25 | 2005-11-24 | Boojamra Constantine G | Nucleoside phosphonate analogs |
CN101410120A (en) * | 2003-04-25 | 2009-04-15 | 吉里德科学公司 | Anti-inflammatory phosphonate compounds |
US20050153990A1 (en) * | 2003-12-22 | 2005-07-14 | Watkins William J. | Phosphonate substituted kinase inhibitors |
US20070281907A1 (en) * | 2003-12-22 | 2007-12-06 | Watkins William J | Kinase Inhibitor Phosphonate Conjugates |
SG149075A1 (en) * | 2003-12-30 | 2009-01-29 | Gilead Sciences Inc | Phosphonates, monophosphonamidates, bisphosphonamidates for the treatment of viral diseases |
US8416242B1 (en) | 2004-05-14 | 2013-04-09 | Nvidia Corporation | Method and system for interpolating level-of-detail in graphics processors |
US8411105B1 (en) | 2004-05-14 | 2013-04-02 | Nvidia Corporation | Method and system for computing pixel parameters |
US7079156B1 (en) | 2004-05-14 | 2006-07-18 | Nvidia Corporation | Method and system for implementing multiple high precision and low precision interpolators for a graphics pipeline |
US8432394B1 (en) | 2004-05-14 | 2013-04-30 | Nvidia Corporation | Method and system for implementing clamped z value interpolation in a raster stage of a graphics pipeline |
PT2258376T (en) * | 2004-07-27 | 2019-05-31 | Gilead Sciences Inc | Phosphonate analogs of hiv inhibitor compounds |
EP2842559A3 (en) * | 2005-04-08 | 2015-03-18 | Chimerix, Inc. | Compounds, compositions and methods for the treatment of viral infections and other medical disorders |
WO2006110655A2 (en) | 2005-04-08 | 2006-10-19 | Chimerix, Inc. | Compounds, compositions and methods for the treatment of poxvirus infections |
US8076303B2 (en) | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
CN100396689C (en) * | 2006-03-07 | 2008-06-25 | 中国医学科学院医药生物技术研究所 | Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity |
WO2008007392A2 (en) | 2006-07-12 | 2008-01-17 | Matrix Laboratories Limited | Process for the preparation of tenofovir |
US7951789B2 (en) | 2006-12-28 | 2011-05-31 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
AU2008302676B2 (en) * | 2007-06-26 | 2013-02-28 | University Of Wyoming Research Corporation D/B/A Western Research Institute | Treatment and prevention systems for acid mine drainage and halogenated contaminants |
US8441497B1 (en) * | 2007-08-07 | 2013-05-14 | Nvidia Corporation | Interpolation of vertex attributes in a graphics processor |
CA2713105C (en) * | 2008-01-25 | 2016-06-07 | Chimerix, Inc. | Methods of treating viral infections |
NZ588796A (en) | 2008-04-25 | 2012-07-27 | Cipla Ltd | Crystalline form of tenofovir disoproxil and a process for its preparation |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
CA2729168A1 (en) * | 2008-07-02 | 2010-02-04 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
EA019341B1 (en) | 2008-12-23 | 2014-02-28 | Джилид Фармассет, Ллс. | Nucleoside phosphoramidates |
PA8855701A1 (en) | 2008-12-23 | 2010-07-27 | NUCLEOSID ANALOGS | |
WO2010075554A1 (en) * | 2008-12-23 | 2010-07-01 | Pharmasset, Inc. | Synthesis of purine nucleosides |
US8614200B2 (en) | 2009-07-21 | 2013-12-24 | Chimerix, Inc. | Compounds, compositions and methods for treating ocular conditions |
ES2629165T3 (en) | 2010-02-12 | 2017-08-07 | Chimerix, Inc. | Methods of treating a viral infection |
PL3290428T3 (en) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate |
BR112012024884A2 (en) | 2010-03-31 | 2016-10-18 | Gilead Pharmasset Llc | stereo-selective synthesis of phosphorus-containing assets |
CA2795054A1 (en) | 2010-04-01 | 2011-10-06 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
EP2563367A4 (en) | 2010-04-26 | 2013-12-04 | Chimerix Inc | Methods of treating retroviral infections and related dosage regimes |
EP2646453A1 (en) | 2010-11-30 | 2013-10-09 | Gilead Pharmasset LLC | Compounds |
CA2819548C (en) | 2010-12-10 | 2019-04-09 | Sigmapharm Laboratories, Llc | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
ZA201103820B (en) | 2010-12-13 | 2012-01-25 | Laurus Labs Private Ltd | Process for the preparation of tenofovir |
WO2012154321A1 (en) | 2011-03-31 | 2012-11-15 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US9550803B2 (en) | 2011-05-06 | 2017-01-24 | University Of Southern California | Method to improve antiviral activity of nucleotide analogue drugs |
AU2014215976B2 (en) * | 2011-10-07 | 2016-06-30 | Gilead Sciences, Inc. | Methods for preparing anti-viral nucleotide analogs |
AU2016228317B2 (en) * | 2011-10-07 | 2018-07-19 | Gilead Sciences, Inc. | Methods for preparing anti-viral nucleotide analogs |
CN103842366B (en) | 2011-10-07 | 2017-06-16 | 吉利德科学公司 | The method for preparing antiviral nucleotide analogs |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
CA2863662A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections |
AU2012327170A1 (en) | 2012-02-03 | 2013-08-22 | Gilead Sciences, Inc. | Therapeutic compounds |
CN102899327B (en) * | 2012-11-06 | 2014-06-11 | 清华大学深圳研究生院 | Antiviral small nucleic acid and temperature-sensitive type gel preparation and application thereof |
US9730940B2 (en) * | 2012-11-16 | 2017-08-15 | Merck Sharp & Dohme | Purine inhibitors of human phosphatidylinositol 3-kinase delta |
CN103848868B (en) * | 2012-12-04 | 2017-04-12 | 蚌埠丰原涂山制药有限公司 | method for preparing tenofovir |
CN103848869B (en) * | 2012-12-04 | 2016-12-21 | 上海医药工业研究院 | The method preparing tenofovir |
CN104072539B (en) * | 2013-03-25 | 2017-03-29 | 安徽贝克联合制药有限公司 | Double (4 acetaminophenol epoxide) esters of tenofovir and preparation method thereof and its application |
JP6262848B2 (en) * | 2013-05-21 | 2018-01-17 | 成都先導薬物開発有限公司 | How to capture drug targets |
EP2860185A1 (en) | 2013-10-09 | 2015-04-15 | Zentiva, k.s. | An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof |
IN2014MU00118A (en) | 2014-01-14 | 2015-08-28 | Mylan Lab Ltd | |
TWI660965B (en) * | 2014-01-15 | 2019-06-01 | 美商基利科學股份有限公司 | Solid forms of tenofovir |
CN104804042B (en) * | 2014-01-24 | 2018-01-19 | 齐鲁制药有限公司 | Phosphonate-nucleotide ester class compound, its pharmaceutical composition, Preparation method and use |
WO2015120057A1 (en) | 2014-02-05 | 2015-08-13 | Gilead Sciences, Inc. | Pharmaceutical combinations against co-infection with hiv and tuberculosis |
WO2015127848A1 (en) * | 2014-02-27 | 2015-09-03 | 四川海思科制药有限公司 | Substituted phosphoramidate derivative, preparation method therefor, and uses thereof |
CN105001262B (en) * | 2014-04-18 | 2017-09-01 | 四川海思科制药有限公司 | The phosphonaminate of aryl substitution and its application medically |
WO2015161785A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing phosphoramidate derivative and intermediates thereof, and method for preparing intermediates |
CN105085571A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Tenofovir alafenamide compound, preparation method and purpose thereof |
KR101703257B1 (en) | 2014-09-30 | 2017-02-06 | 한미정밀화학주식회사 | Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity |
KR101703258B1 (en) | 2014-12-30 | 2017-02-06 | 한미정밀화학주식회사 | Preparation method for (r)-9-[2-(phosphonomethoxy)propyl]adenine with high purity |
EP3203995A4 (en) | 2014-10-09 | 2019-05-15 | Board of Regents of the University of Nebraska | Compositions and methods for the delivery of therapeutics |
CN108191913A (en) * | 2014-11-12 | 2018-06-22 | 四川海思科制药有限公司 | A kind of tenofovir Chinese mugwort draws phenol amine crystal form a and preparation method thereof |
CN104558036A (en) * | 2014-12-11 | 2015-04-29 | 杭州和泽医药科技有限公司 | Tenofovir alafenamide hemi-fumarate crystal form and preparation method thereof |
JP2018502118A (en) | 2015-01-03 | 2018-01-25 | マイラン・ラボラトリーズ・リミテッドMylan Laboratories Limited | Process for preparing amorphous tenofovir arafenamide hemifumarate and its premix |
WO2016187160A1 (en) * | 2015-05-16 | 2016-11-24 | Godx, Inc. | Point of need testing device and methods of use thereof |
CA2987085A1 (en) * | 2015-06-17 | 2016-12-22 | Gilead Sciences, Inc. | Co-crystals, salts and solid forms of tenofovir alafenamide |
CN107849071B (en) | 2015-08-10 | 2021-03-09 | 默沙东公司 | Antiviral beta amino acid ester phosphorodiamidate compounds |
TWI616452B (en) * | 2015-08-26 | 2018-03-01 | Preparation method of nucleoside analog and intermediate thereof | |
WO2017037608A1 (en) * | 2015-08-28 | 2017-03-09 | Laurus Labs Private Limited | Solid forms of tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof |
EP3386512B1 (en) | 2015-12-10 | 2023-11-22 | Merck Sharp & Dohme LLC | Antiviral phosphodiamide prodrugs of tenofovir |
US10450335B2 (en) | 2015-12-15 | 2019-10-22 | Merck Sharp & Dohme Corp. | Antiviral oxime phosphoramide compounds |
CN107709288A (en) * | 2016-02-03 | 2018-02-16 | 四川海思科制药有限公司 | A kind of phosphinylidyne amine derivative and preparation method and purposes |
CN108350007B (en) * | 2016-03-01 | 2020-04-10 | 深圳市塔吉瑞生物医药有限公司 | Substituted adenine compound and pharmaceutical composition thereof |
CN107179355B (en) * | 2016-03-11 | 2021-08-10 | 广东东阳光药业有限公司 | Method for separating and detecting tenofovir alafenamide and related substances thereof |
CN107226826A (en) * | 2016-03-25 | 2017-10-03 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition |
WO2017211325A1 (en) | 2016-06-05 | 2017-12-14 | 上海诚妙医药科技有限公司 | New crystal form of tenofovir alafenamide salt, preparation method and use thereof |
CN107698621A (en) * | 2016-06-20 | 2018-02-16 | 杭州和泽医药科技有限公司 | A kind of phosphonate prodrugs of adenine derivative and its application in medicine |
WO2017221189A1 (en) * | 2016-06-22 | 2017-12-28 | Laurus Labs Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
FI3597646T3 (en) | 2016-08-19 | 2023-09-07 | Gilead Sciences Inc | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
CN106317116A (en) * | 2016-08-19 | 2017-01-11 | 张红利 | Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition |
US10449208B2 (en) | 2016-08-25 | 2019-10-22 | Merck Sharp & Dohme Corp. | Antiviral prodrugs of tenofovir |
CN106380484A (en) * | 2016-08-29 | 2017-02-08 | 杭州百诚医药科技股份有限公司 | New crystal form of tenofovir alafenamide and preparation method thereof |
WO2018042331A1 (en) | 2016-08-31 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Combinations and uses and treatments thereof |
WO2018051250A1 (en) | 2016-09-14 | 2018-03-22 | Viiv Healthcare Company | Combination comprising tenofovir alafenamide, bictegravir and 3tc |
US10736908B2 (en) | 2016-10-26 | 2020-08-11 | Merck Sharp & Dohme Corp. | Antiviral aryl-amide phosphodiamide compounds |
CN106565785B (en) * | 2016-11-09 | 2019-11-12 | 周雨恬 | One kind having the active nucleoside phosphoramidate class compound of Anti-HBV activity/HIV and its salt and purposes |
CN108129514A (en) * | 2016-12-01 | 2018-06-08 | 北京美倍他药物研究有限公司 | The individual isomer and its medical usage of phosphoric acid/phosphonate derivative |
TW201829412A (en) | 2016-12-22 | 2018-08-16 | 美商默沙東藥廠 | Antiviral aliphatic ester prodrugs of tenofovir |
CN110035760A (en) | 2016-12-22 | 2019-07-19 | 默沙东公司 | Antiviral benzyl amine phosphordiamidite compounds |
US20190374557A1 (en) * | 2017-02-28 | 2019-12-12 | Alexandre Vasilievich Ivachtchenko | Cyclobutyl (S)-2-[[[(R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]-propanoates, and production process and application thereof |
CN106866739B (en) * | 2017-03-10 | 2018-11-02 | 华东师范大学 | The preparation method of one kind (R) -1- (6- amino -9H- purine -9- bases) 2- phenyl esters |
CA3054822A1 (en) | 2017-03-20 | 2018-09-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Hiv post-exposure prophylaxis |
CN108794530A (en) * | 2017-04-26 | 2018-11-13 | 上海医药工业研究院 | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application |
KR102379965B1 (en) * | 2017-05-19 | 2022-03-29 | 주식회사 종근당 | Efficient preparation method of Tenofovir |
CN107266499B (en) * | 2017-06-05 | 2019-07-02 | 珠海优润医药科技有限公司 | A kind of antiviral compound and preparation method thereof |
US20200113919A1 (en) | 2017-06-30 | 2020-04-16 | Cipla Limited | Pharmaceutical Compositions |
WO2019021319A1 (en) | 2017-07-27 | 2019-01-31 | Cipla Limited | Pharmaceutical compositions |
AR112412A1 (en) | 2017-08-17 | 2019-10-23 | Gilead Sciences Inc | CHOLINE SALT FORMS OF AN HIV CAPSID INHIBITOR |
CN107655987B (en) * | 2017-09-08 | 2020-11-03 | 厦门蔚扬药业有限公司 | HPLC detection method for tenofovir alafenamide and isomer thereof |
CN107522743A (en) * | 2017-09-30 | 2017-12-29 | 深圳科兴生物工程有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method |
WO2019084020A1 (en) | 2017-10-24 | 2019-05-02 | Gilead Sciences, Inc. | Methods of treating patients co-infected with a virus and tuberculosis |
CN109942632B (en) * | 2017-12-20 | 2021-08-31 | 上海博志研新药物研究有限公司 | Preparation method of tenofovir alafenamide intermediate |
CN109942633B (en) * | 2017-12-20 | 2021-08-31 | 上海新礼泰药业有限公司 | Preparation method of tenofovir alafenamide intermediate |
US20200407382A1 (en) | 2017-12-30 | 2020-12-31 | Cipla Limited | Polymorphic forms of (9-[(r)-2-[[(s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]phenoxy phosphinyl]methoxy]propyl] adenine and pharmaceutically acceptable salts thereof |
KR20200108330A (en) * | 2018-01-10 | 2020-09-17 | 누코리온 파마슈티컬스, 인코포레이티드. | Phosphor (phosphorone) amidatacetal and phosph (one) atalcetal compounds |
EP3737359A4 (en) * | 2018-01-12 | 2021-11-03 | Board of Regents of the University of Nebraska | Antiviral prodrugs and formulations thereof |
CA3089590C (en) | 2018-02-15 | 2022-12-06 | Gilead Sciences, Inc. | Pyridine derivatives and their use for treating hiv infection |
PL3752496T3 (en) | 2018-02-16 | 2023-11-27 | Gilead Sciences, Inc. | Methods and intermediates for preparing a therapeutic compound useful in the treatment of retroviridae viral infection |
CN108101943B (en) * | 2018-02-28 | 2020-11-24 | 顾世海 | Tenofovir prodrug or pharmaceutically acceptable salt and application thereof in medicine |
US11458136B2 (en) | 2018-04-09 | 2022-10-04 | Board Of Regents Of The University Of Nebraska | Antiviral prodrugs and formulations thereof |
CN112423750A (en) | 2018-07-16 | 2021-02-26 | 吉利德科学公司 | Capsid inhibitors for the treatment of HIV |
US11826375B2 (en) | 2018-07-19 | 2023-11-28 | Merck Sharp & Dohme Llc | Phosphinic amide prodrugs of tenofovir |
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US20220372171A1 (en) * | 2019-09-20 | 2022-11-24 | Abbott Rapid Diagnostics International Unlimited Company | Antibody directed against tenofovir and derivatives thereof |
US11807625B2 (en) | 2019-11-26 | 2023-11-07 | Gilead Sciences, Inc. | Capsid inhibitors for the prevention of HIV |
CN115605493A (en) | 2020-03-20 | 2023-01-13 | 吉利德科学公司(Us) | Prodrugs of4'-C-substituted-2-halo-2' -deoxyadenosine nucleosides and methods of making and using the same |
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US11680064B2 (en) | 2020-06-25 | 2023-06-20 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of HIV |
CN113970612B (en) * | 2020-07-22 | 2023-08-01 | 北京四环制药有限公司 | Method for measuring related substances of propiophenone tenofovir by high performance liquid chromatography |
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AU2021377614A1 (en) | 2020-11-11 | 2023-06-22 | Gilead Sciences, Inc. | METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH gp120 CD4 BINDING SITE-DIRECTED ANTIBODIES |
CN113214322B (en) * | 2021-04-30 | 2022-10-25 | 山东立新制药有限公司 | Green and environment-friendly preparation method of tenofovir |
WO2022251594A1 (en) * | 2021-05-27 | 2022-12-01 | Antios Therapeutics, Inc. | Pharmacokinetics and dose-related improvments in subjects treated with phosphoramidate clevudine prodrugs |
WO2023102529A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
TW202342447A (en) | 2021-12-03 | 2023-11-01 | 美商基利科學股份有限公司 | Therapeutic compounds for hiv virus infection |
AU2022401696A1 (en) | 2021-12-03 | 2024-05-09 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
CN114369120A (en) * | 2022-01-28 | 2022-04-19 | 石家庄龙泽制药股份有限公司 | Preparation method of key intermediate of prophenoltenofovir |
TW202400172A (en) | 2022-04-06 | 2024-01-01 | 美商基利科學股份有限公司 | Bridged tricyclic carbamoylpyridone compounds and uses thereof |
WO2024006982A1 (en) | 2022-07-01 | 2024-01-04 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
WO2024044477A1 (en) | 2022-08-26 | 2024-02-29 | Gilead Sciences, Inc. | Dosing and scheduling regimen for broadly neutralizing antibodies |
WO2024076915A1 (en) | 2022-10-04 | 2024-04-11 | Gilead Sciences, Inc. | 4'-thionucleoside analogues and their pharmaceutical use |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0481214A1 (en) | 1990-09-14 | 1992-04-22 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
WO1995007920A1 (en) | 1993-09-17 | 1995-03-23 | Gilead Sciences, Inc. | Nucleotide analogs |
WO1996029336A1 (en) | 1995-03-13 | 1996-09-26 | Medical Research Council | Chemical compounds |
US5798340A (en) | 1993-09-17 | 1998-08-25 | Gilead Sciences, Inc. | Nucleotide analogs |
US5977061A (en) | 1995-04-21 | 1999-11-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | N6 - substituted nucleotide analagues and their use |
US5977089A (en) | 1996-07-26 | 1999-11-02 | Gilead Sciences, Inc. | Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CS233665B1 (en) | 1983-01-06 | 1985-03-14 | Antonin Holy | Processing of isomere o-phosphonylmethylderivative of anantiomere racemic vicinal diene |
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 |
CS264222B1 (en) | 1986-07-18 | 1989-06-13 | Holy Antonin | N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them |
US5650510A (en) | 1986-11-18 | 1997-07-22 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiviral phosphonomethoxyalkylene purine and pyrimidine derivatives |
US5057301A (en) | 1988-04-06 | 1991-10-15 | Neorx Corporation | Modified cellular substrates used as linkers for increased cell retention of diagnostic and therapeutic agents |
US5053215A (en) * | 1988-05-26 | 1991-10-01 | University Of Florida | NMR-assayable ligand-labelled trifluorothymidine containing composition and method for diagnosis of HSV infection |
US5744600A (en) | 1988-11-14 | 1998-04-28 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Phosphonomethoxy carbocyclic nucleosides and nucleotides |
US5688778A (en) | 1989-05-15 | 1997-11-18 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Nucleoside analogs |
JP2648516B2 (en) | 1989-07-27 | 1997-09-03 | ダイセル化学工業株式会社 | Separation of stereoisomers |
US5624898A (en) * | 1989-12-05 | 1997-04-29 | Ramsey Foundation | Method for administering neurologic agents to the brain |
JP2925753B2 (en) | 1990-02-23 | 1999-07-28 | ダイセル化学工業株式会社 | Optical isomer separation method |
DE69110528T2 (en) * | 1990-04-20 | 1996-03-14 | Inst Of Organic Chemistry And | Chiral 2- (phosphonomethoxy) propyl guanine as an antiviral agent. |
US5302585A (en) | 1990-04-20 | 1994-04-12 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Use of chiral 2-(phosphonomethoxy)propyl guanines as antiviral agents |
SK280313B6 (en) | 1990-04-24 | 1999-11-08 | �Stav Organick� Chemie A Biochemie Av �R | N-(3-fluoro-2-phosphonylmethoxypropyl) derivatives of purine and pyrimidine heterocyclic bases, process for their preparation and their use |
US5627165A (en) * | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
US5177064A (en) * | 1990-07-13 | 1993-01-05 | University Of Florida | Targeted drug delivery via phosphonate derivatives |
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 |
KR100221981B1 (en) | 1990-08-10 | 1999-09-15 | 안토닌 포레이트 | Novel process for the preparation of nucleotides |
US5827819A (en) * | 1990-11-01 | 1998-10-27 | Oregon Health Sciences University | Covalent polar lipid conjugates with neurologically active compounds for targeting |
US5208221A (en) | 1990-11-29 | 1993-05-04 | Bristol-Myers Squibb Company | Antiviral (phosphonomethoxy) methoxy purine/pyrimidine derivatives |
CZ284678B6 (en) | 1991-05-20 | 1999-01-13 | Ústav Organické Chemie A Biochemie Avčr | Di(2-propyl)esters of 1-fluoro-2-phosphonomethoxy-3-p-toluenesulfonyloxypropanes, process of their preparation and use |
US5498752A (en) | 1991-08-22 | 1996-03-12 | Daicel Chemical Industries, Ltd. | Process for recovering optical isomers and solvent, process for using solvent by circulation and process for reusing optical isomers in optical resolution |
JP3010816B2 (en) | 1991-08-22 | 2000-02-21 | ダイセル化学工業株式会社 | Method for recovering optical isomer and solvent in optical resolution, method for recycling solvent, and method for reusing optical isomer |
CA2120743C (en) | 1991-10-11 | 2005-03-08 | John C. Martin | Antiviral acyclic phosphonomethoxyalkyl substituted, alkenyl and alkynyl purine and pyrimidine derivatives |
US6057305A (en) | 1992-08-05 | 2000-05-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
IL106998A0 (en) * | 1992-09-17 | 1993-12-28 | Univ Florida | Brain-enhanced delivery of neuroactive peptides by sequential metabolism |
US6413949B1 (en) * | 1995-06-07 | 2002-07-02 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
JPH09506333A (en) * | 1993-09-17 | 1997-06-24 | ギリアード サイエンシーズ,インコーポレイテッド | Method of administering therapeutic compound |
US5656745A (en) * | 1993-09-17 | 1997-08-12 | Gilead Sciences, Inc. | Nucleotide analogs |
PT828749E (en) * | 1995-05-26 | 2003-11-28 | Genta Inc | COMPOSITIONS AND METHODS FOR SYNTHESIS OF ORGANOPHOSPHORUS DERIVATIVES |
CA2239020A1 (en) | 1995-12-29 | 1997-07-10 | Norbert W. Bischofberger | Nucleotide analogs |
US5717095A (en) * | 1995-12-29 | 1998-02-10 | Gilead Sciences, Inc. | Nucleotide analogs |
US5874577A (en) * | 1996-04-03 | 1999-02-23 | Medichem Research, Inc. | Method for the preparing 9-12-(Diethoxyphosphonomethoxy)ethyl!adenine and analogues thereof |
JP4033494B2 (en) * | 1996-07-26 | 2008-01-16 | ギリヤド サイエンシーズ, インコーポレイテッド | Nucleotide analogs |
US5739314A (en) | 1997-04-25 | 1998-04-14 | Hybridon, Inc. | Method for synthesizing 2'-O-substituted pyrimidine nucleosides |
TR200000224T2 (en) | 1997-07-25 | 2000-07-21 | Gilead Sciences, Inc. | Nucleotide analog compositions. |
SG106657A1 (en) | 1997-07-25 | 2004-10-29 | Gilead Sciences Inc | Nycleotide analog composition and sythesis method |
US5935946A (en) | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
WO1999030727A1 (en) * | 1997-12-17 | 1999-06-24 | Enzon, Inc. | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
PT1045897E (en) | 1998-01-23 | 2002-07-31 | Newbiotics Inc | THERAPEUTIC AGENTS BY ENZYMATIC CATALOG |
US6169078B1 (en) * | 1998-05-12 | 2001-01-02 | University Of Florida | Materials and methods for the intracellular delivery of substances |
US6348185B1 (en) * | 1998-06-20 | 2002-02-19 | Washington University School Of Medicine | Membrane-permeant peptide complexes for medical imaging, diagnostics, and pharmaceutical therapy |
US6169879B1 (en) * | 1998-09-16 | 2001-01-02 | Webtv Networks, Inc. | System and method of interconnecting and using components of home entertainment system |
GB9821058D0 (en) † | 1998-09-28 | 1998-11-18 | Univ Cardiff | Chemical compound |
TWI230618B (en) * | 1998-12-15 | 2005-04-11 | Gilead Sciences Inc | Pharmaceutical compositions of 9-[2-[[bis[(pivaloyloxy)methyl]phosphono]methoxy]ethyl]adenine and tablets or capsules containing the same |
ES2200820T3 (en) † | 1999-02-12 | 2004-03-16 | Glaxo Group Limited | PHOSPHORAMIDATE, AND MONO-, DI- AND TRI-ESTERES PHOSPHATE OF (1R, CIS) -4- (6-AMINO-9H-PURIN-9-IL) -2-CYCLOPENTEN-1-METHANOL IN QUALITY OF ANTIVIRAL AGENTS. |
PT1301519E (en) * | 2000-07-21 | 2015-06-11 | Gilead Sciences Inc | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
EP1345956A2 (en) * | 2000-10-13 | 2003-09-24 | University of Lausanne | Intracellular delivery of biological effectors by novel transporter peptide sequences |
US20020119433A1 (en) * | 2000-12-15 | 2002-08-29 | Callender Thomas J. | Process and system for creating and administering interview or test |
-
2001
- 2001-07-20 PT PT1961695T patent/PT1301519E/en unknown
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0481214A1 (en) | 1990-09-14 | 1992-04-22 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
US5663159A (en) | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
WO1995007920A1 (en) | 1993-09-17 | 1995-03-23 | Gilead Sciences, Inc. | Nucleotide analogs |
US5798340A (en) | 1993-09-17 | 1998-08-25 | Gilead Sciences, Inc. | Nucleotide analogs |
WO1996029336A1 (en) | 1995-03-13 | 1996-09-26 | Medical Research Council | Chemical compounds |
US5977061A (en) | 1995-04-21 | 1999-11-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | N6 - substituted nucleotide analagues and their use |
US5977089A (en) | 1996-07-26 | 1999-11-02 | Gilead Sciences, Inc. | Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability |
Non-Patent Citations (10)
Title |
---|
AARONS, L.; BODDY, A.; PETRAK, K.: "Novel Drug Delivery and Its Therapeutic Application", 1989, pages: 121 - 126 |
BANERJEE, P. K.; AMIDON, G. L.: "Design of Prodrugs", 1985, pages: 118 - 121 |
BUNDGAARD, H.: "Design of Prodrugs", 1985, pages: 70 - 74,79-92 |
CONNORS, T. A.: "Design of Prodrugs", 1985, pages: 291 - 316 |
JONES, G.: "Design of Prodrugs", 1985, pages: 199 - 241 |
NOTARI, R. E.: "Design of Prodrugs", 1985, pages: 135 - 156 |
OLIYAI ET AL., PHARMACEUTICAL RESEARCH, vol. 16, no. 11, 1999, pages 1687 - 1693 |
See also references of EP1301519A2 |
STELLA ET AL., J. MED. CHEM., vol. 23, no. 12, 1980, pages 1275 - 1282 |
STELLA, V. J.; HIMMELSTEIN, K. J: "Design of Prodrugs", 1985, pages: 177 - 198 |
Cited By (165)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7803788B2 (en) | 2000-07-21 | 2010-09-28 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucoleotide analogues |
US7390791B2 (en) * | 2000-07-21 | 2008-06-24 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues |
WO2004096818A2 (en) * | 2002-04-26 | 2004-11-11 | Gilead Sciences, Inc. | Method and compositions for identifying anti-hiv therapeutic compounds |
WO2004096818A3 (en) * | 2002-04-26 | 2005-04-07 | Gilead Sciences Inc | Method and compositions for identifying anti-hiv therapeutic compounds |
US7462608B2 (en) | 2002-04-26 | 2008-12-09 | Gilead Sciences, Inc. | Non nucleoside reverse transcriptase inhibitors |
US7649015B2 (en) | 2002-04-26 | 2010-01-19 | Gilead Sciences, Inc. | Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds |
US7214668B2 (en) | 2002-05-13 | 2007-05-08 | Metabasis Therapeutics, Inc. | Phosphonic acid based prodrugs of PMEA and its analogues |
JP2006515624A (en) * | 2003-01-14 | 2006-06-01 | ギリアード サイエンシーズ, インコーポレイテッド | Compositions and methods for combination antiviral therapy |
US8716264B2 (en) * | 2003-01-14 | 2014-05-06 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US9744181B2 (en) | 2003-01-14 | 2017-08-29 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
WO2004064846A1 (en) * | 2003-01-14 | 2004-08-05 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US9457036B2 (en) * | 2003-01-14 | 2016-10-04 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US8592397B2 (en) * | 2003-01-14 | 2013-11-26 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
EP3025718A1 (en) | 2003-01-14 | 2016-06-01 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
EP1923063A2 (en) | 2003-01-14 | 2008-05-21 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US20150111855A1 (en) * | 2003-01-14 | 2015-04-23 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US7429565B2 (en) | 2003-04-25 | 2008-09-30 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
US7427636B2 (en) | 2003-04-25 | 2008-09-23 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
US8871785B2 (en) | 2003-04-25 | 2014-10-28 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
WO2005002626A2 (en) * | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
WO2005002626A3 (en) * | 2003-04-25 | 2005-05-26 | Gilead Sciences Inc | Therapeutic phosphonate compounds |
US7417055B2 (en) | 2003-04-25 | 2008-08-26 | Gilead Sciences, Inc. | Kinase inhibitory phosphonate analogs |
US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
WO2004096286A3 (en) * | 2003-04-25 | 2005-06-16 | Gilead Sciences Inc | Antiviral phosphonate analogs |
US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
US7273716B2 (en) | 2003-04-25 | 2007-09-25 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds with GS-7340 ester hydrolase |
US7645747B2 (en) | 2003-04-25 | 2010-01-12 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
US7300924B2 (en) | 2003-04-25 | 2007-11-27 | Gilead Sciences, Inc. | Anti-infective phosphonate analogs |
US8022083B2 (en) | 2003-04-25 | 2011-09-20 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
EA014685B1 (en) * | 2003-04-25 | 2010-12-30 | Джилид Сайэнс, Инк. | Phosphonate-containing antiviral compounds (variants) and pharmaceutical composition based thereon |
US7273717B2 (en) | 2003-10-24 | 2007-09-25 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds with GS-9005 ester hydrolase B |
US7273715B2 (en) | 2003-10-24 | 2007-09-25 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds with GS-9005 ester hydrolase A |
US7432273B2 (en) | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
US7427624B2 (en) | 2003-10-24 | 2008-09-23 | Gilead Sciences, Inc. | Purine nucleoside phosphorylase inhibitory phosphonate compounds |
US7432272B2 (en) | 2003-12-22 | 2008-10-07 | Gilead Sciences, Inc. | Antiviral analogs |
WO2005072748A1 (en) * | 2004-01-21 | 2005-08-11 | Gilead Sciences, Inc. | Use of adefovir or tenofovir for inhibiting mmtv-like viruses involved in breast cancer and primary biliary cirrhosis |
US7582758B2 (en) | 2004-06-08 | 2009-09-01 | Metabasis Therapeutics, Inc. | Lewis acid mediated synthesis of cyclic esters |
CN100359315C (en) * | 2005-05-26 | 2008-01-02 | 林维宣 | Animal remedy residual ability verification sample and method for preparing same |
US9018192B2 (en) | 2005-06-13 | 2015-04-28 | Bristol-Myers Squibb & Gilead Sciences, Inc. | Unitary pharmaceutical dosage form |
US9545414B2 (en) | 2005-06-13 | 2017-01-17 | Bristol-Myers Squibb & Gilead Sciences, Llc | Unitary pharmaceutical dosage form |
US8598185B2 (en) | 2005-06-13 | 2013-12-03 | Bristol-Myers Squibb & Gilead Sciences, Inc. | Unitary pharmaceutical dosage form |
US8871271B2 (en) | 2005-06-13 | 2014-10-28 | Gilead Sciences, Inc. | Method and composition for pharmaceutical product |
US8435969B2 (en) | 2006-05-16 | 2013-05-07 | Gilead Sciences, Inc. | Method and compositions for treating hematological malignancies |
US8735372B2 (en) | 2007-03-30 | 2014-05-27 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US9085573B2 (en) | 2007-03-30 | 2015-07-21 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US11642361B2 (en) | 2007-03-30 | 2023-05-09 | Gilead Sciences, Inc. | Nucleoside phosphoramidate prodrugs |
US10183037B2 (en) | 2007-03-30 | 2019-01-22 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
EP2308885A2 (en) | 2008-02-20 | 2011-04-13 | Gilead Sciences, Inc. | Novel compounds and methods for therapy |
US9783568B2 (en) | 2008-07-08 | 2017-10-10 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
US9637512B2 (en) | 2009-05-20 | 2017-05-02 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US9206217B2 (en) | 2009-05-20 | 2015-12-08 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US9284342B2 (en) | 2009-05-20 | 2016-03-15 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US10988498B2 (en) | 2009-09-21 | 2021-04-27 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs |
US9090642B2 (en) | 2010-07-19 | 2015-07-28 | Gilead Sciences, Inc. | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
US9487544B2 (en) | 2010-07-19 | 2016-11-08 | Gilead Sciences, Inc. | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
US11492353B2 (en) | 2010-07-22 | 2022-11-08 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
US10696679B2 (en) | 2010-07-22 | 2020-06-30 | Gilead Sciences, Inc. | Methods and compounds for treating paramyxoviridae virus infections |
US10065958B2 (en) | 2010-07-22 | 2018-09-04 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
EP3199537A1 (en) | 2011-05-19 | 2017-08-02 | Gilead Sciences, Inc. | Processes and intermediates for preparing anti-hiv agents |
US8987437B2 (en) | 2011-05-19 | 2015-03-24 | Gilead Sciences, Inc. | Processes and intermediates for preparing anti-HIV Agents |
US9783567B2 (en) | 2011-05-19 | 2017-10-10 | Gilead Sciences, Inc. | Processes and intermediates for preparing anti-HIV agents |
EP3450438A1 (en) | 2011-05-19 | 2019-03-06 | Gilead Sciences, Inc. | Processes and intermediates for preparing anti-hiv agents |
US9296779B2 (en) | 2011-05-19 | 2016-03-29 | Gilead Sciences, Inc. | Processes and intermediates for preparing anti-HIV agents |
US10196419B2 (en) | 2011-05-19 | 2019-02-05 | Gilead Sciences, Inc. | Processes and intermediates for preparing anti-HIV agents |
AU2012296622C1 (en) * | 2011-08-16 | 2017-02-16 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
EA027768B1 (en) * | 2011-08-16 | 2017-08-31 | Джилид Сайэнс, Инк. | Tenofovir alafenamide hemifumarate |
JP2016169228A (en) * | 2011-08-16 | 2016-09-23 | ギリアード サイエンシス インコーポレーテッド | Tenofovir alafenamide hemifumarate |
US8754065B2 (en) | 2011-08-16 | 2014-06-17 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
EP2744810B1 (en) | 2011-08-16 | 2016-10-05 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
KR101612642B1 (en) | 2011-08-16 | 2016-04-14 | 길리애드 사이언시즈, 인코포레이티드 | Tenofovir alafenamide hemifumarate |
AU2012296622B2 (en) * | 2011-08-16 | 2014-09-11 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
US9296769B2 (en) | 2011-08-16 | 2016-03-29 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
JP2018065870A (en) * | 2011-08-16 | 2018-04-26 | ギリアード サイエンシス インコーポレーテッド | Tenofovir alafenamide hemifumarate |
AU2014271320B2 (en) * | 2011-08-16 | 2017-02-23 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
JP2014528924A (en) * | 2011-08-16 | 2014-10-30 | ギリアード サイエンシス インコーポレーテッド | Tenofovir arafenamide hemifumarate |
AP3639A (en) * | 2011-08-16 | 2016-03-13 | Gilead Sciences Inc | Tenofovir alafenamide hemifumarate |
JP2015038149A (en) * | 2011-08-16 | 2015-02-26 | ギリアード サイエンシス インコーポレーテッド | Tenofovir alafenamide hemifumarate |
EP3070088A1 (en) * | 2011-08-16 | 2016-09-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
WO2013025788A1 (en) * | 2011-08-16 | 2013-02-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
EP3831832A1 (en) * | 2011-08-16 | 2021-06-09 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
US10456414B2 (en) | 2011-09-16 | 2019-10-29 | Gilead Pharmasset Llc | Methods for treating HCV |
US10035814B2 (en) | 2011-12-22 | 2018-07-31 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US10562926B2 (en) | 2011-12-22 | 2020-02-18 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US9593137B2 (en) | 2011-12-22 | 2017-03-14 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US11279720B2 (en) | 2011-12-22 | 2022-03-22 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
EP2891658A4 (en) * | 2012-08-30 | 2016-04-27 | Jiangsu Hansoh Pharmaceutical | Tenofovir prodrug and pharmaceutical uses thereof |
WO2014032481A1 (en) | 2012-08-30 | 2014-03-06 | 上海源力生物技术有限公司 | Tenofovir prodrug and pharmaceutical uses thereof |
WO2014033688A1 (en) * | 2012-09-03 | 2014-03-06 | Ithemba Pharmaceuticals (Proprietary) Limited | A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa) |
AU2013340559B2 (en) * | 2012-10-29 | 2018-03-15 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
US9227990B2 (en) | 2012-10-29 | 2016-01-05 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
WO2014068265A1 (en) * | 2012-10-29 | 2014-05-08 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US9676803B2 (en) | 2013-06-07 | 2017-06-13 | Cipla Limited | Efficient process for separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine |
WO2014195724A1 (en) | 2013-06-07 | 2014-12-11 | Cipla Limited | An efficient process for separation of diastereomers of 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy]propyl]adenine |
US11707479B2 (en) | 2013-08-27 | 2023-07-25 | Gilead Sciences, Inc. | Combination formulation of two antiviral compounds |
US11116783B2 (en) | 2013-08-27 | 2021-09-14 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
WO2015040640A3 (en) * | 2013-09-20 | 2015-06-04 | Laurus Labs Private Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
WO2015079455A3 (en) * | 2013-11-27 | 2015-08-27 | Laurus Labs Private Limited | A recycling process for preparing tenofovir alafenamide diastereomers |
US11278559B2 (en) | 2014-02-13 | 2022-03-22 | Ligand Pharmaceuticals Incorporated | Prodrug compounds and their uses |
US10449210B2 (en) | 2014-02-13 | 2019-10-22 | Ligand Pharmaceuticals Inc. | Prodrug compounds and their uses |
WO2015197006A1 (en) * | 2014-06-25 | 2015-12-30 | 四川海思科制药有限公司 | Substituted amino acid thioester compound, and composition and application thereof |
US9994600B2 (en) | 2014-07-02 | 2018-06-12 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
US10150788B2 (en) | 2014-07-02 | 2018-12-11 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses thereof |
JP2017535520A (en) * | 2014-09-30 | 2017-11-30 | ハンミ・ファイン・ケミカル・カンパニー・リミテッドHanmi Fine Chemical Co., Ltd. | Method for producing high purity (R) -9- [2- (phosphonomethoxy) propyl] adenine |
US10695357B2 (en) | 2014-10-29 | 2020-06-30 | Gilead Sciences, Inc. | Methods for treating filoviridae virus infections |
US11344565B2 (en) | 2014-10-29 | 2022-05-31 | Gilead Sciences, Inc. | Methods for the preparation of ribosides |
US9724360B2 (en) | 2014-10-29 | 2017-08-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US9949994B2 (en) | 2014-10-29 | 2018-04-24 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US10251898B2 (en) | 2014-10-29 | 2019-04-09 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US11266666B2 (en) | 2014-10-29 | 2022-03-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US10233202B2 (en) | 2015-05-29 | 2019-03-19 | Jiangsu Tasly Diyi Pharmaceutical Co., Ltd. | Tenofovir monobenzyl ester phosphamide prodrug, preparation method and use thereof |
WO2016192692A1 (en) | 2015-06-05 | 2016-12-08 | Zentiva K.S. | Solid forms of tenofovir alafenamide |
EP4070788A1 (en) | 2015-06-30 | 2022-10-12 | Gilead Sciences, Inc. | Pharmaceutical formulations |
EP4070787A1 (en) | 2015-06-30 | 2022-10-12 | Gilead Sciences, Inc. | Pharmaceutical formulations |
EP4233846A2 (en) | 2015-06-30 | 2023-08-30 | Gilead Sciences, Inc. | Pharmaceutical formulations |
EP3607939A1 (en) | 2015-06-30 | 2020-02-12 | Gilead Sciences, Inc. | Pharmaceutical formulations |
TWI620754B (en) * | 2015-08-26 | 2018-04-11 | Method for preparing amino phosphate derivative and preparation method thereof | |
TWI616453B (en) * | 2015-08-27 | 2018-03-01 | Substituted amino acid thioester compounds, materials and uses thereof | |
US11382926B2 (en) | 2015-09-16 | 2022-07-12 | Gilead Sciences, Inc. | Methods for treating Arenaviridae and Coronaviridae virus infections |
US10695361B2 (en) | 2015-09-16 | 2020-06-30 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US10251904B2 (en) | 2015-09-16 | 2019-04-09 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US11007208B2 (en) | 2015-09-16 | 2021-05-18 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
EP3632415A1 (en) | 2015-11-09 | 2020-04-08 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
WO2017083304A1 (en) | 2015-11-09 | 2017-05-18 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
CN106800573A (en) * | 2015-11-25 | 2017-06-06 | 四川海思科制药有限公司 | A kind of phosphonate-nucleotide ester monohydrate and preparation method thereof and in application pharmaceutically |
CN106866737B (en) * | 2015-12-11 | 2020-11-20 | 南京圣和药物研发有限公司 | Phosphonic acid derivatives and their use |
CN106866737A (en) * | 2015-12-11 | 2017-06-20 | 南京圣和药业股份有限公司 | Phosphonate derivative and its application |
WO2017118928A1 (en) | 2016-01-06 | 2017-07-13 | Lupin Limited | Process for the separation of diastereomers of tenofovir alafenamide |
WO2017134089A1 (en) | 2016-02-02 | 2017-08-10 | Sandoz Ag | Crystalline forms of tenofovir alafenamide monofumarate |
WO2017157352A1 (en) | 2016-03-17 | 2017-09-21 | Zentiva, K.S. | A preparation method of diastereomerically pure tenofovir alafenamide or its salts |
WO2018115046A1 (en) | 2016-12-23 | 2018-06-28 | Sandoz Ag | Crystalline solid forms of tenofovir alafenamide |
US11440928B2 (en) | 2017-01-31 | 2022-09-13 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
WO2018144390A1 (en) | 2017-01-31 | 2018-08-09 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
US10287307B2 (en) | 2017-01-31 | 2019-05-14 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
WO2018153977A1 (en) | 2017-02-24 | 2018-08-30 | Hexal Ag | Stable composition of tenofovir alafenamide |
WO2018160088A1 (en) | 2017-02-28 | 2018-09-07 | Александр Васильевич ИВАЩЕНКО | Nucleotides containing an n-[(s)-1-cyclobutoxycarbonyl]phosphoramidate fragment, analogs thereof, and use thereof |
US11260070B2 (en) | 2017-03-14 | 2022-03-01 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
US10682368B2 (en) | 2017-03-14 | 2020-06-16 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
US10836787B2 (en) | 2017-05-01 | 2020-11-17 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate |
US11597742B2 (en) | 2017-05-01 | 2023-03-07 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate |
US11975017B2 (en) | 2017-07-11 | 2024-05-07 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US10675296B2 (en) | 2017-07-11 | 2020-06-09 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US11266681B2 (en) | 2017-07-11 | 2022-03-08 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US10851125B2 (en) | 2017-08-01 | 2020-12-01 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate |
US11970482B2 (en) | 2018-01-09 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
WO2021011891A1 (en) | 2019-07-18 | 2021-01-21 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
WO2021035214A1 (en) * | 2019-08-22 | 2021-02-25 | Emory University | Nucleoside prodrugs and uses related thereto |
US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
WO2021165995A1 (en) | 2020-02-20 | 2021-08-26 | Cipla Limited | Novel salts and/or co-crystals of tenofovir alafenamide |
US11613553B2 (en) | 2020-03-12 | 2023-03-28 | Gilead Sciences, Inc. | Methods of preparing 1′-cyano nucleosides |
WO2021202669A2 (en) | 2020-04-01 | 2021-10-07 | Reyoung Corporation | Nucleoside and nucleotide conjugate compounds and uses thereof |
US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
US11566041B2 (en) | 2020-04-21 | 2023-01-31 | Ligand Pharmaceuticals, Inc. | Nucleotide prodrug compounds |
US11975012B2 (en) | 2020-05-29 | 2024-05-07 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11491169B2 (en) | 2020-05-29 | 2022-11-08 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11903953B2 (en) | 2020-05-29 | 2024-02-20 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
US11926645B2 (en) | 2020-08-27 | 2024-03-12 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11667656B2 (en) | 2021-01-27 | 2023-06-06 | Apotex Inc. | Crystalline forms of Tenofovir alafenamide |
US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
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