WO2018055071A1 - Promédicaments de phosphonates de nucléosides acycliques fluorés - Google Patents
Promédicaments de phosphonates de nucléosides acycliques fluorés Download PDFInfo
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- WO2018055071A1 WO2018055071A1 PCT/EP2017/073988 EP2017073988W WO2018055071A1 WO 2018055071 A1 WO2018055071 A1 WO 2018055071A1 EP 2017073988 W EP2017073988 W EP 2017073988W WO 2018055071 A1 WO2018055071 A1 WO 2018055071A1
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- Prior art keywords
- alkyl
- mmol
- mhz
- nmr
- virus
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- -1 fluorinated acyclic nucleoside phosphonates Chemical class 0.000 title abstract description 107
- 239000002777 nucleoside Substances 0.000 title abstract description 15
- 229940002612 prodrug Drugs 0.000 title abstract description 15
- 239000000651 prodrug Substances 0.000 title abstract description 15
- 241000700721 Hepatitis B virus Species 0.000 claims abstract description 22
- 241000701085 Human alphaherpesvirus 3 Species 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 19
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- 230000009385 viral infection Effects 0.000 claims abstract description 16
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- 208000015181 infectious disease Diseases 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 129
- 238000000034 method Methods 0.000 claims description 73
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 42
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 40
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 32
- 229940104302 cytosine Drugs 0.000 claims description 26
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 24
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 18
- 229930024421 Adenine Natural products 0.000 claims description 16
- 241001465754 Metazoa Species 0.000 claims description 16
- 229960000643 adenine Drugs 0.000 claims description 16
- 241000282414 Homo sapiens Species 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 15
- 230000002265 prevention Effects 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 229940113082 thymine Drugs 0.000 claims description 13
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 150000003254 radicals Chemical class 0.000 claims description 11
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- 125000004429 atom Chemical group 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
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- 229940079593 drug Drugs 0.000 claims description 6
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- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 abstract description 4
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- 238000004519 manufacturing process Methods 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 225
- 229910052739 hydrogen Inorganic materials 0.000 description 141
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 137
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- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 75
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- 238000004440 column chromatography Methods 0.000 description 67
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- BBHJTCADCKZYSO-UHFFFAOYSA-N 4-(4-ethylcyclohexyl)benzonitrile Chemical compound C1CC(CC)CCC1C1=CC=C(C#N)C=C1 BBHJTCADCKZYSO-UHFFFAOYSA-N 0.000 description 46
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- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 38
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- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 28
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 28
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- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 25
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 20
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- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
-
- 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
Definitions
- the present invention relates to novel phosphonoamidate prodrugs of acyclic nucleoside phosphonates with a 3-fluoro-2-(phosphonomethoxy)propyl side chain.
- the invention also relates to the use of these novel phosphonate-modified nucleosides to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with viruses such as the hepatitis B virus, the human immunodeficiency virus, the human cytomegalovirus and the varicella zoster virus.
- Acyclic nucleoside phosphonates are a key class of antiviral drugs. Their main structural features are : (1 ) an aliphatic side chain instead of the cyclic sugar moiety and (2) the presence of a phosphonate group, attached to this acyclic nucleoside moiety.
- the phosphonomethoxy functionality (P-C-O), as present in the ANPs, can be considered as an isoster of the naturally occurring phospho-oxymethyl (P-O-C) moiety in nucleosidemonophosphate.
- P-O-C phospho-oxymethyl
- a phosphonate is not susceptible to phosphodiesterase and phosphatase hydrolysis and hence is enzymatically stable.
- the success of this motif is due to the fact that it is isopolar and isosteric with the phosphate group. Hence, they can undergo enzymatic phosphorylation that converts them into the corresponding phosphonate diphosphates, which act as analogues of the natural nucleoside triphosphates.
- ANPs As this phosphonate moiety is a phosphate mimicking group, ANPs only need two (instead of three for regular nucleoside analogues) phosphorylation steps to reach their biologically active stage. This is advantageous as the first phosphorylation is very often inefficient and rate-limiting in the formation of nucleoside-triphosphate. Flexibility in the acyclic sugar side chain allows these compounds, once dephosphorylated to adopt a conformation appropriate for interaction with the active sites of DNA polymerase or reverse transcriptase.
- Cidofovir HPMPC, (S)-1 -(3-hydroxy-2-phosphonylmethoxypropyl)cytosine
- Cidofovir received marketing approval for the treatment of CMV retinitis in AIDS patients.
- Adefovir PMEA, 9-(2-phosphonylmethoxyethyl)adenine
- PMPA tenofovir
- R tenofovir
- ANPs with a fluorinated side chain have been synthesized and tested for antiviral activity.
- the best studied class of fluorinated ANPs are the 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) derivatives.
- FPMP 3-fluoro-2-(phosphonomethoxy)propyl
- Both enantiomers of FPMPA and FPMPG Figure 2) are completely devoid of antiviral activity against a broad range of DNA viruses (HSV-1 , HSV-2, CMV, VZV, VV).
- (S)-FPMPA shows potent and selective antiviral activity against HIV-1 and HIV-2, with EC50 values in the 8 ⁇ range.
- Phosphonates are negatively charged at physiological pH and hence, are not able to penetrate the lipid-rich cell membrane, which hampers their antiviral activity.
- Various prodrug or 'pronucleotide' approaches have been investigated to promote passive diffusion through the lipophilic cell membranes and to liberate the parent nucleotide intracellular ⁇ , where it can be further phosphorylated to the pharmacologically active species.
- the present invention is based on the unexpected finding that phosphoramidate prodrugs of fluorinated ANPs with a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain show unexpected biological properties, in particular have significant antiviral activity against the hepatitis B virus, the human immunodeficiency virus, the human cytomegalovirus and the varicella zoster virus.
- FPMP 3-fluoro-2-(phosphonomethoxy)propyl
- the present invention relates to novel phosphoramidate and phosphorodiamidate prodrugs of acyclic nucleoside phosphonates (ANPs), and their use as agents for treating viral diseases. It is based on the unexpected finding that certain nucleoside prodrugs show unexpected biological properties, in particular have significant activity against the hepatitis B virus, the human immunodeficiency virus, the human cytomegalovirus and the varicella zoster virus.
- B is any natural or modified nucleobase
- R 1 has the general formula I I
- R 3 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, Cs-Cs-cycloalkyl, C3- Cs-cycloalkyl-alkyl, aryl(Ci-C6)alkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl C1-C10 alkyl, halo C1-C10 alkyl, and alkoxyalkyl;
- X is aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or Cs-Cs-cycloalkyl, and wherein said aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, Cs-Cs-cycloalkyl optionally contains one or more functions, atoms or radicals independently selected from the group consisting of halogen, halo-alkyl, cyano, C1-C7 alkoxy; and
- R 5 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, Cs-Cs- cycloalkyl, C3-Cscycloalkyl-alkyl, aryl(Ci-C6)alkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl Ci- C10 alkyl, halo C1-C10 alkyl, and alkoxyalkyl;
- R 2 is O-Ar, wherein Ar is a fused bicyclic aryl moiety or a monocyclic aryl moiety, either of which aryl moieties is carbocyclic or heterocyclic and is optionally substituted with a halogen, C1-C6 alkyl, C1-C6 alkoxy;
- R 2 has the general formula I I wherein R 1 and R 2 can be identical or different; and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
- R 4 is X-COOR 5 and wherein X is aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or Cs-Cs-cycloalkyl, and wherein said aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, Cs-Cs-cycloalkyl optionally contains one or more functions, atoms or radicals independently selected from the group consisting of halogen, halo-alkyl, cyano, C1-C7 alkoxy; and wherein R 5 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, Cs-Cs-cycloalkyl, C3-Cscycloalkyl-alkyl, aryl(Ci-C6)alkyl, C2-C10 alkenyl,
- HBV hepatitis B virus
- HCV human immunodeficiency virus
- VZV varicella-zoster virus
- CMV cytomegalovirus
- VV vaccinia virus
- HSV herpes simplex virus
- BK virus Epstein-barr virus
- ESV Epstein-barr virus
- papillomavirus Monkeypox virus
- Cowpox virus hepatitis C virus
- RSV respiratory syncytial virus
- dengue virus influenza virus, adenovirus, parainfluenza virus and/or rhinovirus.
- a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of statements 1 to 8 and one or more pharmaceutically acceptable excipients.
- composition according to statement 13 further comprising one or more biologically active drugs being selected from the group consisting of antiviral drugs and/or anti-proliferative drugs.
- a method of prevention or treatment of a viral infection in an animal, mammal or human comprising the administration of a therapeutically effective amount of a compound according to any one of statements 1 to 8, optionally in combination with one or more pharmaceutically acceptable excipients.
- a method of prevention or treatment of a proliferative disorder in an animal, mammal or human comprising the administration of a therapeutically effective amount of a compound according to any one of statements 1 to 8, optionally in combination with one or more pharmaceutically acceptable excipients.
- Scheme 1 schematically shows a method for the synthesis of the acyclic fluorinated phosphonate esters 4a/b that are the key building blocks for the preparation of ANPs bearing a 3-fluoro-2-(phosphonomethoxy)propyl side chain. They were prepared according to a modified literature report (Baszczynski, O.; Jansa, P.; Dracinsky, M.; Klepetarova, B.; Holy, A.; Votruba, I.; Clerck, E, D.; Balzarini, J.; Janeba, Z. Bioorg. Med. Chem.
- Reagents and conditions (a) KHF 2 , PhCI, cat. BU4NH2F3, 135 °C, 15 h; (b) diethyl tosyloxymethylphosphonate, NaH, THF, 0 °C to rt, 5 h; (c) 80% AcOH, 90 °C, 1 h.
- Scheme 2 shows a method for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl ANP with thymidine as nucleobase. Condensation of 4a/b with A ⁇ -Bom-thymine delivered compounds 6a/b in high yields. Removal of the A ⁇ -Bom group by catalytic hydrogenation using 10% palladium on carbon provided compounds 7a/b, which was followed by hydrolysis of the diester groups with TMSBr in dry acetonitrile overnight to form the corresponding phosphonate acids 8a/b.
- Reagents and conditions (a) Ph 3 P, DIAD, THF, rt, 12 h; (b) Pd/C, H 2 , EtOH, rt, 24 h; (c) TMSBr, 2,6-lutidine, CH 3 CN, rt, 12 h.
- Scheme 3 shows a method for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl ANPs with adenine as nucleobase. Mitsunobu reaction in the presence of 6-chloropurine proceeded smoothly affording compounds 10a/b in 60% and 65% yield, respectively. The chloropurine moiety was then converted into adenine by treatment with NH3 in EtOH under pressure, and finally the phosphonate esters were cleaved with TMSBr to provide compounds 12a/b in 65 and 70% yields, respectively.
- Scheme 4 shows a method for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl ANP with cytosine as nucleobase. Moderate yields were achieved with /V sobutyrylcytosine along with the unexpected formation of O-2-alkylated products 15a/b (ratio 1 :1 , 0-2:/V-1 alkylation). After the removal of the /V sobutyryl protecting groups in ⁇ / ⁇ and cleavage of the phosp
- Reagents and conditions (a) Ph 3 P, DIAD, THF, rt, 12 h; (b) NH 3 /MeOH, 45 °C, 15 h; (c) TMSBr, 2,6-lutidine, CH 3 CN, rt, 12 h.
- Scheme 5 shows a method for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl ANPs with guanosine as nucleobase.
- the reaction between 6-O-benzylguanine 20 and compounds 4a/b gave a mixture of compounds 21 a/b and the corresponding triphenylphosphine adducts (not shown).
- This crude mixture residue was then refluxed for several hours in THF/H2O to remove the undesired triphenylphosphine adducts.
- Sequential removal of the 6-O-benzyl protecting group using 10% palladium on carbon and treatment with TMSBr provided the desired products.
- Reagents and conditions (a) Ph 3 P, DIAD, THF, rt, 12 h; (b) Pd/C, H 2 , EtOAc, 10 h.; (c) TMSBr, 2,6-lutidine, CH 3 CN, rt, 12 h.
- Reagents and conditions (a) L-Aspartic acid amyl diester HCI salt, PhOH, 2,2'-dithiodipyridine, PPh 3 , Et 3 N, Pyr, 60 °C, 12 h.
- Reagents and conditions (a) L-Aspartic acid amyl diester HCI salt, PhOH, 2,2'-dithiodipyridine, PPh 3 , Et 3 N, Pyr, 60 °C, 12 h; (b) 1 M HCI, 0 °C to rt, 1 h.
- Scheme 8 shows a method for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl ANPs with 2-amino-6-(4-methoxy-thiophenol)purine as nucleobase.
- 2-amino-6-chloropurine 30 condensed with precursors 4a/b to provide compounds 31 a/b with the concomitant formation of the corresponding triphenylphosphine adducts.
- Reagents and conditions (a) (i) Ph 3 P, DIAD, THF, rt, 24 h; (ii) THF/H 2 0, reflux, 24 h; (b) Et 3 N, DMF, 100 °C, 4 h; (c) TMSBr, 2,6-lutidine, CH 3 CN, rt, 12 h.
- Scheme 9 shows a method for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl ANPs with 7-deaza-guanine and 7-deaza-7-fluoro-guanine as nucleobase.
- the preparation of 4- chloro-5-fluoro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidine 35 started from commercially available 30.
- Selectfluor was chosen as a fluorinating reagent following a literature protocol (Seela, F.; Xu, K.; Chittepu, P.
- Fluorinated pyrrolo[2,3-d]pyrimidine nucleosides 7-fluoro-7- deazapurine 2'-deoxyribofuranosides and 2'-deoxy-2'-fluoroarabinofuranosyl derivatives. Synthesis 2006, 12, 2005-2012).
- the phosphonate diethyl esters 36a/b and 37a/b were prepared using the standard Mitsunobu conditions (Ph 3 P, DIAD). Sequential replacement of chloro with hydroxyl and deprotection of pivaloyl group was achieved by DABCO/K2C0 3 and NH 3 /MeOH, respectively, affording compounds 38a/b and 39a/b. Hydrolysis of the phosphonate esters groups yielded compounds 40a/b and 41a/b.
- Scheme 10 shows a method for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl ANPs with 7-deaza-7-cyano-guanine as nucleobase.
- Synthesis of the heterocyclic building block 46 (Llona-Minguez, S.; Mackay, S. P. Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQO).
- PreQO nucleoside Q precursor
- Beilstein J. Org. Chem. 2014, 10, 1333-1338 started by formylation of chloroacetonitrile 42 with methyl formate.
- the resulting unstable chloroaldehyde 43 was used for the next step immediately without further purification to afford cyclocondensation compound 44.
- Reagents and conditions (a) Methyl formate, NaH, THF, 0 °C, 5 h; (b) 2,6-diamino-6- hydroxyprimidine, NaOAc, H 2 0, 100 °C, 24 h; (c) PivCI, Pyr, 85 °C, 2 h; (d) POCI 3 , DMA, BnEtsNCI, MeCN, 90 °C, 1 h.
- Scheme 11 shows a method for synthesizing an aryloxyphosphonoamidate prodrug 50 and a phosphonobisamidate prodrug 51 , from the corresponding free phosphonic acid 40a.
- Compound 51 was prepared from the parent nucleoside phosphonate 40a using 2,2'- dithiodipyridine and triphenylphosphine as activating agents and utilizing a mixture of phenol and the appropriate amino acid ester.
- the phosphonobisamidate prodrug 51 was prepared in a similar way, using the desired amino acid ester.
- Reagents and conditions (a) L-Aspartic acid amyl diester HCI salt, PhOH, 2,2'-dithiodipyridine, PPh 3 , Et 3 N, Pyr, 60 °C, 12 h for 50; L-Aspartic acid amyl diester HCI salt, 2,2'-dithiodipyridine, PPh 3 , Et 3 N, Pyr, 60 °C, 12 h for 51.
- the present invention encompasses compounds of the general formula I :
- B is any natural or modified nucleobase
- R 1 has the general formula II
- R 3 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, Cs-Cs-cycloalkyl, C3- Cs-cycloalkyl-alkyl, aryl(Ci-C6)alkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl C1-C10 alkyl, halo C1-C10 alkyl, and alkoxyalkyl;
- X is aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or Cs-Cs-cycloalkyl, and wherein said aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, Cs-Cs-cycloalkyl optionally contains one or more functions, atoms or radicals independently selected from the group consisting of halogen, halo-alkyl, cyano, C1-C7 alkoxy; and wherein R 5 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, C3-C8- cycloalkyl, Cs-Cscycloalkyl-alkyl, aryl(Ci-C6)alkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl Ci- C10 alkyl, hal
- R 2 is O-Ar, wherein Ar is a fused bicyclic aryl moiety or a monocyclic aryl moiety, either of which aryl moieties is carbocyclic or heterocyclic and is optionally substituted with a halogen, C1-C6 alkyl, C1-C6 alkoxy;
- R 2 has the general formula II
- R 1 and R 2 can be identical or different
- Said base (B) is selected from the group of the pyrimidine and purine bases.
- bases include natural bases, such as adenine, thymine, cytosine, uracyl, guanine and modified bases or modifications of said natural bases.
- said base is a guanine, cytosine, adenine, thymine, cytosine, or uracyl.
- said base is a adenine or guanine.
- said base is a cytosine.
- said base is a thymine.
- said base is uracil.
- said base is attached to the rest of the compound via its nitrogen atom, such as in examples 31 , 32, 33, 34, 35, 36, 39, 40, 67 and 68.
- said base is attached to the rest of the compound via an oxygen atom, such as in examples 37 and 38.
- said base (attached to the rest of formula I via its oxygen atom) is selected from the list consisting of:
- R is selected from the group consisting of H , halogen, and methyl.
- said base is
- R 1 and R 2 can have any values as described herein.
- the present invention concerns a compound according to the invention, including the compound of formula I, lb, or any subgroup thereof, wherein Ar is a fused bicyclic aryl moiety or a monocyclic aryl moiety, either of which aryl moieties is carbocyclic or heterocyclic and is optionally substituted with a halogen, C1-C6 alkyl, C1-C6 alkoxy.
- said Ar is phenyl.
- the compound of formula I, lb, or any subgroup thereof can have any value for R 1 as described herein, wherein Ar is phenyl.
- R 3 is C1-C10 alkyl. In another specific embodiment said R 3 is C3-C10 alkyl. In another specific embodiment said R 3 is C1-C5 alkyl. In yet another specific embodiment said R 3 is C3-C5 alkyl. In yet another specific embodiment said R 3 is C5 alkyl.
- said R 4 is selected from the group consisting of C1-C10 alkyl or X-COOR 5 , wherein R 5 can have any values as described herein.
- said R 5 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, C3- Cs-cycloalkyl, Cs-Cscycloalkyl-alkyl, aryl(Ci-C6)alkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl C1-C10 alkyl, halo C1-C10 alkyl, and alkoxyalkyl.
- R 5 is C1-C7 alkyl or C3-C8 cycloalkyi; in a more specific embodiment R 5 is C1-C5 alkyl, and in another more specific embodiment R 5 is C3-C7 alkyl, in an even more specific embodiment R 5 is C3-C5 alkyl. In a yet more specific embodiment R 5 is C5 alkyl. In another specific embodiment, R 5 is aryl- (Ci-C2)alkyl; in another more specific embodiment, R 5 is benzyl or phenyl-methyl.
- X is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl or Cs-Cs-cycloalkyl, and wherein said aryl, heteroaryl, C1-C10 alkyl, and Cs-Cs-cycloalkyl optionally contains one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocar
- X is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, or Cs-Cs-cycloalkyl, more specifically said X is a C1-C6 alkyl, even more specifically said X is a C1-C3 alkyl or C1-C2 alkyl or -CH2-.
- Special novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
- the present invention also concerns a compound having formula I , lb, or any subgroup thereof, or stereoisomeric forms thereof, for use as a medicine.
- the present invention also concerns a compound having formula I, lb, or any subgroup thereof, or stereoisomeric forms thereof, for use as a medicine for the prevention or treatment of viral disorders and oncological disorders in an animal, preferably in a mammal.
- said disorder is a viral disorder, including a disease caused by a viral infection, for example an infection with HBV, HIV, HCV, RSV, dengue virus, influenza virus, VZV, CMV, adenovirus, parainfluenza, rhinovirus, BK virus, and/or HSV; in another embodiment said disorder is an oncological disorder, which may be acute or chronic, including a proliferative disorder, especially cancer.
- said mammal is a human being.
- said compounds for use as a medicine, in particular for the prevention or treatment of viral disorders are the compounds of formula I and lb, including any subgroups thereof.
- said compounds of formula I have as a base B a pyrimidine base, more specifically a pyrimidine base represented by the structural formula
- R 7 and R 9 are independently selected from the group consisting of H, -OH, -SH, -IMH2, and - NH-Me;
- R 8 and R 10 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, hydroxyl, amino, ethylamino, trifluoromethyl, cyano and halogen; and
- X 1 and Y 1 are independently selected from CR 11 and N, wherein R 11 is selected from the group consisting of H, halogen and cyano.
- the present invention also concerns the use of the compounds of formula I, lb, or any subgroup thereof, or stereoisomeric forms thereof, for the manufacture of a medicament for the prevention or treatment of a viral disorder and/or an oncological disorder in an animal.
- said animal is a mammal, preferably said mammal is a human being.
- said viral disorder is a disease caused by a viral infection, for example an infection with HBV, HIV, HCV, RSV, dengue virus, influenza virus, CMV, VZV, adenovirus, parainfluenza, rhinovirus, BK virus, and/or HSV.
- said viral disorder is a disease caused by a viral infection with HBV and/or HIV.
- said viral disorder is a disease caused by a viral infection with HBV.
- said viral disorder is a disease caused by a viral infection with HIV1 .
- the present invention also concerns a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula I, lb, or any subgroup thereof, or stereoisomeric forms thereof and one or more pharmaceutically acceptable excipients.
- Said composition may further comprise one or more biologically active drugs being selected from the group consisting of antiviral drugs, and antineoplastic drugs.
- the present invention also concerns a method of prevention or treatment of a viral disorder in an animal, comprising the administration of a therapeutically effective amount of a compound having formula I, lb, or any subgroup thereof, or stereoisomeric forms thereof, optionally in combination with one or more pharmaceutically acceptable excipients.
- the present invention also concerns a method of prevention or treatment of an oncological disorder in an animal, comprising the administration of a therapeutically effective amount of a compound having formula I, lb, or any subgroup thereof, or stereoisomeric forms thereof, optionally in combination with one or more pharmaceutically acceptable excipients.
- the salts of the compounds of formula I or lb will be pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
- a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
- the compounds of the invention carry an acidic moiety, e.g.
- suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
- alkali metal salts e.g. sodium or potassium salts
- alkaline earth metal salts e.g. calcium or magnesium salts
- suitable organic ligands e.g. quaternary ammonium salts.
- the present invention includes within its scope solvates of the compounds of formula I and lb above.
- Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
- the solvates of the compounds of formula I and lb may be formed with water, in which case they will be hydrates.
- the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various animal, mammal or human ailments or diseases.
- viral diseases such as diseases caused by a viral infection, for example an infection with HBV, HIV, HCV, RSV, dengue virus, influenza virus, herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV or HHV-4), human cytomegalovirus (HCMV or HHV-5), human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus (KSHV, also known as HHV-8), adenovirus, parainfluenza, rhinovirus, and/or BK virus; and oncological disorders such as proliferative disorders (eg. cancer).
- viral diseases such as diseases caused by a viral infection, for example an infection with HBV,
- Viral diseases include infections caused by various families of virus, including the Hepadnaviridae, Retroviridae, Herpesviridae, Papovaviridae, Papillomaviridae or pappilomaviruses, Flaviviridae, Picornaviridae.
- Various genera within the Hepadnaviridae include the genera Orthohepadnavirus and the Avihepadnavirus; Members of the Orthohepadnavirus genus include Hepatitis B virus (HBV) and the Woodchuck hepatitis virus.
- Members of the Avihepadnavirus genus include the Duck hepatitis B virus.
- Retroviridae family Various genera within the Retroviridae family include Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus and Spumavirus.
- Lentivirus genus include human immunodeficiency virus 1 (HIV-1 ) and human immunodeficiency virus 2 (HIV-2).
- Herpesviridae family Various genera within the Herpesviridae family include (i) within the subfamily of the Alphaherpesvirinae: Varicellovirus, Scutavirus, lltovirus, Mardivirus, Simplexvirus; (ii) within the subfamily of the Betaherpesvirinae: Cytomegalovirus, Muromegalovirus, Proboscivirus, Roseolovirus; and (iii) within the subfamily of the Gammaherpesvirinae: Lymphocryptovirus, Macavirus, Percavirus, Rhadinovirus.
- Varicellovirus genus include Varicella zoster virus (VZV); Simian varicella virus; Phocine herpesvirus 1 ; Suid herpesvirus 1 ; Feline herpesvirus 1 ; Equine herpesvirus 1 , 3, 4, 8 and 9; Cervine herpesvirus 1 , and 2; Cercopithecine herpesvirus 9; Caprine herpesvirus 1 ; Bovine herpesvirus 1 and 5; Bubaline herpesvirus 1 ; Canine herpesvirus 1 .
- Members of the Simplexvirus genus include Human herpesvirus 1 and 2.
- Members of the Scutavirus genus include Chelonid herpesvirus 5.
- Members of the lltovirus genus include Gallid herpesvirus 1 .
- Members of the Mardivirus genus include Gallid herpesvirus 2.
- Members of the Cytomegalovirus genus include Human cytomegalovirus (CMV).
- Members of the Proboscivirus genus include Elephantid herpesvirus 1 .
- Members of the Muromegalovirus genus include Murid herpesvirus 1 .
- Members of the Roseolovirus genus include Human herpesvirus 6A, 6B and 7.
- Members of the Lymphocryptovirus genus include Human herpesvirus 4.
- Members of the Macavirus genus include Alcelaphine herpesvirus 1 .
- Members of the Percavirus genus include Equid herpesvirus 2.
- Rhadinovirus Members of the Rhadinovirus genus include Saimierine herpesvirus 2, Kaposi's sarcoma-associated virus.
- Flavivirus Various genera within the Flaviviridae family include Flavivirus, Pestivirus, Hepacivirus and Hepatitis G Virus.
- the Papovaviridae family include the genus Polyomavirus (e.g. JC virus; BK virus; Merkel cell polyomavirus; Trichodysplasia spinulosa polyomavirus; Human polyomavirus 6, 7, 9 and 12; New Jersey polyomavirus; Kl polyomavirus; WU polyomavirus; MW polyomavirus; STL polyomavirus).
- Polyomavirus e.g. JC virus; BK virus; Merkel cell polyomavirus; Trichodysplasia spinulosa polyomavirus; Human polyomavirus 6, 7, 9 and 12; New Jersey polyoma
- the Pappilomaviridae or pappilomaviruses include the human pappilomaviruses (HPV).
- HPV human pappilomaviruses
- Flavivirus genus include Dengue fever virus, yellow fever virus, West Nile encephalitis virus and Japanese encephalitis virus.
- Members of the Pestivirus genus include bovine viral diarrhoea virus (BVDV), classical swine fever virus and border disease virus 2 (BDV-2).
- BVDV bovine viral diarrhoea virus
- BDV-2 border disease virus 2
- HCV hepatitis C virus
- Picornaviridae family Various genera within the Picornaviridae family include Aphthovirus, Avihepatovirus, Cardiovirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Parechovirus, Sapelovirus, Senecavirus, Teschovirus and Tremovirus.
- Enterovirus genus include poliovirus, coxsackie A virus, coxsackie B virus and rhinovirus.
- Oncological disorders which may be acute or chronic, include proliferative disorders, especially cancer, in animals, including mammals, especially humans.
- Particular categories of cancer include haematological malignancy (including leukaemia and lymphoma) and non- haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma).
- Chronic leukaemia may be myeloid or lymphoid.
- leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplastic syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythroleukaemia.
- CML chronic myelogenous leukaemia
- CLL chronic lymphocytic/lymphoid leukaemia
- ALL acute lymphoblastic leukaemia
- AML acute myelogenous leukaemia
- lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma.
- non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle.
- the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
- compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
- the quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition or disease will vary depending on the compound chosen and the condition of the animal, mammal or human patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
- daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration,
- pyrimidine and purine bases includes, but is not limited to, adenine, thymine, cytosine, uracyl, guanine, 2,6-diaminopurine, 5-fluorocytosine, 5- fluorouracil, 7-deazaguanosine, 7-deazaadenine and analogues thereof.
- a purine or pyrimidine base as used herein includes a purine or pyrimidine base found in naturally occurring nucleosides as mentioned above.
- An analogue thereof is a base which mimics such naturally occurring bases in such a way that their structures (the kinds of atoms and their arrangement) are similar to the naturally occurring bases but may either possess additional or lack certain of the functional properties of the naturally occurring bases.
- Such analogues include those derived by replacement of a CH moiety by a nitrogen atom (e.g. 5-azapyrimidines such as 5-azacytosine) or vice versa (e.g. 7-deazapurines, such as 7-deazaadenine or 7- deazaguanine) or both (e.g., 7-deaza, 8-azapurines).
- derivatives of such bases or analogues are meant those bases wherein ring substituents are either incorporated, removed, or modified by conventional substituents known in the art, e.g. halogen, hydroxyl, amino, (Ci- Ce)alkyl and others.
- ring substituents e.g. halogen, hydroxyl, amino, (Ci- Ce)alkyl and others.
- purine or pyrimidine bases, and analogues thereof are well known to those skilled in the art, e.g. as shown at pages 20-38 of WO 03/093290.
- purine and pyrimidine analogues B for the purpose of the present invention may be selected from the group comprising pyrimidine bases represented by the structural formula (IV):
- R 7 and R 9 are independently selected from the group consisting of H, -OH, -SH, -Nhb, and - NH-Me;
- R 8 and R 10 are independently selected from the group consisting of H, methyl, ethyl, isopropyl, hydroxyl, amino, ethylamino, trifluoromethyl, cyano and halogen; and
- X 1 and Y 1 are independently selected from CR 11 and N, wherein R 11 is selected from the group consisting of H, halogen and cyano.
- substituted uracils with the formula (IV) wherein X 1 is CH, R 7 is hydroxyl, and R 8 is selected from the group consisting of methyl, ethyl, isopropyl, amino, ethylamino, trifluoromethyl, cyano, fluoro, chloro, bromo and iodo.
- alkyl refers to a straight (normal) or branched (eg. secondary, or tertiary) hydrocarbon chains having the number of carbon atoms as indicated (or where not indicated, preferably having 1 -20, more preferably 1 -6 carbon atoms).
- C1-C6 alkyl refers to such hydrocarbon chains having from 1 to 6 carbon atoms.
- Examples thereof are methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-methyl-1 -propyl(i-Bu), 2-butyl (s-Bu) 2-methyl-2- propyl (t-Bu), 1 -pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3- methyl-1 -butyl, 2-methyl-1 -butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3- dimethyl-2-butyl, n-pentyl, n-hexyl.
- C2-C10 alkenyl designate a straight and branched acyclic hydrocarbon monovalent radical having one or more ethylenic unsaturations and having from 2 to 10 carbon atoms such as, for example, vinyl, 1 -propenyl, 2-propenyl (allyl), 1 -butenyl, 2-butenyl, 2-pentenyl, 3- pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl, 2-heptenyl, 1 ,3-butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl, 2-octenyl and the like, including all possible isomers thereof.
- C2-C10 alkynyl defines straight and branched chain hydrocarbon radicals containing one or more triple bonds and optionally at least one double bond and having from 2 to 10 carbon atoms such as, for example, acetylenyl, 1 -propynyl, 2- propynyl, 1 -butynyl, 2-butynyl, 2- pentynyl, 1 -pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl, 1 -penten-4-ynyl, 3-penten-1 - ynyl, 1 ,3-hexadien-1 -ynyl and the like.
- cycloalkyl means a monocyclic saturated hydrocarbon monovalent radical having the number of carbon atoms as indicated (or where not indicated, preferably having 3-20, more preferably 3-10 carbon atoms, more preferably 3-8 or 3-6 carbon atoms).
- C3-C8 cycloalkyl refers to such monocyclic saturated hydrocarbon monovalent radical having from 3 to 8 carbon atoms, such as for instance cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
- alkoxy refers to the group alkyl-O-, where alkyl is as defined above.
- (C1-C6) alkoxy as used herein includes but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy.
- halogen or halo means any atom selected from the group consisting of fluorine (F), chlorine (CI), bromine (Br) and iodine
- aryl means a monovalent unsaturated aromatic carbocyclic radical having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic.
- An aryl group may optionally be substituted by one, two, three or more substituents as set out in this invention with respect to optional substituents that may be present on the group Ar or aryl.
- Preferred aryl groups are: an aromatic monocyclic ring containing 6 carbon atoms; an aromatic bicyclic or fused ring system containing 7, 8, 9 or 10 carbon atoms; or an aromatic tricyclic ring system containing 10, 1 1 , 12, 13 or 14 carbon atoms.
- Non- limiting examples of aryl include phenyl and naphthyl.
- Preferred Ar are phenyl, bromophenyl and naphthyl.
- stereoisomer refers to all possible different isomeric as well as conformational forms which the compounds of formula I and lb may possess, in particular all possible stereochemical and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.
- enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
- High-resolution mass spectra were obtained on a quadruple orthogonal acceleration time-of-flight mass spectrometer (Synapt G2 HDMS, Waters, Milford, MA). Samples were infused at 3 ⁇ _/ ⁇ " ⁇ , and spectra were obtained in positive (or in negative) ionization mode with a resolution of 15 000 (fwhm) using leucine enkephalin as the lock mass. Pre-coated aluminum sheets (254 nm) were used for TLC. Products were purified by column chromatography on silica gel (60 A, 0.035-0.070 mm, Acros Organics).
- Preparative RP-HPLC purifications were performed on a Phenomenex Gemini 1 1 OA column (C18, 10 m, 21 .2 mm ⁇ 250 mm) using H 2 0/CH 3 CN with 50 mmol TEAB or H 2 0/CH 3 CN as eluent gradient.
- Compound 6b was obtained as a colorless oil (460 mg, 70%) according to the procedure used for the preparation of 6a, starting from compound 4b 1 (300 mg, 1.23 mmol), compound 5 (360 mg, 1.47 mmol), Ph 3 P (640 mg, 2.46 mmol), and DIAD (0.48 mL, 2.46 mmol) in anhydrous THF (8 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 80:1 , v/v; DCM/MeOH, 50:1 , v/v).
- reaction mixture was concentrated under reduced pressure and the resulting crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 30:1 , v/v; DCM/MeOH, 20:1 , v/v) to give 7a (160 mg, 90%) as a colorless oil.
- Bromotrimethylsilane (0.15 mL, 1.14 mmol) was added dropwise to a solution of diethyl phosphonate ester 7a (100 mg, 0.28 mmol) and 2,6-lutidine (0.26 mL, 2.27 mmol) in anhydrous acetonitrile (5 mL) at 0 °C. After the addition was completed, the mixture was slowly warmed to room temperature and set aside in the dark for 12 h. The reaction was quenched with 0.1 M TEAB and was then concentrated under reduced pressure.
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH/Et3N, 10:5:1 , v/v/v; 7.5:5:1 , v/v/v).
- the collected eluate was freeze-dried repeatedly until constant mass to give the desired phosphonate acid triethylammonium salt 8a (59 mg, 70%) as a white foam.
- Spectral data are in accordance with literature data (Pomeisl, K.; Pohl, R.; Holy, A.; Votruba, I. Collect. Czech. Chem. Commun. 2005, 70, 1465-1481 ).
- Compound 8b was obtained as a white foam (176 mg, 70%) according to the procedure used for the preparation of 8a, starting from compound 7b (300 mg, 0.85 mmol), bromotrimethylsilane (0.45 mL, 3.41 mmol), and 2,6-lutidine (0.79 mL, 6.81 mmol) in anhydrous acetonitrile (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH/Et 3 N, 10:5:1 , v/v/v; 7.5:5:1 , v/v/v).
- Spectral data are in accordance with literature data (Pomeisl, K.; Pohl, R.; Holy, A.; Votruba, I. Collect. Czech. Chem. Commun. 2005, 70, 1465-1481 ).
- Compound 10a was obtained as a colorless oil (190 mg, 60%) according to the procedure used for the preparation of 6a, starting from compound 4a (200 mg, 0.82 mmol), compound 9 (150 mg, 0.98 mmol), Ph 3 P (430 mg, 1 .64 mmol), and DIAD (0.32 mL, 1 .64 mmol) in anhydrous THF (6 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 50:1 , v/v; DCM/MeOH, 30:1 , v/v).
- Compound 10b was obtained as a colorless oil (300 mg, 65%) according to the procedure used for the preparation of 6a, starting from compound 4b (300 mg, 1.23 mmol), compound 9 (230 mg, 1.50 mmol), Ph 3 P (640 mg, 2.46 mmol), and DIAD (0.48 mL, 2.46 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 50:1 , v/v; DCM/MeOH, 30:1 , v/v).
- Compound 12a was obtained as a white foam (38 mg, 65%) according to the procedure used for the preparation of 8a, starting from compound 11 a (70 mg, 0.19 mmol), bromotrimethylsilane (0.10 mL, 0.77 mmol), and 2,6-lutidine (0.18 mL, 1.59 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 6:1 :1 , v/v/v).
- Compound 12b was obtained as a white foam (148 mg, 70%) according to the procedure used for the preparation of 8a, starting from compound 11 b (250 mg, 0.67 mmol), bromotrimethylsilane (0.37 mL, 2.77 mmol), and 2,6-lutidine (0.64 mL, 5.54 mmol) in anhydrous acetonitrile (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 6:1 :1 , v/v/v).
- Compound 14a was obtained as a colorless oil (130 mg, 40%) according to the procedure used for the preparation of 6a, starting from compound 4a (200 mg, 0.82 mmol), compound 13 (180 mg, 0.98 mmol), Ph 3 P (430 mg, 1 .63 mmol), and DIAD (0.33 mL, 1 .63 mmol) in anhydrous THF (6 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 30:1 , v/v; DCM/MeOH, 25:1 , v/v).
- Compound 14b was obtained as a colorless oil (260 mg, 40%) according to the procedure used for the preparation of 6a, starting from compound 4a (400 mg, 1 .64 mmol), compound 9 (360 mg, 1.96 mmol), Ph 3 P (860 mg, 3.26 mmol), and DIAD (0.66 mL, 3.26 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 30:1 , v/v; DCM/MeOH, 25:1 , v/v).
- Compound 15a was obtained as a colorless oil (150 mg, 45%) according to the procedure used for the preparation of 6a, starting from compound 4a (200 mg, 0.82 mmol), compound 13 (180 mg, 0.98 mmol), Ph 3 P (430 mg, 1 .63 mmol), and DIAD (0.33 mL, 1 .63 mmol) in anhydrous THF (6 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 80:1 , v/v; DCM/MeOH, 50:1 , v/v).
- Compound 15b was obtained as a colorless oil (300 mg, 45%) according to the procedure used for the preparation of 6a, starting from compound 4b (400 mg, 1.64 mmol), compound 13 (360 mg, 1 .96 mmol), Ph 3 P (860 mg, 3.26 mmol), and DIAD (0.66 mL, 3.26 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 80:1 , v/v; DCM/MeOH, 50:1 , v/v).
- Compound 16b was obtained as a white foam (140 mg, 82%) according to the procedure used for the preparation of 16a, starting from compound 14b (200 mg, 0.49 mmol) in 30% methanolic ammonia (20 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 10:1 , v/v; DCM/MeOH, 8:1 , v/v).
- Compound 17a was obtained as a white foam (58 mg, 70%) according to the procedure used for the preparation of 8a, starting from compound 16a (100 mg, 0.30 mmol), bromotrimethylsilane (0.16 mL, 1.19 mmol), and 2,6-lutidine (0.27 mL, 2.37 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 6:1 :1 , v/v/v; acetone/H 2 0/Et 3 N, 5:1 :1 , v/v/v).
- Spectral data are in accordance with literature data (Yu, K. L; Bronson, J. J.; Yang, H.; Patick, A.; Alam, M.; Brankovan, V.; Datema, R.; Hitchcock, M. J. M.; Martin, J.C. J. Med. C em. 1993, 36, 2726-2738).
- Compound 17b was obtained as a white foam (82 mg, 70%) according to the procedure used for the preparation of 8a, starting from compound 16b (140 mg, 0.42 mmol), bromotrimethylsilane (0.22 mL, 1.66 mmol), and 2,6-lutidine (0.38 mL, 3.32 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 6:1 :1 , v/v/v; acetone/H 2 0/Et 3 N, 5:1 :1 , v/v/v).
- Spectral data are in accordance with literature data (Yu, K. L.; Bronson, J. J.; Yang, H.; Patick, A.; Alam, M.; Brankovan, V.; Datema, R.; Hitchcock, M. J. M.; Martin, J.C. J. Med. Chem. 1993, 36, 2726-2738).
- Compound 18a was obtained as a white foam (100 mg, 82%) according to the procedure used for the preparation of 16a, starting from compound 15a (150 mg, 0.37 mmol) in 30% methanolic ammonia (15 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 25: 1 , v/v; DCM/MeOH, 20: 1 , v/v).
- Compound 18b was obtained as a white foam (190 mg, 90%) according to the procedure used for the preparation of 16a, starting from compound 15b (250 mg, 0.60 mmol) in 30% methanolic ammonia (20 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 25: 1 , v/v; DCM/MeOH, 20: 1 , v/v).
- Compound 19a was obtained as a white foam (82 mg, 70%) according to the procedure used for the preparation of 8a, starting from compound 18a (100 mg, 0.30 mmol), bromotrimethylsilane (0.16 mL, 1.20 mmol), and 2,6-lutidine (0.27 mL, 2.37 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 5:1 :1 , v/v/v; acetone/H 2 0/Et 3 N, 4:1 :1 , v/v/v).
- Compound 19b was obtained as a white foam (160 mg, 70%) according to the procedure used for the preparation of 8a, starting from compound 18b (200 mg, 0.60 mmol), bromotrimethylsilane (0.32 mL, 2.20 mmol), and 2,6-lutidine (0.54 mL, 4.80 mmol) in anhydrous acetonitrile (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 5:1 :1 , v/v/v; acetone/H 2 0/Et 3 N, 4:1 :1 , v/v/v).
- Compound 21 a was obtained as a colorless oil (290 mg, 50%) according to the procedure used for the preparation of 6a, starting from compound 4a (300 mg, 1 .23 mmol), compound 20 (360 mg, 1 .47 mmol), Ph 3 P (650 mg, 2.46 mmol), and DIAD (0.48 mL, 2.46 mmol) in anhydrous THF (8 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 40: 1 , v/v; DCM/MeOH, 30: 1 , v/v).
- Compound 21 b was obtained as a colorless oil (250 mg, 44%) according to the procedure used for the preparation of 6a, starting from compound 4b (300 mg, 1 .23 mmol), compound 20 (360 mg, 1 .47 mmol), Ph 3 P (650 mg, 2.46 mmol), and DIAD (0.48 mL, 2.46 mmol) in anhydrous THF (8 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 40: 1 , v/v; DCM/MeOH, 30: 1 , v/v).
- Compound 23b was obtained as a colorless foam (160 mg, 80%) according to the general procedure used for the preparation of 22a, starting from compound 21 b (250 mg, 0.54 mmol) and Pd/C on charcoal (10% w/w, 120 mg) in EtOAc (30 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 10:1 , v/v; 7:1 , v/v).
- Compound 23a was obtained as a white foam (87 mg, 60%) according to the procedure used for the preparation of 8a, starting from compound 22a (170 mg, 0.45 mmol), bromotrimethylsilane (0.24 mL, 1.80 mmol), and 2,6-lutidine (0.42 mL, 3.60 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 5:1 :1 , v/v/v; acetone/H 2 0/Et 3 N, 4:1 :1 , v/v/v).
- Spectral data are in accordance with literature data (Baszczynski, O.; Hockova, D.; Janeba, Z.; Holy, A.; Jansa, P.; Dracinsky, M.; Keough, D. T; Guddat, L. W. Eur. J. Med. C em. 2013, 67, 81 -89).
- Compound 23b was obtained as a white foam (87 mg, 60%) according to the procedure used for the preparation of 8a, starting from compound 22b (160 mg, 0.42 mmol), bromotrimethylsilane (0.22 ml_, 1.70 mmol), and 2,6-lutidine (0.39 ml_, 3.40 mmol) in anhydrous acetonitrile (5 ml_).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/H 2 0/Et 3 N, 5:1 :1 , v/v/v; acetone/H 2 0/Et 3 N, 4:1 :1 , v/v/v).
- Spectral data are in accordance with literature data (Baszczynski, O.; Hockova, D.; Janeba, Z.; Holy, A.; Jansa, P.; Dracinsky, M.; Keough, D. T; Guddat, L. W. Eur. J. Med. C em. 2013, 67, 81 -89).
- Examples 31 - 40 Synthesis of aryloxyphosphonoamidate prodrugs of the free phosphonates 8a-b, 12a-b, 17a-b, 19a-b and 23a-b.
- Compound 24a was obtained as a colorless oil (45 mg, 45%) according to the general procedure, starting from compound 8a (50 mg, 0.17 mmol), aspartic acid ester HCI salt (90 mg, 0.29 mmol), PhOH (70 mg, 0.75 mmol), Et 3 N (0.24 mL, 1.7 mmol), 2,2'-dithiodipyridine (260 mg, 1.20 mmol), and PPh 3 (310 mg, 1.20 mmol) in anhydrous pyridine (5 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 60:1 , v/v; 50:1 , v/v).
- Example 32 (/?)-1 - ⁇ 3-Fluoro-2-[phenyloxy-bis(amyl-L- aspartvDphosphoryllmethoxylpropyDthymine (24b)
- Compound 24b was obtained as a colorless oil (80 mg, 50%) according to the general procedure, starting from compound 8b (80 mg, 0.27 mmol), aspartic acid ester HCI salt (142 mg, 0.46 mmol), PhOH (112 mg, 1 .20 mmol), Et 3 N (0.38 mL, 2.70 mmol), 2,2'-dithiodipyridine (420 mg, 1.90 mmol), and PPh 3 (500 mg, 1.90 mmol) in anhydrous pyridine (5 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 60:1 , v/v; 50:1 , v/v).
- Compound 25a was obtained as a colorless oil (26 mg, 40%) according to the general procedure, starting from compound 12a (30 mg, 0.10 mmol), aspartic acid ester HCI salt (52 mg, 0.17 mmol), PhOH (40 mg, 0.43 mmol), Et 3 N (0.14 mL, 1.00 mmol), 2,2'-dithiodipyridine (150 mg, 0.69 mmol), and PPh 3 (180 mg, 0.69 mmol) in anhydrous pyridine (3 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 25:1 , v/v; 20:1 , v/v).
- Compound 25b was obtained as a colorless oil (110 mg, 55%) according to the general procedure, starting from compound 12b (80 mg, 0.26 mmol), aspartic acid ester HCI salt (140 mg, 0.45 mmol), PhOH (110 mg, 1 .15 mmol), Et 3 N (0.36 mL, 2.60 mmol), 2,2'-dithiodipyridine (400 mg, 1.83 mmol), and PPh 3 (480 mg, 1.83 mmol) in anhydrous pyridine (5 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 25:1 , v/v; 20:1 , v/v).
- Compound 26a was obtained as a colorless oil (23 mg, 26%) according to the general procedure, starting from compound 17a (40 mg, 0.14 mmol), aspartic acid ester HCI salt (75 mg, 0.24 mmol), PhOH (59 mg, 0.63 mmol), Et 3 N (0.20 mL, 1.40 mmol), 2,2'-dithiodipyridine (220 mg, 1.00 mmol), and PPh 3 (260 mg, 1.00 mmol) in anhydrous pyridine (3 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 20:1 , v/v; 10:1 , v/v).
- Example 36 (/?)-1 - ⁇ 3-Fluoro-2-[phenyloxy-bis(amyl-L- aspartvDphosphoryllmethoxylpropyDcytosine (26b)
- Compound 26b was obtained as a colorless oil (20 mg, 20%) according to the general procedure, starting from compound 17b (40 mg, 0.14 mmol), aspartic acid ester HCI salt (75 mg, 0.24 mmol), PhOH (59 mg, 0.63 mmol), Et 3 N (0.20 mL, 1.40 mmol), 2,2'-dithiodipyridine (220 mg, 1.00 mmol), and PPh 3 (260 mg, 1.00 mmol) in anhydrous pyridine (3 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 20:1 , v/v; 10:1 , v/v).
- Compound 27a was obtained as a colorless oil (12 mg, 28%) according to the general procedure, starting from compound 19a (20 mg, 0.07 mmol), aspartic acid ester HCI salt (38 mg, 0.12 mmol), PhOH (30 mg, 0.32 mmol), Et 3 N (0.10 mL, 0.70 mmol), 2,2'-dithiodipyridine (110 mg, 0.50 mmol), and PPh 3 (130 mg, 0.50 mmol) in anhydrous pyridine (3 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 40:1 , v/v; 30:1 , v/v).
- Example 38 (/?)-0 2 - ⁇ 3-Fluoro-2-[phenyloxy-bis(amyl-L- aspartvDphosphoryllmethoxylpropyDcytosine (27b)
- Compound 27b was obtained as a colorless oil (31 mg, 24%) according to the general procedure, starting from compound 19b (60 mg, 0.21 mmol), aspartic acid ester HCI salt (114 mg, 0.36 mmol), PhOH (90 mg, 0.96 mmol), Et 3 N (0.30 mL, 2.10 mmol), 2,2'-dithiodipyridine (330 mg, 1.50 mmol), and PPh 3 (390 mg, 1.50 mmol) in anhydrous pyridine (5 mL). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 40:1 , v/v; 30:1 , v/v).
- Compound 31 b was obtained as a colorless oil (300 mg, 70%) according to the procedure used for the preparation of 31 a, starting from 30 (250 mg, 1 .47 mmol), 4b (300 mg, 1 .23 mmol), Ph 3 P (640 mg, 2.46 mmol), and DIAD (0.48 mL, 2.46 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 50:1 , v/v; 30:1 , v/v; 25:1 , v/v).
- Compound 32b was obtained as a colorless oil (160 mg, 67%) according to the procedure used for the preparation of 32a, starting from 31 b (190 mg, 0.48 mmol), 4-methoxythiophenol (0.12 mL, 0.96 mmol) and triethylamine (0.07 mL, 0.48 mmol) in anhydrous DMF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 60:1 , v/v; 50:1 , v/v; 40:1 , v/v).
- Compound 36b was obtained as a colorless oil (230 mg, 79%) according to the procedure used for the preparation of 36a, starting from 34 (180 mg, 0.74 mmol), 4b (150 mg, 0.61 mmol), Ph 3 P (300 mg, 1 .20 mmol), and DIAD (0.24 mL, 1.20 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 60:1 , v/v; 40:1 , v/v; 30:1 , v/v).
- Compound 37a was obtained as a colorless oil (70 mg, 25%) according to the procedure used for the preparation of 36a, starting from 35 (200 mg, 0.74 mmol), 4a (150 mg, 0.61 mmol), Ph 3 P (300 mg, 1 .20 mmol), and DIAD (0.24 mL, 1.20 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 80:1 , v/v; 60:1 , v/v; 40:1 , v/v).
- Compound 37b was obtained as a colorless oil (100 mg, 33%) according to the procedure used for the preparation of 36a, starting from 35 (200 mg, 0.74 mmol), 4b (150 mg, 0.61 mmol), Ph 3 P (300 mg, 1 .20 mmol), and DIAD (0.24 mL, 1.20 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 80:1 , v/v; 60:1 , v/v; 40:1 , v/v).
- Compound 38b was obtained as a colorless oil (50 mg, 64%) according to the procedure used for the preparation of 38a, starting from 36b (100 mg, 0.21 mmol), DABCO (23 mg, 0.21 mmol) and K 2 C03 (29 mg, 0.21 mmol) in mixture solvent of dioxane and H 2 0 (6 ml_, 5:1 , v/v), and ⁇ / ⁇ (20 ml_). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 20:1 , v/v; 15:1 , v/v; 10:1 , v/v).
- Compound 39a was obtained as a colorless oil (20 mg, 30%) according to the procedure used for the preparation of 38a, starting from 37a (60 mg, 0.12 mmol), DABCO (14 mg, 0.12 mmol) and K 2 C03 (17 mg, 0.12 mmol) in mixture solvent of dioxane and H 2 0 (6 ml_, 5:1 , v/v), and ⁇ / ⁇ (20 ml_).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 18:1 , v/v; 15: 1 , v/v; 10: 1 , v/v).
- Compound 39b was obtained as a colorless oil (25 mg, 35%) according to the procedure used for the preparation of 38a, starting from 37b (90 mg, 0.18 mmol), DABCO (20 mg, 0.18 mmol) and K 2 C03 (25 mg, 0.18 mmol) in mixture solvent of dioxane and H 2 0 (6 ml_, 5:1 , v/v), and ⁇ / ⁇ (20 ml_). The crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH , 18: 1 , v/v; 15: 1 , v/v; 10: 1 , v/v).
- Compound 47a was obtained as a colorless oil (220 mg, 80%) according to the procedure used for the preparation of 36a, starting from 46 (150 mg, 0.54 mmol), 4a (120 mg, 0.49 mmol), Ph 3 P (260 mg, 0.98 mmol), and DIAD (0.19 mL, 0.98 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 50:1 , v/v; 40:1 , v/v; 30:1 , v/v).
- Compound 47b was obtained as a colorless oil (150 mg, 60%) according to the procedure used for the preparation of 36a, starting from 46 (150 mg, 0.54 mmol), 4b (120 mg, 0.49 mmol), Ph 3 P (260 mg, 0.98 mmol), and DIAD (0.19 mL, 0.98 mmol) in anhydrous THF (10 mL).
- the crude residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 50:1 , v/v; 40:1 , v/v; 30:1 , v/v).
- Compound 48a was obtained as a colorless oil (50 mg, 30%) according to the procedure used for the preparation of 38a, starting from 47a (220 mg, 0.44 mmol), DABCO (33 mg, 0.30 mmol) and K 2 C0 3 (61 mg, 0.44 mmol) in mixture solvent of dioxane and H 2 0 (6 mL, 5:1 , v/v), and NH 3 /MeOH (20 mL). The residue was purified by column chromatography on silica gel (gradient DCM/MeOH, 20:1 , v/v; 15:1 , v/v; 10:1 , v/v).
- Bromotrimethylsilane (0.43 mL, 3.20 mmol) was added dropwise to a solution of diethyl phosphonate ester 32a (200 mg, 0.40 mmol) and 2,6-lutidine (0.74 mL, 6.40 mmol) in anhydrous acetonitrile (10 mL) at 0 °C. After the addition was completed, the mixture was slowly warmed to room temperature and set aside in the dark for 12 h. The reaction was quenched with 0.1 M TEAB and was then concentrated under reduced pressure.
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et.3N/H20, 6:1 :1 , v/v/v), followed by RP-HPLC (linear gradient, 2-98% CH 3 CN in 0.05 M TEAB solution) to give the desired phosphonate acid triethylammonium salt 33a (120 mg, 70%) as a white foam.
- Compound 33b was obtained as a white foam (86 mg, 65%) according to the procedure used for the preparation of 33a, starting from compound 32b (150 mg, 0.30 mmol), bromotrimethylsilane (0.32 ml_, 2.40 mmol), and 2,6-lutidine (0.56 ml_, 4.80 mmol) in anhydrous acetonitrile (10 ml_).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et 3 N/H 2 0, 6:1 :1 , v/v/v).
- Compound 40a was obtained as a white foam (59 mg, 70%) according to the procedure used for the preparation of 33a, starting from compound 38a (100 mg, 0.26 mmol), bromotrimethylsilane (0.28 ml_, 2.12 mmol), and 2,6-lutidine (0.50 ml_, 4.24 mmol) in anhydrous acetonitrile (10 ml_).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et 3 N/H 2 0, 4:1 :1 , v/v/v).
- Compound 40b was obtained as a white foam (30 mg, 70%) according to the procedure used for the preparation of 33a, starting from compound 38b (50 mg, 0.13 mmol), bromotrimethylsilane (0.14 mL, 1.06 mmol), and 2,6-lutidine (0.25 mL, 2.12 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et 3 N/H 2 0, 4:1 :1 , v/v/v).
- Compound 41a was obtained as a white foam (9 mg, 50%) according to the procedure used for the preparation of 33a, starting from compound 39a (20 mg, 0.05 mmol), bromotrimethylsilane (0.05 mL, 0.40 mmol), and 2,6-lutidine (0.09 mL, 0.81 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et 3 N/H 2 0, 4:1 :1 , v/v/v).
- Compound 41 b was obtained as a white foam (10 mg, 60%) according to the procedure used for the preparation of 33a, starting from compound 39b (20 mg, 0.05 mmol), bromotrimethylsilane (0.05 mL, 0.40 mmol), and 2,6-lutidine (0.09 mL, 0.81 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et 3 N/H 2 0, 4:1 :1 , v/v/v).
- Compound 49a was obtained as a white foam (30 mg, 70%) according to the procedure used for the preparation of 33a, starting from compound 48a (50 mg, 0.13 mmol), bromotrimethylsilane (0.13 mL, 1.00 mmol), and 2,6-lutidine (0.23 mL, 2.00 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et 3 N/H 2 0, 5:1 :1 , v/v/v).
- Compound 49b was obtained as a white foam (51 mg, 75%) according to the procedure used for the preparation of 33a, starting from compound 48b (80 mg, 0.20 mmol), bromotrimethylsilane (0.21 mL, 1.60 mmol), and 2,6-lutidine (0.37 mL, 3.20 mmol) in anhydrous acetonitrile (5 mL).
- the crude residue was purified by column chromatography on silica gel (gradient acetone/Et 3 N/H 2 0, 5:1 :1 , v/v/v).
- Example 68 Tetraamyl 2,2'-((((((R)-1 -(2-amino-4-oxo-3,4-dihydro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3-fluoropropan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(2S,2'S)- disuccinate (51 )
- 2,2 ' -Dithiodipyridine (55 mg, 0.25 mmol) was mixed in a separate flask with PP i3 (65 mg, 0.25 mmol) in anhydrous pyridine (2 mL) and the resultant mixture was stirred for 10-15 min to give a clear light yellow solution. This solution was then added to the above solution and the combined mixture was stirred at 60 °C for 12 h. The mixture was then concentrated under reduced pressure to give a residue that was redissolved in EtOAc (50 mL). This solution was washed with saturated aq. NaHCC>3 (25 mL) and brine (25 mL), the organic layer was separated, dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure.
- the crude residue was purified by silica gel chromatography (gradient DCM/MeOH, 30:1 , v/v; 20:1 , v/v) and then purified by RP-HPLC (linear gradient, 5-95% CH3CN in water) to compound 51 (5 mg, 20%) as a white powder.
- the primary anti-HBV assay is performed as previously described (Korba, BF and Milman, G. A cell culture assay for compound which inhibit hepatitis B virus replication. Antiviral Res. 1991 , 15, 217-228; and Korba, BF and Gerin, JL. Use of a standardized cell culture assay to assess activities of nucleoside analogs again hepatitis B virus replication. Antiviral Res. 1992, 19, 55-70) with modifications to use real-time qPCR (TaqMan) to measure extracellular HBV DNA copy number associated with virions released from HepG2 2.2.15 cells.
- the HepG2 2.2.15 cell line is a stable human hepatoblastoma cell line that contains two copies of the HBV wild-type strain aywl genome and constitutively produces high levels of HBV.
- Antiviral compounds blocking any late step of viral replication such as transcription, translation, pregenome encapsidation, reverse transcription, particle assembly and release can be identified and characterized using this cell line.
- HepG2 2.2.15 cells are plated in 96-well microtiter plates at 1 .5x10 4 cells/well in Dulbecco's Modified Eagle's Medium supplemented with 2% FBS, 380 ⁇ g mL G418, 2.0 mM L-Glutamine, 100 units/mL Penicillin, 100 ⁇ g mL Streptomycin, and 0.1 mM non-essential amino acids. Only the interior wells are utilized to reduce "edge effects" observed during cell culture; the exterior wells are filled with complete medium to help minimize sample evaporation.
- the confluent monolayer of HepG2 2.2.15 cells is washed and the medium is replaced with complete medium containing various concentrations of a test compound in triplicate.
- Lamivudine (3TC) and entecavir were used as the positive control, while media alone is added to cells as a negative control (virus control, VC).
- the culture medium is replaced with fresh medium containing the appropriately diluted test compounds.
- the cell culture supernatant is collected, treated with pronase and then used in a real-time quantitative TaqMan qPCR assay.
- the PCR-amplified HBV DNA is detected in real-time by monitoring increases in fluorescent signal that result from the exonucleolytic degradation of a quenched fluorescent probe molecule that hybridizes to the amplified HBV DNA.
- a standard curve is simultaneously generated using dilutions of purified HBV DNA.
- Antiviral activity is calculated from the reduction in HBV DNA levels (EC50 & EC90 values determined).
- a tetrazolium dye (MTS; 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium; CellTiter®96 Reagent, Promega) uptake assay is then employed to measure cell viability, which is used to calculate toxicity (CC50).
- the Selectivity Index (SI50) is calculated as CC50/IC50. The data are shown in Table 1 .
- Example 70 Antiviral activity against the HIV-1 X4 strain NL4.3 and HIV-1 R5 strain BaL
- TZM-bl cells (Montefiori, D.C. Methods Mol. Biol. 2009, 485, 395-405) were seeded in transparent 96-well plates at 1 x 104 cells per well in DMEM (Dulbecco's Modified Eagle Medium; Life Technologies, Waltham, MA, USA) with 10% Fetal Bovine Serum (FBS) and 10 mM HEPES. Subsequently, compounds were added and the cell/compound mixture was incubated at 37°C. After 30 min, virus was added at 100 pg p-24 per well. After 48 h of incubation, the assay plates were analyzed. For the analysis, steadylite plus substrate solution (PerkinElmer, Waltham, MA, USA) was added to the assay plates.
- steadylite plus substrate solution PerkinElmer, Waltham, MA, USA
- the luminescent signal of the lysed cell suspension was analyzed in white 96-well plates on a SpectraMax L luminescence microplate reader (Molecular Devices, Sunnyvale, CA, USA) after a 10 min incubation period in the dark. Luciferase activity induced by HIV-1 Tat protein expression was measured as an assessment of the amount of HIV replication. The data are shown in Table 2.
- Example 71 Antiviral activity against the varicella-zoster virus and human cytomegalovirus
- VZV varicella-zoster virus
- TK thymidine kinase deficient
- HCMV human cytomegalovirus
- the antiviral assays were based on inhibition of virus- induced cytopathicity or plaque formation in human embryonic lung (HEL) fibroblasts.
- Confluent cell cultures in microtiter 96-well plates were inoculated with 100 CCID 5 o of HCMV (1 CCID 5 o being the virus dose to infect 50% of the cell cultures) or with 20 plaque forming units (PFU) (VZV).
- HMV viral cytopathicity
- VZV plaque formation
- EC50 EC50 or concentration (expressed in micromolar) required for reducing virus-induced cytopathogenicity or viral plaque formation by 50%. Cytostatic measurements were based on the inhibition of cell growth. HEL cells were seeded at a rate of 5 ⁇ 10 3 cells/well into 96-well microtiter plates and allowed to proliferate for 24 h.
- cytostatic concentration (expressed in micromolar) was calculated as the CC50 or the compound concentration required for reducing cell proliferation by 50% relative to the number of cells in the untreated controls.
- CC50 values were estimated from graphic plots of the number of cells (percentage of control) as a function of the concentration of the test compounds.
- cytotoxicity of the test compounds was expressed as the minimum cytotoxic concentration (MCC) or the compound concentration that caused a microscopically detectable alteration of cell morphology.
- MCC minimum cytotoxic concentration
- Ganciclovir and cidofovir are included as positive controls for HCMV testing, whereas acyclovir and brivudin are used as reference drugs in the VZV assays. The data are shown in Table 3.
- a EC50 effective concentration (expressed in ⁇ ) required to reduce virus-induced cytopathicity by 50%.
- b MCC minimum concentration (expressed in ⁇ ) required to cause a microscopically detectable alteration of cell morphology.
- c CC50 cytotoxic concentration (expressed in ⁇ ) required to reduce cell growth by 50%.
- d ND not determined
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Abstract
La présente invention concerne de nouveaux promédicaments de phosphonoamidates de phosphonates de nucléosides acycliques à chaîne latérale 3-fluoro-2-(phosphonométhoxy)propyl. L'invention concerne également l'utilisation de ces nouveaux nucléosides modifiés par phosphonate en vue de traiter ou de prévenir des infections virales et leur utilisation pour fabriquer un médicament permettant de traiter ou de prévenir des infections virales, en particulier des infections par des virus tels que le virus de l'hépatite B, le virus de l'immunodéficience humaine, le cytomégalovirus humain et le virus varicelle-zona.
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CN201780001997.4A CN108137630A (zh) | 2016-09-23 | 2017-09-22 | 氟化无环核苷膦酸酯的前药 |
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GB1620710.2 | 2016-12-06 | ||
GBGB1620710.2A GB201620710D0 (en) | 2016-12-06 | 2016-12-06 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
GBGB1702321.9A GB201702321D0 (en) | 2017-02-13 | 2017-02-13 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
GB1702321.9 | 2017-02-13 | ||
GBGB1709147.1A GB201709147D0 (en) | 2017-06-08 | 2017-06-08 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
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JANSA, PETR ET AL: "A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 9, 23 May 2011 (2011-05-23), pages 3748 - 3754, XP002777413, ISSN: 0223-5234, DOI: 10.1016/J.EJMECH.2011.05.040 * |
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