US20220033416A1 - Compounds useful to treat influenza virus infections - Google Patents
Compounds useful to treat influenza virus infections Download PDFInfo
- Publication number
- US20220033416A1 US20220033416A1 US17/297,407 US202017297407A US2022033416A1 US 20220033416 A1 US20220033416 A1 US 20220033416A1 US 202017297407 A US202017297407 A US 202017297407A US 2022033416 A1 US2022033416 A1 US 2022033416A1
- Authority
- US
- United States
- Prior art keywords
- dihydrodibenzo
- oxazino
- pyrido
- selenepin
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 210
- 241000712461 unidentified influenza virus Species 0.000 title abstract description 32
- 230000009385 viral infection Effects 0.000 title abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims description 103
- 239000012453 solvate Substances 0.000 claims description 72
- -1 (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl Chemical group 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 23
- ITFBHIXXJXZODU-UHFFFAOYSA-N pyrido[2,1-f][1,2,4]triazine-6,8-dione Chemical compound N=1N2C(C=NC=1)=CC(CC2=O)=O ITFBHIXXJXZODU-UHFFFAOYSA-N 0.000 claims description 22
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 20
- 206010022000 influenza Diseases 0.000 claims description 19
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 10
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- QLSHGPRJKVXEOF-CTNGQTDRSA-N (3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H]1C(C=CC=C2)=C2[Se]CC2=C1C=CC(F)=C2F QLSHGPRJKVXEOF-CTNGQTDRSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- QLSHGPRJKVXEOF-UHFFFAOYSA-N 2-(7,8-difluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl)-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC(C(C=C1)=O)=C(C(N2C3COCC2)=O)N1N3C1C(C=CC=C2)=C2[Se]CC2=C1C=CC(F)=C2F QLSHGPRJKVXEOF-UHFFFAOYSA-N 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
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- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 3
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 claims description 3
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical compound COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 claims description 3
- RCIJMMSZBQEWKW-UHFFFAOYSA-N methyl propan-2-yl carbonate Chemical compound COC(=O)OC(C)C RCIJMMSZBQEWKW-UHFFFAOYSA-N 0.000 claims description 3
- OHRSDUICXUPLMB-NFBKMPQASA-N (3R)-2-[(11S)-7,8,10-trifluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound O=C(C=C1)C=C(C(N2[C@H]3COCC2)=O)N1N3[C@H](C(C=CC=C1)=C1[Se]C1)C(C(F)=C2)=C1C(F)=C2F OHRSDUICXUPLMB-NFBKMPQASA-N 0.000 claims description 2
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- FDXRGCIPLSFETN-DTERAVRUSA-N 1-[[(3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-9,12-dioxo-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-dien-11-yl]oxy]ethyl methyl carbonate Chemical compound CC(OC(OC)=O)OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H]1C(C=CC=C2)=C2[Se]CC2=C1C=CC(F)=C2F FDXRGCIPLSFETN-DTERAVRUSA-N 0.000 claims description 2
- STFITYSJMATEFR-TZIWHRDSSA-N (3R)-2-[(11S)-7,10-difluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@H](C(C=CC=C1)=C1[Se]C1)C2=C1C(F)=CC=C2F STFITYSJMATEFR-TZIWHRDSSA-N 0.000 claims 2
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- NMTCTTLMJRYZCD-RTWAWAEBSA-N (3R)-2-[(11S)-7-fluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H]1C(C=CC=C2)=C2[Se]CC2=C1C=CC=C2F NMTCTTLMJRYZCD-RTWAWAEBSA-N 0.000 claims 1
- DOTKDCWYDHXNLB-NHCUHLMSSA-N (3R)-2-[(11S)-8,9-difluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@H](C(C=CC=C1)=C1[Se]C1)C(C=C2F)=C1C=C2F DOTKDCWYDHXNLB-NHCUHLMSSA-N 0.000 claims 1
- VHKUEZHZZIJKTH-NHCUHLMSSA-N (3R)-2-[(11S)-9-fluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@H](C(C=CC=C1)=C1[Se]C1)C2=C1C=CC(F)=C2 VHKUEZHZZIJKTH-NHCUHLMSSA-N 0.000 claims 1
- VXTIDRRPPYRYOC-NLFIYDQTSA-N 1-[[(3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-9,12-dioxo-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-dien-11-yl]oxy]ethyl (2S)-2-amino-3-methylbutanoate Chemical compound CC(C)[C@@H](C(OC(C)OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H]1C(C=CC=C2)=C2[Se]CC2=C1C=CC(F)=C2F)=O)N VXTIDRRPPYRYOC-NLFIYDQTSA-N 0.000 claims 1
- GXTPEQLRUBTFGH-GGAORHGYSA-N [(3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzoselenepin-11-yl]-9,12-dioxo-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-dien-11-yl] acetate Chemical compound CC(OC(C(C=C1)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H]1C(C=CC=C2)=C2[Se]CC2=C1C=CC(F)=C2F)=O GXTPEQLRUBTFGH-GGAORHGYSA-N 0.000 claims 1
- 208000036142 Viral infection Diseases 0.000 abstract description 7
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- This disclosure relates generally to compounds and compositions that may be useful for treatment of viral infections.
- Influenza occurs in annual outbreaks each fall and winter worldwide. Influenza typically causes a self-limited respiratory illness with fever that lasts from 3 to 7 days. In spite of the availability of influenza vaccines, across the globe, there are an estimated 1 billion cases of influenza, 3-5 million are severe cases and 290000-650000 lead to influenza-related respiratory deaths each year (WHO: Global Influenza Strategy 2019-2030 and torto A D et al. Lancet. 2018, 391, 1285-300).
- Influenza viruses belong to the family Orthomyxoviridae, which are enveloped viruses containing a single-stranded, negative-sense RNA genome.
- Two classes of anti-Influenza viruses therapies, M2 ion-channel inhibitors and neuraminidase inhibitors, are commonly available in the past decades. However, resistance to M2 ion-channel inhibitors has been widely observed, and the emergence of antiviral resistance to neuraminidase inhibitors remains a threat.
- Matrix Protein 2 (M2) Inhibitors inhibit influenza A virus replication by occluding the M2 proton channel, but lack activity against influenza B virus (Gu R, Liu L A, Wei D, Trends Pharmacol Sci 2013, 34, 571).
- Influenza viral RNA—dependent RNA polymerase (RdRp) with endonuclease activity cleaves a section of the capped 5′-end of cellular mRNA and use them to prime transcription of viral mRNA, the process known as “cap-snatching”.
- RdRp dependent RNA polymerase
- the influenza virus polymerase complex has received considerable attention as a target to small molecule inhibitors for the treatment of influenza virus infection (Stevaert, A. & Naesens, L, Medicinal Research Reviews 2016, 36, 1127-1173).
- baloxavir marboxil Xofluza
- CEN cap-dependent endonuclease
- Baloxavir marboxil is a prodrug that is converted through hydrolysis to its active form, baloxavir.
- Baloxavir inhibits influenza virus polymerase acidic (PA) protein endonuclease resulting in inhibition of viral RNA synthesis.
- PA influenza virus polymerase acidic
- FIG. 1A and FIG. 1B illustrate antivirus efficacy in influenza virus PR/8/34 mouse model.
- FIG. 1A shows the body weight change and
- FIG. 1B shows the percent survival, when Compound B-1, Compound C-1, Oseltamivir Phosphate or vehicle was administered.
- R 1 , R 2 , R 3 , R 4 , m, n, p, and G are as detailed herein.
- R 1 , R 2 , R 3 , R 4 , m, n, p, and G are as detailed herein.
- the compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof is of Formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), as detailed herein.
- a method of treating influenza comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (II), or pharmaceutically acceptable salt, stereoisomer or solvate thereof.
- compositions comprising: (A) a compound detailed herein, such as a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and (B) a pharmaceutically acceptable carrier or excipient.
- Kits comprising a compound detailed herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof and optionally instructions for use are also provided.
- Compounds as detailed herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof are provided for use as a medicament.
- Compounds as detailed herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof are also provided for the manufacture of a medicament for the treatment or prevention of influenza virus infections.
- the terms “about” and “approximately,” when used in connection with a value contemplate a variation within ⁇ 15%, within ⁇ 10%, within ⁇ 5%, within ⁇ 4%, within ⁇ 3%, within ⁇ 2%, within ⁇ 1%, or within ⁇ 0.5% of the specified value.
- Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
- Alkyl refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbon atoms).
- Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkyl”), having 1 to 10 carbon atoms (a “C 1 -C 10 alkyl”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkyl”), having 1 to 6 carbon atoms (a “C 1 -C 6 alkyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkyl”), or having 1 to 4 carbon atoms (a “C 1 -C 4 alkyl”).
- alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
- Cycloalkyl refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C 3 -C 10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms.
- a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C 3 -C 8 cycloalkyl”), having 3 to 6 carbon atoms (a “C 3 -C 6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a “C 3 -C 4 cycloalkyl”).
- Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
- Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, and from 1 to 4 ring heteroatoms, preferably from 1 to 3 heteroatoms, and more preferably from 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
- Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems.
- one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
- the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties.
- Halo or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85.
- Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
- An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.”
- a preferred perhaloalkyl group is trifluoromethyl (—CF 3 ).
- “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
- a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
- coordinates with an organic base e.
- Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
- Acceptable inorganic bases which can be used to prepared salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
- Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
- a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
- a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
- excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
- a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
- Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
- Stereoisomer or “stereoisomers” refer to compounds that differ in the stereogenicity of the constituent atoms such as, without limitation, in the chirality of one or more stereocenters or related to the cis or trans configuration of a carbon-carbon or carbon-nitrogen double bond. Stereoisomers include enantiomers and diastereomers.
- treatment is an approach for obtaining beneficial or desired results including clinical results.
- beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of an individual.
- an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
- beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
- beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
- an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence.
- An effective dosage can be administered in one or more administrations.
- an effective dosage of compound or a salt thereof, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
- the term “subject” is a mammal, including humans.
- a subject includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the subject is human.
- substantially pure intends a composition that contains no more than 10% impurity, such as a composition comprising less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurity.
- the invention provides a compound of Formula (I):
- each R is selected from the group consisting of C 1 -C 6 alkyl, phenyl, pyridyl, C 3 -C 6 cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O and S as ring members, wherein the C 1 -C 6 alkyl, phenyl, pyridyl, C 3 -C 6 cycloalkyl, and 4-6 membered heterocyclic ring of R are independently optionally substituted with one or two substituents selected from the group consisting of H, halo, CN, OH, NH 2 , C 1 -C 3 alkyl, phenyl, C 1 -C 4 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy; and
- each R′ is independently selected from the group consisting of H and C 1 -C 3 alkyl.
- R 1 , R 2 , R 3 , R 4 , m, n, p, and G are as detailed herein for Formula (I).
- provides is a compound selected from the group consisting of:
- the invention provides a compound of Formula (II):
- each R is selected from the group consisting of C 1 -C 6 alkyl, phenyl, pyridyl, C 3 -C 6 cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O and S as ring members, wherein the C 1 -C 6 alkyl, phenyl, pyridyl, C 3 -C 6 cycloalkyl, and 4-6 membered heterocyclic ring of R are independently optionally substituted with one or two substituents selected from the group consisting of H, halo, CN, OH, NH 2 , C 1 -C 3 alkyl, phenyl, C 1 -C 4 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy; and
- each R′ is independently selected from the group consisting of H and C 1 -C 3 alkyl.
- R 1 , R 2 , R 3 , R 4 , m, n, p, and G are as detailed herein for Formula (II).
- the invention provides a compound of Formula (I), (I-1), (I-2), (I-3), (II), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein G is hydrogen or is selected from the group consisting of:
- compositions of any of the compounds detailed herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof are embraced by this disclosure.
- the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
- the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
- Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
- a compound as detailed herein or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
- Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
- a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
- the compounds herein are synthetic compounds prepared for administration to an individual.
- compositions are provided containing a compound in substantially pure form.
- the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier.
- methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
- a compound detailed herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
- oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
- parenteral e.g., intramuscular, subcutaneous or intravenous
- topical or transdermal delivery form e.g., topical or transdermal delivery form.
- a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
- suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
- One or several compounds described herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
- a pharmaceutically acceptable carrier such as those mentioned above.
- the carrier may be in various forms.
- pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
- Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
- Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington's Pharmaceutical Sciences , Mack Publishing Company, Philadelphia, Pa., 20 th ed. (2000), which is incorporated herein by reference.
- Compounds or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
- Examples of carriers, which may be used for the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
- Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
- pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
- any of the compounds described herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
- the invention includes methods of using the same as further described herein.
- the compounds of Formula (I) and (II), including all formulae (I-1), (I-2), (I-3), (II-1), (II-2), and (II-3), are inhibitors of the endonuclease function of influenza viruses as shown by the data provided herein, and they inhibit replication of influenza viruses. Accordingly, these compounds are useful to treat or prevent influenza virus infections in humans.
- the invention provides pharmaceutical compositions comprising a compound of Formula (I) or (II), such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), and (II-3), administered with at least one pharmaceutically acceptable carrier or excipient, optionally administered with two or more pharmaceutically acceptable carriers or excipients.
- a compound of Formula (I) or (II) such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), and (II-3), administered with at least one pharmaceutically acceptable carrier or excipient, optionally administered with two or more pharmaceutically acceptable carriers or excipients.
- the compounds may be used as pharmaceutically acceptable salts and hydrates.
- the invention provides a method to treat a subject infected with influenza A, B or C, which comprises administering to a subject in need of such treatment an effective amount of a compound of Formula (I) or (II), such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or any subgenus or species thereof as described herein, or a pharmaceutical composition comprising such compound.
- a compound of Formula (I) or (II) such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or any subgenus or species thereof as described herein, or a pharmaceutical composition comprising such compound.
- the subject is a human, although the compounds and methods of the invention are suitable for treatment of other species that contract Influenza A, Influenza B, or influenza C, as well as other influenza viruses.
- compounds of the invention are useful in the treatment of an infection caused by an influenza virus, particularly Influenza A, Influenza B or Influenza C, especially in human subjects having or at risk of contracting an influenza viral infection.
- subjects having pre-existing conditions related to autoimmune or respiratory diseases that can be greatly exacerbated by an influenza infection may be treated with the methods or compounds of the invention before exhibiting symptoms of an influenza infection.
- the subject for treatment is one diagnosed as having symptoms consistent with an influenza infection.
- the present invention provides the use of compounds as described herein as therapeutics.
- the compounds are suitable for use to treat a subject having or at particularly high risk for an influenza virus viral infection, especially Influenza A, Influenza B, or Influenza C.
- the invention provides a method of treating a disease which is caused by an influenza virus, comprising administration of a therapeutically effective amount of a compound of formula (I) or (II) as described herein, such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, to a subject in need of such treatment.
- the compound or a pharmaceutically acceptable salt, stereoisomer, solvate thereof is administered orally.
- the disease is selected from Influenza A, Influenza B, and Influenza C.
- the method typically comprises administering an effective amount of a compound as described herein, or a pharmaceutical composition comprising an effective amount of such compound, to a subject in need of such treatment.
- the compound may be administered by any suitable method such as those described herein, and the administration may be repeated at intervals which may be selected by a physician. In some aspects, the compound or pharmaceutical composition is administered orally.
- the present invention provides the use of a compound of formula (I) or (II), such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, for the manufacture of a medicament.
- the medicament is for treatment of an influenza virus infection, especially Influenza A, Influenza B, or Influenza C.
- the compound of the present invention may be administered either simultaneously with, or before or after, one or more therapeutic(s).
- the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the therapeutic(s).
- Suitable therapeutic(s) for use with the compounds of the invention include antivirals active on influenza viruses, such as neuraminidase inhibitors including oseltamivir, peramivir, zanamivir and laninamivir, laninamivir octanoate, and adamantanes such as amantadine and rimantadine.
- the compounds can be combined with an M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, favipiravir, fludase, beraprost, Neugene®, ribavirin, Flu Mist Quadrivalent®, Fluarix® Quadrivalent, Fluzone® Quadrivalent, Flucelvax® and FluBlok®.
- the invention provides a product comprising a compound of formula (I) or (II), such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, and at least another therapeutic as a combined preparation for simultaneous, separate or sequential use in therapy.
- a compound of formula (I) or (II) such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, and at least another therapeutic as a combined preparation for simultaneous, separate or sequential use in therapy.
- the invention also provides a therapeutic for use in a method of treating a viral infection caused by an influenza virus, particularly Influenza A, Influenza B or Influenza C, wherein the a therapeutic is administered with a compound of formula (I) or (II), such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof.
- a compound of formula (I) or (II) such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof.
- the invention also provides the use of a compound of formula (I) or (II), such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, for treating a viral infection caused by an influenza virus, particularly influenza, such as Influenza A, Influenza B or Influenza C, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent.
- a compound of formula (I) or (II) such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, for treating a viral infection caused by an influenza virus, particularly influenza, such as Influenza A, Influenza B or Influenza C, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent.
- the invention also provides the use of another therapeutic agent for treating a viral infection caused by an influenza virus, particularly Influenza A, Influenza B or Influenza C, wherein the patient has previously (e.g., within 24 hours) been treated with a compound of formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof.
- the combination therapeutics is selected from antivirals purported to be useful for treating infections caused by influenza viruses, such as neuraminidase inhibitors including oseltamivir, peramivir, zanamivir and laninamivir, and adamantanes such as amantadine and rimantadine.
- influenza viruses such as neuraminidase inhibitors including oseltamivir, peramivir, zanamivir and laninamivir, and adamantanes such as amantadine and rimantadine.
- the pharmaceutical composition or combination of the present invention in human is dependent on the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
- the effective dose is determined by a physician or clinician to prevent, treat or inhibit the progress of the disorder or disease.
- the above cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
- the invention further includes processes to make the compounds of Formulae (I) and (II), such as a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), as disclosed herein.
- a therapeutically effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt or ester thereof is administered via any of the usual and acceptable methods known in the art, either singly or in combination.
- the compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions.
- buccal cavity e.g., buccal cavity
- parenterally e.g., intramuscularly, intravenously, or subcutaneously
- rectally e.g., by suppositories or washings
- transdermally e.g., skin electrop
- the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.
- the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.
- the dose of a compound administered to an individual may vary with the particular compound or salt thereof, the method of administration, and the particular disease being treated.
- the effective amount of the compound may, in one aspect, be a daily dose of between about 0.01 and about 100 mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg of body weight.
- the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day.
- Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject's health status, condition, and weight.
- An exemplary dose is in the range of about from about 0.1 mg to 10 g daily.
- an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day
- an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the pharmacokinetics.
- a compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life.
- the compound is administered on a daily or intermittent schedule.
- the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
- the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
- the dosing frequency can be more than once daily, e.g., twice or three times daily.
- the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
- a drug holiday e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more.
- the present disclosure further provides articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging.
- the article of manufacture is for use in any of the methods described herein.
- suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
- An article of manufacture may further be sterilized and/or sealed.
- kits for carrying out the methods of the disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
- the kits may employ any of the compounds disclosed herein.
- the kit employs a compound described herein or a pharmaceutically acceptable salt thereof.
- the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of disease described herein.
- Kits generally comprise suitable packaging.
- the kits may comprise one or more containers comprising any compound described herein.
- Each component if there is more than one component
- kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
- kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein (e.g., hypertension) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
- Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
- kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
- the instructions included with the kit generally include information as to the components and their administration to an individual.
- the invention provides selenium and/or phosphine containing compounds.
- Embodiment 1 A compound of Formula (A):
- R 3 is selected from H, F, Cl, Br, Me, CN, and P(O)Me2;
- G is H or is a group selected from C(O)R, C(O)OR, C(O)NR′R, C(R′)2-O—C(O)R, C(R′)2-OC(O)OR, and C(R′)2-O—C(O)NR, where each R is a group selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S as ring members; and each R is optionally
- Embodiment 6 The compound of embodiment 1, which is of the formula B:
- Embodiment 8 The compound of embodiment 1, which is of the formula C:
- G is H or a group selected from C(O)R, C(O)OR, C(O)NR′R, C(R′)2-O—C(O)R, C(R′)2-O—C(O)OR, and C(R′)2-O—C(O)NR, where each R is a group selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S as ring members; and each R is optionally substituted with one or two groups selected from H, halo, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and each R′ is independently selected from
- Embodiment 9 The compound of embodiment 8, which is of the formula D:
- G is H or a group selected from C(O)R, C(O)OR, C(O)NR′R, C(R′)2-O—C(O)R, C(R′)2-O—C(O)OR, and C(R′)2-O—C(O)NR, where each R is a group selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S as ring members; and each R is optionally substituted with one or two groups selected from H, halo, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and each R′ is independently selected from the group consisting of H and C1-C3 alkyl, or a pharmaceutically acceptable
- Embodiment 11 A pharmaceutical composition comprising a compound of embodiment 1, or a pharmaceutically acceptable salt and solvate thereof, and one or more pharmaceutically acceptable carriers.
- Embodiment 12 A method of treating influenza, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of embodiment 1, or a pharmaceutically acceptable salt and solvate thereof.
- Reagents and solvates used below can be obtained from commercial sources.
- 1 H NMR spectra were recorded on Varian III plus 300 MHz and TMS was used as an internal standard. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons.
- solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), ethyl acetate (EA or EtOAc), dichloromethane (DCM), diethyl ether, methanol, pyridine, formic acid (FA) and the like.
- the solvates used in the reactions of the present invention are inert organic solvates, and the reactions are carried out under an inert gas, preferably nitrogen and argon.
- A-1-P1 and A-1-P2 each are both a mixture of two diastereomers.
- a mixture of stereoisomers may be separated by any suitable method, including, but not limited to, chiral HPLC.
- chiral HPLC When a mixture of stereoisomers is separated by HPLC, it is to be appreciated that the resultant individual stereoisomers or mixtures will be assigned sequential labels (e.g., P1, P2, etc.), the order of which implies the order in which the isomers eluted from the HPLC column.
- provided herein is a compound selected from the group consisting of:
- provided herein is a compound selected from the group consisting of:
- provided herein is a compound selected from the group consisting of.
- provided herein is a compound selected from the group consisting of:
- Step 1 To a suspension of compound 11 (150 mg, 0.458 mmol) in EA (3.2 mL) was added hexane (1.25 mL), stirred at r.t for 10 min, added T 3 P (1.5 g, 2.36 mmol) and the mixture was stirred at r.t. for 30 min, added 7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol (175 mg, 0.51 mmol) and the reaction mixture was stirred at 35° C.
- Step 2 To a mixture of 7-(benzyloxy)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (50 mg, 0.087 mmol) in CCl 4 (10 mL) and DMF (0.2 mL) was added NBS (31 mg). Then the mixture was stirred at r.t. overnight, washed with water and dried over Na 2 SO 4 .
- Step 1 7-(benzyloxy)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (16a and 16 b)
- Step 2 Synthesis of 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (E-1a and E-1b)
- E-1a and E-1b each are a mixture of two diastereomers.
- Step 1 Synthesis of (((R)-9-bromo-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (18)
- provided herein is a compound selected from the group consisting of:
- Step 1 To a solution of compound 20 (200 mg, 0.307 mmol) in MeCN (9 mL) was added diethylphosphine oxide (390 mg, 3.68 mmol), TEA (220 mg, 2.18 mmol), Pd(dppf)Cl 2 (60 mg), filled with N 2 for 3 times. Under N 2 , the reaction was stirred at 90° C. for 20 h. Cooled to rt, the mixture was evaporated to dryness and diluted with water, extracted with EA (5 mL*3), dried over Na 2 SO 4 and evaporated.
- diethylphosphine oxide 390 mg, 3.68 mmol
- TEA 220 mg, 2.18 mmol
- Pd(dppf)Cl 2 60 mg
- Step 2 To a suspension of compound 22 (150 mg, 0.22 mmol) in NMP (1 mL) was added LiCl (93 mg, 2.2 mmol), then stirred at 80° C. overnight. The reaction was directly purified by Prep-HPLC (0.1% TFA) to afford compound F-1 (77 mg, 59.2%) as a white solid.
- the activity of a compound according to the present invention can be assessed by the following in vitro and in vivo methods.
- test assays described herein Using the test assays described herein, representative compounds of the invention are tested by in vitro assays.
- CV Max (SD Max /Mean Max )*100%
- MDCK cells were seeded in 96 well plates at a density of 15,000 cells/well and cultured at 37° C. and 5% CO 2 overnight. Next day, serially diluted compounds and viruses were added in to cells. The resulting cultures were kept at 35° C. or 37° C. and 5% CO 2 for additional 5 days until virus infection in the virus control (cells infected with virus, without compound treatment) display significant cytopathic effect (CPE). Antiviral activity of the compounds was calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.
- CPE cytopathic effect
- Cytotoxicity of the compounds was assessed under the same conditions, but without virus infection, in parallel. Cell viability was measured with CCK8 following the manufacturer's manual.
- Antiviral activity and cytotoxicity of the compounds are expressed as % Inhibition and % Viability, respectively, and calculated with the formulas below:
- Raw data CPD indicates the values of the sample-treated wells; Average VC , Average CC and Average MC indicate the average values of the virus control, cell control (cells without virus infection or compound treatment) and medium control (medium only) wells, respectively.
- EC 50 and CC 50 values were calculated using the GraphPad Prism software with equation “log(inhibitor) vs. response—Variable slope”. Data are listed in Table 2. Representative compounds, in particular, B-1 showed potent antivirus activity and little cytotoxicity.
- Balb/c mice of 6-8 week old were used in this study.
- the influenza virus PR/8/34 diluent was pipetted by a pipette and inoculated via intranasal route at the amount of 1,000 PFU in 50 ⁇ L/animal after animals were deeply anesthetized on the day of inoculation (day 0).
- B-1 dosing solutions were prepared in 5% DMSO/40% PEG400/55% water at 0.5 mg/mL.
- C-1 dosing solutions were prepared in 5% DMSO/40% PEG400/55% water at 0.15 mg/mL and 0.5 mg/mL.
- Oseltamivir Phosphate dosing solutions were prepared in PBS X1 at 1 mg/ml.
- the vehicle was 5% DMSO/40% PEG400/55% water solution.
- B-1, C-1, Oseltamivir Phosphate or vehicle was administered via PO route following the regimen of BID (8/16 h) from day 1 to day 7 at 10 mL/kg/day, with first dose given at 24 hours post virus inoculation. Animal body weight and survival were continuously monitored from day 0 to day 14. Animals that lose more than 35 percent of their body weight will be euthanized and included into the death number. The body weight and survival rate of the animals were statistically analyzed to evaluate the in vivo efficacy of B-1, C-1, Oseltamivir Phosphate and vehicle in the influenza mouse infection model. The results were summarized in FIG. 1A and FIG. 1B .
- Liver microsomal assay was used to evaluate the metabolic stability of A-1-P2.
- A-1-P2 at the concentration of 1 ⁇ M was incubated with 0.5 mg/mL liver microsome in the presence of NADPH and UDPGA as the co-factors for 0, 15, 30, 45 and 60 minutes. The incubation was carried out at 37° C. with 5% CO 2 and saturating humidity. Disappearance of the compound was monitored by LC/MS/MS and t 1/2 and intrinsic clearance were calculated from the disappearance of the compound.
- the determined t 1/2 and intrinsic clearance of A-1-P2 in different species is described herein in Table 3.
- B-1 was administered to non-fasted male SD rats (6-8 weeks old, 200-300 grams, 3 animals each group) via intravenous (IV) bolus at 0.25 mg/kg and by oral gavage (PO) at 3 mg/kg.
- C-1 was administered to 3 non-fasted male SD rats via oral gavage at 3 mg/kg.
- Blood samples ( ⁇ 0.2 mL each time point) were collected via the jugular vein into tubes containing potassium ethylenediaminetetraacetic acid (K 2 EDTA) as the anticoagulant at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose for IV administration and 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose for PO administration.
- K 2 EDTA potassium ethylenediaminetetraacetic acid
- the blood samples were then centrifuged for 5 minutes in a centrifuge refrigerated at 4° C.
- the resultant plasma samples were analyzed using LC/MS/MS to determine concentrations of B-1.
- Non-compartmental model with WinNonlin (PhoenixTM, version 8.0) software was used to calculate pharmacokinetic (PK) parameters.
- the PK results are listed in Table 4.
- the oral bioavailability of B-1 following oral gavage administration of B-1 in rats is 14%; and the oral bioavailability of B-1 following oral gavage administration of the prodrug C-1 is 30%.
- baloxavir marboxil NDA document the oral bioavailability of baloxavir in rats is 0.69% following oral administration of baloxavir, and the oral bioavailability of baloxavir in rats is 9.8-14.7% following administration of its prodrug baloxavir marboxil (Baloxavir marboxil NDA document).
- B-1 was administered to male CD-1 mice (4-6 weeks old, 20-30 grams, 3 animals each group) via intravenous (IV) bolus at 1 mg/kg and by oral gavage (PO) at 10 mg/kg.
- C-1 was administered to 3 male CD-1 mice via oral gavage at 10 mg/kg. All animals had free access to food and water prior to dosing.
- Blood samples ( ⁇ 0.03 mL each time point) were collected via the jugular vein into tubes containing sodium heparin as the anticoagulant at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose for IV administration and 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose for PO administration.
- the blood samples were then centrifuged for 5 minutes in a centrifuge refrigerated at 4° C.
- the resultant plasma samples were analyzed using LC/MS/MS to determine concentrations of B-1.
- Non-compartmental model with WinNonlin (PhoenixTM, version 8.0) software was used to calculate pharmacokinetic (PK) parameters.
- the PK results are listed in Table 5.
- the oral bioavailability of B-1 following oral gavage administration of B-1 in mice is 35%; and the oral bioavailability of B-1 following oral gavage administration of the prodrug C-1 is 55%.
- B-1 was administered to male cynomolgus monkeys (2-5 years old, 2-5 kg, 3 animals each group) via intravenous (IV) bolus at 0.25 mg/kg and by oral gavage (PO) at 1 mg/kg; Animals in the IV group had free access to food and water (non-fasted) and animals in the PO group were fasted overnight prior to dosing (fasted).
- C-1 was administered to male cynomolgus monkeys (fasted or non-fasted, 3 each group) via oral gavage at 1 mg/kg.
- Plasma samples ( ⁇ 0.5 mL each time point) were collected via the jugular vein into tubes containing potassium ethylenediaminetetraacetic acid (K 2 EDTA) as the anticoagulant at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose for IV administration and 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose for PO administration.
- K 2 EDTA potassium ethylenediaminetetraacetic acid
- the blood samples were then centrifuged for 10 minutes in a centrifuge refrigerated at 2-8° C.
- the resultant plasma samples were analyzed using LC/MS/MS to determine concentrations of B-1.
- Non-compartmental model with WinNonlin (PhoenixTM, version 6.1) software was used to calculate pharmacokinetic (PK) parameters.
- the PK results are listed in Table 6.
- the oral bioavailability of B-1 following oral gavage administration of B-1 in monkeys is 27%.
- the oral bioavailability of B-1 following oral gavage administration of the prodrug C-1 is 57% and 53% at fasted and non-fasted conditions, respectively; and feeding condition did not impact oral absorption of C-1.
- baloxavir marboxil NDA document the oral bioavailability of baloxavir following administration of its prodrug baloxavir marboxil was largely affected by feeding conditions.
- the oral bioavailability of baloxavir was 10.5-11.5% and 50.6%, respectively, following oral administration of baloxavir marboxil to non-fasted and fasted monkeys (Baloxavir marboxil NDA document).
- C-1 Sprague Dawley (SD) rats.
- C-1 at 20, 100 and 500 mg/kg or vehicle (0.5% w/v CMC-Na and 0.1% v/v Tween-80 in DI water) was administered via oral gavage to Sprague Dawley rats (7-9 weeks, about 250-300 grams each for males and about 200-250 grams each for females) once daily for 7 days. 8 females and 8 males in each dose group were used.
- No C-1-related toxic findings including abnormal clinical observation, alterations in body weight, change in food consumption and change in gross pathology) were observed at all the dose levels.
- C-1 was well tolerated and the maximum tolerated dose (MTD) was greater than 500 mg/kg/day in Sprague Dawley rats.
- MTD maximum tolerated dose
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TW202308646A (zh) * | 2021-05-10 | 2023-03-01 | 大陸商南京征祥醫藥有限公司 | 治療流感化合物的晶型及應用 |
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CN113004304B (zh) | 2015-04-28 | 2022-03-18 | 盐野义制药株式会社 | 经取代的多环性吡啶酮衍生物及其前药 |
SG11201804348SA (en) * | 2015-12-15 | 2018-06-28 | Shionogi & Co | Medicine for treating influenza characterized by comprising combination of cap-dependent endonuclease inhibitor with anti-influenza drug |
BR112019001911A2 (pt) * | 2016-08-10 | 2019-05-07 | Shionogi & Co., Ltd. | derivado de piridona policíclica substituída e pró-fármaco contendo composição farmacêutica do mesmo |
WO2019052565A1 (fr) * | 2017-09-18 | 2019-03-21 | 广东东阳光药业有限公司 | Inhibiteur de la réplication du virus de la grippe et son utilisation |
CN109503625A (zh) * | 2018-01-19 | 2019-03-22 | 赵蕾 | 一种多环吡啶酮化合物及其药物组合和用途 |
KR20220034827A (ko) | 2019-07-11 | 2022-03-18 | 난징 젱시앙 파마슈티칼스 컴퍼니 리미티드 | 인플루엔자 바이러스 감염의 치료에 유용한 화합물 |
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2020
- 2020-07-10 KR KR1020227004191A patent/KR20220034827A/ko unknown
- 2020-07-10 US US17/297,407 patent/US20220033416A1/en not_active Abandoned
- 2020-07-10 CA CA3142030A patent/CA3142030A1/fr active Pending
- 2020-07-10 BR BR112022000503A patent/BR112022000503A2/pt unknown
- 2020-07-10 WO PCT/US2020/041578 patent/WO2021007506A1/fr unknown
- 2020-07-10 CN CN202080004760.3A patent/CN113226327B/zh active Active
- 2020-07-10 MX MX2022000453A patent/MX2022000453A/es unknown
- 2020-07-10 AU AU2020310921A patent/AU2020310921A1/en active Pending
- 2020-07-10 JP JP2022500920A patent/JP2022541404A/ja active Pending
- 2020-07-10 TW TW109123422A patent/TWI841759B/zh active
- 2020-07-10 CN CN202210528727.1A patent/CN114907378A/zh active Pending
- 2020-07-10 EP EP20836808.4A patent/EP3996716A4/fr active Pending
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2022
- 2022-01-05 US US17/569,367 patent/US11466029B2/en active Active
- 2022-01-06 IL IL289655A patent/IL289655A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180118760A1 (en) * | 2015-04-28 | 2018-05-03 | Shionogi & Co., Ltd. | Substituted polycyclic pyridone derivatives and prodrugs thereof |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11466029B2 (en) | 2019-07-11 | 2022-10-11 | Nanjing Zhengxiang Pharmaceuticals Co., Ltd. | Compounds useful to treat influenza virus infections |
Also Published As
Publication number | Publication date |
---|---|
KR20220034827A (ko) | 2022-03-18 |
AU2020310921A1 (en) | 2022-02-10 |
CN113226327B (zh) | 2022-05-17 |
US20220127282A1 (en) | 2022-04-28 |
WO2021007506A1 (fr) | 2021-01-14 |
EP3996716A4 (fr) | 2023-07-26 |
CN113226327A (zh) | 2021-08-06 |
CA3142030A1 (fr) | 2021-01-14 |
IL289655A (en) | 2022-03-01 |
MX2022000453A (es) | 2022-04-18 |
JP2022541404A (ja) | 2022-09-26 |
TW202118763A (zh) | 2021-05-16 |
BR112022000503A2 (pt) | 2022-06-07 |
CN114907378A (zh) | 2022-08-16 |
US11466029B2 (en) | 2022-10-11 |
EP3996716A1 (fr) | 2022-05-18 |
TWI841759B (zh) | 2024-05-11 |
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