[go: up one dir, main page]

WO2010011819A1 - Composés chimiques - Google Patents

Composés chimiques Download PDF

Info

Publication number
WO2010011819A1
WO2010011819A1 PCT/US2009/051504 US2009051504W WO2010011819A1 WO 2010011819 A1 WO2010011819 A1 WO 2010011819A1 US 2009051504 W US2009051504 W US 2009051504W WO 2010011819 A1 WO2010011819 A1 WO 2010011819A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
compound
difluorophenyl
dioxo
oxy
Prior art date
Application number
PCT/US2009/051504
Other languages
English (en)
Inventor
Brian Alvin Johns
Jason Gordon Weatherhead
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2010011819A1 publication Critical patent/WO2010011819A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • ARC Al DS-related complex
  • HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase.
  • Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.
  • a required step in HIV replication in human T-cells is the insertion by virally-encoded integrase of proviral DNA into the host cell genome. Integration is believed to be mediated by integrase in a process involving assembly of a stable nucleoprotein complex with viral DNA sequences, cleavage of two nucleotides from the 3' termini of the linear proviral DNA and covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The repair synthesis of the resultant gap may be accomplished by cellular enzymes.
  • HIV integrase is an attractive target for the discovery of new therapeutics due to its important role in viral infections, particularly HIV infections.
  • Integrase inhibitors are disclosed in WO2006/116724. Integrase inhibitors are disclosed in WO2006/116724.
  • the compounds of the present invention were designed to deliver active therapeutic agents.
  • the present invention features compounds that are prodrugs of HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.
  • the present invention features compounds of formula (I):
  • heterocyclyl optionally substituted with C 1 - C 8 alkyl or C(O)OR 2 wherein R 2 is C 1 - C 8 alkyl; b) NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of H and XR 5 , wherein X is alkylene and R 5 is heterocyclyl,
  • R 6 wherein R 6 is C 1 - C 8 alkyl, P(O)(OH) 2 , or C(O)OR 7 wherein R 7 is C 1 - C 8 alkyl heterocyclylalkyl, or XR 8 wherein R 8 is C 6-1 oaryl;
  • Figure 1 Plasma concentrations of (4R,12aS)- ⁇ /-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4- methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2/-/-pyrido[1 ',2':4,5]pyrazino[2,1-6][1 ,3]oxazine-9- carboxamide (compound 1 a of Scheme 2) and a prodrug, Example 2 .
  • the present invention features compounds of formula (I):
  • heterocyclyl optionally substituted with C 1 - C 8 alkyl or C(O)OR 2 wherein R 2 is C 1 - C 8 alkyl; b) NR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of H and XR 5 , wherein X is alkylene and R 5 is heterocyclyl,
  • R 6 wherein R 6 is C 1 - C 8 alkyl, P(O)(OH) 2 , or C(O)OR 7 wherein R 7 is C 1 - C 8 alkyl heterocyclylalkyl, or XR 8 wherein R 8 is C 6-1 oaryl;
  • the present invention also features compounds of formula (I) selected from the group consinsting of:
  • alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to twelve carbon atoms, unless otherwise defined.
  • alkylene examples include, but are not limited to, methylene, ethylene, propylene, butylene, isobutylene and the like.
  • aryl alone or in combination with any other term, refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-10 carbon atoms.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2- naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 -phenanthridinyl, 2-phenanthridinyl, 3- phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • heterocycle refers to a 3- to 7- membered monocyclic heterocyclic ring or 8-to 11- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, and which may be optionally benzofused if monocyclic.
  • Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized, and including any bicyclic group in which any of the above- defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any carbon or heteroatom, provided that the attachment results in the creation of a stable structure.
  • Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles.
  • Heteroaromatics or “heteroaryl” are included within the heterocycles as defined above and generally refers to a heterocycle in which the ring system is an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P.
  • heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8 - 10 membered bicyclic heteroaryls.
  • heterocycle “heterocyclic” or “heterocyclyl” is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring.
  • heterocycle, “heterocyclic” or “heterocyclyl” also included each possible positional isomer of a heterocyclic radical, such as in 1-indolinyl, 2-indolinyl, 3-indolinyl.
  • heterocycles include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, oxadiazol
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) ⁇ N + -O " ⁇ and sulfur such as S(O) and S(O) 2 , and the quaternized form of any basic nitrogen.
  • structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers of the present compounds are expressly included within the scope of the invention. Although the specific compounds exemplified herein may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are also within the scope of this invention.
  • tautomeric forms of the present compounds are within the scope of the invention. Unless otherwise indicated, the representation of either tautomer is meant to include the other.
  • pharmaceutically effective amount refers to an amount effective in treating a virus infection, for example an HIV infection, in a patient either as monotherapy or in combination with other agents.
  • treating refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent.
  • prophylactically effective amount refers to an amount effective in preventing a virus infection, for example an HIV infection, or preventing the occurrence of symptoms of such an infection, in a patient.
  • patient refers to a mammal, including a human.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiviral agent.
  • treatment refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. Treatment includes prophylaxis which refers to preventing a disease or condition or preventing the occurrence of symptoms of such a disease or condition, in a patient.
  • the term “patient” refers to a mammal, including a human.
  • subject refers to a patient, animal or a biological sample.
  • biological sample includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • acids examples include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW 4 + (wherein W is C 1-4 alkyl) and other amine salts.
  • alkali metal e.g. sodium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., ammonium
  • NW 4 + wherein W is C 1-4 alkyl
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids
  • inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a Ci -4 alkyl group).
  • Preferred salts include sodium, calcium, potassium and hydrochloride.
  • Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof.
  • Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.
  • One aspect of the instant invention relates to methods of treating or preventing viral infection, for example an HIV infection, in a biological sample comprising contacting the biological sample with compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • Another aspect of the instant invention relates to methods of treating or preventing viral infection, for example, an HIV infection, in a patient comprising administering to the patient a therapeutically effective amount of compounds of formula (I) or pharmaceutically acceptable salt thereof.
  • the compounds according to the invention are particularly suited to the treatment or prophylaxis of HIV infections and associated conditions.
  • compositions are a pharmaceutical composition, which comprises a compound of formula (I) and pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the composition comprises an amount of a compound of the present invention effective to treat or prevent viral infection, for example an HIV infection, in a biological sample or in a patient.
  • compounds of this invention and pharmaceutical compositions thereof which comprise an amount of a compound of the present innovation effective to inhibit viral replication or to treat or prevent a viral infection or disease or disorder, for example an HIV infection, and a pharmaceutically acceptable carrier, adjuvant or vehicle, may be formulated for administration to a patient, for example, for oral administration.
  • the present invention features compounds according to the invention for use in medical therapy, for example for the treatment or prophylaxis of a viral infection, for example an HIV infection and associated conditions.
  • the compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
  • AIDS related complex ARC
  • PDL progressive generalized lymphadenopathy
  • Kaposi's sarcoma Kaposi's sarcoma
  • thromobocytopenic purpura AIDS-related neurological conditions
  • AIDS dementia complex such as AIDS dementia complex, multiple sclerosis or tropical paraperesis
  • anti-HIV antibody-positive and HIV-positive conditions including such conditions in asymptomatic patients.
  • the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises administering to said patient a pharmaceutically effective amount of a compound according to the invention.
  • the viral infection is a retroviral infection, in particular an HIV infection.
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for administration to a subject for the treatment of a viral infection, in particular and HIV infection.
  • the compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
  • the present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention.
  • the present invention also includes a method for the treatment or prophylaxis of any of the aforementioned diseases or conditions.
  • Reference herein to treatment extends to prophylaxis as well as the treatment of established conditions, disorders and infections, symptoms thereof, and associated.
  • the above compounds according to the invention and their pharmaceutically acceptable salts may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions.
  • Combination therapies according to the present invention comprise the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof and another pharmaceutically active agent.
  • the active ingredient(s) and pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Examples of other therapeutic agents include:
  • Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
  • Non-nucleotide reverse transcriptase inhibitors include an agent having anti- oxidation activity such as immunocal, oltipraz, etc.
  • an agent having anti- oxidation activity such as immunocal, oltipraz, etc.
  • Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, raltegravir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;
  • Entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-Helix and similar agents; lntegrase inhibitors such as L-870,810, raltegravir and similar agents; Budding inhibitors such as PA-344 and PA-457, and similar agents; and CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449 and similar agents.
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least another therapeutic agent, such as those defined hereinbefore.
  • Compounds of the present invention may be administered with an agent known to inhibit or reduce the metabolism of compounds, for example ritonavir.
  • the present invention features a method for the treatment or prophylaxis of a disease as hereinbefore described by administration of a compound of the present invention in combination with a metabolic inhibitor. Such combination may be administered simultaneously or sequentially.
  • a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g.
  • a human per day, preferably in the range of 0.01 to 100 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally.
  • the desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 1 to 1000 mg, 20 to 500 mg, 10 to 500 mg, or 1 to 400 mg of active ingredient per unit dosage form.
  • compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
  • Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
  • Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical
  • compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the present invention further includes a pharmaceutical composition as hereinbefore defined wherein a compound of the present invention or a pharmaceutically acceptable salt thereof and another therapeutic agent are presented separately from one another as a kit of parts.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches suitably contain the active compound 1 ) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer.
  • a suitable concentration of the active compound is about 1% to 25%, preferably about 3% to 15%.
  • the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6). 318 (1986).
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross- linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray.
  • Pharmaceutical compositions may contain in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art.
  • a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Unit dosage pharmaceutical compositions include those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
  • compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • the compounds of the present invention may be prepared according to the following reactions schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known to those of ordinary skill in the art.
  • (4R,12aS)- ⁇ /-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a- hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1- ⁇ b][1 ,3]oxazine-9-carboxamide may be made by methods known to those skilled in the art, including methods disclosed in_WO2006/116724.
  • Example 1 ⁇ [(4R,12aS)-9-( ⁇ [(2,4-Difluorophenyl)methyl1amino ⁇ carbonyl)-4-methyl-6,8-dioxo- 3,4,6,8,12,12a-hexahvdro-2H-pyridori',2':4,5lpyrazinor2,1-bin ,3loxazin-7-ylloxy ⁇ methyl 1- pyrrolidinecarboxylate.
  • the title compound was prepared from ⁇ [(4R,12aS)-9-( ⁇ [(2,4- difluorophenyl)methyl]amino ⁇ carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- pyrido[1',2':4,5]pyrazino[2,1-b][1 ,3]oxazin-7-yl]oxy ⁇ methyl 4-nitrophenyl carbonate (200 mg, 0.325 mmol) morpholine (0.06 ml_, 0.651 mmol), triethylamine (0.14 ml_.
  • Example 3 ⁇ r(4R,12aS)-9-( ⁇ r(2,4-Difluorophenyl)methyl1amino ⁇ carbonyl)-4-methyl-6,8-dioxo- 3,4,6,8,12,12a-hexahvdro-2H-pyridori',2':4,5lpyrazinor2,1-bin ,3loxazin-7-ylloxy ⁇ methyl [2- (methyloxy)ethylicarbamate.
  • the title compound was prepared from ⁇ [(4R,12aS)-9-( ⁇ [(2,4- difluorophenyl)methyl]amino ⁇ carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- pyrido[1',2':4,5]pyrazino[2,1-b][1 ,3]oxazin-7-yl]oxy ⁇ methyl 4-nitrophenyl carbonate (200 mg, 0.325 mmol) [2-(methyloxy)ethyl]amine (0.06 ml_, 0.651 mmol), triethylamine (0.14 mL.
  • Example 4 ⁇ r(4R,12aS)-9-( ⁇ r(2,4-Difluorophenyl)methyllamino ⁇ carbonyl)-4-methyl-6,8-dioxo- 3.4.6.8.12.12a-hexahvdro-2H-pyridori'.2':4.5lpyrazinor2.1-bi ⁇ .3loxazin-7-ylloxy>methyl [2-(4- morpholinvDethyllcarbamate formic acid salt.
  • the title compound was prepared from ⁇ [(4R,12aS)-9-( ⁇ [(2,4- difluorophenyl)methyl]amino ⁇ carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- pyrido[1',2':4,5]pyrazino[2,1-b][1 ,3]oxazin-7-yl]oxy ⁇ methyl 4-nitrophenyl carbonate (200 mg, 0.325 mmol), [2-(4-morpholinyl)ethyl]amine (0.09 mL, 0.651 mmol), triethylamine (0.14 mL.
  • Example 5 ⁇ r(4R,12aS)-9-( ⁇ r(2,4-Difluorophenyl)methyllamino ⁇ carbonyl)-4-methyl-6,8-dioxo- 3.4.6.8.12.12a-hexahvdro-2H-pyridori'.2':4.5lpyrazinor2.1-bi ⁇ .3loxazin-7-ylloxy>methyl 4- methyl-1-piperazinecarboxylate formic acid salt.
  • the title compound was prepared from ⁇ [(4R,12aS)-9-( ⁇ [(2,4- difluorophenyl)methyl]amino ⁇ carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- pyrido[1',2':4,5]pyrazino[2,1-b][1 ,3]oxazin-7-yl]oxy ⁇ methyl 4-nitrophenyl carbonate (200 mg, 0.325 mmol), 1-methylpiperazine (0.07 ml_, 0.651 mmol), triethylamine (0.14 mL.
  • Fasted male CD rats received the compound of Example 2 as an oral suspension dose (5 mg parent equivalent/kg in 0.1% hydroxypropylmethylcellulose/0.1% Tween-80) administered via an oral gavage needle.
  • Blood samples (0.2 mL each) were drawn from a surgically implanted femoral vein cannula at timed intervals for 24 h following dose administration; all samples were drawn using EDTA-treated syringes.
  • Each blood sample was combined with 0.02 mL of a protease inhibitor solution [e-amino-n-caproic acid, benzamide HCI, and 4-(2-aminoethyl) benzenesulfonyl fluoride HCI in water] to inhibit ex vivo conversion of prodrug to parent, vortexed to mix, and centrifuged (4000 x g, 4° C, 20 min) to harvest plasma.
  • Prodrug and parent concentrations in plasma samples were quantitated by LC/MS/MS analysis. Area under the plasma concentration-time curve was estimated using noncompartmental analysis methods (WinNonlin Professional 4.1 )

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés qui sont des précurseurs d’inhibiteurs de l’intégrase du VIH et qui sont donc utiles pour l’inhibition de la réplication du VIH, la prévention et/ou le traitement d’une infection par le VIH, et dans le traitement du SIDA et/ou du syndrome apparenté au SIDA.
PCT/US2009/051504 2008-07-25 2009-07-23 Composés chimiques WO2010011819A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8361308P 2008-07-25 2008-07-25
US61/083,613 2008-07-25

Publications (1)

Publication Number Publication Date
WO2010011819A1 true WO2010011819A1 (fr) 2010-01-28

Family

ID=41570599

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/051504 WO2010011819A1 (fr) 2008-07-25 2009-07-23 Composés chimiques

Country Status (1)

Country Link
WO (1) WO2010011819A1 (fr)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011129095A1 (fr) * 2010-04-12 2011-10-20 塩野義製薬株式会社 Dérivé de pyridone ayant une activité inhibitrice de l'intégrase
EP2549870A1 (fr) 2010-03-23 2013-01-30 VIIV Healthcare Company Processus permettant de préparer des dérivés et des produits intermédiaires de carbamoylpyridone
WO2013038407A1 (fr) 2011-09-14 2013-03-21 Mapi Pharma Ltd. Forme amorphe de dolutegravir
JPWO2012018065A1 (ja) * 2010-08-05 2013-10-03 塩野義製薬株式会社 Ｈｉｖインテグラーゼ阻害活性を有する化合物の製造方法
JPWO2012039414A1 (ja) * 2010-09-24 2014-02-03 塩野義製薬株式会社 置換された多環性カルバモイルピリドン誘導体のプロドラッグ
CN105121409A (zh) * 2014-03-19 2015-12-02 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
WO2015110897A3 (fr) * 2014-01-21 2015-12-03 Laurus Labs Private Limited Nouveau procédé de préparation de dolutégravir et de ses sels pharmaceutiquement acceptables
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
AU2014277831B2 (en) * 2008-12-11 2016-06-02 Shionogi & Co. Ltd. Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates
US9421214B2 (en) 2013-07-12 2016-08-23 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9458159B2 (en) 2013-07-12 2016-10-04 Gilead Sciences, Inc. Substituted pyrido[1′,2′:4,5]pyrazino[1,2-a]azepines for treating viral infections
US9522912B2 (en) 2014-12-23 2016-12-20 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9630978B2 (en) 2015-04-02 2017-04-25 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9682084B2 (en) 2014-06-20 2017-06-20 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9,-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
WO2019070059A1 (fr) 2017-10-06 2019-04-11 塩野義製薬株式会社 Procédé pour la production stéréosélective d'un dérivé de pyridone polycyclique substitué
US10385067B2 (en) 2014-06-20 2019-08-20 Gilead Sciences, Inc. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate
US10442769B2 (en) 2013-07-04 2019-10-15 Hetero Research Foundation Process for the preparation of intermediate of dolutegravir
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US11084832B2 (en) 2019-03-22 2021-08-10 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
WO2022107755A1 (fr) 2020-11-17 2022-05-27 塩野義製薬株式会社 Nouveau sel d'acridinium et son procédé de production
WO2022140705A1 (fr) * 2020-12-24 2022-06-30 Orn Almarsson Promédicaments d'agents pharmaceutiques
US11613546B2 (en) 2021-01-19 2023-03-28 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
US11697652B2 (en) 2020-02-24 2023-07-11 Gilead Sciences, Inc. Tetracyclic compounds and uses thereof
US12024528B2 (en) 2022-04-06 2024-07-02 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
US12421235B2 (en) 2020-09-30 2025-09-23 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7211572B2 (en) * 2003-08-13 2007-05-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
US20070124152A1 (en) * 2004-02-11 2007-05-31 Johns Brian A Hiv Integrase Inhibitors
US20080004265A1 (en) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company HIV Integrase Inhibitors
US20080009490A1 (en) * 2004-03-09 2008-01-10 Williams Peter D Hiv Integrase Inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7211572B2 (en) * 2003-08-13 2007-05-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
US20070124152A1 (en) * 2004-02-11 2007-05-31 Johns Brian A Hiv Integrase Inhibitors
US20080009490A1 (en) * 2004-03-09 2008-01-10 Williams Peter D Hiv Integrase Inhibitors
US20080004265A1 (en) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company HIV Integrase Inhibitors

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014277831C1 (en) * 2008-12-11 2022-10-06 Shionogi & Co. Ltd. Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates
AU2014277831B2 (en) * 2008-12-11 2016-06-02 Shionogi & Co. Ltd. Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates
US10233196B2 (en) 2010-03-23 2019-03-19 Viiv Healthcare Company Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
JP2013522366A (ja) * 2010-03-23 2013-06-13 ヴィーブ ヘルスケア カンパニー カルバモイルピリドン誘導体及び中間体を調製するための方法
US10174051B2 (en) 2010-03-23 2019-01-08 Viiv Healthcare Company Substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US9643981B2 (en) 2010-03-23 2017-05-09 Viiv Healthcare Company Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
US10654871B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing (3S,11aR)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes
US9938296B2 (en) 2010-03-23 2018-04-10 Viiv Healthcare Company Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
US10647728B2 (en) 2010-03-23 2020-05-12 Viiv Healthcare Company Process for preparing (3S,11aR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid
US9120817B2 (en) 2010-03-23 2015-09-01 Viiv Healthcare Company Process for preparing (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′ ,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid
EP3260457A1 (fr) * 2010-03-23 2017-12-27 VIIV Healthcare Company Processus permettant de préparer des dérivés et des produits intermédiaires de carbamoylpyridone
US10654870B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
EP2549870A1 (fr) 2010-03-23 2013-01-30 VIIV Healthcare Company Processus permettant de préparer des dérivés et des produits intermédiaires de carbamoylpyridone
US9216995B2 (en) 2010-04-12 2015-12-22 Shionogi & Co., Ltd. Pyridone derivative having integrase inhibitory activity
WO2011129095A1 (fr) * 2010-04-12 2011-10-20 塩野義製薬株式会社 Dérivé de pyridone ayant une activité inhibitrice de l'intégrase
EP3127908A3 (fr) * 2010-08-05 2017-02-15 Shionogi & Co., Ltd Procédé pour préparer un composé ayant une activité inhibitrice d'intégrase de vih
US9650394B2 (en) 2010-08-05 2017-05-16 Shionogi & Co., Ltd. Methods of producing substituted (3S,11aR)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamides
CN106083891B (zh) * 2010-08-05 2018-03-23 盐野义制药株式会社 具有hiv整合酶抑制活性的化合物的制造方法
EP3456721A3 (fr) * 2010-08-05 2019-03-27 Shionogi & Co., Ltd Procédé de production de composés présentant une activité inhibitrice de l'intégrase du vih
CN106083891A (zh) * 2010-08-05 2016-11-09 盐野义制药株式会社 具有hiv整合酶抑制活性的化合物的制造方法
EP3456721A2 (fr) 2010-08-05 2019-03-20 Shionogi & Co., Ltd Procédé de production de composés présentant une activité inhibitrice de l'intégrase du vih
US9969750B2 (en) 2010-08-05 2018-05-15 Shionogi And Co., Ltd. Method of producing (3S,11aR)-6,8-dihalo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-diones
US9802959B2 (en) 2010-08-05 2017-10-31 Shionogi & Co., Ltd. Method of producing (4R,12aS)-7,9-dihalo-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-diones
EP3127908A2 (fr) 2010-08-05 2017-02-08 Shionogi & Co., Ltd Procédé pour préparer un composé ayant une activité inhibitrice d'intégrase de vih
EP2602260A4 (fr) * 2010-08-05 2014-01-01 Shionogi & Co Procédé pour préparer un composé ayant une activité inhibitrice d'intégrase de vih
US9321789B2 (en) 2010-08-05 2016-04-26 Shinogi & Co., Ltd. Methods of producing substituted (4R,12AS)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-B][1,3]oxazine-9-carboxamides
US10000508B2 (en) 2010-08-05 2018-06-19 Shionogi & Co., Ltd Crystalline dimethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate
JPWO2012018065A1 (ja) * 2010-08-05 2013-10-03 塩野義製薬株式会社 Ｈｉｖインテグラーゼ阻害活性を有する化合物の製造方法
US10125146B2 (en) 2010-08-05 2018-11-13 Shionogi & Co., Ltd. Crystalline methyl (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate
US10125147B2 (en) 2010-08-05 2018-11-13 Shionogi & Co., Ltd. Crystalline methyl (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate
US8987441B2 (en) 2010-09-24 2015-03-24 Shionogi & Co., Ltd. Substituted polycyclic carbamoyl pyridone derivative prodrug
US10202379B2 (en) 2010-09-24 2019-02-12 Shionogi & Co., Ltd. Substituted polycyclic carbamoyl pyridone derivative prodrug
US9758515B2 (en) 2010-09-24 2017-09-12 Shionogi & Co., Ltd. Substituted polycyclic carbamoyl pyridone derivative prodrug
JPWO2012039414A1 (ja) * 2010-09-24 2014-02-03 塩野義製薬株式会社 置換された多環性カルバモイルピリドン誘導体のプロドラッグ
US9206197B2 (en) 2011-09-14 2015-12-08 Mapi Pharma Ltd. Amorphous form of dolutegravir
US20140350004A1 (en) * 2011-09-14 2014-11-27 Mapi Pharma Ltd. Amorphous form of dolutegravir
WO2013038407A1 (fr) 2011-09-14 2013-03-21 Mapi Pharma Ltd. Forme amorphe de dolutegravir
US10035809B2 (en) 2012-12-21 2018-07-31 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydro-1,5-methanopyrido[1′,2′:4,5]pyrazino[1,2-a][1,3]diazepines and methods for treating viral infections
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
US10689399B2 (en) 2012-12-21 2020-06-23 Gilead Sciences, Inc. Substituted 3,4,5,6,8,10,14,14a-octahydro-2h-2,6-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazocines and methods for treating viral infections
US9732092B2 (en) 2012-12-21 2017-08-15 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]OXAZEPINES and methods for treating viral infections
US11548901B2 (en) 2012-12-21 2023-01-10 Gilead Sciences, Inc. Substituted 1,4-methanopyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidines for treating viral infections
US9663528B2 (en) 2012-12-21 2017-05-30 Gilead Sciences, Inc. Substituted 1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazines and methods for treating viral infections
US10442769B2 (en) 2013-07-04 2019-10-15 Hetero Research Foundation Process for the preparation of intermediate of dolutegravir
US9700554B2 (en) 2013-07-12 2017-07-11 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US11213523B2 (en) 2013-07-12 2022-01-04 Gilead Sciences, Inc. Substituted pyrido[1,2-a]pyrrolo[1,2-d]pyrazines for treating viral infections
US10668064B2 (en) 2013-07-12 2020-06-02 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9421214B2 (en) 2013-07-12 2016-08-23 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US10456395B2 (en) 2013-07-12 2019-10-29 Gilead Sciences, Inc. Substituted dipyrido[1,2-a:1′,2′-d]pyrazines for treating viral infections
US11883397B2 (en) 2013-07-12 2024-01-30 Gilead Sciences, Inc. Substituted pyrido[1,2-a]pyrrolo[1,2-d]pyrazines for treating viral infections
US9458159B2 (en) 2013-07-12 2016-10-04 Gilead Sciences, Inc. Substituted pyrido[1′,2′:4,5]pyrazino[1,2-a]azepines for treating viral infections
WO2015110897A3 (fr) * 2014-01-21 2015-12-03 Laurus Labs Private Limited Nouveau procédé de préparation de dolutégravir et de ses sels pharmaceutiquement acceptables
CN106831819B (zh) * 2014-03-19 2019-01-04 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
CN107056813B (zh) * 2014-03-19 2019-07-30 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
CN106866701B (zh) * 2014-03-19 2019-03-19 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
CN105121409A (zh) * 2014-03-19 2015-12-02 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
CN106831819A (zh) * 2014-03-19 2017-06-13 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
CN106866701A (zh) * 2014-03-19 2017-06-20 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
CN107056813A (zh) * 2014-03-19 2017-08-18 杭州普晒医药科技有限公司 德罗格韦钠盐的晶型及其制备方法
US10975096B2 (en) 2014-06-20 2021-04-13 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US10385067B2 (en) 2014-06-20 2019-08-20 Gilead Sciences, Inc. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate
US11202780B2 (en) 2014-06-20 2021-12-21 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US9682084B2 (en) 2014-06-20 2017-06-20 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9,-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
US10098886B2 (en) 2014-06-20 2018-10-16 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13A- octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-B] [1,3] oxazepine-10-carboxamide
US9795602B2 (en) 2014-12-23 2017-10-24 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US10646486B2 (en) 2014-12-23 2020-05-12 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9522912B2 (en) 2014-12-23 2016-12-20 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9630978B2 (en) 2015-04-02 2017-04-25 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US11286262B2 (en) 2017-10-06 2022-03-29 Shionogi & Co., Ltd. Stereoselective process for preparing substituted polycyclic pyridone derivatives
WO2019070059A1 (fr) 2017-10-06 2019-04-11 塩野義製薬株式会社 Procédé pour la production stéréosélective d'un dérivé de pyridone polycyclique substitué
KR20200066644A (ko) 2017-10-06 2020-06-10 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체의 입체 선택적인 제조 방법
US11548902B1 (en) 2019-03-22 2023-01-10 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
US11084832B2 (en) 2019-03-22 2021-08-10 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
US12227520B2 (en) 2019-03-22 2025-02-18 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
US11697652B2 (en) 2020-02-24 2023-07-11 Gilead Sciences, Inc. Tetracyclic compounds and uses thereof
US12122776B2 (en) 2020-02-24 2024-10-22 Gilead Sciences, Inc. Tetracyclic compounds and uses thereof
US12421235B2 (en) 2020-09-30 2025-09-23 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2022107755A1 (fr) 2020-11-17 2022-05-27 塩野義製薬株式会社 Nouveau sel d'acridinium et son procédé de production
WO2022140705A1 (fr) * 2020-12-24 2022-06-30 Orn Almarsson Promédicaments d'agents pharmaceutiques
US11613546B2 (en) 2021-01-19 2023-03-28 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
US11897892B2 (en) 2021-01-19 2024-02-13 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
US12187734B2 (en) 2021-01-19 2025-01-07 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
US12024528B2 (en) 2022-04-06 2024-07-02 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
US12054496B2 (en) 2022-04-06 2024-08-06 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof

Similar Documents

Publication Publication Date Title
EP2320908B1 (fr) Prodrugs de dolutegravir
US9707246B2 (en) Substituted (3S,11AR)-N-[(2,4-difluorophenyl)methyl]-6-oxy-3-methyl-5,7-dioxo-2,3,5,7,11,11A-hexahydro[1,3]oxazolo[3,2-A]pyrido[1,2-D]pyrazine-8-carboxamides as HIV agents
US8691823B2 (en) Prodrugs of (4aS, 13ar)-N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9-11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3:4]imidazo[1,2-d]pyrazine-8-carboxamide and their use in the treatment of HIV infection
WO2010011819A1 (fr) Composés chimiques
WO2010011815A1 (fr) Composés chimiques
WO2010011818A1 (fr) Composés chimiques
WO2011011483A1 (fr) Composés chimiques
HK1190711A (en) Chemical compounds as synthetic intermediates

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09800996

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09800996

Country of ref document: EP

Kind code of ref document: A1