WO2018060317A1 - Pyrimidine prodrugs for the treatment of viral infections and further diseases - Google Patents

Pyrimidine prodrugs for the treatment of viral infections and further diseases Download PDF

Info

Publication number
WO2018060317A1
WO2018060317A1 PCT/EP2017/074600 EP2017074600W WO2018060317A1 WO 2018060317 A1 WO2018060317 A1 WO 2018060317A1 EP 2017074600 W EP2017074600 W EP 2017074600W WO 2018060317 A1 WO2018060317 A1 WO 2018060317A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
substituted
formula
polymorph
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.)
Ceased
Application number
PCT/EP2017/074600
Other languages
English (en)
French (fr)
Inventor
David Craig Mc Gowan
Florence Marie HERSCHKE
Bart Henri Theresia STOOPS
Werner Constant Johan Embrechts
Jacques Armand Henri BOLLEKENS
Jérôme Émile Georges GUILLEMONT
Pierre Jean-Marie Bernard Raboisson
Tim Hugo Maria Jonckers
Laurent Jacques Emile CALMUS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Sciences Ireland ULC
Original Assignee
Janssen Sciences Ireland ULC
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
Priority to US16/338,256 priority Critical patent/US10968184B2/en
Priority to JP2019517045A priority patent/JP7274415B2/ja
Priority to CN201780060077.XA priority patent/CN109790154B/zh
Priority to EA201990834A priority patent/EA038646B1/ru
Priority to AU2017335205A priority patent/AU2017335205B2/en
Priority to KR1020197008938A priority patent/KR102450287B1/ko
Application filed by Janssen Sciences Ireland ULC filed Critical Janssen Sciences Ireland ULC
Priority to CA3037989A priority patent/CA3037989A1/en
Priority to EP17781044.7A priority patent/EP3519406B1/en
Priority to ES17781044T priority patent/ES2912945T3/es
Publication of WO2018060317A1 publication Critical patent/WO2018060317A1/en
Anticipated expiration legal-status Critical
Priority to US17/212,806 priority patent/US20210214317A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention relates to pyrimidine prodrug derivatives and the use of said pyrimidine prodrug derivatives in the treatment of viral infections, immune disorders, and cancer, or as a vaccine adjuvant, whereby the induction of a T helper 1 (Th1 ) immune response is desired.
  • Th1 T helper 1
  • Th1 response to reinvigorate exhausted virus-specific CD8 + T cells in the infected organs would be highly beneficial ⁇ Science 1999, 284, 825-829; J. Virol. 2003, 77, 68-76).
  • TLR Toll-like receptors
  • TLR8 agonists induce one of the strongest Th1 response in human cells, via the secretion of IL-12p70 and the upregulation of CD40 or OX40L activation markers and indirectly IFNy (J Immunol.
  • RIA is selected from hydrogen, a substituted or unsubstituted C1-3 alkyl, heterocycle, a substituted or unsubstituted phosphoramidate,
  • RIB is selected from hydrogen, a substituted or unsubstituted C1-3 alkyl, heterocycle, a substituted or unsubstituted phosphoramidate, with the exception that RIA and RIB are not both hydrogen,
  • R2 is a Ci-8 alkyl, which is optionally substituted by a hydroxyl group.
  • the present invention concerns a prodrug composition of a pharmaceutical compound.
  • the pharmaceutical compound is characterized by bioavailability of 50% or less and a molecular weight in the range of 100-1000 Daltons.
  • a method of delivering a pharmaceutical compound to an individual including the step of orally administering said prodrug to an individual.
  • the prodrug moiety is attached to the pharmaceutical compound wherein the modification allows the TLR8 agonist potential to be attenuated.
  • the prodrug is enzymatically cleaved prior to or at the site of the liver to yield the pharmaceutical compound, such that the pharmaceutical compound is delivered to the individual limiting TLR8 agonism prior to the liver.
  • the present invention provides compounds of formula (I) wherein R-iA and/ or R-m are a substituted or unsubstituted phosphoramidate and wherein R2 is a C1-6 alkyl preferably substituted by a hydroxyl group.
  • R-iA and/ or R-m are a substituted or unsubstituted phosphoramidate and wherein R2 is a C1-6 alkyl preferably substituted by a hydroxyl group.
  • R2 is a C1-6 alkyl preferably substituted by a hydroxyl group.
  • RIA and/or RIB are methyl and wherein R2 is a C6-alkyl substituted by a hydroxyl group.
  • the compounds of formula (I) in any stereochemical form and their pharmaceutically acceptable salt, solvate or polymorph thereof have activity as pharmaceuticals, in particular as inducers of interferon.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof according to the current invention, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used as a medicament.
  • Another aspect of the invention is that a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, or said pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used accordingly in the treatment of a disorder in which the induction of interferon is involved.
  • alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms.
  • Heterocycle refers to molecules that are saturated or partially saturated and include tetrahydrofuran, tetrahydropyran, dioxane or other cyclic ethers. Heterocycles containing nitrogen include, for example azetidine, morpholine, piperidine, piperazine, pyrrolidine, and the like. Other heterocycles include, for example, thiomorpholine, dioxolinyl, and cyclic sulfones.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Suitable base salts are formed from bases which form nontoxic salts.
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • polymorph refers to the ability of the compound of the invention to exist in more than one form or crystal structure.
  • the compounds of the present invention may be administered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral, rectal, or percutaneous administration.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Also included are solid form preparations that can be converted, shortly before use, to liquid forms.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • the compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • diethyl chlorophosphate (0.3 ml_, 2.08 mmol) was added dropwise to a suspension of 1 (For synthesis of 1 see WO2012/136834 )(0.5g, 2.08 mmol) in CHC (20 mL) at room temperature for 5 min, and then ⁇ (0.38 ml_, 2.71 mmol) was added dropwise.
  • the reaction mixture was heated to 55°C. The solvent was removed under reduced pressure.
  • the crude was purified by reverse phase chromatography.
  • Step 1 Preparation of 7.
  • TBDMSCI (7.53 g, 49.9 mmol) was added to a solution of 1 (10.0 g, 41 .6 mmol) and Et 3 N (1 1.6 mL, 83.2 mmol) in DMF (120 ml_). The mixture was stirred at rt for 70h. EtOAc and a 10% aq. NaHCC>3 was poured into the solution. The layers were separated and the organic layer was washed with brine (twice).
  • Step 3 Then 7 (729 mg, 2.06 mmol) in anhydrous 2-methyltetrahydrofuran (17 mL) was added and the mixture was stirred at rt for 2h.
  • the reaction mixture was diluted with EtOAc and water, the organic layer was washed with brine (twice), dried over MgS0 4 , the solids were removed by filtration, and the solvent of the filtrate was removed under reduced pressure, then purified by silica column chromatography using a mobile phase gradient: from heptane/EtOAc (80/20 to 0/100) to give 290 mg of 8 as a colorless oil.
  • DOWEX(R) 50WX2 (100-200 mesh) resin (one spatula) was added at room temperature to a mixture of 1 (4 g, 1 1.3 mmol), 2,3-dihydrofuran (1031 ⁇ _, 13.5 mmol, 1 .2 eq.) in anhydrous dichloroethane (99 ml_). The mixture was stirred at 80°C for 20h. Additional 2,3-dihydrofuran (688 ⁇ _, 9.03 mmol, 0.8 eq.) was added and the mixture was stirred at 80°C for 20h. An extraction was performed with CH2CI2 and water, and the layers were separated. The organic layer was dried over MgS0 4 , filtered, and the solvent was removed under reduced pressure to afford the titled compound.
  • Compound 10 was prepared according to the procedure to prepare 9, with the exception that 3,4-dihydro-2/-/-pyran was used.
  • CLmt Intrinsic clearance
  • rat and human liver microsomes were determined in rat and human liver microsomes. Incubations were performed at 37°C, at a concentration of 1 ⁇ of compound, and a microsomal protein concentration of 1 mg/ml_. Serial samples were removed at intervals of up to 60 min and analyzed for the concentration of compound to determine its intrinsic clearance rate.
  • Compound was incubated in rat and human hepatocytes (10 6 cells/mL) at 1 ⁇ for 0, 10, 20, 40, 60 and 120 min. Serial samples were removed at intervals of up to 120 min and analyzed for the concentration of compound to determine its intrinsic clearance rate.
  • P-gp P-glycoprotein
  • Plasma stability is measured in rat and human plasma for 7 or 24 h at 37 ° C. Compounds are incubated at 1 ⁇ . Incubations are performed manually in a 24-well plate and serial samples (100 ⁇ _) are removed at various time points prior to quenching with acetonitrile.
  • Prodrugs were administered orally to SD rats using aqueous solution at 5 mg/kg eq dose. Plasma samples were collected at different time points and the concentration of parent and prodrug was analyzed using LC-MS/MS. PK parameters were calculated using Phoenix WinNonlin 6.3. C ma x (ng/mL) and AUC(o-iast) (ng.h/mL) were determined for both prodrug and parent. Table 1: Permeability in MDCK-MDR1 cell line.
  • Table 3 Stability in simulated gastric fluid (SGF) and fasted simulated intestinal fluid (FASSIF) and stability in rat and human plasma.
  • Table 4 Oral administration of 1 and prodrugs in rat.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/EP2017/074600 2016-09-29 2017-09-28 Pyrimidine prodrugs for the treatment of viral infections and further diseases Ceased WO2018060317A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CA3037989A CA3037989A1 (en) 2016-09-29 2017-09-28 Pyrimidine prodrugs for the treatment of viral infections and further diseases
JP2019517045A JP7274415B2 (ja) 2016-09-29 2017-09-28 ウイルス感染症および他の疾患を処置するためのピリミジンプロドラッグ
CN201780060077.XA CN109790154B (zh) 2016-09-29 2017-09-28 用于治疗病毒感染和另外的疾病的嘧啶前药
EA201990834A EA038646B1 (ru) 2016-09-29 2017-09-28 Пиримидиновые пролекарства для лечения вирусных инфекций и других заболеваний
AU2017335205A AU2017335205B2 (en) 2016-09-29 2017-09-28 Pyrimidine prodrugs for the treatment of viral infections and further diseases
US16/338,256 US10968184B2 (en) 2016-09-29 2017-09-28 Pyrimidine prodrugs for the treatment of viral infections and further diseases
ES17781044T ES2912945T3 (es) 2016-09-29 2017-09-28 Profármacos de pirimidina para el tratamiento de infecciones virales y otras enfermedades
KR1020197008938A KR102450287B1 (ko) 2016-09-29 2017-09-28 바이러스 감염 및 추가적인 질환의 치료를 위한 피리미딘 프로드러그
EP17781044.7A EP3519406B1 (en) 2016-09-29 2017-09-28 Pyrimidine prodrugs for the treatment of viral infections and further diseases
US17/212,806 US20210214317A1 (en) 2016-09-29 2021-03-25 Pyrimidine prodrugs for the treatment of viral infections and further diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16191568 2016-09-29
EP16191568.1 2016-09-29

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/338,256 A-371-Of-International US10968184B2 (en) 2016-09-29 2017-09-28 Pyrimidine prodrugs for the treatment of viral infections and further diseases
US17/212,806 Continuation US20210214317A1 (en) 2016-09-29 2021-03-25 Pyrimidine prodrugs for the treatment of viral infections and further diseases

Publications (1)

Publication Number Publication Date
WO2018060317A1 true WO2018060317A1 (en) 2018-04-05

Family

ID=57047069

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/074600 Ceased WO2018060317A1 (en) 2016-09-29 2017-09-28 Pyrimidine prodrugs for the treatment of viral infections and further diseases

Country Status (12)

Country Link
US (2) US10968184B2 (https=)
EP (1) EP3519406B1 (https=)
JP (1) JP7274415B2 (https=)
KR (1) KR102450287B1 (https=)
CN (1) CN109790154B (https=)
AU (1) AU2017335205B2 (https=)
CA (1) CA3037989A1 (https=)
EA (1) EA038646B1 (https=)
ES (1) ES2912945T3 (https=)
MA (1) MA46340A (https=)
SG (1) SG10202010317VA (https=)
WO (1) WO2018060317A1 (https=)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020255035A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and pyrimidine derivatives

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080234251A1 (en) 2005-08-19 2008-09-25 Array Biopharma Inc. 8-Substituted Benzoazepines as Toll-Like Receptor Modulators
US20100029585A1 (en) 2008-08-01 2010-02-04 Howbert J Jeffry Toll-like receptor agonist formulations and their use
WO2012045089A2 (en) 2010-10-01 2012-04-05 Ventirx Pharmaceuticals, Inc. Methods for the treatment of allergic diseases
WO2012136834A1 (en) 2011-04-08 2012-10-11 Janssen R&D Ireland Pyrimidine derivatives for the treatment of viral infections
WO2014053516A1 (en) * 2012-10-01 2014-04-10 Centre National De La Recherche Scientifique (Cnrs) 1,2,4-triazine derivatives for the treatment of viral infections.
WO2014053595A1 (en) * 2012-10-05 2014-04-10 Janssen R&D Ireland Acylaminopyrimidine derivatives for the treatment of viral infections and further diseases

Family Cites Families (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2610889B2 (ja) 1987-09-03 1997-05-14 日本臓器製薬株式会社 新規架橋アデニン誘導体
ES2232871T3 (es) 1996-07-03 2005-06-01 Sumitomo Pharmaceuticals Company, Limited Nuevos derivados de purina.
JP3621706B2 (ja) 1996-08-28 2005-02-16 ファイザー・インク 置換された６，５―ヘテロ―二環式誘導体
ATE229527T1 (de) 1996-10-04 2002-12-15 Kyorin Seiyaku Kk Pyrazolopyridylpyrazinon-derivate und ein verfahren zu ihrer herstellung
AR012634A1 (es) 1997-05-02 2000-11-08 Sugen Inc Compuesto basado en quinazolina, composicion famaceutica que lo comprende, metodo para sintetizarlo, su uso, metodos de modulacion de la funcion deserina/treonina proteinaquinasa con dicho compuesto y metodo in vitro para identificar compuestos que modulan dicha funcion
US6339089B2 (en) 1997-08-13 2002-01-15 Fujirebio Inc. Pyrimidine nucleus-containing compound and a medicament containing the same for a blood oxygen partial pressure amelioration, and a method for preparing the same
DE69817393T2 (de) 1997-11-28 2004-06-17 Sumitomo Pharmaceuticals Co., Ltd. Neue heterozyklische verbindungen
TW572758B (en) 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
US6187777B1 (en) 1998-02-06 2001-02-13 Amgen Inc. Compounds and methods which modulate feeding behavior and related diseases
EA200000840A1 (ru) 1998-02-17 2001-02-26 Туларик, Инк. Антивирусные производные пиримидина
US6110929A (en) 1998-07-28 2000-08-29 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
JP4315300B2 (ja) 1998-08-10 2009-08-19 大日本住友製薬株式会社 新規なキナゾリン誘導体
JP4342007B2 (ja) 1998-08-10 2009-10-14 大日本住友製薬株式会社 キナゾリン誘導体
ES2221414T3 (es) 1998-08-27 2004-12-16 Sumitomo Pharmaceuticals Company, Limited Derivados de pirimidina.
WO2000048606A1 (en) * 1999-02-18 2000-08-24 Oxigene, Inc. Compositions and methods for use in targeting vascular destruction
US6583148B1 (en) 1999-04-08 2003-06-24 Krenitsky Pharmaceuticals, Inc. Neurotrophic substituted pyrimidines
US6503908B1 (en) 1999-10-11 2003-01-07 Pfizer Inc Pharmaceutically active compounds
WO2002088079A2 (en) 2001-05-01 2002-11-07 Bristol-Myers Squibb Company Dual inhibitors of pde 7 and pde 4
WO2003055890A1 (en) 2001-12-21 2003-07-10 Bayer Pharmaceuticals Corporation Thienopyrimidine derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents
TW200407143A (en) 2002-05-21 2004-05-16 Bristol Myers Squibb Co Pyrrolotriazinone compounds and their use to treat diseases
US7091232B2 (en) 2002-05-21 2006-08-15 Allergan, Inc. 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds
JPWO2003104230A1 (ja) 2002-06-07 2005-10-06 協和醗酵工業株式会社 二環性ピリミジン誘導体
MXPA05003193A (es) 2002-09-27 2005-06-08 Sumitomo Pharma Compuesto de adenina novedoso y uso del mismo.
US8455458B2 (en) 2002-10-16 2013-06-04 Arthrodynamic Technologies, Animal Health Division, Inc. Composition and method for treating connective tissue damage
MXPA05013922A (es) 2003-06-20 2006-02-24 Coley Pharm Group Inc Antagonistas de receptor tipo toll de molecula pequena.
JP2007504232A (ja) 2003-09-05 2007-03-01 アナディス ファーマシューティカルズ インク Ｃ型肝炎ウイルス感染治療用のｔｌｒ７リガンド及びそのプロドラッグの投与
US8012964B2 (en) 2004-03-26 2011-09-06 Dainippon Sumitomo Pharma Co., Ltd. 9-substituted 8-oxoadenine compound
WO2005092892A1 (ja) 2004-03-26 2005-10-06 Dainippon Sumitomo Pharma Co., Ltd. ８−オキソアデニン化合物
WO2007084413A2 (en) 2004-07-14 2007-07-26 Ptc Therapeutics, Inc. Methods for treating hepatitis c
US7923554B2 (en) 2004-08-10 2011-04-12 Janssen Pharmaceutica N.V. HIV inhibiting 1,2,4-triazin-6-one derivatives
MX2007001713A (es) * 2004-08-11 2007-07-13 Donald L Barbeau Compuestos farmaceuticos no cardiotoxicos.
WO2006050843A1 (en) 2004-11-09 2006-05-18 F. Hoffmann-La Roche Ag Aminoquinazolines compounds
US7498409B2 (en) 2005-03-24 2009-03-03 Schering Corporation Screening assay for TLR7, TLR8 and TLR9 agonists and antagonists
AU2006242920A1 (en) 2005-05-04 2006-11-09 Pfizer Limited 2-amido-6-amino-8-oxopurine derivatives as Toll-Like receptor modulators for the treatment of cancer and viral infections, such as hepatitis C
TW200716631A (en) 2005-05-12 2007-05-01 Tibotec Pharm Ltd Pyrido[2,3-d]pyrimidines useful as HCV inhibitors, and methods for the preparation thereof
US7994360B2 (en) 2005-05-16 2011-08-09 Xtl Biopharmaceuticals Ltd. Benzofuran compounds
EP1924564B1 (en) 2005-09-01 2016-11-09 F.Hoffmann-La Roche Ag Diaminopyrimidines as p2x3 and p2x2/3 modulators
JPWO2007034881A1 (ja) 2005-09-22 2009-03-26 大日本住友製薬株式会社 新規アデニン化合物
WO2007056208A2 (en) 2005-11-02 2007-05-18 Cytovia, Inc. N-arylalkyl-thienopyrimidin-4-amines and analogs as activators of caspases and inducers of apoptosis and the use thereof
WO2007063934A1 (ja) 2005-12-02 2007-06-07 Mitsubishi Tanabe Pharma Corporation 脂環式複素環化合物
JP2009528989A (ja) 2006-02-17 2009-08-13 ファイザー・リミテッド Ｔｌｒ７変調剤としての３−デアザプリン誘導体
WO2008009078A2 (en) 2006-07-20 2008-01-24 Gilead Sciences, Inc. 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections
WO2008009077A2 (en) 2006-07-20 2008-01-24 Gilead Sciences, Inc. 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives and pharmaceutical compositions useful for treating viral infections
RU2470936C2 (ru) 2006-12-07 2012-12-27 Дженентек, Инк. Соединения-ингибиторы фосфоинозитид 3-киназы и способы применения
CN103224506A (zh) 2006-12-20 2013-07-31 P.安杰莱蒂分子生物学研究所 抗病毒的吲哚
CN101790380B (zh) 2007-02-07 2013-07-10 加利福尼亚大学董事会 合成tlr激动剂的缀合物及其应用
JP2008222557A (ja) 2007-03-08 2008-09-25 Kotobuki Seiyaku Kk ピロロ［３，２−ｄ］ピリミジン誘導体及びこれを有効成分とする医薬組成物
ES2457316T3 (es) 2007-03-19 2014-04-25 Astrazeneca Ab Compuestos 8-oxo-adenina 9 sustituidos como moduladores del receptor similares a toll (TLR7)
AR065784A1 (es) 2007-03-20 2009-07-01 Dainippon Sumitomo Pharma Co Derivados de 8-oxo adenina,medicamentos que los contienen y usos como agentes terapeuticos para enfermedades alergicas, antivirales o antibacterianas.
JPWO2008114819A1 (ja) 2007-03-20 2010-07-08 大日本住友製薬株式会社 新規アデニン化合物
US9150556B2 (en) 2007-05-22 2015-10-06 Boehringer Ingelheim International Gmbh Benzimidazolone chymase inhibitors
CA2691444C (en) 2007-06-29 2016-06-14 Gilead Sciences, Inc. Purine derivatives and their use as modulators of toll-like receptor 7
CA2695989A1 (en) 2007-08-10 2009-02-19 Glaxosmithkline Llc Certain nitrogen containing bicyclic chemical entities for treating viral infections
EA017252B1 (ru) 2007-08-28 2012-11-30 Айрм Ллк Производные 2-бифениламино-4-аминопиримидина в качестве ингибиторов киназ
WO2009030998A1 (en) 2007-09-05 2009-03-12 Coley Pharmaceutical Group, Inc. Pyrimidine compounds as toll-like receptor (tlr) agonists
PE20091236A1 (es) 2007-11-22 2009-09-16 Astrazeneca Ab Derivados de pirimidina como immunomoduladores de tlr7
AU2008339917B2 (en) 2007-12-24 2013-02-07 Tibotec Pharmaceuticals Macrocyclic indoles as hepatitis C virus inhibitors
EA201001264A1 (ru) 2008-02-07 2011-04-29 Дзе Регентс Оф Дзе Юниверсити Оф Калифорния Способ лечения заболеваний мочевого пузыря с помощью активатора tlr7
AU2009241445A1 (en) 2008-04-28 2009-11-05 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8946239B2 (en) 2008-07-10 2015-02-03 Duquesne University Of The Holy Spirit Substituted pyrrolo, -furano, and cyclopentylpyrimidines having antimitotic and/or antitumor activity and methods of use thereof
UY31982A (es) 2008-07-16 2010-02-26 Boehringer Ingelheim Int Derivados de 1,2-dihidropiridin-3-carboxamidas n-sustituidas
AU2010250923A1 (en) 2009-05-21 2011-11-17 Astrazeneca Ab Novel pyrimidine derivatives and their use in the treatment of cancer and further diseases
US8637525B2 (en) 2009-07-31 2014-01-28 Bristol-Myers Squibb Company Compounds for the reduction of beta-amyloid production
TWI468402B (zh) 2009-07-31 2015-01-11 必治妥美雅史谷比公司 降低β－類澱粉生成之化合物
CN102666537A (zh) 2009-10-20 2012-09-12 艾格尔生物制药股份有限公司 治疗黄病毒科病毒感染的氮杂吲唑
JP5694345B2 (ja) 2009-10-22 2015-04-01 ギリアード サイエンシーズ， インコーポレイテッド Ｔｏｌｌ様受容体の調節因子
KR101094446B1 (ko) 2009-11-19 2011-12-15 한국과학기술연구원 단백질 키나아제 저해활성을 가지는 2,4,7-치환된 티에노［3,2-ｄ］피리미딘 화합물
JP2013032290A (ja) 2009-11-20 2013-02-14 Dainippon Sumitomo Pharma Co Ltd 新規縮合ピリミジン誘導体
DE102010040233A1 (de) 2010-09-03 2012-03-08 Bayer Schering Pharma Aktiengesellschaft Bicyclische Aza-Heterocyclen und ihre Verwendung
WO2012066335A1 (en) 2010-11-19 2012-05-24 Astrazeneca Ab Phenol compounds als toll -like receptor 7 agonists
WO2012067269A1 (en) 2010-11-19 2012-05-24 Dainippon Sumitomo Pharma Co., Ltd. Aminoalkoxyphenyl compounds and their use in the treatment of disease
AU2012258220B2 (en) 2011-05-18 2017-01-19 Janssen Sciences Ireland Uc Quinazoline derivatives for the treatment of viral infections and further diseases
JP6349256B2 (ja) 2011-11-09 2018-06-27 ヤンセン・サイエンシズ・アイルランド・ユーシー ウイルス感染の治療のためのプリン誘導体
SG11201404743TA (en) 2012-02-08 2014-09-26 Janssen R & D Ireland Piperidino-pyrimidine derivatives for the treatment of viral infections
MX371331B (es) 2012-04-24 2020-01-27 Vertex Pharma Inhibidores de la proteina cinasa dependiente de acido desoxirribonucleico(adn-pk).
EA035790B1 (ru) 2012-07-13 2020-08-11 Янссен Сайенсиз Айрлэнд Юси Макроциклические пурины для лечения вирусных инфекций
MX369417B (es) 2012-08-10 2019-11-07 Janssen Sciences Ireland Uc Derivados de alquilpirimidina para el tratamiento de infecciones víricas y otras enfermedades.
DK2906563T3 (en) 2012-10-10 2018-06-06 Janssen Sciences Ireland Uc PYRROLO [3,2-D] PYRIMIDINE DERIVATIVES FOR TREATING VIRUS INFECTIONS AND OTHER DISEASES
EA035431B1 (ru) 2012-11-16 2020-06-15 Янссен Сайенсиз Айрлэнд Юси Гетероциклические замещенные производные 2-амино-хиназолина в качестве модуляторов tlr7 и/или tlr8 для лечения вирусных инфекций
SG11201506639XA (en) * 2013-02-21 2015-09-29 Janssen Sciences Ireland Uc 2-aminopyrimidine derivatives for the treatment of viral infections
CN110590809B (zh) 2013-03-29 2022-04-19 爱尔兰詹森科学公司 用于治疗病毒感染的大环脱氮-嘌呤酮
SG11201509520QA (en) 2013-05-24 2015-12-30 Janssen Sciences Ireland Uc Pyridone derivatives for the treatment of viral infections and further diseases
PT3030563T (pt) 2013-06-27 2017-11-15 Janssen Sciences Ireland Uc Derivados de pirrolo[3,2-d]pirimidina para o tratamento de infeções virais e outras doenças
DK3027624T3 (en) 2013-07-30 2019-01-07 Janssen Sciences Ireland Uc THIENO [3,2-D] PYRIMIDINE DERIVATIVES FOR TREATING VIRUS INFECTIONS
US9701661B2 (en) 2014-07-11 2017-07-11 Northwestern University 2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
MA45539A (fr) 2016-07-01 2019-05-08 Janssen Sciences Ireland Unlimited Co Dihydropyranopyrimidines pour le traitement d'infections virales

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080234251A1 (en) 2005-08-19 2008-09-25 Array Biopharma Inc. 8-Substituted Benzoazepines as Toll-Like Receptor Modulators
US20100029585A1 (en) 2008-08-01 2010-02-04 Howbert J Jeffry Toll-like receptor agonist formulations and their use
WO2012045089A2 (en) 2010-10-01 2012-04-05 Ventirx Pharmaceuticals, Inc. Methods for the treatment of allergic diseases
WO2012136834A1 (en) 2011-04-08 2012-10-11 Janssen R&D Ireland Pyrimidine derivatives for the treatment of viral infections
WO2014053516A1 (en) * 2012-10-01 2014-04-10 Centre National De La Recherche Scientifique (Cnrs) 1,2,4-triazine derivatives for the treatment of viral infections.
WO2014053595A1 (en) * 2012-10-05 2014-04-10 Janssen R&D Ireland Acylaminopyrimidine derivatives for the treatment of viral infections and further diseases

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
CANCER IMMUNOL. IMMUNOTHER., vol. 62, 2013, pages 1347
CLIN. CANCER RES., vol. 20, 2014, pages 3683
CLIN. TRANSL. IMMUNOL., vol. 5, no. 5, 2016, pages e85
DAVID MCGOWAN ET AL: "Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 17, 8 September 2016 (2016-09-08), US, pages 7936 - 7949, XP055316160, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b00747 *
HUM IMMUNOL., vol. 72, no. 1, January 2011 (2011-01-01), pages 24 - 31
J IMMUNOL., vol. 176, no. 12, 2006, pages 7438 - 46
J LEUKOC BIOL., vol. 91, no. 1, 2012, pages 105 - 17
J. EXP. MED., vol. 211, 2014, pages 2047 - 2059
J. VIROL., vol. 77, 2003, pages 68 - 76
PLOS PATH., vol. 9, 2013, pages e1003490
PLOS PATHOG., vol. 10, 2014, pages e1004210
PLOS PATHOG., vol. 9, 2013, pages e1003208
SCIENCE, vol. 284, 1999, pages 825 - 829

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020255035A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and pyrimidine derivatives

Also Published As

Publication number Publication date
AU2017335205B2 (en) 2021-11-04
ES2912945T3 (es) 2022-05-30
CN109790154A (zh) 2019-05-21
EA201990834A1 (ru) 2019-08-30
CA3037989A1 (en) 2018-04-05
AU2017335205A1 (en) 2019-04-04
EP3519406A1 (en) 2019-08-07
US20200031779A1 (en) 2020-01-30
KR20190053200A (ko) 2019-05-17
SG10202010317VA (en) 2020-11-27
US20210214317A1 (en) 2021-07-15
MA46340A (fr) 2019-08-07
CN109790154B (zh) 2023-06-23
US10968184B2 (en) 2021-04-06
JP7274415B2 (ja) 2023-05-16
KR102450287B1 (ko) 2022-09-30
EA038646B1 (ru) 2021-09-28
JP2019530692A (ja) 2019-10-24
EP3519406B1 (en) 2022-02-23

Similar Documents

Publication Publication Date Title
EP2709989B1 (en) Quinazoline derivatives for the treatment of viral infections and further diseases
US9284304B2 (en) Substituted pyrimidines as toll-like receptor modulators
IL228317A (en) Pyrimidine derivatives and pharmaceutical preparations containing a signal
AU2013326486A1 (en) Acylaminopyrimidine derivatives for the treatment of viral infections and further diseases
CA3091076A1 (en) 2,4-diaminoquinazoline derivatives and medical uses thereof
CN107382966B (zh) 一类荜茇酰胺-川芎嗪杂合物、制备方法及医药用途
WO2017143842A1 (zh) 一种取代的二氨基嘧啶类化合物及包含该化合物的组合物及其用途
AU2021328979A1 (en) Pyrazole boronic acid compound, pharmaceutical composition containing same, and uses thereof
US10968184B2 (en) Pyrimidine prodrugs for the treatment of viral infections and further diseases
HK40012759A (en) Pyrimidine prodrugs for the treatment of viral infections and further diseases
HK40012759B (en) Pyrimidine prodrugs for the treatment of viral infections and further diseases
HK40081568A (en) 2,4-diaminoquinazoline derivatives and medical uses thereof
HK40044874B (en) 2,4-diaminoquinazoline derivatives and use thereof in the treatment of virus infections, cancer or allergies
CN111454278A (zh) Pak1抑制剂及其合成和在制备抗肿瘤药物中的应用
HK1207636B (zh) 用於治疗病毒感染和另外的疾病的烷基嘧啶衍生物

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: 17781044

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3037989

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 20197008938

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019517045

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017335205

Country of ref document: AU

Date of ref document: 20170928

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017781044

Country of ref document: EP

Effective date: 20190429