US20100120799A1 - Purine derivatives as immunomodulators - Google Patents

Purine derivatives as immunomodulators Download PDF

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US20100120799A1
US20100120799A1 US12/527,820 US52782008A US2010120799A1 US 20100120799 A1 US20100120799 A1 US 20100120799A1 US 52782008 A US52782008 A US 52782008A US 2010120799 A1 US2010120799 A1 US 2010120799A1
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tetrahydro
pyran
purin
compound
formula
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Linos Lazarides
Stephen Allan Smith
Richard Stocker
Colin Jack Theobald
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms

Definitions

  • the present invention relates to compounds, processes for their preparation, compositions containing them, to their use in the treatment of various disorders in particular infectious diseases, cancer, and allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, and as vaccine adjuvants.
  • Vertebrates are constantly threatened by the invasion of microorganisms and have evolved mechanisms of immune defence to eliminate infective pathogens.
  • this immune system comprises two branches; innate immunity and acquired immunity.
  • the first line of host defence is the innate immune system, which is mediated by macrophages and dendritic cells.
  • Acquired immunity involves the elimination of pathogens at the late stages of infection and also enables the generation of immunological memory. Acquired immunity is highly specific, due to the vast repertoire of lymphocytes with antigen-specific receptors that have undergone gene rearrangement.
  • PRRs germline-encoded pattern-recognition receptors
  • PAMPs pathogen-associated molecular patterns
  • TLRs Toll-like receptors
  • NLRs nucleotide oligomerisation domain-like receptors
  • RLRs retinoic acid-inducible gene-like receptors
  • Interferon was first described as a substance which could protect cells from viral infection (Isaacs & Lindemann, J. Virus Interference. Proc. R. Soc. Lon. Ser. B. Biol. Sci. 1957, 147:258-267).
  • the type I interferons are a family of related proteins encoded by genes on chromosome 9 and encoding at least 13 isoforms of interferon alpha (IFN ⁇ ) and one isoform of interferon beta (IFN ⁇ ).
  • Recombinant IFN ⁇ was the first approved biological therapeutic and has become an important therapy in viral infections and in cancer.
  • interferons are known to be potent modulators of the immune response, acting on cells of the immune system.
  • interferon combinations can be highly effective at reducing viral load and in some subjects in eliminating viral replication.
  • many patients fail to show a sustained viral response and in these patients viral load is not controlled.
  • therapy with injected interferon may be associated with a number of unwanted adverse effects which are shown to affect compliance (Dudley T, O'Donnell K, Haydon G, Mutimer D. Gut. 2006 55(9):1362-3).
  • pDCs plasmacytoid dendritic cells
  • TLR7 and TLR9 plasmacytoid dendritic cells
  • stimulation of these receptors with viral RNA or DNA respectively can induce expression of interferon alpha.
  • TLR7 agonists include imidazoquinoline compounds such as imiquimod and resiquimod, oxoadenine analogues and also nucleoside analogues such as Ioxoribine and 7-thia-8-oxoguanosine which have long been known to induce interferon alpha.
  • the compounds of the invention have been shown to be inducers of human interferon and may possess an improved profile with respect to known inducers of human interferon, for example enhanced potency.
  • Compounds which induce human interferon may be useful in the treatment of various disorders, for example the treatment of infectious diseases, cancer, and allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, and may also be useful as vaccine adjuvants.
  • R 1 is C 1-6 alkylamino, C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkylamino, C 3-7 cycloalkylC 1-6 alkoxy, C 1-3 alkoxyC 2-3 alkoxy, or Het b -C 1-3 alkoxy.
  • R 1 is n-butoxy, n-butylamino, 2,2-dimethylpentyloxy, n-pentylamino, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 2-methylbutylamino, 3-methylbutylamino, 1-methylbutylamino, 2-(cyclopropyl)ethoxy, 2-(ethoxy)ethoxy, (1-methyl-2-methoxy)ethoxy, cyclohexylmethylamino, cyclopentylmethylamino, 2-(cyclopropyl)ethylamino, 2-(methyl)propoxy, cyclohexylmethoxy, methoxyethoxy, (2-tetrahydrofuranyl)methoxy, (2-tetrahydro-2H-pyranyl)methoxy, or 2-(iso-propoxy)ethoxy.
  • R 1 is n-butylamino, n-butoxy, or 2-(cyclopropyl)ethoxy.
  • R 1 is n-butylamino, n-butoxy, (R)-1-methylbutyloxy, (S)-1-methylbutyloxy, or 2-(cyclopropyl)ethoxy.
  • n 1
  • n is 2.
  • n 3.
  • n 4.
  • Het is tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, or tetrahydro-2H-pyran-2-yl.
  • Het is tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, or tetrahydrofuran-3-yl.
  • Het is tetrahydro-2H-pyran-3-yl.
  • Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, or tetrahydro-2H-pyran-2-yl.
  • n when n is 1, then Het is tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, or tetrahydro-2H-pyran-2-yl.
  • n 2H-pyran-4-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, or tetrahydrofuran-3-yl.
  • R 2 is tetrahydro-2H-pyran-4-yl or tetrahydrofuran-3-yl.
  • n 2 when n is 2, then Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, or tetrahydrofuran-2-yl.
  • n 3
  • Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, or tetrahydrofuran-2-yl.
  • n 4
  • Het is tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-2-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, or tetrahydrofuran-2-yl.
  • R 1A is n-butoxy or n-butylamino.
  • n A is 1 or 2.
  • n A when n A is 1, then Het A is tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, or tetrahydro-2H-pyran-4-yl.
  • a method for the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the invention thus provides, in a further aspect, a combination comprising at least one compound of formula (I), or pharmaceutically acceptable salts or solvates thereof, together with at least one other therapeutically active agent.
  • composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable diluents or carriers.
  • a process for preparing a pharmaceutical composition which comprises admixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, with one or more pharmaceutically acceptable diluents or carriers.
  • R 1 and R 2 are as hereinbefore defined for a compound of formula (I) and R 3 is C 1-6 alkyl, and thereafter, if required, carrying out one or more of the following optional steps:
  • a compound of formula (IIA) may be prepared by reaction of a compound of formula (II):
  • R 1 is as hereinbefore defined for a compound of formula (I) and R 3 is as hereinbefore defined for a compound of formula (IIA), with a compound of formula (IIB):
  • R 2 is as hereinbefore defined for a compound of formula (I) and L is a suitable leaving group, for example an alkylsulphonyloxy group such as a methanesulphonyloxy group, or a halogen atom, such as bromine.
  • a compound of formula (II) is used in the form of a salt, for example the trifluoroacetate salt.
  • This salt results from the deprotection of a compound of formula (III) with, for example, trifluoroacetic acid, as hereinbelow described.
  • a compound of formula (I) may be prepared by reaction of a compound of formula (II) as hereinbefore defined, typically as a salt, for example the trifluoroacetate salt, with a compound of formula (IIB) as hereinbefore defined, without isolation of the intermediate compound (IIA).
  • a compound of formula (II) may be prepared by reaction of a compound of formula (III):
  • R 1 is as hereinbefore defined for a compound of formula (I)
  • P is a protecting group, typically a tetrahydro-2H-pyran-2-yl group
  • R 3 is as hereinbefore defined for a compound of formula (IIA)
  • a suitable deprotecting agent for example trifluoroacetic acid (the use of trifluoroacetic acid results in a compound of formula (II) being formed as a trifluoroacetate salt).
  • a compound of formula (IIB) wherein L is a halogen atom may be prepared by reaction of a compound of formula (IX):
  • R 2 is as hereinbefore defined for a compound of formula (I) and OG is a leaving group, for example an alkanesulphonate group such as a methanesulphonate group, with an anhydrous alkali metal halide such as anhydrous lithium bromide.
  • a compound of formula (IX), or a compound of formula (IIB) wherein L is an alkylsulphonyl group may be prepared by reaction of a compound of formula (X):
  • R 2 is as hereinbefore defined for a compound of formula (I), with a suitable activating agent, for example an alkylsulphonyl halide such as methanesulphonyl chloride.
  • a suitable activating agent for example an alkylsulphonyl halide such as methanesulphonyl chloride.
  • a compound of formula (X) may be prepared by reaction of a compound of formula (XI):
  • Het and n are as hereinbefore defined for a compound of formula (I) with a suitable reducing agent, such as lithium aluminium hydride.
  • a compound of formula (X) wherein Het is 3-tetrahydropyranyl and n is an integer having a value of 2 may be prepared by reaction of the compound of formula (XII):
  • Het is 3-tetrahydropyranyl, with a suitable reducing agent, for example sodium borohydride.
  • a suitable reducing agent for example sodium borohydride.
  • a compound of formula (XII) may be prepared by reaction of a compound of formula (XIII):
  • Het is 3-tetrahydropyranyl, with a suitable mineral acid, for example hydrochloric acid.
  • a compound of formula (XIII) may be prepared by reaction of the compound of formula (XIV):
  • Het is 3-tetrahydropyranyl, with a compound of formula (XV):
  • a compound of formula (XIV) may be prepared by hydrogenation of the compound of formula (XVI):
  • a compound of formula (III) may be prepared by reaction of a compound of formula (IV):
  • R 1 is as hereinbefore defined for a compound of formula (I)
  • P is as hereinbefore defined for a compound of formula (III)
  • X is a halogen atom, for example bromine, with an alkali metal alkoxide, for example sodium methoxide.
  • a compound of formula (IV) may be prepared by reaction of a compound of formula (V):
  • R 1 is as hereinbefore defined for a compound of formula (I) and P is as hereinbefore defined for a compound of formula (III), with a suitable halogenating agent, for example N-bromosuccinimide.
  • a compound of formula (V), wherein R 1 is C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, or Het b -C 1-3 alkoxy may be prepared by reaction of a compound of formula (VI):
  • R 1 is C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, or Het b -C 1-3 alkoxy, in the presence of a strong base of appropriate strength, for example sodium metal, sodium hydride, or sodium tert-butoxide.
  • a compound of formula (V), wherein R 1 is C 1-8 alkylamino or C 3-7 cycloalkylC 1-6 alkylamino may be prepared by reaction of a compound of formula (VI) as hereinbefore defined, with a compound of formula (VIB):
  • R 1 is C 1-6 alkylamino or C 3-7 cycloalkylC 1-6 amino.
  • a compound of formula (VI) may be prepared by reaction of a compound of formula (VII):
  • P is as hereinbefore defined for a compound of formula (III)
  • Y is as hereinbefore defined for a compound of formula (VI)
  • Z is a halogen atom, for example chlorine, with an alcoholic solution of ammonia.
  • a compound of formula (VII) may be prepared from a compound of formula (VIII):
  • Y is as hereinbefore defined for a compound of formula (VI) and Z is as hereinbefore defined for a compound of formula (VII), by reaction with a suitable protecting reagent, for example 3,4-dihydro-2H-pyran.
  • a suitable protecting reagent for example 3,4-dihydro-2H-pyran.
  • R 1 and R 2 are as hereinbefore defined for a compound of formula (I) and X is as hereinbefore defined for a compound of formula (IV).
  • a compound of formula (XXI) wherein may be prepared by halogenation of a compound of formula (XX):
  • R 1 and R 2 are as hereinbefore defined for a compound of formula (I).
  • a compound of formula (XX), wherein R 1 is C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, or Het b -C 1-3 alkoxy may be prepared by reaction of a compound of formula (XIX):
  • a compound of formula (XIX) may be prepared by reaction of a compound of formula (XVIII):
  • Y is as hereinbefore defined for a compound of formula (VI)
  • Z is as hereinbefore defined for a compound of formula (VII)
  • R 2 is as hereinbefore defined for a compound of formula (I), with ammonia.
  • a compound of formula (XIX) may also be prepared by reaction of a compound of formula (XVII):
  • a compound of formula (XVIII) may be prepared by reaction of a compound of formula (VIII) as hereinbefore defined with a compound of formula R 2 —OH, wherein R 2 is as hereinbefore defined for a compound of formula (I).
  • a compound of formula (XVII) may be prepared by reaction of a compound of formula (VIII) as hereinbefore defined with ammonia.
  • a compound of formula (I), wherein R 1 is C 1-8 alkylamino or C 3-7 cycloalkylC 1-6 alkylamino may be prepared by reaction of a compound of formula (XXIII):
  • Y is as hereinbefore defined for a compound of formula (VI)
  • R 2 is as hereinbefore defined for a compound of formula (I)
  • R 3 is as hereinbefore defined for a compound of formula (IIA), with a compound of formula (VIB) as hereinbefore defined.
  • a compound of formula (XXIII) may be prepared by reaction of a compound of formula (XXII):
  • X is as hereinbefore defined for a compound of formula (IV)
  • Y is as hereinbefore defined for a compound of formula (VI)
  • R 2 is as hereinbefore defined for a compound of formula (I), with a source of alkoxide anion.
  • references to ‘alkyl’ include references to both straight-chain and branched-chain aliphatic isomers of the corresponding alkyl, suitably containing up to eight carbon atoms, for example up to four carbon atoms or up to three carbon atoms. Such references to ‘alkyl’ are also applicable when an alkyl group is part of another group, for example an alkylamino or alkoxy group. Examples of such alkyl groups and groups containing alkyl groups are C 1-4 alkyl, C 1-6 alkylamino, C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkylamino, C 3-7 cycloalkylC 1-6 alkoxy, and C 1-3 alkoxyC 2-3 alkoxy.
  • heterocycle or ‘heterocyclyl’ refer to monocyclic saturated heterocyclic aliphatic rings containing 5 or 6 carbon atoms, and one heteroatom, which heteroatom is oxygen. Examples of such heterocyclic rings are tetrahydrofuranyl and tetrahydropyranyl.
  • cycloalkyl refers to monocyclic alkyl groups containing between three and seven carbon atoms, for example three carbon atoms, or five carbon atoms, or six carbon atoms. Examples of such cycloalkyl groups are cyclopropyl, cyclopentyl, and cyclohexyl.
  • halogen refers to iodine, bromine, chlorine or fluorine, typically bromine or chlorine.
  • references hereinafter to compounds of the invention mean a compound of formula (I) as the free base, or as a salt, or as a solvate.
  • Salts of the compounds of formula (I) include pharmaceutically acceptable salts and salts which may not be pharmaceutically acceptable but may be useful in the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof. Salts may be derived from certain inorganic or organic acids, or certain inorganic or organic bases.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • salts are pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts.
  • suitable salts see Berge et al., J. Pharm. Sci., 66:1-19 (1977).
  • Examples of pharmaceutically acceptable acid addition salts of a compound of formula (I) include hydrobromide, hydrochloride, sulphate, p-toluenesulphonate, methanesulphonate, naphthalenesulphonate, and phenylsulphonate salts.
  • Examples of pharmaceutically acceptable base salts include alkali metal salts such as those of sodium and potassium, and alkaline earth metal salts such as those of calcium and magnesium.
  • Salts may be formed using techniques well-known in the art, for example by precipitation from solution followed by filtration, or by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable strong acid (such as hydrobromic, hydrochloric, sulphuric, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acids), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable strong acid such as hydrobromic, hydrochloric, sulphuric, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acids
  • solvates can form complexes with solvents in which they are reacted or from which they are precipitated or crystallised. These complexes are known as “solvates”.
  • a complex with water is known as a “hydrate”.
  • Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, ethanol, iso-propyl alcohol, and N-methyl pyrrolidinone may be used to form solvates.
  • Solvates of the compounds of formula (I) are within the scope of the invention.
  • the term solvate encompasses solvates of both a free base compound as well as any salt thereof.
  • Certain of the compounds of the invention may contain chiral atoms and/or multiple bonds, and hence may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the stereoisomers of the compounds of the invention, including geometric isomers and optical isomers, whether as individual stereoisomers or as mixtures thereof including racemic modifications.
  • Any stereoisomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of any other stereoisomer.
  • any optical isomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of its antipode.
  • the terms “Isomer 1” and “Isomer 2” and “Diastereoisomer 1” and “Diastereoisomer 2” refer to the first- and second-eluting isomer or diastereoisomer respectively when the separations are performed using the chromatographic conditions specified in the relevant text. It will be appreciated that the order of elution may change depending on the particular chromatographic conditions employed.
  • Certain of the compounds of the invention may exist in tautomeric forms. It will be understood that the present invention encompasses all of the tautomers of the compounds of the invention whether as individual tautomers or as mixtures thereof.
  • the compounds of the invention may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of the invention may exist as polymorphs, all of which are included within the scope of the present invention. The most thermodynamically stable polymorphic form or forms of the compounds of the invention are of particular interest.
  • Examples of disease states in which the compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof have potentially beneficial effects include infectious diseases, cancer, allergic diseases and other inflammatory conditions.
  • the compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof are also of potential use as vaccine adjuvants.
  • the compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may therefore be useful in the treatment of various disorders, in particular the treatment of infectious diseases including, but not limited to, those caused by hepatitis viruses (e.g. hepatitis B virus, hepatitis C virus), human immunodeficiency virus, papillomaviruses, herpesviruses, respiratory viruses (e.g. influenza viruses, respiratory syncytial virus, rhinovirus, metapneumovirus, parainfluenzavirus, SARS), and West Nile virus.
  • the compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may also be useful in the treatment of microbial infections caused by, for example, bacteria, fungi, or protozoa.
  • tuberculosis bacterial pneumonia, aspergillosis, histoplasmosis, candidosis, pneumocystosis, leprosy, chlamydia, cryptococcal disease, cryptosporidosis, toxoplasmosis, leishmania, malaria, and trypanosomiasis.
  • the compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may therefore be useful in the treatment of inflammation, including but not limited to inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, eosinophilic pneumonitis, delayed-type hypersensitivity, atherosclerosis, pancreatitis, gastritis, osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, respiratory distress syndrome, bronchiolitis, chronic obstructive pulmonary disease, sinusitis, cystic fibrosis, and dermatitis.
  • inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, eosinophilic pneumonitis, delayed-type hypersensitivity, atherosclerosis, pancreatitis, gastritis, osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, respiratory distress syndrome, bronchiolitis, chronic obstructive pulmonary
  • the compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may also be useful in the treatment of autoimmune diseases including but not limited to rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, sjöegrens disease, ankylosing spondylitis, scleroderma, diabetes, graft rejection, including graft-versus-host disease, inflammatory bowel diseases including, but not limited to, Crohn's disease and ulcerative colitis.
  • autoimmune diseases including but not limited to rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, sjöegrens disease, ankylosing spondylitis, scleroderma, diabetes, graft rejection, including graft-versus-host disease, inflammatory bowel diseases including, but not limited to, Crohn's disease and ulcerative colitis.
  • the compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may also be useful in the treatment of various cancers, in particular the treatment of cancers that are known to be responsive to immunotherapy and including, but not limited to, renal cell carcinoma, lung cancer, breast cancer, colo-rectal cancer, bladder cancer, melanoma, leukaemia, lymphomas and ovarian cancer.
  • compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may be useful as therapeutic agents.
  • the present invention includes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic agent.
  • the present invention also includes a method for the treatment of infectious diseases, cancer, allergic diseases and other inflammatory conditions, which method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also includes a method for the treatment of allergic rhinitis, which method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also includes a method for the treatment of asthma, which method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds according to the invention, and pharmaceutically acceptable salts and solvates thereof, may be formulated for administration in any convenient way.
  • the compounds according to the invention, and pharmaceutically acceptable salts and solvates thereof may, for example, be formulated for oral, topical, inhaled, intranasal, buccal, parenteral (for example intravenous, subcutaneous, intradermal, or intramuscular) or rectal administration.
  • the compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof are formulated for oral administration.
  • the compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof are formulated for topical administration, for example intranasal administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents
  • Formulations for intranasal administration include aqueous formulations administered to the nose by drops or by pressurised pump. Suitable formulations contain water as the diluent or carrier for this purpose. Aqueous formulations for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose or other regions of the respiratory tract by nebulisation.
  • Formulations for inhaled administration include aqueous, organic or aqueous/organic mixtures, dry powder or crystalline formulations administered to the respiratory tract by pressurised pump or inhaler.
  • Suitable formulations contain water as the diluent or carrier for this purpose and may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like.
  • Aqueous formulations may also be administered to the nose and other regions of the respiratory tract by nebulisation.
  • Such formulations may be aqueous solutions or suspensions or aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and may contain a compound of formula (I) or a salt or solvate thereof and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof.
  • the aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid or derivative thereof e.g. as described in WO 94/21229 and WO 98/34596 (Minnesota Mining and Manufacturing Company) and co-solvents e.g. ethanol.
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
  • Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, wool-fat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
  • the compounds according to the invention and pharmaceutically acceptable salts or solvates thereof may, for example, be formulated for transdermal delivery by formulation into patches or other devices (e.g. pressurised gas devices) which deliver the active component into the skin.
  • devices e.g. pressurised gas devices
  • compositions may take the form of tablets or lozenges formulated in the conventional manner.
  • the compounds and pharmaceutically acceptable salts or solvates thereof may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds according to the invention or pharmaceutically acceptable salts or solvates thereof may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multidose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • the compounds according to the invention or pharmaceutically acceptable salts or solvates thereof may also be formulated with vaccines as adjuvants to modulate their activity.
  • Such formulations may contain antibody(ies) or antibody fragment(s) or an antigenic component including but not limited to protein, DNA, live or dead bacteria and/or viruses or virus-like particles, together with one or more components with adjuvant activity including but not limited to aluminium salts, oil and water emulsions, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists such as CpG DNA or similar agents, cytokines such as GM-CSF or IL-12 or similar agents.
  • the compounds of the present invention or pharmaceutically acceptable salts or solvates thereof may be employed alone or in combination with other therapeutic agents.
  • the compound(s) of the present invention or pharmaceutically acceptable salts or solvates thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound(s) of the present invention and pharmaceutically acceptable salts or solvates thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and pharmaceutically acceptable salts or solvates thereof with other treatment agents may be in combination by administration concomitantly in a unitary pharmaceutical composition including both compounds, or in separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the present invention may be used in combination with one or more agents useful in the prevention or treatment of viral infections.
  • agents include; polymerase inhibitors such as those disclosed in WO 2004/037818-A1, as well as those disclosed in WO 2004/037818 and WO 2006/045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, as well as those disclosed in WO 2006/018725, WO 2004/074270, WO 2003/095441, US2005/0176701, WO 2006/020082, WO 2005/080388, WO 2004/064925, WO 2004/065367, WO 2003/007945, WO 02/04425, WO 2005/014543, WO 2003/000254, EP 1065213, WO 01/47883, WO 2002/057287, WO 2002/057245 and similar agents; replication inhibitors such as acyclovir, famciclovir, ganciclovir
  • the present invention may also be used in combination with one or more other agents which may be useful in the prevention or treatment of viral infections for example immune therapies (e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists and similar agents); and therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs and similar agents.
  • immune therapies e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists and similar agents
  • therapeutic vaccines e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists and similar agents
  • antifibrotic agents e.g., antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs and similar agents.
  • combinations of compounds of this invention and pharmaceutically acceptable salts or solvates thereof with antiviral agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of viral disease.
  • the compounds of the present invention and pharmaceutically acceptable salts or solvates thereof and other antiviral agents may be administered separately or in conjunction.
  • one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention and pharmaceutically acceptable salts or solvates thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of allergic disease, inflammatory disease, autoimmune disease or similar, for example; antigen immunotherapy, anti-histamines, steroids, non-steroidal anti-inflammatory agents, bronchodilators (e.g. beta 2 agonists, adrenergic agonists, anticholinergic agents, theophylline), methotrexate, leukotriene modulators and similar agents; monoclonal antibody therapy such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; receptor therapies e.g.
  • antigen non-specific immunotherapies e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and similar agents.
  • the compounds of the present invention and pharmaceutically acceptable salts or solvates thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of cancer, for example chemotherapeutics such as alkylating agents, topoisomerase inhibitors, antimetabolites, antimitotic agents, kinase inhibitors and similar agents; monoclonal antibody therapy such as trastuzumab, gemtuzumab and other similar agents; immunotherapies (e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and similar agents); and hormone therapy such as tamoxifen, goserelin and similar agents.
  • chemotherapeutics such as alkylating agents, topoisomerase inhibitors, antimetabolites, antimitotic agents, kinase inhibitors and similar agents
  • monoclonal antibody therapy such as trastuzumab, gemtuzumab and other similar
  • compositions according to the invention may also be used alone or in combination with at least one other therapeutic agent in other therapeutic areas, for example gastrointestinal disease.
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • the invention includes a combination comprising at least one compound of formula (I), or (a) pharmaceutically acceptable salt(s) or solvate(s) thereof, together with at least one other therapeutically active agent.
  • compositions comprising a combination as defined above together with at least one pharmaceutically acceptable diluent or carrier thereof represent a further aspect of the invention.
  • a therapeutically effective amount of a compound of the present invention or pharmaceutically acceptable salts or solvates thereof will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician. Regardless, an effective amount of a compound of the present invention for the treatment of humans suffering from frailty, generally, should be in the range of 0.01 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 0.1 to 10 mg/kg body weight per day.
  • an actual amount per day would usually be from 7 to 700 mg.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a pharmaceutically acceptable salt or solvate of a compound of formula (I) may be determined as a proportion of the effective amount of the compound of the present invention per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.
  • Compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may also be administered at any appropriate frequency e.g. 1-7 times per week.
  • the precise dosing regimen will of course depend on factors such as the therapeutic indication, the age and condition of the patient, and the particular route of administration chosen.
  • compositions may be presented in unit-dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of of formula (I) or pharmaceutically acceptable salts or solvates thereof, depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.
  • Preferred unit-dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well-known in the pharmacy art.
  • composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable diluents or carriers.
  • R 1 and R 2 are as hereinbefore defined for a compound of formula (I) and R 3 is C 1-6 alkyl, and thereafter, if required, carrying out one or more of the following optional steps:
  • a compound of formula (IIA) is dissolved in a suitable solvent, for example methanol, and treated with a solution of a suitable mineral acid in a suitable solvent, for example 4N hydrogen chloride in 1,4-dioxane.
  • a suitable temperature for example room temperature
  • a suitable period of time for example 4-18 hours
  • the solvent removed under reduced pressure to give a material that is then suspended in water.
  • a sufficient amount of a suitable alcohol, for example methanol may be added until a solution is obtained.
  • a suitable aqueous base for example 2N sodium hydroxide solution, is added to bring the mixture to pH7, and the solution may be concentrated until a suspension is formed.
  • the solid is then filtered and washed with water before being dried to give a compound of formula (I).
  • the reaction mixture may be neutralised without prior removal of the solvent, and the resultant product recovered by filtration before or after removal of a proportion of the solvent.
  • a compound of formula (IIA) may be prepared by reaction of a compound of formula (II):
  • R 1 is as hereinbefore defined for a compound of formula (I) and R 3 is as hereinbefore defined for a compound of formula (IIA), with a compound of formula (IIB):
  • R 2 is as hereinbefore defined for a compound of formula (I) and L is a suitable leaving group, for example an alkylsulphonyloxy group such as a methanesulphonyloxy group, or a halogen atom, such as bromine.
  • the trifluoroacetate salt of a compound of formula (II) is heated to a suitable temperature, for example 60° C., for a suitable period of time, for example 1 hour, with anhydrous potassium carbonate in a suitable dry solvent, for example dry DMF, and allowed to cool to room temperature before adding a compound of formula (IIB).
  • a suitable temperature for example 60° C.
  • anhydrous potassium carbonate in a suitable dry solvent for example dry DMF
  • the reaction may be stirred at room temperature for a suitable period of time, for example 20-40 hours, and may be heated if necessary for a suitable period of time, for example 1-2 hours, at a suitable temperature, for example up to 90° C.
  • the reaction mixture is poured into water and extracted into a suitable solvent, for example ethyl acetate.
  • reaction times and reaction temperatures required to effect the reaction of a compound of formula (II) with a compound of formula (IIB) to give a compound of formula (IIA) will vary depending on the precise nature of the individual reactants used, for example reaction times and reaction temperatures must be chosen to ensure that a compound of formula (IIA) is obtained, but that N-alkylation at the 7-position is minimised or avoided.
  • a compound of formula (II) may be used in the form of a salt, for example the trifluoroacetate salt. This salt results from the deprotection of a compound of formula (III) with, for example, trifluoroacetic acid, as hereinbelow described.
  • a compound of formula (I) may be prepared by reaction of a compound of formula (II) as hereinbefore defined, typically as a salt, for example the trifluoroacetate salt, with a compound of formula (IIB) as hereinbefore defined, without isolation of the intermediate compound (IIA).
  • a suitable solvent for example dry N,N-dimethyl formamide (DMF)
  • a suitable base for example anhydrous potassium carbonate
  • the mixture is heated to a suitable temperature, for example 60° C., for a suitable period of time, for example 1 hour, and cooled to room temperature.
  • a compound of formula (IIB) is then added and the reaction mixture heated to a suitable temperature, for example 50° C., for a suitable period of time, for example 12-18 hours.
  • the reaction is quenched with water and extracted with a suitable solvent, for example ethyl acetate.
  • the organic phase is separated and dried.
  • reaction times and reaction temperatures required to effect the reaction of a trifluoroacetate salt of a compound of formula (II) with a compound of formula (IIB) to give a compound of formula (IIA) will vary depending on the precise nature of the individual reactants used, for example reaction times and reaction temperatures must be chosen to ensure that a compound of formula (IIA) is obtained, but that N-alkylation at the 7-position is minimised or avoided.
  • a compound of formula (II) may be prepared by reaction of a compound of formula (III):
  • R 1 is as hereinbefore defined for a compound of formula (I)
  • P is a protecting group, typically a tetrahydro-2H-pyran-2-yl group
  • R 3 is as hereinbefore defined for a compound of formula (IIA)
  • a suitable deprotecting agent for example trifluoroacetic acid (the use of trifluoroacetic acid results in a compound of formula (II) being formed as a trifluoroacetate salt).
  • a suitable solvent for example dry methanol
  • a suitable deprotecting agent for example trifluoroacetic acid
  • the reaction mixture is concentrated to a slurry before being diluted with a suitable solvent, for example ethyl acetate.
  • a suitable solvent for example ethyl acetate.
  • the slurry is filtered and washed with a small volume of solvent, for example ethyl acetate, until the filtrate is colourless.
  • the solid remaining is dried by air and then in vacuo to give, in the case where trifluoroacetic acid is used as the deprotecting agent, the trifluoroacetate salt of a compound of formula (II).
  • the filtrate obtained previously may be concentrated to give a slurry which is then diluted with a small volume of solvent, for example ethyl acetate and then filtered and dried to yield a second crop of the trifluoroacetate salt of a compound of formula (II).
  • reaction mixture may be concentrated under reduced pressure to yield a solid, which solid may then be triturated in the presence of a suitable solvent, for example diethyl ether.
  • a suitable solvent for example diethyl ether.
  • a compound of formula (IIB) wherein L is a halogen atom may be prepared by reaction of a compound of formula (IX):
  • R 2 is as hereinbefore defined for a compound of formula (I) and OG is a leaving group, for example an alkanesulphonate group such as a methanesulphonate group, with an anhydrous alkali metal halide such as anhydrous lithium bromide.
  • a compound of formula (IX) and a suitable halogenating agent for example anhydrous lithium bromide
  • a suitable solvent for example, acetone
  • a suitable solvent for example, acetone
  • the solvent is removed under reduced pressure, the residue treated with water, and extracted with a suitable solvent, for example dichloromethane.
  • the combined solvent extracts are washed, dried, and the solvent removed under reduced pressure to give a compound of formula (IIB).
  • a compound of formula (IX), or a compound of formula (IIB) wherein L is an alkylsulphonyl group may be prepared by reaction of a compound of formula (X):
  • R 2 is as hereinbefore defined for a compound of formula (I), with a suitable activating agent, for example an alkylsulphonyl halide such as methanesulphonyl chloride.
  • a suitable activating agent for example an alkylsulphonyl halide such as methanesulphonyl chloride.
  • a suitable dry solvent for example dry dichloromethane
  • a suitable activating agent for example methanesulphonyl chloride.
  • the mixture is allowed to warm slowly to ambient temperature over a suitable period of time, for example 16 hours, then washed with saturated sodium hydrogen carbonate.
  • the aqueous layer is further extracted with a suitable organic solvent, for example dichloromethane, and the organic extracts washed, dried, and the solvent removed under reduced pressure to give a compound of formula (IX).
  • a compound of formula (X) may be prepared by reaction of a compound of formula (XI):
  • Het and n are as hereinbefore defined for a compound of formula (I) with a suitable reducing agent, such as lithium aluminium hydride.
  • a stirring solution of a compound of formula (XI) in a suitable dry solvent for example dry tetrahydrofuran
  • a suitable dry solvent for example dry tetrahydrofuran
  • a solution of lithium aluminium hydride in a suitable solvent for example dry tetrahydrofuran
  • a suitable temperature for example less than 15° C.
  • the reaction is allowed to warm to ambient temperature and, after a suitable period of time, for example 3 hours, re-cooled using, for example, an ice-bath, and a suitable base, for example 5N sodium hydroxide added while maintaining a suitable temperature, for example less than 10° C.
  • a suitable organic solvent for example diethyl ether, is then added and the resulting solid filtered and washed with further organic solvent, for example diethyl ether.
  • the combined filtrate is then evaporated to give a compound of formula (X).
  • a compound of formula (X) wherein Het is 3-tetrahydropyranyl and n is an integer having a value of 2 may be prepared by reaction of the compound of formula (XII):
  • Het is 3-tetrahydropyranyl, with a suitable reducing agent, for example sodium borohydride.
  • a suitable reducing agent for example sodium borohydride.
  • a suspension of a suitable reducing agent for example sodium borohydride
  • a suitable solvent for example ethanol
  • a solution of the compound of formula (XII) in a suitable solvent for example ethanol added dropwise with stirring over a suitable period of time, for example 10 minutes.
  • a suitable period of time for example 15 minutes
  • the ice-bath is removed and after a further period of time, for example 3 hours, the mixture is heated at a suitable temperature, for example 50° C. for a suitable period of time, for example 1 hour.
  • the solvent is evaporated and the residue treated with water and extracted with a suitable organic solvent, for example dichloromethane.
  • the combined extracts were washed, dried, and evaporated to give the compound of formula (X) wherein Het is 3-tetrahydropyranyl and n is an integer having a value of 2.
  • the compound of formula (XII) may be prepared by reaction of a compound of formula (XIII):
  • Het is 3-tetrahydropyranyl, with a suitable mineral acid, for example hydrochloric acid.
  • a suitable solvent for example tetrahydrofuran
  • a suitable mineral acid for example 2N hydrochloric acid
  • the mixture is diluted with water and extracted with a suitable organic solvent, for example ether.
  • the organic extract is then washed, dried, and evaporated to give the compound of formula (XII).
  • a compound of formula (XIII) may be prepared by reaction of the compound of formula (XIV):
  • Het is 3-tetrahydropyranyl, with a compound of formula (XV):
  • a suspension of a compound of formula (XV) in a suitable dry solvent for example dry tetrahydrofuran
  • a suitable temperature for example minus 40° C.
  • a suitable strong base for example potassium tert-butoxide in a suitable dry solvent, for example dry tetrahydrofuran
  • a suitable atmosphere for example an atmosphere of nitrogen.
  • the compound of formula (XIV) may be prepared by hydrogenation of the compound of formula (XVI):
  • the compound of formula (XVI) in a suitable solvent for example ethanol
  • a suitable atmosphere for example an atmosphere of nitrogen
  • hydrogenated at ambient temperature and pressure for a suitable period of time, for example 30 minutes.
  • the catalyst removed by filtration and the filtrate evaporated to give the compound of formula (XIV).
  • the compound of formula (XVI) may be prepared from acrolein.
  • a compound of formula (III) may be prepared by reaction of a compound of formula (IV):
  • R 1 is as hereinbefore defined for a compound of formula (I)
  • P is as hereinbefore defined for a compound of formula (III)
  • X is a halogen atom, for example bromine, with an alkali metal alkoxide, for example sodium methoxide.
  • a compound of formula (IV) is heated to a suitable temperature, for example to reflux temperature to or just below reflux temperature, with an alcoholic solution of an alkali metal alkoxide, for example 25% sodium methoxide in methanol, in a suitable solvent, for example methanol, for a suitable period of time, for example 2-8 hours.
  • the reaction mixture is concentrated under reduced pressure and partitioned between suitable aqueous and non-aqueous phases, for example ethyl acetate and saturated ammonium chloride solution.
  • suitable aqueous and non-aqueous phases for example ethyl acetate and saturated ammonium chloride solution.
  • the organic phase is separated and the aqueous phase extracted repeatedly into ethyl acetate.
  • the combined organic phases are washed, dried, evaporated, and then placed under reduced pressure to give a compound of formula (III).
  • a compound of formula (IV) may be prepared by reaction of a compound of formula (V):
  • R 1 is as hereinbefore defined for a compound of formula (I) and P is as hereinbefore defined for a compound of formula (III), with a suitable halogenating agent, for example N-bromosuccinimide.
  • a compound of formula (V) is dissolved in a suitable solvent, for example chloroform, and cooled to a suitable temperature, for example 0° C.
  • a suitable solvent for example chloroform
  • N-bromosuccinimide portionwise N-bromosuccinimide
  • the resulting mixture is stirred at a suitable temperature, for example 2-3° C., for a suitable period of time, for example 30 minutes, before allowing to warm to room temperature and then stirring for a further period of time, for example 6 hours.
  • the reaction mixture is then washed with water.
  • the organic phase is dried/separated using a hydrophobic frit and evaporated to give a crude compound of formula (IV), which may be purified.
  • a compound of formula (V), wherein R 1 is C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, or Het b -C 1-3 alkoxy, may be prepared by reaction of a compound of formula (VI):
  • R 1 is C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, or Het b -C 1-3 alkoxy, in the presence of a strong base of appropriate strength, for example sodium metal, sodium hydride, or sodium tert-butoxide.
  • a strong base for example sodium tert-butoxide.
  • the mixture is stirred until homogeneous before a compound of formula (VI) is added to the solution.
  • the reaction mixture is then heated to a suitable temperature, for example 100° C., for a suitable period of time, for example 12-18 hours.
  • the reaction mixture is placed under reduced pressure to remove as much of a compound of formula (VIA) as possible before being partitioned between a suitable organic solvent, for example diethyl ether, and water.
  • a suitable organic solvent for example diethyl ether, and water.
  • the organic phase is separated and the aqueous phase may be re-extracted with further organic solvent.
  • a compound of formula (V), wherein R 1 is C 1-8 alkylamino or C 3-7 cycloalkylC 1-6 alkylamino may be prepared by reaction of a compound of formula (VI) as hereinbefore defined, with a compound of formula (VIB):
  • R 1 is C 1-6 alkylamino or C 3-7 cycloalkylC 1-6 amino.
  • a compound of formula (VI) for example, in a suitable dry solvent, for example dry ethylene glycol, at a suitable temperature, for example room temperature, and under a suitable atmosphere, for example an atmosphere of nitrogen, is added a compound of formula (VIB).
  • a suitable temperature for example 120° C.
  • a suitable period of time for example 12-18 hours.
  • the reaction is cooled to room temperature, diluted with a suitable solvent, for example ethyl acetate, and washed with water.
  • the organic layer is dried over a suitable drying agent, for example anhydrous magnesium sulphate, filtered and concentrated in vacuo to afford a compound of formula (V) wherein R 1 is C 1-6 alkylamino.
  • a compound of formula (VI) may be prepared by reaction of a compound of formula (VII):
  • P is as hereinbefore defined for a compound of formula (III)
  • Y is as hereinbefore defined for a compound of formula (VI)
  • Z is a halogen atom, for example chlorine, with an alcoholic solution of ammonia.
  • a compound of formula (VII) is heated with 2M solution of ammonia in a suitable alcohol, for example, iso-propyl alcohol, at a suitable temperature, for example 50° C., for a suitable period of time, for example 5 hours.
  • a suitable temperature for example 50° C.
  • a further quantity of the alcoholic ammonia is added to break up the resultant cake and the reaction mixture heated for a further suitable period of time, for example 9 hours, until the reaction is complete.
  • water and the solid product filtered off.
  • the solid is then washed, for example with a mixture of iso-propyl alcohol and water, and then air-dried under suction to give a first crop.
  • the filtrate may be re-filtered after standing for 12-18 hours to afford a second crop and the crops then dried in vacuo.
  • a compound of formula (VII) may be prepared from a compound of formula (VIII):
  • Y is as hereinbefore defined for a compound of formula (VI) and Z is as hereinbefore defined for a compound of formula (VII), by reaction with a suitable protecting reagent, for example 3,4-dihydro-2H-pyran.
  • a suitable protecting reagent for example 3,4-dihydro-2H-pyran.
  • a compound of formula (VIII) is added a suitable solvent, for example ethyl acetate, followed by p-toluenesulfonic acid.
  • a suitable solvent for example ethyl acetate
  • p-toluenesulfonic acid for example 1,3-dihydro-2H-pyran
  • the reaction mixture is then heated at a suitable temperature, for example 50° C., for a suitable period of time, for example 4 hours.
  • the reaction mixture is then evaporated in vacuo to give a compound of formula (VII).
  • the present invention includes a process for the preparation of a compound of formula (I), which process comprises the hydrolysis of a compound of formula (XXI):
  • R 1 and R 2 are as hereinbefore defined for a compound of formula (I) and X is as hereinbefore defined for a compound of formula (IV).
  • a suitable concentrated mineral acid for example concentrated hydrochloric acid
  • a suitable temperature for example ambient temperature.
  • the reaction is then heated to a suitable temperature, for example 80-120° C. for a suitable period of time, for example 0.5-8 hours.
  • the volume of the reaction mixture is then was reduced, for example by concentration in vacuo, water added, and the mixture neutralised by the addition of a suitable aqueous base, for example sodium hydroxide solution.
  • the product is then isolated and purified by conventional means, for example the product may be isolated by filtration and purified by chromatography.
  • a compound of formula (XXI) may be prepared by halogenation of a compound of formula (XX):
  • R 1 and R 2 are as hereinbefore defined for a compound of formula (I).
  • a suitable dry solvent for example dry chloroform
  • a suitable temperature for example ambient temperature
  • N-bromosuccinimide N-bromosuccinimide
  • the reaction mixture is stirred at a suitable temperature, for example ambient temperature, for a suitable period of time, for example one hour.
  • the reaction mixture is then diluted with a suitable solvent, for example dichloromethane, and washed with water.
  • the organic phase is then dried, for example by passage through a hydrophobic frit, and concentrated.
  • R 1 is C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkoxy, C 1-3 alkoxyC 2-3 alkoxy, or Het b -C 1-3 alkoxy
  • the halogenation of a compound of formula (XX) may be undertaken, for example, as follows:
  • a compound of formula (XX) is dissolved in glacial acetic acid before adding sodium acetate.
  • the mixture is then cooled to a suitable temperature, for example in an ice-bath, and bromine gradually added.
  • the reaction mixture is warmed to a suitable temperature, for example ambient temperature, before being heated to a suitable temperature, for example in a heating device set to a temperature of 60-80° C. for a suitable period of time, for example 3-6 hours.
  • the reaction mixture is quenched with sodium thiosulphate solution and then the pH adjusted to 6-7 by the addition of a suitable base, for example aqueous sodium hydroxide solution.
  • the mixture is then extracted into a suitable organic solvent, for example ethyl acetate, the organic layer separated, dried, and the solvent removed.
  • a compound of formula (XX), wherein R 1 is C 1-8 alkoxy, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, or Het b -C 1-3 alkoxy may be prepared by reaction of a compound of formula (XIX):
  • a compound of formula (XIX) is added to a suspension of a compound of formula (VIA) and a strong base, for example sodium tert-butoxide.
  • the reaction mixture is then heated, for example in a microwave oven, for a suitable period of time, for example 20-45 minutes at a suitable temperature, for example 90-120° C.
  • the reaction mixture is then diluted with a suitable solvent, for example ethyl acetate, and washed with water.
  • the organic phase is separated and dried, for example by passage through a hydrophobic frit, and concentrated.
  • the compound of formula (XX) may be isolated by conventional means, for example trituration followed by filtration.
  • a compound of formula (XX), wherein R 1 is C 1-8 alkylamino, C 3-7 cycloalkylC 1-6 alkylamino may be prepared by reaction of a compound of formula (XIX) with a compound of formula (VIB) as hereinbefore defined.
  • a solution of a compound of formula (XIX) in a suitable solvent for example cyclohexylamine
  • a suitable temperature for example 150-180° C.
  • a suitable period of time for example five minutes.
  • the crude reaction mixture is then purified by, for example chromatography.
  • a compound of formula (XIX) may be prepared by reaction of a compound of formula (XVIII):
  • Y is as hereinbefore defined for a compound of formula (VI)
  • Z is as hereinbefore defined for a compound of formula (VII)
  • R 2 is as hereinbefore defined for a compound of formula (I), with ammonia.
  • a compound of formula (XVIII) (which may contain residual triphenylphosphine oxide as an impurity from the synthesis of a compound of formula (XVIII), is heated with an alcoholic solution of ammonia, for example 2M ammonia in iso-propyl alcohol, at a suitable temperature, for example 40-60° C., for a suitable period of time, for example 12-18 hours.
  • the reaction mixture is then evaporated to dryness and the product purified by recrystallisation from a suitable solvent, for example methanol.
  • a compound of formula (XIX) may also be prepared by reaction of a compound of formula (XVII):
  • a compound of formula (XVIII) may be prepared by reaction of a compound of formula (VIII) as hereinbefore defined with a compound of formula R 2 —OH, wherein R 2 is as hereinbefore defined for a compound of formula (I).
  • a mixture of a compound of formula (VIII) and a compound of formula R 2 —OH is dissolved in a suitable dry solvent, for example dry tetrahydrofuran.
  • a suitable dry solvent for example dry tetrahydrofuran.
  • triphenylphosphine followed by diisopropyl azodicarboxylate (dropwise).
  • the temperature of the reaction mixture is kept below about 45° C. by cooling, for example with a water-bath.
  • the reaction mixture is then stirred for a suitable period of time, for example 12-18 hours, at a suitable temperature, for example ambient temperature, quenched with water, and extracted into a suitable organic solvent, for example ethyl acetate.
  • the organic phase is separated, washed with water, and then dried by, for example, passage through a hydrophobic frit, and concentrated under reduced pressure.
  • the crude product may be purified by conventional means, for example chromatography.
  • a compound of formula (XVII) may be prepared by reaction of a compound of formula (VIII) as hereinbefore defined with ammonia.
  • a mixture of a compound of formula (VIII) and ammonia solution in a suitable solvent for example iso-propyl alcohol, is stirred and heated at a suitable temperature, for example 100-140° C. in an autoclave for a suitable period of time, for example 12-18 hours.
  • a suitable temperature for example 100-140° C. in an autoclave for a suitable period of time, for example 12-18 hours.
  • the reaction is then cooled and concentrated to give a compound of formula (XVII).
  • the present invention includes a synthetic process for, a compound of formula (I), wherein R 1 is C 1-8 alkylamino or C 3-7 cycloalkylC 1-6 alkylamino, which may be prepared by reaction of a compound of formula (XXIII):
  • Y is as hereinbefore defined for a compound of formula (VI)
  • R 2 is as hereinbefore defined for a compound of formula (I)
  • R 3 is as hereinbefore defined for a compound of formula (IIA), with a compound of formula (VIB) as hereinbefore defined.
  • a mixture of a compound of formula (XXIII) and a compound of formula (VI B) is heated, for example in a microwave oven, at a suitable temperature, for example 150-190° C. for a suitable period of time, for example 10-20 minutes.
  • the reaction mixture is then concentrated to yield a crude product which is purified by conventional means, for example chromatography.
  • a compound of formula (XXIII) may be prepared by reaction of a compound of formula (XXII):
  • X is as hereinbefore defined for a compound of formula (IV)
  • Y is as hereinbefore defined for a compound of formula (VI)
  • R 2 is as hereinbefore defined for a compound of formula (I), with a source of alkoxide anion.
  • a solution of a compound of formula (XXII) in a suitable solvent for example dry methanol
  • a suitable base for example aqueous sodium hydroxide solution
  • the reaction mixture is cooled to a suitable temperature, for example ambient temperature, and concentrated.
  • the residue obtained is triturated with water and extracted with a suitable solvent, for example ethyl acetate.
  • the organic layer is separated, washed, dried, filtered and concentrated to give a solid product which may be purified by conventional means, for example chromatography.
  • a compound of formula (XXII) may be prepared by reaction of a compound of formula (XIX) as hereinbefore defined, with a halogenating agent.
  • a suitable temperature for example 50-70° C. for a suitable period of time, for example 5-7 hours.
  • the reaction mixture is cooled, for example to ambient temperature, taken up in a suitable solvent, for example dichloromethane, and washed with water.
  • the organic phase is then dried by, for example passage through a hydrophobic frit, and concentrated.
  • conventional methods of heating and cooling may be employed, for example temperature-regulated oil-baths or temperature-regulated hot-blocks, and ice/salt baths or dry ice/acetone baths respectively.
  • Conventional methods of isolation for example extraction from or into aqueous or non-aqueous solvents may be used.
  • Conventional methods of drying organic solvents, solutions, or extracts such as shaking with magnesium sulphate, or sodium sulphate, or passing through a hydrophobic frit, may be employed.
  • Conventional methods of purification for example crystallisation and chromatography, for example silica chromatography or reverse-phase chromatography, may be used as required.
  • Crystallisation may be performed using conventional solvents such as methanol, ethanol, or butanol, or aqueous mixtures thereof. It will be appreciated that specific reaction times temperatures may typically be determined by reaction-monitoring techniques, for example thin-layer chromatography and LC-MS.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • UV Detection Range 215 to 330 nm
  • Solvents A: 0.1% formic acid + 10 mM ammonium acetate
  • UV Detection Range 220 to 330 nm
  • Solvents A: 0.1% formic acid + 10 mM ammonium acetate
  • Chromatographic purification was typically performed using pre-packed silica gel cartridges.
  • the Flashmaster II is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, Solid Phase Extraction (SPE) cartridges (2 g to 100 g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions.
  • the system is equipped with a Knauer variable wavelength UV-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.
  • A 10 mM aqueous Ammonium Bicarbonate adjusted to pH 10 with Ammonia solution.
  • a flow rate of 20 ml/min was employed.
  • a typical gradient was:
  • the UV detection was an averaged signal from wavelength of 210 nm to 350 nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
  • 2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (36.9 g) was heated with 2M ammonia in isopropanol (250 mL) at 50° C. for 5 hours. After standing at ambient temperature overnight, a further quantity of 2M ammonia in isopropanol (100 mL) was added to break up the resultant cake and the reaction mixture was heated for a further 9 hours until the reaction was complete. To the reaction mixture was added water (70 mL) and the yellow solid filtered off. The solid was washed with isopropyl alcohol:water (5:1 (v/v), 60 mL) and then air-dried under suction to give a first crop.
  • the filtrate was re-filtered after standing overnight to isolate precipitate and both solids were dried in vacuo.
  • the first crop was pure with the second crop material showing a very minor impurity (isolated broad signal 3.5 ppm not seen in first crop) but was otherwise identical.
  • Solid first crop 28.4 g
  • solid second crop (3.42 g).
  • the organic phase was passed through a hydrophobic frit after separating aqueous and was evaporated to give a light brown gum which was placed under high vacuum to give a foam (7.52 g) which collapsed to a gum (7.34 g) at ambient pressure and solidified overnight to give the title compound as a yellow amorphous solid.
  • 2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.5 g) was heated to 60° C. for 1 hour with anhydrous potassium carbonate (0.79 g) in dry DMF (10 mL) and allowed to cool to room temperature before adding 4-(bromomethyl)tetrahydro-2H-pyran (0.26 g). The reaction was stirred at room temperature for 39 hours and heated for 2 hours at 50° C. The reaction was poured into water and extracted into ethyl acetate (twice).
  • N 2 -butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt 500 mg
  • dry N,N-dimethylformamide 8 ml
  • potassium carbonate 1.17 g
  • 4-(bromomethyl)tetrahydro-2H-pyran 0.3 ml was added in one go and the reaction heated at 50° C. overnight.
  • the reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic layer was separated and concentrated in vacuo.
  • the product was purified by C 18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford the title compound as a yellow viscous oil (315 mg, 90% clean).
  • the reaction mixture was then partitioned between water (300 mL) and ethyl acetate (300 mL). The organic was separated and the aqueous layer was re-extracted with further ethyl acetate (300 mL). The organic extracts were combined and washed with brine (500 mL). The organic was dried by passing through a hydrophobic frit (after separating the brine layer). The organic was evaporated under reduced pressure to give a crude brown mobile oil (16.01 g) that solidified to a wet solid (over 2 days). This material in ⁇ 3 g batches was purified using reverse phase chromatography ⁇ ISCO [column (C18) 330 g] (20-60% acetonitrile: water) ⁇ . The appropriate pure fractions from all purifications were combined and evaporated under reduced pressure to give clean title compound as a light-tan powdery solid (5.1530 M.
  • a further batch of product was obtained by acidifying the aqueous solution with 2N hydrochloric acid, saturating with sodium chloride and extracting three times with dichloromethane. These extracts were treated as above and the batches combined to give a total yield of 1.54 g (81%).
  • the product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a colourless oil (3.5 g).
  • the crude material was purified by normal phase chromatography (ISCO) using 5-20% methanol/EtOAc as eluent to give a pale oil (181 mg).
  • the material was re-purified by normal phase chromatography (ISCO) using 0-15% methanol/EtOAc as eluent to give the title compound (161 mg).

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070190071A1 (en) * 2004-03-26 2007-08-16 Dainippon Sumitomo Pharma Co., Ltd. 9-Substituted 8-oxoadenine compound
US20080085909A1 (en) * 2006-02-17 2008-04-10 Pharmacopeia Drug Discovery, Inc. Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US20090047249A1 (en) * 2007-06-29 2009-02-19 Micheal Graupe Modulators of toll-like receptor 7
US20090118263A1 (en) * 2005-09-22 2009-05-07 Dainippon Sumitomo Pharma Co., Ltd. Novel Adenine Compound
US20090131458A1 (en) * 2007-02-19 2009-05-21 Smithkline Beecham Corporation Compounds
US20090281075A1 (en) * 2006-02-17 2009-11-12 Pharmacopeia, Inc. Isomeric purinones and 1h-imidazopyridinones as pkc-theta inhibitors
US20100087443A1 (en) * 2007-03-19 2010-04-08 Roger Victor Bonnert 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators
US20100093998A1 (en) * 2007-03-20 2010-04-15 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
US20100240623A1 (en) * 2006-07-05 2010-09-23 Anthony Cook 8-oxoadenine derivatives acting as modulators of tlr7
US20100280001A1 (en) * 2007-05-08 2010-11-04 Roger Victor Bonnert Imidazoquinolines with immuno-modulating properties
US20110046369A1 (en) * 2008-01-17 2011-02-24 Dainippon Sumitomo Pharma Co., Ltd. Method for preparing adenine compound
US20110054168A1 (en) * 2008-01-17 2011-03-03 Ayumu Kurimoto Method for preparing adenine compound
US20110098248A1 (en) * 2009-10-22 2011-04-28 Gilead Sciences, Inc. Modulators of toll-like receptors
US20110136801A1 (en) * 2009-12-03 2011-06-09 Dainippon Sumitomo Pharma Co. Ltd. Novel Compounds
US20110150836A1 (en) * 2009-12-22 2011-06-23 Gilead Sciences, Inc. Methods of treating hbv and hcv infection
US8044056B2 (en) * 2007-03-20 2011-10-25 Dainippon Sumitomo Pharma Co., Ltd. Adenine compound
US8067426B2 (en) * 2008-08-11 2011-11-29 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US8067411B2 (en) * 2006-12-14 2011-11-29 Astrazeneca Ab Compounds
US8067413B2 (en) * 2007-03-19 2011-11-29 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (TLR7 ) modulators
WO2012010855A1 (en) 2010-07-23 2012-01-26 Medical Research Council Intracellular immunity
US8673907B2 (en) 2007-12-17 2014-03-18 Astrazeneca Ab Pharmaceutically acceptable salts of methyl (3-{ [[3-(6-amino- 2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl) propyl] (3-morpholin-4-ylpropyl) amino] methyl }phenyl) acetate and their use in therapy
US8895570B2 (en) 2010-12-17 2014-11-25 Astrazeneca Ab Purine derivatives
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
US9173872B2 (en) 2012-08-24 2015-11-03 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9428512B2 (en) 2012-11-20 2016-08-30 Glaxosmithkline Llc Compounds
US9540383B2 (en) 2012-11-20 2017-01-10 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9550785B2 (en) 2012-11-20 2017-01-24 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US10112946B2 (en) 2011-07-22 2018-10-30 Glaxosmithkline Llc Composition
US10202384B2 (en) 2014-09-16 2019-02-12 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US10981917B2 (en) 2017-02-07 2021-04-20 Daewoong Pharmaceutical Co., Ltd. Heterocyclic compound, its preparation method, and pharmaceutical composition comprising the same
US11110091B2 (en) 2008-12-09 2021-09-07 Gilead Sciences, Inc. Modulators of toll-like receptors
US11116774B2 (en) 2014-07-11 2021-09-14 Gilead Sciences, Inc. Modulators of toll-like receptors for the treatment of HIV

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG193149A1 (en) * 2008-08-11 2013-09-30 Glaxosmithkline Llc Novel adenine derivatives
EP2324025A1 (en) * 2008-08-11 2011-05-25 Smithkline Beecham Corporation Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
ES2433371T3 (es) * 2008-08-11 2013-12-10 Glaxosmithkline Llc Derivados de purina para uso en el tratamiento de enfermedades alérgicas, inflamatorias e infecciosas
US8802684B2 (en) 2008-08-11 2014-08-12 Glaxosmithkline Llc Adenine derivatives
WO2010018132A1 (en) * 2008-08-11 2010-02-18 Smithkline Beecham Corporation Compounds
WO2010088924A1 (en) 2009-02-06 2010-08-12 Telormedix Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
EP2417140B1 (en) 2009-04-09 2014-11-26 Boehringer Ingelheim International GmbH Inhibitors of hiv replication
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PT2477987T (pt) 2009-09-14 2018-03-13 Gilead Sciences Inc Moduladores de recetores do tipo toll
PT2534149E (pt) 2010-02-10 2014-12-23 Glaxosmithkline Llc Maleato de 6-amino-2-{[(1s)-1-metilbutil]oxi}-9-[5-(1- piperidinil)pentil]-7,9-di-hidro-8h-purin-8-ona
WO2011098451A1 (en) 2010-02-10 2011-08-18 Glaxosmithkline Llc Purine derivatives and their pharmaceutical uses
NZ603155A (en) 2010-04-30 2014-06-27 Telormedix Sa Phospholipid drug analogs
US9050319B2 (en) 2010-04-30 2015-06-09 Telormedix, Sa Phospholipid drug analogs
WO2012031140A1 (en) 2010-09-01 2012-03-08 Novartis Ag Adsorption of immunopotentiators to insoluble metal salts
EP2680885B8 (en) 2011-03-02 2018-07-25 GlaxoSmithKline Biologicals SA Combination vaccines with lower doses of antigen and/or adjuvant
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US20150132339A1 (en) 2012-03-07 2015-05-14 Novartis Ag Adjuvanted formulations of streptococcus pneumoniae antigens
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CA3057813A1 (en) 2017-03-29 2018-10-04 Sumitomo Dainippon Pharma Co., Ltd. Vaccine adjuvant formulation
EP3730152A4 (en) 2017-12-21 2022-01-12 Sumitomo Dainippon Pharma Co., Ltd. COMBINATION DRUGS WITH TLR7 AGONIST
CA3107409A1 (en) 2018-07-23 2020-01-30 Japan As Represented By Director General Of National Institute Of Infectious Diseases Composition containing influenza vaccine

Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962479A (en) * 1994-06-08 1999-10-05 Pfizer Inc. Corticotropin releasing factor antagonists
US20010020030A1 (en) * 1998-06-04 2001-09-06 Stewart Andrew O. Cell adhesion-inhibiting antiinflammatory compounds
US6376501B1 (en) * 1997-12-22 2002-04-23 Japan Energy Corporation Type 2 helper T cell-selective immune response suppressors
US6552192B1 (en) * 1999-01-26 2003-04-22 Ustau Experimentalni Botaniky Av-Cr Substituted nitrogen heterocyclic derivatives and pharmaceutical use thereof
US20030187261A1 (en) * 2000-01-07 2003-10-02 Libor Havlicek Purine derivatives, process for their preparation and use thereof
US20030236216A1 (en) * 2001-06-12 2003-12-25 Devos Rene Robert 4'-substituted nucleoside derivatives as inhibitors of HCV RNA replication
US20050054590A1 (en) * 2003-09-05 2005-03-10 Averett Devron R. Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis C virus
US20060029642A1 (en) * 2004-08-03 2006-02-09 Dusan Miljkovic Methods and compositions for improved chromium complexes
US20060148805A1 (en) * 2003-07-01 2006-07-06 Meng Hsin Chen Opthalmic compositions for treating ocular hypertension
US7125880B1 (en) * 1995-06-06 2006-10-24 Pfizer Inc. Corticotropin releasing factor antagonists
US20060264448A1 (en) * 2005-05-04 2006-11-23 Pfizer Limited Purine derivatives
US20070190071A1 (en) * 2004-03-26 2007-08-16 Dainippon Sumitomo Pharma Co., Ltd. 9-Substituted 8-oxoadenine compound
US20070197478A1 (en) * 2006-02-17 2007-08-23 Pfizer Limited Novel pharmaceuticals
US20080008682A1 (en) * 2006-07-07 2008-01-10 Chong Lee S Modulators of toll-like receptor 7
US20080269240A1 (en) * 2005-09-22 2008-10-30 Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan Novel Adenine Compound
US20080300244A1 (en) * 2006-12-14 2008-12-04 Astrazeneca Ab Novel compounds
US20090047249A1 (en) * 2007-06-29 2009-02-19 Micheal Graupe Modulators of toll-like receptor 7
US20090082332A1 (en) * 2005-09-22 2009-03-26 Philip Abbot Purine derivatives for the treatment of viral or allergic diseases and cancers
US20090099216A1 (en) * 2005-09-22 2009-04-16 Astrazeneca Aktiebolag A Corporation Of Sweden Novel adenine compound
US20090105212A1 (en) * 2005-09-22 2009-04-23 Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan Novel adenine compound
US20090118263A1 (en) * 2005-09-22 2009-05-07 Dainippon Sumitomo Pharma Co., Ltd. Novel Adenine Compound
US20090131458A1 (en) * 2007-02-19 2009-05-21 Smithkline Beecham Corporation Compounds
US20090143400A1 (en) * 2005-09-16 2009-06-04 Mcinally Thomas Purine derivatives having immuno-modulating properties
US20090192153A1 (en) * 2005-09-22 2009-07-30 Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan Novel adenine compound
US20090324551A1 (en) * 2005-08-22 2009-12-31 The Regents Of The University Of California Office Of Technology Transfer Tlr agonists
US20090325877A1 (en) * 2008-05-25 2009-12-31 Wyeth Combination Product of Receptor Tyrosine Kinase Inhibitor and Fatty Acid Synthase Inhibitor for Treating Cancer
US20100075995A1 (en) * 2008-08-11 2010-03-25 Smithkline Beecham Corporation Compounds
US20100087443A1 (en) * 2007-03-19 2010-04-08 Roger Victor Bonnert 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators
US20100093998A1 (en) * 2007-03-20 2010-04-15 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
US20100099870A1 (en) * 2007-03-20 2010-04-22 Dainippon Sumitomo Phama Co., Ltd Novel adenine compound

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101111085B1 (ko) * 2002-09-27 2012-04-12 다이닛본 스미토모 세이야꾸 가부시끼가이샤 신규 아데닌 화합물 및 그 용도
US20100152230A1 (en) 2005-09-02 2010-06-17 Pfizer Inc. Hydroxy substituted 1h-imidazopyridines and methods
CN1947717B (zh) 2005-10-14 2012-09-26 卓敏 选择性抑制腺苷酸环化酶1的化合物在制备用于治疗神经性疼痛和炎性疼痛的药物中的应用
JP2009542645A (ja) * 2006-07-05 2009-12-03 アストラゼネカ・アクチエボラーグ Ｔｌｒ７のモジュレーターとして作用する８−オキソアデニン誘導体
SI2132209T1 (sl) 2007-03-19 2014-05-30 Astrazeneca Ab Spojine 9-substituiranega-8-okso-adenina, kot modulatorji Toll-like receptorja (TLR7)
WO2010018132A1 (en) * 2008-08-11 2010-02-18 Smithkline Beecham Corporation Compounds
ES2433371T3 (es) * 2008-08-11 2013-12-10 Glaxosmithkline Llc Derivados de purina para uso en el tratamiento de enfermedades alérgicas, inflamatorias e infecciosas
EP2324025A1 (en) * 2008-08-11 2011-05-25 Smithkline Beecham Corporation Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
SG193149A1 (en) * 2008-08-11 2013-09-30 Glaxosmithkline Llc Novel adenine derivatives

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962479A (en) * 1994-06-08 1999-10-05 Pfizer Inc. Corticotropin releasing factor antagonists
US7125880B1 (en) * 1995-06-06 2006-10-24 Pfizer Inc. Corticotropin releasing factor antagonists
US6376501B1 (en) * 1997-12-22 2002-04-23 Japan Energy Corporation Type 2 helper T cell-selective immune response suppressors
US20010020030A1 (en) * 1998-06-04 2001-09-06 Stewart Andrew O. Cell adhesion-inhibiting antiinflammatory compounds
US6552192B1 (en) * 1999-01-26 2003-04-22 Ustau Experimentalni Botaniky Av-Cr Substituted nitrogen heterocyclic derivatives and pharmaceutical use thereof
US20030187261A1 (en) * 2000-01-07 2003-10-02 Libor Havlicek Purine derivatives, process for their preparation and use thereof
US20030236216A1 (en) * 2001-06-12 2003-12-25 Devos Rene Robert 4'-substituted nucleoside derivatives as inhibitors of HCV RNA replication
US20060148805A1 (en) * 2003-07-01 2006-07-06 Meng Hsin Chen Opthalmic compositions for treating ocular hypertension
US20050054590A1 (en) * 2003-09-05 2005-03-10 Averett Devron R. Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis C virus
US20070190071A1 (en) * 2004-03-26 2007-08-16 Dainippon Sumitomo Pharma Co., Ltd. 9-Substituted 8-oxoadenine compound
US20060029642A1 (en) * 2004-08-03 2006-02-09 Dusan Miljkovic Methods and compositions for improved chromium complexes
US20060264448A1 (en) * 2005-05-04 2006-11-23 Pfizer Limited Purine derivatives
US7642350B2 (en) * 2005-05-04 2010-01-05 Pfizer Limited Purine derivatives
US20090324551A1 (en) * 2005-08-22 2009-12-31 The Regents Of The University Of California Office Of Technology Transfer Tlr agonists
US20090143400A1 (en) * 2005-09-16 2009-06-04 Mcinally Thomas Purine derivatives having immuno-modulating properties
US20080269240A1 (en) * 2005-09-22 2008-10-30 Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan Novel Adenine Compound
US20090082332A1 (en) * 2005-09-22 2009-03-26 Philip Abbot Purine derivatives for the treatment of viral or allergic diseases and cancers
US20090099216A1 (en) * 2005-09-22 2009-04-16 Astrazeneca Aktiebolag A Corporation Of Sweden Novel adenine compound
US20090105212A1 (en) * 2005-09-22 2009-04-23 Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan Novel adenine compound
US20090118263A1 (en) * 2005-09-22 2009-05-07 Dainippon Sumitomo Pharma Co., Ltd. Novel Adenine Compound
US20090192153A1 (en) * 2005-09-22 2009-07-30 Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan Novel adenine compound
US20070197478A1 (en) * 2006-02-17 2007-08-23 Pfizer Limited Novel pharmaceuticals
US20090202484A1 (en) * 2006-07-07 2009-08-13 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US20080008682A1 (en) * 2006-07-07 2008-01-10 Chong Lee S Modulators of toll-like receptor 7
US20080300244A1 (en) * 2006-12-14 2008-12-04 Astrazeneca Ab Novel compounds
US20090131458A1 (en) * 2007-02-19 2009-05-21 Smithkline Beecham Corporation Compounds
US20100087443A1 (en) * 2007-03-19 2010-04-08 Roger Victor Bonnert 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators
US20100093998A1 (en) * 2007-03-20 2010-04-15 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
US20100099870A1 (en) * 2007-03-20 2010-04-22 Dainippon Sumitomo Phama Co., Ltd Novel adenine compound
US20090047249A1 (en) * 2007-06-29 2009-02-19 Micheal Graupe Modulators of toll-like receptor 7
US20090325877A1 (en) * 2008-05-25 2009-12-31 Wyeth Combination Product of Receptor Tyrosine Kinase Inhibitor and Fatty Acid Synthase Inhibitor for Treating Cancer
US20100075995A1 (en) * 2008-08-11 2010-03-25 Smithkline Beecham Corporation Compounds

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575180B2 (en) 2004-03-26 2013-11-05 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8969362B2 (en) 2004-03-26 2015-03-03 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8012964B2 (en) * 2004-03-26 2011-09-06 Dainippon Sumitomo Pharma Co., Ltd. 9-substituted 8-oxoadenine compound
US20070190071A1 (en) * 2004-03-26 2007-08-16 Dainippon Sumitomo Pharma Co., Ltd. 9-Substituted 8-oxoadenine compound
US20090118263A1 (en) * 2005-09-22 2009-05-07 Dainippon Sumitomo Pharma Co., Ltd. Novel Adenine Compound
US20080085909A1 (en) * 2006-02-17 2008-04-10 Pharmacopeia Drug Discovery, Inc. Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US20090281075A1 (en) * 2006-02-17 2009-11-12 Pharmacopeia, Inc. Isomeric purinones and 1h-imidazopyridinones as pkc-theta inhibitors
US7989459B2 (en) * 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US20100240623A1 (en) * 2006-07-05 2010-09-23 Anthony Cook 8-oxoadenine derivatives acting as modulators of tlr7
US8067411B2 (en) * 2006-12-14 2011-11-29 Astrazeneca Ab Compounds
US20090131458A1 (en) * 2007-02-19 2009-05-21 Smithkline Beecham Corporation Compounds
US7977344B2 (en) * 2007-02-19 2011-07-12 Glaxosmithkline Llc Compounds
US8067413B2 (en) * 2007-03-19 2011-11-29 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (TLR7 ) modulators
US8063051B2 (en) * 2007-03-19 2011-11-22 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (TLR7) modulators
US20100087443A1 (en) * 2007-03-19 2010-04-08 Roger Victor Bonnert 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators
US20110028715A1 (en) * 2007-03-20 2011-02-03 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
US20100093998A1 (en) * 2007-03-20 2010-04-15 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
US8044056B2 (en) * 2007-03-20 2011-10-25 Dainippon Sumitomo Pharma Co., Ltd. Adenine compound
US20100280001A1 (en) * 2007-05-08 2010-11-04 Roger Victor Bonnert Imidazoquinolines with immuno-modulating properties
US8436178B2 (en) 2007-05-08 2013-05-07 Astrazeneca Ab Imidazoquinolines with immuno-modulating properties
US20110236348A1 (en) * 2007-06-29 2011-09-29 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US9611268B2 (en) 2007-06-29 2017-04-04 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US8993755B2 (en) 2007-06-29 2015-03-31 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US20090047249A1 (en) * 2007-06-29 2009-02-19 Micheal Graupe Modulators of toll-like receptor 7
US7968544B2 (en) * 2007-06-29 2011-06-28 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US8673907B2 (en) 2007-12-17 2014-03-18 Astrazeneca Ab Pharmaceutically acceptable salts of methyl (3-{ [[3-(6-amino- 2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl) propyl] (3-morpholin-4-ylpropyl) amino] methyl }phenyl) acetate and their use in therapy
US20110054168A1 (en) * 2008-01-17 2011-03-03 Ayumu Kurimoto Method for preparing adenine compound
US20110046369A1 (en) * 2008-01-17 2011-02-24 Dainippon Sumitomo Pharma Co., Ltd. Method for preparing adenine compound
US8865896B2 (en) 2008-01-17 2014-10-21 Astrazeneca Aktiebolag Method for preparing adenine compound
US10117873B2 (en) 2008-08-11 2018-11-06 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US9233962B2 (en) 2008-08-11 2016-01-12 Glaxosmithkline Llc Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
US9877968B2 (en) 2008-08-11 2018-01-30 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US8067426B2 (en) * 2008-08-11 2011-11-29 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US9346806B2 (en) 2008-08-11 2016-05-24 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US11110091B2 (en) 2008-12-09 2021-09-07 Gilead Sciences, Inc. Modulators of toll-like receptors
US8507507B2 (en) 2009-10-22 2013-08-13 Gilead Sciences, Inc. Modulators of toll-like receptors
US8962652B2 (en) 2009-10-22 2015-02-24 Gilead Sciences, Inc. Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections
US20110098248A1 (en) * 2009-10-22 2011-04-28 Gilead Sciences, Inc. Modulators of toll-like receptors
US9161934B2 (en) 2009-10-22 2015-10-20 Gilead Sciences, Inc. Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections
US20110136801A1 (en) * 2009-12-03 2011-06-09 Dainippon Sumitomo Pharma Co. Ltd. Novel Compounds
US20110150836A1 (en) * 2009-12-22 2011-06-23 Gilead Sciences, Inc. Methods of treating hbv and hcv infection
WO2012010855A1 (en) 2010-07-23 2012-01-26 Medical Research Council Intracellular immunity
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
US8895570B2 (en) 2010-12-17 2014-11-25 Astrazeneca Ab Purine derivatives
US10112946B2 (en) 2011-07-22 2018-10-30 Glaxosmithkline Llc Composition
US10022442B2 (en) 2012-08-24 2018-07-17 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9555036B2 (en) 2012-08-24 2017-01-31 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9662336B2 (en) 2012-08-24 2017-05-30 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9173872B2 (en) 2012-08-24 2015-11-03 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9907847B2 (en) 2012-11-20 2018-03-06 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9550785B2 (en) 2012-11-20 2017-01-24 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9540383B2 (en) 2012-11-20 2017-01-10 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9428512B2 (en) 2012-11-20 2016-08-30 Glaxosmithkline Llc Compounds
US11116774B2 (en) 2014-07-11 2021-09-14 Gilead Sciences, Inc. Modulators of toll-like receptors for the treatment of HIV
US10202384B2 (en) 2014-09-16 2019-02-12 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US10508117B2 (en) 2014-09-16 2019-12-17 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11072615B2 (en) 2014-09-16 2021-07-27 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11773098B2 (en) 2014-09-16 2023-10-03 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US10981917B2 (en) 2017-02-07 2021-04-20 Daewoong Pharmaceutical Co., Ltd. Heterocyclic compound, its preparation method, and pharmaceutical composition comprising the same

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