+

WO2012067269A1 - Composés aminoalcoxyphényle et leur utilisation dans le traitement de maladies - Google Patents

Composés aminoalcoxyphényle et leur utilisation dans le traitement de maladies Download PDF

Info

Publication number
WO2012067269A1
WO2012067269A1 PCT/JP2011/077275 JP2011077275W WO2012067269A1 WO 2012067269 A1 WO2012067269 A1 WO 2012067269A1 JP 2011077275 W JP2011077275 W JP 2011077275W WO 2012067269 A1 WO2012067269 A1 WO 2012067269A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
cancer
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/JP2011/077275
Other languages
English (en)
Inventor
Seiji Hori
Thomas Mcinally
Daisuke Urabe
Original Assignee
Dainippon Sumitomo Pharma Co., Ltd.
Astrazeneca Aktiebolag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dainippon Sumitomo Pharma Co., Ltd., Astrazeneca Aktiebolag filed Critical Dainippon Sumitomo Pharma Co., Ltd.
Publication of WO2012067269A1 publication Critical patent/WO2012067269A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel aminoalkoxyphenyl compounds and, more particularly, to novel aminoalkoxyphenyl compounds that act as TLR7 agonists. This invention also relates to methods for the preparation of such compounds and novel
  • TLR7 TLR7
  • TLRs Toll-like receptors
  • DCs dendritic cells
  • TLRs recognise molecular motifs on pathogens called pathogen-associated molecular patterns (PAMPs).
  • PAMPs pathogen-associated molecular patterns
  • TLRs recognise different pathogen- derived ligands, for example TLRs 2 (bacterial lipoproteins), 3 (double-stranded RNA/poly (I:C)), 4 (lipopolysaccharides), 5 (flagellin), 7 (single-stranded RNA) and 9 (CpG-containing DNA).
  • TLRs 2 bacterial lipoproteins
  • 3 double-stranded RNA/poly (I:C)
  • 4 lipopolysaccharides
  • 5 flagellin
  • 7 single-stranded RNA
  • 9 CpG-containing DNA
  • TLR7 and TLR9 are expressed by plasmacytoid dendritic cells (pDCs) and ligand recognition leads to the secretion of interferon-a (INF-a).
  • pDCs plasmacytoid dendritic cells
  • INF-a interferon-a
  • imidazoquinoline imiquimod
  • imiquimod which has been used to treat a number of dermatological conditions e.g. genital warts, molluscum contagiosum and melanoma.
  • topically applied imiquimod AldaraTM, Graceway Pharmaceuticals, Bristol, TN
  • BCC superficial basal cell carcinoma
  • imiquimod is likely to function through the induction of type 1 IFN and IFN-inducible genes, which in turn can have direct effects on tumour cell growth and/or harness components of the adaptive immune system.
  • 852A is another imidazoquinoline, which unlike imiquimod, is suitable for systemic administration.
  • 852A is in phase II clinical trials in a number of cancer indications, including melanoma.
  • TLR7 agonists which are more effective in the treatment of disease, for example cancer, by reason of their superior potency and/or advantageous physical properties (for example, higher permeability, and/or lower plasma protein binding) and/or favourable toxicity profiles and/or favourable metabolic profiles in comparison with other known TLR7 agonists, for example 852A.
  • the arninoalkoxyphenyl compounds of the present invention are capable of activating TLR7 in vitro.
  • the arninoalkoxyphenyl compounds of the present invention are expected to have value in the prevention or treatment of human disease, for example cancer, either as a monotherapy or in combination with other chemotherapeutic agents or radiotherapy regimens.
  • TLR7 and TLR8 differ in their cellular expression and as a result stimulation with selective agonists induces different cytokine profiles.
  • TLR8 stimulation results in enhanced levels of pro-inflammatory cytokines including TNFa, IL- ⁇ and IL-6 (Gorden et al (2005) J. Immunol. 174, 1259-1268). Conversely, TLR8 stimulation results in lower levels of IFNa.
  • a TLR7 selective agonist would favour induction of IFNa, which is important in suppression of Th2 cytokines (Huber et al (2010) J. Immunol. 185; 813- 817) that are elevated in allergic disease.
  • Th2 cytokines Hauber et al (2010) J. Immunol. 185; 813- 817) that are elevated in allergic disease.
  • compounds selective for TLR7 compared to TLR8 the induction of proinflammatory cytokines would be reduced thus avoiding inflammatory responses in man.
  • compounds of the invention also have a surprisingly advantageous hERG profile.
  • Compounds that have significant activities against the hERG ion channel are relevant to inducing QT prolongation and are disfavored because such activity is implicated in the development of Torsades de Pointes and cardiac death.
  • n 1, 2 or 3;
  • n 1 or 2;
  • p 1 or 2;
  • R is Ci -4 alkyl or hydroxy C 2-4 alkyl and R is hydrogen or C 1-4 alkyl;>
  • R 1 and R 2 together with the nitrogen to which they are attached form piperazin- 1 -yl optionally substituted on the available nitrogen by C 1-3 alkyl, or pyrrolidin-l-yl.
  • the "available nitrogen" of a piperazin- 1-yl is at the 4 position of the piperazin- 1-yl.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • C 1-4 alkyl is intended to mean a saturated carbon chain of 1 to 4 carbon atoms in length which may be straight chained or branched.
  • references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as tert-butyl are specific for the branched chain version only.
  • C 1-4 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.
  • C 2-4 alkyl and “C 1-3 alkyl” are to be construed accordingly.
  • hydroxyC 2-4 alkyl is intended to mean a saturated carbon chain of 2 to 4 carbon atoms in length, which may be straight-chained or branched, wherein one of the hydrogen atoms has been replaced by a hydroxy group.
  • hydroxyC 2-4 alkyl includes, but is not limited to, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- hydroxyisopropyl and 4-hydroxybutyl.
  • R , R and m, p and n may take any of the values defined herein for R , R and m, p and n respectively.
  • variable groups R , R and m, p and n may also take the values as indicated below. Such values may be used together with any of the definitions, claims, aspects or embodiments defined herein to provide further embodiments or claims of the invention, and unless the context does not permit, any number of said variable group definitions may be used in any combination with each other to form further embodiments, aspects and claims.
  • paragraphs (3), (6), (8) and (10) could be combined to provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein p represents 1 , m and n represent 2, R 1 represents methyl or 2-hydroxyethyl, and R 2 represents hydrogen.
  • paragraphs (3), (6) and (15) could be combined to provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein p represents 1, m and n represent 2, R 1 and R 2 combined with the nitrogen to which they are attached form piperazin-l-yl.
  • R 1 represents methyl or 2 -hydroxy ethyl.
  • R 2 represents hydrogen or methyl.
  • R 1 represents methyl and R 2 represents hydrogen.
  • R 1 and R 2 both represent methyl.
  • R 1 represents 2 -hydroxy ethyl and R 2 represents hydrogen.
  • R and R together with the nitrogen to which they are attached form pyrroli din- 1- yl or piperazin-l -yl optionally substituted by C 1-3 alkyl.
  • Particular novel compounds of Formula (I) include, but are not limited to, the following compounds:
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, an acid-addition salt of a compound of the Formula (I), for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid.
  • an acid-addition salt of a compound of the Formula (I) for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in-vivo cleavable amide derivatives that may be formed at an amino group in a compound of the Formula (I).
  • the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses an amino group is, for example, an in-vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with C 1-10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the
  • phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N V- dialkylaminomethyl, morpholinomethyl, piperazin-l-ylmethyl and 4-(C 1-4 alkyl)piperazin-l- ylmethyl.
  • the in-vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in-vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • a compound of Formula (IV) can be prepared by reaction of a compound of Formula (III) with a compound of Formula (II) wherein PG 1 represents a suitable protecting group, for example a tert-butyldimethylsilyl group, as shown in Scheme 1.
  • the reaction may be carried - out in the presence of acetic acid and piperidine in a suitable solvent, such as toluene, and at a suitable temperature, for example 50-150°C.
  • a compound of Formula (V) can be prepared by reduction of a compound of Formula (IV), as shown in Scheme 2.
  • the reaction may be carried out with a catalyst such as Pd/C under an atmosphere of H 2 (1-20 bar) in a suitable solvent, such as MeOH, and at a suitable temperature, for example 20-100°C.
  • a compound of Formula (V) can be synthesized by alternative methods, shown in Scheme 3.
  • a compound of Formula (V) may be prepared by a Heck reaction between a compound of Formula (VI) and a compound of Formula (VII) as shown in Scheme 1 wherein Hal represents bromo or iodo.
  • the reaction may be carried out using a palladium catalyst, such as Pd(OAc) 2 , bis(tri-o-tolylphosphine)palladium(II) dichloride or l,l-bis(di-tert- butylphosphino)feirocenepalladium(II) choloride (Pd-1 18), a base such as NaHC0 3 , triethylamine or dicyclohexylmethylamine, and tetrabutylammonium chloride or bromide.
  • the reaction is performed in a suitable solvent, such as THF, DMF or DMA, and at a suitable temperature, for example 50-150°C.
  • a compound of Formula (V) may be prepared by reacting a compound of Formula (IX) with a base, such as NaH, in a suitable solvent, such as THF or DMF, at a suitable temperature, for example 0°C to r.t., followed by addition of a compound of Formula (VIII) wherein LG 1 represents a suitable leaving group, for example bromo or chloro.
  • a suitable solvent such as THF or DMF
  • a compound of Formula (X) may be prepared by reacting a compound of Formula (V) with guanidine or guanidine carbonate in a suitable solvent, such, as MeOH or EtOH, and at a suitable temperature, for example 50-150 °C.
  • a suitable solvent such as MeOH or EtOH
  • a compound of Formula (XI) may be prepared by reacting a compound of Formula (X) with POCl 3 , at a suitable temperature, for example 50-100°C, when LG 2 represents chloro.
  • a compound of Formula (XI) may be prepared by reacting a compound of Formula (X) with a sulfonyl chloride of formula R S0 2 C1, wherein R represents C 1-3 alkyl or optionally substituted aryl such as phenyl, 4-methylphenyl or 2,4, ' 6-trimethylphenyl.
  • the reaction may be carried out in a suitable solvent, such as DCM or THF, in the presence of a suitable base, such as N,N V',iV'-tetramethyl-l,3-propanediamine or triethylamine, at a suitable solvent, such as DCM or THF, in the presence of a suitable base, such as N,N V',iV'-tetramethyl-l,3-propanediamine or triethylamine, at a
  • suitable temperature for example 0-50°C, when LG represents -OS0 2 R .
  • a compound of Formula (XIII) may be prepared by reacting a compound of Formula (XI) with an excess of amine of Formula (XII) wherein PG 2 represents a suitable protecting group which can not be removed in a deprotection condition for PG 1 , for example benzyl group, in a suitable, solvent, such as butanol, propionitrile, butyl acetate or 1 ,4-dioxane, and at a suitable temperature, for example 50-150°C, optionally in the presence of an additive such as trifluoroacetic acid or N,N-diisopropylethylamine.
  • the reaction may be performed in a microwave at a suitable temperature, for example 50-200°C.
  • a compound of Formula (XIII) may be prepared by reacting a compound of Formula (XI) with a compound of Formula (XII-2):
  • a compound of Formula (XIV) may be prepared by reacting a compound of Formula (XIII) with a de-protective agent for the protective group: PG 1 .
  • a compound of Formula (XIV) may be prepared by reacting a compound of Formula (XIII) with
  • hydrochloric acid or trifluoroacetic acid in a suitable solvent, such as MeOH, and at a suitable temperature, for example 0-50 °C, when PG 1 is a group removable under acidic conditions.
  • a compound of Formula (XV) may be prepared by reacting a compound of Formula (XIV) with an alkyl sulphonyl chloride of Formula R 4 S0 2 C1, wherein R 4 represents a d. 3 alkyl, in a suitable solvent, such as DCM or THF, in the presence of a suitable base, such as triethylamine, at a suitable temperature, for example 0-50 °C, wherein LG 3 represents -OS0 2 R 4 .
  • a compound of Formula (XVI) may be prepared by reacting a compound of Formula (XVI)
  • a compound of Formula (I) may be prepared by de-protection of a compound of Formula (XVI).
  • PG 2 represents benzyl
  • the reaction may be carried out with a catalyst such as Pd/C under an atmosphere of H 2 (1 -20 bar) in a suitable solvent, such as MeOH, and at a suitable temperature, for example 20-100°C, optionally in the presence of an additive such as hydrochloric acid or acetic acid.
  • reaction of a compound of Formula (XVII) with a compound of Formula (XVIII) may give a compound of Formula (I), as shown in Scheme 1 1.
  • a compound of Formula (XVII) may be prepared by the method described in Scheme 13 Step (i) to Step (vi), wherein an appropriate protective group "PG 2 " may be introduced in Step (v) in Scheme 13.
  • PG 2 may be a tri(Ci_4alkyl)silyl group (such as TBDMS or TMS).
  • Compounds of Formula (I) may be prepared by reacting a compound of a Formula (XVII) with a compound of Formula (XVIII), in the presence of suitable base (such as
  • a compound of Formula (XX) is obtained by protecting the amino group of a compound of Formula (XIX) with protective group: PG 3 such as terf-butoxycarbonyl.
  • a compound of Formula (XXI) may be prepared by protecting the hydroxyl group of a compound of Formula (XX) with protective group: PG 2 such as benzyl.
  • a compound of Formula (XII) may be prepared by de-protecting amino group. The reaction conditions used for each step are described in the examples in this specification.
  • the R SA group may be a substituted or unsubstituted hydrocarbyl group.
  • R 5A may be a hydrocarbyl group selected from benzyl and Ci -4 alkyl, for example methyl or ethyl.
  • LG 4 represents halogen atom (such as chloro), or Ci -3 alkylsulfonyl (such as mesyl), or an optionally substituted arylsulfonyl (such as 2,4,6-triisopropylbenzenesulfonyl, 2,4,6- trimethylbenzenesulfonyl or -toluenesulfonyl).
  • Step (i): Compounds of a Formula (XLIII) may be prepared by reacting compounds of Formula (XLI) and (XLII) in a suitable solvent such as DMF in the presence of Pd-1 18 (1 ,1 -bis(di- err-butylphosphino)-ferrocenepalladium(II) dichloride), tetrabuty lammonium chloride, hydrate and N-cyclohexyl-N " -methylcyclo-hexanamine at a sutiable temperature, for example 100°C.
  • LG 5 is a leaving group, for example a chloro or bromo.
  • PG 5 is a suitable protecting group, for example a benzyl-based protecting group, for example benzyl.
  • Step (ii): Compounds of Formula (XLIV) may be prepared by reacting a compound of Formula (XLIII) with guanidine or guanidine carbonate, in a suitable solvent, such as MeOH or EtOH, and at a suitable temperature, for example 50-150°C.
  • Step (iii): Compounds of Formula (XLV) may be prepared by reacting a compound of Formula (XLIV) with POCI3, at a suitable temperature, for example 50-1 10°C.
  • Step (iv): Compounds of Formula (XL VI) may be prepared by reacting a compound of Formula (XLV) with an excess of the appropriate amine, in a suitable solvent, such as propionitrile, butanol or 1 ,4-dioxane, in the presence of TFA at a suitable temperature, for example 50-150°C. Alternatively, the reaction may be performed in a microwave at a suitable temperature, for example 50-200°C.
  • a suitable solvent such as propionitrile, butanol or 1 ,4-dioxane
  • Step (v): Compounds of Formula (XL VII) may be prepared by reacting a compound of Formula (XL VI) with a suitable protecting group.
  • PG 6 may be a tri(Ci.
  • PG 6 4alkyl)silyl group, for example TBDMS or TMS.
  • PG 6 may be added using, for example TBDMSC1, or TMSC1, in the presence of a suitable base, for example imidazole, in a suitable solvent such as DMF.
  • Step (vi): Compounds of Formula (XLVIII) may be prepared by using standard deprotection conditions that are known to be suitable for removing a PG 5 group.
  • PG 5 is benzyl
  • Step (vii): Compounds of Formula (XLIX) may be prepared by reacting a compound of a Formula (XLVIII) with the appropriate amino alcohol, in a suitable solvent such as THF using Mitsunobu conditions, for example using diisopropyl azodicarboxylate and
  • Step (viii): Compounds of Formula (I) may be prepared by using appropriate deprotection conditions known to be suitable for removing the PG 6 group.
  • PG 6 were a silicon-based protecting group such as TBDMS
  • the deprotection could involve reaction of a compound of Formula (XLIX) with a fluoride salt, for example tetra-n- butylammonium fluoride (TBAF), in a suitable solvent such as CH 2 C1 2 .
  • a fluoride salt for example tetra-n- butylammonium fluoride (TBAF)
  • TBAF tetra-n- butylammonium fluoride
  • SCX resin strong cation exchange resin
  • Formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
  • a pharmaceutical composition which comprises a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.
  • the pharmaceutical composition may be used in the treatment of cancer.
  • the composition may be in a form suitable for oral administration, for example as a tablet or capsule; for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion; for topical
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof could also be administered as an air spray for inhalation.
  • the air spray e.g., spray, aerosol, dry powder preparation, etc.
  • a dry powder preparation may also be used.
  • An aerosol appropriate for inhalation may be either a suspension or solution, and would typically contain the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and any appropriate propellants such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or a mixture thereof.
  • hydrofluoroalkane particularly 1 , 1,1 ,2- tetrafluoroethane, heptafluoroalkane (HFA) such as 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane, or a mixture thereof.
  • HFA heptafluoroalkane
  • An aerosol may optionally contain an additional preparation excipient well- known to those skilled in the art such as surfactant (e.g., oleic acid or lecithin) and cosolvent (e.g., ethanol), etc.
  • an aerosol preparation could be delivered using the inhaler known as "TurbuhalerTM".
  • the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • solutions containing the compound of the invention the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • preparations may contain colouring agents, flavouring agents, saccharine and/or
  • carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compound of Formula (I) will normally be administered to a warm blooded animal at a unit dose within the range 5-5000 mg/m 2 body area of the animal, i.e.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1 -250 mg of active ingredient.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • treatment is intended to have its normal everyday meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • prophylaxis is intended to have its normal everyday meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • the compounds defined in the present invention are effective activators of TLR7 in vitro. Accordingly, the compounds of the present invention are expected to be potentially useful agents in the treatment of diseases or medical conditions mediated alone or in part by TLR7. For example, the following diseases and conditions listed in paragraphs 1 to 8 below may be treatable with compounds of the present invention.
  • obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
  • COPD chronic obstructive pulmonary disease
  • lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid,
  • epidermolysis bullosa urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • oncology treatment of common cancers including bladder, head and neck, prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • infectious diseases virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
  • virus diseases such as genital warts, common warts, plantar war
  • the compound of Formula (I) will be administered to a mammal, more particularly a human being.
  • the compound of Formula (I) will be administered to a mammal, more particularly a human being.
  • said disease mediated through TLR7 is cancer.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and
  • said disease mediated through TLR7 is asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease mediated through TLR7.
  • said disease mediated through TLR7 is cancer.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • said disease mediated through TLR7 is asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • a method of using a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof, for the treatment of cancer comprises administering to said animal an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • a method of treating a human suffering from a disease in which activation of TLR7 is beneficial comprising the steps of administering to a person in need thereof of a therapeutically effective amount of a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof.
  • the disease in which activation of TLR7 is beneficial is cancer.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • the disease in which activation of TLR7 is beneficial is asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • the cancer may be bladder cancer.
  • the cancer may be head and neck cancer.
  • the cancer may be prostate cancer.
  • the cancer may be breast cancer.
  • the cancer may be lung cancer.
  • the cancer may be uterus cancer.
  • the cancer may be pancreatic cancer.
  • the cancer may be liver cancer.
  • the cancer may be renal cancer.
  • the cancer may be ovarian cancer.
  • the cancer may be colon cancer.
  • the cancer may be stomach cancer.
  • the cancer may be skin cancer.
  • the cancer may be cerebral tumor.
  • the cancer may be malignant myeloma cancer.
  • the cancer may be lymphoproliferative tumors.
  • anti-tumour agents may include one or more of the following categories of anti-tumour agents:-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis platin, oxaliplatin, miriplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, amrubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids
  • epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-l -yl]-2-methylpyrimidin-4- ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetra
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB l antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, ppl 1-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU1 1248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin- 1 -ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linom
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669,
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • (x) immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti idiotypic antibodies, approaches to decrease the function of immune suppressive cells such as regulatory T cells, myeloid-derived suppressor cells or IDO (indoleamine 2,3,-deoxygenase)-expressing dendritic cells, and approaches using cancer vaccines consisting of proteins or peptides derived from tumour-associated antigens such as NY-ESO-1 , MAGE-3, WT1 or Her2/neu.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • a pharmaceutical product comprising a compound of the Formula (I) as defined hereinbefore and an additional anti tumour substance as defined hereinbefore for the conjoint treatment of cancer.
  • a pharmaceutical product comprising a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer.
  • a pharmaceutical product comprising a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, and an additional anti-tumour substance for the conjoint treatment of cancer.
  • a combination suitable for use in the treatment of cancer comprising a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and any one of the anti tumour agents listed under (i) - (ix) above.
  • “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above, in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above, in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a compound of the Formula (I), or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above for use in the treatment of cancer in a warm-blooded animal, such as man.
  • a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above.
  • kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above.
  • a kit comprising:
  • an anti-tumour agent selected from one listed under (i) - (ix) herein above; in a second unit dosage form;
  • kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an additional anti-tumour agent.
  • a kit comprising:
  • a second anti-tumour agent in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • the compounds of Formula (I) may be useful as vaccine adjuvants.
  • the invention still further provides a method of treating, or reducing the risk of, a disease or condition, which method comprises administering to a patient in need thereof a therapeutically effective amount of a vaccine and a compound of Formula (I), or a
  • the invention still further provides a method of increasing the response to a vaccine in a patient, which method comprises administering to a patient in need thereof a therapeutically effective amount of a vaccine and a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • Electrospray ionization mass spectrometry (ESI mass) spectra were recorded using Waters Micromass ZQTM mass spectrometer, Waters Waters 2790 AllianceTM separation module and Imtakt Cadenza CD-C 18TM columneluting with a gradient of A (MeCN) , B (H 2 0) and C (2% formic acid/ 98% MeCN).
  • 0.0-0.1 min A 95%, B 2% and C 3%.
  • 0.1-3.1 min linear gradient from A 95%, B 2% and C 3% to A 1%, B 96% and C 3%.
  • 3.1-3.5 min A 1%, B 96% and C 3%.
  • EtOAc ethyl acetate
  • DCM dichloromethane
  • NMP N-methylpyrrolidinone
  • DMF N.iV-dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • MeOH methanol
  • EtOH ethanol
  • MeCN acetonitrile
  • TFA trifluoroacetic acid
  • TBDMS or TBS tert-butyldimethylsilyl
  • TMS trimethylsilyl
  • Boc rr-butoxycarbonyl
  • Pd/C palladium on carbon
  • DMAP 4- dimethylaminopyridine
  • the title compound may be prepared by the steps described below:
  • Methyl acetoacetate (4.18 mL, 38.9 mmol) was added to the suspension of NaH (55% oil dispersion, 1.70 g, 38.9 mmol) in DMF (60 mL) at 0°C and stirred at r.t. for 0.5h.
  • the product from step (iii) (10.0 g) in DMF (60 mL) and I (4.73 g, 28.5 mmol) were added to the mixture and stirred at 80°C for 6h.
  • the mixture was cooled to r.t. and diluted with water and extracted with EtOAc. And the combined organic solutions were washed with water and brine, dried (Na 2 S0 4 ) and concentrated.
  • Trifluoroacetic acid (98 ⁇ , 1.27 mmol) was added to a solution of the product from step (vi) (781 mg, 1.27 mmol) and the product from step (ix) (789 mg, 3.81 mmol) at r.t. and stirred at 120°C for 15h. The resulting mixture was cooled to r.t. and concentrated. The residue was diluted with 40% K 2 C0 3 aq. and extracted with CHCl 3 /EtOH (3/1). The combined organic solutions were dried (Na 2 S0 4 ) and concentrated. The residue was diluted with EtOAc, stirred, filtered, and concentrated.
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below: (i (S -A ⁇ -[l-(Benzyloxy hexan-3-yl]-5- ⁇ 2-m
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • Methyl 2-[4-(benzyloxy)-2-methoxybenzyl]-3-oxobutanoate (870 mg) was dissolved in CH 3 OH (14 mL) and guanidine hemicarbonate (687 mg) was added. The mixture was then heated to 60°C for 5h and allowed to cool to RT. The mixture was then filtered and washed with diethyl ether and water. The filtrate was concentrated in vacuo and more diethyl ether and water added.
  • the crude material was purified by HPLC using a Gemini-NX CI 8 5 ⁇ 1 1 OA 30x100 AXIA column and eluting with a gradient of 29-64% MeCN in water (containing 0.1% NH 3 ). Appropriate fractions were concentrated in vacuo to provide the sub-title compound (31 1 mg, 53 %) as a yellow foam;
  • Diisopropyl azodicarboxylate ( 1 17 iL) was added to 4-[(2-amino-4- ⁇ [(3S)- l - ⁇ [1 ⁇ 2rr- bu1yl(dimethyl)silyl]oxy ⁇ hexan-3-yl]amino ⁇ -6-methyl-pyrimidin-5-yl)methyl]-3- methoxyphenol (94 mg), 2-(dimethylamino)ethanol (99 and triphenylphosphine ( 156 mg) in THF (2 mL) under N 2 at 0°C.
  • Recombinant human TLR7 was stably expressed in a HEK293 cell line already stably expressing the pNiFty2-SEAP reporter plasmid; integration of the reporter gene was maintained by selection with the antibiotic zeocin.
  • the most common variant sequence of human TLR7 (represented by the EMBL sequence AF240467) was cloned into the
  • Concentration dependent induction of SEAP production by compounds was expressed as the concentration of compound which produced half of the maximal level of SEAP induction for that compound (EC50).
  • TLR7 activity for compounds of the present invention was assessed using the human TLR7 assay and the results are shown in Table 1 below wherein the degree of TLR7 activation for each compound is expressed as a pEC 50 value.
  • TLR8/NF-KB/SEAPorterTM HEK 293 Cell Line (Imgenex Corporation) is a stably co- transfected cell line which expresses full-length human TLR8 and the secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NF- ⁇ response element.
  • SEAP alkaline phosphatase
  • TLR8-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37°C with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the concentration of compound which produced half of the maximal level of SEAP induction for that compound (EC50). TLR8 activity for compounds of the present invention was assessed using the human TLR8 assay and the results are shown in Table 2 below wherein the degree of TLR8 activation for each compound is expressed as a pECso value.
  • DMSO dimethylsulfoxide
  • the hERG potassium current is measured in a hERG-stably-expressing Chinese hamster ovary l (CHO) cells.
  • the experiments were performed using an automated planar patch-clamp system QPatch HT (Sophion Bioscience A/S).
  • QPatch HT Sophion Bioscience A/S
  • the application of pressure for forming gigaseals and whole-cell patch clamp configuration were established using the QPatch assay software. Patch-clamp experiments were performed in voltage-clamp mode and whole-cell currents were recorded from individual cells. The following stimulation protocol was applied to investigate the effects of compounds on hERG potassium channel.
  • the membrane potential was held at -80 mV and repetitively (every 15 s) depolarized to +20 mV for 5 s after the pulse to -50 mV for 20 ms served to define the baseline, followed by repolarizing step to -50 mV for 5 s to evaluate of the tail current amplitude.
  • Experiments were conducted at room temperature (22 ⁇ 2°C).
  • the test solution includes:
  • Extracellular solution 2mM of CaCl 2 , lmM of MgCl 2 , l OmM of HEPES, 4mM of KC1, 145 mM of NaCl, and l OmM of glucose; and
  • Intracellular solution 5.4mM of CaCl 2 , 1.8mM of MgCl 2 , lOmM of HEPES, 31mM of KOH, l OmM of EGTA. 120mM of KCL and 4mM of ATP.
  • Cells are then detached from the bottom of the flask by gentle tapping and lOmL of Dulbecco's Phosphate-Buffered Saline containing calcium (0.9mM) and magnesium (0.5mM) (PBS; Invitrogen) is then added to the flask and aspirated into a 15mL centrifuge tube prior to centrifugation (50g, for 4 mins). The resulting supernatant is discarded and the pellet gently re-suspended in 3mL of PBS.
  • PBS Dulbecco's Phosphate-Buffered Saline containing calcium (0.9mM) and magnesium (0.5mM)
  • a 0.5mL aliquot of cell suspension is removed and the number of viable cells (based on trypan blue exclusion) is determined in an automated reader (Cedex; Innovatis) so that the cell re-suspension volume can be adjusted with PBS to give the desired final cell concentration. It is the cell
  • CHO- vl .5 cells which are used to adjust the voltage offset on Ion WorksTM HT, are maintained and prepared for use in the same way.
  • a ⁇ -test IonWorksTM HT from Essen Instrument was used. There is no capability to warm solutions in this device hence it is operated at ⁇ r.t. (-21 °C), as follows.
  • the reservoir in the "Buffer” position is loaded with 4 mL of PBS and that in the "Cells” position with the CHO- hERG cell suspension described above.
  • a 96-well plate (V-bottom, Greiner Bio-one) containing the compounds to be tested (at 3-fold above their final test concentration) is placed in the "Plate 1" position and a PatchPlateTM is clamped into the PatchPlateTM station.
  • Each compound plate is laid-out in 12 columns to enable ten, 8-point concentration-effect curves to be constructed; the remaining two columns on the plate are taken up with vehicle (final concentration 0.33% DMSO), to define the assay baseline, and a supra-maximal blocking concentration of cisapride (final concentration 10 ⁇ ) to define the 100% inhibition level.
  • the fluidics-head (F-Head) of Ion WorksTM HT then adds 3.5 ⁇ of PBS to each well of the PatchPlateTM and its underside is perfused with "internal" solution that had the following composition (in mM): -Gluconate (100 parts), KC1 (40 parts), MgCl 2 (3.2 parts), EGTA(3 parts) and HEPES (5 parts, pH 7.25-7.30 using 10M OH).
  • the electronics-head (E-head) then moves round the PatchPlateTM performing a hole test (i.e. applying a voltage pulse to determine whether the hole in each well is open).
  • the F-head then dispenses 3.5 ⁇ , of the cell suspension described above into each well of the PatchPlateTM and the cells are given 200 seconds to reach and seal to the hole in each well. Following this, the E-head moves round the PatchPlateTM to determine the seal resistance obtained in each well.
  • the solution on the underside of the PatchPlateTM is changed to "access" solution that has the following composition (in mM): KG (140 parts), EGTA (1 part), MgCl 2 (1 part) and HEPES (20 parts, pH 7.25-7.30 using 10M KOH) plus 100 ⁇ g/mL of amphotericin B (Sigma- Aldrich).
  • the E-head moves round the PatchPlateTM 48 wells at a time to obtain pre-compound hERG current measurements.
  • the F-head then adds 3.5 ⁇ of solution from each well of the compound plate to 4 wells on the PatchPlateTM (the final DMSO concentration is 0.33% in every well). This is achieved by moving from the most dilute to the most concentrated well of the compound plate to minimise the impact of any compound carry-over.
  • the E-head then moves around all 384-wells of the PatchPlateTM to obtain post-compound hERG current measurements. In this way, non-cumulative concentration-effect curves can be produced where, providing the acceptance criteria are achieved in a sufficient percentage of wells (see below), the effect of each concentration of test compound is based on recording from between 1 and 4 cells.
  • the pre- and post-compound hERG current is evoked by a single voltage pulse consisting of a 20 second period holding at -70mV, a 160millisecond step to -60mV (to obtain an estimate of leak), a 1 OOmillisecond step back to -70mV, a 1 second step to + 40mV, a 2 second step to - 30mV and finally a 500 millisecond step to -70mV.
  • a single voltage pulse consisting of a 20 second period holding at -70mV, a 160millisecond step to -60mV (to obtain an estimate of leak), a 1 OOmillisecond step back to -70mV, a 1 second step to + 40mV, a 2 second step to - 30mV and finally a 500 millisecond step to -70mV.
  • Currents are leak-subtracted based on the estimate of current evoked during the +10mV step at the start of the voltage pulse protocol. Any voltage offsets in Ion
  • a depolarising voltage ramp is applied to CHO-Kvl .5 cells and the voltage noted at which there was an inflection point in the current trace (i.e. the point at which channel activation is seen with a ramp protocol).
  • the voltage at which this occurred has previously been determined using the same voltage command in conventional electrophysiology and found to be -15mV (data not shown); thus an offset potential could be entered into the Ion WorksTM HT software using this value as a reference point.
  • any offset is adjusted by determining the hERG tail current reversal potential in Ion WorksTM HT, comparing it with that found in conventional electrophysiology (-82mV) and then making the necessary offset adjustment in the Ion WorksTM HT software.
  • the current signal is sampled at 2.5kHz.
  • Pre- and post-scan hERG current magnitude was measured automatically from the leak subtracted traces by the Ion WorksTM HT software by taking a 40ms average of the current during the initial holding period at -70 mV (baseline current) and subtracting this from the peak of the tail current response.
  • the acceptance criteria for the currents evoked in each well are: pre-scan seal resistance >60 ⁇ , pre-scan hERG tail current amplitude >150pA; post- scan seal resistance >60 ⁇ .
  • the degree of inhibition of the hERG current can be assessed by dividing the post-scan hERG current by the respective pre-scan hERG current for each well. References: Persson, F. et al, J Cardiovasc.ElectrophysioL, 16, 329-341 (2005), and
  • the compounds of the invention exhibit favourable hERG inhibition activity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de Formule (I) : (I) où n, m, p, R1 et R2 sont tels que définis dans la description. La présente invention concerne également des procédés de préparation de tels composés, de nouveaux intermédiaires utiles dans la préparation de tels composés, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement de maladies, par exemple du cancer.
PCT/JP2011/077275 2010-11-19 2011-11-18 Composés aminoalcoxyphényle et leur utilisation dans le traitement de maladies WO2012067269A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41568610P 2010-11-19 2010-11-19
US61/415,686 2010-11-19

Publications (1)

Publication Number Publication Date
WO2012067269A1 true WO2012067269A1 (fr) 2012-05-24

Family

ID=45218823

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/077275 WO2012067269A1 (fr) 2010-11-19 2011-11-18 Composés aminoalcoxyphényle et leur utilisation dans le traitement de maladies

Country Status (1)

Country Link
WO (1) WO2012067269A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2712866A1 (fr) * 2012-10-01 2014-04-02 Centre National de la Recherche Scientifique (CNRS) Dérivés de 1,2,4-triazine pour le traitement d'infections virales
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
US9376398B2 (en) 2012-05-18 2016-06-28 Sumitomo Dainippon Pharma Co., Ltd Carboxylic acid compounds
WO2017061532A1 (fr) * 2015-10-07 2017-04-13 大日本住友製薬株式会社 Composé pyrimidine
WO2018181420A1 (fr) 2017-03-29 2018-10-04 大日本住友製薬株式会社 Formulation d'adjuvant vaccinal
US10253003B2 (en) 2012-11-16 2019-04-09 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US10259814B2 (en) 2012-10-10 2019-04-16 Janssen Sciences Ireland Uc Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10259793B2 (en) 2013-02-21 2019-04-16 Janssen Sciences Ireland Uc 2-aminopyrimidine derivatives for the treatment of viral infections
US10266543B2 (en) 2013-03-29 2019-04-23 Janssen Sciences Ireland Uc Macrocyclic deaza-purinones for the treatment of viral infections
US10272085B2 (en) 2011-04-08 2019-04-30 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10280167B2 (en) 2011-11-09 2019-05-07 Janssen Sciences Ireland Uc Purine derivatives for the treatment of viral infections
US10280180B2 (en) 2012-07-13 2019-05-07 Janssen Sciences Ireland Uc Macrocyclic purines for the treatment of viral infections
US10316043B2 (en) 2013-07-30 2019-06-11 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US10377738B2 (en) 2013-05-24 2019-08-13 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
US10385054B2 (en) 2013-06-27 2019-08-20 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10968184B2 (en) 2016-09-29 2021-04-06 Janssen Sciences Ireland Unlimited Company Pyrimidine prodrugs for the treatment of viral infections and further diseases
US11053256B2 (en) 2016-07-01 2021-07-06 Janssen Sciences Ireland Unlimited Company Dihydropyranopyrimidines for the treatment of viral infections
US11597704B2 (en) 2018-03-01 2023-03-07 Janssen Sciences Ireland Unlimited Company 2,4-diaminoquinazoline derivatives and medical uses thereof
US12059462B2 (en) 2018-07-23 2024-08-13 Japan As Represented By Director General Of National Institute Of Infectious Diseases Composition containing influenza vaccine

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000040529A1 (fr) 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire
WO2000041669A2 (fr) 1999-01-15 2000-07-20 Angiogene Pharmaceuticals Ltd. Agents de degradation vasculaire aux benzimidazoles
WO2000047212A1 (fr) 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2001092224A1 (fr) 2000-05-31 2001-12-06 Astrazeneca Ab Derives d'indole possedant une activite endommageant les vaisseaux sanguins
WO2001094341A1 (fr) 2000-06-06 2001-12-13 Astrazeneca Ab Derives de la quinazoline pour le traitement de tumeurs
WO2002004434A1 (fr) 2000-07-07 2002-01-17 Angiogene Pharmaceuticals Limited Derives de colchinol utilises comme agents de degradation vasculaire
WO2002008213A1 (fr) 2000-07-07 2002-01-31 Angiogene Pharmaceuticals Limited Derives de colchinol utiles comme inhibiteurs de l'angiogenese
WO2009067081A1 (fr) * 2007-11-22 2009-05-28 Astrazeneca Ab Dérivés de pyrimidine pour le traitement de l'asthme, de la broncho-pneumopathie chronique obstructive (copd), de la rhinite allergique, de la conjonctivite allergique, de la dermatite atopique, du cancer, de l'hépatite b, de l'hépatite c, du vih, du vpp, des infections bactériennes et de la dermatose
WO2010133885A1 (fr) * 2009-05-21 2010-11-25 Astrazeneca Ab Nouveaux dérivés pyrimidines et leur utilisation dans le traitement d'un cancer et autres maladies

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000040529A1 (fr) 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire
WO2000041669A2 (fr) 1999-01-15 2000-07-20 Angiogene Pharmaceuticals Ltd. Agents de degradation vasculaire aux benzimidazoles
WO2000047212A1 (fr) 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2001092224A1 (fr) 2000-05-31 2001-12-06 Astrazeneca Ab Derives d'indole possedant une activite endommageant les vaisseaux sanguins
WO2001094341A1 (fr) 2000-06-06 2001-12-13 Astrazeneca Ab Derives de la quinazoline pour le traitement de tumeurs
WO2002004434A1 (fr) 2000-07-07 2002-01-17 Angiogene Pharmaceuticals Limited Derives de colchinol utilises comme agents de degradation vasculaire
WO2002008213A1 (fr) 2000-07-07 2002-01-31 Angiogene Pharmaceuticals Limited Derives de colchinol utiles comme inhibiteurs de l'angiogenese
WO2009067081A1 (fr) * 2007-11-22 2009-05-28 Astrazeneca Ab Dérivés de pyrimidine pour le traitement de l'asthme, de la broncho-pneumopathie chronique obstructive (copd), de la rhinite allergique, de la conjonctivite allergique, de la dermatite atopique, du cancer, de l'hépatite b, de l'hépatite c, du vih, du vpp, des infections bactériennes et de la dermatose
WO2010133885A1 (fr) * 2009-05-21 2010-11-25 Astrazeneca Ab Nouveaux dérivés pyrimidines et leur utilisation dans le traitement d'un cancer et autres maladies

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Medicinal Chemistry", vol. 5, 1990, PERGAMON PRESS
"Design of Pro-drugs", 1985, ELSEVIER
"Methods in Enzymology", vol. 42, 1985, ACADEMIC, PRESS, pages: 309 - 396
"Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
E. ROCHE: "Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
GORDEN ET AL., J. IMMUNOL., vol. 174, 2005, pages 1259 - 1268
H. BUNDGAARD ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 77, 1988, pages 285
H. BUNDGAARD, ADVANCED DRUG DELIVERY REVIEWS, vol. 8, 1992, pages 1 - 38
H. BUNDGAARD: "Drug Design and Development", 1991, article "Design and Application of Pro-drugs", pages: 113 - 191
HUBER ET AL., J. IMMUNOL., vol. 185, 2010, pages 813 - 817
J. MED. CHEM., vol. 47, 2004, pages 6658 - 6661
N. KAKEYA ET AL., CHEM. PHANN. BULL., vol. 32, 1984, pages 692
PERSSON,F. ET AL., J CARDIOVASC.ELECTROPHYSIOL., vol. 16, 2005, pages 329 - 341
SCHROEDER, K., JBIOMOL SCREEN, vol. 8, 2003, pages 50 - 64
STEM ET AL., CRITICAL REVIEWS IN ONCOLOGY/HAEMATOLOGY, vol. 54, 2005, pages 11 - 29
T. HIGUCHI; V. STELLA, PRO-DRUGS AS NOVEL DELIVERY SYSTEMS, vol. 14
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
US10780089B2 (en) 2011-04-08 2020-09-22 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10420767B2 (en) 2011-04-08 2019-09-24 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US11541050B2 (en) 2011-04-08 2023-01-03 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10272085B2 (en) 2011-04-08 2019-04-30 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10280167B2 (en) 2011-11-09 2019-05-07 Janssen Sciences Ireland Uc Purine derivatives for the treatment of viral infections
US11104678B2 (en) 2011-11-09 2021-08-31 Janssen Sciences Ireland Unlimited Company Purine derivatives for the treatment of viral infections
US9376398B2 (en) 2012-05-18 2016-06-28 Sumitomo Dainippon Pharma Co., Ltd Carboxylic acid compounds
US10562861B2 (en) 2012-05-18 2020-02-18 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US10150743B2 (en) 2012-05-18 2018-12-11 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US12077510B2 (en) 2012-05-18 2024-09-03 Sumitomo Pharma Co., Ltd. Carboxylic acid compounds
RU2636146C2 (ru) * 2012-05-18 2017-11-21 Сумитомо Дайниппон Фарма Ко., Лтд. Соединения карбоновых кислот
US11299465B2 (en) 2012-05-18 2022-04-12 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US10822349B2 (en) 2012-07-13 2020-11-03 Janssen Sciences Ireland Unlimited Company Macrocyclic purines for the treatment of viral infections
US10280180B2 (en) 2012-07-13 2019-05-07 Janssen Sciences Ireland Uc Macrocyclic purines for the treatment of viral infections
KR102138393B1 (ko) 2012-10-01 2020-08-14 쌩뜨레 나티오날 데 라 르세르쉬 생띠끄 (씨. 엔. 알. 에스) 바이러스 감염의 치료를 위한 1,2,4-트라이아진 유도체
CN104812747B (zh) * 2012-10-01 2017-03-08 国家科学研究中心 用于治疗病毒感染的1,2,4‑三嗪衍生物
US9416114B2 (en) 2012-10-01 2016-08-16 Centre National De La Recherche Scientifique (Cnrs) 1,2,4-triazine derivatives for the treatment of viral infections
CN104812747A (zh) * 2012-10-01 2015-07-29 国家科学研究中心 用于治疗病毒感染的1,2,4-三嗪衍生物
KR20150084791A (ko) * 2012-10-01 2015-07-22 쌩뜨레 나티오날 데 라 르세르쉬 생띠끄 (씨. 엔. 알. 에스) 바이러스 감염의 치료를 위한 1,2,4-트라이아진 유도체
EA026236B1 (ru) * 2012-10-01 2017-03-31 Сантр Насьональ Де Ля Решерш Сьентифик (Снрс) Производные 1,2,4-триазина для лечения вирусных инфекций
EP2712866A1 (fr) * 2012-10-01 2014-04-02 Centre National de la Recherche Scientifique (CNRS) Dérivés de 1,2,4-triazine pour le traitement d'infections virales
WO2014053516A1 (fr) * 2012-10-01 2014-04-10 Centre National De La Recherche Scientifique (Cnrs) Dérivés 1,2,4-triazines pour le traitement d'infections virales
US10259814B2 (en) 2012-10-10 2019-04-16 Janssen Sciences Ireland Uc Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US11220504B2 (en) 2012-10-10 2022-01-11 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d] pyrimidine derivatives for the treatment of viral infections and other diseases
US10253003B2 (en) 2012-11-16 2019-04-09 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US10723707B2 (en) 2012-11-16 2020-07-28 Janssen Sciences Ireland Unlimited Company Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US10647684B2 (en) 2013-02-21 2020-05-12 Janssen Sciences Ireland Unlimited Company 2-aminopyrimidine derivatives for the treatment of viral infections
US10259793B2 (en) 2013-02-21 2019-04-16 Janssen Sciences Ireland Uc 2-aminopyrimidine derivatives for the treatment of viral infections
US10829494B2 (en) 2013-03-29 2020-11-10 Janssen Sciences Ireland Unlimited Company Macrocyclic deaza-purinones for the treatment of viral infections
US11702426B2 (en) 2013-03-29 2023-07-18 Janssen Sciences Ireland Unlimited Company Macrocyclic deaza-purinones for the treatment of viral infections
US10266543B2 (en) 2013-03-29 2019-04-23 Janssen Sciences Ireland Uc Macrocyclic deaza-purinones for the treatment of viral infections
US10377738B2 (en) 2013-05-24 2019-08-13 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
US10865193B2 (en) 2013-05-24 2020-12-15 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
US10385054B2 (en) 2013-06-27 2019-08-20 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10781216B2 (en) 2013-06-27 2020-09-22 Janssen Sciences Ireland Unlimited Company Pyrrolo [3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10316043B2 (en) 2013-07-30 2019-06-11 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US10822347B2 (en) 2013-07-30 2020-11-03 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
CN108290845B (zh) * 2015-10-07 2021-08-03 大日本住友制药株式会社 嘧啶化合物
CN108290845A (zh) * 2015-10-07 2018-07-17 大日本住友制药株式会社 嘧啶化合物
JP2021001210A (ja) * 2015-10-07 2021-01-07 大日本住友製薬株式会社 ピリミジン化合物
TWI718188B (zh) * 2015-10-07 2021-02-11 日商大日本住友製藥股份有限公司 嘧啶化合物
US11911466B2 (en) 2015-10-07 2024-02-27 Sumitomo Pharma Co., Ltd. Substituted pyrimidines as vaccine adjuvants
KR20180056774A (ko) * 2015-10-07 2018-05-29 다이닛본 스미토모 세이야꾸 가부시끼가이샤 피리미딘 화합물
WO2017061532A1 (fr) * 2015-10-07 2017-04-13 大日本住友製薬株式会社 Composé pyrimidine
EP3868741A1 (fr) * 2015-10-07 2021-08-25 Sumitomo Dainippon Pharma Co., Ltd. Composé de pyrimidine
KR102651207B1 (ko) * 2015-10-07 2024-03-25 스미토모 파마 가부시키가이샤 피리미딘 화합물
JPWO2017061532A1 (ja) * 2015-10-07 2018-08-02 大日本住友製薬株式会社 ピリミジン化合物
JP2022010266A (ja) * 2015-10-07 2022-01-14 大日本住友製薬株式会社 ピリミジン化合物
AU2016334826B2 (en) * 2015-10-07 2020-08-27 Sumitomo Pharma Co., Ltd. Pyrimidine compound
US11266738B2 (en) 2015-10-07 2022-03-08 Sumitomo Dainippon Pharma Co., Ltd. Substituted pyrimidines as vaccine adjuvants
US10632192B2 (en) 2015-10-07 2020-04-28 Sumitomo Dainippon Pharma Co., Ltd. Pyrimidine compounds and their use as vaccine adjuvants
JP7195398B2 (ja) 2015-10-07 2022-12-23 住友ファーマ株式会社 ピリミジン化合物
US11053256B2 (en) 2016-07-01 2021-07-06 Janssen Sciences Ireland Unlimited Company Dihydropyranopyrimidines for the treatment of viral infections
US10968184B2 (en) 2016-09-29 2021-04-06 Janssen Sciences Ireland Unlimited Company Pyrimidine prodrugs for the treatment of viral infections and further diseases
US11253476B2 (en) 2017-03-29 2022-02-22 Sumitomo Dainippon Pharma Co., Ltd. Vaccine adjuvant formulation
US11833247B2 (en) 2017-03-29 2023-12-05 Sumitomo Pharma Co., Ltd. Vaccine adjuvant formulation
WO2018181420A1 (fr) 2017-03-29 2018-10-04 大日本住友製薬株式会社 Formulation d'adjuvant vaccinal
CN110650729A (zh) * 2017-03-29 2020-01-03 大日本住友制药株式会社 疫苗佐剂制剂
US11597704B2 (en) 2018-03-01 2023-03-07 Janssen Sciences Ireland Unlimited Company 2,4-diaminoquinazoline derivatives and medical uses thereof
US12059462B2 (en) 2018-07-23 2024-08-13 Japan As Represented By Director General Of National Institute Of Infectious Diseases Composition containing influenza vaccine

Similar Documents

Publication Publication Date Title
WO2012067269A1 (fr) Composés aminoalcoxyphényle et leur utilisation dans le traitement de maladies
US12077510B2 (en) Carboxylic acid compounds
WO2012066335A1 (fr) Composés phénol en tant qu'agonistes du récepteur 7 de type toll
EP2432768B1 (fr) Nouveaux dérivés pyrimidines et leur utilisation dans le traitement d'un cancer et autres maladies
WO2012066336A1 (fr) Composés de benzylamine à titre d'agonistes du récepteur toll-like 7
WO2012067268A1 (fr) Composés d'amides cycliques et leur utilisation dans le traitement de la maladie
AU2020342202A1 (en) Pyrimidine compound and preparation method therefor
RU2790017C1 (ru) Пиримидиновое соединение и способ его получения
WO2013144532A1 (fr) Dérivés de pyrimidine 3-cyano-5-arylamino -7-cycloalkylaminopyrrolo [1, 5-a] et leurs utilisations comme agents antitumoraux

Legal Events

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

Ref document number: 11793879

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11793879

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载