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WO2013060881A1 - Pyridopyrimidines et leur utilisation thérapeutique - Google Patents

Pyridopyrimidines et leur utilisation thérapeutique Download PDF

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Publication number
WO2013060881A1
WO2013060881A1 PCT/EP2012/071321 EP2012071321W WO2013060881A1 WO 2013060881 A1 WO2013060881 A1 WO 2013060881A1 EP 2012071321 W EP2012071321 W EP 2012071321W WO 2013060881 A1 WO2013060881 A1 WO 2013060881A1
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WIPO (PCT)
Prior art keywords
aryl
alkyl
heteroaryl
pyrimidin
pyrido
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PCT/EP2012/071321
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English (en)
Inventor
Rogier SMITS
Herman LIM
Tiffany VAN DER MEER
Rob Leurs
Iwan DE ESCH
Mounir Andaloussi
Original Assignee
Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg
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Publication of WO2013060881A1 publication Critical patent/WO2013060881A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to compounds based on the pyrido[2,3- d]pyrimidine scaffold, and their therapeutic use. More particularly, it relates to compounds, pharmaceutical compositions containing them, and their use for the modulation of the histamine H 4 receptor and for the treatment of disease states, disorders and conditions mediated by histamine H 4 receptor activity.
  • the histamine H 4 receptor (H 4 R) is a recently identified receptor for histamine. It is part of the histamine receptor family that also consists of the histamine Hi receptor (H-
  • WO2008/009078 describes quinazoline derivatives for treating viral infections. Further prior art in this general area includes WO2005/105761 , WO98/02434, WO2006/039718, WO2008/009078, WO2009/047255 WO2010/108059 and WO2010/030757.
  • WO2009/083608 discloses quinazolines, the role of H 4 R and the utility of antagonists.
  • WO2010/146173 discloses quinazolines and their use as H 4 R antagonists.
  • WO2006/135993 discloses pyrido (3,2,-D) pyrimidines for treating hepatitis C.
  • WO2009/003669 discloses pyrido (3,2,-D) pyrimidines for use as immunosuppressive agents.
  • the invention relates to compounds of formula (I) A compound according to claim 1 , for use in the therapy of a condition selected from inflammatory disorders, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders.
  • At least one of X and Y is N and the other of X or Y is either N or CR 2 ;
  • R 2 is H, Ci-C 4 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl;
  • R 6 , R 7 and R 8 are independently selected from H, halogen, Ci -4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, Ci -4 alkoxy, Ci -4 alkylthio, (CH 2 ) 0 -3C 3 - 7 cycloalkyl, O-C 3 -6 cycloalkyl, aryl, O-aryl, NH-aryl, S-aryl, 0-Ci -4 alkyl-aryl, Ci -4 alkyl-aryl, CF 3 , O- CF 3 , S-CF 3 , hydroxy, nitro, cyano, 0-Ci -4 alkyl-N(CH 3 ) 2 , heteroaryl, O-heteroaryl, NH - heteroaryl, S-heteroaryl, d-C 4 alkyl-heteroaryl, Ci-C 4 alkyl-heteroaryl and NRmRn, wherein Rm and Rn are
  • R 3 and R 4 are independently selected from H, halogen, Ci -4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, Ci -4 alkoxy, Ci -4 alkylthio, (CH 2 ) 0 - 3 C 3 - 7 cycloalkyl, O-C 3 -6 cycloalkyl, aryl, O-aryl, NH-aryl, S-aryl, O-Ci -4 alkyl-aryl, Ci -4 alkyl-aryl, CF 3 , O- CF 3 , S-CF 3 , hydroxy, nitro, cyano, O-Ci -4 alkyl-N(CH 3 ) 2 , heteroaryl, O-heteroaryl, NH - heteroaryl, S-heteroaryl, Ci-C 4 alkyl-heteroaryl, Ci-C 4 alkyl-heteroaryl and NRmRn, wherein Rm and Rn are independently selected from H
  • any alkyl, cycloalkyl, aryl or heteroaryl group mentioned above can independently be optionally substituted with one or more substituents selected from halogen Ci -4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, Ci -4 alkoxy, Ci -4 alkylthio, (CH 2 ) 0 - 3 C 3 - 7 cycloalkyl, O-C 3-6 cycloalkyl, aryl, O-aryl, heteroaryl, NH- aryl, S-aryl, O-Ci -4 alkyl-aryl, Ci -4 alkyl-aryl, CF 3 , O-CF 3 , S-CF 3 , hydroxy, nitro amino, cyano and O-Ci -4 alkyl-N(CH 3 ) 2 ;
  • n 1 , 2 or 3;
  • n 0, 1 or 2
  • alkyl as used herein includes straight-chain and branched hydrocarbon groups. Examples are methyl, ethyl, propyl and isopropyl.
  • it contains 1 to 6, more preferably 1 to 4 carbon atoms.
  • alkenyl as used herein includes straight-chain and branched hydrocarbon groups as above with at least one carbon-carbon double bond
  • (sp 2 ) Preferably, it contains 2 to 6, more preferably 2 to 4 carbon atoms.
  • alkynyl as used herein includes straight-chain and branched hydrocarbon groups as above with at least one carbon-carbon triple bond (sp). Hydrocarbons having a mixture of double bonds and triple bonds are grouped as alkynyls herein. Preferably, it contains 2 to 6, more preferably 2 to 4 carbon atoms.
  • alkoxy as used herein includes straight-chain and branched alkyl groups with a terminal oxygen linking the alkyl group to the rest of the molecule.
  • Alkyl is as defined above.
  • aryl as used herein includes any functional group or substituent comprising an aromatic ring and from 4 to 8 ring atoms.
  • the aryl may be selected from moieties comprising a phenyl, benzyl, naphtyl or biphenyl.
  • the aryl may comprise one or more heteroatoms, in which case the aryl may be referred to as "heteroaryl".
  • Preferred examples of heteroaryl groups include pyridine, furane, thiophene, pyrrole, imidazole, thiazole, oxazole, and triazole.
  • cycloalkyl as used herein includes saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 7 ring atoms per carbocycle. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.1.1.]hex-2-ylidene.
  • heterocyclic refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 4 to 8 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen and sulfur.
  • the ring structure may optionally contain up to two oxo groups in carbon or sulfur ring members.
  • All groups defined above may be optionally substituted by one or more substituents (preferably 1 , 2 or 3, with the upper limit dependent on the valency of the member being substituted, and known to the skilled person) selected from halogen Ci -4 alkyl, C 2 -5 alkenyl, C 2 -5 alkynyl, Ci -4 alkoxy, Ci -4 alkylthio, (CH 2 ) 0 - 3 C 3- 7 cycloalkyl, 0-C 3 -6 cycloalkyl, aryl, O-aryl, heteroaryl, NH-aryl, S-aryl, 0-Ci -4 alkyl-aryl, Ci -4 alkyl-aryl, CF 3 , 0-CF 3 , S-CF 3 , hydroxy, nitro amino, cyano and O- Ci -4 alkyl-N(CH 3 ) 2 .
  • substituents preferably 1 , 2 or 3, with the upper limit dependent on the valency of the member being substituted, and known
  • substitutions and combinations of substitutions recited herein refer to substitutions that are consistent with the valency of the member being substituted.
  • R 3 and R 4 are H.
  • R 4 is H.
  • R 4 is H and R3 is selected from Ci-C 4 alkyl, cycloalkyl, cyano or halogen.
  • Ri is structure K or B or I.
  • each R 6 is independently selected from H or Ci-C 4 alkyl.
  • X is N.
  • Y is CR 2 .
  • R 2 is H.
  • R 2 is H.
  • the "pharmaceutically acceptable salt, ester or solvate thereof refers to those salts, ester forms and solvates of the compounds of the present invention that would be apparent to the pharmaceutical chemist, i.e. those that are nontoxic and that would favourably affect the pharmacological properties of said compounds of the present invention.
  • Those compounds having favourable pharmacological properties would be apparent to the pharmaceutical chemist, i.e. those that are non-toxic and that possess such pharmacological properties to provide sufficient palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, that are important in the selection are cost of raw materials, ease of crystallisation, yield, stability, hygroscopicity, and flowability of the resulting bulk drug.
  • Representative bases that may be used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
  • esters examples include Ci -7 alkyl, C 5 - 7 cycloalkyl, phenyl, substituted phenyl, and phenyl-d-6 alkyl esters.
  • Preferred esters include methyl esters.
  • any formula given herein is also intended to represent unlabelled forms as well as isotopically labelled forms of the compounds.
  • Isotopically labelled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 CI, 125 l, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labelled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the present invention includes prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the bio-active compound.
  • the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but that converts to the specified compound in vivo after administration to the patient.
  • the term "compound”, when applied to compounds of this invention, shall encompass any specific compound according to the present invention or any compound (or prodrug) that converts to the specifically disclosed compound in vivo after administration, even if such prodrug is not explicitly disclosed herein.
  • prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino or hydroxyl group of a compound of formula (I).
  • amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • the present invention also relates to pharmaceutically active metabolites of compounds of formula (I), and uses of such metabolites in the methods of the invention.
  • a "pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of formula (I) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40, 201 1 -2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res.
  • An active agent of the present invention may be administered to treat inflammation.
  • Inflammation may be associated with various diseases, disorders, or conditions, such as inflammatory disorders, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders and cancer, including the more specific conditions and diseases given below.
  • inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.
  • Illustrative types of inflammation treatable with a histamine H 4 receptor- modulating agent according to the invention include inflammation due to any one of a plurality of conditions such as allergy, asthma, dry eye, chronic obstructed pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including colitis, Crohn's disease, and ulcerative colitis), psoriasis, pruritis, itchy skin, atopic dermatitis, urticaria (hives), ocular inflammation (e.g., post-surgical ocular inflammation), conjunctivitis (e.g.
  • COPD chronic obstructed pulmonary disease
  • allergic conjunctivitis or vernal keratoconjunctivitis dry eye
  • nasal polyps allergic rhinitis
  • nasal itch allergic rhinitis
  • nasal itch scleroderma
  • autoimmune thyroid diseases immune- mediated diabetes mellitus and lupus, which are characterised by excessive or prolonged inflammation at some stage of the disease.
  • immune- mediated diabetes mellitus and lupus which are characterised by excessive or prolonged inflammation at some stage of the disease.
  • autoimmune diseases that lead to inflammation include Myasthenia gravis, autoimmune neuropathies, such as Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides, such as Wegener's granulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliary cirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune disease of the adrenal gland, polymyositis, dermatomyositis, spondyloarthropathies, such as ankylosing spondylitis, and Sjogren's syndrome.
  • autoimmune neuropathies such as Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune
  • Pruritis treatable with a histamine H 4 receptor-modulating agent according to the invention includes that which is a symptom of cutaneous diseases (such as atopic dermatitis, urticaria and hives) and other metabolic disorders (such as chronic renal failure, hepatic cholestasis, and diabetes mellitus). Pruritis treatable with a histamine H 4 receptor-modulating agent according to the invention includes that which is a side-effect of administered drugs (i.e. drug-induced pruritis). A well known example is opiate-induced pruritis resulting from the administration of opiates.
  • an active agent of the present invention is administered to treat allergy, asthma, autoimmune diseases, or pruritis.
  • the active agents may be used to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated through histamine H 4 receptor activity.
  • the term "treat” or “treating” as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of histamine H 4 receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of histamine H 4 receptor activity.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • Modemators include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate histamine H 4 receptor expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up-regulate histamine H 4 receptor expression or activity.
  • an effective amount of at least one active agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
  • An "effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
  • an “effective amount” means an amount sufficient to affect the activity of such receptor. Measuring the activity of the target receptor may be performed by routine analytical methods. Target receptor modulation is useful in a variety of settings, including assays.
  • Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modelling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • routine methods such as modelling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An exemplary dose is in the range of from about 0.001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID).
  • a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the active agents of the invention may be used in combination with additional active ingredients in the treatment of the above conditions.
  • the additional active ingredients may be co-administered separately with an active agent of formula (I) or included with such an agent in a pharmaceutical composition according to the invention.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by histamine H 4 receptor activity, such as another histamine H 4 receptor modulator or a compound active against another target associated with the particular condition, disorder, or disease.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.
  • a pharmaceutical composition of the invention comprises an effective amount of at least one active agent in accordance with the invention.
  • Such compositions may further comprise a pharmaceutically acceptable excipient.
  • a "pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art.
  • the compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
  • the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • the compositions are formulated for intravenous infusion, topical administration, or oral administration.
  • the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • the active agents may be formulated to yield a dosage of, e.g., from about 0.05 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilised or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
  • compositions may be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 [mu]/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle.
  • a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle.
  • Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.
  • Active agents may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • the compounds of the invention can be prepared according to processes within the skill of the art and/or according to processes of this invention, such as those described in the schemes and examples that follow and by matrix or combinatorial methods.
  • a Reagents and conditions i. potassium vinyl trifluoroborate, Pd(PPh 3 ) 4 , PhCH 3 , trifluoroethanol, MW, 130 °C. ii. H 2 /Pd/10% C, EtOH, r.t. iii. a. Choroform amidine, dimethyl sulfone, sulfolane, 165 °C. b. TsCI, K 2 CO 3 , CH 3 CN, ⁇ . iv. methylpiperazine, DIPEA, 1 ,4-dioxane, rt. Ethyl 3-amino-5-vinylpicolinate
  • a Reagents and conditions i. Urea, 160 °C, 0.2 M NaOH. ii. POCI 3 , DIPEA, PhCH 3 , 130 °C. iii. a. azetidin-3-ylmethyl-carbamic acid tert-butyl ester, DIPEA, 1 ,4-Dioxane, rt; b. NH 3 /EtOH, MW, 150 °C. iv. a. potassium vinyltetrafluoroborate, Pd(PPh 3 ) 4 , PhCH 3 , EtOH, Mw, 130 °C; b. H 2 /Pd/10% C, EtOH, r.t.. v.
  • the organic layer was dried, filtered and the solvent removed by evaporation.
  • the obtained crude was purified by silica gel column chromatography eluting with ethyl acetate.
  • the compound was dissolved in a saturated solution of ethanol- ammonia (10 mL) and the solution heated by microwave irradiation at 150 °C for 30 minutes. Then, the solvent removed and the crude purified by a silica gel column chromatography eluted with gradient of ethyl acetate and MeOH 100:0 to 95:5, v/v.
  • the solvent was removed, the crude dissolved in ethyl acetate and extracted, the organic layers dried over MgSO 4 , filtered and the solvent removed by evaporation.
  • the crude was purified by column chromatography eluting with ethyl acetate:hexanes, 1 :1 , v/v.
  • the obtained compound was dissolved in ethanol and Pd/10% C (24 mg) was added.
  • the resulting suspension was stirred under a hydrogen atmosphere at room temperature overnight.
  • the suspension was filtered over celite and the solvent removed by evaporation.
  • a Reagents and conditions i. 2-cyano-3-nitro-5-bromo pyridine, CaCI 2 , H 2 0 , EtOH, rt. ii. chloroform amidine hydrochloride, dimethyl sulfone, sulfolane, 165 °C. iii. Ac 2 O, ⁇ . iv. a. POCI 3 , DIEA, PhCH 3 , ⁇ . b. N,N-methyl-BOC-pyrolidine, DIPEA, 1 ,4-dioxane, rt. v. a.
  • N-(7-bromo-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide was synthesized according to a procedure from literature (Herdwijn, P. A.; Maurits, M. WO2006/135993).
  • the solvent was removed by evaporation and the crude was purified by silica gel column chromatography eluting with a gradient of ethyl acetate and methanol from 100:0 to 97.5:2.5, v/v.
  • the purified compound was disolved in ethanol 10 mL and Pd/ on 10% C was added.
  • the suspension was stirred at room temperature under a hydrogen atmosphere for 3 hours. Then, the suspension was filtered over celite and the solvent removed by evaporation.
  • a Reagents and conditions i. Urea, 160 °C, 0.2 M NaOH. ii. PCI 5 , POCI 3 , Mw, 160 °C. iii. a. azetidin-3-ylmethyl-carbamic acid tert-butyl ester , DIPEA, 1 ,4- Dioxane, rt. iv. Pd(OAc) 2 , Xantphos, K 2 C0 3 , AcNH 2 , Mw, 130 °C. v. a.
  • 2,4,7-trichloropyrido[3,2-d]pyrimidine was synthesized according to a procedure from literature(Abdellatif Tikad, Sylvain Routier, Mohamed Akssira, Jean-Michel Leger, Christian Jarry, and Gerald Bryant. Org. letters.; 2007, 4673-4676).
  • a mixture of tert-butyl (1 -(2-acetamido-7-chloropyrido[3,2- d]pyrimidin-4-yl)azetidin-3-yl)(methyl)carbamate 120 mg, 300 ⁇
  • palladium tetrakis 36 mg, 30 ⁇
  • 2-(Cyclopenten-1 -yl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane 70 mg, 360 ⁇
  • K 2 C0 3 80 mg, 900 ⁇
  • PhCH 3 /H 2 0 2.6/1.4 mL
  • the mixture was heated at 130 C for 2 hour by microwave irradiation, cooled down to rt, filtered, washed with EtOH (25 mL) and the solvent was removed by evaporation.
  • the crude was purified by silica gel column chromatography eluting with EtOAc 100% to EtOAc/MeOH, 95/5.
  • the suspension of the obtained compound, Pd/10% C (32 m) and EtOH (5 mL) was stirred at rt for 20 hours under a Hydrogen atmosphere. Then, the mixture was filtered over celite and washed with EtOH. The solvent was removed by evaporation and the crude purified by silica gel column chromatography eluting with EtOAc 100% to 95% and 5% MeOH.
  • 2,4,7-trichloropyrido[3,2-d]pyrimidine (650 mg, 2.77 mmol) was dissolved in dried 1 ,4-dioxane (10 mL).azetidin-3-ylmethyl-carbamic acid tert-butyl ester (1.1 1 g, 5.54 mmol) and DIPEA (1.03 mL, 5.82 mmol) were added and the mixture was stirred at room temperature for 3 hours. Then, the solvent was removed, the crude dissolved in ethyl acetate, and the solution washed with water (20 ml_x2), brine (20 ml_x2) and saturated ammonium chloride solution (20 ml_x2).
  • a Reagents and conditions i. Urea, 160 °C, 0.2 M NaOH. ii. PCI 5 , POCI 3 , MW, 160 °C. iii. a. azetidin-3-ylmethyl-carbamic acid tert-butyl ester, DIPEA, 1 ,4- Dioxane, r.t. iv. Pd(OAc) 2 , Xantphos, K 2 C0 3 , AcNH 2 , Mw, 130 °C. v.
  • hERG is associated with an increased risk of suffering from sudden death as a result of QT prolongation and cardiac arrest.
  • Binding of compounds to the hERG channel can be studied as described in the exemplified [ 3 H]astemizole binding assay given below.
  • the [ 3 H]astemizole binding assay is performed in a buffer containing 130 mM NaCI, 60 mM KCI, 10 mM HEPES, 1 mM EGTA, 0.8 mM MgS0 4 (pH 7.4 at 22°C), 0.5% BSA, approximately 0.5 nM [ 3 H]astemizole, and membrane of HEK 293T cells transiently expressing hERG channel (mRNA accession number NM_000238.2), in the absence or presence of test compounds, in a total volume of 100 ⁇ .
  • the membranes are harvested on a 96-well GF-C plate (PerkinElmer, USA) that is pretreated with 0.5% PEI solution, followed by three washes using ice-cold buffer containing 50 mM Tris and NaCI (pH 7.4 at 4°C). The residual radioactivity is quantified in a MicroBeta scintillation counter (PerkinElmer, USA), and the data are analyzed with Prism Graphpad 5.0.
  • Binding of compounds to the histamine H 4 R receptor can be studied as described in the exemplified [ 3 H]Histamine binding assay given below.
  • HEK 293T cells were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 50 lU/ml penicillin, and 50 ⁇ g/ml streptomycin in 5% C02 humidified atmosphere at 37 ° C. Approximately 4 million cells were seeded in a 10-cm dish and cultured overnight before transfection. For transfection of each dish of cells, the transfection mixture was prepared in 1 ml serum-free DMEM and contained 5 ⁇ g of human H 4 R receptor plasmid and 15 ⁇ of 1 mg/ml 25 kDa linear polyethyleneimine (Polyscience, Inc., USA).
  • DMEM Dulbecco's modified Eagle medium
  • FBS fetal bovine serum
  • streptomycin 50 ⁇ g/ml streptomycin
  • the saturation binding assay was performed using different concentrations of [ 3 H]histamine (Perkin-Elmer Life Science, Inc., USA), while non-specific binding was determined by incubation in the presence of 3-10 ⁇ of JNJ 7777120 in a total assay volume of 200 ⁇ .
  • the membranes were typically incubated with 10 "4 to 10 "11 M of ligands (stock concentration was 10 mM 1 DMSO) in the presence of [ 3 H]histamine in a total volume of 200 ⁇ .
  • reaction mixtures were incubated for 1 hour at room temperature (22°C), and harvested on 96-well glass fiber C plates that were pretreated with 0.3% 750 kDa PEL
  • the binding assay data were analyzed using Prism 4.0 (Graphpad Software Inc., USA).

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Abstract

L'invention concerne un composé de formule (I) où au moins un de X et Y est N et l'autre de X ou Y est soit N soit CR2. De tels composés peuvent être utiles dans la thérapie de troubles inflammatoires, de troubles allergiques, de troubles dermatologiques, d'une maladie auto-immune, de troubles lymphatiques et de troubles d'immunodéficience.
PCT/EP2012/071321 2011-10-27 2012-10-26 Pyridopyrimidines et leur utilisation thérapeutique WO2013060881A1 (fr)

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WO2016141092A1 (fr) * 2015-03-04 2016-09-09 Gilead Sciences, Inc. Composés 4,6-diamino-pyrido[3,2-d]pyrimidine modulateurs du récepteur de type toll
WO2019018354A1 (fr) * 2017-07-18 2019-01-24 Merck Patent Gmbh Antagonistes de tlr7/8 et leurs utilisations
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US10640499B2 (en) 2016-09-02 2020-05-05 Gilead Sciences, Inc. Toll like receptor modulator compounds
US20220087991A1 (en) * 2019-01-14 2022-03-24 Innate Tumor Immunity, Inc. Nlrp3 modulators
US11286257B2 (en) 2019-06-28 2022-03-29 Gilead Sciences, Inc. Processes for preparing toll-like receptor modulator compounds
US11396509B2 (en) 2019-04-17 2022-07-26 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11512069B2 (en) 2016-08-08 2022-11-29 Merck Patent Gmbh TLR7/8 antagonists and uses thereof
US11583531B2 (en) 2019-04-17 2023-02-21 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11629134B2 (en) 2015-12-17 2023-04-18 Merck Patent Gmbh TLR7/8 antagonists and uses thereof
WO2024199000A1 (fr) * 2023-03-27 2024-10-03 西安新通药物研究股份有限公司 Dérivé de pyrido[3,2-d]pyrimidine substitué par alcynyle et son utilisation en tant qu'agoniste de tlr8

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JP2021046456A (ja) * 2015-03-04 2021-03-25 ギリアード サイエンシーズ， インコーポレイテッド Ｔｏｌｌ様レセプター調節４，６−ジアミノ−ピリド［３，２−ｄ］ピリミジン化合物
CN107108615A (zh) * 2015-03-04 2017-08-29 吉利德科学公司 Toll样受体调节性4,6‑二氨基‑吡啶并[3,2‑D]嘧啶化合物
WO2016141092A1 (fr) * 2015-03-04 2016-09-09 Gilead Sciences, Inc. Composés 4,6-diamino-pyrido[3,2-d]pyrimidine modulateurs du récepteur de type toll
JP2017203033A (ja) * 2015-03-04 2017-11-16 ギリアード サイエンシーズ， インコーポレイテッド Ｔｏｌｌ様レセプター調節４，６−ジアミノ−ピリド［３，２−ｄ］ピリミジン化合物
JP2017509667A (ja) * 2015-03-04 2017-04-06 ギリアード サイエンシーズ， インコーポレイテッド Ｔｏｌｌ様レセプター調節４，６−ジアミノ−ピリド［３，２−ｄ］ピリミジン化合物
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US10285990B2 (en) 2015-03-04 2019-05-14 Gilead Sciences, Inc. Toll like receptor modulator compounds
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EA035093B1 (ru) * 2015-03-04 2020-04-27 Джилид Сайэнс, Инк. 4,6-диаминопиридо[3,2-d]пиримидиновые соединения, модулирующие toll-подобные рецепторы
US9670205B2 (en) 2015-03-04 2017-06-06 Gilead Sciences, Inc. Toll like receptor modulator compounds
CN112174960A (zh) * 2015-03-04 2021-01-05 吉利德科学公司 Toll样受体调节性4,6-二氨基-吡啶并[3,2-D]嘧啶化合物
CN107108615B (zh) * 2015-03-04 2020-11-20 吉利德科学公司 Toll样受体调节性4,6-二氨基-吡啶并[3,2-D]嘧啶化合物
US11629134B2 (en) 2015-12-17 2023-04-18 Merck Patent Gmbh TLR7/8 antagonists and uses thereof
US11512069B2 (en) 2016-08-08 2022-11-29 Merck Patent Gmbh TLR7/8 antagonists and uses thereof
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WO2019018354A1 (fr) * 2017-07-18 2019-01-24 Merck Patent Gmbh Antagonistes de tlr7/8 et leurs utilisations
EP4248968A3 (fr) * 2017-07-18 2023-12-06 Merck Patent GmbH Antagonistes de tlr7/8 et leurs utilisations
IL272016B (en) * 2017-07-18 2022-10-01 Merck Patent Gmbh Pyrrolidine history and their use as tlr7/8 antagonists
US20220087991A1 (en) * 2019-01-14 2022-03-24 Innate Tumor Immunity, Inc. Nlrp3 modulators
US11583531B2 (en) 2019-04-17 2023-02-21 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
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US11286257B2 (en) 2019-06-28 2022-03-29 Gilead Sciences, Inc. Processes for preparing toll-like receptor modulator compounds
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