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WO2011028740A1 - Bloqueurs du canal enac - Google Patents

Bloqueurs du canal enac Download PDF

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Publication number
WO2011028740A1
WO2011028740A1 PCT/US2010/047422 US2010047422W WO2011028740A1 WO 2011028740 A1 WO2011028740 A1 WO 2011028740A1 US 2010047422 W US2010047422 W US 2010047422W WO 2011028740 A1 WO2011028740 A1 WO 2011028740A1
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WO
WIPO (PCT)
Prior art keywords
compound
phenyl
compounds
administration
enac
Prior art date
Application number
PCT/US2010/047422
Other languages
English (en)
Inventor
Dramane Ibrahim Laine
Hongxing Yan
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2011028740A1 publication Critical patent/WO2011028740A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms

Definitions

  • the present invention relates to quaternary amide analogs, pharmaceutical compositions containing them and their use as ENaC blockers.
  • the epithelial sodium channel is a membrane-bound ion-channel that is permeable for Li + , protons and especially Na + . It is a 'constitutively active' channel, i.e. does not require a gating stimulus and is open at rest.
  • ENaC is a heteromeric protein comprised of three different subunits a SCNN1A), ⁇ (SCNN1 B), and ⁇ SCNN1 G).
  • ENaC is located in the apical membrane of polarized epithelial cells particularly in the kidney, the lung and the colon. It is involved in the transepithelial Na + -ion transport which it accomplishes together with the Na+/K+-ATPase. It plays a major role in the Na + - and K + -ion homeostasis of blood, epithelia and
  • ENaC extraepithelial fluids by resorption of Na + -ions.
  • the activity of ENaC in colon and kidney is modulated by the mineralcorticoid aldosterone.
  • ENaC can furthermore be found in taste receptor cells, where it plays an important role in salt taste perception.
  • the airways are lined with a film of liquid about 10 microm deep that is in two layers.
  • the cilia Around the cilia is the watery periciliary sol. Over this is a mucous blanket that traps inhaled particles.
  • the mucus layer itself traps inhaled pathogens/particles, allowing their removal via ongoing mucociliary clearance, without the need to trigger a potentially injurious inflammatory response.
  • the low viscosity of the periciliary sol allows the cilia to beat and propel the mucous blanket along airways to the mouth. In large airways, mucus comes predominantly from the mucous glands but also from goblet cells in the surface epithelium.
  • Water is added to the airway surface by gland secretion that is driven by active CI secretion by serous cells. Water is removed by Na transport via ENaC across the surface epithelium. In airway diseases, the balance is shifted from water secretion to mucus secretion.
  • Widdicombe, JH and Widdicombe JG (2002) Regulation of airway surface liquid. Respir. Physiol. 93: 3-12; Randell, SH and Boucher, RC (2006) Effective Mucus Clearance is Essential for Respiratory Health. Am. J Resp. Cell Mol. Biol. 35: 20- 28, Kunzelmann, K, Schreiber, R, Boucherot, A.
  • Blockade of ENaC would reverse this imbalance, thus restoring mucociliary clearance.
  • Blockers of ENaC would be useful in the treatment of cystic fibrosis, COPD, and (non- cystic fibrosis) bronchiectasis.
  • this invention provides for quaternary amide analogs
  • this invention provides for the use of the compounds of Formula (I) as ENaC blockers.
  • this invention provides for the use of the compounds of Formula (I) for treating and preventing conditions associated with ENaC imbalance.
  • this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of cystic fibrosis, COPD, and non-cystic fibrosis bronchiectasis.
  • the ENaC blocker may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of: advair, tiotropium, tobi, pulmozyme, azithromycin, hypertonic saline, albuterol, pancreatic enzymes, oral antibiotics, and oral steroids.
  • the present invention provides for compounds of Formula (I):
  • Y is CI or Br
  • R-i, R 2 , and R 3 are independently Ci -3 alkyl; wherein R-i is substituted with phenyl;
  • X " is a physiologically acceptable anion selected from the group consisting of: chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • Ci -3 alkyl refers to an alkyl group having from 1 to 3 member atoms.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, and propyl (n- propyl and isopropyl).
  • Substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture).
  • the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a compound of Formula (I) or “the compound of Formula (I)” refers to one or more compounds according to Formula (I).
  • the compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 1 1 C, 13C, 14C, 15N, 170, 180, 31 P, 32P, 35S, 18F, 36CI, 1231 and 1251.
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 1 1 C and 18F isotopes are particularly useful in PET
  • Isotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • Y is CI or Br
  • R-i, R 2 , and R 3 are independently Ci -3 alkyl; wherein R-i is substituted with phenyl;
  • X " is a physiologically acceptable anion selected from the group consisting of: chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
  • Y is CI
  • Ri, R 2 , and R 3 are independently Ci alkyl
  • X " is a physiologically acceptable anion selected from the group consisting of: chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
  • compounds of the present invention include the following: 2- ⁇ [(3,5-Diamino-6-chloro-2-pyrazinyl)carbonyl]amino ⁇ -N,N-dimethyl-N-( ⁇ 2- [(trifluoromethyl)thio]phenyl ⁇ methyl)ethanaminium bromide; and
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Reagents and conditions a) 2, MeOH, microwave reactor; b) Ketone or aldehyde,
  • the compounds according to Formula (I) are ENaC blockers, and are useful in the treatment or prevention of cystic fibrosis, COPD, (non-cystic fibrosis) bronchiectasis., and obliterative bronchiolitis.
  • the biological activity of the compounds according to Formula (I) can be determined using any suitable assay for determining the activity of a candidate compound as an ENaC blockers, as well as tissue and in vivo models.
  • ENaC inhibitors were assessed in recombinant cells expressing the three ENaC subunits required to give functional ENaC sodium currents, the a-subunit (SCNN 1 A, NCBI Reference Sequence Accession NM_001 159576), the ⁇ -subunit
  • a HEK293 cell line was generated which stably co-expressed variants of the SCN N 1 B and SCN N 1 G subunits, SCNN 1 B-(P618A,Y620L) and SCNN 1 G-(P624stop).
  • HEK293 cells were grown in DMEM- F12 with 10%FBS and 2mM glutamine.
  • the stable HEK293- SCNN 1 B-(P618A,Y620L)/ SCNN 1 G-(P624stop) cell line was generated following transfection (by Amaxa
  • Transduction of the HEK293- SCNN1 B-(P618A,Y620L)/ SCNN1 G-(P624stop) cell line with the SCNNIA-BacMam virus was carried out 24 hours prior to assay by adding 10% virus (at approximately 1 .37 x10 8 pfu/ml) to 1 x10 7 cells, and continuing to incubate at 37°C, in the presence of the selection agents (G418 & hygromycin).
  • Recombinant cell cultures were prepared according to the platform manufacturers protocol (MDC Corp, Sunnyvale, CA / Finkel et al, J. Biomol. Screen. 2006; 1 1 : 488-496) using TrypLETM Express (Gibco / Invitrogen, Paisley, Renfrewshire, UK, Cat # 12604) in place of the specified Versene solution.
  • TrypLETM Express Gibco / Invitrogen, Paisley, Renfrewshire, UK, Cat # 12604
  • Sodium-ion flux across the cell membrane via ENaC generates a measurable current (l E Nac) that is assessed by the lonWorks platform (lonWorks QuattroTM model, MDC Corp, Sunnyvale, CA). Inhibition of the l EN ac with ENaC blockers was used to assess their potency.
  • l E Nac was measured (lonWorks PPC-mode) under voltage clamp conditions from a mean of up to 64 cells in each of up to 384 wells both before and after addition of compounds.
  • the effect of the compound is calculated by normalizing the post compound addition data to the naive state and comparing this against high (100% block by 10 ⁇ amiloride gold standard) and low ("zero"-effect; 1 % v/v DMSO) control data.
  • composition milli-molar: sodium gluconate, 120; sodium chloride, 20; potassium chloride, 5; 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-Hydroxyethyl)piperazine-N'- (2-ethanesulfonic acid) (HEPES), 10; calcium chloride, 2; magnesium chloride, 1 , and pluronic F-127 0.03% w/v, pH 7.35 - 7.40), and added to a 384 well disposable plate (compound plate), which was loaded in to the lonWorks platform.
  • HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-Hydroxyethyl)piperazine-N'- (2-ethanesulfonic acid)
  • HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N
  • the lonWorks was programmed to transfer an appropriate volume from the compound plate to the assay well to give a further 1 :3 diltution, at approximately 3 mins prior to the post-compound reading.
  • the data corresponding to the series of dilutions of test compounds were then used to estimate the concentration of compound required to produce a 50 % decrease of the ENaC-mediated current response (IC 50 ). Potency was reported as plC 50 (-log IC 50 ).
  • the potency of ENaC inhibitors was assessed in commercially available (MatTek Corporation, 200 Homer Ave., Ashland, MA 01721 ) human bronchial epithelial cells grown in Air-Liquid Interface (Cat # AIR-1 12-SNP). Epithelial cell cultures were mounted in Ussing Chambers filled with Krebs bicarbonate buffer solution (KBS) continuously bubbled with 95% oxygen/5% carbon dioxide. Sodium transport across the epithelium via ENaC generates a measurable current that is assessed my measuring short-circuit current (Isc). Inhibition of the Isc with ENaC blockers was used to assess their potency. Isc was measured (Physiologic Instruments, Model VCC MC6) under voltage clamp conditions so that active ion transport was the dominant ion transport process generating Isc.
  • Test compounds were prepared as 10mM solutions in DMSO and working solutions were prepared by serial 10 fold dilutions in KBS. Cumulatively increasing concentrations (0.5 logs) of test compound are added to the chamber bathing the apical surface of the epithelium. Concentration response curves were used to calculate the concentration of compound that causes a 50 % decrease of the IsC (EC 50). Potency was reported as plC50 (-log EC50).
  • the compounds of the invention are ENac blockers, and are useful in the treatment or prevention of cystic fibrosis, COPD, non-cystic fibrosis bronchiectasis, and obliterative bronchiolitis. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
  • "treat" in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular compound chosen (e.g.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral
  • transdermal, or by inhalation and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Typical daily dosages may vary depending upon the particular route of
  • Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
  • the pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a
  • each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in
  • compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
  • Compounds of Formula (I) may be administered parenterally, that is by
  • intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the agents of the present invention are delivered via oral inhalation or intranasal administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the compounds may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
  • dichlorotetrafluoroethane a hydrofluoroalkane such as tetrafluoroethane or
  • heptafluoropropane carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di or poly-saccharides (e.g. lactose or starch). Use of lactose is preferred.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example see International Patent Application No. WO 02/00196 (SmithKline Beecham).
  • the compounds may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of advair, tiotropium, tobi, pulmozyme, azithromycin, hypertonic saline, albuterol, pancreatic enzymes, oral antibiotics, and oral steroids.
  • the naming program used is ACD Name Pro 6.02.
  • the eluent was a mixture composed of solvents A and B. Either one of three different solvent combinations were used:
  • Solvent A 0.1 % trifluoroacetic acid in water
  • Solvent B 0.1 % trifluoroacetic acid in acetonitrile
  • Solvent A 0 1 % NH4OH in water
  • Solvent B 0 1 % NH4OH in acetonitrile
  • Solvent A 0.1 % NH 4 OH in water
  • Solvent B 0.1 % NH 4 OH in acetonitrile

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur des analogues d'amide quaternaire, sur des compositions pharmaceutiques les contenant et sur leur utilisation en tant que bloqueurs du canal ENaC.
PCT/US2010/047422 2009-09-03 2010-09-01 Bloqueurs du canal enac WO2011028740A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US23952609P 2009-09-03 2009-09-03
US61/239,526 2009-09-03
US28907909P 2009-12-22 2009-12-22
US61/289,079 2009-12-22

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Cited By (13)

* Cited by examiner, † Cited by third party
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US8685418B2 (en) 2011-10-24 2014-04-01 Endo Pharmaceuticals Inc. Cyclohexylamines
WO2014071122A1 (fr) 2012-11-02 2014-05-08 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques pour le traitement de maladies médiées par cftr
WO2015018754A1 (fr) * 2013-08-08 2015-02-12 Boehringer Ingelheim International Gmbh Nouveaux composés pyrazine-amides
WO2015140527A1 (fr) * 2014-03-18 2015-09-24 Astrazeneca Ab Composés chimiques
JP2018502865A (ja) * 2015-01-12 2018-02-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 呼吸器系疾患の治療に有用な置換ベンズイミダゾリウム化合物
JP2018504401A (ja) * 2015-01-12 2018-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 呼吸器系疾患の治療に有用な置換ベンズイミダゾリウム化合物
JP2018506521A (ja) * 2015-01-12 2018-03-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 呼吸器系疾患の治療に有用な四置換及び五置換ベンズイミダゾリウム化合物
WO2018175302A1 (fr) 2017-03-20 2018-09-27 Sienna Biopharmaceuticals, Inc. Conjugués polymères ciblant c-src à exposition réduite
WO2018175340A1 (fr) 2017-03-20 2018-09-27 Sienna Biopharmaceuticals, Inc. Conjugués d'exposition réduite modulant des cibles thérapeutiques
WO2019220147A1 (fr) 2018-05-18 2019-11-21 Enterprise Therapeutics Limited Composés
US10759785B2 (en) 2016-06-21 2020-09-01 Enterprise Therapeutics Limited Compounds
US10941149B2 (en) 2016-11-22 2021-03-09 Enterprise Therapeutics Limited Substituted benzodiazoliums as ENaC inhibitors
US11370778B2 (en) 2017-10-17 2022-06-28 Enterprise Therapeutics Limited Bis(pentahydroxyhexyl)amino substituted 2-{[(3-amino-pyrazin-2-yl)formamido]methyl}-1H-1,3-benzodiazol-3-ium derivatives as ENaC inhibitors for treating respiratory diseases

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Cited By (27)

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US8685418B2 (en) 2011-10-24 2014-04-01 Endo Pharmaceuticals Inc. Cyclohexylamines
US9180115B2 (en) 2011-10-24 2015-11-10 Asana Biosciences, Llc Cyclohexylamines
WO2014071122A1 (fr) 2012-11-02 2014-05-08 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques pour le traitement de maladies médiées par cftr
EP4556008A2 (fr) 2012-11-02 2025-05-21 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques pour le traitement de maladies médiées par cftr
EP3470063A1 (fr) 2012-11-02 2019-04-17 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques pour le traitement de maladies induites par cftr
WO2015018754A1 (fr) * 2013-08-08 2015-02-12 Boehringer Ingelheim International Gmbh Nouveaux composés pyrazine-amides
US9096548B2 (en) 2013-08-08 2015-08-04 Boehringer Ingelheim International Gmbh Pyrazine amide compounds
JP2016529248A (ja) * 2013-08-08 2016-09-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規ピラジンアミド化合物
EA029952B1 (ru) * 2014-03-18 2018-06-29 Астразенека Аб Химические соединения
JP2017512830A (ja) * 2014-03-18 2017-05-25 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ 化合物
US10954211B2 (en) 2014-03-18 2021-03-23 Astrazeneca Ab Chemical compounds
TWI687410B (zh) * 2014-03-18 2020-03-11 瑞典商阿斯特捷利康公司 化學化合物
US9873678B2 (en) 2014-03-18 2018-01-23 Astrazeneca Ab Chemical compounds
WO2015140527A1 (fr) * 2014-03-18 2015-09-24 Astrazeneca Ab Composés chimiques
US10336725B2 (en) 2014-03-18 2019-07-02 Astrazeneca Ab Chemical compounds
JP2018502865A (ja) * 2015-01-12 2018-02-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 呼吸器系疾患の治療に有用な置換ベンズイミダゾリウム化合物
JP2018506521A (ja) * 2015-01-12 2018-03-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 呼吸器系疾患の治療に有用な四置換及び五置換ベンズイミダゾリウム化合物
JP2018504401A (ja) * 2015-01-12 2018-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 呼吸器系疾患の治療に有用な置換ベンズイミダゾリウム化合物
US10759785B2 (en) 2016-06-21 2020-09-01 Enterprise Therapeutics Limited Compounds
US11739094B2 (en) 2016-11-22 2023-08-29 Enterprise Therapeutics Limited Substituted benzodiazoliums as ENaC inhibitors
US12371436B2 (en) 2016-11-22 2025-07-29 Enterprise Therapeutics Limited Substituted benzodiazoliums as ENaC inhibitors
US10941149B2 (en) 2016-11-22 2021-03-09 Enterprise Therapeutics Limited Substituted benzodiazoliums as ENaC inhibitors
WO2018175302A1 (fr) 2017-03-20 2018-09-27 Sienna Biopharmaceuticals, Inc. Conjugués polymères ciblant c-src à exposition réduite
WO2018175340A1 (fr) 2017-03-20 2018-09-27 Sienna Biopharmaceuticals, Inc. Conjugués d'exposition réduite modulant des cibles thérapeutiques
US11370778B2 (en) 2017-10-17 2022-06-28 Enterprise Therapeutics Limited Bis(pentahydroxyhexyl)amino substituted 2-{[(3-amino-pyrazin-2-yl)formamido]methyl}-1H-1,3-benzodiazol-3-ium derivatives as ENaC inhibitors for treating respiratory diseases
US12037336B2 (en) 2018-05-18 2024-07-16 Enterprise Therapeutics Limited Compounds with activity as inhibitors of the epithelial sodium channel (ENaC)
WO2019220147A1 (fr) 2018-05-18 2019-11-21 Enterprise Therapeutics Limited Composés

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