WO2011050325A1 - Compositions for treatment of cystic fibrosis and other chronic diseases - Google Patents

Compositions for treatment of cystic fibrosis and other chronic diseases Download PDF

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Publication number
WO2011050325A1
WO2011050325A1 PCT/US2010/053852 US2010053852W WO2011050325A1 WO 2011050325 A1 WO2011050325 A1 WO 2011050325A1 US 2010053852 W US2010053852 W US 2010053852W WO 2011050325 A1 WO2011050325 A1 WO 2011050325A1
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compound
formula
alkyl
pharmaceutical composition
optionally substituted
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PCT/US2010/053852
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English (en)
French (fr)
Inventor
Fredrick F. Van Goor
William Lawrence Burton
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Priority to CA2777245A priority Critical patent/CA2777245A1/en
Priority to MX2012004792A priority patent/MX2012004792A/es
Priority to AU2010310449A priority patent/AU2010310449A1/en
Priority to CN2010800578878A priority patent/CN102665715A/zh
Priority to EP10773489A priority patent/EP2490687A1/en
Priority to JP2012535433A priority patent/JP2013508414A/ja
Publication of WO2011050325A1 publication Critical patent/WO2011050325A1/en
Anticipated expiration legal-status Critical
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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Definitions

  • the present invention relates to compositions for the treatment of cystic fibrosis (CF) and other chronic diseases, methods for preparing the compositions and methods for using the compositions for the treatment of CF and other chronic diseases, including chronic diseases involving regulation of fluid volumes across epithelial membranes.
  • CF cystic fibrosis
  • Cystic fibrosis is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.
  • CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator
  • CFTR CFTR gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues.
  • Small molecule drugs known as potentiators that increase the probability of CFTR channel opening, represent one potential therapeutic strategy to treat CF. Potentiators of this type are disclosed in WO 2006/002421, which is herein incorporated by reference in its entirety.
  • Another potential therapeutic strategy involves small molecule drugs known as CF correctors that increase the number and function of CFTR channels. Correctors of this type are disclosed in WO 2005/075435, which are herein incorporated by reference in their entirety.
  • CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins.
  • epithelia cells normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
  • CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain.
  • the two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • R regulatory
  • CFTR cystic fibrosis
  • Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
  • CF patients In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene within the population.
  • the most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as AF508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
  • CFTR transports a variety of molecules in addition to anions
  • this role represents one element in an important mechanism of transporting ions and water across the epithelium.
  • the other elements include the epithelial Na+ channel (“ENaC”), Na+/2C1-/K+ co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+ channels, that are responsible for the uptake of chloride into the cell.
  • ENaC epithelial Na+ channel
  • Na+/2C1-/K+ co-transporter Na+-K+-ATPase pump
  • basolateral membrane K+ channels that are responsible for the uptake of chloride into the cell.
  • Each of WR W2 and WR W4 is independently selected from CN, CF 3 , halo, C 2 -6 straight or branched alkyl, C 3 .12 membered cycloaliphatic, phenyl, a 5-10 membered heteroaryl or 3-7 membered heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WR W2 and WR W4 is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , SR', S(0)R', S0 2 R', -SCF 3 , halo, CN, -COOR', -COR', -0(CH 2 ) 2 N(R') 2 , - 0(CH 2 )N(R') 2 , -CON(R') 2 , -(CH 2 ) 2 OR ⁇ -(CH 2 )
  • Each R' is independently selected from an optionally substituted group selected from a Ci-8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that:
  • WR W2 , WR W4 and WR W5 are not -OCH 2 CH 2 Ph, -OCH 2 CH 2 (2-trifluoromethyl-phenyl), -OCH 2 CH 2 -(6,7- dimethoxy-l,2,3,4-tetrahydroisoquinolin-2-yl), or substituted l/f-pyrazol-3-yl;
  • T is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, -C(CH 3 ) 2 -, or -C(O)-;
  • Ri' is H, Ci_6 aliphatic, halo, CF 3 , CHF 2 , 0(Ci_6 aliphatic);
  • Z D is a bond, CONH, S0 2 NH, S0 2 N(Ci_ 6 alkyl), CH 2 NHS0 2 , CH 2 N(CH 3 )S0 2 , CH 2 NHCO, COO, S0 2 , or CO; and R 9 is H, Ci_ 6 aliphatic, or aryl;
  • Each R is independently H, OH, OCH 3 or two R taken together form -OCH 2 0- or -OCF 2 0-;
  • Each R 4 is independently H or alkyl
  • R 5 is H or F
  • R 6 is H or CN
  • R 7 is H, -CH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH;
  • the pharmaceutical composition comprises an ENaC inhibitor and at least one Compound of Formula I, Formula II and Formula III.
  • composition comprises at least one Compound of
  • an ENaC inhibitor selected from amiloride, benzamil, dimethyl- amiloride camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, and aero lytic.
  • the ENaC inhibitor is a compound of Formula IV
  • the pharmaceutical composition comprises an inhibitor of ENaC activity and Compound 1.
  • the ENaC inhibitor is selected from amiloride, benzamil, and dimethyl- amiloride.
  • the pharmaceutical composition comprises an inhibitor of ENaC activity and Compound
  • the ENaC inhibitor is selected from amiloride, benzamil, and dimethyl- amiloride.
  • the pharmaceutical composition comprises an inhibitor of ENaC activity and Compound 3.
  • the ENaC inhibitor is selected from amiloride, benzamil, and dimethyl- amiloride.
  • the invention is directed to a composition, preferably a pharmaceutical composition comprising at least one component from: Column A of Table I, or Column B of Table I, or Column C of Table I, in combination with at least one component from Column D of Table I.
  • a composition preferably a pharmaceutical composition comprising at least one component from: Column A of Table I, or Column B of Table I, or Column C of Table I, in combination with at least one component from Column D of Table I.
  • Column A can comprise the first component, and any embodiment or group of embodiments of Column D can comprise the second component.
  • the Column A component is Compound 1
  • the invention is directed to method of treating a CFTR mediated disease in a human comprising administering to the human, an effective amount of a pharmaceutical composition comprising an ENaC inhibitor component of Column D and an CF modulator component selected from at least one of Columns A, B, or C according to Table I.
  • compositions of the present invention include the combination of a modulator of CF Modulator activity or cAMP/ATP-mediated anion channel, Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR”) and a modulator of ENaC activity.
  • CFTR Cystic Fibrosis Transmembrane Conductance Regulator
  • the combination compounds are provided to treat a variety of diseases and disorders mediated by CF Modulators and/or ENaC.
  • the combination composition can include a modulator of an CF Modulator corresponding to one or more of Formulas I, II and III and an inhibitor of ENaC, for example, compounds of Formula IV.
  • While the methods for treating said variety of diseases and disorders mediated by CF Modulators and/or ENaC comprises a combination of a an ENaC inhibitor component of Column D and an CF modulator component selected from at least one of Columns A, B, or C according to Table I, the individual active agents can be administered in a single dose unit, as separate dosage units, administered simultaneously, or may be administered sequentially, optionally within a specified time period of the other's administration.
  • the invention is directed to method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a ENaC inhibitor component of Column D and at least one of Compounds 1, 2, or 3 according to Table I.
  • the invention is directed to method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a ENaC inhibitor component of Column D and at least one solid form component of Columns A, B, or C according to Table I.
  • Methods are provided to treat CF and other chronic diseases mediated by dysregulation or dysfunctional CF Modulator activity or cAMP/ATP-mediated anion channel and epithelial sodium channel (ENaC) activity using the pharmaceutical compositions described herein.
  • the invention is directed to a kit for the treatment of a CFTR mediated disease in a human, the kit comprising an ENaC inhibitor component of Column D and an CF modulator component selected from at least one of Columns A, B, or C according to Table I, and optionally, instructions for preparing and administering a pharmaceutical composition for the treatment of said disease.
  • the invention relates to a combination, particularly a pharmaceutical combination, such as a combined preparation or pharmaceutical composition, respectively, which comprises 1) a modulator of ATP-Binding Cassette ("ABC”) transporters or fragments thereof, including Cystic Fibrosis
  • ABSC ATP-Binding Cassette
  • Transmembrane Conductance Regulator (“CFTR”)and 2) an epithelial sodium channel inhibitor (“ENaC”), for simultaneous, separate or sequential use, especially in the prevention, delay of progression or treatment of conditions mediated by CFTR and ENaC, conditions directly caused by CF Modulator and/or CFTR activities and alleviation of symptoms of diseases not directly caused by CF Modulator and/or CFTR anion channel activities.
  • CFTR Transmembrane Conductance Regulator
  • ENaC epithelial sodium channel inhibitor
  • CFTR and/or ENaC activity include, but are not limited to, Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial
  • hypercholesterolemia Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/T ay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophysiol DI, Nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus- Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis
  • the present invention also provides for the use of such combination of active agents, for the preparation of a pharmaceutical composition, for the prevention, delay, of progression or treatment of such conditions, diseases and disorders; and for providing kits comprising such combinations for the treatment of a mammal.
  • ABS-transporter as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment thereof is present in vivo or in vitro.
  • binding domain as used herein means a domain on the ABC- transporter that can bind to a modulator. See, e.g., Hwang, T. C. et al, J. Gen. Physiol. (1998): 111(3), 477-90.
  • CFTR cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, AF508 CFTR, R117H CFTR, and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).
  • API active pharmaceutical ingredient
  • CF potentiators N-[2,4-bis(l,l- dimethylemyl)-5-hydroxyphenyl]-l,4-dmydro-4-oxoquinoline-3-carboxarnide (Compound 1) and N-(4- (7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-l,4- dihydroquinoline-3-carboxamide (Compound 2).
  • Exemplary APIs also include the CF correctors 3-(6- (l-(2,2-Difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 3) and (R)-l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2- (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide (Compound 3).
  • modulating means increasing or decreasing by a measurable amount.
  • normal CFTR or "normal CFTR function” as used herein means wild-type like CFTR without any impairment due to environmental factors such as smoking, pollution, or anything that produces inflammation in the lungs.
  • reduced CFTR or "reduced CFTR function” as used herein means less than normal CFTR or less than normal CFTR function.
  • amorphous refers to a solid material having no long range order in the position of its molecules.
  • Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order.
  • Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD).
  • XRPD X-ray power diffraction
  • one or several broad peaks appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. See, US 2004/0006237 for a comparison of XRPDs of an amorphous material and crystalline material.
  • substantially amorphous refers to a solid material having little or no long range order in the position of its molecules.
  • substantially amorphous materials have less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity).
  • 'substantially amorphous' includes the descriptor, 'amorphous', which refers to materials having no (0%) crystallinity.
  • the term "dispersion” refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle).
  • the size of the dispersed phase can vary considerably (e.g. single molecules, colloidal particles of nanometer dimension, to multiple microns in size).
  • the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids.
  • a solid dispersion can include: an amorphous drug in an amorphous polymer; an amorphous drug in crystalline polymer; a crystalline drug in an amorphous polymer; or a crystalline drug in crystalline polymer.
  • a solid dispersion can include an amorphous drug in an amorphous polymer or an amorphous drug in crystalline polymer.
  • a solid dispersion includes the polymer constituting the dispersed phase, and the drug constitutes the continuous phase.
  • a solid dispersion includes the drug constituting the dispersed phase, and the polymer constitutes the continuous phase.
  • solid dispersion generally refers to a solid dispersion of two or more components, usually one or more drugs (e.g., one drug (e.g., Compound 1)) and polymer, but possibly containing other components such as surfactants or other pharmaceutical excipients, where the drug(s) (e.g., Compound 1) is substantially amorphous (e.g., having about 15% or less (e.g., about 10% or less, or about 5% or less)) of crystalline drug (e.g., N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]- l,4-dihydro-4-oxoquinoline-3-carboxamide) or amorphous (i.e., having no crystalline drug), and the physical stability and/or dissolution and/or solubility of the substantially amorphous or amorphous drug is enhanced by the other components.
  • drugs e.g., one drug (e.g., Compound 1)
  • polymer but
  • Solid dispersions typically include a compound dispersed in an appropriate carrier medium, such as a solid state carrier.
  • a carrier comprises a polymer (e.g., a water-soluble polymer or a partially water-soluble polymer) and can include optional excipients such as functional excipients (e.g., one or more surfactants) or nonfunctional excipients (e.g., one or more fillers).
  • Another exemplary solid dispersion is a co-precipitate or a co-melt of N-[2,4-bis(l,l- dimethylemyl)-5-hydroxyphenyl]-l,4-dmydro-4-oxoquinoline-3-carboxarnide with at least one polymer.
  • a "Co-precipitate” is a product after dissolving a drug and a polymer in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the polymer can be suspended in the solvent or solvent mixture.
  • the solvent or solvent mixture includes organic solvents and supercritical fluids.
  • a "co-melt” is a product after heating a drug and a polymer to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent if applicable, and cooling to room temperature at a selected rate.
  • crystalline refers to compounds or compositions where the structural units are arranged in fixed geometric patterns or lattices, so that crystalline solids have rigid long range order.
  • the structural units that constitute the crystal structure can be atoms, molecules, or ions.
  • Crystalline solids show definite melting points.
  • substantially crystalline means a solid material that is arranged in fixed geometric patterns or lattices that have rigid long range order.
  • substantially crystalline materials have more than about 85% crystallinity (e.g., more than about 90% crystallinity or more than about 95% crystallinity).
  • the term 'substantially crystalline' includes the descriptor 'crystalline', which is defined in the previous paragraph.
  • crystallinity refers to the degree of structural order in a solid.
  • Compound 1, which is substantially amorphous has less than about 15% crystallinity, or its solid state structure is less than about 15% crystalline.
  • Compound 1, which is amorphous has zero (0%) crystallinity.
  • an “excipient” is an inactive ingredient in a pharmaceutical composition.
  • excipients include fillers or diluents, surfactants, binders, glidants, lubricants, disintegrants, and the like.
  • a "disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion.
  • disintegrants include sodium croscarmellose and/or sodium starch glycolate.
  • a "diluent” or “filler” is an excipient that adds bulkiness to a pharmaceutical composition.
  • fillers include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof.
  • a "surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability.
  • surfactants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., TweenTM), or any combination thereof.
  • a "binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness). Examples of binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).
  • glidant is an excipient that imparts a pharmaceutical compositions with enhanced flow properties.
  • examples of glidants include colloidal silica and/or talc.
  • a "colorant” is an excipient that imparts a pharmaceutical composition with a desired color.
  • examples of colorants include commercially available pigments such as FD&C Blue # 1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.
  • a "lubricant” is an excipient that is added to pharmaceutical compositions that are pressed into tablets.
  • the lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press.
  • examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
  • Friability refers to the property of a tablet to remain intact and withhold its form despite an external force of pressure. Friability can be quantified using the mathematical expression presented in equation 1 :
  • Friability is measured using a standard USP testing apparatus that tumbles experimental tablets for 100 revolutions. Some tablets of the present invention have a friability of less than about 1 % (e.g., less than about 0.75%, less than about 0.50%, or less than about 0.30%)
  • mean particle diameter is the average particle diameter as measured using techniques such as laser light scattering, image analysis, or sieve analysis.
  • bulk density is the mass of particles of material divided by the total volume the particles occupy. The total volume includes particle volume, inter -particle void volume and internal pore volume. Bulk density is not an intrinsic property of a material; it can change depending on how the material is processed.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” "cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-20 aliphatic carbon atoms.
  • aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 -6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C 3 -C 8 hydrocarbon or bicyclic or tricyclic C 8 -Ci 4 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo- octyl, or bridged tricyclic such as adamantyl.
  • heteroaliphatic means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.
  • heterocycle means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom.
  • heterocycle means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom.
  • heterocyclyl has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or
  • aryloxyalkyl refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl also refers to heteroaryl ring systems as defined hereinbelow.
  • An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents.
  • Optional substituents on the aliphatic group of R * are selected from NH 2 , aliphatic), N(Ci_ 4 aliphatic) 2 , halo, Ci_ 4 aliphatic, OH, 0(Ci 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci_ 4 aliphatic), 0(halo Ci_ 4 aliphatic), or halo(Ci_ aliphatic), wherein each of the foregoing groups of R is unsubstituted.
  • Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R + , -N(R + ) 2 , -C(0)R + , -C0 2 R + , -C(0)C(0)R + , -C(0)CH 2 C(0)R + , -S0 2 R + , -S0 2 N(R + ) 2 ,
  • R + is hydrogen, an optionally substituted Ci_ 6 aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH 2 (Ph), optionally substituted -(CH 2 ) !
  • Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(Ci_ aliphatic), N(Ci_ aliphatic) 2 , halo, aliphatic, OH, 0(Ci_ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (C w aliphatic), 0(halo Ci_ 4 aliphatic), or halo(Ci_ 4 aliphatic), wherein each of the foregoing Ci_ aliphatic groups of R + is unsubstituted.
  • two independent occurrences of R are taken together with the atom(s) to which each variable is bound to form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Exemplary rings that are formed when two independent occurrences of R (or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R (or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R ) 2 , where both occurrences of R' are taken together with the nitrogen atom to form a piperidin-l-yl, piperazin-l-yl, or morpholin-4-yl group; and b) two independent occurrences of R (or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of OR these two occurrences of R° are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing
  • a substituent bond in, e.g., a bicyclic ring system, as shown below, means that the substituent can be attached to any substitutable ring atom on either ring of the bicyclic ring system:
  • protecting group represents those groups intended to protect a functional group, such as, for example, an alcohol, amine, carboxyl, carbonyl, etc., against undesirable reactions during synthetic procedures. Commonly used protecting groups are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • nitrogen protecting groups include acyl, aroyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, i-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate groups such as benzyloxycarbonyl, p- chlorobenzyl
  • methoxycarbonyl methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl,
  • Preferred iV-protecting groups are feri-butyloxycarbonyl (Boc).
  • Examples of useful protecting groups for acids are substituted alkyl esters such as 9- fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,
  • Preferred protecting groups for acids are methyl or ethyl esters.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Suitable solvents are, but not limited to, water, methanol, dichloro methane
  • DCM dimethylformamide
  • EtOAc ethyl acetate
  • IPA isopropyl alcohol
  • IP Ac isopropyl acetate
  • THF tetrahydrofuran
  • MEK methyl ethyl ketone
  • NMP N-methyl pyrrolidone
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an
  • the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a compound of Formula I. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a compound of Formula II. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a compound of Formula ⁇ .
  • the pharmaceutical composition includes a combination of an
  • composition includes a combination of an ENaC inhibitor component from Column D and Compound II. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and Compound III. In another embodiment, the
  • the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a Compound 1 solid form. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a Compound 2 solid form. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a Compound 3 solid form. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a Compound 1 formulation. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a Compound 2 formulation. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor component from Column D and a Compound 3 formulation. In another embodiment, the pharmaceutical composition includes a combination of an ENaC inhibitor of Column D, at least one component of Columns A, B, or C and at least one additional therapeutic agent.
  • the at least one additional therapeutic agent includes a CFTR modulator other than the components from Columns A, B and/or C, i.e., an agent that has the effect of modulating CFTR activity.
  • Each of WR W2 and WR W4 is independently selected from CN, CF 3 , halo, C 2 -6 straight or branched alkyl, C 3 . 12 membered cycloaliphatic, phenyl, a 5-10 membered heteroaryl or 3-7 membered heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WR W2 and WR W4 is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , SR', S(0)R', S0 2 R', -SCF 3 , halo, CN, -COOR', -COR', -0(CH 2 ) 2 N(R') 2 , - 0(CH 2 )N(R') 2 , -CON(R') 2 , -(CH 2 ) 2 OR ⁇ -(CH 2 )
  • Each R' is independently selected from an optionally substituted group selected from a Ci-8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • WR W2 , WR W4 and WR W5 are not -OCH 2 CH 2 Ph, -OCH 2 CH 2 (2-trifluoromethyl-phenyl), -OCH 2 CH 2 -(6,7- dimethoxy-l,2,3,4-tetrahydroisoquinolin-2-yl), or substituted l/f-pyrazol-3-yl.
  • each of WR W2 and WR W4 is independently selected from CN, CF 3 , halo, C 2 . 6 straight or branched alkyl, C 3 _i 2 membered cycloaliphatic, or phenyl, wherein said WR W2 and WR W4 is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , -SCF 3 , halo, - COOR', -COR', -0(CH 2 ) 2 N(R') 2 , -0(CH 2 )N(R') 2 , -CON(R') 2 , -(CH 2 ) 2 OR ⁇ -(CH 2 )OR ⁇ optionally substituted phenyl, -N(R') 2 , -NC(0)OR', -NC(0)R', -(CH 2
  • NHC(0)OR' NHC(0)OR', -NHS0 2 R', -CH 2 OH, -C(0)OR', -S0 2 NHR', or -CH 2 NHC(0)0-R').
  • each of WR W2 and WR W4 is independently selected from -CN, -CF 3 , C 2 . 6 straight or branched alkyl, C 3 _i 2 membered cycloaliphatic, or phenyl, wherein each of said WR W2 and WR W4 is independently and optionally substituted with up to three substituents selected from -OR' , -CF 3 , -OCF 3 , - SCF 3 , halo, -COOR', -COR', -0(CH 2 ) 2 N(R') 2 , -0(CH 2 )N(R') 2 , -CON(R') 2 , -(CH 2 ) 2 OR ⁇ -(CH 2 )OR', optionally substituted phenyl, -N(R') 2 , -NC(0)OR', -NC(0)R', -(CH 2 ) 2 N(R') 2 , or -
  • WR W2 is a phenyl ring optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , -SR', -S(0)R', -S0 2 R', -SCF 3 , halo, -CN, -COOR', - COR', -0(CH 2 ) 2 N(R') 2 , -0(CH 2 )N(R') 2 , -CON(R') 2 , -(CH 2 ) 2 OR', -(CH 2 )OR', -CH 2 CN, optionally substituted phenyl or phenoxy, -N(R') 2 , -NR'C(0)OR', -NR'C(0)R', -(CH 2 ) 2 N(R') 2 , or -(CH 2 )N(R') 2 ;
  • WR W4 is C 2 _6
  • each of WR W2 and WR W4 is independently -CF 3 , -CN, or a C 2 _6 straight or branched alkyl.
  • each of WR W2 and WR W4 is C 2 _6 straight or branched alkyl optionally substituted with up to three substituents independently selected from -OR', -CF 3 , -OCF 3 , -SR', -S(0)R' , - S0 2 R', -SCF 3 , halo, -CN, -COOR' , -COR' , -0(CH 2 ) 2 N(R') 2 , -0(CH 2 )N(R') 2 , -CON(R') 2 , -(CH 2 ) 2 OR', - (CH 2 )OR' , -CH 2 CN, optionally substituted phenyl or phenoxy, -N(R') 2 ,
  • each of WR W2 and WR W4 is independently selected from optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, l,l-dimethyl-2-hydroxyethyl, l ,l -dimethyl-2- (ethoxycarbonyl)-ethyl, l, l-dimethyl-3-(t-butoxycarbonyl-amino) propyl, or n-pentyl.
  • WR W5 is selected from -CN, -NHR', -N(R') 2 , -CH 2 N(R') 2 , - NHC(0)R', -NHC(0)OR' , -OH, C(0)OR' , or -S0 2 NHR' .
  • WR W5 is selected from -CN, -NH(Ci_ 6 alkyl), -N(Ci_ 6 alkyl) 2 , - NHC(0)( Ci_6 alkyl), -CH 2 NHC(0)0(Ci_ 6 alkyl), -NHC(0)0(Ci_ 6 alkyl), -OH, -0(Ci_ 6 alkyl), -C(0)0(Ci_ 6 alkyl), -CH 2 0(d_ 6 alkyl), or -S0 2 NH 2 .
  • WR W5 is selected from -OH, -CH 2 OH,
  • WR W2 is C 2 _6 straight or branched alkyl
  • WR W4 is C 2 _6 straight or branched alkyl or monocyclic or bicyclic aliphatic
  • WR W5 is selected from -CN, -NH(Ci_ 6 alkyl), -N(d -6 alkyl) 2 , -NHC(0)( Ci_ 6 alkyl), -
  • WR W2 is C 2 _6 alkyl, -CF 3 , -CN, or phenyl optionally substituted with up to 3 substituents selected from Ci_ 4 alkyl, -0(Ci_ 4 alkyl), or halo;
  • WR W4 is -CF 3 , C 2 . 6 alkyl, or C 6 . 10 cycloaliphatic;
  • WR W5 is -OH, -NH(Ci_ 6 alkyl), or -N(Ci_ 6 alkyl) 2 .
  • WR W2 is feri-butyl.
  • WR W4 is feri-butyl.
  • WR W5 is -OH. II.A.2. COMPOUND 1
  • the compound of Formula I is Compound 1.
  • Compound 1 is known by the name N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]- l,4-dihydro-4-oxoquinoline-3-carboxamide and by the name N-(5-hydroxy-2,4-di-ieri-butyl-phenyl)-4- oxo-lH-quinoline-3-carboxamide.
  • Amine precursors of compounds of Formula I are prepared as depicted in Scheme 1-2, wherein WR W2 , WR W4 , and WR W5 are as defined previously.
  • ortho alkylation of the para-substituted benzene in step (a) provides a tri-substituted intermediate.
  • Optional protection when WR W5 is OH provides the trisubstituted nitrated intermediate.
  • Optional deprotection (step d) and hydrogenation (step e) provides the desired amine moiety.
  • Compounds of Formula I are prepared by coupling an acid moiety with an amine moiety as depicted in Scheme 1-3.
  • the coupling reaction requires a coupling reagent, a base, as well as a solvent. Examples of conditions used include HATU, DIEA; BOP, DIEA, DMF; HBTU, Et 3 N, CH 2 C1 2 ;
  • Compound 1 can be prepared generally as provided in Schemes 1-3 through 1-6, wherein an
  • Ethyl 4-oxo- l,4-dihydroquinoline-3-carboxylate (25).
  • Compound 23 (4.77 g, 47.7 mmol) was added dropwise to Compound 22 (10 g, 46.3 mmol) with subsurface N 2 flow to drive out ethanol below 30 °C for 0.5 hours. The solution was then heated to 100-110 °C and stirred for 2.5 hours. After cooling the mixture to below 60 °C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 °C for 1.5 hours with subsurface N 2 flow to drive out ethanol.
  • Compound 25 (1.0 eq) was suspended in a solution of HCl (10.0 eq) and H 2 0 (11.6 vol). The slurry was heated to 85 - 90 °C, although alternative temperatures are also suitable for this hydrolysis step.
  • the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 °C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 °C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 °C (e.g., from about 82.5 to about 92.5 °C or from about 86 to about 89 °C).
  • the reaction mixture was then slowly heated to 23 - 28 °C and stirred for 20 hours.
  • the reaction was then cooled to 10 - 15 °C and charged with 150 mL water.
  • the mixture was stirred at 15 - 20 °C for 35 - 45 minutes and the aqueous layer was then separated and extracted with 150 mL methylene chloride.
  • the organic layers were combined and neutralized with 2.5% HC1 (aq) at a temperature of 5 - 20 °C to give a final pH of 5 - 6.
  • the organic layer was then washed with water and concentrated in vacuo at a temperature below 20 °C to 150 mL to give Compound 30 in methylene chloride.
  • the resulting filtrate was distilled under vacuum at no more than 50 °C to 8.00 vol. Water (2.00 vol) was added at 45 °C +/- 5 °C. The resultant slurry was cooled to 0 °C +/- 5 . The slurry was held at 0 °C +/- 5 °C for no less than 1 hour, and filtered. The cake was washed once with 0 °C +/- 5 °C MeOH/H 2 0 (8:2) (2.00 vol). The cake was dried under vacuum (-0.90 bar and -0.86 bar) at 35 °C - 40 °C to give Compound 32.
  • the reaction was quenched with 1 N HC1 (10.0 vol), and washed with 0.1 N HC1 (10.0 vol).
  • the organic solution was polish filtered to remove any particulates and placed in a second reactor.
  • the filtered solution was concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol.
  • CH 3 CN was added to 40 vol and the solution concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) to 20 vol.
  • the addition of CH 3 CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH 3 CN and 4 concentrations to 20 vol.
  • the filtered solution was concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol.
  • CH 3 CN was added to 40 vol and the solution concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) to 20 vol.
  • the addition of CH 3 CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH 3 CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH 3 CN was charged followed by 4.0 vol of H 2 0 to make a final concentration of 40 vol of 10% H 2 0/CH 3 CN relative to the starting acid.
  • This slurry was heated to 78.0 °C +/- 5.0 °C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 20 to 25 °C over 5 hours, and filtered. The cake was washed with CH 3 CN (5 vol) heated to 20 to 25 °C 4 times. The resulting solid (Compound 1) was dried in a vacuum oven at 50.0 °C +/- 5.0 °C.
  • T is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, -C(CH 3 ) 2 -, or -C(O)-;
  • Ri' is H, Ci_6 aliphatic, halo, CF 3 , CHF 2 , 0(Ci_6 aliphatic);
  • Z D is a bond, CONH, S0 2 NH, S0 2 N(Ci_ 6 alkyl), CH 2 NHS0 2 , CH 2 N(CH 3 )S0 2 , CH 2 NHCO, COO, S0 2 , or CO; and R 9 is H, Ci_6 aliphatic, or aryl.
  • the compound of Formula II is Compound 2, depicted below, which is also known by its chemical name 3-(6-(l-(2,2-Difluorobenzo[d] [l,3]dioxol-5- yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.
  • Compound 2 can be prepared by coupling an acid chloride moiety with an amine moiety according to following Schemes 2-1 to 2-3.
  • Scheme 2-1 depicts the preparation of l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride, which is used in Scheme 2-3 to make the amide linkage of Compound 2.
  • the starting material, 2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid is commercially available from Saltigo (an affiliate of the Lanxess Corporation). Reduction of the carboxylc acid moiety in 2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl 2 ), provides 5- (chloromethyl)-2,2-difluorobenzo[d][l,3]dioxole, which is subsequently converted to 2-(2,2- difluorobenzo[d] [l,3]dioxol-5-yl)acetonitrile using sodium cyanide.
  • Saltigo an affiliate of the Lanxess Corporation
  • nitrile moiety in l-(2,2- difluorobenzo[d] [l,3]dioxol-5-yl)cyclopropanecarbonitrile is converted to a carboxylic acid using base to give l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.
  • Scheme 2-2 depicts the preparation of the requisite tert-butyl 3-(6-amino-3- methylpyridin-2-yl)benzoate, which is coupled with l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride in Scheme 3-3 to give Compound 2.
  • Palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid gives tert-butyl 3-(3- methylpyridin-2-yl)benzoate, which is subsequently converted to the desired compound.
  • Scheme 2-3 depicts the coupling of l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate using triethyl amine and 4-dimethylaminopyridine to initially provide the tert-butyl ester of Compound 2.
  • Treatment of the tert-butyl ester with an acid such as HC1 gives the HC1 salt of Compound 2, which is typically a crystalline solid.
  • Vitride® sodium bis(2-methoxyethoxy)aluminum hydride
  • NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 ], 65 wgt% solution in toluene) was purchased from Aldrich Chemicals.
  • DMAP 4-(N,N-dimethyl)aminopyridine
  • l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60 °C. SOCl 2 (1.4 eq) was added via addition funnel. The toluene and SOCl 2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. ieri-Butyl-3-(3-methylpyridin-2-yl)benzoate.
  • the solid was collected by filtration, washed with 1 : 1 (by volume) acetonitrile/water (2 x 1 volumes based on crude product), and partially dried on the filter under vacuum.
  • the solid was dried to a constant weight ( ⁇ 1% difference) in a vacuum oven at 60 °C with a slight N 2 bleed to afford 3-(6-(l-(2,2- difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate as a brown solid.
  • R is H, OH, OCH 3 or two R taken together form -OCH 2 0- or -OCF 2 0-;
  • R 4 is H or alkyl
  • R 5 is H or F
  • R 6 is H or CN
  • R 7 is H, -CH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH;
  • R 8 is H, OH, -CH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 7 and R 8 taken together form a five membered ring.
  • the compound of Formula III is Compound 3, which is known by its chemical name (R)-l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro- 2-(l-hydroxy-2-methylprop e.
  • Compound 3 can be prepared by coupling an acid chloride moiety with an amine moiety according to Schemes 3-1 through 3-3.
  • Vitride® sodium bis(2-methoxyethoxy)aluminum hydride
  • NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 ], 65 wgt% solution in toluene) was purchased from Aldrich Chemicals.
  • the hydrogenator was charged with 5wt% Pt(S)/C (1.5 mol%) and the mixture was stirred under N 2 at 30 °C (internal temperature). The reaction was flushed with N 2 followed by hydrogen. The hydrogenator pressure was adjusted to 1 Bar of hydrogen and the mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite® and washed with dichloromethane (10 vol). The filtrate was concentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on a rotavap to dryness.
  • the aqueous phase (pH 9) was drained off and discarded. The remaining organic phase was washed with water (2 L, 2 vol). The organic phase was concentrated in vacuo using a 22 L rotary evaporator, providing the crude product as an orange oil.
  • the phases were allowed to settle and then the aqueous phase (pH 10-11) was drained off and discarded.
  • the organic phase was washed with a solution of KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol).
  • the organic phase was then concentrated down using a rotary evaporator, yielding the title material as a yellow-orange oil. Typical purity of this material was in the 80% range with primarily a single impurity present.
  • Benzylglocolated 4-ammonium-2-bromo-5-flouroaniline tosylate salt was freebased by stirring the solid in EtOAc (5 vol) and saturated NaHC0 3 solution (5 vol) until a clear organic layer was achieved. The resulting layers were separated and the organic layer was washed with saturated NaHC0 3 solution (5 vol) followed by brine and concentrated in vacuo to obtain benzylglocolated 4-ammonium-2- bromo-5-flouroaniline tosylate salt as an oil.
  • Deloxan-II® THP (5 wt% based on the theoretical yield of iV43enzylglycolated-5-amino-2-(243enzyloxy-l, l-dimethylethyl)-6- fluoroindole) was added and stirred at room temperature overnight. The mixture was then filtered through a pad of silica (2.5 inch depth, 6 inch diameter filter) and washed with EtOAc (4 vol). The filtrate was concentrated down to a dark brown residue, and used as is in the next reaction.
  • a 20 L autoclave was flushed three times with nitrogen gas and then charged with palladium on carbon (Evonik E 101 NN/W, 5% Pd, 60% wet, 200 g, 0.075 mol, 0.04 equiv). The autoclave was then flushed with nitrogen three times.
  • a solution of crude benzyl protected Compound 3 (1.3 kg, about 1.9 mol) in THF (8 L, 6 vol) was added to the autoclave via suction.
  • the vessel was capped and then flushed three times with nitrogen gas. With gentle stirring, the vessel was flushed three times with hydrogen gas, evacuating to atmosphere by diluting with nitrogen.
  • the autoclave was pressurized to 3 Bar with hydrogen and the agitation rate was increased to 800 rpm. Rapid hydrogen uptake was observed (dissolution). Once uptake subsided, the vessel was heated to 50 °C.
  • the thermostat was shut off at the end of every work-day.
  • the vessel was pressurized to 4 Bar with hydrogen and then isolated from the hydrogen tank.
  • reaction mixture was filtered through a Celite® pad.
  • the vessel and filter cake were washed with THF (2 L, 1.5 vol).
  • the Celite® pad was then wetted with water and the cake discarded appropriately.
  • the combined filtrate and THF wash were concentrated using a rotary evaporator yielding the crude product as a black oil, 1 kg.
  • the thermostat was set to 48 °C (below the boiling temp of the MTBE-methanol azeotrope, which is 52 °C).
  • the mixture was cooled to 20 °C over 2 h, during which time a relatively fast crystallization occurred.
  • heptane (20 mL, 0.05 vol) was added and the mixture was stirred overnight (16 h).
  • the mixture was filtered using a Buchner funnel and the filter cake was washed with 3:1 MTBE-heptane (800 mL, 2 vol).
  • the filter cake was air-dried for 1 h and then vacuum dried at ambient temperature for 16 h, furnishing 130 g of Compound 3 as an off-white solid.
  • Benzyl protected Compound 3 was dissolved and flushed with THF (3 vol) to remove any remaining residual solvent. Benzyl protected Compound 3 was redissolved in THF (4 vol) and added to the hydrogenator containing 5 wt% Pd/C (2.5 mol%, 60% wet, Degussa E5 E101 NN/W). The internal temperature of the reaction was adjusted to 50 °C, and flushed with N 2 (x5) followed by hydrogen (x3). The hydrogenator pressure was adjusted to 3 Bar of hydrogen and the mixture was stirred rapidly (>1100 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite® and washed with THF (1 vol).
  • Compound 3 may also be prepared by one of several synthetic routes disclosed in US published patent application US 2009/0131492, incorporated herein by reference.
  • Table 3-1 Physical Data for Compound 3.
  • the present invention is directed to pharmaceutical compositions comprising an CF modulator component as provided by Columns A-C in Table I and at least one ENaC inhibitor as provided in Column D of Table I.
  • the invention also provides methods for treating CF and other chronic diseases, methods for preparing the compositions and methods for using the compositions for the treatment of CF and other chronic diseases, including chronic diseases involving regulation of fluid volumes across epithelial membranes, using compositions containing an CF Modulator modulator compound and ENaC inhibitor compounds.
  • the ENaC inhibitors of Column D compounds can include ENaC inhibitors of Formula IV which are fully described and exemplified in International Patent Application No. PCT/EP2008/067110 filed: 12/152008 and is Assigned to Novartis AG. All of the compounds recited in PCT/EP2008/067110, are useful in the present invention and the compounds and methods for making such compounds are hereby incorporated into the present disclosure in their entirety.
  • ENaC inhibitors can also include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, aerolytic, amiloride, benzamil, dimethyl-amiloride, and ENaC inhibitor compounds disclosed in International Applications: PCT/EP2006/003387 filed October 19, 2006; PCT/EP2006/012314 filed June 28, 2007 and PCT/EP2006/012320 filed June 28, 2007. All of these International Patent Application disclosures are hereby incorporated by reference herein in their entireties.
  • the ENaC inhibitor is amiloride. Methods for determining whether a compound is an ENaC inhibitor are known in the art and can be used to identify an ENaC inhibitor that can be used in the combination with CF modulator component described herein. II.D.2 COMPOUNDS OF FORMULA IV
  • the invention provides ENaC inhibitor compounds according to Formula
  • R 1 is H, halogen, Ci-C 8 -alkyl, CiC 8 -haloalkyl, Ci-C 8 -haloalkoxy, C 3 Ci5-carbocyclic group, nitro, cyano, a C6-C15- membered aromatic carbocyclic group, or a Ci-C 8 -alkyl substituted by a C 6 -Ci 5 -membered aromatic carbocyclic group;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from H and C 1 -C6 alkyl;
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from H; S0 2 R 16 ; aryl optionally substituted by one or more Z groups; a C3-C 10 carbocyclic group optionally substituted by one or more Z groups; C 3 -C 14 heterocyclic group optionally substituted by one or more Z groups; Ci-C 8 alkyl optionally substituted by an aryl group which is optionally substituted by one or more Z groups, a C 3 -C 10 carbocyclic group optionally substituted by one or more Z groups or a C 3 -C 14 heterocyclic group optionally substituted by one or more Z groups; or is represented by the formula 2:
  • R 6 and R 7 together with the atoms to which they are attached form a 3- to 10- membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, and the heterocyclic group being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -C 10 carbocyclic group; a C 3 -C 14 heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2;
  • R 7 and R 8 together with the carbon atom to which they are attached form a 3- to 10- membered carbocyclic or a 3- to 10-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, and the carbocyclic and heterocyclic groups being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group; a C 3 -Ci heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2;
  • R 9 and R 10 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic or a 3- to 10-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, and the carbocyclic and heterocyclic groups being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group; a C 3 -Ci heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2;
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, and the carbocyclic and heterocyclic groups being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group; a C 3 -Ci 4 heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2;
  • R 10 and R 11 together with the atoms to which they are attached form a 3- to 10- membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, and the heterocyclic group being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group; a C 3 -Ci 4 heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2;
  • A is selected from a bond, -NR 13 (S0 2 )-, -(S0 2 )NR 13 -, -(S0 2 )-, -NR 13 C(0)-, -C(0)NR 13 -, -NR 13 C(0)NR 14 -, -NR 13 C(0)0-, -NR 13 -, C(0)0, OC(O), C(O), O and S;
  • B is selected from a bond, -(C 2 -C alkenyl group)-, -(C 2 -C alkynyl group)-, -NH-, aryl, O-aryl, NH-aryl, a C 3 -Ci carbocyclic group and a 3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, wherein the aryl, carbocyclic and heterocyclic groups are each optionally substituted by one or more Z groups;
  • X is selected from a bond, -NR 15 (S0 2 )-, -(S0 2 )NR 15 -, -(S0 2 )-, -NR 15 C(0)-, -C(0)NR 15 - , -NR 15 C(0)NR 17 -, -NR 15 C(0)0-, -NR 15 -, C(0)0, OC(O), C(O), O and S;
  • R 12 is selected from Ci-C 8 alkylene, Ci-C 8 alkenylene, -C 3 -C 8 cycloalkyl-, -Ci-C 8 alkylene-C 3 -C 8 cycloalkyl-, and -aryl-, wherein the alkylene, cycloalkyl and aryl groups are optionally substituted by one or more Z groups;
  • R 13 , R 14 , R 15 and R 17 are each independently selected from H and Ci-C6 alkyl;
  • R 16 is selected from Ci-C 8 alkyl, aryl and a 3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S;
  • Z is independently selected from OH, aryl, O-aryl, C 7 -Ci 4 aralkyl, O-C7-C 14 aralkyl, Ci- C 6 alkyl, d-C 6 alkoxy, NR 19 (S0 2 )R 21 , (S0 2 )NR 19 R 21 , (S0 2 )R 20 , NR 19 C(0)R 20 , C(0)NR 19 R 20 ,
  • R 18 and R 20 are each independently selected from H and C 1 -C6 alkyl
  • R 19 and R 21 are each independently selected from H; Ci-C 8 alkyl; C 3 -C 8 cycloalkyl; C 1 -C4 alkoxy-Ci-C 4 alkyl; (C 0 -C 4 alkyl)-aryl optionally substituted by one or more groups selected from C 1 -C6 alkyl, C 1 -C6 alkoxy and halogen; (C 0 -C 4 alkyl)- 3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C 1 -C6 alkyl and C(0)Ci-C6 alkyl; (C 0 -C 4 alkyl)-0-aryl optionally substituted by one or more groups selected from C 1 -C6 alkyl, C 1 -C6 alkoxy and halogen; and (C 0 -C4 alkyl)-0-
  • R 19 and R 20 together with the nitrogen atom to which they attached form a 5- to 10- membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(0) 2 -aryl; S(0) 2 -Ci-C6 alkyl; C 1 -C6 alkyl optionally substituted by one or more halogen atoms; C 1 -C6 alkoxy optionally substituted by one or more OH groups or C 1 -C4 alkoxy; and C(0)OCi-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C 1 -C6 alkyl, C 1 -C6 haloalkyl or C 1 -C6 alkoxy;
  • R 22 is selected from H, halogen, Ci-C 8 alkyl, Ci-C 8 alkoxy, aryl, O-aryl, S(O) 2 -aryl, S(0) 2 -Ci-C 6 alkyl, S(O) 2 NR 23 R 24 , NHS(0) 2 NR 23 R 24 , a C 3 -Ci 4 carbocyclic group, a 3-to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, and 0-(3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S), wherein the alkyl, aryl, carbocyclic and heterocyclic groups are each optionally substituted by one or more Z groups;
  • R 23 and R 24 are each independently selected from H, Ci-C 8 alkyl and C 3 -C 8 cycloalkyl; or
  • R 23 and R 24 together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic group, optionally including one or more further heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more Z groups;
  • q 0, 1, 2 or 3;
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from H; S0 2 R 16 ; aryl optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group optionally substituted by one or more Z groups; C 3 -Ci heterocyclic group optionally substituted by one or more Z groups; Ci-C 8 alkyl optionally substituted by an aryl group, a C 3 -Ci 0 carbocyclic group optionally substituted by one or more Z groups or a C 3 -Ci heterocyclic group optionally substituted by one or more Z groups; or is represented by the formula 2a:
  • R 7 and R 8 together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic or a 3- to 7-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, and the carbocyclic and heterocyclic groups being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group; a C 3 -Ci 4 heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2a;
  • R 9 and R 10 together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic or a 3- to 7-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, and the carbocyclic and heterocyclic groups being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group; a C 3 -Ci 4 heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2a;
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, and the carbocyclic and heterocyclic groups being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C 3 -Ci 0 carbocyclic group; a C 3 -Ci heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula (IV)2a;
  • A is selected from a bond, -NR 13 (S0 2 )-, -(S0 2 )NR 13 -, -(S0 2 )-, -NR 13 C(0)-, -(O)NR 13 , -NR 13 C(0)NR 14 -, -NR 13 C(0)0-, -NR 13 -, C(0)0, OC(O), C(O), O and S;
  • B is selected from a bond, aryl, a C 3 -Ci carbocyclic group and a C 3 -Ci heterocyclic group, wherein the ring systems are optionally substituted by one or more Z groups;
  • X is selected from a bond, -NR 15 (S0 2 )-, -(S0 2 )NR 15 -, -(S0 2 )-, -NR 15 C(0)-, -C(0)NR 15 - , -NR 15 C(0)NR 17 -, -NR 15 C(0)0-, -NR 15 -, C(0)0, OC(O), C(O), O and S;
  • R 12 is selected from H, Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, C C 8 alkyl- C 3 -C 8 cycloalkyl, C C 8 alkyl-aryl and aryl, wherein the alkyl, cycloalkyl and aryl groups are optionally substituted by one or more Z groups;
  • R 13 _ R 14 , R 15 and R 17 are each independently selected from H and Ci-C6 alkyl;
  • R 16 is selected from Ci-C 8 alkyl, aryl and a 3- to 14-membered heterocyclic group; Z is independently selected from OH, aryl, O-aryl, C7-C14 aralkyl, 0-C 7 -Ci aralkyl, Ci-C6 alkyl, Ci-C6 alkoxy, NR 19 (S0 2 )R 21 , (S0 2 )NR 19 R 21 , (S0 2 )R 20 , NR 19 C(0)R 20 , C(0)NR 19 R 20, NR 19 C(O)NR 20 R 18 , NR 19 C(0)OR 20 , NR 19 R 21 C(0)OR 19 , C(0)R 19 , SR 19 , OR 19 , oxo, CN, N0 2 , and halogen, wherein the alkyl, alkoxy, aralkyl and aryl groups are each optionally substituted by one or more substituents selected from OH, halogen, Ci-C halo
  • R 18 , R 19 and R 20 are each independently selected from H and Ci-C6 alkyl;
  • R 21 is selected from Ci-C 8 alkyl, aryl and a 3- to 14-membered heterocyclic group
  • R 22 is selected from H and Ci-C 8 alkyl
  • n 0, 1 or 2;
  • p are each independently an integer from 0 to 6;
  • q 0, 1, 2 or 3;
  • R 6 is selected from
  • R 23 is H or Ci-C 6 alkyl
  • d is an integer from 1 to 5 (optionally 2 to 4).
  • R 7 is H or Ci-
  • R 8 is selected from H, Ci-C6 alkyl; (CH 2 ) e phenyl, where the phenyl group is optionally substituted by one or more groups selected from halo and OR 24 ; (CH 2 ) £ COOR 25 ; (CH 2 ) g OCi-C6 alkyl, where the alkyl group is optionally substituted by 1 to 3 groups selected from OH, C 1 -C3 alkyl and phenyl; and (CH 2 ) h NHC0 2 (CH 2 )iphenyl;
  • R 24 is H or C 1 -C6 alkyl, where the alkyl group is optionally substituted by 1 to 3 groups selected from OH and OC 1 -C3 alkyl;
  • R 25 is H or C 1 -C3 alkyl
  • e is 0, 1, 2, 3, 4 or 5 (optionally 0, 1, 2, 3 or 4);
  • f, g and h are each independently an integer from 1 to 4.
  • i 1 or 2;
  • R 7 and R 8 together with the carbon atom to which they attached form a 5- or 6- membered non-aromatic carbocyclic ring system or a 5- or 6- membered non-aromatic heterocyclic ring system containing one or more heteroatoms selected from N, O and S, the ring systems being optionally substituted by one or more Z groups; S0 2 R 16 ; C6-Ci5-aromatic carbocyclic group optionally substituted by one or more Z groups; a C3-C 10 carbocyclic group; a C3-C14 heterocyclic group optionally substituted by one or more Z groups; or a group represented by the formula 2 or 2a.
  • the ring system defined by R 7 , R 8 and the carbon to which they are attached is optionally substituted by C 1 -C3 alkyl, halo or benzyl.
  • f is 2 or 3.
  • g may be 2 or 3.
  • h may be 2, 3 or 4.
  • i may be 1.
  • each sub-definition may be combined with more other sub-definitions or they may be combined with the definitions for the relevant variables given above.
  • R 9 is H, C 1 -C6 alkyl or phenyl
  • R 8 and R 9 together with the carbon atoms to which they attached form a 5-, 6- or 7-membered non-aromatic carbocyclic ring system or a 5-, 6- or 7- membered non-aromatic heterocyclic ring system containing one or more heteroatoms selected from N, O and S, the ring systems being optionally substituted by C 1 -C3 alkyl, halo or benzyl.
  • R 11 is H, S0 2 Ci-C6 alkyl or S0 2 phenyl.
  • R 6 and R 11 are both
  • a further embodiment of the invention provides a compound according to the formula
  • R is -A-(C 0 -C 6 alkylene)-B-(X-R 12 ) q -R 22 and A, B, X, R 12 , q and R 22 are as defined anywhere herein.
  • Optionally substituted means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
  • Halo or "halogen”, as used herein, may be fluorine, chlorine, bromine or iodine.
  • Ci-Cs-Alkyl denotes straight chain or branched alkyl having 1-8 carbon atoms. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • Ci-C 8 -Alkoxy denotes straight chain or branched alkoxy having 1-8 carbon atoms. If a different number of carbon atoms is specified, such as Ce or C 3 , then the definition is to be amended accordingly.
  • alkylene denotes a straight chain or branched saturated hydrocarbon chain containing between 1 and 8 carbon atoms. If a different number of carbon atoms is specified, such as Ce or C 3 , then the definition is to be amended accordingly.
  • amino-Ci-Cs-alkyl and "amino-Ci-C 8 -alkoxy” denote amino attached by a nitrogen atom to Ci-C 8 -alkyl, e.g., NH 2 -(C C 8 )-, or to C C 8 -alkoxy, e.g., NH 2 -(C C 8 )-0-. If a different number of carbon atoms is specified, such as Ce or C 3 , then the definition is to be amended accordingly.
  • Ci-C 8 -Alkylamino and di(Ci-C 8 -alkyl)amino denote C C 8 -alkyl, as hereinbefore defined, attached by a carbon atom to an amino group.
  • the Ci-C 8 -alkyl groups in di(Ci-C 8 -alkyl)amino may be the same or different. If a different number of carbon atoms is specified, such as Ce or C 3 , then the definition is to be amended accordingly.
  • Amino-(hydroxy)-Ci-C 8 -alkyl denotes amino attached by a nitrogen atom to Ci-C 8 - alkyl and hydroxy attached by an oxygen atom to the same Ci-C 8 -alkyl. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • C 3 -C 8 -Cycloalkylcarbonyl denotes C 3 -C 8 -cycloalkyl, as hereinbefore defined, attached by a carbon atom to a carbonyl group. If a different number of carbon atoms is specified, such as C6 or C 3 , then the definition is to be amended accordingly.
  • C 7 -Ci 4 -Aralkyl denotes alkyl, e.g., Ci-C 4 -alkyl, as hereinbefore defined, substituted by a C6-Ci 0 -aromatic carbocyclic group, as herein defined. If a different number of carbon atoms is specified, such as C6 or C 3 , then the definition is to be amended accordingly.
  • C 3 -Ci5-Carbocyclic group denotes a carbocyclic group having 3- to
  • C 3 - Ci5-carbocyclic groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group, such as bicyclooctyl, bicyclononyl including indanyl and indenyl and bicyclodecyl. If a different number of carbon atoms is specified, such as C6, then the definition is to be amended accordingly.
  • aryl or "C 6 -Ci 5 -Aromatic carbocyclic group", as used herein, denotes an aromatic group having 6- to 15-ring carbon atoms.
  • C6-Ci5-aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, benzenetriyl, naphthyl, naphthylene, naphthalenetriyl or anthrylene. If a different number of carbon atoms is specified, such as Ci 0 , then the definition is to be amended accordingly.
  • 10-membered heterocyclic group refers, respectively, to 4- to 8- membered, 5- to 6-membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered and 5- to 14- membered heterocyclic rings containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, which may be saturated, partially saturated or unsaturated (aromatic).
  • the heterocyclic group includes single ring groups, fused ring groups and bridged groups.
  • heterocyclic groups include, but are not limited to, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, triazine, oxazine, tetrahyrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4- oxathiane, indazole, quinoline, indazole, indole, 8-aza-bicyclo[3.2.1]octane or thiazole.
  • a second aspect of the present invention provides for the use of a compound of formula
  • An embodiment of the present invention provides for the use of a compound of formula
  • the compounds represented by formula (IV) may be capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula (IV) include those of inorganic acids, e.g., hydrohalic acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, e.g., aliphatic monocarboxylic acids, such as formic acid, acetic acid, trifluoro acetic acid, propionic acid and butyric acid; aliphatic hydroxy acids, such as lactic acid, citric acid, tartaric acid or malic acid; dicarboxylic acids, such as maleic acid or succinic acid; aromatic carboxylic acids, such as benzoic acid, j-chlorobenzoic acid, diphenylacetic acid, para-biphenyl benzoic acid or triphenylacetic acid; aromatic hydroxy
  • Compounds of formula (IV) which may contain acidic, e.g., carboxyl, groups, are also capable of forming salts with bases, in particular, pharmaceutically acceptable bases, such as those well- known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts; or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases, such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula (IV) by known salt-forming procedures.
  • Stereoisomers are those compounds where there is an asymmetric carbon atom.
  • the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g., as diastereomeric mixtures.
  • the present invention embraces both individual optically active R and S isomers, as well as mixtures thereof.
  • Individual isomers can be separated by methods well-known to those skilled in the art, e.g., chiral high performance liquid chromatography (HPLC).
  • Tautomers are one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
  • compounds of Formula la where R 6 and/or R 11 are hydrogen may exist in one or both of the following tautomeric forms:
  • Examples of tautomers include but are not limited to those compounds defined in the claims.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol.
  • solvent molecules e.g., ethanol.
  • hydrate is employed when said solvent is water.
  • intermediate 1 can be reacted with intermediate 2 in an organic solvent to provide compound 3 which can be isolated as the free base.
  • the free base can then be converted to a salt form by treatment with an appropriate acid.
  • CR 9 R 10 n is 0; and R 7 , R 8 , R 9 and R 10 are also as defined above.
  • n is 1 or 2
  • R 7 , R 8 , R 9 and R 10 are also as defined above.
  • n is 1 or 2
  • the appropriate methylene or ethylene linking groups are inserted between X and Y in the diamine reactant 2.
  • Compounds of formula (IV), in free form, may be converted into salt form, and vice versa, in a conventional manners understood by those skilled in the art.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization.
  • Compounds of formula (IV) can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as stereoisomers, may be obtained in a conventional manner, e.g., by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g., optically active, starting materials.
  • the compounds of formula (IV) can be prepared, e.g., using the reactions and techniques described below and in the Examples.
  • the reactions may be performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • compounds of formula (IV), in free or pharmaceutically acceptable salt form hereinafter alternately referred to as "agents of the invention", in combination with an CF Modulator modulator of Columns A, B, or C are useful in the treatment of conditions which respond to the blockade of the epithelial sodium channel, particularly conditions benefiting from mucosal hydration.
  • Diseases mediated by blockade of the epithelial sodium channel include diseases associated with the regulation of fluid volumes across epithelial membranes.
  • the volume of airway surface liquid is a key regulator of mucociliary clearance and the maintenance of lung health.
  • the blockade of the epithelial sodium channel will promote fluid accumulation on the mucosal side of the airway epithelium thereby promoting mucus clearance and preventing the accumulation of mucus and sputum in respiratory tissues (including lung airways).
  • Such diseases include respiratory diseases, such as cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, respiratory tract infections (acute and chronic; viral and bacterial) and lung carcinoma.
  • Diseases mediated by blockade of the epithelial sodium channel also include diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye).
  • blockade of the epithelial sodium channel in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
  • Treatment in accordance with the invention may be symptomatic or prophylactic.
  • Asthma includes both intrinsic (non- allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez-infant syndrome".)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs, e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory. Prophylactic benefit in asthma may, in particular, be apparent in subjects prone to "morning dipping".
  • “Morning dipping” is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4-6 am, i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular, other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • the agents of the invention may also be useful as acid-sensing ion channel (ASIC) blockers. Thus they may be useful in the treatment of conditions which respond to the blockade of the acid-sensing ion channel.
  • ASIC acid-sensing ion channel
  • the suitability of epithelial sodium channel blocker as a treatment of a disease benefiting from mucosal hydration may be tested by determining the inhibitory effect of the channel blocker on ENaC in a suitable cell-based assay.
  • ENaC a suitable cell-based assay.
  • single cells or confluent epithelia endogenously expressing or engineered to over express ENaC can be used to assess channel function using electrophysiological techniques or ion flux studies. See methods described in: Hirsh et al., J Pharm Exp Ther (2004); Moody et al, Am J Physiol Cell Physiol (2005).
  • Epithelial sodium channel blockers including the compounds of formula (IV), are also useful as co-therapeutic agents for use in combination with other drug substances, such as antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of cystic fibrosis or obstructive or inflammatory airways diseases such as those mentioned hereinbefore, e.g., as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • drug substances such as antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of cystic fibrosis or obstructive or inflammatory airways diseases such as those mentioned hereinbefore, e.g., as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • the epithelial sodium channel blocker may be mixed with the CF Modulator active agent in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes as a further aspect a combination of ENaC inhibitor and an CF Modulator modulator selected from at least one of Columns A, B, or C, optionally, with osmotic agents (hypertonic saline, dextran, mannitol, Xylitol) + modifiers of CFTR function, both wild- type and mutant (correctors + potentiators), e.g., those described in WO 2007/021982, WO 2006/099256, WO 2006/127588, WO 2004/080972, WO 2005/026137, WO 2005/035514, WO 2005/075435, WO 2004/111014, WO 2006/101740, WO 2004/110352, WO 2005/120497 and US 2005/0176761, an antiinflammatory, bronchodilatory, antihistamine, anti-tussive, antibiotic or DNase drug substance, said epithelial sodium channel blocker and said drug substance being in the same or different pharmaceutical
  • Suitable antibiotics include macrolide antibiotics, e.g., tobramycin ( ⁇ TM).
  • Suitable DNase drug substances include dornase alfa (PulmozymeTM), a highly-purified solution of recombinant human deoxyribonuclease I (rhDNase), which selectively cleaves DNA.
  • rhDNase a highly-purified solution of recombinant human deoxyribonuclease I
  • Dornase alfa is used to treat cystic fibrosis.
  • ENaC inhibitors and CF Modulator modulator selected from at least one of Columns A, B, or C include combinations with anti-inflammatory drugs, e.g. those with antagonists of chemokine receptors, e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as iV-[[4-[[[[6,7-dihydro-2-(4-methyl-phenyl)-5/f-benzo-cyclohepten-8- yl]carbonyl]amino]phenyl]-methyl]tetrahydro-iV, iV-dimethyl-2/f-pyran-4-a
  • Suitable anti-inflammatory drugs include steroids, in particular, glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; nonsteroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, USP 3,714,357, USP 5,171,744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO 04/05285.
  • anticholinergic or antimuscarinic agents in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, USP 3,714,357, USP 5,171,744, WO 01/04118, WO 02/0065
  • Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist/muscarinic antagonists such as those disclosed in USP 2004/0167167, WO 04/74246 and WO 04/74812.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine, as well as those disclosed in JP 2004107299, WO 03/099807 and WO 04/026841.
  • the invention also provides as a further aspect a method for the treatment of a condition responsive to blockade of the epithelial sodium channel, e.g., diseases associated with the regulation of fluid volumes across epithelial membranes, particularly an obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula (IV), in free form or in the form of a pharmaceutically acceptable salt.
  • a condition responsive to blockade of the epithelial sodium channel e.g., diseases associated with the regulation of fluid volumes across epithelial membranes, particularly an obstructive airways disease
  • the invention provides a compound of formula (IV), in free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition responsive to blockade of the epithelial sodium channel, particularly an obstructive airways disease, e.g., cystic fibrosis and COPD.
  • a condition responsive to blockade of the epithelial sodium channel particularly an obstructive airways disease, e.g., cystic fibrosis and COPD.
  • the agents of the invention may be administered by any appropriate route, e.g. orally, e.g., in the form of a tablet or capsule; parenterally, e.g., intravenously; by inhalation, e.g., in the treatment of an obstructive airways disease; intranasally, e.g., in the treatment of allergic rhinitis;
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (IV), in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier.
  • the composition may contain a co-therapeutic agent, such as an anti-inflammatory, broncho-dilatory, antihistamine or anti-tussive drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g., patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, e.g., a hydro-fluoro-alkane (HFA) propellant, such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art, such as ethanol (up to 20% by weight), and/or one or more surfactants, such as oleic acid or sorbitan trioleate, and/or one or more bulking agents, such as lactose.
  • HFA hydro-fluoro-alkane
  • the composition comprises a dry powder formulation, it preferably contains, e.g., the compound of formula (IV) having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, e.g., magnesium stearate.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation, it preferably contains, e.g., the compound of formula (IV) either dissolved, or suspended, in a vehicle containing water, a co-solvent, such as ethanol or propylene glycol and a stabilizer, which may be a surfactant.
  • a compound of formula (IV) in inhalable form e.g., in an aerosol or other atomisable composition or in inhalable particulate, e.g., micronised form;
  • an inhalable medicament comprising a compound of formula (IV) in inhalable form
  • a pharmaceutical product comprising a compound of formula (IV) in inhalable form in association with an inhalation device
  • an inhalation device containing a compound of formula IV in inhalable form.
  • Dosages of compounds of formula (IV) employed in practicing the present invention will of course vary depending, e.g., on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.005-10 mg, while for oral administration suitable daily doses are of the order of 0.05-100 mg.
  • compositions of formula (IV) and their pharmaceutically acceptable salts are useful as pharmaceuticals.
  • the compounds have good ENaC blocker activity and may be tested in the following assays.
  • HBECs Human Bronchial Epithelial cells
  • HBECs were cultured using a modification of the method described by Gray and colleagues (Gray et al., 1996). Cells were seeded in plastic T-162 flasks and were grown in bronchial epithelial cell growth medium (BEGM; Cambrex) supplemented with bovine pituitary extract (52
  • BEGM bronchial epithelial cell growth medium
  • BEGM bronchial epithelial cell growth medium
  • BEGM bron
  • Amphotericin B was removed from all media 3 feeds prior to use in the Ussing Chambers. Cells were used between days 7 and 21 after establishment of the apical-air interface. At all stages of culture, cells were maintained at 37°C in 5% C0 2 in an air incubator.
  • ISC Short circuit current
  • Snapwell inserts were mounted in Vertical Diffusion Chambers (Costar) and were bathed with continuously gassed Ringer solution (5% C0 2 in 0 2 ; pH 7.4) maintained at 37°C containing (in mM): 120 NaCl, 25 NaHC0 3 , 3.3 KH 2 P0 4 , 0.8 K 2 HP0 4 , 1.2 CaCl 2 , 1.2 MgCl 2 , and 10 glucose.
  • the solution osmolarity was between 280 and 300 mOsmol/kg H 2 0 for all physiological salt solutions used.
  • Cells were voltage clamped to 0 mV (model EVC4000; WPI).
  • RT was measured by applying a 1- or 2- mV pulse at 30-s intervals and calculating RT by Ohm's law. Data were recorded using a PowerLab workstation (AD Instruments).
  • Test compounds were prepared as a 10 mM stock solution in DMSO (95%). Serial 3-fold dilutions were freshly prepared in an appropriate vehicle (distilled H 2 0 or Ringers solution). The initial concentration was added to the apical chamber as a lOOOx concentrate in 5 ⁇ , resulting in a final lx concentration the 5 mL volume of the Ussing chamber. Subsequent additions of compound were added in a 3.3 ⁇ volume of the lOOOx serially diluted stock solution. At the completion of the concentration- response experiment, amiloride (10 ⁇ ) was added into the apical chamber to enable the total amiloride- sensitive current to be measured. An amiloride control IC 50 was established at the start of each experiment.
  • Results are expressed as the mean % inhibition of the amiloride-sensitive ISC.
  • Concentration-response curves were plotted and IC 50 values generated using GraphPad Prism 3.02. Cell inserts were typically run in duplicate and the IC 50 calculated on the mean % inhibition data.
  • Formula IV (b) are shown in Table ILD-2. Methods for preparing such compounds are described hereinafter. The table also shows mass spectrometry [M+H] + data.
  • LCMS are recorded using a Phenomenex Gemini 50 mm x 3.0 mm, 3um column.
  • Low pH methods use a gradient of 5-95% acetonitrile in water -0.1 % TFA, high pH methods use 5-95% acetonitrile in water -0.1% NH 3 .
  • [M+H] + refer to monoisotopic molecular weights.
  • PEAX PE-anion exchange e.g. Isolute® PE-AX columns from Biotage
  • SCX-2 strong cation exchange e.g. Isolute® SCX-2 columns from Biotage
  • Examples 2, 9, and 10 are racemic mixtures.
  • Examples 4 ,13 and 29 are mixtures of diastereomers.
  • Examples 24 and 25 are single enantiomers wherein the stereochemistry of the unassigned stereocentre is not determined. All other examples are single enantiomers of defined stereochemistry.
  • the compounds are recovered from reaction mixtures and purified using conventional techniques such as flash chromatography, filtration, recrystallisation and trituration.
  • This compound is prepared analogously to Example 1 by replacing l,2-diamino-2- methylpropane with N 1 -[4-(4-methoxy-phenyl)-butyl]-ethane-l,2-diamine (Intermediate C); [M+H] + 418.
  • This compound is prepared analogously to Example 1 by replacing l,2-diamino-2- methylpropane with 4,5-Diaminopentanoic acid dihydro chloride (Intermediate F); [M+H] + 328.

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