WO2012095781A1 - Dérivés d'indazole comme inhibiteurs des canaux sodiques - Google Patents

Dérivés d'indazole comme inhibiteurs des canaux sodiques Download PDF

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WO2012095781A1
WO2012095781A1 PCT/IB2012/050102 IB2012050102W WO2012095781A1 WO 2012095781 A1 WO2012095781 A1 WO 2012095781A1 IB 2012050102 W IB2012050102 W IB 2012050102W WO 2012095781 A1 WO2012095781 A1 WO 2012095781A1
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methyl
indazole
carboxamide
methylsulfonyl
chloro
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PCT/IB2012/050102
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English (en)
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Andrew Simon Bell
Marcel John De Groot
Russell Andrew Lewthwaite
Ian Roger Marsh
Nunzio Sciammetta
Robert Ian Storer
Nigel Alan Swain
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Pfizer Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the invention relates to acyl sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
  • Voltage-gated sodium channels are found in all excitable cells including myocytes of muscle and neurons of the central and peripheral nervous system. In neuronal cells, sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper and appropriate function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (see Hubner CA, Jentsch TJ, Hum. Mol. Genet, 11 (20): 2435-45 (2002) for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et ai, Curr.
  • VGSC voltage-gated sodium channel
  • the VGSC family has been phylogenetically divided into two subfamilies Na v 1.x (all but SCN6A) and Na v 2.x (SCN6A).
  • the Navl .x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX- sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX- resistant or TTX-r).
  • the Na v 1 .7 (PN 1 , SCN9A) VGSC is sensitive to blocking by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons.
  • the SCN9A gene has been cloned from a number of species, including human, rat, and rabbit and shows -90 % amino acid identity between the human and rat genes (Toledo-Aral et ai, Proc. Natl. Acad. Sci. USA, 94(4): 1527-1532 (1997)).
  • An increasing body of evidence suggests that Na v 1 .7 may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain.
  • Na v 1 .7 protein has been shown to accumulate in neuromas, particularly painful neuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144(8): 803-10 (2002)).
  • Gain of function mutations of Na v 1 .7, both familial and sporadic, have been linked to primary erythermalgia, a disease characterized by burning pain and inflammation of the extremities (Yang et al., J.
  • Nav 1 .7 inhibitors are therefore potentially useful in the treatment of a wide range of disorders, particularly pain, including: acute pain; chronic pain; neuropathic pain; inflammatory pain; visceral pain; nociceptive pain including post-surgical pain; and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.
  • WO-A-2005/013914 discloses heteroarylamino sulfonylphenyl derivatives, WO-A-2008/1 18758 aryl sulphonamides and WO-A-2009/012242 N-thiazolyl benzenesulfonamides.
  • compounds are selective Nav1 .7 channel inhibitors.
  • they should show an affinity for the Nav1 .7 channel which is greater than their affinity for Nav1 .5 channels.
  • compounds should show little or no affinity for the Nav1 .5 channel.
  • Selectivity for the Nav1 .7 channel over Nav1 .5 may potentially lead to one or more improvements in side-effect profile. Without wishing to be bound by theory, such selectivity is thought to reduce any cardiovascular side effects which may be associated with affinity for the Nav1 .5 channel.
  • Preferably compounds demonstrate a selectivity of 10-fold, more preferably 30-fold, most preferably 100-fold, for the Nav 1 .7 channel when compared to their selectivity for the Nav1 .5 channel whilst maintaining good potency for the Nav1 .7 channel.
  • preferred compounds should have one or more of the following properties: be well absorbed from the gastrointestinal tract; be metabolically stable; have a good metabolic profile, in particular with respect to the toxicity or allergenicity of any metabolites formed; or possess favourable pharmacokinetic properties whilst still retaining their activity profile as Nav1 .7 channel inhibitors. They should be non-toxic and demonstrate few side-effects. Ideal drug candidates should exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • R° and U are independently H or F
  • V is (Ci-C 4 )alkyl, optionally substituted by one to three F;
  • W is H, (C C 4 )alkyl or (C 3 -C 4 )cycloalkyl;
  • X is O or NR 2 or is absent
  • Y is H, F or CI
  • R 1 and R 2 are independently H; (Ci-C8)alkyl optionally substituted by one to three atoms or groups selected from F, (C3-C8)cycloalkyl, (CrC6)alkyloxy, phenyl optionally substituted by F, or Het; Het; or (C3-C8)cycloalkyl; wherein (C3-C8)cycloalkyl may be optionally fused to a phenyl ring or may be substituted by one to three atoms or groups selected from F, (d-C6)alkyl optionally substituted by one to three F, or (CrC6)alkyloxy; or
  • R 1 and R 2 are attached to the same nitrogen atom they may, together with that nitrogen, form: (i) a saturated, monocyclic, 4 to 7-membered ring which may optionally contain oxygen as an additional ring member or may optionally be fused to a phenyl ring, which 4 to 7-membered ring may also optionally be substituted with one to three atoms or groups selected from halo, (CrC6)alkyl, (CrC 4 )alkyloxy(Co-C 4 )alkylene or (C3-C8)cycloalkyl; or (ii) a saturated, bridged, 7 to 9-membered ring; and
  • Het is 'C-linked', 3- to 8-membered, saturated, monoheterocycloalkyi comprising one or two ring members selected from -NH- or -0-.
  • E1 A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.
  • E4 A compound according to E1 wherein X is absent.
  • E5 A compound according to any one of E1 to E4 wherein U is H.
  • E6 A compound according to any one of E1 to E4 wherein U is F.
  • E7 A compound according to any one of E1 to E6 wherein V is (C-
  • E8 A compound according to any one of E1 to E7 wherein W is (CrC 4 )alkyl, such as methyl.
  • E9 A compound according to any one of E1 to E8 wherein Y is CI.
  • E1 1 A compound according to any one of E1 to E10 wherein R 1 is (CrC8)alkyl optionally substituted by a (C3-C8)cycloalkyl group; or (C3-C8)cycloalkyl; wherein
  • (C3-C8)cycloalkyl is optionally substituted by a (d-C6)alkyl group.
  • E12 A compound according to any one of E1 to E1 1 wherein R 1 is (CrC 4 )alkyl optionally substituted by a (C3-C5)cycloalkyl group; or (C3-C5)cycloalkyl; wherein (C3-C5)cycloalkyl is optionally substituted by a (CrC3)alkyl group.
  • Alkyl, alkylene, and alkoxy groups containing the requisite number of carbon atoms, can be unbranched or branched.
  • alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.
  • alkylene include methylene, 1 , 1 -ethylene, 1 , 2-ethylene, 1 , 1 -propylene, 1 , 2-propylene, 1 , 3-propylene and 2, 2-propylene.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Halo means fluoro, chloro, bromo or iodo.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the skilled person will appreciate that the aforementioned salts include ones wherein the counterion is optically active, for example d-lactate or l-lysine, or racemic, for example dl-tartrate or dl-arginine.
  • compositions of formula (I) may be prepared by one or more of three methods:
  • 'hydrate' is employed when said solvent is water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone and de-DMSO.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid.
  • Such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks.
  • Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • multi-component complexes other than salts and solvates of compounds of formula (I) or pharmaceutically acceptable salts thereof wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts.
  • Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, XT., 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference.
  • Chem Commun, XT., 1889-1896 by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference.
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
  • the compounds of the invention may be administered as prodrugs.
  • prodrugs certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in a compound of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
  • prodrugs examples include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert-butyl) phosphate prodrugs. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
  • metabolites of compounds of formula (I) that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include, where the compound of formula (I) contains a phenyl (Ph) moiety, a phenol derivative thereof (-Ph > -PhOH);
  • Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Included within the scope of the invention are all stereoisomers of the compounds of the invention and mixtures of one or more thereof.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1 - phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1 - phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • Stereoisomers may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994.
  • the scope of the invention includes all crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomerates) thereof.
  • Stereoisomeric conglomerates may also be separated by the conventional techniques described herein just above.
  • the scope of the invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Certain isotopically-labelled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I).
  • the invention includes all polymorphs of the aforementioned species and crystal habits thereof.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure.
  • the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either.
  • the skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of formula (I). It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
  • the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions.
  • the protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fourth edition, (John Wiley and Sons, 2006), in particular chapter 7 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.
  • R is alkyl, such as (Cr Ce)alkyl (e.g. methyl) or, when part of the moiety -B(OR) 2 , may also be H or each R, together with the O atom to which it is attached, forms a cyclic boronic ester moiety, such as
  • Compounds of formula (IV) may be prepared by reaction of a compound of formula (II) with a boronic acid or ester of formula (III).
  • the reaction is typically carried out in an inert solvent or mixture of inert solvents (e.g. one or more of dimethyl sulphoxide, dimethylformamide, dichloromethane), in the presence of a base (e.g. pyridine, triethylamine), a copper salt (e.g. copper acetate), at a temperature ranging from ambient to elevated and in the presence of air or oxygen.
  • a base e.g. pyridine, triethylamine
  • a copper salt e.g. copper acetate
  • molecular sieves may be added to the reaction mixture and the reaction may be accelerated by heating using microwave irradiation.
  • the reaction is carried out open to air in dimethylformamide in the presence of copper acetate and pyridine at 50-80°C.
  • compounds of formula (I) may be prepared as shown in Scheme 2 by reaction of a compound of formula (II) with a boronic acid or ester of formula (VI) in an analogous manner to that described for the preparation of compounds of formula (IV) in Scheme 1.
  • Scheme 2
  • the reaction is carried out neat or in a suitable inert solvent or mixture of solvents (e.g. dimethyl sulphoxide and/or dimethylformamide) in the presence of a base (e.g. potassium carbonate, cesium carbonate, sodium hydride) and at elevated temperature.
  • a base e.g. potassium carbonate, cesium carbonate, sodium hydride
  • a metal salt e.g. copper (I) iodide
  • heating of the reaction mixture may be carried out using microwave irradiation.
  • the reaction is carried out in dimethyl sulphoxide at 150°C.
  • reaction is carried out in a suitable inert solvent or mixture of inert solvents (e.g. dichloromethane and/or dimethylformamide), in the presence of a base (e.g. 4-dimethylaminopyridine, ⁇ , ⁇ -diisopropylethylamine) and a suitable coupling agent (e.g 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
  • a base e.g. 4-dimethylaminopyridine, ⁇ , ⁇ -diisopropylethylamine
  • a suitable coupling agent e.g 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Compounds of formula (IX) may be prepared by saponification of a solution of a compound of formula (XI) in a suitable solvent or mixture of solvents (e.g. one or more of tetrahydrofuran, methanol, water, dichloromethane), in the presence of a base (e.g. sodium hydroxide, lithium hydroxide, potassium hydroxide) and at ambient to elevated temperature.
  • a base e.g. sodium hydroxide, lithium hydroxide, potassium hydroxide
  • the reaction is carried out in a mixture of tetrahydrofuran, methanol and water in the presence of lithium hydroxide at reflux.
  • Compounds of formula (XI) may be prepared by reaction of a compound of formula (XII) with a boronic acid or ester of formula (VI) in an analogous manner to that described for the preparation of compounds of formula (IV) in Scheme 1.
  • compounds of formula (I) wherein X is O and Y is H or CI may be prepared as shown in Scheme 5 by reaction of a compound of formula (IX) with a compound of formula (X) in an analogous manner to that described for the preparation of compounds of formula (I) in Scheme 4.
  • Compounds of formula (IX) may be prepared from compounds of formula (XI) in a manner also analogous to that described in Scheme 4.
  • Compounds of formula (XI) may be prepared by reaction of an alcohol of formula (V) with a compound of formula (XIII).
  • the reaction is typically carried out in an inert solvent (e.g. dimethyl sulphoxide, tetrahydrofuran, dimethylformamide), in the presence of a base (e.g. sodium hydride, lithium bis(trimethylsilyl)amide, cesium carbonate, potassium carbonate) and at an elevated temperature for a period of 2 to 72 hours.
  • a mixture of the alcohol of formula (V), compound of formula (XIII) and potassium carbonate in dimethylformamide is heated at 70°C for 16 hours.
  • Compounds of formula (XI) may be prepared by reaction of a compound of formula (XII) with an aryl halide of formula (XIV) in the presence of a copper salt, ligand and base, in a solvent.
  • the reaction is carried out in the presence of copper (I) iodide, potassium phosphate tribasic and trans-N,N'-dimethylcyclohexane-1 ,2- diamine, in toluene, at 1 10°C.
  • compounds of formula (I) may be prepared as shown in Scheme 7 by reaction of a compound of formula (XVI) with a boronic acid or ester of formula (XVII), wherein W is as defined in formula (I) or is an unsaturated or partially unsaturated precursor thereof.
  • the reaction is typically carried out in a suitable inert solvent or mixture of inert solvents (e.g. one or more of dimethoxyethane, toluene, dimethylformamide, dioxane, water), in the presence of a base (e.g. cesium carbonate, potassium carbonate, potassium phoshate) and a catalyst (e.g. palladium tetrakis, [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane), and at a temperature ranging from ambient to elevated.
  • a suitable inert solvent or mixture of inert solvents e.g. one or more of dimethoxyethane, toluene, dimethylformamide, dioxane, water
  • a base e.g. cesium carbonate, potassium carbonate, potassium phoshate
  • a catalyst e.g. palladium tetraki
  • the reaction is carried out in a mixture of dioxane/water, in the presence of cesium carbonate and palladium tetrakis, and at 100°C.
  • substituent W is an unsaturated or partially unsaturated precursor of the desired alkyl moiety, it may be reduced to give the saturated alkyl analogue using an appropriate method. In a preferred method the reduction is carried out in ethanol as solvent by the action of triethyl silane and palladium on carbon as a catalyst.
  • Compounds of formula (XVI) may be prepared by reaction of a compound of formula (XV) with a compound of formula (X) in an analogous manner to that described for the preparation of compounds of formula (I) in Scheme 4.
  • Compounds of formula (XV) may be prepared by saponification of a compound of formula (XVIII) in an analogous manner to that described for the preparation of compounds of formula (IX) in Scheme 4.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • the term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable excipients.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
  • Suitable modes of administration include oral, parenteral, topical, inhaled/intranasal, rectal/intravaginal, and ocular/aural administration.
  • Formulations suitable for the aforementioned modes of administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V_ (6). 981-986, by Liang and Chen (2001 ).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1 -14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(dl-lactic-coglycolic)acid
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • compositions of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3- heptafluoropropane.
  • a suitable propellant such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ to 10 ⁇ .
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from ⁇ g to 100mg of the compound of formula (I).
  • the overall daily dose will typically be in the range ⁇ g to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in I nternational Patent Applications Nos. WO 91/1 1 172, WO 94/02518 and WO 98/55148.
  • the total daily dose of the compounds of the invention is typically in the range 1 mg to 10g, such as 10mg to 1 g, for example 25mg to 500mg depending, of course, on the mode of administration and efficacy.
  • oral administration may require a total daily dose of from 50mg to 100mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the compounds of the invention are useful because they exhibit pharmacological activity in animals, i.e., Nav1 .7 channel inhibition. More particularly, the compounds of the invention are of use in the treatment of disorders for which a Nav1 .7 inhibitor is indicated.
  • the animal is a mammal, more preferably a human.
  • a compound of the invention for use as a medicament.
  • a method of treating a disorder in an animal comprising administering to said animal a therapeutically effective amount of a compound of the invention.
  • Nav1 .7 inhibitor for which a Nav1 .7 inhibitor is indicated include pain, particularly neuropathic, nociceptive and inflammatory pain.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol. , 57, 1 -164 for a review).
  • These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
  • A-delta fibres myelinated
  • C fibres non-myelinated
  • the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated. Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain.
  • Acute pain does not generally result in any persistent psychological response.
  • chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems.
  • Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
  • Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1 ) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
  • Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141 -S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • Gl gastrointestinal
  • FBD functional bowel disorder
  • I BD inflammatory bowel disease
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (I BS) and functional abdominal pain syndrome (FAPS), and, in respect of I BD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.
  • Other types of pain include:
  • heart and vascular pain including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;
  • head pain such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders;
  • orofacial pain including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
  • a Nav1.7 inhibitor may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. Such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.
  • the compound of the invention may be administered simultaneously, sequentially or separately in combination with the other therapeutic agent or agents.
  • a Nav1.7 inhibitor of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, may be administered in combination with one or more agents selected from:
  • an alternative Nav1.7 channel modulator such as another compound of the present invention or a compound disclosed in WO 2009/012242; an alternative sodium channel modulator, such as a Nav1 .3 modulator (e.g. as disclosed in WO2008/1 18758); or a Nav1 .8 modulator (e.g. as disclosed in
  • WO 2008/135826 more particularly N-[6-Amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl]-1 -methyl-1 H-pyrazole-5-carboxamide);
  • an inhibitor of nerve growth factor signaling such as: an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagoinsist;
  • a compound which increases the levels of endocannabinoid such as a compound with fatty acid amid hydrolase inhibitory (FAAH) activity, in particular those disclosed in WO 2008/047229 (e.g. N-pyridazin-3-yl-4-(3- ⁇ [5-(trifluoromethyl)pyridine-2- yl]oxy ⁇ benzylidene)piperidene-1 -carboxamide);
  • FAAH fatty acid amid hydrolase inhibitory
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, ***e, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • NSAI D nonsteroidal antiinflammatory drug
  • NSAI D nonsteroidal antiinflammatory drug
  • diclofenac diflusinal, etodolac
  • fenbufen fenoprofen
  • flufenisal flurbiprofen
  • ibuprofen indomethacin
  • ketoprofen ketorolac
  • meclofenamic acid mefenamic acid
  • meloxicam nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac
  • NSAI D nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • an Hi antagonist having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
  • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g.
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido- 1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate;
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g.
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;
  • ⁇ a vanilloid receptor agonist e.g. resinferatoxin
  • antagonist e.g. capsazepine
  • a beta-adrenergic such as propranolol
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT-I B /-ID agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • eletriptan eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • a 5-HT 2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • a 5-HT 3 antagonist such as ondansetron
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1- methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12, 12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)- pyrazino[2',1 ':6, 1]-pyrido[3,4-b]indole-1 ,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1- f][1 ,2,4]triazin-4-one (vardenafil), 5-
  • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (1 a,3a,5a)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-
  • mGluRI metabotropic glutamate subtype 1 receptor
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
  • noradrenaline (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1 - iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1 -iminoethyl)-amino]ethyl]-4,4-dioxo- L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2- methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1 R,3S)-3-amino-4- hydroxy-1- (5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1 R,3S)-3-amino-4- hydroxy-1-(5-thiazo
  • an acetylcholinesterase inhibitor such as donepezil
  • a prostaglandin E 2 subtype 4 (EP4) antagonist such as / ⁇ /-[( ⁇ 2-[4-(2-ethyl-4,6- dimethyl-1 H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl ⁇ amino)-carbonyl]-4- methylbenzenesulfonamide or 4-[(1 S)-1-( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl ⁇ amino)ethyl]benzoic acid;
  • microsomal prostaglandin E synthase type 1 (mPGES-1 ) inhibitor a microsomal prostaglandin E synthase type 1 (mPGES-1 ) inhibitor
  • a leukotriene B4 antagonist such as 1 -(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7- yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4- methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-1 1870;
  • a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3, 4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1 -methyl-2-quinolone (ZD-2138), or
  • a compound of the invention together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients.
  • Increasing the exposure in such a manner is known as boosting.
  • This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose.
  • the metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes.
  • agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes.
  • the isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP 3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2- ⁇ [(4- methoxypyridin-3-yl)amino]sulfonyl ⁇ benzamide and N-(1 -(2-(5-(4-fluorobenzyl)-3- (pyridin-4-yl)-1 H-pyrazol-1 -yl)acetyl)piperidin-4-yl)methanesulfonamide.
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the invention provides a pharmaceutical product (such as in the form of a kit) comprising a compound of the invention together with one or more additional therapeutically active agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a disorder for which a Nav1.7 inhibitor is indicated. It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
  • CS2CO3 means caesium carbonate
  • Cu(acac)2 means copper (II) acetylacetonate
  • Cul means copper (I) iodide
  • Cu(OAc) 2 means copper (II) acetate
  • DAD means diode array detector
  • DCM means dichloromethane; methylene chloride;
  • DIPEA N-ethyldiisopropylamine, N,N-diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • DMF means N,N-dimethylformamide
  • DMSO means dimethyl sulphoxide
  • EDTA means ethylenediaminetetraacetic acid
  • ELSD means evaporative light scattering detection
  • Et 2 0 means diethyl ether
  • HCI hydrochloric acid
  • lr 2 (OMe) 2 COD 2 means bis(1 ,5-cyclooctadiene)di ⁇ -methoxydiiridium (I)
  • K2CO3 means potassium carbonate;
  • KHS0 4 means potassium hydrogen sulphate
  • KOAc potassium acetate
  • KOH potassium hydroxide
  • K 3 P0 4 means potassium phosphate tribasic
  • LiOH means lithium hydroxide
  • MgS0 4 means magnesium sulphate
  • NaH means sodium hydride
  • NaHCC>3 sodium hydrogencarbonate
  • Na 2 C0 3 means sodium carbonate
  • NaHSC sodium bisulphite
  • NaHS0 4 sodium hydrogensulphate
  • NaOH sodium hydroxide
  • Na 2 S0 4 means sodium sulphate
  • Pd/C means palladium on carbon
  • Pd(PPh 3 ) 4 means palladium tetrakis
  • Pd(dppf) 2 CI 2 means [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane;
  • THF means tetrahydrofuran
  • THP means tetrahydropyran
  • TLC means thin layer chromatography
  • WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Mobile phase A 0.1 % formic acid in water
  • Mobile phase A 0.1 % formic acid in water
  • Mobile phase A 0.1 % formic acid in water
  • Mobile phase A 0.1 % formic acid in water
  • Mobile Phase A 0.0375% trifluoroacetic acid in water
  • mobile Phase B 0.01875% trifluoroacetic acid in acetonitrile
  • Mobile Phase A 0.0375% trifluoroacetic acid in water
  • mobile Phase B 0.01875% trifluoroacetic acid in acetonitrile
  • Mobile Phase A 0.0375% trifluoroacetic acid in water
  • mobile Phase B 0.01875% trifluoroacetic acid in acetonitrile
  • Mobile Phase A 0.05% ammonium hydroxide in water
  • mobile Phase B 100% acetonitrile
  • CS2CO3 (380mg, 1 .15mmol) was weighed into a reaction vial and a solution of 1 -(5- chloro-6-fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 7] (300mg, 0.55mmol) in DMSO (4ml) added followed by 1 - methylcyclopropylmethanol (473mg, 5.5mmol). The vial was capped and the mixture heated at 100°C for 16 hours. The mixture was added to an aqueous solution of KHS0 4 (30ml, 0.5M) and the resulting solid was collected by filtration, washed with water and dried by suction.
  • the alcohol of formula (V) was prepared as a 0.45M solution in DMSO and 500 ⁇ of solution (225 ⁇ , 3.0eq) was dispensed into the appropriate vial.
  • CS2CO3 225 ⁇ , 3.0eq was added to each vial and the vials were capped and shaken at 100°C for 18 hours.
  • the reaction mixtures were filtered and the filtrate evaporated using a vacuum centrifuge and the crude material purified by preparative HPLC to afford the compound of formula (I).
  • Tables 1 and 2 Examples prepared using, respectively, General Procedures 1 and 2 (wherein: 'P hplc' denotes Preparative HPLC Method, ⁇ hplc' denotes Analytical HPLC Method and ⁇ rt' denotes Analytical retention time (min)).
  • Example 59 1 -i5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N-imethylsulfonyl)-1 H- indazole-5-carboxamide
  • Example 62 1 -f5-chloro-6-fisobutyl(methyl)amino1pyridin-3-yl ⁇ -3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide
  • Example 63 1 -r5-chloro-6-(oxetan-3-ylmethoxy)pyridin-3-vn-3-cvclopropyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide
  • Table 3 Examples prepared using General Procedures 3, 4, 5 or 6, as indicated (wherein: 'GP' denotes General Procedure, 'P hplc' denotes Preparative HPLC Method, ⁇ hplc' denotes Analytical HPLC Method and ⁇ rt' denotes Analytical retention time (min)).
  • Table 4 Examples prepared using General Procedure 7 (wherein: 'P hplc' denotes Preparative HPLC Method, ⁇ hplc' denotes Analytical HPLC Method and ⁇ rt' denotes Analytical retention time (min)). Table 4
  • Example 149 1 -i5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N- trifluoro methyl )sulfonyl1-1 H-indazole-5-carboxamide
  • Example 151 1 -r5-chloro-6-ioxetan-3-ylmethoxy)pyridin-3-vn-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide
  • Example 152 3-methyl-N-(methylsulfonyl)-1 -r6-(2,2,2-trifluoroethoxy)pyridin-3-vn-
  • the aqueous phase was washed with further DCM/MeOH (20ml) then the organics combined, passed through a phase separation cartridge and concentrated in vacuo to give the intermediate acid, which was used without further purification.
  • the intermediate acid was suspended in DCM (3ml) then DMAP (130mg, 1 .07mmol) added followed by WSCDI (205mg, 1 .07mmol). The reaction mixture was stirred under nitrogen at room temperature for 15 minutes, then methanesulphonamide (68mg, 0.712mmol) was added and the reaction mixture stirred under nitrogen at room temperature over the weekend.
  • Example 153 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-cvclopropyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide
  • Example 154 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-ethyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide
  • Example 157 1 -f6-(isobutylamino)pyridin-3-yl1-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide
  • Example 159 1 -(5-chloro-6-cvclopropylpyridin-3-yl)-3-methyl-N-(methylsulfonyl)- 1 H-indazole-5-carboxamide
  • Example 160 1 -i5-chloro-6-cvclopropylpyridin-3-yl)-4-fluoro-3-methyl-N-
  • the mixture was diluted with water (20 mL) and extracted with DCM (3 x 30 mL), washed with 0.1 M aqueous HCI (2 x 10 mL), water (10 mL) and dried over MgS0 4 .
  • the solvent was removed in vacuo to leave a yellow residue.
  • the crude material was purified by flash column chromatography on silica, eluting first with cyclohexane, followed by cyclohexane:ethyl acetate 1 : 1 to afford the title compound as an off white solid (62 mg, 56 %).
  • the mixture was diluted with water (20 mL) and extracted with DCM (3 x 30 mL), washed with 0.1 M aqueous HCI (2 x 20 mL), water (30 mL) and dried over MgS0 4 .
  • the solvent was removed in vacuo to leave a yellow residue.
  • the crude material was purified by flash column chromatography on silica, eluting first with cydohexane, followed by cyclohexane:ethyl acetate 70:30 to afford the title compound as an off white solid (225 mg, 41 %).
  • the reaction mixture was cooled to room temperature, diluted with EtOAc (200ml) and washed with water (3 x 500ml). (NB: the product is in suspension in the organic phase). The organics were concentrated in vacuo and a yellow paste isolated.
  • the product was suspended in THF (100ml) and LiOH (1.26g, 52.6mmol) added as a solution in water. The reaction mixture was heated to 70°C for 5 hours. The reaction mixture was then washed with DCM (100ml) and EtOAc (100ml).
  • the aqueous phase was acidified and extracted with EtOAc: MeOH 9:1 (2x500ml) and after evaporation of the volatiles in vacuo, 4g of a mixture of hydrolysed starting material and desired product was isolated.
  • the desired product was purified by reverse phase column chromatography to afford the title compound (1 .9g).
  • Trifluoroethanol (96 ⁇ _, 1 .32mmol) was dissolved in DMF (0.5ml). Potassium carbonate (182mg, 1 .32mmol) was added and the mixture stirred under nitrogen at room temperature for 15 minutes.
  • Methyl 1 -(6-fluoropyridin-3-yl)-3-methyl-1 H-indazole-5- carboxylate [preparation 19] (188mg, 0.66mmol) was added and the reaction mixture stirred under nitrogen at 70°C for 16 hours. The mixture was diluted with DCM (25ml), and washed with water (25ml, then 15ml), then passed through a phase separation cartridge and concentrated in vacuo.
  • 2-bromo-3-chloropyridine 70 g, 363.8 mmol
  • cycloproyl boronic acid 31 .3 g, 363.8 mmol
  • potassium phosphate tribasic (193 g, 909.5 mmol) were suspended in a mixture of toluene (600 mL) and water (120 mL) with rapid stirring.
  • the suspension was heated to 80 °C, and the solvent de-gassed by direct bubbling of N 2 gas through the suspension for 30 mins.
  • the reaction was then heated to 95 °C, and tricyclohexyl phosphine (10.2 g, 36.4 mmol) rapidly followed by palladium acetate (4.10 g, 18.2 mmol) were added.
  • the reaction was left to stir and heated at 95 °C for 18 hours.
  • the reaction was cooled to room temperature, and run through a plug of arbocel, eluting with ethyl acetate.
  • the solvent was removed to leave a dark yellow oil.
  • TBME was added (300 mL), and the organics washed with 2M HCI solution (3 x 200 mL). The organics were discarded.
  • TBME (300 mL) was added to the combined aqueous layers, and solid sodium bicarbonate was added until the aqueous layer reached pH 7.
  • the mixture was transferred to a separating funnel, the organic layer was removed, and the aqueous layer was extracted into TBME (2 x 100 mL).
  • the reaction mixture was diluted with dichloromethane (50 mL), and washed with a saturated aqueous solution of EDTA (100 mL). The reaction mixture was further extracted into dichloromethane (3 x 50 mL). The combined organics were dried over MgS04, filtered and the solvent removed to leave a brown oil. The crude material was purified by flash column chromatography (silica), eluting with 2: 1 heptane:ethyl acetate to afford the title compound as a white solid (65 mg, 55%).

Abstract

L'invention porte sur des dérivés acylsulfonamides, sur leur utilisation en médecine, sur des compositions les contenant, sur des procédés pour leur préparation et sur des intermédiaires utilisés dans de tels procédés. Plus particulièrement, l'invention porte sur de nouveaux inhibiteurs de Nav1.7 acylsulfonamides de formule (I) : ou un sel pharmaceutiquement acceptable de ceux-ci, dans laquelle formule U, V, W, X, Y, R° et R1 sont tels que définis dans la description. Les inhibiteurs de Nav1.7 sont potentiellement utiles dans le traitement d'un large éventail de troubles, en particulier de la douleur.
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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014066491A1 (fr) * 2012-10-26 2014-05-01 Merck Sharp & Dohme Corp. Composés indazole sulfonamide n-substitués ayant une activité sélective dans les canaux sodiques potentiel-dépendants
US8933236B2 (en) 2012-05-22 2015-01-13 Xenon Pharmaceuticals Inc. N-substituted benzamides and methods of use thereof
WO2015036734A1 (fr) * 2013-09-16 2015-03-19 Ucl Business Plc Combinaison synergique de médicaments analgésiques
WO2016044386A1 (fr) * 2014-09-16 2016-03-24 Abbvie Inc. Urées d'indazole et procédé d'utilisation
JP2016169241A (ja) * 2012-07-27 2016-09-23 佐藤製薬株式会社 ジフルオロメチレン化合物
WO2016150971A1 (fr) * 2015-03-24 2016-09-29 Almirall, S.A. Dérivés amino-indazoles utilisés comme inhibiteurs des canaux sodiques
US9481677B2 (en) 2011-10-31 2016-11-01 Xenon Pharmaceuticals Inc. Biaryl ether sulfonamides and their use as therapeutic agents
US9493429B2 (en) 2013-03-15 2016-11-15 Genentech, Inc. Substituted benzoxazoles and methods of use thereof
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US9630929B2 (en) 2011-10-31 2017-04-25 Xenon Pharmaceuticals Inc. Benzenesulfonamide compounds and their use as therapeutic agents
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CN107108517A (zh) * 2015-02-11 2017-08-29 株式会社大熊制药 钠通道阻断剂
US10005724B2 (en) 2014-07-07 2018-06-26 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10071957B2 (en) 2012-07-06 2018-09-11 Genentech, Inc. N-substituted benzamides and methods of use thereof
CN109071434A (zh) * 2016-04-20 2018-12-21 百时美施贵宝公司 酰基磺酰胺NaV1.7抑制剂
US10179767B2 (en) 2015-05-22 2019-01-15 Genentech, Inc. Substituted benzamides and methods of use thereof
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US10759804B2 (en) 2015-06-29 2020-09-01 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase
US10766858B2 (en) 2016-03-30 2020-09-08 Genentech, Inc. Substituted benzamides and methods of use thereof
US10787446B2 (en) 2015-09-28 2020-09-29 Genentech, Inc. Therapeutic compounds and methods of use thereof
WO2020192588A1 (fr) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 Dérivé d'alkylsulfamoyl indazole carboxamide, son procédé de préparation et son utilisation pharmaceutique
US10793550B2 (en) 2017-03-24 2020-10-06 Genentech, Inc. 4-piperidin-n-(pyrimidin-4-yl)chroman-7-sulfonamide derivatives as sodium channel inhibitors
US10947251B2 (en) 2018-03-30 2021-03-16 Genentech, Inc. Therapeutic compounds and methods of use thereof
US11028075B2 (en) 2018-02-26 2021-06-08 Genentech, Inc. Therapeutic compounds and methods of use thereof
US11130726B2 (en) 2015-08-27 2021-09-28 Genentech, Inc. Therapeutic compounds and methods of use thereof
US11667651B2 (en) 2017-12-22 2023-06-06 Hibercell, Inc. Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (fr) 1990-01-23 1991-08-08 The University Of Kansas Derives de cyclodextrines presentant une solubilite aqueuse amelioree et utilisation de ceux-ci
WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
WO1998055148A1 (fr) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2005013914A2 (fr) 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
WO2008047229A2 (fr) 2006-10-18 2008-04-24 Pfizer Products Inc. Composés d'urée de bisaryle éther
WO2008118758A1 (fr) 2007-03-23 2008-10-02 Icagen, Inc. Inhibiteurs de canaux ioniques
WO2008135826A2 (fr) 2007-05-03 2008-11-13 Pfizer Limited Dérivés de la pyridine
US20080293737A1 (en) * 2007-05-25 2008-11-27 Esther Martinborough Ion channel modulators and methods of use
WO2009012242A2 (fr) 2007-07-13 2009-01-22 Icagen, Inc. Inhibiteurs des canaux sodiques

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (fr) 1990-01-23 1991-08-08 The University Of Kansas Derives de cyclodextrines presentant une solubilite aqueuse amelioree et utilisation de ceux-ci
WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
WO1998055148A1 (fr) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
WO2005013914A2 (fr) 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
WO2008047229A2 (fr) 2006-10-18 2008-04-24 Pfizer Products Inc. Composés d'urée de bisaryle éther
WO2008118758A1 (fr) 2007-03-23 2008-10-02 Icagen, Inc. Inhibiteurs de canaux ioniques
WO2008135826A2 (fr) 2007-05-03 2008-11-13 Pfizer Limited Dérivés de la pyridine
US20080293737A1 (en) * 2007-05-25 2008-11-27 Esther Martinborough Ion channel modulators and methods of use
WO2009012242A2 (fr) 2007-07-13 2009-01-22 Icagen, Inc. Inhibiteurs des canaux sodiques

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
AHMAD ET AL., HUM MOL GENET., vol. 16, no. 17, 1 December 2006 (2006-12-01), pages 2114 - 21
CANNON, SC, KIDNEY INT., vol. 57, no. 3, 2000, pages 772 - 9
COX, NATURE, vol. 444, no. 7121, 2006, pages 894 - 8
E. L. ELIEL; S. H. WILEN: "Stereochemistry of Organic Compounds", 1994, WILEY
FERTLEMAN ET AL., NEURON, vol. 52, no. 5, 2006, pages 767 - 74
FINNIN; MORGAN, J PHARM SCI, vol. 88, no. 10, October 1999 (1999-10-01), pages 955 - 958
GOLDBERG ET AL., CLIN GENET., vol. 71, no. 4, 2007, pages 311 - 9
GRENNAN; JAYSON: "Textbook of Pain", 1994, pages: 397 - 407
H BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
H. LIEBERMAN; L. LACHMAN: "Pharmaceutical Dosage Forms: Tablets", vol. 1, 1980, MARCEL DEKKER
HALEBLIAN, J PHARM SCI, vol. 64, no. 8, August 1975 (1975-08-01), pages 1269 - 1288
HOUGE; MERSFELDER, ANN PHARMACOTHER., vol. 36, 2002, pages 679 - 686
HUBNER CA; JENTSCH TJ, HUM. MOL. GENET., vol. 11, no. 20, 2002, pages 2435 - 45
K. R. MORRIS: "Polymorphism in Pharmaceutical Solids", 1995, MARCEL DEKKER
KRETSCHMER ET AL., ACTA. NEUROCHIR. (WIEN, vol. 144, no. 8, 2002, pages 803 - 10
LEGROUX-CREPEL ET AL., ANN. DERMATOL VENEREOL., vol. 130, pages 429 - 433
LEVINE; TAIWO: "Textbook of Pain", 1994, pages: 45 - 56
LIANG; CHEN, EXPERT OPINION IN THERAPEUTIC PATENTS, vol. 11, no. 6, 2001, pages 981 - 986
MCCARTH ET AL.: "Textbook of Pain", 1994, pages: 387 - 395
MILLAN, PROG. NEUROBIOL., vol. 57, 1999, pages 1 - 164
N. H. HARTSHORNE; A. STUART: "Crystals and the Polarizing Microscope", 1970
NASSAR ET AL., PROC NATL ACAD SCI USA, vol. 101, no. 34, 2004, pages 12706 - 11
NOBLE D., PROC. NATL. ACAD. SCI. USA, vol. 99, no. 9, 2002, pages 5755 - 6
O. ALMARSSON; M. J. ZAWOROTKO, CHEM COMMUN, vol. 17, 2004, pages 1889 - 1896
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
T HIGUCHI; W STELLA: "Pro-drugs as Novel Delivery Systems", vol. 14, ACS SYMPOSIUM SERIES
THEODORA W GREENE; PETER G M WUTS: "Protection for the Amino Group", 2006, JOHN WILEY AND SONS, article "Greene's Protective Groups in Organic Synthesis"
TOLEDO-ARAL ET AL., PROC. NATL. ACAD. SCI. USA, vol. 94, no. 4, 1997, pages 1527 - 1532
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14
WAXMAN, SG, NEUROLOGY, vol. 69, no. 6, 7 December 2006 (2006-12-07), pages 505 - 7
WOOD, JN ET AL., J. NEUROBIOL., vol. 61, no. 1, 2004, pages 55 - 71
WOOLF; DECOSTERD, PAIN, vol. 6, 1999, pages S141 - S147
WOOLF; MANNION, LANCET, vol. 353, 1999, pages 1959 - 1964
WOOLF; SALTER, SCIENCE, vol. 288, 2000, pages 1765 - 1768
YANG ET AL., J. MED. GENET., vol. 41, no. 3, 2004, pages 171 - 4
YOGEESWARI ET AL., CURR. DRUG TARGETS, vol. 5, no. 7, 2004, pages 589 - 602

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9771376B2 (en) 2000-05-22 2017-09-26 Genentech, Inc. N-substituted benzamides and methods of use thereof
US9630929B2 (en) 2011-10-31 2017-04-25 Xenon Pharmaceuticals Inc. Benzenesulfonamide compounds and their use as therapeutic agents
US9481677B2 (en) 2011-10-31 2016-11-01 Xenon Pharmaceuticals Inc. Biaryl ether sulfonamides and their use as therapeutic agents
US8933236B2 (en) 2012-05-22 2015-01-13 Xenon Pharmaceuticals Inc. N-substituted benzamides and methods of use thereof
US8952169B2 (en) 2012-05-22 2015-02-10 Xenon Pharmaceuticals Inc. N-substituted benzamides and methods of use thereof
US10071957B2 (en) 2012-07-06 2018-09-11 Genentech, Inc. N-substituted benzamides and methods of use thereof
JP2016169241A (ja) * 2012-07-27 2016-09-23 佐藤製薬株式会社 ジフルオロメチレン化合物
US9388179B2 (en) 2012-10-26 2016-07-12 Merck Sharp & Dohme Corp. N-substituted indazole sulfonamide compounds with selective activity in voltage-gated sodium channels
WO2014066491A1 (fr) * 2012-10-26 2014-05-01 Merck Sharp & Dohme Corp. Composés indazole sulfonamide n-substitués ayant une activité sélective dans les canaux sodiques potentiel-dépendants
JP2015535252A (ja) * 2012-10-26 2015-12-10 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． 電位作動型ナトリウムチャネルにおいて選択的活性を有するｎ−置換インダゾールスルホンアミド化合物
US9550775B2 (en) 2013-03-14 2017-01-24 Genentech, Inc. Substituted triazolopyridines and methods of use thereof
US9493429B2 (en) 2013-03-15 2016-11-15 Genentech, Inc. Substituted benzoxazoles and methods of use thereof
WO2015036734A1 (fr) * 2013-09-16 2015-03-19 Ucl Business Plc Combinaison synergique de médicaments analgésiques
US9694002B2 (en) 2013-11-27 2017-07-04 Genentech, Inc. Substituted benzamides and methods of use thereof
US9546164B2 (en) 2013-11-27 2017-01-17 Genentech, Inc. Substituted benzamides and methods of use thereof
US10125098B2 (en) 2014-07-07 2018-11-13 Genentech, Inc. Therapeutic compounds and methods of use thereof
US11149002B2 (en) 2014-07-07 2021-10-19 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10526285B2 (en) 2014-07-07 2020-01-07 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10005724B2 (en) 2014-07-07 2018-06-26 Genentech, Inc. Therapeutic compounds and methods of use thereof
WO2016044386A1 (fr) * 2014-09-16 2016-03-24 Abbvie Inc. Urées d'indazole et procédé d'utilisation
JP2017527628A (ja) * 2014-09-16 2017-09-21 アッヴィ・インコーポレイテッド インダゾール尿素および使用方法
US10590078B2 (en) 2015-02-11 2020-03-17 Daewoong Pharmaceutical Co., Ltd. Sodium channel blockers
EP3256449A4 (fr) * 2015-02-11 2018-11-14 Daewoong Pharmaceutical Co., Ltd. Bloqueurs des canaux sodiques
CN107108517B (zh) * 2015-02-11 2021-05-07 株式会社大熊制药 钠通道阻断剂
JP2018507256A (ja) * 2015-02-11 2018-03-15 デウン ファーマシューティカル カンパニー リミテッド ナトリウムチャネル遮断剤
CN107108517A (zh) * 2015-02-11 2017-08-29 株式会社大熊制药 钠通道阻断剂
WO2016150971A1 (fr) * 2015-03-24 2016-09-29 Almirall, S.A. Dérivés amino-indazoles utilisés comme inhibiteurs des canaux sodiques
US10173985B2 (en) 2015-03-24 2019-01-08 Almirall, S.A. Aminoindazole derivatives as sodium channel inhibitors
US10179767B2 (en) 2015-05-22 2019-01-15 Genentech, Inc. Substituted benzamides and methods of use thereof
US10759804B2 (en) 2015-06-29 2020-09-01 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase
US11466011B2 (en) 2015-06-29 2022-10-11 Imperial College Innovations Limited Compounds and their use as inhibitors of N-myristoyl transferase
US11130726B2 (en) 2015-08-27 2021-09-28 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10787446B2 (en) 2015-09-28 2020-09-29 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10899732B2 (en) * 2015-11-25 2021-01-26 Genentech, Inc. Substituted benzamides useful as sodium channel blockers
WO2017091592A1 (fr) * 2015-11-25 2017-06-01 Genentech, Inc. Benzamides substitués utiles en tant que bloqueurs de canaux sodiques
US20210253548A1 (en) * 2015-11-25 2021-08-19 Genentech, Inc. Substituted benzamides and methods of use thereof
US20180346441A1 (en) * 2015-11-25 2018-12-06 Genentech, Inc. Substituted benzamides useful as sodium channel blockers
US10766858B2 (en) 2016-03-30 2020-09-08 Genentech, Inc. Substituted benzamides and methods of use thereof
US11203572B2 (en) 2016-03-30 2021-12-21 Genentech, Inc. Substituted benzamides and methods of use thereof
CN109071434A (zh) * 2016-04-20 2018-12-21 百时美施贵宝公司 酰基磺酰胺NaV1.7抑制剂
US10457654B2 (en) 2016-10-17 2019-10-29 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10793550B2 (en) 2017-03-24 2020-10-06 Genentech, Inc. 4-piperidin-n-(pyrimidin-4-yl)chroman-7-sulfonamide derivatives as sodium channel inhibitors
US11667651B2 (en) 2017-12-22 2023-06-06 Hibercell, Inc. Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors
US11028075B2 (en) 2018-02-26 2021-06-08 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10947251B2 (en) 2018-03-30 2021-03-16 Genentech, Inc. Therapeutic compounds and methods of use thereof
WO2020192553A1 (fr) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 Dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale
WO2020192588A1 (fr) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 Dérivé d'alkylsulfamoyl indazole carboxamide, son procédé de préparation et son utilisation pharmaceutique

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