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WO2016067143A1 - Composés n- (2-alkylèneimino-3-phénylpropyl)acétamide et leur utilisation contre la douleur et le prurit par inhibition des canaux trpa1 - Google Patents

Composés n- (2-alkylèneimino-3-phénylpropyl)acétamide et leur utilisation contre la douleur et le prurit par inhibition des canaux trpa1 Download PDF

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Publication number
WO2016067143A1
WO2016067143A1 PCT/IB2015/057884 IB2015057884W WO2016067143A1 WO 2016067143 A1 WO2016067143 A1 WO 2016067143A1 IB 2015057884 W IB2015057884 W IB 2015057884W WO 2016067143 A1 WO2016067143 A1 WO 2016067143A1
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Prior art keywords
trifluoromethyl
piperidin
pain
compounds
fluorophenyl
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Inventor
Nigel Alan Swain
David Cameron Pryde
David James Rawson
Thomas Ryckmans
Sarah Elizabeth Skerratt
George Salvatore Amato
Brian Edward Marron
Steven Michael Reister
Christopher William West
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to carboxamide derivatives. More particularly, it relates to A/-(2-alkyleneimino-3-phenylpropyl)acetamide derivatives.
  • the carboxamide derivatives of the present invention modulate the activity of the TrpA1 ion channel. They are useful in the treatment of a number of conditions, including pain and pruritus.
  • TrpA1 is a member of the Transient Receptor Potential (Trp) family of ion channels. It was first described as being activated in response to noxious cold. It is activated by a number of exogenous chemical compounds and some endogenous inflammatory mediators. It has also been reported to be activated in response to mechanical stress.
  • Trp Transient Receptor Potential
  • TrpA1 in the physiology of pain, including neuropathic and inflammatory pain, and in pruritus (itch). For example, see:
  • R A and R B are each independently (C C 3 )alkyl, or R A and R B together are— (CH 2 ) ;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, halo, OH, CH 3 , CF 3 , OCH 3 , and CN;
  • X is H or OH
  • Y is C(H) or N; a is 2, 3, 4 or 5; and n is 1 or 2.
  • the invention provides for a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is for use in the treatment of pain.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is for use in the treatment of pruritus.
  • the invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention provides for a method of treating pain comprising administering a therapeutically effective amount of a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, to an individual in need of such treatment.
  • the invention provides for a method of treating pruritus comprising administering a therapeutically effective amount of a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, to an individual in need of such treatment.
  • the invention provides for the use of a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating pain.
  • the invention provides for the use of a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating pruritus.
  • the invention provides for the use of a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, for the treatment of pain.
  • the invention provides for the use of a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, for the treatment of pruritus.
  • the invention provides for a combination comprising a compound of formula (I) as described above, or in any one of the preferred embodiments, or a pharmaceutically acceptable salt thereof, and a second pharmaceutically active agent.
  • AlkyI groups containing the requisite number of carbon atoms, can be unbranched or branched.
  • (Ci-C3)Alkyl includes methyl, ethyl, n-propyl (1-propyl) and isopropyl (2- propyl, 1-methylethyl).
  • halo includes fluoro (-F), chloro (-CI), bromo (-Br) and iodo (-I).
  • polyfluoroalkyl denotes an alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms.
  • Polyfluoroalkyl includes perfluoroalkyl, which denotes an alkyl group in which all the hydrogen atoms are replaced by fluorine atoms.
  • (CrC 3 )Polyfluoroalkyl includes, but is not limited to, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3- pentafluoropropyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.
  • embodiment E3 there is provided a compound according to embodiment E2, or a pharmaceutically acceptable salt thereof, wherein R A and R B together are— (CH2) a — and Y is C(H).
  • Compounds of Embodiment E3 may be represented by formula (l B ).
  • embodiment E4 there is provided a compound according to any one of embodiments E1 , E2 or E3 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, F, CI, Br, CH 3 , CF 3 , OCH 3 , and CN; and R 2 and R 3 are both H.
  • embodiment E5 there is provided a compound according to any one of embodiments E1 , E2, E3 or E4, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, F, CI, Br, CH 3 , CF 3 , OCH 3 , and CN; and R 5 and R 6 are both H.
  • embodiment E6 there is provided a compound according to embodiment E1 , or a table salt thereof, wherein R A and R B together are— (CH 2 ) a — ;
  • R 1 is selected from H and F; R 2 and R 3 are both H; R 4 is
  • Compounds Embodiment E6 may be represented by formula (l c ).
  • a compound according to embodiment E8 that is 1-(4-chlorophenyl)-/V-[2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3-phenylpropyl]- cyclopentanecarboxamide, or a pharmaceutically acceptable salt thereof.
  • This compound is represented by formula (l E ).
  • Compounds of formula (I) include one or more stereogenic centers and so may exist as optical isomers, such as enantiomers and disastereomers. All such isomers and mixtures thereof are included within the scope of the present invention. More specifically, compounds of formula (I) include a stereogenic center at the position marked with a * in the structural formula below.
  • embodiment E20 there is provided a compound according to embodiment E9 that is 1-(4-chlorophenyl)-/V-[2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3- phenylpropyl]-cyclopentanecarboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound is racemic.
  • a compound according to embodiment E9 that is 1-(4-chlorophenyl)-/V- ⁇ (2S)-[2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3- phenylpropyl] ⁇ cyclopentanecarboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound is enriched with the (2S) enantiomer.
  • enantiomeric excess may be, for example, at least 50%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99% or at least 99.5%.
  • a compound according to embodiment E9 that is 1-(4-chlorophenyl)-/V- ⁇ (2f?)-[2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3- phenylpropyl] ⁇ cyclopentanecarboxamide, or a pharmaceutically acceptable salt thereof, wherein the compound is enriched with the (2R) enantiomer.
  • enantiomeric excess may be, for example, at least 50%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99% or at least 99.5%.
  • 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.
  • references to compounds of the invention include compounds of formula (I) or pharmaceutically acceptable salts, solvates, or multi-component complexes thereof, or pharmaceutically acceptable solvates or multi-component complexes of pharmaceutically acceptable salts of compounds of formula (I), as discussed in more detail below.
  • Preferred compounds of the invention are compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • 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
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate salts.
  • salts include ones wherein the counterion is optically active, for example d-lactate, or racemic, for example dl- tartrate.
  • suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • compositions of formula (I) may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molcular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molcules, for example, ethanol.
  • the term '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 O, d 6 -acetone and d 6 -DMSO.
  • Isolated site hydrates are ones in which the water molcules are isolated from direct contact with each other by intervening organic molcules.
  • channel hydrates the water molcules lie in lattice channels where they are next to other water molcules.
  • metal-ion coordinated hydrates the water molcules 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 molcular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically 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 molcular 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 molcular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molcule 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, 17, 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).
  • 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).
  • 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); and where the compound of formula (I) contains a methyl (-CH 3 ) group, the hydroxymethyl derivative thereof (-CH 3 > -CH 2 OH).
  • 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.
  • isotopically-labelled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • Substitution with 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. Also within the scope of the invention are 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 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, 4 th edition, (John Wiley and Sons, 2006), in particular chapters 7 ("Protection for the Amino Group") and 5 (“Protection for the Carboxyl Group”), incorporated herein by reference, which also describes methods for the removal of such groups.
  • compounds of formula (I) may be prepared from compounds of formula (II) and (III) as illustrated by Scheme 1 ,
  • Compounds of formula (I) may be prepared from compounds of formula (II) and (III) according to process step (i), an amide bond formation reaction.
  • Typical conditions employ activation of the carboxylic acid (II) using a suitable organic base and a suitable coupling agent.
  • Preferred coupling agents are either EDCI with HOBt, HATU, HBTU or BOP.
  • Preferred organic bases comprise either DIPEA or triethylamine in a suitable organic solvent such as DMF, DMA or MeCN, shaken or stirred at room temperature (See Methods 1 -5).
  • Hal is Bromo or lodo
  • Compounds of formula (l y ) may be prepared from compounds of formula (l x ) according to process step (ii), a palladium catalysed cyanation reaction.
  • Typical conditions employ a suitable palladium catalyst with a metal cyanide in a polar solvent at elevated temperatures.
  • Preferred conditions comprise tetrakistriphenylphosphine palladium (0) with zinc cyanide in DMF at 110°C.
  • compounds of formula (III) may be prepared from compounds of formula (IV) and (V) as illustrated by Scheme 3,
  • Racemic compounds of formula (III) may be chirally separated into enantiomers or diastereomers using appropriate chiral chromatography.
  • Compounds of formula (III) may be prepared from compounds of formula (IV) and (V) according to process step (iii), a modified Strecker reaction where the intermediate nitrile is reduced to an aminomethylene instead of hydrolysis to an acid.
  • Preferred conditions comprise catalytic zinc iodide with TMSCN in diethyl ether at reflux followed by reduction with either LiAIH 4 or by hydrogenation over Raney Nickel.
  • M is a metal such as magnesium or zinc
  • NPth is pthalimido
  • Compounds of formula (III) may be prepared from compounds of formula (VI) according to process step (iv), a deprotection under basic reaction conditions.
  • Preferred conditions comprise hydrazine monohydrate in ethanol at reflux.
  • Compounds of formula (VI) may be prepared from compounds of formula (VII) and (VIII) according to process step (v) an alkyl Grignard or zincate displacement of a benzotriazole.
  • Preferred conditions comprise reacting compounds of formula (VII) with synthesised or commercially available zincates of formula (VIII) in THF at from -60°C to 0°C.
  • Compounds of formula (VII) may be prepared from compounds of formula (V) and (IX) with benzotriazole according to process step (vi), a Katritzky reaction.
  • Preferred conditions comprise heating in toluene at reflux under Dean-Stark conditions.
  • Compounds of formula (III) may be prepared from compounds of formula (X) according to process step (i) an amide bond formation reaction as described in Scheme 1 , followed by process step (vii), a reduction reaction.
  • Preferred conditions comprise carbonyldiimidazole in THF with ammonium hydroxide followed by LiAIH 4 in DME at elevated temperatures of 50-65°C.
  • Compounds of formula (X) may be prepared from compounds of formula (XI) according to process step (viii), a hydrolysis reaction under acidic reaction conditions. Preferred conditions comprise heating in cHCI at 90°C for 18 hours.
  • Compounds of formula (XI) may be prepared from compounds of formula (XII) and (V) according to process step (ix), a nucleophilic substitution reaction.
  • Preferred conditions comprise potassium phosphate in EtOAc at room temperature.
  • Compounds of formula (XII) may be prepared from compounds of formula (XIII) according to process step (x), a transformation of an alcohol into a leaving group such as triflate.
  • Preferred conditions comprise trifluoromethanesulfonic anhydride with 2.6- lutidine in DCM at room temperature.
  • 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.
  • excipients 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.
  • 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, intraurethral, 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.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions 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).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • the compounds 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.
  • 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.
  • 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 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ to 100 ⁇ .
  • 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 macromolcular 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 macromolcular 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 International Patent Applications Nos. WO 91/1 1172, 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 5mg to 1 g, for example 10mg to 500mg depending, of course, on the mode of administration and efficacy.
  • oral administration may require a total daily dose of from 25mg to 250mg.
  • Smaller doses may be effective when administered topically to a small area of skin.
  • 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, i.e. TrpA1 ion channel inhibition.
  • the compounds of the invention are accordingly of use in the treatment of disorders in animals for which a TrpA1 ion channel inhibitor is indicated.
  • the animal is a mammal. In other embodiments the animal is a human.
  • a compound of the invention for the treatment of a disorder for which a TrpA1 ion channel inhibitor is indicated.
  • a compound of the invention for the preparation of a medicament for the treatment of a disorder for which a TrpA1 ion channel inhibitor is indicated.
  • a method of treating a disorder in an animal comprising administering to said animal a therapeutically effective amount of a compound of the invention.
  • TrpA1 ion channel inhibitors of formula (I) may be used:
  • analgesics for example for the treatment of pain, including acute pain, chronic pain, neuropathic pain, nociceptive (including inflammatory) pain, somatic pain, visceral pain, and dysfunctional pain, as further discussed below; or
  • antipruritic agents for example for the treatment of itch associated with inflammatory and other dermatological conditions, such as psoriasis and atopic dermatitis, as further discussed below.
  • TrpA1 ion channel inhibitors of formula (I) include the treatment of: respiratory diseases such as asthma, chronic obstructive pulmonary disorder (COPD), bronchoconstriction and cough; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS); neurodegenration following stroke or acute cerebral ischemia; multiple sclerosis; urinary tract diseases such as incontinence, bladder overactivity, bladder cystits, micturition disorder and renal colic; inflammatory conditions such as rheumatoid arthritis, osteoarthritis oral mucositis, inflammatory bowel disease (IBD), colitis and Crohn's disease; gastrointestinal disorders such as gastroesophagal reflux disease (GERD), dysphagia, irritable bowel syndrome (IBS) and emesis such as chemotherapt-induced emesis; burns; hypertension; and exposure to riot control agents such as CS and CR.
  • respiratory diseases such as asthma, chronic
  • Pain may be either acute or chronic and additionally may be of central and/or peripheral origin. Pain may be of a neuropathic and/or nociceptive and/or inflammatory nature, such as pain affecting either the somatic or visceral systems, as well as dysfunctional pain affecting multiple systems.
  • 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 Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter"!).
  • These sensory fibres are known as nociceptors, and are characteristically small diameter axons with slow conduction velocities, of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
  • 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.
  • 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
  • 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, although not always, associated with a specific cause such as a defined injury, is often sharp and severe and can result from numerous origins such as surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation may be altered such that there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place.
  • pain The clinical manifestation of 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 can 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., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapterl). 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. Apart from acute or chronic, pain can also be broadly categorized into: nociceptive pain, affecting either the somatic or visceral systems, which can be inflammatory in nature (associated with tissue damage and the infiltration of immune cells); or neuropathic pain.
  • Nociceptive pain can be defined as the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors, and can be 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., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter"!).
  • 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 strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, pain associated with gout, 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. in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy).
  • Back pain may be due to herniated or ruptured intervertabral 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.
  • Nociceptive pain can also be related to inflammatory states.
  • 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 (McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter3).
  • a common inflammatory condition assoiciated with pain is arthritis. It has been estimated that almost 27 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most patients with osteoarthritis seek medical attention because of the associated pain.
  • OA symptomatic osteoarthritis
  • degenerative joint disease Lawrence et al., 2008, Arthritis Rheum, 58, 15-35
  • Rheumatoid arthritis is an immune- mediated, chronic, inflammatory polyarthritis disease, mainly affecting peripheral synovial joints. It is one of the commonest chronic inflammatory conditions in developed countries and is a major cause of pain.
  • visceral pain results from the activation of nociceptors of the thoracic, pelvic, or abdominal organs (Bielefeldt and Gebhart, 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter48). This includes the reproductive organs, spleen, liver, gastrointestinal and urinary tracts, airway structures, cardiovascular system and other organs contained within the abdominal cavity.
  • visceral pain refers to pain associated with conditions of such organs, such as painful bladder syndrome, interstitial cystitis, prostatitis, ulcerative colitis, Crohn's disease, renal colic, irritable bowl syndrome, endometriosis and dysmenorrhea!
  • Neuropathic pain is currently defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory 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 (Dworkin, 2009, Am J Med, 122, S1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21).
  • 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).
  • fibromyalgia and chronic regional pain syndrome which are often described as dysfunctional pain states e.g. fibromyalgia or complex regional pain syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744), but which are included in classifications of chronic pain states (Classification of Chronic Pain, available at http://www.iasp-pain.org).
  • Pruritus is a sensation that stimulates the desire or reflex to scratch. It may be either localized or generalized, and it may be either acute or chronic. The sensation is unpleasant and can cause significant discomfort. Scratching as a result of pruritus can lead to damage to the skin which may cause scarring, and may exacerbate a preexisting inflammatory condition.
  • Pruritus may be caused by, or be a component of, a number of dermatological disorders and diseases.
  • disorders and diseases include: acne vulgaris; aquagenic pruritus; puttosis; dermatitis, such as atopic dermatitis, nervous dermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis and caterpillar dermatitis; eczema; fungal infections such as yeast infections, diaper rash, vaginal itch and athlete's foot; impetigo; lichen, such as lichen planus, lichen simplex, lichen simplex chronicus and lichen sclerosis; photosensitive dermatosis; prurigo, including prurigo nodularis; psoriasis; tinea; viral infections such as herpes and chicken pox, including post-herpetic pruritis; and xerosis. Pruritis may be associated with physical damage to the skin, for example burns, scalds, and
  • Pruritus may also be caused by, or associated with, systemic disorders and diseases.
  • disorders and diseases include: anemia; cancer; cholestatic pruritus; diabetes mellitus; haemorrhoids; hepatic diseases; Hodgkin's lymphoma; hyperparathyroidism; hyperthyroidism; neurological conditions including brachioradial pruritus, neuropathic pruritus, and multiple sclerosis associated pruritus; polycythemia vera; primary biliary cirrhosis; primary sclerosis cholangitis; renal failure, uremic pruritus;
  • Pruritus may also be caused by, or associated with, non-pathological conditions such as pregnancy.
  • Pruritus has been associated with the use of several classes of pharmaceutical agent.
  • examples of such agents include: allopurinol; antibiotics such as ampicillins, neomycin penicillins, sulphonamides and tetracyclines; cancer chemotherapies;
  • Pruritus has also been associated with non-pharmacological medical procedures such as hemodialysis and peritoneal dialysis.
  • Pruritus may result from contact with an allergen or irritant, or from an insect bite or sting. Examples include: allergic conjunctivitis; allergic rhinitis; urticaria caused by a plant such as poison ivy or stinging nettle; itch associated with a flea or mite bite; itch associated with a bee, mosquito or wasp sting; and itch associated with a parasitic infestation such as scabies or lice.
  • pruritus In some cases of pruritus there is no identifiable cause. These cases may be classified as generalized pruritus, idiopathic pruritus, intractable pruritus, psychogenic pruritus or senile pruritus.
  • a TrpA1 ion channel 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 or pruritus. Such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.
  • TrpA1 ion channel 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:
  • a selective Nav1.3 channel modulator such as a compound disclosed in WO2008/118758;
  • a selective Nav1.7 channel modulator such as a compound disclosed in WO2010/079443, e.g. 4-[2-(5-amino-1 H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro- 2-fluoro-N-1 ,3-thiazol-4-ylbenzenesulfonamide or 4-[2-(3-amino-1 H-pyrazol-4-yl)- 4-(trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1 ,3-thiazol-4- ylbenzenesulfonamide, or a pharmaceutically acceptable salt of either;
  • a compound which modulates activity at more than one Nav channel including a non-selective modulator such as bupivacaine, carbamazepine, lamotrigine, lidocaine, mexiletine or phenytoin;
  • NGF nerve growth factor
  • an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling e.g. tanezumab
  • TrkA antagonist or a p75 antagoinsist e.g. tanezumab
  • an agent that inhibits downstream signaling in regard to NGF stimulated TrkA or P75 signalling e.g. tanezumab
  • TrkA antagonist or a p75 antagoinsist e.g. tanezumab
  • an agent that inhibits downstream signaling in regard to NGF stimulated TrkA or P75 signalling e.g. tanezumab
  • an agent that binds to nerve growth factor (NGF) e.g. tanezumab, fasinumab or fulranumab
  • nerve growth factor e.g. tanezumab, fasinumab or fulranumab
  • BDNF brain-derived neurotrophic factor
  • NT-3 neurotrophin-3
  • NT-4 neurotrophin-4
  • a compound which increases the levels of endocannabinoid such as a compound with fatty acid amid hydrolase inhibitory (FAAH) or monoacylglycerol lipase (MAGL) activity;
  • FAAH fatty acid amid hydrolase inhibitory
  • AML monoacylglycerol lipase
  • an analgesic in particular paracetamol
  • an opioid analgesic such as: buprenorphine, butorphanol, cocaine, codeine, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, levallorphan levorphanol, meperidine, methadone, morphine, nalmefene, nalorphine, naloxone, naltrexone, nalbuphine, oxycodone, oxymorphone, propoxyphene or pentazocine; an opioid analgesic which preferentially stimulates a specific intracellular pathway, for example G-protein as opposed to beta arrestin recruitment, such as TRV130; an opioid analgesic with additional pharmacology, such as: noradrenaline (norepinephrine) reuptake inhibitory (NRI) activity, e.g. tapentadol; serotonin and norepinephrine reuptake inhibitory (NR
  • NSAID nonsteroidal antiinflammatory drug
  • COX non-selective cyclooxygenase
  • COX non-selective cyclooxygenase
  • a non-selective cyclooxygenase inhibitor e.g. aspirin, 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; or a COX
  • EP4 prostaglandin E2 subtype 4
  • microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor a microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor
  • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a GABAA modulator with broad subtype modulatory effects mediated via the benzodiazepine binding site such as chlordiazepoxide, alprazolam, diazepam, lorazepam, oxazepam, temazepam, triazolam, clonazepam or clobazam;
  • GABAA modulator acting via alternative binding sites on the receptor, such as barbiturates, e.g. amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobartital, secobarbital, or thiopental; neurosteroids such as alphaxalone, alphadolone or ganaxolone; ⁇ -subunit ligands, such as etifoxine; or ⁇ -preferring ligands, such as gaboxadol;
  • barbiturates e.g. amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobartital, secobarbital, or thiopental
  • neurosteroids such as alphaxalone, alphadolone or ganaxolone
  • ⁇ -subunit ligands such as
  • a GlyR3 agonist or positive allosteric modulator • a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxolone, methocarbamol or orphrenadine;
  • a glutamate receptor antagonist or negative allosteric modulator such as an NMDA receptor antagonist, e.g. dextromethorphan, dextrorphan, ketamine or, memantine; or an mGluR antagonist or modulator;
  • an alpha-adrenergic such as clonidine, guanfacine or dexmetatomidine
  • a beta-adrenergic such as propranolol
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • a tachykinin (NK) antagonist such as aprepitant or maropitant
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), varenicline or nicotine;
  • TRPV1 Transient Receptor Potential V1 (TRPV1) receptor agonist (e.g. resinferatoxin or capsaicin) or antagonist (e.g. capsazepine or mavatrap);
  • TRPV1 receptor agonist e.g. resinferatoxin or capsaicin
  • antagonist e.g. capsazepine or mavatrap
  • TRPM8 Transient Receptor Potential M8 (TRPM8) receptor agonist (e.g. menthol or icilin) or antagonist;
  • TRPV3 Transient Receptor Potential V3
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HTI B/ID agonist, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
  • a PDEV inhibitor such sildenafil, tadalafil or vardenafil
  • an alpha-2-delta ligand such as gabapentin, gabapentin enacarbil or pregabalin, ;
  • SRI serotonin reuptake inhibitor
  • sertraline demethylsertraline
  • fluoxetine norfluoxetine
  • fluvoxamine paroxetine
  • citalopram desmethylcitalopram
  • escitalopram d,l-fenfluramine
  • femoxetine ifoxetine
  • cyanodothiepin litoxetine
  • nefazodone cericlamine and trazodone
  • NRI such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine, especially a selective noradrenaline reuptake inhibitor such as reboxetine;
  • an SNRI such as venlafaxine, O-desmethylvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • iNOS inducible nitric oxide synthase
  • a 5-lipoxygenase inhibitor such as zileuton
  • a potassium channel opener or positive modulator such as an opener or positive modulator of KCNQ/Kv7 (e.g. retigabine or flupirtine), a G protein-coupled inwardly-rectifying potassium channel (GIRK), a calcium-activated potassium channel (Kca) or a potassium voltage-gated channel such as a member of subfamily A (e.g. Kv1.1), subfamily B (e.g. Kv2.2) or subfamily K (e.g. TASK, TREK or TRESK);
  • a P2X 3 receptor antagonist e.g. AF219 or an antagonist of a receptor which contains as one of its subunits the P2X 3 subunit, such as a P2X 2 /3 heteromeric receptor;
  • T-type Ca v 3.2 calcium channel blocker
  • TrpA1 ion channel inhibitor of formula (I), or a pharmaceutically acceptable salt thereof, as defined above may be administered in combination with one or more agents such as:
  • an alpha-2-delta ligand such as pregabalin or gabapentin
  • an antihistamine such as loratidine or cetirizine
  • a calcineurin inhinbitor such as tacrolimus or pimecrolimus
  • a cannabinoid such as N-palmitoylethanolamine
  • a corticosteroid such as hydrocortisone
  • a kappa opioid agonist such as butorphanol or nalfurafine
  • a local anesthetic such as lidocaine, prilocaine
  • a neurokinin NK1 receptor antagonist such as aprepitant
  • NRI norepinephrine re-uptake inhibitor
  • SSRI selective serotonin re-uptake inhibitor
  • 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 Nav1.8 modulator is indicated.
  • BOP is (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; br is broad;
  • °C is degrees celcius
  • CDCI3 is deuterochloroform
  • CHCI 3 is chloroform
  • CO 2 is carbon dioxide
  • DCM is dichloromethane; methylene chloride;
  • DEA diethylamine
  • DIPEA is N-ethyldiisopropylamine, N,N-diisopropylethylamine;
  • DMA is dimethylacetamide
  • DMF is N,N-dimethylformamide
  • DMSO dimethyl sulphoxide
  • EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EtOAc is ethyl acetate
  • HATU 1-[bis(dimethylamino)methylene]-1H-1 ,2,3-triazolo[4,5- 5]pyridinium 3-oxid hexafluorophosphate
  • HBTU is /V,/V,A/',/ ⁇ /-Tetramethyl-0-(1 H-benzotriazol-1-yl)uronium
  • HCI is hydrochloric acid
  • HOBt is N-hydroxybenzotriazole hydrate
  • HPLC high pressure liquid chromatography
  • IPA is isopropyl alcohol
  • KHMDS is potassium bis(trimethylsilyl)amide
  • L1AIH4 is lithium aluminium hydride
  • m is multiplet
  • M is molar
  • MeCN is acetonitrile
  • MeOH is methanol
  • MHz is mega Hertz
  • ml_ is millilitre
  • MS m/z is mass spectrum peak
  • NaHCCb sodium hydrogencarbonate
  • NaOH sodium hydroxide
  • NH 3 or NH4OH is ammonia or ammonium hydroxide or 880 ammonia
  • NMM is N-methyl morpholine
  • NMR nuclear magnetic resonance
  • Pd/C is palladium on carbon
  • pH is power of hydrogen
  • ppm is parts per million
  • Rt is retention time
  • TBME is tert-butyl methyl ether
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • ⁇ _ is microlitre
  • Example 1 may also be prepared according to the following method:
  • Mobile phase A CO2; Mobile phase B: MeOH with 0.2% ammonium hydroxide Gradient: 5% B at 0.00 mins, 60% B at 9.00 mins; hold to 9.5 mins and return to 5% B at 10 mins. Flow rate 3 mL/min.
  • Example 2 may also be prepared from rac-1-(4-chlorophenyl)-N- ⁇ 2-[4-hydroxy-4-
  • the compound of Example 2 prepared from the chiral separation method is identical by a-rotation and retention time to the compound of Example 2 prepared as the single enantiomer described above.
  • the two single enantiomers have unknown stereochemistry and are arbitrarily assigned as:
  • the title compound was prepared according to Method 2 using rac-1 -[1-amino-3-(4- fluorophenyl)propan-2-yl]-3-(trifluoromethyl)pyrrolidin-3-ol (Preparation 10) and 1-(4- fluorophenyl)cyclopentanecarboxylic acid.
  • the residue was purified using silica gel column chromatography eluting with 0-100% EtOAc in heptanes in 64% yield.
  • Mobile phase A C0 2 and mobile phase B: MeOH; 0-1 min 95% A, 9 min 40% A and back to 5% A at 10 min.
  • Mobile phase A C0 2 and mobile phase B: MeOH; 0-1 min 95% A, 9 min 40% A and back to 5% A at 10 min.
  • the title compound was prepared according to Method 2 using rac-1 -[1-amino-3-(4- fluorophenyl)propan-2-yl]-3-(trifluoromethyl)pyrrolidin-3-ol (Preparation 10) and 1-(4- chlorophenyl)cyclopropanecarboxylic acid.
  • the residue was purified using silica gel column chromatography eluting with 0-100% EtOAc in heptanes in 74% yield.
  • racemic title compound was prepared according to Method 1 using TEA in DCM with rac-1-[1-amino-3-(2-fluorophenyl)propan-2-yl]-4-(trifluoromethyl)piperidin-4-ol (Preparation 6) and 1-(4-fluorophenyl)cyclobutanecarboxylic acid in 46% yield.
  • the racemate was separated into two enantiomers by chiral chromatography using an
  • racemic title compound was prepared according to Method 1 using TEA in DCM with rac-1-[1-amino-3-(3-fluorophenyl)propan-2-yl]-4-(trifluoromethyl)piperidin-4-ol (Preparation 7) and 1-(4-fluorophenyl)cyclobutanecarboxylic acid in 33% yield.
  • the racemate was separated into two enantiomers by chiral chromatography using an
  • Examples 23-46 were prepared according to Methods 1 -4 above using the appropriate amines and acids as described below. Purification is as described below or as otherwise stated in the aforementioned methods.
  • R A -CH 3
  • R B -CH 3
  • R c -(CH 2 ) 2 CH 3
  • X H
  • R A -CH 3
  • R B -CH 3
  • R c -CF 3
  • X H
  • R A -CH 3
  • R B -CH 3
  • R c -CH2CF3
  • X H
  • the title compound was prepared according to Method 1 using the fourth eluting diastereoisomer of 1-[1-amino-3-(4-fluorophenyl)propan-2-yl]-3-(trifluoromethyl)- pyrrolidin-3-ol of unknown stereochemistry (Preparation 13) and 1-(4-fluorophenyl)- cyclobutanecarboxylic acid in 65% yield.
  • Examples 48-54 were prepared according to the method described for Library Protocol 1 as described below:
  • R A -CH3
  • R B -CH3
  • R c -(CH2)2CH3
  • R A -CH 3
  • R B -CH 3
  • R c -CH 2 CH 3
  • the title compound may also be prepared as described above using rac-1-(1-amino- 3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 2) followed by separation of the enantiomers using preparative chiral chromatography as described below:
  • the title compound may be prepared according to the method described for Preparation 2 using 4-(fluorophenyl)acetaldehyde and 4-(trifluoromethyl)piperidin-4-
  • Zinc dust (247 mg, 1.31 mmol) was flushed with nitrogen before the addition of a solution of 1 ,2-dibromoethane (6.2 mg, 0.033 mmol) in THF (2 mL). The suspension was heated to reflux for 10 minutes and cooled to room temperature. A solution of 4- methoxybenzylbromide (263 mg, 1.31 mmol) in THF (2 mL) was added and the reaction stirred at room temperature for 1.5 hours.
  • Mobile phase A water with 0.1 % TFA
  • Mobile phase B MeCN with 0.1 % TFA.
  • hTRPA1/293-T-REx cell lines were selected in 150 ug/ml hygromycin and 5 ug/ml blasticidin and cultured in DMEM/high glucose (HyClone, Logan, UT) media supplemented with 2 mM Na pyruvate, 10 mM HEPES, 10% fetal bovine serum and incubated at 37°C in 10% CO 2 . Culture selection was maintained with 75 ⁇ g/ml hygromycin and 5 ⁇ g/ml blasticidin. hTRPAI expression was induced with ⁇ g/ml tetracycline 24 hours prior to electrophysiological recording.
  • Poly-D-lysine coated cover slips containing hTRPAI /293-T-REx cells were placed in a bath on the stage of an inverted microscope and perfused (approximately 1 ml/min) with extracellular solution of the following composition: (in mM) 132 NaCI, 5.4 KCI, 1.8 CaCI 2 , 0.8 MgCI 2 , 10 HEPES, and 5 Glucose, pH adjusted to 7.4 with NaOH .
  • Pipettes were filled with an intracellular solution of the following composition: (in mM) 90 CsCI, 32 CsF, 10 HEPES, 10 EGTA, 10 Cs 4 BAPTA, 1 MgCI 2 , 5 Mg ATP, and 0.1 Na GTP, pH adjusted to 7.3 with CsOH and had a resistance of 1 to 2 megaohms.
  • the osmolarity of the extracellular and intracellular solutions was 300 mOsm/kg and 296 mOsm/kg, respectively. All recordings were made at room temperature (22-24°C) using AXOPATCH 200B amplifiers and PCLAMP software (Molecular Devices, Sunnyvale, CA). hTRPAI currents were measured using the whole-cell configuration of the patch-clamp technique.
  • Uncompensated series resistance was typically 2 to 5 megaohms and >85% series resistance compensation was routinely achieved. As a result, voltage errors were negligible Current records were acquired at 4 KHz and filtered at 1 KHz.
  • hTRPAI expressing cells were viewed under Hoffman contrast optics and placed in front of an array of flow pipes emitting either control or compound-containing extracellular solutions. All compounds were dissolved in dimethyl sulfoxide to make 10 mM stock solutions, which were then diluted into extracellular solution to attain the final concentrations desired. The final concentration of dimethyl sulfoxide ( ⁇ 0.1 % dimethyl sulfoxide) was found to have no significant effect on hTRPAI currents.
  • hTRPAI cells were grown as above to 50% - 80% confluency and harvested by trypsinization. Trypsinized cells were washed and resuspended in extracellular buffer at a concentration of 1x10 6 cells/ml. The onboard liquid handling facility of the PatchXpress was used for dispensing cells and application of test compounds. Results

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Abstract

La présente invention concerne de nouveaux dérivés de carboxamide. Plus particulièrement, elle concerne des dérivés de N-(2-alkylèneimino-3-phénylpropyl)acétamide de formule (I) et des sels pharmaceutiquement acceptables de ceux-ci,R1, R2, R3, RA, RB, RC, X et n étant tels que définis dans la description. Les dérivés de N-(2-alkylèneimino-3-phénylpropyl)acétamide de la présente invention modulent l'activité du canal ionique TrpA1. Ils sont utiles dans le traitement d'un certain nombre d'affections, y compris la douleur et le prurit.
PCT/IB2015/057884 2014-10-28 2015-10-14 Composés n- (2-alkylèneimino-3-phénylpropyl)acétamide et leur utilisation contre la douleur et le prurit par inhibition des canaux trpa1 Ceased WO2016067143A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018109155A1 (fr) 2016-12-16 2018-06-21 Galderma Research & Development Antagonistes de trpa1 destinés à être utilisés dans le traitement de la dermatite atopique
CN112867705A (zh) * 2018-04-04 2021-05-28 埃皮欧黛公司 阿片样物质受体调节剂以及与其相关的产品和方法
WO2022058946A1 (fr) 2020-09-18 2022-03-24 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d'alzheimer
IT202100015098A1 (it) 2021-06-09 2022-12-09 Flonext S R L Composto antagonista del canale trpa1 per uso in patologie degenerative della retina

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018109155A1 (fr) 2016-12-16 2018-06-21 Galderma Research & Development Antagonistes de trpa1 destinés à être utilisés dans le traitement de la dermatite atopique
CN112867705A (zh) * 2018-04-04 2021-05-28 埃皮欧黛公司 阿片样物质受体调节剂以及与其相关的产品和方法
WO2022058946A1 (fr) 2020-09-18 2022-03-24 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d'alzheimer
FR3114235A1 (fr) 2020-09-18 2022-03-25 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d’alzheimer
IT202100015098A1 (it) 2021-06-09 2022-12-09 Flonext S R L Composto antagonista del canale trpa1 per uso in patologie degenerative della retina

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