WO2012120398A1 - Dérivés de carboxamide substitués par aryle en tant que modulateurs de trpm8 - Google Patents

Dérivés de carboxamide substitués par aryle en tant que modulateurs de trpm8 Download PDF

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WO2012120398A1
WO2012120398A1 PCT/IB2012/050834 IB2012050834W WO2012120398A1 WO 2012120398 A1 WO2012120398 A1 WO 2012120398A1 IB 2012050834 W IB2012050834 W IB 2012050834W WO 2012120398 A1 WO2012120398 A1 WO 2012120398A1
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methyl
pain
formula
compounds
amino
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Paul Alan Glossop
Michael John Palmer
Mark David Andrews
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Pfizer Ltd Great Britain
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Pfizer Ltd Great Britain
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Definitions

  • This invention relates to amide derivatives. More particularly, this invention relates to aryl substituted amide derivatives and to compositions containing and the uses of such derivatives.
  • the amide derivatives of the present invention are TRPM8 blockers and have a number of therapeutic applications in the propylaxis or treatment of a wide range of diseases, conditions or syndromes affected by the blocking of TRPM8, including urological diseases, conditions or syndromes including over active bladder or interstitial cystitis and pain diseases, conditions or syndromes, including cold allodynia regardless of cause, trigeminal neuralgia, glossopharyngeal neuralgia, Raynauld's syndrome, and schlerodema.
  • a preferred use is in the treatment of cold allodynia or Raynauld's syndrome.
  • TRP channels are one of the largest groups of ion channels.
  • the super family is known to consist of at least 28 non-selective cation channels divided into 6 sub families including TRPM (melastatin).
  • TRPM melastatin
  • the TRP channels are cation selective and are activated by a variety of physical (eg temperature, osmolarity, mechanical) and chemical stimuli.
  • the great majority of functionally characterised TRP channels are permeable to Ca 2+ , are known to be widely distributed and also to participate in various cellular functions.
  • the best characterised example of the TRP family is the capasicin - and heat - sensitive TRPV1 receptor (Caterina et al, Science 288, 306-313, 2000), but much less is known about cool-sensitive TRP's.
  • TRPM8 (or Cold-Menthol receptor 1 ; CMR1 ), is a member of the TRP channel family and the 8 th member of the TRPM family which was first cloned in 2002 (McKemy et al, Nature 2002, 416(6876), 52-58). It is activated by innocuous cool temperatures (with 50% activation around 18-19°C), noxious cold ( ⁇ 15°C) and by menthol and icilin, two substances which produce a cold sensation.
  • TRPM8 is located on primary nociceptive neurons (A-delta and C-fibres) and expressed by a subpopulation of sensory neurons in dorsal root ganglia and trigeminal ganglia where response to cooling correlate well with mRNA expression and menthol sensitivity.
  • Cold intolerance and pain induced by chemical or thermal cooling closely parallel symptoms seen in a wide range of clinical disorders and thus provides a rationale for the development of TRPM8 modulators as novel antihyperalgesic or antiallodynic agents.
  • TRPM8 is also known to be expressed in brain, lungs, bladder, gastrointestinal tract, blood vessels, prostatic and immune cells, thereby providing the possibility for therapeutic modulation of a wide range of maladies.
  • TRPM8 agonists and TRPM8 antagonists Small molecule approaches to modulating TRPM8 receptors, including for example TRPM8 agonists and TRPM8 antagonists, are known in the art. Examples of such disclosures include those in international patent application WO-A-2006/040136 (publication date 26 th April 2006); international patent application WO-A-2007/017093 (publication date 15 th February 2007); international patent application WO-A- 2007/134107 (publication date 22 nd November 2007); international patent application WO-A-2009/012430 (publication date 22 nd January 2009); international patent application WO-A-2009/038812 (publication date 26 th March 2009); international patent application WO-A-2009/073203 (publication date 1 1 th June 2009); and international patent application WO-A-2010/125831 (publication date 4 th November 2010). Also disclosed are the uses of these compounds as medicaments for the prophylaxis or treatment of diseases associated with TRPM8 activity, including urological disorders, pain disorders,
  • the compounds of the present invention described herein are small molecule TRPM8 blockers.
  • the compounds of the present invention are therefore potentially useful in the propylaxis or treatment of a wide range of diseases, conditions or syndromes.
  • diseases, conditions or syndromes include urological diseases, conditions or syndromes including, for example, over active bladder (detrusor overactivity), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, painful bladder syndrome, interstitial cystitis and lower urinary tract symptoms.
  • TRPM8 blockers of the present invention may also be useful in the propylaxis or treatment of include inflammation diseases, conditions or syndromes including, for example, inflammatory bowel disease, rheumatoid arthritis; neurological diseases, conditions or syndromes including, for example, those diseases, conditions or syndromes associated with the modulation of the senstation of saiety perception including obesity, anorexia, weight maintenance, metabolic energy levels inflammatory conditions; and respiratory diseases, conditions or syndromes including, for example, including rhinitis, allergic rhinitis, asthma for example allergen induced asthma, exercise induced asthma, pollution induced asthma, viral induced asthma or cold induced asthma; chronic obstructive pulmonary disease (COPD) including chronic bronchitis; ailments that involve inflammation of one or more components of the respiratory system including emphysema, asthmatic bronchitis, bullous disease, and other pulmonary diseases involving inflammation which include cystic fibrosis, pigeon fancier's disease, farmer's lung
  • TRPM8 blockers suitable for further development as drug candidates. It is a further object of the present invention that the compounds are useful for the treatment of a wide range of diseases, conditions or syndromes, which disease, condition or syndrome is affected by the at least partial blocking of TRPM8, and in particular urological diseases, conditions or syndromes, including over active bladder, painful bladder syndrome, and interstitial cystitis; and pain diseases, conditions or syndromes, including cold allodynia regardless of cause, trigeminal neuralgia, glossopharyngeal neuralgia, Raynauld's syndrome, and schlerodema.
  • the compounds of the present invention described herein selectively bind at the TRPM8 channels as opposed to other ion channels, in particular other TRP channels.
  • Compounds of formula (I) also preferably have a kinetic interaction with the TRPM8 target such that they are effective for use for the propylaxis or treatment of a wide range of diseases, conditions or syndromes, which disease, condition or syndrome is affected by the at least partial blocking of TRPM8, whilst at the same time demonstrating a reduced side effect profile.
  • the compounds of the present invention should also preferably be well absorbed from the Gl tract, be metabolically stable and possess favourable pharmacokinetic properties. They should preferably be non-toxic to mammals, more preferably be non-toxic to humans. In addition they should preferably not form metabolites which have a toxic or allergic profile. Furthermore, the most preferred compounds will exist in a physical form which is stable, non-hygroscopic, and easily formulated.
  • Embodiment (1 ) a compound of the formula (I):
  • A is (i) phenyl substituted at the 1 position by the carboxylic acid and the 3
  • R 1 is an 8 to 12 membered unsaturated or partially unsaturated fused bicyclic
  • R 1 being optionally substituted with one or more substituents each independently selected from the group consisting of halo, (Ci-C 3 )alkyl, halo(Ci-C 3 )alkyl, (d-C 3 )alkoxy, and halo(C 1 -C 3 )alkoxy;
  • R 2 is methyl or ethyl
  • R 3 is: (i) phenyl optionally substituted by one or more halo atoms, or
  • alkyl means an alicyclic, saturated hydrocarbon chain of the formula CnH 2n +i containing the requisite number of carbon atoms, which may be linear or branched.
  • alkyl means an alicyclic, saturated hydrocarbon chain of the formula CnH 2n +i containing the requisite number of carbon atoms, which may be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • alkoxy means an alicyclic, saturated hydrocarbon chain of the formula OC n H 2n +i containing the requisite number of carbon atoms, which may be linear or branched. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.
  • Haloalkyl and haloalkoxy mean an alkyl or alkoxy group, according to the definitions provided above, containing the requisite number of carbon atoms, substituted with one or more halo atoms as hereinbefore defined.
  • 5- or 6- membered aromatic heterocycles include oxiranyl, aziridinyl, oxetanyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which may be optionally substituted as specified.
  • 8 to 12 membered unsaturated or partially unsaturated fused bicyclic carbocycles include indenyl and naphthalenyl, each of which may be optionally substituted as specified.
  • 8 to 12 membered unsaturated or partially unsaturated fused bicyclic heterocycles containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur include, but are not limited to, benzodihydrofuranyl, benzodioxolanyl, benzofuranyl, benzimidazolyl, benzoxadiazolyl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, chromanyl, cinnolinyl, dihydroindanolyl, imidazopyridinyl, imidazopyridyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, 1 ,8-naphthyridinyl, pyridopyridyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, tetrahydobenzo
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Embodiment (1 ), wherein the A ring is phenyl.
  • A is phenyl it is preferred that it has no further substituents or is substituted at the 4 position by fluoro.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Embodiment (1 ), wherein A is pyridyl.
  • A is pyridyl, it is preferred that it has no further substituents.
  • the invention provies compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Embodiment (1 ), wherein A is phenyl and has no further substituents.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 is an 8 to 10 membered unsaturated or partially unsaturated fused bicyclic carbocycle or an 8 to 10 membered unsaturated or partially unsaturated fused bicyclic heterocycle containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said R 1 being optionally substituted with one or more substituents independently selected from the group consisting of halo, (C C 3 )alkyl, halo(C C 3 )alkyl, (C C 3 )alkoxy, and halo(C C 3 )alkoxy.
  • R 1 is an 8 to 10 membered unsaturated or partially unsaturated fused bicyclic carbocycle or an 8 to 10 membered unsaturated or partially unsaturated fused bicyclic heterocycle containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 an 8 to 12 membered unsaturated or partially unsaturated fused bicyclic carbocycle or an 8 to 12 membered unsaturated or partially unsaturated fused bicyclic heterocycle containing 1 , 2 or 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, providing that said carbocycle or heterocycle is not 1 -methyl-1 H-benzotriazol-5-yl, quinolin-2-yl, 2-methyl-1 H- benzimidazol-5-yl, imidazo[1 ,2-a]pyrimidin-2-yl, indolizin-2-yl, 2,3-dihydro-1 ,4- benzodioxin-2-yl, 4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridin-3-yl, 1 H-inda
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 is selected from benzodioxolanyl, benzofuranyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, imidazopyridinyl, indolyl, isoquinolinyl, naphthalenyl, pyrrolopyridinyl, quinolinyl, 5,6-dihydro-4H-pyrrolo[1 ,2- b]pyrazolyl, 1 H-pyrrolo[2,3-c]pyridinyl, 4,5,6,7-tetrahydro-1 H-indazolyl, benzdihydrofuranyl, benzoxadiazolyl, benztriazolyl, chromanyl, dihydroindano
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 is selected from benzodioxolanyl, which is unsubstituted; benzofuranyl which is unsubstituted; benzimidazolyl which is unsubstituted, or substituted with halo, for example fluoro; or (Ci-C 3 )alkyl, for example methyl; benzopyrazolyl which is unsubstituted or substituted with (Ci-C 3 )alkyl, for example methyl; benzothiazolyl which is unsubstituted; benzothiophenyl which is unsubstituted or substituted with (Ci-C 3 )alkyl, for example methyl; cinnolinyl which is unsubstituted; imidazopyridinyl which is unsubstituted; ind
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 is selected from benzodioxolanyl, which is unsubstituted; benzofuranyl which is unsubstituted; benzimidazol-2-yl which is unsubstituted, or substituted with halo, for example fluoro; or (C 1 -C 3 )alkyl, for example methyl; benzopyrazolyl which is unsubstituted or substituted with (C 1 -C 3 )alkyl, for example methyl; benzothiazolyl which is unsubstituted; benzothiophenyl which is unsubstituted or substituted with (C 1 -C 3 )alkyl, for example methyl; cinnolinyl which is unsubstituted; imidazopyridinyl which is unsubstituted; imidazopyr
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 is quinolinyl, which is unsubstituted or is substituted by one or more substituents selected from (Ci-C 3 )alkyl, for example methyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 is quinolin-3-yl, which is unsubstituted or is substituted by one or more substituents selected from (Ci-C 3 )alkyl, for example methyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (4), wherein R 1 is quinolin-3-yl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (12), wherein R 3 is phenyl which is unsubstituted, or optionally substituted by one or more halo atoms, for example fluoro, chloro or bromo (preferably fluoro), to form, for example, fluorophenyl, difluorophenyl, chlorophenyl, or dibromo, fluorophenyl.
  • R 3 is phenyl which is unsubstituted, or optionally substituted by one or more halo atoms, for example fluoro, chloro or bromo (preferably fluoro)
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (12), wherein R 3 is furanyl, optionally substituted with (C 1 -C 3 )alkyl, for example methyl to form methylfuranyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (12), wherein R 3 is 4-fluorophenyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (15), wherein R 2 is methyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (15), wherein R 2 is ethyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Embodiment (1 ), wherein A is phenyl; R 1 is selected from benzodioxolanyl, benzofuranyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, imidazopyridinyl, indolyl, isoquinolinyl, naphthalenyl, pyrrolopyridinyl, quinolinyl, 5,6-dihydro-4H-pyrrolo[1 ,2- b]pyrazolyl, 1 H-pyrrolo[2,3-c]pyridinyl, and 4,5,6,7-tetrahydro-1 H-indazolyl; R 2 is methyl or ethyl; and R 3 is phenyl or furanyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Embodiment (1 ), wherein A is pyridyl; R 1 is selected from benzodioxolanyl, benzofuranyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, cinnolinyl, imidazopyridinyl, indolyl, isoquinolinyl, naphthalenyl, pyrrolopyridinyl, quinolinyl, 5,6-dihydro-4H-pyrrolo[1 ,2- b]pyrazolyl, 1 H-pyrrolo[2,3-c]pyridinyl, and 4, 5, 6, 7-tetrahydro-1 H-indazolyl; R 2 is methyl or ethyl; and R 3 is phenyl or furanyl.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments (1 ) to (19), which has the absolute (R) stereochemistry at the chiral carbon atom bearing the R 2 and R 3 substituents.
  • Particularly preferred compounds of formula (I) include:
  • a more particularly preferred compound of formula (I) is 3-( ⁇ [(1 R)-1 -(4- fluorophenyl)ethyl](quinolin-3-ylcarbonyl)amino ⁇ methyl)benzoic acid, or a pharmaceutically acceptable salt thereof.
  • Figure 1 provides in vivo data demonstrating the effects of Example 71 at 16.3, 46.67 and 153.33ug/kg/min on Menthol Induced Reduction in Bladder Capacity in the Anaesthetised Guinea Pig.
  • references to compounds of the formula (I) below are to be construed to include a reference to any one of the Embodiments described above, any of the preferred compounds or groups of compounds alluded to above and any of the Examples specifically disclosed below.
  • Some compounds of the formula (I) may exist in several different tautomeric forms. Tautomerism, or tautomeric isomerism, occurs where structural isomers are interconvertible via a low energy barrier. It can take the form of proton tautomerism, so called valence tautomerism in compounds which contain an aromatic moiety. In some compounds different tautomeric isomers may exist with respect to the position of certain protecting groups or prodrug moieties. All references to compounds of formula (I) should be taken to include tautomers thereof, whether illustrated or not. Furthermore, one of ordinary skill would understand that certain intermediates used in the preparation of compounds capable of tautomerising are themselves capable of existing in different tautomeric forms. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isothionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and triflu
  • 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.
  • a pharmaceutically acceptable salt of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the compounds of formula (I) and their pharmaceutically acceptable salts may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of formula (I) and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • the compounds of formula (I) and their pharmaceutically acceptable salts may also exist as complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • Such complexes also include complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • references to compounds of formula (I) include references to pharmaceutically acceptable salts, solvates and complexes thereof and to solvates and complexes of said salts.
  • the invention covers compounds of formula (I), as hereinbefore defined, as well as polymorphs, prodrugs (including tautomeric forms of such prodrugs), and isomers thereof (including optical, geometric and tautomeric isomers).
  • compounds of formula (I) have a chiral centre.
  • compounds of Formula (I) include the R-isomers of compounds of Formula (I); the S- isomers of compounds of formula (I); and mixtures thereof, including the racemate, usually defined as a 50:50 mixture of the R-isomer and the S-isomer.
  • Preferred compounds of the present invention are those of Formula (IA) which can be depicted to have the following stereochemical orientation indicated below:
  • the invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined.
  • 'prodrugs' of the compounds of formula (I) are so-called 'prodrugs' of the compounds of formula (I).
  • 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 in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds 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).
  • prodrug forms of compounds of the present invention are possible.
  • prodrugs in accordance with the invention include:
  • a particularly useful prodrug of compounds of Formula (I) is formed by esterifi cation of the acid group bonded to ring A with R' wherein R' is (Ci-C 4 ) alkyl.
  • Such compounds are prepared by reaction of the COOH group of compounds of Formula (I), with a suitable alcohol, or pharmaceutically acceptable salts thereof.
  • Such prodrug compounds can generally be schematically represented as shown below by Formula (IB):
  • prodrugs as set out in Formula (I B) above, and pharmaceutically acceptable salts, thereof.
  • prodrugs are particularly useful because of their potential for improved bioavailability when compared to the parent compound, i.e. that with the unsubstituted acid group moiety.
  • Compounds of formula (I) may contain one or more asymmetric carbon atoms in addition to the chiral centre discussed above and exist in a number of stereoisomeric forms. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL- arginine.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • 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, an acid or base such as tartaric acid or 1-phenylethylamine.
  • 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, an acid or base such as tartaric acid or 1-phenylethylamine.
  • 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 formula (I) 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% isopropanol, typically from 2 to 20%, and from 0 to 5% 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% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) 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 usually found in nature.
  • isotopes suitable for inclusion in the compounds of formula (I) 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, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, 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, and 125 l 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.
  • 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 reagents in place of the non-labeled reagent previously employed.
  • the compounds of formula (I) are comprised of atoms such that the average atomic mass or mass number for each atom of each element prsent corresponds to the average atomic mass or mass number for that element as it occurs in nature.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone, de-DMSO.
  • the compounds of formula (I), being TRPM8 blockers, are potentially useful in the treatment of a range of disorders.
  • TRPM8 blocker is taken to mean a compound that causes a decrease in the activation of TRPM8 by agonist (menthol or WS-12), cold or voltage stimulation.
  • a TRPM8 blocker may be identified though measuring the inhibition of Ca 2+ signal in cells containing TRPM8 ion channels using a method such as the in vitro assay described herein.
  • a TRPM8 blocker can be identified by electrophysiological approaches, for example using those methods disclosed in McKemy et al, Nature 2002, 416(6876), 52-58.
  • Urological diseases, conditions or syndromes which may be usefully treated or prevented with the compounds of formula (I) include, but are not limited to, over active bladder (detrusor overactivity), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, painful bladder syndrome, interstitial cystitis and lower urinary tract symptoms.
  • over active bladder detrusor overactivity
  • urinary incontinence urinary incontinence
  • neurogenic detrusor overactivity detrusor hyperflexia
  • idiopathic detrusor overactivity detrusor instability
  • benign prostatic hyperplasia painful bladder syndrome
  • interstitial cystitis and lower urinary tract symptoms.
  • OAB Over Active Bladder
  • OAB Wet and OAB Dry describe OAB patients with or without urinary incontinence respectively.
  • the cardinal symptom of OAB was believed to be urinary incontinence.
  • this is clearly not meaningful for the large number of sufferers who are not incontinent (i.e. OAB Dry patients).
  • a recent study from Liberman et al ['Health Related Quality of Life Among Adults with Symptoms of Over active Bladder:Results From A US Community-Based Survey'; Urology 57(6), 1044-1050, 2001 ] examined the impact of all OAB symptoms on the quality of life of a community-based sample of the US population. This study demonstrated that individuals suffering from OAB without any demonstrable loss of urine have an impaired quality of life when compared with controls.
  • Urinary incontinence any condition in which there is an involuntary leakage of urine
  • stress urinary incontinence urge urinary incontinence and mixed urinary incontinence
  • active bladder with associated urinary incontinence
  • enuresis nocturnal enuresis
  • continuous urinary incontinence and situational urinary incontinence such as incontinence during sexual intercourse.
  • Interstitial cystitis is a chronic bladder disease, of unknown origin, characterized by symptoms of pain, such as pelvic pain, and lower urinary tract symptoms (LUTS) such as increased urinary frequency or urgency. More recently terminology has evolved to include painful bladder syndrome (PBS) (MacDiarmid SA et al, Rev Urol, 9(1 ), 9-16 (2007)) or bladder pain syndrome (BPS) (van der Merve et al, European Urology, 53, 60-67 (2008)), along with IC, that is IC/PBS/BPS to collectively describe this symptom complex.
  • PBS painful bladder syndrome
  • BPS bladder pain syndrome
  • IC that is IC/PBS/BPS to collectively describe this symptom complex.
  • Prevalence rates of IC/PBS/BPS vary from 67 to 230 per 100,000 women having clinically confirmed disease, although the number is likely higher than this due to under- or mis-diagnosis, commonly as endometriosis, recurrent urinary tract infection, over active bladder or vulvodynia (Forrest J B et al, Clinical Courier 24(3), 1 -8 (2006)).
  • IC has a significant impact on quality of life, affecting travel, family relationships, and employment (Slade et al, Urol., 49 (5A Suppl), 10-3(1997)), as well as being associated with depressive symptoms (Rothrock et al, J. Urol., 167: 1763- 1767(2002)).
  • LUTS comprise three groups of urinary symptoms, which may be defined as storage (irritative), voiding (obstructive) and post-micturition symptoms.
  • Storage symptoms comprise urgency, frequency, nocturia, urgency incontinence and stress
  • Voiding symptoms comprise hesitancy, poor flow, intermittency, straining and dysuria.
  • Post-micturition symptoms comprise terminal dribbling, post-void dribbling and a sense of incomplete emptying.
  • BPH is a chronically progressive disease that can lead to complications such as acute urinary retention, recurrent urinary tract infections, bladder stones and renal dysfunction.
  • the prevalence and average severity of LUTS associated with BPH in men increases with age.
  • BPH leads to an increase in prostate volume, creating urethral and bladder outflow obstruction as well as secondary changes in bladder function.
  • the effects of this are manifested by both storage (irritative) and voiding (obstructive) symptoms.
  • Pain diseases, conditions or syndromes which may be usefully treated or prevented with the compounds of formula (I) include, but are not limited to, cold allodynia regardless of cause, thermal hyperalgesia, headaches, migraine, post operative pain, osteoarthritis, acute pain, chronic pain, cutaneous pain, somatic pain, visceral pain, referred pain including myocardial ischaemia, phantom pain, neuropathic pain (neuralgia), neuralgias such as trigeminal neuralgia, glossopharyngeal neuralgia, postherpatic neuralgia and causalgia, pain arising from injuries, cancer pain, pain arising from use of chemotherapeutic agents, pain arising from neurological diseases such as Parkinson's disease, pain arising from spine and peripheral nerve surgery, brain tumors, traumatic brain injury, spinal cord trauma, chronic pain syndromes, chronic fatigue syndrome, pain arising from lupus, sarcoidosis, arachnoiditis, arthritis, rheumatic disease,
  • the treatment of pain using a compound of formula (I) is a preferred embodiment of the invention.
  • the treatment of cold allodynia is a particularly preferred embodiment.
  • the treatment of Raynauld's syndrome is another particularly preferred embodiment.
  • 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. In contrast, 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.
  • neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
  • back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • 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, postoperative 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
  • IBD 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 (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, 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.
  • 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.
  • Repiratory diseases, conditions or syndromes which may be usefully treated or prevented with the compounds of formula (I) include, but are not limited to, diseases, conditions or syndromes including, for example, including rhinitis, allergic rhinitis, asthma for example allergen induced asthma, exercise induced asthma, pollution induced asthma, viral induced asthma or cold induced asthma; chronic obstructive pulmonary disease (COPD) including chronic bronchitis; aliments that involve inflammation of one or more components of the respiratory system including emphysema, asthmatic bronchitis, bullous disease, and other pulmonary diseases involving inflammation which include cystic fibrosis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, pneumonia, aspiration or inhalation injury, fat embolism in the lung, acidosis inflammation of the lung, acute pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reaction
  • Types of asthma include atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whez infant syndrome and bronchiolytis.
  • the treatment of asthma includes palliative treatment for the symptoms and conditions of asthma such as wheezing, coughing, shortness of breath, tightness in the chest, shallow or fast breathing, nasal flaring (nostril size increases with breathing), retractions (neck area and between or below the ribs moves inward with breathing), cyanosis (gray or bluish tint to skin, beginning around the mouth), runny or stuffy nose, and headache.
  • Inflammation diseases, conditions or syndromes which may be usefully treated or prevented with the compounds of formula (I) include, but are not limited to, inflammatory bowel disease, rheumatoid arthritis.
  • Neurological diseases, conditions or syndromes which may be usefully treated or prevented with the compounds of formula (I) include, but are not limited to, those diseases, conditions or syndromes associated with the modulation of the senstation of saiety perception including obesity, anorexia, weight maintenance, metabolic energy levels inflammatory conditions.
  • TRPM8 may have utility include those such as treatment of stroke, traumatic brain injury, neonatal trauma including neonatal encephalopathy and neonatal asphyxia.
  • treatment means administration of the compound, pharmaceutical composition or combination to effect preventative, palliative, supportive, restorative or curative treatment.
  • treatment encompasses any objective or subjective improvement in a subject with respect to a relevant condition or disease.
  • prevention treatment means that the compound, pharmaceutical composition or combination is administered to a subject to inhibit or stop the relevant condition from occurring in a subject, particularly in a subject or member of a population that is significantly predisposed to the relevant condition.
  • palliative treatment means that the compound, pharmaceutical composition or combination is administered to a subject to remedy signs and/or symptoms of a condition, without necessarily modifying the progression of, or underlying etiology of, the relevant condition.
  • support treatment means that the compound, pharmaceutical composition or combination is administered to a subject as a part of a regimen of therapy, but that such therapy is not limited to administration of the compound, pharmaceutical composition or combination.
  • supportive treatment may embrace preventive, palliative, restorative or curative treatment, particularly when the compounds or pharmaceutical compositions are combined with another component of supportive therapy.
  • restorative treatment means that the compound, pharmaceutical composition or combination is administered to a subject to modify the underlying progression or etiology of a condition.
  • Non-limiting examples include an increase in forced expiratory volume in one second (FEV 1 ) for lung disorders, decreased rate of a decline in lung function over time, inhibition of progressive nerve destruction, reduction of biomarkers associated and correlated with diseases or disorders, a reduction in relapses, improvement in quality of life, reduced time spent in hospital during an acute exacerbation event and the like.
  • curative treatment means that compound, pharmaceutical composition or combination is administered to a subject for the purpose of bringing the disease or disorder into complete remission, or that the disease or disorder is undetectable after such treatment.
  • Compounds of formula (I) intended for pharmaceutical use may be administered as crystalline or amorphous products. 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.
  • 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.
  • 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).
  • the compounds of formula (I) 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 (including muco-adhesive), ovules, sprays and liquid formulations.
  • 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 formula (I) may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001 ).
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% 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 wt% to 25 wt%, preferably from 5 wt% to 20 wt% 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 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% 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 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% 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.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed- , controlled-, targeted and programmed release.
  • 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 Verma et al, Pharmaceutical Technology On-line, 25(2), 1 -14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of formula (I) 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 formula (I) 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 PGLA microspheres.
  • the compounds of formula (I) 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 examples include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free ⁇ e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed- , controlled-, targeted and programmed release.
  • Topical administration of the compounds of formula (I) is particularly preferred, especially in the treatment of cold allodynia and/or Reynauld's syndrome.
  • the compounds of formula (I) 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 HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of formula (I), a suitable powder base such as lactose or starch and a performance modifier such as /-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 formula (I) 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.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • 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 the compound of formula (I).
  • the overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of formula (I) may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal 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 formula (I) 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 non-biodegradable (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.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds of formula (I) 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 International Patent Applications Nos. WO 91/1 1 172, WO 94/02518 and WO 98/55148.
  • 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 formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • 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 total daily dose of the compounds of formula (I) depends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous dose.
  • the total daily dose may be administered in single or divided doses.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • a TRPM8 blocker may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of urological diseases, conditions or syndromes, more specifically over active bladder, painful bladder syndrome, and interstitial cystitis; and pain diseases, conditions or syndromes, more specifically cold allodynia regardless of cause, trigeminal neuralgia, glossopharyngeal neuralgia, Raynauld's syndrome, and schlerodema.
  • TRPM8 blockers particularly a compound of formula (I), or a pharmaceutically acceptable salt, thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
  • a muscarinic antagonist eg oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine, and ipratropium;
  • beta 3 adrenergic receptor agonist such as mirabegron or solabegron
  • a local anaesthetic such as lidocaine or mexiletine
  • a sodium channel modulator such as a Nav1.3 modulator, for example those disclosed in WO 2008/1 18758;
  • a Nav1.7 modulator for example those disclosed in WO 2009/012242 or WO 2010/079443; or a Nav1.8 modulator, for example those 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 opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • NSAID nonsteroidal antiinflammatory drug
  • NSAID 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
  • NSAID nonsteroidal antiinflammatory drug
  • H-i antagonist e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
  • an histamine type 2 receptor antagonist e.g. loratidine, fexofenadine, desloratidine, levocetirizine, methapyrilene or cetirizine;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • 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 COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib
  • a prostaglandin E 2 subtype 4 (EP4) antagonist such as A/-[( ⁇ 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;
  • coal-tar analgesic in particular paracetamol
  • 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) or antagonist (e.g. capsazepine);
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist for example a 5-HT 1 B/ ID agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; a 5-HT2c receptor agonist, or a 5-HT 2 A receptor antagonist such as R(+)-alpha-(2,3- dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL- 100907);
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-i 7 34), (E)-N- methyl-4-(3-pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2- azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDE inhibitor such as a PDE3 inhibitor, a PDE4 inhibitor, a PDE5 inhibitor, or a PDE9a inhibitor, such as theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast;
  • 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)- 3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3- chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1 R,5R,6S)-6- (aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1 -aminomethyl- cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-
  • 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-hep
  • an acetylcholinesterase inhibitor such as donepezil
  • 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 2,3,5-trimethyl-6-(3-pyridylmethyl),1 ,4-benzoquinone (CV-6504);
  • a 5-HT3 antagonist such as ondansetron
  • FLAP 5-lipoxygenase activating protein
  • LTRA leukotriene antagonist
  • LTC 4 an antagonist of LTB 4 , LTC 4 , LTD 4 , LTE 4 , CysLT-i or CysLT 2 , e.g. montelukast or zafirlukast
  • CysLT-i or CysLT 2 e.g. montelukast or zafirlukast
  • an ⁇ 1 -adrenoceptor or 32-adrenoceptor agonist such as phenylephrine, methoxamine, oxymetazoline or methylnorephrine;
  • an anti-inflammatory monoclonal antibody such as infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab;
  • a ⁇ 2 agonist e.g. salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularly a long-acting ⁇ 2 agonist
  • an intigrin antagonist such as natalizumab
  • an adhesion molecule inhibitor such as a VLA-4 antagonist
  • an immunosuppressive agent such as an inhibitor of the IgE pathway (e.g. omalizumab) or cyclosporine;
  • MMP matrix metalloprotease
  • a dopamine receptor agonist e.g. ropinirole
  • a dopamine D2 receptor agonist e.g. bromocriptine
  • a modulator of the N FKB pathway such as an IKK inhibitor
  • a modulator of a cytokine signalling pathway such as an inhibitor of syk kinase, JAK kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK- 2;
  • EaC epithelial sodium channel
  • EaC Epithelial sodium channel
  • nucleotide receptor agonist such as a P2Y2 agonist
  • HPGDS haematopoietic prostaglandin D2 synthase
  • a soluble human TNF receptor e.g. Etanercept
  • Such combinations may offer significant advantages, including synergistic activity, in therapy.
  • co-administration As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to a combination of a compound of formula (I) and one or more other therapeutic agents, includes the following:
  • 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 formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • 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.
  • compounds of formula (I) may be prepared from compounds of formula (III) by the process illustrated in Scheme 1 .
  • Compounds of formula (III) can be prepared in reaction step (i) by reductive amination of compounds of formula (VI) with compounds of formula (VII) using a suitable reducing agent, such as sodium borohydride or sodium triacetoxyborohydride, in a suitable solvent, such as methanol, toluene or diclhloromehtane, from 0°C to ambient temperature.
  • a suitable reducing agent such as sodium borohydride or sodium triacetoxyborohydride
  • a suitable solvent such as methanol, toluene or diclhloromehtane
  • the reaction may optionally be buffered with a suitable base such as triethylamine, or dehydrate with molecular sieves and para-toluene sulphonic acid monohydrate.
  • compounds of formula (III) can be prepared in reaction step (ii) by an alternative reductive amination of compounds (VIII) or (IX) using a suitable reducing agent, such as sodium borohydride or sodium triacetoxyborohydride, in a suitable solvent, such as methanol, toluene or dichloromethane, from 0°C to ambient temperature.
  • a suitable reducing agent such as sodium borohydride or sodium triacetoxyborohydride
  • a suitable solvent such as methanol, toluene or dichloromethane
  • the reaction may optionally be buffered with a suitable base such as triethylamine, or dehydrate with molecular sieves and para-toluene sulphonic acid monohydrate.
  • Compounds of formula (VIII) or (IX) are either commercially available, or can be readily prepared by methods described in the literature. Compounds of formula (II) can then be prepared from compounds of formula (III) in reaction step (iii) by formation of the amide via amide coupling with compounds of formula (IV), using a suitable activating agent, such as hydrosybenzotriazoly urea (HBTU), water soluble carbodiamide (WSCDI), propyl phosphonic anhydride (T3P), chloro-N, N, N', N' - tetramethylformaamidinium hexafluorophosphate (Gohsez reagent), or 2-chloro-1 ,3-dimethylimidazolinium chloride with a suitable base, such as triethylamine or Hunig's base, in a suitable solvent such as dichlormethane, THF or diethylacetamide from ambient temperature to 65°C.
  • a suitable activating agent such as hydros
  • the compounds of formula (II) can be prepared from compounds of formula (III), again in reaction step (iii), by reaction with an acid chloride, compounds of formula (V), in a suitable solvent, such as dichloromethane, in the presence of a suitable base, such as triethylamine or Hunig's base, at ambient temperatures.
  • a suitable solvent such as dichloromethane
  • a suitable base such as triethylamine or Hunig's base
  • compounds of formula (I) may be prepared from compounds of formula (V) and compounds of formula (VII) by the process illustrated in Scheme 2.
  • LG is a suitable leaving group, preferably halo for example chloro, bromo; tosyl; or mesylate.
  • halo for example chloro, bromo; tosyl; or mesylate.
  • Compounds of formula (X) can be prepared from compounds of formula (VII) in reaction step (v) by reaction with compounds of formula (V) in a suitable solvent, such as dichloromethane, in the presence of a suitable base, such as triethylamine or Hunig's base, at ambient temperatures.
  • a suitable solvent such as dichloromethane
  • a suitable base such as triethylamine or Hunig's base
  • Compounds of formula (II) may then be prepared from compounds of formula (X) in reaction step (vi) by deprotonation with a suitable base, for example sodium hydride, lithium hydride or lithium hexamethyldisilazide in a suitable solvent such as THF N- methylpyrolidinone, followed by amide alkylation with compounds of formula (XI), wherein LG is a suitable leaving group such as halo for example chloro, bromo; tosyl; or mesylate.
  • Suitable reaction conditions are at a temperature of from -20°C to 50°C.
  • protecting groups are present, these will be generally interchangeable with other protecting groups of a similar nature, e.g. where a sulfonamide is described as being protected with a tert-butyl or dimethoxybenzyl group, this may be readily interchanged with any suitable sulfonamide protecting group.
  • Suitable protecting groups are described in 'Protective Groups in Organic Synthesis' by T. Greene and P. Wuts (3 rd edition, 1999, John Wiley and Sons).
  • the present invention also relates to novel intermediate compounds as defined above, 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.
  • NMR Nuclear magnetic resonance
  • Mass spectroscopy was carried out using a Finnigan Navigator single quadrupole electrospray mass spectrometer or a Finnigan aQa APCI mass spectrometer.
  • CDCI 3 deuterochloroform
  • d 6 -DMSO deuterodimethylsulphoxide
  • CD 3 OD deuteromethanol
  • THF tetrahydrofuran.
  • Ammonia' refers to a concentrated solution of ammonia in water possessing a specific gravity of 0.88.
  • reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions.
  • the ester from Preparation 27 (1 .692g, 3.687mmol) was dissolved in methanol (50ml_). 1 M aqueous sodium hydroxide (20ml_) was added and the mixture stirred at 50 C for 2 hours. The reaction was concentrated in vacuo and the residue was dissolved in water (50ml_) and washed with methyl t-butyl ether (25ml_). The aqueous layer was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate (50ml_), dried (MgS0 4 ), filtered and concentrated in vacuo.
  • Examples 2-60 were similarly prepared according to the method described above for example 1 , starting from the ap ropriate ester.
  • the lower layer was removed and water (75ml_) was added to the other layers giving a bi- phasic system which was washed with ethyl acetate (60ml_).
  • the aqueous layer was acidified to pH 5-6 by addition of a 36.5% hydrochloric acid (1 ml_) prior to being extracted with ethyl acetate (75ml_).
  • the aqueous layer was re-acidified to pH 4 by addition of a 36.5% hydrochloric acid (2ml_) before being extracted with ethyl acetate (75ml_).
  • Methyl 3-(aminomethyl)benzoate (245mg, 1 .48mmol) was dissolved in toluene (8ml_) and 1 -(2,4-difluorophenyl)ethanone (0.19ml_, 1.48mmol), p-toluenesulfonic acid (10mg, catalytic) and 4A sieve was added. The reaction mixture was heated at reflux over night. The reaction mixture was concentrated in vacuo to give a brown oil which was dissolved in methanol (4ml_) and sodium borohydride (56mg, 1 .48mmol) was added. The reaction mixture was stirred at room temperature under argon for 1 hour. Water was added and the methanol was removed in vacuo.
  • the title compound was prepared according to the method of preparation 9 from methyl 3-(aminomethyl)benzoate (0.26g, 1.57mmol) and 1-(2-fluorophenyl)ethanone (217mg, 1.57mmol) to give the title compound as a yellow oil (230mg, 51%).
  • the title compound was prepared according to the method of Preparation 13 from methyl 3-formylbenzoate (58.9mg, 0.359mmol) and (1 R)-1-(5-methyl-2-furyl)propan- 1 -amine (50mg, 0.36mmol) to give the title compound (78mg, 76%).
  • Pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (44.4mg, 0.274mmol) was suspended in dichloromethane (1 ml_) and treated with 1-Chloro-/V,/V,2-trimethyl-1 -propenylamine (109uL, 0.823mmol). The mixture was stirred at room temperature for 30 minutes during this time a solution was given. This solution was then used straight away.
  • Preparations 28-60 were similarly prepared according to the method described above for preparation 27, starting from the appropriate amine from preparations 1 -3,9- 16, 100 and the appropriate acid chloride.
  • Preparations 61 -66 were similarly prepared according to the method described above for preparation 27, starting from the appropriate amine from preparations 17-19 and the appropriate acid chloride.
  • the ester from preparation 67 (1.0g, 4.90mmol) was dissolved in methanol (10ml_) and 2.5M aqueous lithium hydroxide (5.88ml_, 14.7mmol) was added, the reaction mixture was then stirred at room temperature over night. The methanol was removed in vacuo and the residue dissolved in water (7.5ml_), acidified with 2M aqueous HCI to pH4 and the solid collected by filtration. The solid was washed with water and dried to give the title compound as a white solid (580mg, 56%).
  • lsoquinoline-3-carboxylic acid (32.6mg, 0.188mmol) was dissolved in dichloromethane (4ml_) and HBTU (77.4mg, 0.204mmol) was added followed by triethylamine (65.7 ⁇ _, 0.471 mmol). The resulting solution was allowed to stir at room temperature for 10mins prior to the addition of amine from preparation 4 (50mg, 0.16mmol). The resulting reaction mixture was then allowed to stir at room temperature over night.
  • Preparations 70-80 were similarly prepared according to the method described above for preparation 69, starting from the appropriate amine from preparations 2-4,100 and the appropriate acid.
  • Preparations 83-96 were similarly prepared according to the method described above for Preparation 82, starting from the appropriate amine from Preparations 5-7 and the appropriate acid.

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Abstract

La présente invention concerne un composé de formule (I) : dans lequel A, R1, R2 et R3 sont tels que définis dans la description, ou un sel pharmaceutiquement acceptable de celui-ci. De tels composés sont des antagonistes de TRPM8 à petite molécule et sont par conséquent utiles dans la prophylaxie ou le traitement d'une large gamme de maladies, affections ou syndromes, comprenant l'allodynie froide et le syndrome de Raynaud.
PCT/IB2012/050834 2011-03-04 2012-02-23 Dérivés de carboxamide substitués par aryle en tant que modulateurs de trpm8 Ceased WO2012120398A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
WO2015108136A1 (fr) * 2014-01-17 2015-07-23 キッセイ薬品工業株式会社 Dérivé de glycinamide substitué en alpha
WO2016039448A1 (fr) * 2014-09-12 2016-03-17 田辺三菱製薬株式会社 Composé aromatique d'amide d'acide carboxylique
WO2017044458A1 (fr) * 2015-09-08 2017-03-16 The University Of Toledo Traitement du phénomène de raynaud par inhibition de mélastatine de potentiel de récepteur transitoire 8 (trpm-8)
WO2018172852A1 (fr) * 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
WO2018181892A1 (fr) * 2017-03-31 2018-10-04 国立大学法人 長崎大学 Composé de quinolinone et médicament anti-virus à arn
WO2022105986A1 (fr) * 2020-11-17 2022-05-27 Symrise Ag Nouveaux agents de refroidissement et préparations les contenant

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US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
WO2015108136A1 (fr) * 2014-01-17 2015-07-23 キッセイ薬品工業株式会社 Dérivé de glycinamide substitué en alpha
JPWO2015108136A1 (ja) * 2014-01-17 2017-03-23 キッセイ薬品工業株式会社 α−置換グリシンアミド誘導体
WO2016039448A1 (fr) * 2014-09-12 2016-03-17 田辺三菱製薬株式会社 Composé aromatique d'amide d'acide carboxylique
US11612560B2 (en) 2015-09-08 2023-03-28 The University Of Toledo Treatment of Raynaud's phenomenon by inhibition of transient receptor potential melastatin-8 (TRPM-8)
WO2017044458A1 (fr) * 2015-09-08 2017-03-16 The University Of Toledo Traitement du phénomène de raynaud par inhibition de mélastatine de potentiel de récepteur transitoire 8 (trpm-8)
WO2018172852A1 (fr) * 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
US11098010B2 (en) 2017-03-21 2021-08-24 Arbutus Biopharma Corporation Substituted dihydroindene-4-carboxamides and analogs thereof, and methods using same
JPWO2018181892A1 (ja) * 2017-03-31 2020-04-16 国立大学法人 長崎大学 キノリノン化合物および抗ｒｎａウイルス薬
JP7061394B2 (ja) 2017-03-31 2022-04-28 国立大学法人 長崎大学 キノリノン化合物および抗ｒｎａウイルス薬
WO2018181892A1 (fr) * 2017-03-31 2018-10-04 国立大学法人 長崎大学 Composé de quinolinone et médicament anti-virus à arn
WO2022105986A1 (fr) * 2020-11-17 2022-05-27 Symrise Ag Nouveaux agents de refroidissement et préparations les contenant
WO2022106452A3 (fr) * 2020-11-17 2022-07-14 Symrise Ag Nouveaux rafraîchissants et préparations les contenant
CN116685575A (zh) * 2020-11-17 2023-09-01 西姆莱斯股份公司 新型清凉物质以及包含这些清凉物质的制剂

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