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WO2010092342A1 - Composés d'organosilicium et leur utilisation en tant que modulateurs du récepteur trpv1 - Google Patents

Composés d'organosilicium et leur utilisation en tant que modulateurs du récepteur trpv1 Download PDF

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Publication number
WO2010092342A1
WO2010092342A1 PCT/GB2010/000246 GB2010000246W WO2010092342A1 WO 2010092342 A1 WO2010092342 A1 WO 2010092342A1 GB 2010000246 W GB2010000246 W GB 2010000246W WO 2010092342 A1 WO2010092342 A1 WO 2010092342A1
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alkyl
methyl
compound according
optionally substituted
trimethylsilyl
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Andrew Paul Ayscough
Graham Andrew Showell
Martin Richard Teall
Hannah Elizabeth Temple
Saleh Ahmed
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si

Definitions

  • the present invention relates to compounds and their use.
  • it relates to novel silicon-containing compounds having pharmacological activity, to pharmaceutical compositions containing them, and to their use in therapy.
  • the compounds function as modulators at the TrpVl receptor and therefore have potential use in the treatment or prevention of conditions having an association with the vanilloid receptor 1, TrpVl.
  • TrpVl The mammalian transient receptor potential (TRP) channels are a superfamily (including TRPC, TRPV, TRPP, TRPM, TRPA, TRPML and TRPN families) of ion channels that have a diverse range of physiological functions and are present in many tissues and almost all cell types.
  • TrpVl also known as VRl
  • TrpVl is a member of the TRPV family represented by TRPV1-TRPV6 in addition to Osm-9 from C. elegans and Nanchung (Nan) from Drosophila. TrpVl was first identified in 1997 (1) as a non-selective cation channel and the target for capsaicin, the active ingredient in hot peppers.
  • TrpVl is activated or sensitized by moderate heat and a number of different inflammatory mediators such as capsaicin, vanilloid, endocannabinoid, eicosanoids, anandamides and low pH.
  • the receptor is highly expressed in small to medium sensory neurons of the dorsal root and trigeminal ganglia (1), and innervates many visceral organs including bone, bladder, dermis, lungs and gastrointestinal tract. It is also expressed in other neuronal and non-neuronal tissues including the CNS nuclei, kidney, stomach and T-cells.
  • TrpVl as a sensory mediator has resulted in the development of agonists and antagonists with potential in the treatment of a diverse range of chronic inflammatory conditions, for example neuropathic pain and more recently arthritis (2).
  • TrpVl is associated with the transduction of painful thermal stimuli (1) and disruption of the VRl gene in mice resulted in a lack of response to capsaicin-, acid-, and heat-gated responses previously reported in small diameter dorsal root ganglion neurons and impaired thermal inflammatory hyperalgesia (3,4).
  • This research confirms that VRl plays an essential role in human pain pathways and antagonists have utility in the treatment of a diverse range of pain conditions, for example TrpVl antagonist SB-705498 effectively reduces hyperalgesia and allodynia in animal models (5).
  • TrpVl antagonist SB-705498 effectively reduces hyperalgesia and allodynia in animal models (5).
  • Expression of TrpVl on sensory nerves that innervate maxillary molar teeth suggests that activation of the channel contributes to tooth pain (6).
  • VRl antagonist compounds e.g.
  • BCTC BCTC, GRC-621 1, ABT-102, JNJ-17203212, JNJ-38748021, NGD-8243 and SPM-955 are currently being investigated for use in the treatment of pain, including migraine, dental pain, neuropathic pain and urinary incontinence-associated pain.
  • TrpVl Over-expression of TrpVl in the gastrointestinal tract has been shown in inflammatory bowel disease, Crohn's Disease and ulcerative colitis; therefore receptor activation is implicated in gastrointestinal inflammation and function (7).
  • TrpVl antagonists JNJ-17203212 and JNJ-38748021 are currently in clinical development for the treatment of inflammatory bowel disease, particularly colitis. TrpVl is implicated directly in the pathogenesis of pancreatitis (8) as many of the mediators that participate in the development of the condition also act on TrpVl expressed on the sensory fibres (9). The ability of capsaicin to induce a cough and the presence of TrpVl on the sensory respiratory nerves together provide strong evidence that TrpVl is implicated in cough induction.
  • antagonists may have use in the treatment of asthma, cough and chronic obstructive pulmonary disease (COPD) (10, 11).
  • COPD chronic obstructive pulmonary disease
  • Clinical evidence supports an increase in TrpVl sensitivity to capsaicin-induced cough in patients suffering from respiratory infection or allergic asthma (12, 13).
  • Antagonist compound JNJ- 17203212 is in development for the treatment of cough and has been shown to reduce the number of capsaicin-induced coughs in animal models.
  • TrpVl is functionally expressed in the uroepithelium and implicated in the development of the micturition reflex in both normal and pathological conditions (14).
  • Antagonists to TrpVl have been shown to have efficacy in models of bladder disorders, for example GRC- 6211 completely abolished increased bladder reflex activity in models of cystitis, supporting the role of TrpVl in bladder inflammation (15).
  • TrpVl is expressed on sensory neurons innervating the pancreas and recent research using TrpVl knock out models suggest that antagonists may have benefit in the treatment of type I (automimmune) diabetes (16).
  • TrpVl is reported as a promising new target for therapeutic interventions in obesity related disorders, and type II diabetes (17).
  • WO200208221 discloses TrpVl antagonist diary 1 piperazines useful in the treatment of chronic and acute pain, urinary incontinence and itch.
  • WO2003066595 discloses TrpVl antagonist piperazine compounds useful in the treatment of pain, urinary incontinence, inflammatory conditions and neurodegenerative diseases.
  • WO2008002247 discloses pyridine P2Yi 2 antagonist compounds useful in the treatment of thrombotic conditions and cardiovascular diseases.
  • WO200401 1441 discloses pyridazinylpiperazine mGluRl antagonists useful in the treatment of pain, urinary incontinence, inflammatory bowel disease and irritable bowel syndrome.
  • TrpVl modulators that demonstrate improved drug-like properties.
  • Sila-substitution (C/Si-exchange) of drugs is a relatively recent approach for searching for organo-silicon compounds which have beneficial biological properties.
  • the approach involves the replacement of specific carbon atoms in compounds by silicon. A review of this approach is provided in Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986).
  • Xi, X 2 , X 3 and X 4 independently represent CH or N;
  • R 1 , R 2 and R 3 independently represent Ci. 6 alkyl, C 3-8 cycloalkyl or C 3 . 8 cycloalkylCi_ 6 alkyl, each of which groups may be optionally substituted with one or more substituents independently selected from halogen and haloCi -6 alkyl;
  • R 4 , R 5 , R 6 , R7, Re and R 9 independently represent H, Ci -6 alkyl, C 3-8 cycloalkyl or -Qi-ORi 4 , or R 4 and R 9 may join to form a bridging Ci -6 alkylene chain;
  • Rio represents aryl or heteroaryl, each of which may be optionally substituted by one or more substituents, independently selected from halogen, Ci -6 alkyl, haloCi_ 6 alkyl, hydroxyC ⁇ alkyl, haloC].
  • Qi and Q 2 independently represent a covalent bond, Ci -6 alkylene, or C 1-6 alkylene substituted with hydroxy;
  • R 12 and R 13 independently represent a H atom, or a C 1-6 alkyl or C 3-8 cycloalkyl group, in which each group may be optionally substituted with one or more Q -6 alkoxy; or when Ri 2 and R 13 are attached to the same nitrogen atom they may join to form a nitrogen containing heterocyclyl ring, which may be optionally substituted with one or more substituents independently selected from Ci -6 alkyl and C 1-6 alkoxy;
  • R M represents a H atom, or a Q -6 alkyl or C 3-8 cycloalkyl group, in which each group may be optionally substituted with one or more C 1-6 alkoxy;
  • Y represents a covalent bond, C 1-6 alkylene, or -O-.
  • m represents O, 1 or 2;
  • Rn which is optionally present and may be attached to any available carbon atom X 1 to X 4 instead of H, represents halogen, haloC 1-6 alkyl, C )-6 alkoxy, haloCi -6 alkoxy, cyano or Ci -6 alkyl which may be optionally substituted with one or more substituents independently selected from halogen, haloC 1-6 alkyl and OR 16 ; q represents 0, 1 or 2;
  • W represents -(CH 2 ),,-, which may be optionally substituted with one or more substituents independently selected from Ci -6 alkyl, C 3 . 8 cycloalkyl and -Q 3 -ORi 5 ; n represents 1 or 2;
  • Q 3 represents a covalent bond or C ]-6 alkylene
  • Ri 5 represents H, C] -6 alkyl, or C 3-8 cycloalkyl
  • R] 6 is as defined for R] 4 ; or a pharmaceutically acceptable salt or ester thereof.
  • the compounds of the invention have been found to modulate the TrpVl receptor.
  • the compounds possess antagonist activity at this receptor.
  • the compounds may have the potential to display useful selectivity for the TrpVl receptor.
  • any group in the compound of formula (I) above is referred to as being optionally substituted, this group may be unsubstituted or substituted by one or more substituents. Typically any such group will be unsubstituted, or substituted by one or two substituents.
  • C] -6 alkyl refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • Ci -6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl and hexyl.
  • 'C x-y alkylene' refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from 'C x-y alkyl' above.
  • Q -6 alkylene groups include methylene, ethylene, propylene, methylmethylene and dimethylmethylene.
  • 'C x-y alkoxy' refers to an -O-C x-y alkyl group wherein C x-y alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • C 3-8 cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms.
  • Examples of C 3-8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • CycloalkylCi -6 alkyl' refers to a Ci -6 alkyl group as defined herein wherein a hydrogen atom is replaced with a C 3-8 cycloalkyl group. Examples include cyclopropylmethyl.
  • 'halogen' as used herein refers to a fluorine, chlorine, bromine or iodine atom, unless otherwise specified.
  • cyano represents a -CN group.
  • hydroxy represents a -OH group.
  • 'hydroxyCi- 6 alkyl' refers to a Q -6 alkyl group as defined herein wherein at least one (preferably one to three) hydrogen atom is replaced with hydroxy. Examples of such groups include hydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl and hydroxyisopropyl.
  • 'haloC) -6 alkyl' refers to a Ci -6 alkyl group as defined herein wherein at least one (preferably one to three) hydrogen atom is replaced with halogen.
  • examples of such groups include fluoroethyl, trifluoromethyl and trifluoroethyl.
  • group as defined herein wherein at least one (preferably one to three) hydrogen atom is replaced with halogen examples include trifluoromethoxy and difluoromethoxy.
  • 'aryl' refers to a C 6- ⁇ monocyclic or bicyclic hydrocarbon group which comprises at least one aromatic ring. Examples of such groups include phenyl, naphthyl and tetrahydronaphthalenyl.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic group which comprises monocyclic or bicyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
  • Examples of such monocyclic aromatic groups include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
  • bicyclic aromatic groups include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindoly], indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and imidazopyridyl.
  • the nitrogen atom may be oxidized.
  • pyridyl as the 'heteroaryl' may be its N-oxide.
  • heterocyclyl refers to a 4-7 membered monocyclic group or a fused 8-12 membered bicyclic group which may be saturated or partially unsaturated, which monocyclic or bicyclic group contains 1 to 4 heteroatoms selected from oxygen, nitrogen, silicon or sulphur.
  • Examples of such monocyclic groups include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl and azepanyl.
  • bicyclic groups examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-lH-3- benzazepine and tetrahydroisoquinolinyl.
  • the term 'nitrogen containing heterocycJyl ring' refers to a ring containing at least one nitrogen atom and selected from rings corresponding to the 'heterocyclyl' groups mentioned above. Examples of such rings include pyrrolidine, azetidine, piperidine, piperazine, morpholine and thiomorpholine.
  • 'Pharmaceutically acceptable salts' of compounds of Formula (1) of the present invention include but are not limited to acid addition salts (for example, phosphates, nitrates, sulphates, borates acetates, maleates, citrates, fumarates, succinates, methanesulfonates, benzoates, salicylates and hydrohalides), salts derived from inorganic bases (such as lithium, potassium and sodium), salts of amino acids "(such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine, proline), organic bases (such as triethylamine, hydroxide, choline, thiamine, and N-N'-diacetylethylenediamine).
  • Other pharmaceutically acceptable salts include ammonium salts, substituted ammonium salts and aluminium salts. Further pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of formula I.
  • the compound of Formula 1 of the present invention may be in either hydrate or non-hydrate form.
  • esters' of compounds of Formula (1) are derivatives in which one or more carboxyl (i.e. -C(O)OH) groups of the said compounds are modified by reaction with an alcoholic moiety G- OH so as to yield -C(O)OG groups, wherein G may be C M8 alkyl (e.g. Ci -6 alkyl), aryl, heteroaryl, C 3-8 cycloalkyl or combinations thereof.
  • G may be C M8 alkyl (e.g. Ci -6 alkyl), aryl, heteroaryl, C 3-8 cycloalkyl or combinations thereof.
  • compounds of the invention may be prepared as isomeric mixtures or racemates, although the invention relates to all such enantiomers or isomers, whether present in an optically pure form or as mixtures with other isomers.
  • Individual enantiomers or isomers may be obtained by methods known in the art, such as optical resolution of products or intermediates (for example chiral chromatographic separation (e.g. chiral HPLC)), or an enantiomeric synthesis approach.
  • compounds of the invention may exist as alternative tautomeric forms (e.g. keto/enol, amide/imidic acid)
  • the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions.
  • two of the four groups selected from X 1 , X 2 , X 3 and X 4 independently represent N.
  • one of the groups selected from Xi, X 2 , X 3 and X 4 represents N (e.g. X 4 )
  • X In another embodiment X], X 2 , X 3 and X 4 each represent CH.
  • R 2 and R 3 independently represent Q -6 alkyl (e.g. methyl, ethyl, n-propyl) in which each group may be optionally substituted with one or more (preferably one to three) substituents independently selected from halogen and haloCi_ 6 alkyl.
  • Q -6 alkyl e.g. methyl, ethyl, n-propyl
  • each group may be optionally substituted with one or more (preferably one to three) substituents independently selected from halogen and haloCi_ 6 alkyl.
  • R 2 and R 3 each represent unsubstituted Ci -6 alkyl (e.g. methyl, ethyl, n-propyl). Even more particularly R 1 , R 2 and R 3 each represent unsubstituted methyl.
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently represent H or C 1-6 alkyl (e.g. methyl). In another embodiment R 4 and R 9 represent C 1-6 alkyl (e.g. methyl) and R 5 , R 6 , R 7 and R 8 represent H. In a further embodiment R 4 , R 5 , R 6 , R 7 , R 8 and R 9 each represent H. In yet another embodiment, R 4 represents C )-6 alkyl (e.g. methyl) and R 5 , R 6 , R 7 , R 8 and R 9 represent H.
  • R 10 represents aryl or heteroaryl, each of which may be optionally substituted by one or more (preferably one to three) substituents, independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, cyano, -Q 2 -CO 2 R 12 , -Q 2 -COR 12 , -Q 2 -CONR 12 R 13 , -Q 2 -OR 12 , -Q 2 -NR 12 R 13 , -Q 2 - SO 2 NR 12 R 13 , and -Q 2 -S(O) m R 12 .
  • substituents independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, cyano, -Q 2 -CO 2 R 12 , -Q 2 -COR 12 , -Q 2 -CONR 12 R 13 , -Q 2 -OR 12 , -Q 2
  • aryl or heteroaryl represented by R 10 include phenyl, imidazolyl, thiazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, quinolinyl and isoquinolinyl.
  • R 1O represents optionally substituted phenyl.
  • R ]0 represents optionally substituted imidazolyl.
  • R 10 represents optionally substituted thiazolyl.
  • R 1O represents optionally substituted pyrimidyl.
  • R 10 represents optionally substituted pyridazinyl.
  • R 1O represents optionally substituted pyrazinyl.
  • R 10 represents optionally substituted pyridyl.
  • R] 0 represents optionally substituted quinolinyl.
  • R 1O represents optionally substituted isoquinolinyl.
  • Rio represents aryl (e.g. phenyl) which may be optionally substituted by one or more (preferably one to three) substituents, which may be independently selected from halogen (e.g. chloro, bromo, fluoro) and haloC 1-6 alkyI (e.g. trifluoromethyl).
  • substituents e.g. chloro, bromo, fluoro
  • haloC 1-6 alkyI e.g. trifluoromethyl
  • R 10 represents heteroaryl (e.g. pyridyl, imidazolyl, thiazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, quinolinyl or isoquinolinyl) optionally substituted by one or more (preferably one to three) substituents, which may be independently selected from halogen, C 1-6 alkyl, haloC] -6 alkyl, hydroxyC 1-6 alkyl, cyano, -Q 2 -CO 2 R 12 , -Q 2 -COR 12 , -Q 2 -CONRi 2 R 13 , -Q 2 -OR 12 , -Q 2 -NR 12 R 13 , -Q 2 -SO 2 NR 12 R 13 and -Q 2 - S(O) 1n R 12
  • substituents which may be independently selected from halogen, C 1-6 alkyl, haloC] -6 alkyl,
  • R 10 represents pyridyl (e.g. pyridin-4-yl or pyridin-2-yl) pyridazinyl (e.g. pyridazyn- 3-yl), thiazolyl (e.g. thiazol-2-yl), quinolinyl (e.g. quinolin-5-yl), isoquinolinyl (e.g. isoquinolin-5-yl), pyrazinyl (e.g. pyrazin-2-yl), pyrimidyl (e.g. pyrimidin-4-yl) or imidazolyl (e.g.
  • halogen e.g. chloro, fluoro
  • haloC 1-6 alkyl e.g. trifluoromethyl
  • C 1-6 alkyl e.g. methyl
  • hydroxyC 1-6 alkyl e.g. hydroxymethyl, hydroxyethyl, 1 -hydroxyethyl, 2-hydroxyisopropyl
  • cyano e.g. ethoxycarbonyl, methoxycarbonyl, methoxycarbonylmethyl, carboxy, carboxymethyl
  • -Q 2 -COR 12 e.g.
  • -Q 2 -CONR 12 R 13 e.g. carbamoyl, pyrrolidin-1-ylcarbonyl, methylcarbamoyl, dimethylcarbamoyl
  • -Q 2 -OR] 2 e.g. methoxymethyl, methoxymethoxymethyl
  • -Q 2 -NR 12 Ri 3 e.g. dimethylaminomethyl
  • -Q 2 - SO 2 NRi 2 R 13 e.g. dimethylaminosulphonyl
  • -Q 2 -S(O) 1n R 12 e.g. methylsulphonyl.
  • Rio include: phenyl, 2,4-dichlorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-trifluoromethylphenyl, 2-fluorophenyl, 2,3- dichlorophenyl, 2,5-dichlorophenyl, pyridin-4-yl, pyridin-2-yl, 3-methylpyridin-2-yl, 3,5-dichloropyridin-4- yl, 3-chloropyridin-2-yl, 3-methylsulphonylpyridin-2-yl, 3-cyanopyridin-2-yl, thiazol-2-yl, quinolin-5-yl, isoquinolin-5-yl, 3-fluoropyridin-2-yl, 3-trifluoromethylpyridin-2-yl, pyrazin-2-yl, 3-cyanopyrazin-2-yl, 3- chloro-5-(ethoxycarbonyl)pyridin-2-yl, 3-chlor
  • Rio is typically unsubstituted or mono- or di-substituted. In one embodiment R ]0 is unsubstituted. In another embodiment R] 0 is monosubstituted. In another embodiment Rio is disubstituted.
  • Qi and Q 2 independently represent a covalent bond or Ci -6 alkylene. (e.g. methylene, ethylene or propylene).
  • Q 2 represents a covalent bond or alkylene (e.g. methylene, dimethylmethylene, methylmethylene or ethylene). In a further embodiment Q 2 represents a methylene or ethylene linkage.
  • Q 2 represents a covalent bond.
  • Ri 2 and Rj 3 independently represent a H atom or a Ci -6 alkyl group which may be optionally substituted with one or more (preferably one to three) C] -6 alkoxy; or when R] 2 and R] 3 are attached to the same nitrogen atom they may join to form a nitrogen containing heterocyclyl ring.
  • R] 2 and Ri 3 independently represent H or Ci- 6 alkyl (e.g. methyl, ethyl, isopropyl) optionally substituted with one or more (preferably one to three) Ci -6 alkoxy (e.g. methoxy).
  • 3 are attached to the same nitrogen atom and may join to form a nitrogen containing heterocyclyl ring (e.g. pyrrolidine) optionally substituted with Ci_ 6 alkyl (e.g. methyl).
  • Ri 2 is H or methyl, methoxymethyl, ethyl or isopropyl.
  • Rn is H or methyl
  • R H represents an H atom or a alkyl (e.g. methyl).
  • Y represents a covalent bond or Ci -6 alkylene (e.g. methylene).
  • n 2
  • Rn which is optionally present, may be attached to any available carbon atom, and represents halogen, cyano or C 1-6 alkyl which may be optionally substituted with one or more (preferably one to three) substituents independently selected from halogen, haloQ. 6 alkyl and OR] 6 .
  • Rn represents halogen (e.g. chloro, fluoro), haloCi -6 alkyl (e.g. trifluoromethyl), cyano or Ci -6 alkyl (e.g. methyl or ethyl).
  • halogen e.g. chloro, fluoro
  • haloCi -6 alkyl e.g. trifluoromethyl
  • cyano or Ci -6 alkyl e.g. methyl or ethyl
  • Ri i is attached to X 4 or X 3 and represents halogen (e.g. chloro or fluoro), ImIoC 1 . 6 alkyl (e.g. trifluoromethyl), cyano or Ci- ⁇ alkyl (e.g. methyl or ethyl).
  • halogen e.g. chloro or fluoro
  • ImIoC 1 . 6 alkyl e.g. trifluoromethyl
  • Ci- ⁇ alkyl e.g. methyl or ethyl
  • q represents 0 or 1. In particular embodiments, q represents 0.
  • W represents -(CH 2 ),,- optionally substituted with one or more (preferably one to three) C, -6 alkyl.
  • W is unsubstituted -CH 2 -.
  • n represents 1. In another embodiment n represents 2.
  • Q 3 represents a covalent bond or C ⁇ alkylene (e.g. methylene or ethylene).
  • R !5 represents H, C] -6 alkyl (e.g. methyl or ethyl).
  • Ri6 represents H, Ci. 6 alkyl (e.g. methyl or ethyl).
  • Xi, X 2 , X3, X4, W, R 1 , R 2 , R3, R4, R5, RO, R7, Rs, R 9, Rn and q are defined as herein, wherein R 17 and R 18 may be present or absent and independently represent halogen, haloCi -6 alkyl, -Q 2 -S(O) 1n Ri 2 - CN, -Q 2- CO 2 R n, -Q 2 -CONR, 2 R 13> hydroxyC 1-6 alkyl, -Q 2 -NR 12 R 13, -Q 2 -OR n or -Q 2 -SO 2 NR 12 R] 3 , or a pharmaceutically acceptable salt or ester thereof, and wherein Q 2 , R n , R ]3 and m are as defined herein.
  • g independently represent halogen (e.g. chloro, or fluoro), haloC 1-6 alkyl (e.g. trifluoromethyl), C I-6 alkyl (e.g. methyl), -Q 2 -S(O) 1n Ri 2 (e.g. methylsulphonyl), -CN, -Q 2- CO 2 R] 2 (e.g. carboxy, ethoxycarbonyl, methoxycarbonyl, carboxymethyl, methoxycarbonylmethyl), -Q 2 -CONR 12 R 13 (e.g.
  • halogen e.g. chloro, or fluoro
  • haloC 1-6 alkyl e.g. trifluoromethyl
  • C I-6 alkyl e.g. methyl
  • -Q 2 -S(O) 1n Ri 2 e.g. methylsulphonyl
  • -CN e.g. carboxy, ethoxycarbonyl, methoxy
  • hydroxyC 1-6 alkyl e.g. hydroxymethyl, hydroxyisopropyl or hydroxyethyl
  • -Q 2 -NR 12 R 13 e.g. dimethylaminomethyl
  • -Q 2 -OR 12 e.g. methoxymethoxymethyl, methoxymethyl
  • -Q 2 -SO 2 NR n R 13 e.g. dimethylaminosulphonyl
  • R 17 is attached at position 3 of the pyridin-2-yl ring.
  • R 17 is attached at position 3 of the pyridin-2-yl ring and represents halogen (e.g. fluoro, chloro).
  • R] 7 is attached at position 3 of the pyridin-2-yl ring and represents chloro.
  • R]g is attached at position 5 of the pyridin-2-yl ring.
  • R ⁇ is attached at position 5 of the pyridin-2-yl ring and represents -Q 2- CO 2 R n (e.g. carboxy, ethoxycarbonyl, methoxycarbonyl, carboxymethyl, methoxycarbonylmethyl), -Q 2 -CONRi 2 Ri 3 (e.g. carbamoyl, dimethylcarbamoyl or pyrrolidine- 1 -ylcarbonyl), -Q 2 -SO 2 NR n R )3 (e.g. dimethylaminosulphonyl), or -Q 2 -OR n, (e.g. methoxymethoxymethyl, methoxymethyl).
  • R n e.g. carboxy, ethoxycarbonyl, methoxycarbonyl, carboxymethyl, methoxycarbonylmethyl
  • -Q 2 -CONRi 2 Ri 3 e.g. carbamoyl, dimethylcarbamoyl or pyrrolidine- 1 -ylcarbon
  • a further subclass of compounds according to the invention is represented by the compounds of formula 1 (B)>
  • X 1 , X 2 , X 3 , X4, W, R 1 , R 2 , R 3 , R4, R5, Re, R7, Rs, R 9, Rn and q are defined as herein, wherein R 19 may be present or absent and represents C ⁇ alkyl (e.g. methyl, ethyl), and wherein R 20 may be present or absent and represents halogen.
  • R 19 is attached at position 4 of the pyridazin-3-yl ring and represents Ci -6 alkyl (e.g.methyl).
  • R 20 represents halogen (e.g. chloro) and is attached at position 6 of the pyridazin-3- yl ring.
  • a further subclass of compounds according to the invention is represented by the compounds of formula l(C):-
  • R 2] may be present or absent and represents -Q 2- CO 2 Rj 2 (e.g. carboxy, methoxycarbonyl), hydroxyC ⁇ alkyl (e.g. hydroxymethyl), or -Q 2 -CONRi 2 Ru (e.g. methylcarbamoyl dimethylcarbamoyl, pyrrolidine- 1-ylcarbonyl).
  • Rj 2 e.g. carboxy, methoxycarbonyl
  • hydroxyC ⁇ alkyl e.g. hydroxymethyl
  • -Q 2 -CONRi 2 Ru e.g. methylcarbamoyl dimethylcarbamoyl, pyrrolidine- 1-ylcarbonyl
  • R 21 is attached at position 4 of the thiazol-2-yl ring. In a further embodiment R 21 is attached at position 5 of the thiazol-2-yl ring.
  • a further subclass of compounds according to the invention is represented by the compounds of formula l(D):-
  • Ru and q are defined as herein, wherein R 22 and R 23 may be present or absent and independently represent Ci ⁇ alkyl (e.g. methyl, ethyl), -Q 2- CO 2 Rn (e.g. methoxycarbonyl, carbonyl), or -Q 2 -CONRi 2 Rn (e.g. aminocarbonyl, methylaminocarbonyl).
  • Ci ⁇ alkyl e.g. methyl, ethyl
  • -Q 2- CO 2 Rn e.g. methoxycarbonyl, carbonyl
  • -Q 2 -CONRi 2 Rn e.g. aminocarbonyl, methylaminocarbonyl
  • R 22 and R 23 independently represent C )-6 alkyI (e.g. methyl), Q 2- CO 2 R 12 (e.g. methoxycarbonyl), or -Q 2 -CONRi 2 Ri 3 (e-g- aminocarbonyl)
  • R 23 is absent and R 22 represents C ⁇ alkyl (e.g. methyl) and may be attached at the 3 position of the pyrazin-2-yl ring.
  • R 22 represents Ci ⁇ alkyl (e.g. methyl) and R 23 represents aminocarbonyl, wherein R 22 may be attached at the 3 position of the pyrazin-2-yl ring.
  • a further subclass of compounds according to the invention is represented by the compounds of formula l(E):-
  • Xi, X 2 , X 3 , X4, W, Ri, R 2 , R 3 , R4, R5, Re, R 7 , Rs, R 9, Rn and q are defined as herein, wherein R ⁇ may be present or absent and represents Ci -6 alkyl (e.g. methyl, ethyl), or halogen (e.g. chloro, fluoro).
  • R 24 is attached at position 5 of the pyrimidin-4-yl ring.
  • R 24 represents halogen (e.g. fluoro), or C ⁇ aHcyl (e.g. methyl).
  • a further subclass of compounds according to the invention is represented by the compounds of formula l(F):-
  • R 2 s may be present or absent and represents Ci ⁇ alkyl (e.g. methyl, ethyl), or halogen (e.g. chloro, fluoro).
  • R 25 is attached to the N at position 1 of the imidazol-2-yl ring.
  • R 25 represents methyl.
  • the pyridyl, pyridazinyl, thiazolyl, pyrazinyl, pyrimidyl and imidazolyl groups, respectively representing R 10 may be selected from the 'Specific examples of R )0 ' given above.
  • a pharmaceutical composition comprising a compound according to the first aspect of the invention, together with one or more pharmaceutically acceptable excipients.
  • compositions of this invention comprise any of the compounds of the first aspect of the present invention, or pharmaceutically acceptable salts and esters thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, rectally, dermally, intra-vesically, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as that described in Ph. HeIv, or a similar alcohol.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
  • the compounds of the present invention may be administered to the subject (preferably a mammal, more preferably a human) in a dose of around 1 to around 20,000 ⁇ g/kg body weight per dose, depending on the condition to be treated or prevented, and the characteristics of the subject being administered with the compound. In many instances, the dose may be around 1 to around 1500 ⁇ g/kg body weight per dose.
  • the dosing regimen for a given compound could readily be determined by the skilled person having access to this disclosure. For instance, the above dose can be given to the subject one to three times per day.
  • compositions of the present invention may contain, in addition to the compounds of the first aspect of the invention, one or more additional active pharmaceutical ingredients known to be efficacious in the treatment or prevention of the conditions indicated herein, or in the treatment of comorbidities of those conditions.
  • the present invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in therapy.
  • the invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in the treatment or prevention of a condition of which the development or symptoms are linked to TrpVl receptor activity.
  • the invention also provides a method of treatment or prevention of a condition of which the development or symptoms are linked to TrpVl receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to the first aspect of the invention, or a composition according to the second aspect.
  • the invention also provides the use of a compound according to the first aspect in the preparation of a medicament for the treatment or prevention of a condition of which the development or symptoms are linked to TrpVl receptor activity.
  • the condition is pain, a urological disorder or urinary dysfunction, an inflammatory disorder or a disorder involving sensory nerve function.
  • the condition to be treated or prevented may be selected from chronic inflammatory pain, musculo-joint pain, (osteo)arthritic pain, rheumatic pain, post-operative pain, dental pain (such as following third molar extraction), post-mastectomy pain, neuropathic pain, pain associated with nerve damage, diabetes-induced neuropathy, pain associated with substance abuse (such as alcohol or narcotic), burn pain (such as sunburn, UV burn, radiant heat burn, chemical burn), glossodynia, cold induced pain (such as frostbite), cold allodynia, pain associated with exposure to TrpVl agonists or animal bites and stings, central pain including fibromyalgia, pain associated with infection (such as post-herpetic neuralgia), HIV- induced neuropathy, chemotherapy induced neuropathy, cancer induced pain (including bone cancer), pain associated with amputations or 'phantom limb pain', nerve entrapment or brachial plexus avulsions,
  • condition to be treated or prevented may be selected from chronic inflammatory pain, (osteo)arthritic pain, dental pain, neuropathic pain, HIV-induced neuropathy, chemotherapy induced neuropathy, cancer induced pain, pain associated with stroke, visceral pain, gastrointestinal disorders, pancreatitis, bladder disorders, respiratory disorders, cough including idiopathic cough, and diabetes.
  • the condition may be selected from urological disorders and pain.
  • the symbols Ri, R 2 , R3, R 4 , R5, Re, R7, Rs, R9, Rio, Rn, W, X 1 , X 2 , X 3 and X 4 when used in the formulae depicted are to be understood to represent those groups as described above in relation to formula (1) unless otherwise indicated.
  • the methods of addition and removal of such protecting groups are those which would conventionally be used in relation to the particular molecule-type or group being protected, for example the methods described in standard works of reference in synthetic methodology, such as Kocienski (2004) Protecting Groups. 4th Edn. Georg Thieme Verlag.
  • deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
  • the compounds of formula (1) may be prepared by a process which comprises reacting a compound of formula (i) with a compound of formula (ii):
  • the leaving group L 1 may be phenoxy.
  • the reaction may conveniently be effected at ambient temperature in a suitable solvent such as a cyclic ether e.g. tetrahydrofuran in the presence of an organic amine such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran or a lower alcohol e.g. ethanol using standard equipment or a microwave reactor.
  • the reaction may also be performed in the presence of an organic amine such as triethylami ⁇ e, typically in the presence of a suitable catalyst such as 4-dimethylaminopyridine (DMAP).
  • the starting material of formula (i) may be prepared by a process which comprises reacting a compound of formula (iii) with a compound of formula R 10 -L 2 :
  • R 4 , R5, R ⁇ , R 7 , Rs, R9, Rio and W are as defined above, and L 2 represents a suitable leaving group attached to a carbon atom adjacent to the ring nitrogen of a nitrogen heteroaryl group Ri 0 .
  • the leaving group L 2 is typically a halogen atom, e.g. chloro, fluoro or bromo.
  • the reaction may be effected at ambient or elevated temperature in a suitable solvent e.g. DMSO, acetonitrile or a lower alcohol e.g. propan-2-ol using standard equipment or a microwave reactor.
  • a suitable solvent e.g. DMSO, acetonitrile or a lower alcohol e.g. propan-2-ol
  • the reaction may be performed in the presence of an organic base such as triethylamine.
  • R] 0 is an aryl group, or a heteroaryl group having a leaving group attached to a carbon atom not adjacent to a ring nitrogen
  • the reaction may be effected by treatment with a palladium catalyst such as Pd(OAc) 2 and BINAP, NaO 1 Bu at elevated temperature, e.g. microwave in a suitable solvent such as toluene.
  • a palladium catalyst such as Pd(OAc) 2 and BINAP, NaO 1 Bu
  • any compound of formula (1) initially obtained from any of the above processes may be further elaborated into a further compound of formula (1) using methods known in the art.
  • a compound of formula (1) wherein Rj 0 is substituted with an ester such as -Q 2 -CO 2 CH 3 Or -Q 2 - CO 2 CH 2 CH 3 , where Q 2 is as herein defined may be hydrolysed to the corresponding carboxylic acid -Q 2 - CO 2 H under basic conditions e.g. using an inorganic base such as NaOH or KOH.
  • the resulting carboxylic acid may be further reacted e.g. with an amine to give the corresponding amide or e.g.
  • a reducing agent such as LiBH 4
  • a compound of formula (1) wherein Rio is substituted with an ester such as -Q 2 -CO 2 CH 3 or -Q 2 -CO 2 CH 2 CH 3 , where Q 2 is as herein defined, may be reduced to the corresponding methylalcohol using a reducing agent such as LiAlH 4 or reacted with ammonium chloride in the presence of 'butylammonium bromide to yield the corresponding amide -Q 2 - CONH 2 .
  • a compound of formula (1) wherein R ]0 is substituted by an amine of formula -Q 2 -NR 12 R 1 3 may be prepared from the corresponding alcohol -Q 2 -OH by initial conversion into a suitable leaving group, e.g. methanesulfonyl formed by reaction of the alcohol with e.g. methanesulfonyl chloride in the presence of an organic base such as triethylamine, followed by displacement with an amine of formula HNRi 2 Ru in the presence of an organic amine such as triethylamine.
  • a suitable leaving group e.g. methanesulfonyl formed by reaction of the alcohol with e.g. methanesulfonyl chloride in the presence of an organic base such as triethylamine, followed by displacement with an amine of formula HNRi 2 Ru in the presence of an organic amine such as triethylamine.
  • a compound of formula (1) may be elaborated into an N-oxide of formula (1) using for example an oxidizing agent such as mCPBA in the presence of sodium bicarbonate in an appropriate solvent e.g. a halogenated hydrocarbon such as dichloromethane.
  • an oxidizing agent such as mCPBA
  • sodium bicarbonate in an appropriate solvent e.g. a halogenated hydrocarbon such as dichloromethane.
  • an appropriate solvent e.g. a halogenated hydrocarbon such as dichloromethane.
  • a halogenated hydrocarbon such as dichloromethane
  • a compound of formula (1) wherein R 10 is substituted with a halogen atom, e.g. chloro, may be hydrogenated in the presence of a palladium catalyst to give a further compound of formula (1) in which the halogen atom has been removed.
  • a halogen atom e.g. chloro
  • Nuclear magnetic resonance (NMR) spectra were recorded at 400MHz; the chemical shifts ( ⁇ ) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5mm BBFO probe (DUL probe prior to October 2008). Instrument control was by Bruker TopSpin 2.1 software.
  • Preparative HPLC was performed using an Agilent Technologies 1100 Series system typically using Waters 19mm id x 100mm long Cl 8 columns such as XBridge or SunFire 5 ⁇ m materials at room temperature.
  • Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1 % formic acid or 0.1% ammonia.
  • Room temperature in the following schemes means the temperature ranging from 2O 0 C to 25 0 C.
  • Phenyl-4-(trimethylsilyl)phenylcarbamate Intermediate 1 A solution of 4-trimethylsilylaniline [Benkeser, Robert A.; Journal of the American Chemical Society 1952, V74, P253-4] (30mmol), phenylchloroformate (33.3mmol) and TEA (104mmol) in DCM (250ml) was stirred at room temperature for 16 hrs. The reaction mixture was washed with citric acid followed by brine and the organic was separated, dried (phase sep.) and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (20-50% DCM in petroleum ether) yielding the product (21.9mmol). 1 H NMR (400 MHz, DMSOd 6 ) ⁇ 7.16 - 7.35 (m, 6H), 6.91 - 7.16 (m, 3H), 0.00 (s, 9H).
  • Rio is an appropriately substituted aryl or heteroaryl group, which may bear optional substituents described by or which can be modified to the optional substituents described for R !0 according to the first aspect of the invention.
  • Reagents and conditions a) melt in microwave 110°C 30 min, b) Intermediate 1 , THF rt 3hrs wherein Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Step (a) of Scheme 2 employs a piperazine, which may be protected (e.g. 1 -Boc-piperazine).
  • Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Reagents and conditions a) KOH, THF, 60 hrs b) EDC, R 12 R 13 NH, TEA, DCM, rt, 3 days c) NH 4 CI, 1 BuNH 3 Br, NH 4 OH(aq)
  • Reagents and conditions a) LiBH 4 , EtOH, rt, 24hrs b) MsCI, TEA, DCM, rt, 2hrs c) R 12 R 13 NH, TEA, DCM, rt, 18hrs wherein Q 2 and R 12 and R 13 are as defined herein. 1.7 Scheme 7
  • Reagents and conditions a) EtOH, H 2 (g), Pd/C 30 min 50 0 C wherewhe rein Z is a group that is described by, or which can be modified to, the optional substituents described for R )o according to the first aspect of the invention.
  • Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Reagents and conditions a) TEA, DCM, MsCI, rt, 2hrs b) TEA, THF(aq), NaCN rt, 2hrs c) NaOH, 2M, microwave 100°C, 20min, d) MeOH, H 2 SO 4 (conc), rt, 2hrs, e) (R) 2-methylpiperazine, TEA, DMSO, 100°C, 18 hrs f) Intermediate 1 , EtOH microwave 30 min 100 0 C, g) KOH, THF(aq) wherein Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Reagents and conditions a) NaHCO 3 , DCM, mCPBA, 0-5 0 C, 1hr then 24hrs at rt
  • wh erein Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Reagents and conditions a) (R)-2-methylpiperazine, MP-Carbonate, propan-2-ol, microwave, 150°C,90min b) Intermediate 1 , TEA, DMAP, EtOH, 100°C, microwave, 30 min whe rein Z is a group that is described by, or which can be modified to, the optional substituents described for R 10 according to the first aspect of the invention.
  • Reagents and conditions a) NaNO 2 , HCI, 0 0 C, water, 1 hr b) NaSMe, Cu(BF 4 J 2 , acetonitrile, 0°C c) mCPBA, DCM, 0°C to rt 48hr, d) (R) 2-methylpiperazine, TEA, DMSO, 100 0 C 18 hrs e) Intermediate 1 , EtOH microwave 30 min 100 °C
  • Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • Z is a group that is described by, or which can be modified to, the optional substituents described for Rio according to the first aspect of the invention.
  • the aqueous was separated and acidified to pH 1 with 2N hydrochloric acid and extracted with ethyl acetate (2 xlOOml). The organics were combined, dried (MgSO 4 ) and concentrated under reduced pressure. The resulting off white solid was triturated with methanol (cold), filtered and dried yielding the title compound in 60 % yield.
  • Example 32 (1.19 mmol) in EtOH was hydrogenated on an H-Cube hydrogenator reactor with 10% palladium on charcoal catalyst at 50 0 C. The reaction was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (0-10 % 2M ammonia in methanol in dichloromethane) yielding the title compound (0.37 mmol).
  • 2,3-Dichloropyridine 1-oxide (CAS 53976-65-1) (l .l ⁇ mmol), (R)-2-methylpiperazine (l.l ⁇ mmol) and MP- Carbonate (2.36mmol) were combined in propan-2-ol (5 ml) in a microwave tube, sealed and heated in the microwave to 150 0 C for 90 minutes. The reaction mixture was cooled, filtered and evaporated to leave a brown gum (252 mg), which was determined to be a mixture of (R)-3-chloro-2-(3-methylpiperazin-l- yl)pyridine 1-oxide (67%) and starting 2,3-dichloropyridine 1-oxide (33%).
  • Example 67 was hydrolysed to the title compound using a procedure similar to that described for Example
  • Example 68 was hydrolysed to the title compound using a procedure similar to that described for Example 28.
  • Example 68 The title compound was synthesised using a procedure similar to that described for Example 31 starting from (R)-Methyl 2-(3-methyl-4-(4-(trimethylsilyl)phenylcarbamoyl)piperazin- 1 -yl)thiazole-4-carboxylate (Example 68).
  • Example 70 The title compound was synthesised using a procedure similar to that described for Example 30 starting from(R)-2-(3-Methyl-4-(4-(trimethylsilyl)phenylcarbamoyl)piperazin-l-yl)thiazole-4-carboxylic acid (Example 70).
  • TrpVl antagonist compounds of the invention were functionally assessed by measurement of the change in intracellular calcium levels induced by the influx of extracellular calcium in response to the TrpVl activator, capsaicin.
  • the ability of compounds to block the influx of calcium by capsaicin in CHO-Kl cells expressing the human TrpVl channel were determined as a measure of the compound's antagonist activity in vitro.
  • CHO-Kl cells (20,000), expressing the human TrpVl channel, were seeded in 30 ⁇ l of normal culture medium into each well of a 384 well assay plate (Black, clear bottom - Greiner) and incubated overnight at standard culture conditions (37 0 C, 5% CO 2 ). Following the overnight incubation the media was aspirated and replaced with 45 ⁇ l assay buffer (IX Hanks buffered saline, 25mM HEPES, 0.1% w/v fatty acid free BSA (bovine serum albumen), pH7.4) containing 2.5mM probenecid, 0.08% pluronic acid and 4 ⁇ M Fluo-4.
  • assay buffer IX Hanks buffered saline, 25mM HEPES, 0.1% w/v fatty acid free BSA (bovine serum albumen), pH7.4
  • Readings from wells that do not contain antagonist allow percentage inhibition curves to be plotted using 4- parameter fit algorithm and the calculation of IC50 values for each compound.

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Abstract

L'invention porte sur un composé représenté par la formule (1) : dans laquelle : X1, X2, X3 et X4 représentent indépendamment CH ou N ; R1, R2 et R3 représentent indépendamment un groupe alkyle en C1-6, cycloalkyle en C3-8 ou (cycloalkyl en C3-8)(alkyle en C1-6), chacun de ces groupes pouvant être éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi un atome d'halogène et un groupe halogéno(alkyle en C1-6) ; R4, R5, R6, R7, R8 et R9 représentent indépendamment H, un groupe alkyle en C1-6, cycloalkyle en C3-8 ou –Q1-OR14, ou R4 et R9 peuvent être reliés pour former une chaîne alkylène en C1-6 de pontage ; R10 représente un groupe aryle ou hétéroaryle, chacun de ceux-ci pouvant être éventuellement substitué par un ou plusieurs substituants, indépendamment choisis parmi un atome d'halogène, un groupe alkyle en C1-6, halogéno(alkyle en C1-6), hydroxy(alkyle en C1-6), halogéno(alcoxy en C1-6), cyano, -Q2-CO2R12, -Q2-COR12, -Q2-CONR12R13, -Q2-OR12, -Q2-NR12Rn, -Q2-NR12SO2R13, -Q2- NR12COR13, -Q2-SO2NR12R13, -Q2-S(O)mR12, -Y-aryle, -Y-hétéroaryle, -Y-(cycloalkyle en C3-8) et -Y-hétérocyclyle ; Q1 et Q2 représentent indépendamment une liaison covalente, un groupe alkylène en C1-6 ou alkylène en C1-6 substitué par un groupe hydroxy ; R12 et R13 représentent indépendamment un atome de H ou un groupe alkyle en C1-6 ou cycloalkyle en C3-8, chacun de ceux-ci pouvant être éventuellement substitué par un ou plusieurs groupes alcoxy en C1-6 ; ou lorsque R12 et R13 sont attachés au même atome d'azote, ils peuvent être reliés pour former un noyau hétérocyclyle contenant de l'azote, qui peut être éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi un groupe alkyle en C1-6 et un groupe alcoxy en C1-6 ; R14 représente un atome de H ou un groupe alkyle en C1-6 ou cycloalkyle en C3-8, chaque groupe pouvant être éventuellement substitué par un ou plusieurs groupes alcoxy en C1-6 ; Y représente une liaison covalente, un groupe alkylène en C1-6 ou -O- ; m représente 0, 1 ou 2 ; R11, qui est éventuellement présent et qui peut être attaché à n'importe quel atome de carbone X1 à X4 disponible au lieu de H, représente un atome d'halogène, un groupe halogéno(alkyle en C1-6), alcoxy en C1-6, halo(alcoxy en C1-6), cyano ou alkyle en C1-6 qui peut être éventuellement substitué par un plusieurs substituants indépendamment choisis parmi un atome d'halogène, un groupe halogéno(alkyle en C1-6) et OR16 ; q représente 0, 1 ou 2 ; W représente -(CH2)n-, qui peut être éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi un groupe alkyle en C1-6, cycloalkyle en C3-8 et -Q3-OR15 ; n représente 1 ou 2 ; Q3 représente une liaison covalente ou un groupe alkylène en C1-6 ; R15 représente H, un groupe alkyle en C1-6 ou cycloalkyle en C3-8 ; et R16 est tel que défini pour R14 ; ou un sel ou ester pharmaceutiquement acceptable de celui-ci. L'invention porte également sur des utilisations des composés en tant que modulateurs du récepteur TrpV1.
PCT/GB2010/000246 2009-02-10 2010-02-10 Composés d'organosilicium et leur utilisation en tant que modulateurs du récepteur trpv1 Ceased WO2010092342A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
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WO2011038662A1 (fr) * 2009-09-30 2011-04-07 Sun Qun Composés utilisés en tant qu'inhibiteurs de trpv1, compositions pharmaceutiques en contenant et leurs utilisations médicales
CN102898452A (zh) * 2011-07-29 2013-01-30 孙群 作为trpv1阻断剂的杂环化合物、药物组合物及其医药用途
EP2709609A4 (fr) * 2011-05-17 2015-08-26 Shionogi & Co Composés hétérocycliques
WO2016071283A1 (fr) * 2014-11-03 2016-05-12 Iomet Pharma Ltd Inhibiteurs de la tryptophane-2,3-dioxygénase ou de l'indoleamine-2,3-dioxygénase
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WO2011038662A1 (fr) * 2009-09-30 2011-04-07 Sun Qun Composés utilisés en tant qu'inhibiteurs de trpv1, compositions pharmaceutiques en contenant et leurs utilisations médicales
US20120184509A1 (en) * 2009-09-30 2012-07-19 Qun Sun Compounds as TRVP1 Blockers, Pharmaceutical Compositions and Medical Uses Thereof
US8748610B2 (en) * 2009-09-30 2014-06-10 Fl Therapeutics Llc Compounds as TRPV1 antagonists, pharmaceutical compositions and medical uses thereof
EP2709609A4 (fr) * 2011-05-17 2015-08-26 Shionogi & Co Composés hétérocycliques
US9156830B2 (en) 2011-05-17 2015-10-13 Shionogi & Co., Ltd. Heterocyclic compounds
CN102898452A (zh) * 2011-07-29 2013-01-30 孙群 作为trpv1阻断剂的杂环化合物、药物组合物及其医药用途
CN102898452B (zh) * 2011-07-29 2016-12-14 珠海贝海生物技术有限公司 作为trpv1阻断剂的杂环化合物、药物组合物及其医药用途
US9962452B2 (en) 2013-02-04 2018-05-08 Zhuhai Beihai Biotech Co., Ltd. Soluble complexes of drug analogs and albumin
US9937259B2 (en) 2014-06-27 2018-04-10 Zhuhai Beihai Biotech Co., Ltd. Abiraterone derivatives and non-covalent complexes with albumin
US10201617B2 (en) 2014-10-24 2019-02-12 Zhuhai Beihai Biotech Co., Ltd. 3-substituted piperidine-2, 6-diones and non-covalent complexes with albumin
WO2016071283A1 (fr) * 2014-11-03 2016-05-12 Iomet Pharma Ltd Inhibiteurs de la tryptophane-2,3-dioxygénase ou de l'indoleamine-2,3-dioxygénase
US10287252B2 (en) 2014-11-03 2019-05-14 Iomet Pharma Ltd. Inhibitors of tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase

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