WO2006016218A1 - Dérivés arylcarbonyliques ou hétéroarylcarbonyliques utiles comme antagonistes du récepteur vanilloïde de type 1 (vr1) - Google Patents

Dérivés arylcarbonyliques ou hétéroarylcarbonyliques utiles comme antagonistes du récepteur vanilloïde de type 1 (vr1) Download PDF

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WO2006016218A1
WO2006016218A1 PCT/IB2005/002183 IB2005002183W WO2006016218A1 WO 2006016218 A1 WO2006016218 A1 WO 2006016218A1 IB 2005002183 W IB2005002183 W IB 2005002183W WO 2006016218 A1 WO2006016218 A1 WO 2006016218A1
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pain
butylphenoxy
alkyl
pyridinyl
compound
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PCT/IB2005/002183
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English (en)
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Yoriko Miyake
Satoshi Nagayama
Kazunari Nakao
Masaki Sudo
Hirotaka Tanaka
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Pfizer Japan Inc.
Pfizer Inc.
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Publication of WO2006016218A1 publication Critical patent/WO2006016218A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

Definitions

  • This invention relates to novel aryl or heteroaryl carbonyl compounds. These compounds are useful as antagonists of VR1 (Type I Vanilloid receptors) receptor, and are thus useful for the treatment of pain, neuralgia, neuropathies, nerve injury, burns, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, bladder disease, inflammation, or the like in mammals, especially humans.
  • VR1 Type I Vanilloid receptors
  • the present invention also relates to a pharmaceutical composition comprising the above compounds.
  • Vanilloid receptor 1 is a ligand gated non-selective cation channel. It is believed to be a member of the transient receptor potential superfamily. VR1 is recognized as a polymodal nociceptor that integrates multiple pain stimuli, e.g., noxious heat, protons, and vanilloids. A major distribution of VR1 is in the sensory (A ⁇ - and C-) fibers, which are bipolar neurons having somata in sensory ganglia. The peripheral fibers of these neurons innervate the skin, the mucosal membranes, and almost all internal organs. It is also recognized that VR1 exists in bladder, kidney, brain, pancreas, and various kinds of organs. A body of studies using VR1 agonists, e.g., capsaicin or resiniferatoxin, have suggested that
  • VR1 positive nerves are thought to participate in a variety of physiological responses, including nociception. Based on both the tissue distribution and the roles of VR1 , VR1 antagonists would have good therapeutic potentials.
  • GB1041982 describes a variety of benzoyl derivatives, which relate to herbicidal agents. Although International Publication Number WO02/080920 describes heteroaryl carbonyl derivatives, they relate to cysteine protease inhibitors. Further, Chemical Pharmaceutical Bulletin, 40 (10), 2712-19, 1992, describes dimethoxybenzoyl derivatives, which have antiulcer activity. Yet further, Justus Liebigs
  • VR1 receptor antagonists It is an object of the invention to provide novel VR1 receptor antagonists. Most desirably the VR1 antagonists should be active by systemic administration and not have drug-drug interactions.
  • aryl or heteroaryl carbonyl compounds are VR1 antagonists with analgesic activity by systemic administration.
  • the compounds of the present invention may show less toxicity, good absorption, distribution, good solubility, low protein binding affinity, less drug-drug interaction, a reduced inhibitory activity at HERG channel and good metabolic stability.
  • the present invention provides a compound of the following formula (I):
  • R 1 , R 2 , R 3 and R 4 each independently represent hydrogen, (Ci-C 6 )alkyl, halogen, cyano, hydroxy, (C 1 -
  • R 5 and R 6 each independently represent halogen, (C 1 -C 6 )alkyl, cyano, hydroxy, hydroxy(C 1 -C 6 )alkyl, (C 1 - C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (CrC 6 )alkylthio, (d-C ⁇ alkylsulfinyl and (d-C ⁇ Jalkylsulfonyl;
  • A represents phenyl or monocyclic 5- or 6-membered heteroaryl; said monocyclic heteroaryl containing 1 or 2 nitrogen atoms and/or 1 oxygen or sulfur; said A is unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, (C 1 -C 6 )alkyl, cyano, hydroxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 JaIkOXy, halo(C 1 -C 6
  • the invention provides the use of compounds of formula (I) without provisos for the treatment of acute cerebral ischemia, pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, menstrual pain, bladder disease, such as incontinence, micturition disorder, renal colic and cystitis, inflammation, such as burns, rheumatoid arthritis and osteoarthritis, neurodegenerative disease, such as stroke, post stroke pain and multiple sclerosis, pulmonary disease, such as asthma, cough, chronic obstructive pulmonary disease (COPD) and broncho constriction
  • COPD chronic
  • the compounds of the present invention are useful for the general treatment of pain, particularly neuropathic pain.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is exclusively activated by noxious stimuli via peripheral transducing mechanisms (Millan 1999 Prog. Neurobio. 57: 1-164 for an integrative Review).
  • These sensory fibres are known as nociceptors and are characterised by 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.
  • Intense acute pain and chronic pain may involve the same pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease states.
  • Pain tend to be quite heterogeneous and may present with various pain symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma, or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, therefore, may require different treatment strategies. Therefore pain can be divided into a number of different areas because of differing pathophysiology, these include nociceptive, inflammatory, neuropathic pain etc. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. Back pain, Cancer pain have both nociceptive and neuropathic components.
  • 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 sensitise 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 transmitted rapidly and are responsible for the sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey the dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to pain from strains/sprains, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Also cancer related acute pain syndromes commonly due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy.
  • Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to, cancer pain which may be tumour related pain, (e.g. bone pain, headache and facial pain, viscera pain) or associated with cancer therapy (e.g.
  • postchemotherapy syndromes chronic postsurgical pain syndromes, post radiation syndromes
  • back pain which 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.
  • Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). 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, Diabetic neuropathy, Post herpetic neuralgia, Back pain, Cancer neuropathy, HIV neuropathy, Phantom limb pain, Carpal Tunnel Syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiencies. 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, or paroxysmal and 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 result in swelling and pain (Levine and Taiwo 1994: Textbook of Pain 45-56). Arthritic pain makes up the majority of the inflammatory pain population. 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 RA is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson 1994 Textbook of Pain 397-407).
  • - Musculoskeletal disorders including but not limited to myalgia, fibromyalgia, spondylitis, sero ⁇ negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, Glycogenosis, polymyositis, pyomyositis.
  • Central pain or 'thalamic pain' as defined by pain caused by lesion or dysfunction of the nervous system including but not limited to central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy.
  • Heart and vascular pain including but not limited to angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma, scleredoma, skeletal muscle ischemia.
  • the viscera encompasses 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. Commonly encountered gastrointestinal (Gl) disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases (IBD).
  • BFD functional bowel disorders
  • IBD inflammatory bowel diseases
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including - for FBD, gastro-esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and - for IBD, Crohn's disease, ileitis, and ulcerative colitis, which all regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.
  • - Head pain including but not limited to migraine, migraine with aura, migraine without aura cluster headache, tension-type headache.
  • Orofacial pain including but not limited to dental pain, temporomandibular myofascial pain.
  • the present invention provides a pharmaceutical composition for the treatment of disease conditions caused by overactivation of VR1 receptor, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
  • the present invention also provides a composition which comprises a therapeutically effective amount of the bicyclic amide compound of formula (I) or its pharmaceutically acceptable salt or ester together with a pharmaceutically acceptable carrier.
  • the composition is preferably useful for the treatment of the disease conditions defined above.
  • the present invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof, as a medicament.
  • the present invention provides a method for the treatment of the disease conditions defined above, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
  • the present invention provides a method for the treatment of the disease conditions defined above in a mammal, preferably a human, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). Yet further, the present invention provides the use of a therapeutically effective amount of a compound of formula (I) in the manufacture of a medicament for the treatment of the disease conditions defined above.
  • halogen means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
  • alkyl means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, ⁇ -propyl, /sopropyl, n-butyl, /so-butyl, seconda/y-butyl, ferf/a/y-butyl.
  • cycloalkyl means a saturated carbocyclic radical ring of 3 to 8 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • alkoxy means alkyl-O-, including, but not limited to methoxy, ethoxy, n- propoxy, /sopropoxy, n-butoxy, /so-butoxy, seconc/a/y-butoxy, terf/a/y-butoxy.
  • alkanoyl means a group having carbonyl such as R'-C(O)- wherein R' is H, Ci. 5 alkyl, phenyl or C 3 . 6 cycloalkyl, including, but not limited to formyl, acetyl, ethyl-C(O)-, n-propyl- C(O)-, /sopropyl-C(O)-, n-butyl-C(O)-, /so-butyl-C(O)-, sec ⁇ ncf ⁇ /y-butyl-C(O)-, ferf/a/y-butyl-C(O)-, cyclopropyl-C(O)-, cyclobutyl-C(O)-, cyclopentyl-C(O)-, cyclohexyl-C(O)-, and the like.
  • the term "monocyclic heteroaryl” means a 5- to 6-membered aromatic or partially saturated hetero mono- or bi-cyclic ring which consists of from 1 to 3 heteroatoms independently selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms including, but not limited to, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl, and the like.
  • haloalkyi means an alkyl radical which is substituted by halogen atoms as defined above including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl and bromomethyl groups and the like.
  • haloalkoxy means haloalkyl-O-, including, but not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy, iodomethoxy and bromomethoxy groups and the like.
  • esters examples include esters with a hydroxy group and esters with a carboxy group.
  • the ester residue may be an ordinary protecting group or a protecting group which can be cleaved in vivo by a biological method such as hydrolysis.
  • alkylthio means alkyl-S- wherein alkyl is defined above, including, but not limited to methylthio, ethylthio, ⁇ -propylthio, /so-propylthio, ⁇ -butylthio, /so-butylthio, secondary- butylthio, fert/a/y-butylthio.
  • Preferable alkylthio groups are methylthio, ethylthio, n-propylthio, n-butylthio.
  • alkylsulfinyl means alkyl-SO- wherein alkyl is defined above, including, but not limited to methylsulfinyl, ethylsulfinyl, ⁇ -propylsulfinyl, /so-propylsulfinyl, ⁇ -butylsulfinyl, iso- butylsulfinyl, seconda/y-butylsulfinyl, f ⁇ rt/a/y-butylsulfinyl.
  • Preferable alkylsulfinyl groups are methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, n-butylsulfinyl.
  • alkylsulfonyl means alkyl-SO 2 - wherein alkyl is defined above, including, but not limited to methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, /so-propylsulfonyl, n-butylsulfonyl, iso- butylsulfonyl, seconc/a/y-butylsulfonyl, terf/a/y-butylsulfonyl.
  • Preferable alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl.
  • alkyl-NH- wherein alkyl is defined above, including, but not limited to methylamino, ethylamino, n-propylamino, /s ⁇ -propylamino, n-butylamino, iso- butylamino, secon ⁇ fary-butylamino, terf/a/y-butylamino.
  • Preferable alkylamino groups are methylamino, ethylamino, ⁇ -propylamino, n-butylamino.
  • the term "[(C 1 -C 6 JaIiCyI] 2 N-” means dialkyl-N- wherein alkyl is defined above, including, but not limited to dimethylamino, diethylamino, methylethylamino, di n-propylamino, methyl n- propylamino, ethyl n-propylamino di/so-propylamino, di n-butylamino, methyl n-butylamino di iso- butylamino, di seconda/y-butylamino, di tert/a/y-butylamino.
  • Preferable dialkylamino groups are dimethylamino, diethylamino, di n-propylamino, di n-butylamino.
  • esters means a protecting group which can be cleaved in vivo by a biological method such as hydrolysis and forms a free acid or salt thereof. Whether a compound is such a derivative or not can be determined by administering it by intravenous injection to an experimental animal, such as a rat or mouse, and then studying the body fluids of the animal to determine whether or not the compound or a pharmaceutically acceptable salt thereof can be detected.
  • Preferred examples of groups for an ester of a carboxyl group or a hydroxy group include: (1) aliphatic alkanoyl groups, for example: alkanoyl groups such as the formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl
  • alkoxycarbonyl groups for example: alkoxycarbonyl groups such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, t- butoxycarbonyl and isobutoxycarbonyl groups; and halogen- or tri(alkyl)silyl-substituted alkoxycarbonyl groups such as the 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups; tetrahydropyranyl or tetrahydrothiopyranyl groups such as: tetrahydropyran-2-yl, 3-bromotetrahydropyran- 2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-
  • substituted ethyl groups for example: alkoxylated ethyl groups such as the 1-ethoxyethyl and 1- (isopropoxy)ethyl groups; and halogenated ethyl groups such as the 2,2,2-trichloroethyl group;
  • aralkyl groups for example: alkyl groups substituted by from 1 to 3 aryl groups such as the benzyl, ⁇ - naphthylmethyl, ⁇ -naphthylmethyl, diphenylmethyl, triphenylmethyl, ⁇ -naphthyldiphenylmethyl and 9- anthrylmethyl groups; alkyl groups substituted by from 1 to 3 substituted aryl groups, where one or more of the aryl groups is substituted by one or more alkyl, alkoxy, nitro, halogen or cyano substituents such as the 4-methylbenzyl, 2,4,6-trimethyl
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • a preferred compound of formula (I) of this invention is that wherein A represents phenyl or monocyclic heteroaryi selected from the group consisting of pyrrole group, furane group, thiophene group, imidazole group, pyrazole group, oxazole group, isoxazole group, thiazole group, isothiazol group, pyridine group, pyrazine group, pyrimidine group and pyridazine group; more preferably A represents phenyl, pyridyl or imidazole group; said phenyl group and pyridine group are unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, (C r C 6 )alkyl, cyano, hydroxy, (C 1 -C 6 JaIkOXy and halo(CrC 6 )alkyl.
  • A represents phenyl or pyridine group; said pheny and pyridine group are optionally substituted by substituent selected from the group consisting of flurorine, chlorine, methyl, methoxy, cyano or trif luoromethyl.
  • A represents chlorophenyl, pyridyl or chloropyridyl.
  • a preferred compound of formula (I) of this invention is that wherein R 5 and R 6 each independently represent halogen, (C 1 -C 6 )BIlCyI, cyano, hydroxy, (CrC 6 )alkoxy, halo(C r C 6 )alkyl, (CrC 6 )alkylthio, (C 1 - C 6 )alkylsulfinyl and (C 1 -C 6 )alkylsulfonyl; more preferably, R 5 and R 6 each independently represent halogen, (C f C ⁇ alkyl, cyano groups, hydroxy, (CrC 6 )alkoxy and halo(C 1 -C 6 )alkyl. Most preferably, R 5 and R 6 each independently represent tert-butyl and trifluoro tert-butyl.
  • a preferred compound of formula (I) of this invention is that wherein R ⁇ , R ⁇ , R3 and R 4 each independently represent hydrogen, (C-i-C 6 )alkyl or halogen; most preferably R 1 , R 2 , R 3 and R 4 each independently represent hydrogen, fluorine or methyl.
  • a preferred compound of formula (I) of this invention is that wherein n represents 1.
  • Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those in which each variable in Formula (I) is selected from the more preferred or most preferred groups for each variable.
  • a preferred individual compound of this invention is selected from
  • the compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example as shown in the following reaction Schemes. Unless otherwise indicated A and R 1 through R 6 in the reaction Schemes and discussion that follow are defined as above.
  • the term "protecting group”, as used hereinafter, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene etal. (John Wiley & Sons, 1999);
  • R a represents an alkyl group having from 1 to 4 carbon atoms or a benzyl group
  • L 1 represents a leaving group, examples of suitable leaving groups include: halogen atoms, such as chlorine, bromine and iodine
  • L 2 represents N 3 , N(CHO) 2 or NHOH and the like
  • PG 1 represents a protecting group.
  • suitable protecting groups include t-butoxycarbonyl group (Boc) or benzyloxycarbonyl group (Z).
  • the compound of the formula 1-2 in which L 1 represents a halogen atom can also be prepared by the halogenating the compound of a formula 1-1 under halogenation conditions with a halogenating reagent in an inert solvent.
  • Suitable solvents include: tetrahydrofuran, 1 ,4-dioxane, /V, ⁇ /-dimethylformamide, acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as dichloromethane, 1 ,2-dichloroethane, chloroform or carbon tetrachloride and acetic acid.
  • Suitable halogenating reagents include, for example, bromine, chlorine, iodine, /V-chlorosuccimide, ⁇ /-bromosuccimide, 1 ,3-dibromo-5,5- dimethylhydantoin, bis(dimethylacetamide)hydrogen tribromide, tetrabutylammonium tribromide, bromodimethylsulfonium bromide, hydrogen bromide-hydrogen peroxide, nitrodibromoacetonitrile or copper(ll) bromide.
  • the reaction can be carried out at a temperature of from 0 C to 200 C, more preferably from 20 °C to 120 C.
  • Step 1 B a compound of formula 1-3 may be prepared by substituion reaction of the compound of formula 1-2 with NH 2 OH, MetN 3 or MetN(CHO) 2 where Met represents an alkali metal, such as potassium or sodium, in the presence of, or absence of a base and a catalyst in an inert solvent.
  • Met represents an alkali metal, such as potassium or sodium
  • suitable solvents include: aromatic hydrocarbons, such as benzene, toluene, xylene, nitrobenzene, and pyridine; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride arid dichloroethane; ethers, such as diethyl ether, diisopropyl ether, DME, tetrahydrofuran and dioxane; ethyl acetate, acetonitrile, W, ⁇ /-dimethylformamide and dimethylsulfoxide.
  • suitable bases include: triethyl amine.
  • the reaction can be carried out at a temperature of from 0 0 C to 250 0 C, more preferably from 0 0 C to 150 0 C. Reaction times are, in general, from 1 minute to 2 days, more preferably from 20 minutes to 24hours. Step 1 C
  • a compound of formula 1-4 may be prepared by the reduction of the compound of formula 1-3, with a reducing agent in an inert solvent, e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran (THF) or mixtures thereof.
  • the reduction may be carried out under known hydrogenation conditions in the presence of a metal catalyst, e.g. nickel catalysts such as Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as Pt ⁇ 2, or ruthenium catalysts such as RuCl2 (Ph3P)3 under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid.
  • a metal catalyst e.g. nickel catalysts such as Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as Pt ⁇ 2, or ruthenium catalysts such as RuCl2 (Ph3P)3 under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid.
  • a compound of formula 1-4 may be prepared by by hydrolysis of the compound of formula 1-3 in a solvent.
  • the hydrolysis may be carried out by conventional procedures.
  • the hydrolysis carried out under the acidic condition, e.g. in the presence of e.g. in the presence of hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; pyridium p-toluenesulfonate; and carboxylic acid, such as acetic acid and trifluoroacetic acid.
  • hydrogen halides such as hydrogen chloride and hydrogen bromide
  • sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid
  • pyridium p-toluenesulfonate pyridium p-toluenesulfonate
  • carboxylic acid such as acetic acid and trifluoroacetic acid.
  • Suitable solvents and/or co-solvents include, for example, alcohols such as methanol, ethanol, propanoi, butanol, 2-methoxyethanol, and ethylene gylcol; water, ethers such as tetrahydrofuran (THF), 1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane; amides such as N,N- dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulfoxide (DMSO).
  • This reaction may be carried out at a temperature in the range from -20 to 100 0 C, usually from 2O 0 C to 65°C for 30 minutes to 24 hours, usually 60 minutes to 10 hours.
  • Step 1 D dimethyl sulfoxide
  • a compound of formula 1-7 can be prepared by the substituion reaction of the compound of formula 1-5 with a compound of formula 1-6 in the presence of a base in a reaction-inert solvent.
  • suitable solvents include: tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether generally or 1 ,4-dioxane.
  • Suitable bases include: alkyl lithiums, such as n-butyllithium, sec-butyllithium or tert- butyllithium; aryllithiums, such as phenyllithium or lithium naphtilide; methalamide such as sodium amide or lithium diisopropylamide; and alkali metal, such as potassium hydride or sodium hydride. This reaction may be carried out at a temperature in the range from -50 0 C to 200 0 C, usually from 0 0 C to
  • an acid compound of formula 1-8 may be prepared by hydrolysis of the ester compound of formula 1 -7 in a solvent.
  • the hydrolysis may be carried out by conventional procedures. In a typical procedure, the hydrolysis carried out under the basic condition, e.g. in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as tetrahydrofuran (THF),
  • amides such as /V, ⁇ /-dimethylformamide (DMF) and hexamethylphospholictriamide
  • sulfoxides such as dimethyl sulfoxide (DMSO).
  • the hydrolysis may also be carried out under the acidic condition, e.g. in the presence of e.g. in the presence of hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; pyridium p-toluenesulfonate; and carboxylic acid, such as acetic acid and trifluoroacetic acid.
  • hydrogen halides such as hydrogen chloride and hydrogen bromide
  • sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid
  • pyridium p-toluenesulfonate pyridium p-toluenesulfonate
  • carboxylic acid such as acetic acid and trifluoroacetic acid.
  • Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as tetrahydrofuran (THF), 1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane; amides such as N,N- dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulfoxide (DMSO).
  • This reaction may be carried out at a temperature in the range from -20 to 100 0 C, usually from
  • the amide compound of formula (I) may be prepared by the coupling reaction of the amine compound of formula 1-4 with the acid compound of formula 1-8 in the presence or absence of a coupling reagent in an inert solvent. If desired, this reaction may be carried out in the presence or absence of an additive such as 1 -hydoroxybenzotriazole (HOBt) or 1 -hydroxyazabenzotriazole.
  • an additive such as 1 -hydoroxybenzotriazole (HOBt) or 1 -hydroxyazabenzotriazole.
  • Suitable solvents include: acetone, nitromethane, DMF, sulfolane, DMSO, NMP, 2- butanone, acetonitrile; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform; and ethers, such as tetrahydrofuran and dioxane. This reaction may be carried out at a temperature in the range from -20 C to 100 0 C, more preferably from about 0 °C to 60 °C for 5 minutes to 1 week, more preferably 30 minutes to 24 hours, will usually suffice.
  • Suitable coupling reagents are those typically used in peptide synthesis including, for example, diimides (e.g., dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC)), O-benzotriazol-1-yl- N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-ethoxy-N-ethoxycarbonyl-1 ,2- dihydroquinoline, 2-bromo-1-ethylpyridiniunn tetrafluoroborate (BEP), 2-chloro-1,3-dimethy!imidazolinium chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylate-triphenylphosphine, diethylcyanophosphate, diethylphosphorylazide, 2-ch
  • the reaction may be carried out in the presence of a base such as, N,N-diisopropylethylamine, N-methylmorpholine, 4-(dimethylamino)pyridine and triethylamine.
  • a base such as, N,N-diisopropylethylamine, N-methylmorpholine, 4-(dimethylamino)pyridine and triethylamine.
  • the amide compound of formula (I) may be formed via an acylhalide, which may be obtained by the reaction with halogenating agents such as oxalylchloride, phosphorus oxychloride and thionyl chloride.
  • the resulting acylhalide may be converted to the corresponding amide compound by treating with the amine compound of formula 1-4 under the similar conditions as described in this Step.
  • the starting materials in the aforementioned general synthesis may be commercially available or obtained by conventional methods known to those skilled in the art.
  • examples of suitable solvents include a mixture of any two or more of those solvents described in each Step.
  • the compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures, such as recrystallization or chromatographic purification.
  • Human VR1 antagonist assay can be determined by the Ca 2+ imaging assay using human VR1 highly expressing cells.
  • the cells that highly express human VR1 receptors are obtainable from several different conventional methods. The one standard method is cloning from human Dorsal Root Ganglion (DRG) or kidney according to the methods such as described in the journal article; Nature, 389, pp816- 824, 1997.
  • VR1 receptors highly expressing human keratinocytes are also known and published in the journal article (Biochemical and Biophysical Research Communications, 291, pp124-129, 2002). In this article, human keratinocytes demonstrated VR1 mediated intracellular Ca 2+ increase by addition of capsaicin.
  • the method to up regulate human VR1 gene which is usually a silent gene or don't produce detectable level of VR1 receptors, is also available to obtain propriety cells.
  • Such genetic modification method was described in detail; Nat. Biotechnol., 19, pp440-445, 2001.
  • the cells that express human VR1 receptors were maintained in culture flask at 37 ° C in an environment containing 5% CO 2 until use in the assay.
  • the intracellular Ca 2+ imaging assay to determine VR1 antagonistic activities were done by following procedures.
  • the culture medium was removed from the flask and fura-2/AM fluorescent calcium indicator was added to the flask at a concentration of 5 ⁇ M in the medium.
  • the flask was placed in CO 2 incubator and incubated for 1 hour. Then the cells expressing the human VR1 receptors were detached from the flask follow by washing with phosphate buffer saline, PBS(-) and re-suspended in assay buffer.
  • the 80 ⁇ l of aliquot of cell suspension (3.75x10 5 cells/ml) was added to the assay plate and the cells were spun down by centrifuge (950 rpm, 20 °C, 3 minutes).
  • the capsaicin-induced changes in the intracellular calcium concentration were monitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometric imaging system.
  • FDSS 6000 Hamamatsu Photonics, Japan
  • fluorometric imaging system The cell suspension in
  • KRH Krebs-Ringer HEPES
  • Glucose 25 mM HEPES, 0.96 mM Na 2 HPO 4 , pH 7.3 were pre-incubated with varying concentrations of the test compounds or KRH buffer (buffer control) for 15 minutes at room temperature under the dark condition. Then capsaicin solution, which gives 300 nM in assay mixture, was automatically added to the assay plate by the FDSS 6000.
  • the Acid-induced changes in the intracellular calcium concentration were monitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometric imaging system.
  • the cell suspension in resting buffer (HBSS supplemented with 1OmM HEPES, pH 7.4) were pre-incubated with varying concentrations of the test compounds or resting buffer (buffer control) for 15 minutes at room temperature under the dark condition.
  • the cells were automatically added the stimulating solution (HBSS supplemented with MES, final assay buffer pH5.8) by the FDSS 6000.
  • the IC 50 values of VR1 antagonists were determined from the half of the increase demonstrated by buffer control samples after acidic stimulation. Determination of antagonist activity
  • CCI Model Chronic Contriction Injury Model
  • CCI chronic constriction injury
  • VFHs von Frey hairs
  • Caco-2 permeability was measured according to the method described in Shiyin Yee, Pharmaceutical Research, 763 (1997).
  • Caco-2 cells were grown on filter supports (Falcon HTS multiwell insert system) for 14 days.
  • the apical buffer consisted of Hanks Balanced Salt
  • the basolateral buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCI 2 and 0.5 mM MgCI 2 (pH 7.4).
  • test compound solution (10 ⁇ M) in buffer was added to the apical compartment.
  • the inserts were moved to wells containing fresh basolateral buffer and incubated for 1 hour. Drug concentration in the buffer was measured by LC/MS analysis.
  • Flux rate (F, mass/time) was calculated from the slope of cumulative appearance of substrate on the receiver side and apparent permeability coefficient (P app ) was calculated from the following equation.
  • Cell paste of HEK-293 cells expressing the HERG product can be suspended in 10-fold volume of 50 mM Tris buffer adjusted at pH 7.5 at 25 °C with 2 M HCI containing 1 mM MgCI 2 , 10 mM KCI.
  • the cells were homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,00Og for 20 minutes at 4°C.
  • the pellet was resuspended, homogenized and centrifuged once more in the same manner. The resultant supernatant was discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds.
  • the membrane homogenate was aliquoted and stored at -8O 0 C until use. An aliquot was used for protein concentration determination using a Protein Assay Rapid Kit and ARVO SX plate reader (Wallac). All-the manipulation, stock solution and equipment were kept on ice at all time. For saturation assays, experiments were conducted in a total volume of 200 ⁇ l. Saturation was determined by incubating 20 ⁇ l of [ 3 H]-dofetilide and 160 ⁇ l of membrane homogenates (20-30 ⁇ g protein per well) for 60 min at room temperature in the absence or presence of 10 ⁇ M dofetilide at final concentrations (20 ⁇ l) for total or nonspecific binding, respectively.
  • the assay was initiated by addition of YSi poly-L-lysine SPA beads (50 ⁇ l, 1 mg/well) and membranes (110 ⁇ l, 20 ⁇ g/well). Incubation was continued for 60 min at room temperature. Plates were incubated for a further 3 hours at room temperature for beads to settle. Receptor-bound radioactivity was quantified by counting Wallac MicroBeta plate counter.
  • HEK 293 cells which stably express the HERG potassium channel were used for electrophysiological study.
  • the methodology for stable transfection of this channel in HEK cells can be found elsewhere (Z.Zhou et al., 1998, Biophysical Journal, 74, pp230-241).
  • the cells were harvested from culture flasks and plated onto glass coverslips in a standard MEM medium with 10% FCS.
  • the plated cells were stored in an incubator at 37°C maintained in an atmosphere of 95%O 2 /5%CO 2 . Cells were studied between 15-28 hours after harvest.
  • HERG currents were studied using standard patch clamp techniques in the whole-cell mode.
  • the cells were superfused with a standard external solution of the following composition (mM); NaCI, 130; KCI, 4; CaCI 2 , 2; MgCI 2 , 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH.
  • mM standard external solution of the following composition
  • Whole-cell recordings was made using a patch clamp amplifier and patch pipettes which have a resistance of 1-3M0hm when filled with the standard internal solution of the following composition (mM); KCI, 130; MgATP 1 5; MgCI 2 , 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH.
  • the voltage protocol was applied to a cell continuously throughout the experiment every 4 seconds (0.25Hz). The amplitude of the peak current elicited around -4OmV during the ramp was measured.
  • vehicle (0.5% DMSO in the standard external solution) was applied for 10-20 min by a peristalic pump. Provided there were minimal changes in the amplitude of the evoked current response in the vehicle control condition, the test compound of either 0.3, 1 , 3, 10DM was applied for a 10 min period. The 10 min period included the time which supplying solution was passing through the tube from solution reservoir to the recording chamber via the pump. Exposing time of cells to the compound solution was more than 5min after the drug concentration in the chamber well reached the attempting concentration. There was a subsequent wash period of a 10-20min to assess reversibility. Finally, the cells was exposed to high dose of dofetilide (5CM), a specific IKr blocker, to evaluate the insensitive endogenous current.
  • 5CM dofetilide
  • This method essentially involves determining the percent inhibition of product formation from fluorescence probe at 3 ⁇ M of the each compound.
  • the assay is carried out as follows.
  • the compounds were pre-incubated with recombinant CYPs, 100 mM potassium phosphate buffer and fluorescence probe as substrate for 5min.
  • Reaction was started by adding a warmed NADPH generating system, which consist of 0.5 mM NADP (expect; for 2D6 0.03 mM), 10 mM MgCI 2 , 6.2 mM DL-lsocitric acid and 0.5 U/ml lsocitric Dehydrogenase (ICD).
  • the assay plate was incubated at 37°C (expect; for 1A2 and 3A4 at 30°C) and taking fluoresce reading every minutes over 20 to 30min.
  • HLM human liver microsomes
  • 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, isethionate, 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 trifluor
  • 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 the invention may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • 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.
  • 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 salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of formula (I) as hereinbefore defined, polymorphs, prodrugs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).
  • the invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined.
  • 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).
  • prodrugs in accordance with the invention include: (i) where the compound of formula (I) contains a carboxylic acid functionality
  • Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. 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.
  • 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 the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% 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.
  • 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 EHeI (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 the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, 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, are particularly useful ior 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.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • Compounds of the invention 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, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the compounds of the instant invention may also optionally be administered with one or more other pharmacologically active agents. Suitable optional agents include:
  • opioid analgesics e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, ***e, codeine, dihydrocodeirie, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;
  • opioid analgesics e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, ***e, codeine, dihydrocodeirie, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,
  • nonsteroidal antiinflammatory drugs e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and their pharmaceutically acceptable salts; (iii) barbiturate sedatives, e.g.
  • benzodiazepines having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts,
  • H 1 antagonists having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts;
  • miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts
  • skeletal muscle relaxants e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orphrenadine and their pharmaceutically acceptable salts
  • NMDA receptor antagonists e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid and their pharmaceutically acceptable salts;
  • alpha-adrenergic active compounds e.g. doxazosin, tamsulosin, clonidine and 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
  • tricyclic antidepressants e.g. desipramine, imipramine, amytriptiline and nortriptiline;
  • NK Tachykinin
  • NK-3, NK-2 and NK-1 e.g. antagonists, ( ⁇ R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H-[1 ,4]diazocino[2,1-g][1 ,7]naphthridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2- [(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1 ,2- dihydro-3H-1 ,2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3-
  • Muscarinic antagonists e.g oxybutin, tolterodine, propiverine, tropsium chloride and darifenacin
  • COX-2 inhibitors e.g. celecoxib, rofecoxib and valdecoxib
  • Non-selective COX inhibitors e.g. nitroflurbiprofen (HCT-1026);
  • coal-tar analgesics in particular, paracetamol
  • neuroleptics such as droperidol
  • Vanilloid receptor agonists e.g. resinferatoxin
  • Beta-adrenergic compounds such as propranolol
  • PDEV inhibitors such as sildenafil, vardenafil or taladafil;
  • serotonin reuptake inhibitors e.g. fluoxetine, paroxetine, citalopram and sertraline;
  • alpha-2-delta ligands e.g. gabapentin and pregabalin.
  • the invention further provides a combination comprising a compound of the invention or a pharmaceutically acceptable salt, solvate or pro-drug thereof, and a compound or class of compounds selected from the group (i)-(xxix), above.
  • a pharmaceutical composition composition comprising such a combination, together with a pharmaceutically acceptable excipient, diluent or carrier, particularly for the treatment of a disease for which a VR1 antagonist is implicated.
  • 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 the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and 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 suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (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 controlled release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, vomtted 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 ef a/, 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 the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include .intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as powdered a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
  • Formulations for use with needle-free injection administration comprise a compound of the invention in powdered form in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified controlled release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi- solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petroiatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified controlled release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • 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 controlled 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 from 1 ⁇ g to 10mg of the compound of formula (I).
  • the overall daily dose will typically be in the range 1 ⁇ g to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, 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 controlled release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and 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 controlled release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172,
  • two or more pharmaceutical 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 the invention is typically in the range 0.1 mg to 3000 mg, preferably from 1 mg to 500mg, depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from 0.1 mg to 3000 mg, preferably from 1mg to 500mg, while an intravenous dose may only require from 0.1 mg to 1000 mg, preferably from 0.1 mg to 300mg.
  • the total daily dose may be administered in single or divided doses.
  • These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM).
  • Low-resolution mass spectral data (El) were obtained on a Integrity (Waters) mass spectrometer.
  • Low-resolution mass spectral data (ESI) were obtained on a ZMD (Micromass) mass spectrometer.
  • IR spectra were measured by a Shimazu infrared spectrometer (IR-470).
  • Step 2 1-(3-Chloro-2-pyridinyl)-2-( ⁇ /. ⁇ /-diformylamino)ethanone Cl O f*°
  • Step 4 ⁇ /-f2-(3-chloro-2-pyridinyl)-2-oxoethv ⁇ -2-(4-ferf-butylphenoxy)acetamide
  • Step 1 2-( ⁇ /, ⁇ /-diformylamino)-1 -(5-methoxy-2-methylphenyl)ethanone
  • reaction mixture was partitioned with MeOH (5.0 ml), evaporated and purified through silica gel column chromatography eluting with gradually from hexane only to hexane/ethylacetate (1 :1) to give 2-(4-fert-butylphenoxy)-2-(2-methyl-5- hydroxyphenyl)oxoethylacetamide (25 mg, 87%).
  • IC 50 the concentration of the individual compound required to reduce Ca influx capsaicin-evoked by 50%.

Abstract

Cette invention concerne un composé de formule (I) : dans laquelle R1 et R2 représentent indépendamment un hydrogène ou un alkyle en C1-C6 ou similaire ; R3 et R4 représentent indépendamment un hydrogène ou un alkyle en C1-C3 ; n représente 1 ou 2 ; A représente un phényle ou un hétéroaryle monocyclique ayant de 5 à 6 atomes ou similaire ; et R5 et R6 représentent chacun indépendamment un halogène, un alkyle en C1-C6, un cyano, un hydroxy, un hydroxyalkyle en C1-C6, un alcoxy en C1-C6, un haloalkyle en C1-C6, un alkylthio en C1-C6, un alkylsulfinyle en C1-C6 et un alkylsulfonyle en C1-C6 ; ou un ester acceptable du point de vue pharmaceutique d'un tel composé ou un sel acceptable du point de vue pharmaceutique de celui-ci. Ces composés sont utiles pour le traitement de maladies provoquées par la suractivation du récepteur VR1, telles que la douleur ou similaire, chez un mammifère. Cette invention concerne également une composition pharmaceutique comprenant le composé ci-dessus.
PCT/IB2005/002183 2004-08-03 2005-07-21 Dérivés arylcarbonyliques ou hétéroarylcarbonyliques utiles comme antagonistes du récepteur vanilloïde de type 1 (vr1) WO2006016218A1 (fr)

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WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
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EP2725010A1 (fr) * 2011-06-24 2014-04-30 Shanghai Institute of Pharmaceutical Industry Amide, son procédé de préparation et ses applications
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WO2015129860A1 (fr) * 2014-02-28 2015-09-03 国立大学法人東北大学 Derives amides
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WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
CN103772312B (zh) * 2009-10-02 2016-08-17 埃维克辛公司 抗炎症的2-羰基噻唑和2-羰基恶唑
WO2011039365A1 (fr) * 2009-10-02 2011-04-07 Avexxin As 2-oxothiazoles et 2-oxooxazoles anti-inflammatoires
AU2010302584B2 (en) * 2009-10-02 2015-09-10 Avexxin As Anti inflammatory 2-oxothiazoles and 2 -oxooxazoles
US10370344B2 (en) 2009-10-02 2019-08-06 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
CN102647984A (zh) * 2009-10-02 2012-08-22 埃维克辛公司 抗炎症的2-羰基噻唑和2-羰基恶唑
JP2013506639A (ja) * 2009-10-02 2013-02-28 アヴェクシン エーエス 抗炎症性２−オキソチアゾールおよび２−オキソオキサゾール
AU2015268638B2 (en) * 2009-10-02 2017-08-31 Avexxin As Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
CN103772312A (zh) * 2009-10-02 2014-05-07 埃维克辛公司 抗炎症的2-羰基噻唑和2-羰基恶唑
US9597318B2 (en) 2009-10-02 2017-03-21 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
EP3431084A1 (fr) * 2009-10-02 2019-01-23 Avexxin AS 2-oxothiazoles antiinflammatoires
CN104892542A (zh) * 2009-10-02 2015-09-09 埃维克辛公司 抗炎症的2-羰基噻唑和2-羰基恶唑
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
EP2725010A4 (fr) * 2011-06-24 2015-02-18 Shanghai Inst Pharm Industry Amide, son procédé de préparation et ses applications
US10428013B2 (en) 2011-06-24 2019-10-01 Shanghai Institute Of Phamaceutical Industry Amide compound, preparation method and uses thereof
JP2014523423A (ja) * 2011-06-24 2014-09-11 上海医薬工業研究院 アミド類化合物、その調製方法及び使用
US20140128463A1 (en) * 2011-06-24 2014-05-08 China State Institute of Pharmaceutic Industry Amide compound, preparation method and uses thereof
EP2725010A1 (fr) * 2011-06-24 2014-04-30 Shanghai Institute of Pharmaceutical Industry Amide, son procédé de préparation et ses applications
US11691959B2 (en) 2013-01-29 2023-07-04 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US10259801B2 (en) 2013-01-29 2019-04-16 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US11034666B2 (en) 2013-01-29 2021-06-15 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
WO2014118195A1 (fr) * 2013-01-29 2014-08-07 Avexxin As Composés 2-oxothiazoles et 2-oxothiophènes anti-inflammatoires et antitumoraux
AU2015223835B2 (en) * 2014-02-28 2019-07-11 Fuso Pharmaceutical Industries, Ltd. Amide derivatives
WO2015129860A1 (fr) * 2014-02-28 2015-09-03 国立大学法人東北大学 Derives amides
US11040937B2 (en) 2014-02-28 2021-06-22 Tohoku University Amide derivative
US10150781B2 (en) 2014-08-01 2018-12-11 Avexxin As 2-oxothiatole compounds having activity as CPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US10851114B2 (en) 2014-08-01 2020-12-01 Avexxin As 2-oxothiatole compounds having activity as cPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases
CN108610285A (zh) * 2017-03-17 2018-10-02 上海柏翱纳吉医药科技有限公司 苯乙酮类化合物、其制备方法及其在防治脂肪肝方面的应用
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