WO2006016218A1 - Aryl or heteroaryl carbonyl derivatives derivatives useful as vanilloid receptor 1 (vr1) antagonists - Google Patents

Abstract

This invention provides a compound of the formula (I): wherein R1 and R2 independently represent hydrogen or (C1-C6)alkyl or the like; R3 and R4 independently represent hydrogen or (C1-C3)alkyl; n represents 1 or 2; A represents phenyl or a monocyclic heteroaryl having from 5 to 6 atoms or the like; and R5 and R6 each independently represent halogen, (C1-C6)alkyl, cyano, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl and (C1-C6)alkylsulfonyl; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof. These compounds are useful for the treatment of disease conditions caused by overactivation of VR1 receptor such of pain, or the like in mammalian. This invention also provides a pharmaceutical composition comprising the above compound.

Description

ARYL OR HETEROARYL CARBONYL DERIVATIVES USEFUL AS VANILLOID RECEPTOR 1 (VRl) ANTAGONISTS

Technical Field

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.

The present invention also relates to a pharmaceutical composition comprising the above compounds.

Background Art

Vanilloid receptor 1 (VR1) 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 (Aδ- 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

Annalen der Chemie, (1), 160-94, 1975, discribes cyanobenzoyl derivatives, which are synthetic intermediates for trypanocidal agents. Yet further, Chemistry of Heterocyclic Compounds, 38 (9), 1055- 61 , 2002, discribes benzoyl derivatives, which are synthetic intermediates for Fisher Synthesis. Yet further, compounds described below are only known for synthetic uses.

- S S-- CCHH₂₂--CC--N NHH [ —-- CC CHHH₂₂2-- C C-- PI h

Ph i-— C— CH2 — NH- C— CH2— i

O O

-Me

S - S- CH₂- C— NH- CH₂- C— Ph N'^" - N „-

I ITL M / 1 I O! I O!

S- CH₂- C- NH- CH2— C—

O O O 0

,0 S— CH₂-¹C- NH- CH₂- 'C— Ph EtO_^ ,S- CH₂-C- NH- CH₂-C-Ph

Jt ^r

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.

Brief Disclosure of the Invention

It has now been found that 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):

(I) wherein

R¹, R², R³ and R⁴ each independently represent hydrogen, (Ci-C₆)alkyl, halogen, cyano, hydroxy, (C₁-

C₆)alkoxy, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, [IaIo(C₁ -C₆)alkyl,

(d-CβJalkylthio, (C_rC₆)alkylsulfinyl, (C_rC₆)alkyIsulfonyl, [(C_rC₆)alkyl]NH- or [(C₁-C₆) alkyl]₂N-; or R¹ and R² groups together form (CrCsJalkylene chain in which one or two non-adjacent carbon atoms are optionally replaced by oxygen or NH; or R³ and R⁴ together form alkenyl; n represents 1 or 2;

R⁵ and R⁶ each independently represent halogen, (C₁-C₆)alkyl, cyano, hydroxy, hydroxy(C₁-C₆)alkyl, (C₁- C₆)alkoxy, halo(C₁-C₆)alkyl, (CrC₆)alkylthio, (d-C^alkylsulfinyl and (d-CβJalkylsulfonyl; 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, (C₁-C₆)alkyl, cyano, hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆JaIkOXy, halo(C₁-C₆)alkyl, (C₁- C₆)alkylthio, (CrC₆)alkylsulfinyl and (C_rC₆)alkylsulfonyl; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.

As a further aspect, 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, gastrointestinal, such as gastroesophageal reflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis and Crohn's disease, ischemia, such as cerebrovascular ischemia, emesis, such as cancer chemotherapy-induced emesis, and obesity, or the like in mammals, especially humans.

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. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and 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. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered. There is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. This leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain these mechanisms can be useful and allow for the repair processes to take place and the hypersensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury. This injury often leads to maladaptation of the afferent fibres (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. 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. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patients quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of 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). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder 2002 Ann Pharmacother. 36: 679-686; McCarthy et al., 1994 Textbook of Pain 387-395). Most patients with OA seek medical attention because of pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Other types of inflammatory pain include but are not limited to inflammatory bowel diseases (IBD),

Other types of pain include but are not limited to; - 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.

- Visceral pain, and gastrointestinal disorders. 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). These 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.

Further, 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.

Also, 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.

Also, 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).

Further, 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.

Detailed Description of the Invention As used herein, the term "halogen" means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

As used herein, the terrη "alkyl" means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, π-propyl, /sopropyl, n-butyl, /so-butyl, seconda/y-butyl, ferf/a/y-butyl.

As used herein, the term "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.

As used herein, the term "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.

As used herein, the term "alkanoyl" means a group having carbonyl such as R'-C(O)- wherein R' is H, Ci.₅ alkyl, phenyl or C₃.₆ 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)-, secσncfø/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.

As used herein, 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.

As used herein the term "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.

As used herein the term "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.

Where the compounds of formula (I) contain hydroxy groups, they may form esters. Examples of such esters 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. As used herein, the term "alkylthio" means alkyl-S- wherein alkyl is defined above, including, but not limited to methylthio, ethylthio, π-propylthio, /so-propylthio, π-butylthio, /so-butylthio, secondary- butylthio, fert/a/y-butylthio. Preferable alkylthio groups are methylthio, ethylthio, n-propylthio, n-butylthio.

As used herein, the term "alkylsulfinyl" means alkyl-SO- wherein alkyl is defined above, including, but not limited to methylsulfinyl, ethylsulfinyl, π-propylsulfinyl, /so-propylsulfinyl, π-butylsulfinyl, iso- butylsulfinyl, seconda/y-butylsulfinyl, ført/a/y-butylsulfinyl. Preferable alkylsulfinyl groups are methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, n-butylsulfinyl.

As used herein, the term "alkylsulfonyl" means alkyl-SO₂- 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.

As used herein, the term "[(Cn-C^allcyriNH-" means alkyl-NH- wherein alkyl is defined above, including, but not limited to methylamino, ethylamino, n-propylamino, /sσ-propylamino, n-butylamino, iso- butylamino, seconαfary-butylamino, terf/a/y-butylamino. Preferable alkylamino groups are methylamino, ethylamino, π-propylamino, n-butylamino. As used herein, the term "[(C₁-C₆JaIiCyI]₂N-" 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. The term "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, 15-rnethylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, icosanoyl and henicosanoyl groups; halogenated alkylcarbonyl groups such as the chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl groups; alkoxyalkanoyl groups such as the methoxyacetyl group; and unsaturated alkanoyl groups such as the acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl and (E)- 2-methyl- 2-butenoyl groups; (2) aromatic alkanoyl groups, for example: arylcarbonyl groups such as the benzoyl, oc-naphthoyl and β-naphthoyl groups; halogenated arylcarbonyl groups such as the 2- bromobenzoyl and 4-chlorobenzoyol groups; alkylated arylcarbonyl groups such as the 2,4,6- trimethylbenzoyl and 4-toluoyl groups; alkoxylated arylcarbonyl groups such as the 4-anisoyl group; nitrated arylcarbonyl groups such as the 4-nitrobenzoyl and 2-nitrobenzoyl groups; alkoxycarbonylated arylcarbonyl groups such . as the 2-(methoxycarbonyl)benzoyl group; and arylated arylcarbonyl groups such as the 4-phenylbenzoyl group; (3) 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-yl, and 4-methoxytetrahydrothiopyran-4-yl groups; tetrahydrofuranyl or tetrahydrothiofuranyl groups such as: tetrahydrofuran-2-yl and tetrahydrothiofuran- 2-yl groups; (5) silyl groups, for example: tri(alkyl)silyl groups such as the trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups; and silyl groups substituted by one or more aryl and alkyl groups such as the diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; (6) alkoxymethyl groups, for example: alkoxymethyl groups such as the methoxymethyl, 1 ,1-dimethyl-1- methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups; alkoxylated alkoxymethyl groups such as the 2-methoxyethoxymethyl group; and halo(alkoxy)methyl groups such as the 2,2,2-trichloroethoxymethy! and bis(2-chloroethoxy)methyl groups; (7) 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; (8) aralkyl groups, for example: alkyl groups substituted by from 1 to 3 aryl groups such as the benzyl, α- naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-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-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4- methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4- cyanobenzyl groups; alkenyloxycarbonyl groups such as the vinyloxycarbonyl; aryloxycarbonyl groups such as phenoxycaronyl; and aralkyloxycarbonyl groups in which the aryl ring may be substituted by 1 or 2 alkoxy or nitro groups, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups.

The term "treating", as used herein, 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. The term "treatment" as used herein 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_rC₆)alkyl, cyano, hydroxy, (C₁-C₆JaIkOXy and halo(CrC₆)alkyl. More preferably 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. Most preferably, A represents chlorophenyl, pyridyl or chloropyridyl.

A preferred compound of formula (I) of this invention is that wherein R⁵ and R⁶ each independently represent halogen, (C₁-C₆)BIlCyI, cyano, hydroxy, (CrC₆)alkoxy, halo(C_rC₆)alkyl, (CrC₆)alkylthio, (C₁- C₆)alkylsulfinyl and (C₁-C₆)alkylsulfonyl; more preferably, R⁵ and R⁶ each independently represent halogen, (C_fC^alkyl, cyano groups, hydroxy, (CrC₆)alkoxy and halo(C₁-C₆)alkyl. Most preferably, R⁵ and R⁶ 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 R⁴ each independently represent hydrogen, (C-i-C₆)alkyl or halogen; most preferably R¹, R², R³ and R⁴ 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

2-(4-fert-butylphenoxy)-Λ/-[2-(2-methylphenyl)-2-oxoethyl]acetamide;

Λ/-[2-(2-chlorophenyl)-2-oxoethylj-2-(4-fe/?-butylphenoxy)acetamide;

2-(4-tert-butylphenoxy)-Λ/-[2-oxo-2-(2-pyridinyl)ethyl]acetamide;

Λ/-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-ifert-butylphenoxy)acetamide; 2-(4-tert-butylphenoxy)-N-[2-(3-methyl-2-pyridinyl)-2-oxoethyl]acetamide;

N-[2-(3-chloro-2-pyridinyI)-2-oxoethyI]-2-(4-fert-butylphenoxy)-2,2-difluoroacetamide;

N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-tert-butylphenoxy)propanamide;

N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-[4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetoamide;

2-(4-fert-butyIphenoxy)-Λ/-[2-(6-methyl-2-pyridinyl)-2-oxoethyl]acetamide; N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-ferf-butylphenoxy)-2-methylpropanamide; 2-(4-te/t-butylphenoxy)-N-[2-(3-ethyl-2-pyridinyi)-2-oxoethyl]acetamide; 2-(4-butyl-3-fluorophenoxy)-N-(2-oxo-2-pyridin-2-ylethyl)acetamide; 2-[4-(1 ,1-dimethylethyl)phenoxy]-2-(2-methyl-5-hydroxyphenyl)oxoethylacetamide; 2-(4-ferf-butylphenoxy)-2-methyl-Λ/-[2-(3-methylpyridin-2-yl)-2-oxoethyl]propanamide; N-[2-(3-methyl-2-pyridinyl)-2-oxoethyl]-2-(4-te/t-butylphenoxy)-2,2-difluoroacetamide; 2-(4-butyl-3-fluorophenoxy)-N-[2-(3-methylpyridin-2-yl)-2-oxo-ethyl]acetamide; 2-(4-ferf-butylphenoxy)-N-[2-(3-methyl-2-pyridinyl)-2-oxoethyl]-2-propenamide; Λ/-[2-(3-methylpyridin-2-yl)-2-oxoethyl]-2-[4-(2,2,2-trifluoro-1 ,1-dimethylethy!)phenoxy]acetamide; 2-(4-terf-butylphenoxy)-Λ/-{2-oxo-2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}acetamide; 2-(4-ferf-buty!phenoxy)-Λ/-[2-oxo-2-(1 ,3-thiazol-2-yl)ethyl]acetamide; and

2-(4-tert-butylphenoxy)-Λ/-[2-(3,6-dimethyl-2-pyridinyl)-2-oxoethyl]acetamide; or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof.

General Synthesis 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 R¹ through R⁶ 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);

The following reaction Schemes illustrate the preparation of compounds of formula (I). Scheme 1 :

This illustrates the preparation of compounds of formula (I).

1-1 1-2 1-3

In the above formula, R^a represents an alkyl group having from 1 to 4 carbon atoms or a benzyl group; L¹ represents a leaving group, examples of suitable leaving groups include: halogen atoms, such as chlorine, bromine and iodine; L² represents N₃, N(CHO)₂ or NHOH and the like; and PG¹ represents a protecting group. Example of suitable protecting groups include t-butoxycarbonyl group (Boc) or benzyloxycarbonyl group (Z). Step 1A

In this step, the compound of the formula 1-2 in which L¹ 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.

Examples of suitable solvents include: tetrahydrofuran, 1 ,4-dioxane, /V,Λ/-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, Λ/-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. Reaction times are, in general, from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours, will usually suffice. Step 1 B In this Step, a compound of formula 1-3 may be prepared by substituion reaction of the compound of formula 1-2 with NH₂OH, MetN₃ 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.

Examples of 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,Λ/-dimethylformamide and dimethylsulfoxide. Examples of suitable bases include: triethyl amine. The reaction can be carried out at a temperature of from 0⁰C to 250⁰C, more preferably from 0⁰C to 150⁰C. Reaction times are, in general, from 1 minute to 2 days, more preferably from 20 minutes to 24hours. Step 1 C

In this Step, 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 Ptθ2, or ruthenium catalysts such as RuCl2 (Ph3P)3 under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, e.g. in the presence of hydrochloric acid or acetic acid. This reaction may be carried out at a temperature in the range from -20 to 100⁰C, usually from 0°C to 5O⁰C for 30 minutes to 24 hours, usually 60 minutes to 10 hours. Alternatively, 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. In a typical procedure, 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. 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 100⁰C, usually from 2O⁰C to 65°C for 30 minutes to 24 hours, usually 60 minutes to 10 hours. Step 1 D

In this step, 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. Examples of suitable solvents include: tetrahydrofuran, Λ/,Λ/-dimethylformamide, dimethylsulfoxide, diethylether, toluene, ethylene glycol dimethylether generally or 1 ,4-dioxane.

Examples of 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 -50⁰C to 200⁰C, usually from 0⁰C to

80⁰C for 5 minutes to 72 hours, usually 30 minutes to 24 hours.

Step 1 E

In this Step, 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),

1 ,2-dimethoxyethane (DME), and 1 ,4-dioxane; amides such as /V,Λ/-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 100⁰C, usually from 20⁰C to 65°C for 30 minutes to

24 hours, usually 60 minutes to 10 hours.

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.. 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 100⁰C, usually from

20⁰C to 65°C for 30 minutes to 24 hours, usually 60 minutes to 10 hours.

Step 1 F

In this Step, 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.

Examples of 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 100⁰C, 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-chloro-1- methylpyridinium iodide, N, N'-carnbonyldiimidazole , benzotriazole-1 -yl diethyl phosphate, ethyl chloroformate or isobutyl chloroformate. If desired, the reaction may be carried out in the presence of 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.

In the above Schemes 1 , 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.

The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product.

Method for assessing biological activities: Human VR1 antagonist assay VR1 antagonistic activity can be determined by the Ca²⁺ 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. Alternatively 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 Ca²⁺ increase by addition of capsaicin. Further more, 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% CO₂ until use in the assay. The intracellular Ca²⁺ 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 μM in the medium. The flask was placed in CO₂ 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 μl of aliquot of cell suspension (3.75x10⁵ cells/ml) was added to the assay plate and the cells were spun down by centrifuge (950 rpm, 20 °C, 3 minutes). Capsaicin stimulation assay:

The capsaicin-induced changes in the intracellular calcium concentration were monitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometric imaging system. The cell suspension in

Krebs-Ringer HEPES (KRH) buffer (115 mM NaCI, 5.4 mM KCI, 1 mM MgSO₄, 1.8 mM CaCI₂, 11 mM D-

Glucose, 25 mM HEPES, 0.96 mM Na₂HPO₄, 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.

Acid stimulation assay:

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 IC₅₀ values of VR1 antagonists were determined from the half of the increase demonstrated by buffer control samples after acidic stimulation. Determination of antagonist activity

The monitoring of the changes in the fluorescence signals (λex = 340 nm/ 380 nm, λem = 510 - 520 nm) was initiated at 1 minute prior to the addition of capsaicin solution or acidic buffer and continued for 5 minute. The IC₅₀ values of VR1 antagonists were determined from the half of the increase demonstrated by buffer control samples after agonist stimulation.

Chronic Contriction Injury Model (CCI Model):

Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) were used.

The chronic constriction injury (CCI) operation was performed according to the method described by

Bennett and Xie (Bennett, G.J. and Xie, Y.K. Pain, 33:87-107, 1988). Briefly, animals were anesthetized with sodium pentobarbital (64.8 mg/kg, i.p.) and the left common sciatic nerve was exposed at the level of the middle of the thigh by blunt dissection through biceps femoris. Proximal to the sciatic's trifurcation was freed of adhering tissue and 4 ligatures (4-0 silk) were tided loosely around it with about 1 mm space.

Sham operation was performed as same as CCI surgery except for sciatic nerve ligation. Two weeks after surgery, mechanical allodynia was evaluated by application of von Frey hairs (VFHs) to the plantar surface of the hind paw. The lowest amount of force of VFH required to elicit a response was recorded as paw withdrawal threshold (PWT). VFH test was performed at 0.5, 1 and 2 hr post-dosing.

Experimental data were analyzed using Kruskal-Wallis test followed by Dunn's test for multiple comparisons or Mann-Whitney U-test for paired comparison.

Caco-2 permeability ' 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.

Culture medium was removed from both the apical and basolateral compartments and the monolayers were preincubated with pre-warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.75 hour at

37°C in a shaker water bath at 50 cycles/min. The apical buffer consisted of Hanks Balanced Salt

Solution, 25 mM D-glucose monohydrate, 20 mM MES Biological Buffer, 1.25 mM CaCI₂ and 0.5 mM

MgCI₂ (pH 6.5). The basolateral buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCI₂ and 0.5 mM MgCI₂ (pH 7.4). At the end of the preincubation, the media was removed and test compound solution (10μM) 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. P_app (cm/sec) = (F^* VD) / (SA^* MD) where SA is surface area for transport (0.3 cm²), VD is the donor volume (0.3ml), MD is the tofal amount of drug on the donor side at t = 0. All data represent the mean of 2 inserts. Monolayer integrity was determined by Lucifer Yellow transport.

Human dofetilide binding

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 MgCI₂, 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 -8O⁰C 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 μl. Saturation was determined by incubating 20 μl of [³H]-dofetilide and 160 μl of membrane homogenates (20-30 μg protein per well) for 60 min at room temperature in the absence or presence of 10 μM dofetilide at final concentrations (20 μl) for total or nonspecific binding, respectively. All incubations were terminated by rapid vacuum filtration over PEI soaked glass fiber filter papers using Skatron cell harvester followed by two washes with 50 mM Tris buffer (pH 7.5 at 25⁰C). Receptor-bound radioactivity was quantified by liquid scintillation counting using Packard LS counter.

For the competition assay, compounds were diluted in 96 well polypropylene plates as 4-point dilutions in semi-log format. All dilutions were performed in DMSO first and then transferred into 50 mM Tris buffer (pH 7.5 at 25⁰C) containing 1 mM MgCI₂, 10 mM KCI so that the final DMSO concentration became equal to 1%. Compounds were dispensed in triplicate in assay plates (4 μl). Total binding and nonspecific binding wells were set up in 6 wells as vehicle and 10 μM dofetilide at final concentration, respectively. The radioligand was prepared at 5.6x final concentration and this solution was added to each well (36 μl). The assay was initiated by addition of YSi poly-L-lysine SPA beads (50 μl, 1 mg/well) and membranes (110 μl, 20 μg/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.

IHFBΠ assay

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). Before the day of experimentation, 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%O₂/5%CO₂. Cells were studied between 15-28 hours after harvest.

HERG currents were studied using standard patch clamp techniques in the whole-cell mode. During the experiment the cells were superfused with a standard external solution of the following composition (mM); NaCI, 130; KCI, 4; CaCI₂, 2; MgCI₂, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. 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; MgATP₁ 5; MgCI₂, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 15MΩ and seal resistances >1GΩ was accepted for further experimentation. Series resistance compensation was applied up to a maximum of 80%. No leak subtraction was done. However, acceptable access resistance depended on the size of the recorded currents and the level of series resistance compensation that can safely be used. Following the achievement of whole cell configuration and sufficient time for cell dialysis with pipette solution (>5min), a standard voltage protocol was applied to the cell to evoke membrane currents. The voltage protocol is as follows. The membrane was depolarized from a holding potential of -80m V to +4OmV for 1000ms. This was followed by a descending voltage ramp (rate 0.5m V msec^"1) back to the holding potential. 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. Once stable evoked current responses were obtained in the external solution, 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.

All experiments were performed at room temperature (23 ± 1⁰C). Evoked membrane currents were recorded on-line on a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at 1-2KHz using the patch clamp amplifier and a specific data analyzing software. Peak current amplitude, which occurred at around -4OmV, was measured off line on the computer.

The arithmetic mean of the ten values of amplitude was calculated under vehicle control conditions and in the presence of drug. Percent decrease of I_N in each experiment was obtained by the normalized current value using the following formula: I_N = (1- l_D/l_c)x100, where I_D is the mean current value in the presence of drug and l_c is the mean current value under control conditions. Separate experiments were performed for each drug concentration or time-matched control, and arithmetic mean in each experiment is defined as the result of the study.

Drug-drug interaction assay

This method essentially involves determining the percent inhibition of product formation from fluorescence probe at 3μM of the each compound.

More specifically, 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 MgCI₂, 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.

Data calculations were preceded as follows; 1. The slope (Time vs. Fluorescence units) was calculated at the linear region 2. The percentage of inhibition in compounds was calculated by the equation ((V₀ - Vi) / v₀} x 100 = % inhibition Wherein v₀ = rate of control reaction (no inhibitor) Vj = rate of reaction in the presence of compounds.

Table 1. Condition for drug-drug interaction assay.

Half-life in human liver microsomes (HLM) Test compounds (1 μM) were incubated with 3.3 mM MgCI₂ and 0.78 mg/mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4) at 37°C on the 96-deep well plate. The reaction mixture was split into two groups, a non-P450 and a P450 group. NADPH was only added to the reaction mixture of the P450 group. An aliquot of samples of P450 group was collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH was added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group was collected at -10 and 65 min time point. Collected aliquots were extracted with acetonitrile solution containing an internal standard. The precipitated protein was spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant was measured by LC/MS/MS system. The half-life value was obtained by plotting the natural logarithm of the peak area ratio of compounds/ internal standard versus time. The slope of the line of best fit through the points yields the rate of metabolism (k). This was converted to a half-life value using following equations:

Half-life = In 2 / k Drug Substance Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 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 trifluoroacetate salts.

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.

For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

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. The term '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. The term 'hydrate' is employed when said solvent is water.

Included within the scope of the invention are 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. Also included are 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. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Hereinafter all 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).

As stated, the invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined.

Also within the scope of the invention are so-called 'prodrugs' of the compounds of formula (I). Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as

'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery

Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include: (i) where the compound of formula (I) contains a carboxylic acid functionality

(-COOH), an ester thereof, for example, replacement of the hydrogen with (CrC₈)alkyl; (ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (CrC₆)alkanoyloxymethyl; and

(iii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH₂ or -NHR where R is not H), an amide thereof, for example, replacement of one or both hydrogens with (C₁- C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

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.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, 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 (and chiral precursors thereof) 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.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as²H and³H, carbon, such as¹¹C,¹³C and¹⁴C, chlorine, such as³⁶CI, fluorine, such as¹⁸F, iodine, such as¹²³I and¹²⁵I, nitrogen, such as¹³N and¹⁵N, oxygen, such as¹⁵O,¹⁷O and¹⁸O, phosphorus, such as³²P, and sulphur, such as³⁵S.

Certain 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.³H, and carbon-14, i.e.¹⁴C, 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.²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as¹¹C,¹⁸F₁¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. 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.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-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. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The compounds of the instant invention may also optionally be administered with one or more other pharmacologically active agents. Suitable optional agents include:

(i) opioid analgesics, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeirie, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

(ii) nonsteroidal antiinflammatory drugs (NSAIDs), 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. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal, thiopental and their pharmaceutically acceptable salts;

(iv) benzodiazepines having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts,

(v) H₁ antagonists having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts;

(vi) miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dichloralphenazone and their pharmaceutically acceptable salts; (vii) skeletal muscle relaxants, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orphrenadine and their pharmaceutically acceptable salts,

(viii) 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;

(ix) 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;

(x) tricyclic antidepressants, e.g. desipramine, imipramine, amytriptiline and nortriptiline;

(xi) anticonvulsants, e.g. carbamazepine and valproate; (xii) Tachykinin (NK) antagonists, particularly NK-3, NK-2 and NK-1 e.g. antagonists, (αR,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-[[2-methoxy-5- (trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine (2S.3S)

(xiii) Muscarinic antagonists, e.g oxybutin, tolterodine, propiverine, tropsium chloride and darifenacin; (xiv) COX-2 inhibitors, e.g. celecoxib, rofecoxib and valdecoxib;

(xv) Non-selective COX inhibitors (preferably with Gl protection), e.g. nitroflurbiprofen (HCT-1026);

(xvi) coal-tar analgesics, in particular, paracetamol;

(xvii) neuroleptics, such as droperidol; (xviii) Vanilloid receptor agonists, e.g. resinferatoxin;

(xix) Beta-adrenergic compounds such as propranolol;

(xx) Local anaesthetics, such as mexiletine;

(xxi) Corticosteriods, such as dexamethasone

(xxii) serotonin receptor agonists and antagonists; (xxiii) cholinergic (nicotinic) analgesics;

(xxiv) miscellaneous agents such as Tramadol®;

(xxv) PDEV inhibitors, such as sildenafil, vardenafil or taladafil;

(xxvi) serotonin reuptake inhibitors, e.g. fluoxetine, paroxetine, citalopram and sertraline;

(xxvii) mixed serotonin-noradrenaline reuptake inhibitors, e.g. milnacipran, venlafaxine and duloxetine; (xxviii) noradrenaline reuptake inhibitors , e.g. reboxetine;

(xxix) alpha-2-delta ligands, e.g. gabapentin and pregabalin.

Thus, 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. There is also provided 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.

Pharmaceutical 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).

ORAL ADMINISTRATION

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).

For tablet dosage forms, depending on dose, 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. In addition to the drug, tablets generally contain a disintegrant. Examples of 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. Generally, 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. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, 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._

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 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.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to be immediate and/or modified controlled release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, tragetted 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.

PARENTERAL ADMINISTRATION 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. 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.

The 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. Thus 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.

TOPICAL ADMINISTRATION

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).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, 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.

INHALED/INTRANASAL ADMINISTRATION

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. For intranasal use, 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.

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.

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 μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100μl. 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. In the case of dry powder inhalers and aerosols, 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 μg to 10mg of the compound of formula (I). The overall daily dose will typically be in the range 1 μg to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

RECTALVINTRAVAGINAL ADMINISTRATION

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.

OCULAR/AURAL ADMINISTRATION 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. 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.

OTHER TECHNOLOGIES

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.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, 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,

WO 94/02518 and WO 98/55148.

KIT-OF-PARTS

In as much as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.

Thus 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. 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. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

DOSAGE For administration to human patients, 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. For example, 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.

For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

EXAMPLES

The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, in the range of 18-25⁰C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60⁰C; reactions were monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; the structure and purity of all isolated compounds were assured by at least one of the following techniques: TLC (Merck silica gel 60 F₂₅₄ precoated TLC plates), mass spectrometry, nuclear magnetic resonance spectra (NMR) or infrared absorption spectra (IR). Yields are given for illustrative purposes only. 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. NMR data was determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300 spectrometer) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br. = broad, etc. IR spectra were measured by a Shimazu infrared spectrometer (IR-470). Chemical symbols have their usual meanings; bp (boiling point), mp (melting point), L (liter(s)), mL (milϋliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), eq. (equivalent(s)), quant, (quantitative yield).

EXAMPLE EXAMPLE 1

2-(4-te/t-Butylphenoxy)-Λ/-r2-(2-methylphenyl)-2-oxoethyllacetamide

2-Amino-1-(2-methylphenyl)ethanone hydrochloride (46 mg, 0.25 mmol, Journal of Pharmaceutical Sciences 1962, 51, 108-113), (4-terf-butylphenoxy)acetic acid (52 mg, 0.25 mmol), 1- hydoroxybenzotriazole (HOBt) (17 mg, 0.13 mmol), triethylamine (25 mg, 0.25 mmol) in N,N- dimethylformamide (DMF) (2 ml) and water soluble carbodiimide (WSC) (144 mg, 0.75 mmol) were reacted at room temperature and the mixture was stirred at room temperature for 16h. The reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :1 ) to furnish the 2-(4-tert- butylphenoxy)-Λ/-[2-(2-methylphenyl)-2-oxoethyl]acetamide (42.4 mg, 50 %).

¹H-NMR (CDCI₃) δ 1.31 (9H, s), 2.58 (3H, s), 4.57 (2H, s), 4.76 (2H, d, J=4.4 Hz), 6.94 (2H, d, J=8.6 Hz), 7.28-7.36 (2H, m), 7.36 (2H, d, J=8.6 Hz), 7.42-7.50 (1 H, m), 7.66 (1 H, NH), 7.74-7.80 (1H, m). White solid. MS (ESI) m/z 340 (M + H)⁺.

EXAMPLE 2

Λ/-r2-(2-chlorophenyl)-2-oxoethvπ-2-(4-tert-butylphenoxy)acetamide

(4-ført-Butylphenoxy)acetyl chloride (108 mg, 0.48 mmol), 2-amino-1-(3-methylphenyl)ethanone hydrochloride (118 mg, 0.57 mmol, Chemical & Pharmaceutical Bulletin 1984, 32, 2536-2543) and pyridine (119 mg, 1.5 mmol) were reacted at 0⁰C and the mixture was stirred at room temperature for 2h. The reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :2) to furnish the Λ/-[2-(2-chlorophenyl)-2-oxoethyl]-2-(4-tert-butylphenoxy)acetamide (86 mg, 50 %).

¹H-NMR (CDCI₃) δ 1.31 (9H, s), 4.55 (2H, s), 4.78 (2H, d, J=5.0 Hz), 6.89-6.96 (2H, m), 7.30-7.50 (5H, m),

7.54 (1H, NH), 7.65-7.72 (1H, m).

White solid.

MS (ESI) m/z 360 (M + H)⁺.

EXAMPLE 3

2-(4-terf-Butylphenoxy)-Λ/-r2-oxo-2-f2-(trifluoromethyl)phenyllethvnacetamide

(4-fert-Butylphenoxy)acetyl chloride (119 mg, 0.53 mmol), 2-amino-1-[2-

(trifluoromethyl)phenyl]ethanone hydrochloride (151 mg, 0.63 mmol) and pyridine (119 mg, 1.5 mmol) were reacted under the condition of Example 2 to furnish the 2-(4-fert-butylphenoxy)-Λ/-[2-oxo-2-[2- (trifluoromethyl)pheny!]ethyl]acetamide (87 mg, 42 %).

¹H-NMR (CDCI₃); δ 1.31 (9H, s), 4.56 (2H, s), 4.63 (2H, d, J=5.1 Hz), 6.88-6.94 (2H, m), 7.32-7.38 (2H, m), 7.47 (1 H, NH), 7.58-7.71 (3H, m), 7.75-7.80 (1 H, m). White solid.

MS (ESI) m/z 394 (M + H)⁺.

EXAMPLE 4 2-(4-fert-Butylphenoxy)-Λ/-r2-oxo-2-(2-pyridinyl)ethyllacetamide

(4-terf-Butylphenoxy)acetyl chloride (65 mg, 0.29 mmol, Journal of the Chemical Society, Abstracts

1938, 753-755), 2-amino-1-pyridin-2-ylethanone dihydrochloride (60 mg, 0.29 mmol) and pyridine (45 mg, 0.57 mmol) were reacted under the condition of Example 2 to furnish the 2-(4-terf-butylphenoxy)-Λ/-[2- oxo-2-(2-pyridinyl)ethyl]acetamide (11 mg, 12 %).

¹H-NMR (CDCI₃); δ 1.31 (9H, s), 4.58 (2H, s), 5.09 (2H, d, J=5.1 Hz), 6.91-6.98 (2H, m), 7.32-7.40 (2H, m), 7.50-7.58 (2H, m), 7.82-7.92 (1H, m), 8.05-8.10 (1 H, m). White solid. MS (ESl) m/z 327 (M + H)⁺.^v'

EXAMPLE 5 2-(4-terf-Butylphenoxy)-Λ/-r2-(2-methoxyphenyl)-2-oxoethvπacetamide

To a solution of 2-amino-1-(2-methoxyphenyl)ethanone (50 mg, 0.25 mmol, commercially available), ([4-(1 ,1-dimethylethyl)phenoxy]acetic acid (52 mg, 0.25 mmol) and triethylamine (36.4 mg, 0.3 mmol) in Λ/./V-dimethylformamide (DMF) (10 ml) were added O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (113.8 mg, 0.05 mmol) at room temperature and the mixture was stirred at room temperature for 16h. The reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :1) to furnish the 2-(4-terf-butylphenoxy)-Λ/-[2-(2-hydroxyphenyl)-2- oxoethyl]acetamide (10 mg, 11 %).

¹H-NMR (CDCI₃); δ 1.31 (9H, s), 3.97 (3H, s), 4.55 (2H, s), 4.79 (1 H, s), 4.80 (1 H, s), 6.85-6.95 (3H, m), 7.00-7.08 (2H, m), 7.26-7.35 (3H, m), 7.53-7.59 (1H, m). White solid. MS (ESI) m/z 356 (M + H)⁺.

EXAMPLE 6 2-(4-terf-Butylphenoxy)-Λ/-r2-(3-hvdroxyphenyl)-2-oxoethvnacetamide

To the CH₂CI₂ (5 ml) solution of 2-(4-ført-butylphenoxy)-Λ/-[2-(3-methoxyphenyl)-2-oxoethyl]-N- acetamide (100 mg, 0.28 mmol) was added 1 M BBr₃-CH₂CI₂ (1.5 ml) at 0⁰C and the mixture was stirred for 3h. The reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :1) to furnish the 2-(4-tert-butylphenoxy)-Λ/-[2-(3-hydroxyphenyl)-2-oxoethyl]acetamide (18.9 mg, 20 %).

¹H-NMR (CDCI₃); δ 1.31 (9H, s), 2.30 (1H, brs), 4.57 (2H, s), 4.79 (1H, s), 4.81 (1H, s), 6.91-6.96 (2H, m), 7.10-7.15 (1H, m), 7.30-7.38 (4H, m), 7.45-7.50 (2H,,m). White solid.

MS (ESI) m/z 341 (M + H)⁺ .

EXAMPLE 7

Λ/-f2-(3-chloro-2-pyridinyl)-2-oxoethvπ-2-(4-te/t-butylphenoxy)acetamide

Step 1 2-Bromo-1-(3-chloro-2-pyridinyl)ethanone hvdrobromide Cl O

¹J_N^N -HBr

To a solution of 1-(3-chloro-2-pyridinyl)ethanone (3.3 g, 21.2 mmol), 25% hydrobromic acid in acetic acid (15 ml) and acetic acid (30 ml) was added bromine (1.2 ml, 23.3 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with diethylether (50ml), then the formed precipitate was filtrated and washed with diethylether to furnish the 2- bromo-1-(3-chloro-2-pyridinyl)ethanone hydrobromide (6.5 g, 98 %).¹H-NMR (DMSO-cfe); δ 4.97 (2H₁ s), 7.69-7.74 (1H, m), 8.12-8.17 (1H, m), 8.68-8.69 (1 H₁ m).

Pale yellow solid.

MS (ESI) m/z 235 (M + H)⁺.

Step 2 1-(3-Chloro-2-pyridinyl)-2-(Λ/.Λ/-diformylamino)ethanone Cl O f*°

To a suspension of 2-bromo-1-(3-chloro-2-pyridinyl)ethanone hydrobromide (Step 1 , 6.5 g, 21 mmol) in acetonitrile (20 ml) was added sodium diformylamide (5.9 g, 62 mmol) portionwise at room temperature and the mixture was stirred at room temperature for 24 hours. The reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :2) to furnish the 1-(3-chloro-2-pyridinyl)-2-(Λ/,Λ/- diformylamino)ethanone (4.0 g, 86 %).

¹H-NMR (CDCI₃); δ 5.31 (2H, s), 7.46-7.53 (1 H, m), 7.84-7.88 (1 H, m), 8.60-8.65 (1H, m), 9.07 (2H, s). White solid.

MS (ESI) m/z 227 (M + H)⁺.

Step 3 2-Amino-1-(3-chloro-2-pyridinyl)ethanone dihvdrochloride

A solution of 1-(3-chloro-2-pyridinyl)-2-(Λ/,Λ/-diformylamino)ethanone (Step 2, 4.0 g, 18 mmol) in ethanol (30 ml) and concentrated HCI (5 ml) was stirred at 50⁰C for 1hour. The mixture was concentrated and co-evaporated with toluene. The formed solid was filtrated and washed with ethyl acetate and diethylether to furnish the 2-amino-1-(3-chloro-2-pyridinyl)ethanone dihydrochloride (2.3 g, 53 %).¹H-NMR (DMSO-cfe); δ 4.55-4.60 (2H, m), 7.77-1.80 (1 H, m), 8.16-8.21 (1 H, m), 8.53 (2H, NH), 8.72-8.75 (1 H, m). White solid. MS (ESI) m/z 171 (M + H)⁺.

Step 4 Λ/-f2-(3-chloro-2-pyridinyl)-2-oxoethvπ-2-(4-ferf-butylphenoxy)acetamide

(4-ferf-Butylphenoxy)acetyl chloride (122 mg, 0.5 mmol), 2-amino-1-(3-chloropyridin-2-yl)ethanone dihydrochloride (Step 3, 113 mg, 0.5 mmol) and pyridine (158 mg, 2.0 mmol) were reacted under the condition of Example 2 to furnish the Λ/-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-tert- butylphenoxy)acetamide (105 mg, 58%).

¹H-NMR (CDCI₃); δ 1.31 (9H, s), 4.57 (2H, s), 5.02 (2H, d, J = 5.0 Hz), 6.90-6.96 (2H, m), 7.32-7.38 (2H, m), 7.45-7.48 (1 H, m), 7.52 (1 H, NH), 7.84-7.87 (1H, m), 8.58-8.60 (1 H, m). White solid.

MS (ESI) m/z 361 (M + H)⁺.

EXAMPLE 8

2-(4-teff-Butylphenoxy)-N-r2-(3-nnethyl-2-pyridinyl)-2-oxoethvnacetamide

Step 1 2-(/V,Λ/-diformylanπino)-1-(3-methyl-2-pyridinyl)ethanone

2-Bromo-1-(3-methyl-2-pyridinyl)ethanone hydrobromide (495 mg, 1.68 mmol), sodium diformylamide (478 mg, 5.03 mmol) and acetonitrile (5 ml) were reacted under the condition of Step 2 of Example 7 to furnish the 2-(Λ/,Λ/-diformylamino)-1-(3-methyl-2-pyridinyl)ethanone (143 mg, 41%).

¹H-NMR (CDCI₃); δ 2.60 (3H, s), 5.36 (2H, s), 7.41 (1H, dd, J=4.6, 7.7 Hz), 7.61-7.64 (1H, m), 8.54-8.56 (1 H, m), 9.05 (2H, s). White solid.

MS (ESI) m/z 207 (M + H)⁺.

Step 2 2-Amino-1 -(3-methyl-2-pyridinyl)ethanone dihvdrochloride

2-(Λ/,Λ/-diformylamino)-1-(3-methyl-2-pyridinyl)ethanone (Step 1 , 142 mg, 0.689 mmol), ethanol (2 ml) and concentrated HCI (0.5 ml) were reacted under the condition of Step 3 of Example 7 to furnish the 2-amino-1-(3-methyl-2-pyridinyl)ethanone dihydrochloride (167 mg, quant.).

¹H-NMR (DMSO-cfe); δ 2.59 (3H, s), 4.20-4.80 (2H, m), 7.65 (1H, dd, J=4.6, 7.8 Hz), 7.90 (1 H, d, J = 7.8 Hz), 8.46 (2H, NH), 8.62 (1 H, d, J = 4.3 Hz). White solid.

MS (ESI) m/z 151 (M + H)⁺.

Step 3 2-(4-fert-Butylphenoxy)-N-[2-(3-methyl-2-pyridinyl)-2-oxoethvπacetamide

(4-terf-ButyIphenoxy)acetyl chloride (122 mg, 0.5 mmol), 2-amino-1-(3-methylpyridin-2-yl)ethanone dihydrochloride (Step 2, 167 mg, 0.75 mmol) and 1-Pr₂Et₂N (258.5 mg, 2.0 mmol) were reacted under the condition of Example 2 to furnish the 2-(4-tert-butylphenoxy)-N-[2-(3-methyl-2-pyridinyl)-2- - 5 oxoethyl]acetamide (82.3 mg, 49 %).

¹H-NMR (CDCI₃); δ 1.31 (9H, s), 2.64 (3H, s), 4.57 (2H, s), 5.07 (2H, s), 6.94 (2H, d, J = 8.6 Hz), 7.26- 7.63 (5H₁ m), 8.54 (1H₁ NH). White solid.

MS (ESI) m/z 341 (M + H)⁺. 10

EXAMPLE 9 N-r2-(3-chloro-2-pyridinyl)-2-oxoethvn-2-(4-te/t-butylphenoxy)-2.2-difluoroacetamide

To the CH₂CI₂ (5 ml) solution of {[4-(1 ,1 -dimethylethyl)phenyl]oxy}(difluoro)acetic acid (100.0 mg, 15 0.41 mmol), oxalyl chloride (0.1 ml) and dimethylamino pyridine (5 mg) were added and the mixture was stirred for 1 hour at room temperature. After the evaporation, crude {[4-(1 ,1 -dimethylethyl)phenyl]oxy} (difluoro)acetyl chloride was dried under reduced pressure. Then, to the CH₂CI₂ (10 ml) and Et₃N (1 ml) solution of 2-amino-1-(3-chloropyridin-2-yl)ethanone dihydrochloride (100 mg, 0.41 mmol), CH₂CI₂ (2 ml) solution of {[4-(1 ,1-dimethylethyl)phenyl]oxy}(difluoro)acetyl chloride was injected at room temperature 20 and additional stirring was allowed for 2 hours at ambient temperature. The reaction was quenched with saturated NaHCO₃ aqueous solution, and the crude product was extracted with ethylacetate and dried over Na₂SO₄. Then, filtration, evaporation, purification through silica gel column chromatography to give N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-tørf-butylphenoxy)-2,2-difluoroacetamide (40 mg, 24 %).:

¹H-NMR (CDCI₃) δ 1.32 (9H, s), 5.04 (1 H, s), 5.06 (1 H, s), 7.11-7.20 (3H, m), 7.37-7.51 (3H, m), 7.86-7.89 25 (1H, m), 8.61-8.63 (1H₁ NH).

White solid. !

MS (ESI) m/z 397 (M + H)⁺.

EXAMPLE 10

30 N-r2-(3-chloro-2-pyridinyl)-2-oxoethyll-2-(4-terf-butylphenoxy)propanamide

2-{[4-(1,1-Dimethylethyl)phenyl]oxy}propanoic acid (100 mg, 0.45 mmol, Chem Lett 2001, 912-913), oxalyl chloride (0.1 ml), dimethylaminopyridine (5 mg), CH₂CI₂ (10 ml), 2-amino-1-(3-chloropyridin-2- yl)ethanone dihydrochloride (109 mg, 0.45 mmol), Et₃N (181 mg, 1.8 mmol) and CH₂CI₂ (7 ml) were treated under the same procedure of Example 9 to furnish the N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4- terf-butylphenoxy)propanamide (390 mg, 23 %).

¹H-NMR (CDCI₃) δ 1.30 (9H, s), 1.62 (3H, d, J = 6.8 Hz), 4.74 (1H, d, J = 6.8 Hz), 4.88 (1 H, d, J = 4.6 Hz), 4.99 (1H, d, J = 5.5 Hz), 6.91 (2H, d, J = 6.8 Hz), 7.27-7.45 (4H, m), 7.81-7.84 (1H, m), 8.56 (1 H, NH). Gum. MS (ESI) m/z 375 (M + H)⁺.

EXAMPLE 11 N-r2-(3-chloro-2-pyridinyl)-2-oxoethvπ-2-r4-(2,2,2-trifluoro-1 ,1-dimethylethyl)phenoxy1-acetoamide

[4-(2,2,2-Trifluoro-1 ,1-dimethylethyl)phenoxy]acetyl chloride (112 mg, 0.38 mmol), 2-amino-1-(3- chloropyridin-2-yl)ethanone dihydrochloride (92 mg, 0.38 mmol) and pyridine (112 mg, 0.46 mmol) were reacted under the condition of Example 2 to furnish the N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-[4-(2,2,2- trifluoro-1 ,1-dimethylethyl)phenoxy]acetoamide (52 mg, 33 %).

¹H-NMR (CDCI₃) δ 1.56 (6H, s), 4.59 (2H, s), 5.02 (2H, d, J = 5.1 Hz), 6.96-7.47 (24H, m), 7.43-7.51 (4H, m), 7.83-7.86 (m, 1 H), 8.58 (1 H, NH). White solid.

MS (ESI) m/z 415 (M + H)⁺.

EXAMPLE 12 2-(4-te/t-Butylphenoxy)-Λ/-[2-(6-methyl-2-pyridinyl)-2-oxoethvn-acetamide

Step 1 2-(Λ/,Λ/-diformylamino)-1-(6-methylpyridin-2-yl)ethanone

2-Bromo-1-(6-methylpyridin-2-yl)ethanone (748 mg, 3.5 mmol, Journal of Medicinal &

Pharmaceutical Chemistry 1961, 3, 561-6), sodium diformylamide (332 mg, 3.5 mmol) and acetonitrile (10 ml) were reacted under the condition of Step 2 of Example 7 to furnish the 2-(Λ/,Λ/-diformylamino)-1-(6- methy!pyridin-2-yl)ethanone (162 mg, 23%).¹H-NMR (CDCI₃) δ 2.61 (3H, s), 5.36 (2H, s), 7.38 (1 H, d, J = 7.7 Hz), 7.72 (1 H, t, J = 7.7 Hz), 7.82 (1 H, d,

J = 7.7 Hz), 9.07 (2H, s).

Colorless oil. MS (ESI) m/z 207 (M + H)⁺.

Step 2 2-Amino-1-(6-methylpyridin-2-yl)ethanoπe dihvdrochloride

2-(Λ/,Λ/-diformylamino)-1-(6-methylpyridin-2-yl)ethanone (Step 1, 162 mg, 0.79 mmol) and concentrated HCI (0.5 ml) in ethanol (2 ml) were reacted under the condition of Step 3 of Example 7 to furnish the 2-amino-1-(6-methylpyridin-2-yl)ethanone dihydrochloride (217 mg, quant.).

¹H-NMR (DMSO-d_e) δ 2.59 (3H, s), 4.56-4.61 (2H, m), 7.65 (1 H, d, J = 7.7 Hz), 7.88 (1 H, d, J = 7.7 Hz), 7.98 (1 H, t, J = 7.7 Hz), 8.42 (2H, NH). Yellow solid.

MS (ESI) m/z 151 (M + H)⁺.

Step 3 2-(4-fe/t-Butylphenoxy)-Λ/-r2-(6-methyl-2-pyridinyl)-2-oxoethyllacetamide

(4-tert-Butylphenoxy)acetyl chloride (88 mg, 0.39 mmol), 2-amino-1-(6-methyl-2-pyridinyl)ethanone dihydrochloride (Step 2, 86 mg, 0.39 mmol) and diisopropylethylamine (200 mg, 1.55 mmol) were reacted under the condition of Example 2 to furnish the 2-(4-terf-butylphenoxy)-Λ/-[2-(6-methyl-2-pyridinyl)-2- oxoethyl]acetamide (9.2 mg, 7%).

¹H-NMR (CDCI₃) δ 1.31 (9H, s), 2.61 (3H, s), 4.58 (2H, s), 5.09 (2H, d, J = 5.0 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.33-7.38 (3H, m), 7.58 (1 H, NH), 7.74 (1 H, t, J = 7.7 Hz), 7.87 (1 H, d, J = 7.7 Hz). White solid. MS (ESI) m/z 341 (M + H)⁺. "

EXAMPLE 13 N-f2-(3-chloro-2-pyridinvn-2-oxoethvπ-2-(r4-(1.1-dimethylethvhphenyl loxy)-2-methylpropanamide

2-{[4-(1 ,1 -Dimethylethyl)phenyl]oxy}-2-methylpropanoic acid (100 mg, 0.42 mmol), oxalyl chloride (0.1 ml), dimethylaminopyridine (5 mg), CH₂CI₂ (10 ml), 2-amino-1-(3-chloropyridin-2-yl)ethanone dihydrochloride (103 mg, 0.42 mmol), Et₃N (1.0 ml) and CH₂CI₂ (5 ml) were treated under the same procedure of Example 9 to furnish the N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-{[4-(1 ,1- dimethylethyl)phenyl]oxy}-2-methylpropanamide (45.9 mg, 29%).¹H-NMR (CDCI₃) δ 1.30 (9H, s), 1.54 (3H, s), 1.58 (9H, s), 4.96 (2H, d, J = 5.2 Hz), 6.93 (2H, m), 7.27- 7.44 (5H, m), 7.84 (1 H₁ NH) White solid.

MS (ESI) m/z 389 (M + H)⁺.

EXAMPLE 14

2-(4-tetf-Butylphenoxy)-N-F2-(3-ethyl-2-pyridinyl)-2-oxoethvHacetamide

Step 1 1-(3-Ethyl-2-pyridinyl)ethanone

To a solution of 3-ethylpyridine-2-carbonitrile (750 mg, 5.7 mmol, Chemical & Pharmaceutical Bulletin 1985, 33, 565-71) in tetrahydrofuran (THF) (20 ml) was added methylmagnesium bromide (6.7 ml of a 0.93M sol., 6.2 mmol) at 0⁰C and the mixture was stirred at room temperature for 1 hour. The reaction was partitioned with saturated NH₄CI and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :4) to furnish the 1- (3-ethyl-2-pyridinyl)ethanone (589 mg, 46%).

¹H-NMR (CDCI₃) δ 1.23 (3H, t, J = 7.5 Hz), 2.71 (3H^", s), 2.97 (2H, q, J = 7.5 Hz), 7.36 (1H, dd, J = 4.5, 7.9 Hz), 7.63 (1 H, d, J = 7.9 Hz), 8.51 (1H, d, J = 4.5 Hz). Colorless oil.

MS (ESI) m/z 150 (M + H)⁺.

Step 2 2-Bromo-1-(3-ethyl-2-pyridinyl)ethanone

To a solution of 1-(3-ethyl-2-pyridinyl)ethanone (Step 1 , 388 mg, 2.6 mmol), 25% hydrobromic acid in acetic acid (1.5 ml) and acetic acid (1.5 ml) was added bromine (338 mg, 2.6 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the 2-bromo-1-(3-ethyl-2-pyridinyl)ethanone (567 mg, 71%).:¹H-NMR (CDCI₃) δ 1.21-1.31 (3H, m), 2.95-3.05 (2H, m), 4.87 (2H, s), 7.36-7.47 (1 H, m), 7.62-7.72 (1 H, m), 8.50-8.52 (1 H, m). Brown oil. MS (ESI) m/z 228 (M + H)⁺. Step 3 2-(A/,Λ/-diformylamino)-1-(3-Θthyl-2-pyridinyl)ethanone

2-Bromo-1-(3-ethyl-2-pyridinyl)ethanone (Step 2, 567 mg, 2.5mmol), sodium diformylamide (237 mg, 2.5 mmol) and acetonitrile (10 ml) were reacted under the condition of Step 2 of Example 7 to furnish the 2-(Λ/,Λ/-diformylamino)-1-(3-ethyl-2-pyridinyl)ethanone (166 mg, 30%).

¹H-NMR (CDCI₃) δ 1.22 (3H₁ 1, J = 7.5 Hz), 3.00 (2H, q, J = 7.5 Hz), 5.35 (2H, s), 7.44 (1H, dd, J = 4.6, 7.9 Hz), 7.67 (1H, cj; J = 7.9 Hz), 8.56 (1 H, d, J = 4.6 Hz), 9.05 (2H, s). White solid. MS (ESI) m/z 221 (M + H)⁺.

Step 4 2-Amino-1-(3-ethyl-2-pyridinyl)ethanone dihydrochloride

2-(Λ/,Λ/-diformylamino)-1-(3-ethyl-2-pyridinyl)ethanone (Step 3, 165 mg, 0.75 mmol) and concentrated HCI (0.5 ml) in ethanol (2 ml) were reacted under the condition of Step 3 of Example 7 to furnish the 2-amino-1-(3-ethyl-2-pyridinyl)ethanone dihydrochloride (276 mg, quant.).

¹H-NMR (DMSOd₆) δ 1.19 (3H, t, J = 7.5 Hz), 2.99 (2H, q, J = 7.5 Hz), 4.56-4.60 (2H, m), 7.68 (1H, dd, J = 4.6, 7.9 Hz), 7.92 (1 H, d, J = 7.9 Hz), 8.37 (2H, NH), 8.62 (1 H, d, J = 4.6 H). Brown oil. MS (ESI) m/z 165 (M + H)⁺.

Step 5 2-(4-terf-Butylphenoxy)-Λ/-r2-(3-ethyl-2-pyridinyl)-2-oxoethyll-acetamide

(4-ferf-Butylphenoxy)acetyl chloride (105 mg, 0.46 mmol), 2-amino-1-(3-ethyl-2-pyridinyl)ethanone dihydrochloride (Step 4, 110 mg, 0.46 mmol) and diisopropylethylamine (240 mg, 1.86 mmol) were reacted under the condition of Example 2 to furnish the 2-(4-tert-butylphenoxy)-/V-[2-(3-ethyl-2-pyridinyl)- 2-oxoethyl]acetamide (33 mg, 20%).

¹H-NMR (CDCI₃) δ 1.25 (3H, t, J = 7.5 Hz), 1.31 (9H, s), 3.03 (2H, q, J = 7.5 Hz), 4.57 (2H, s), 5.05 (2H, d, J = 5.0 Hz), 6.93 (2H, d, J = 8.7 Hz), 7.35 (2H, d, J = 8.7 Hz), 7.41 (1 H, m), 7.62 (1 H, NH), 7.66 (1 H, m), 8.52 (1 H, m). White solid. MS (ESI) m/z 355 (M + H)⁺. Example 15

2-(4-tert-Butyl-3-fluorophenoxy)-N-(2-oxo-2-pyridin-2-ylethyl)acetamide

To the tetrahydrofuran (THF) (3.0 ml) solution of (4-tert-butyl-3-fluorophenoxy)acetic acid (250 mg, 1.1 mmol) was added 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (178 mg, 1.1 mmol) at room temperature and the mixture was stirred for 2 hours followed by the addition stirring for 10h with Et₃N (0.7 ml) and 2-amino-1-pyridin-2-y! ethanone dichrolide (209 mg, 1.0 mmol). The resulting precipitate was removed by filtration followed by evaporated under reduced pressure to give the crude residue which was purified through silica gel (Si-NH) column chromatography eluting with hexane/ethylacetate from 5/1 to 5/2 to furnish the 2-(4-butyl-3-fluorophenoxy)-N-(2-oxo-2-pyridin-2-ylethyl)acetamide (20 mg, 5.8 %).

¹H-NMR (CDCI₃) δ 1.36 (9H, s), 4.56 (2H, s), 5.09 (2H, d, J = 5.1 Hz), 6.72-6.62 (2H, m, 7.22 (1 H, d, J = 9.1 Hz), 7.46 (1 H, bs), 7.54 (1 H, ddd, J = 1.3, 4.8, 7.6 Hz), 7.88 (1 H, dt, J = 1.7, 7.6 Hz), 8.07 (1 H, d, J = 7.7 Hz), 8.70 (1 H, dd, J = 0.7, 3.8 Hz). White solid. MS (ESI) m/z 345 (M + H)⁺.

Example 16

2-(4-fe/t-Butylphenoxy)-2-(2-methyl-5-hvdroxyphenyl)oxoethylacetamide

Step 1 2-(Λ/,Λ/-diformylamino)-1 -(5-methoxy-2-methylphenyl)ethanone

1-(5-Methoxy-2-methylphenyl)ethanone (164 mg, 1.0 mmol, Journal of the American Chemical Society 1987, 109, 7137-41.), 25% hydrobromic acid in acetic acid (1.0 ml), acetic acid (2.0 ml) and bromine (176 mg, 1.1 mmol) were reacted under the condition of Step 3 of Example 14 to furnish the 2- bromo-1-(5-methoxy-2-methylphenyl)ethanone (281 mg, quant.), which was used for the next reaction without purification. 2-bromo-1 -(5-methoxy-2-methylphenyl)ethanone thus obtained, sodium diformylamide (114 mg, 1.2 mmol) and acetonitrile (1.0 ml) were reacted under the condition of Step 2 of Example 7 to furnish the 2-(Λ/,Λ/-diformylamino)-1-(5-methoxy-2-methylphenyl)ethanone (112 mg, 47%).

¹H-NMR (CDCI₃) δ 2.41 (3H, s), 3.84 (3H, s), 4.93 (2H, s), 6.99 (1 H, d, J = 5.4 Hz), 7.18-7.22 (2H, m), 9.02 (2H, s). Brown oil. Step 2 2-Amino-1-(2-methyl-5-methoxyphenyl)ethanone hydrochloride O

<^\ HCI

2-(Λ/,Λ/-diformylamino)-1-(5-methoxy-2-methylphenyl)ethanone (Step 1 , 112 mg, 0.476 mmol) and concentrated HCI (0.7 ml) in ethanol (2.0 ml) were reacted under the condition of Step 3 of Example 7 to _ furnish the 2-amino-1-(2-methyl-5-methoxyphenyl)ethanone hydrochloride, which was used for the next reaction without purification. White solid. MS (ESI) m/z 180 (M + H)⁺.

Step 3 2-(4-fe/t-Butylphenoxy)-2-(2-methyl-5-methoxyphenyl)oxoethylacetamide

(4-tert-Butylphenoxy)acetyl chloride (162 mg, 0.714 mmol), 2-amino-1-(6-methyl-2-pyridinyl)- ethanone dihydrochloride (Step 2) and pyridine (0.5 ml) were reacted under the condition of Example 2 to furnish the 2-(4-fert-butylphenoxy)-2-(2-methyl-5-methoxyphenyl)oxoethylacetamide (175 mg, 53%).¹H-NMR (CDCI₃) δ 1.31 (9H, s), 2.48 (3H, s), 3.83 (3H, s), 4.57 (2H, s), 4.72 (2H, d, J = 5.4 Hz), 6.94 (2H, d, J = 10.8 Hz), 7.00 (1 H, dd, J = 2.7, 8.1 Hz), 7.21 (1H, d, J = 8.1 Hz), 7.25 (1H, d, J = 2.7 Hz), 7.35 (2H, d, J = 10.8 Hz), 7.66 (1H₁ S₁ NH).

White solid.

MS (ESI) m/z 370 (M + H)⁺.

Step 4 2-(4-ferf-Butylphenoxy)-2-(2-methyl-5-hvdroxyphenyl)oxoethylacetamide

To a solution of 2-(4-terf-butylphenoxy)-2-(2-methyl-5-methoxyphenyl)oxoethylacetamide (Step 3, 30 mg, 0.081 mmol) in CH₂CI₂ (1.0 ml) was added BBr₃ (0.8 ml, 1.0 N in CH₂CI₂, 0.8 mmol) dropwise at 0⁰C and the mixture was stirred at the same temperature for 1 h. The 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%).

¹H-NMR (CDCI₃) δ 1.31 (9H₁ s), 1.60 (1 H₁ s, OH), 2.50 (3H, s), 4.61 (2H, s), 4.79 (2H₁ d, J = 5.4 Hz), 6.96 (2H, d, J = 8.1 Hz), 6.95-7.00(1 H, m), 7.17 (1H, d, J = 5.4 Hz)₁ 7.36 (1H₁ d, J = 8.1 Hz), 7.42 (1H₁ d, J = 2.1 Hz), 7.86 (1H₁ S₁ NH). White solid. MS (ESI) m/z 356 (M + H)⁺.

EXAMPLE 17

2-(4-te/t-Butylphenoxy)-2,2-dimethyl-Λ/-r2-(3-methylpyridiπ-2-yl)-2-oxoethyllpropanamide

To a solution of 2-(4-ferf-butylphenoxy)-2,2-dimethylpropanoic acid (118 mg, 0.5 mmol) in dichloromethane (2 ml) was added oxalyl chloride (190 mg, 1.5 mmol) and Λ/,Λ/-dimethylformamide (DMF) (1 drop) at room temperature. After the mixture was stirred for 1 hour, the excess amount of oxalyl chloride was removed in vacuo. To a solution of reaction mixture in dichloromethane (2 ml) was added 2-amino-1-(3-methylpyridin-2-yl)ethanone dihydrochloride (112 mg, 0.5 mmol) and N, N- diisopropylethylamine (194 mg, 1.5 mmol) at 0⁰C and thejnixture was stirred at room temperature for 1 h. The reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :2) to furnish the 2-(4-tert-butylphenoxy)-2,2-methyl-Λ/-[2-(3-methylpyridin-2-yl)-2-oxoethyl]propanamide (76 mg, 41 %).

¹H-NMR (CDCI₃) δ 1.30 (9H, s), 1.54 (6H, s), 2.62 (3H, s), 5.00 (2H, d, J = 5.1 Hz), 6.94 (2H, d, J = 8.7 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.38 (1H, dd, J = 4.6, 7.4 Hz), 7.59-7.68 (2H, m), 8.52-8.54 (1 H, m). White solid.

MS (ESI) m/z 369 (M + H)⁺.

Example 18 N-r2-(3-methyl-2-pyridinyl)-2-oxoethyll-2-(4-feft-butylphenoxy)-2,2-difluoroacetamide

(4-fe/t-Butylphenoxy)difluoroacetic acid (271 mg, 1.1 mmol), oxalyl chloride (0.2 ml) and dimethylamino pyridine (10 mg), CH₂CI₂ (15 ml), 2-amino-1-(3-methylpyridin-2-yl)ethanone dihydrochloride (247 mg, 1.1 mmol), Et₃N (3.0 ml) and CH₂CI₂ (15 ml) were treated under the same procedure of Example 9 to furnish the N-[2-(3-methyl-2-pyridinyl)-2-oxoethyl]-2-(4-fert-butylphenoxy)-2,2- difluoroacetamide (46.8 mg, 11%).¹H NMR (CDCI₃) δ 1.32 (9H, s), 2.65 (3H, s), 5.08 (2H, d, J = 4.8 Hz), 7.18-7.63 (7H, m), 8.54 (1 H, NH). White Solid. MS (ESI) m/z 377 (M + H)⁺.

Example 19

2-(4-terf-Butyl-3-fluorophenoxy)-N-r2-(3-methylpyridin-2-yl)-2-oxo-ethvnacetamide

The mixture of (4-terf-butyl-3-fluorophenoxy)acetic acid (113 mg, 0.5 mmol), 2-chloro-1 ,3- dimethylimidazolinium chloride (CDl) (97 mg, 0.6 mmol), Et₃N (0.35 ml), tetrahydrofuran (3.0 ml) and 2- amino-1 -(3-methylpyridin-2-yl) ethanone dichrolide (123 mg, 0.6 mmol) were mixed in the same procedure described in Example 2 to furnish the 2-(4-butyl-3-fluorophenoxy)-N-[2-(3-methylpyridin-2-yl)-2- oxo-ethyl]acetamide (43.7 mg, 24 %).

¹H NMR (CDCI₃) δ 1.36 (9H, s), 2.64 (3H, s), 4.55 (2H, s), 5.06 (2H, d, J = 5.2 Hz), 6.74-6.63 (2H, m), 7.22 (1H, d, J = 9.0 Hz), 7.40 (1 H, dd, J = 4.6, 7.9 Hz), 7.47 (1 H, bs), 7.63 (1H, d, J = 7.7 Hz), 8.53 (1H, dd, J = 1.4, 4.6 Hz). White Solid.

MS (ESI) m/z 359 (M + H)⁺.

EXAMPLE 20

2-(4-fert-Butylphenoxy)-2,2-difluoro-Λ/-r2-(1-methyl-1 H-imidazol-2-yl)-2-oxoethvnacetamide

Step 1 ferf-Butyl f2-(1 -methyl-1 AY-imidazol-2-yl)-2-oxoethvπcarbamate i O O H H

V VNh O I

To a solution of 1-methylimidazole (328 mg, 4 mmol) in tetrahydrofuran (THF) (20 ml) was added n- butyllithium (2.53 ml of a 1.58M hexane sol., 4 mmol) at -78⁰C over 10 min. After the mixture was stirred at -78⁰C for 1 hour, a solution of fert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (218 mg, 1 mmol) in tetrahydrofuran (THF) (2 ml) was added to the reaction mixture at -78 °C dropwise and the mixture was stirred for 3hours.Then the reaction was partitioned with saturated NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then filtration, evaporation under reduced pressure gave the crude residue which was purified through silica gel column chromatography eluting with ethylacetate/hexane (1 :1 to 3:1) to furnish the tert-butyl [2-(1 -methyl-1 H-imidazol-2-yI)-2- oxoethyl]carbamate. (215 mg, 90%).

¹H-NMR (CDCI₃) .81.47 (9H, s), 4.01 (3H, s), 4.72 (2H, d, J = 5.5 Hz), 5.22 (1 H, br s), 7.06 (1 H, s), 7.16 (1H, s). White solid.

MS (ESI) m/z 240 (M + H)⁺.

Step 2 2-Amino-1 -(1 -methyl- 1 H-imidazol-2-yl)ethanone dihvdrochloride

A mixture of fert-butyl [2-(1-methyl-1 /-/-imidazol-2-yl)-2-oxoethyϊ]carbamate (Step 1 , 108 mg, 0.45 mmol) and 10% HCI-MeOH (2 ml) was stirred at room temperature for 16 hours. The mixture was evaporated and crystallized from ethyl acetate to furnish the 2-amino~1-(1-methyl-1H-imidazol-2- yl)ethanone dihydrochloride. (95 mg, quant.).

¹H-NMR (DMSO-Of₆) .5 3.97 (3H, s), 4.40-4.45 (2H, m), 7.26 (1H, s), 7.69 (1H, s), 8.43 (2H, br s).

White solid.

MS (ESI) m/z 140 (M + H)⁺.

Step 3 2-(4-fe/t-Butylphenoxy)-2,2-dif luoro-Λ/-f2-(1 -methyl-1 H- imidazol-2-yl)-2-oxoethyllacetamide

(4-ferf-Butylphenoxy)(difluoro)acetic acid (87 mg, 0.36 mmol), oxalyl chloride (136 mg, 1.07 mmol), Λ/,Λ/-dimethylformamide (DMF) (1 drop), dichloromethane (2 ml), 2-amino-1-(1-methyl-1 /-/-imidazol-2- yl)ethanone dihydrochloride (Step 3, 95 mg, 0.45 mmol), diisopropylethylamine (184 mg, 1.42 mmol) and dichloromethane (2 ml) were reacted under the condition of Example 9 to furnish the 2-(4-ferf- butylphenoxy)-2,2-difluoro-Λ/-[2-(1 -methyl-1 W-imidazol-2-yl)-2-oxoethyl]acetamide (48 mg, 37%).:

¹H-NMR (CDCI₃) δ 1.32 (9H, s), 4.04 (3H, s), 4.94 (2H, d, J = 5.3 Hz), 7.12-7.21 (4H, m), 7.35-7.42 (2H, m), 7.47 (1 H, br.s), White solid. MS (ESI) m/z 366 (M + H)⁺

EXAMPLE 21

2-(4-tert-Butylphenoxy)-N-r2-(3-methyl-2-pyridinyl)-2-oxoethyll-2-propenamide

Step 1 Methyl-2-(4-fe/t-butylphenoxy)-2-propenoate

To the dimethylformamide solution of methyl 2-bromo-3-(methyloxy)propanoate (34.2 g, 174 mmol, Jornal of organic chemistry 1983, 48, 1377), 4-(1 ,1-dimethylethyl)phenol (26.1 g, 174 mmol) and K₂CO₃ (72.1 g, 522 mmol) were added and the mixture was stirred for 3 hours at 80 °C. Then, the reaction was quenched with saturated NaHCO₃ aqueous solution and crude product was extracted with ethyl acetate, dried over Na₂SO₄. After the filtration, evaporation gave the crude residue which was passed through silica gel column chromatography to give crude oil. This was used for further reaction without purification. MS (ESI) m/z 267 (M + H)⁺.

Step 2 2-(4-terf-Butylphenoxy)-N-f2-(3-methyl-2-pyridinyl)-2-oxoethyl1-2-propenamide

To the methyl 2-(4-terf-butylphenoxy)-2-propenoate (Step 1 , 245 mg, 0.9 mmol), 10 ml of LiOH (20mg) aqueous solution was added and the mixture was stirred for 3 hours at 100⁰C. After acidification with 2N HCI, 1-{[4-(1 ,1-dimethylethyl)phenyl]oxy}ethanol was extracted with ethylacetate and organic layer was dried over Na₂SO₄. Then, filtration, evaporation gave the white solid which was used for further reaction without purification. 1-{[4-(1 ,1-dimethylethyl)phenyl]oxy}ethenol (220 mg, 0.87 mmol), oxalyl chloride (331 mg, 2.61 mmol), dimethylaminopyridine (10mg), dichloromethane (20 ml), (95 mg, 0.45 mmol), 2-amino-1-(3-methylpyridin-2-yl)ethanone dihydrochloride (94 mg, 0.42 mmol), diisopropylethylamine (195 mg, 0.87 mmol), Et₃N (1.5 ml) and dichloromethane (20 ml) were reacted under the condition of Example 9 to furnish the 2-(4-tert-butylphenoxy)~N-[2-(3-methyl-2-pyridinyl)-2- oxoethyl]-2-propenamide (77.0mg, 25%).

¹H-NMR (CDCI₃) δ 1.34 (9H, s), 2.64 (3H, s), 4.54 (1H, d, J = 2.2 Hz), 5.10 (2H , d, J = 4.4 Hz),^" 5.65 (1H, d, J = 2.2 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.27 (1H, s), 7.39-7.68 (4H, m), 8.56 (1 H, NH).

White solid.

MS (ESI) m/z 353 (M + H)⁺.

EXAMPLE 22

Λ/-f2-(3-methylpyridin-2-yl)-2-oxoethyll-2-r4-(2,2,2-trifluoro-1 ,1-dimethylethyl)phenoxylacetamide

[4-(2,2,2-Trifluoro-1 ,1-dimethylethyl)phenoxy]acetic acid (110 mg, 0.42 mmol), oxalyl chloride (160 mg, 1.26 mmol), Λ/,Λ/-dimethylformamide (DMF) (1 drop), dichloromethane (2 ml), 2-amino-1-(3- methylpyridin-2-yl)ethanone dihydrochloride (94 mg, 0.42 mmol), diisopropylethylamine (216 mg, 1.67 mmol) and dichloromethane (2 ml) were reacted under the condition of Example 9 to furnish the Λ/-[2-(3- methylpyridin-2-yl)-2-oxoethyl]-2-[4-(2,2,2-trifluoro-1 ,1 -dimethylethyl)phenoxy]acetamide (15 mg, 9%).

¹H-NMR (CDCI₃) .6 1.57 (6H, s), 2.64 (3H, s), 4.59 (2H, s), 5.07 (2H , d, J = 5.1 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.40 (1 H, dd, J = 4.4, 8.1 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.50 (1 H, br.s), 7.63 (1 H, d, J = 8.1 Hz), 8.54 (1 H, d, J = 4.4 Hz). White solid. MS (ESI) m/z 395 (M + H)⁺. EXAMPLE 23

2-(4-terf-Butylphenoxy)-Λ/-(2-oxo-2-r3-(trifluoronnethyl)pyridin-2-vnethyl)acetamide

Step 1 fert-Butyl{2-oxo-2-r3-(trifluoromethyl)pyridin-2-yllethyl)carbamate

To a solution of 2-bromo-3-trifluoromethylpyridine (446 mg, 1.97 mmol) in toluene (10 ml) was added n-butyllithium (1.28 ml of a 1.54M hexane sol., 1.97 mmol) at -78⁰C dropwise. After the mixture was stirred at -78⁰C for 30 minutes, a solution of terf-butyl {2-[methoxy(methyl)amino]-2- oxoethyljcarbamate (218 mg, 1 mmol) in toluene (2 ml) was added to the reaction mixture at -78 °C dropwise and the mixture was stirred for 2 hours. Then the reaction was partitioned with saturated

NaHCO₃ and ethylacetate and organic layer was separated, dried over Na₂SO₄. Then the mixture was filtrated, evaporated under reduced pressure to furnish the crude product of tert-butyl{2-oxo-2-[3-

(trifluoromethyl)pyridin-2-yl]ethyl}carbamate (210 mg).;¹ H-NMR (CDCI₃) δ 1.47 (9H, s), 4.80 (2H, d, J = 5.1 Hz), 5.35 (1 H, br s), 7.64 (1 H, dd, J = 4.4, 8.1 Hz), 8.15 (1 H, d, J = 8.1 Hz), 8.83 (1 H, d, J = 4.4 Hz). Brown oil.

MS (ESI) m/z 305 (M + H)⁺

Step 2 2-Amino-1 -r3-(trifluoromethv0pyridin-2-vπethanone dihvdrochloride

A mixture of tert-butyl{2->oxo-2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}carbamate (Step 1 , 210 mg) and

10% HCI-MeOH (4 ml) was stirred at room temperature for 4 hours. The mixture was evaporated and crystallized from ethyl acetate to furnish the crude product of 2-amino-1-[3-(trifluoromethyl)pyridin-2- yl]ethanone dihydrochloride (217 mg).

¹H-NMR (DMSO-ofe) δ 4.63-4.69 (2H, m), 7.97 (1 H, dd, J = 4.6, 8.6 Hz), 8.48 (1 H, d, J = 8.6 Hz), 9.02 (1 H, d, J = 4.6 Hz). Black oil. MS (ESI) m/z 205 (M + H)⁺

Step 3 2-(4-terf-Butylphenoxy)-/V-|2-oxo-2-r3-(trifluoromethyl)pyridin-2-vnethyllacetamide

(4-terf-Butylphenoxy)acetyl chloride (113 mg, 0.5 mmol), 2-amino-1-[3-(trifluoromethyl)pyridin-2- yl]ethanone dihydrochloride (Step 2, 217 mg) and diisopropylethylamine (259 mg, 2 mmol) were reacted under the condition of Example 2 to furnish the 2-(4-te/f-butylphenoxy)-Λ/-{2-oxo-2-[3- (trifluoromethyl)pyridin-2-yl]ethyl}acetamide (64 mg, 32% over 3steps).¹H-NMR (CDCI₃) δ 1.31 (9H, s), 4.57 (2H, s), 5.04 (2H , d, J = 5.1 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.49 (1H, br.s), 7.66 (1 H, dd, J = 4.2, 8.1 Hz), 8.18 (1 H, d, J = 8.1 Hz), 8.85 (1 H, d, J = 4.2 Hz).

White solid.

MS (ESI) m/z 395 (M + H)⁺.

EXAMPLE 24 2-(4-fe/t-Butylphenoxy)-/V-r2-oxo-2-(1 ,3-thiazol-2-yl)ethvnacetamide

Step 1 2-(4-te/t-Butylphenoxy)-/V-f2-(methoxymethylamino)-2-oxoethyllacetamide

To a solution of Λ/,O-dimethyl hydroxylamine hydrochloride (732 mg, 7.5 mmol) Λ/-[[4-(1 ,1- dimethylethyl)phenoxy]acetyl]glycine (1.33 g, 5 mmol, Registry Number: 446827-38-9), 1- hydoroxybenzotriazole (HOBt) (338 mg, 2.5 mmol),-triethylamine (1.05 ml, 7.5 mmol) in N₁N- dimethylformamide (DMF) and water soluble carbodiimide (WSC) (1.92 g, 10 mmol) were reacted under the condition of Example 1 to furnish the 2-(4-tert-butylphenoxy)-Λ/-[2-(methoxymethylamino)-2-oxoethyl]- acetamide (1.24 g, 81%).

¹H-NMR (CDCI₃) δ 1.30 (9H, s), 3.24 (3H, s), 3.75 (3H, s), 4.29 (2H, d, J = 4.6 Hz), 4.53 (2H, s), 6.90 (2H, d, J = 9.1 Hz), 7.33 (2H, d, J = 9.1 Hz), 7.43 (1H, NH). Colorless oil. MS (ESI) m/z 309 (M + H)⁺.

Step 2 2-(4-tetf-Butylphenoxy)-/V-r2-oxo-2-(1 ,3-thiazol-2-yl)ethyllacetamide

Thiazole (341 mg, 4 mmol), n-butyllithium (2.6 ml of a 1.54M hexane sol., 4 mmol), tetrahydrofuran (THF) (10 ml) and 2-[4-te/?-butylphenoxy]-Λ/-[2-(methoxymethylamino)-2-oxoethyl]acetamide (Step 1 , 308 mg, 1 mmol) were reacted under the condition of Example 20 to furnish the 2-(4-fert-butylphenoxy)-Λ/-[2- oxo-2-(1 ,3-thiazol-2-yl)ethyl]acetamide (135 mg, 41%).

¹H-NMR (CDCI₃) δ 1.31 (9H, s), 4.59 (2H, s), 5.02 (2H, d, J = 5.1 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.41 (1 H, br s), 7.76 (1 H, d, J = 2.9 Hz), 8.07 (1 H, d, J = 2.9 Hz).

White solid.

MS (ESI) m/z 333 (M + H)⁺.

Example 25

2-r4-terf-Butylphenoxy1-Λ/-r2-(3,6-dimethyl-2-pyridinyl)-2-oxoethvnacetamide

Step 1 2-(Λ/,Λ/-diformylamino)-1 -(3,6-dimethyl-2-pyridinyl)ethanone

1-(3,6-Dimethyl-2-pyridinyl)ethanone (1.0 g, 6.7 mmol, Qual. Foods Beverages: Chem. Technol.,

[Proc. Symp. Int. Flavor Conf.], 2nd 1981, 1, 183-200.), 25% hydrobromic acid in acetic acid (5.0 ml), acetic acid (10.0 ml) and bromine (1.17 g, 7.32 mmol) were reacted under the condition of Step 2 of Example 7 to furnish the 2-bromo-1-(3,6-dimethyl-2-pyridinyl)-ethanone, which was used for the next reaction without purification. 2-Bromo-1-(3,6-dimethyl-2-pyridinyl)ethanone thus obtained, sodium diformylamide (1.91 g, 20.1 mmol) and acetonitrile (8.0 ml) were reacted under the condition of Step 2 of Example 7 to furnish the 2-(Λ/,Λ/-diformylamino)-1-(3,6-dimethyl-2-pyridinyl)ethanone (780 mg, 52%).

¹H-NMR (CDCI₃) δ 2?54 (3H, s), 2.56 (3H, s), 5.37 (2H, s), 7.25 (1 H, d, J = 8.1 Hz), 7.49 (1H, d, J = 8.1 Hz), 9.04 (2H, s). White solid. MS (ESI) m/z 221 (M + H)⁺.

Step 2 2-Amino-1-(3,6-dimethyl -2-pyridinvDethanone dihvdrochloride

2-(Λ/,Λ/-diformylamino)-1-(3,6-dimethyl-2-pyridinyl)ethanone (Step 1 , 780 mg, 3.54 mmol)and concentrated HCI (3.0 ml) in ethanol (6.0 ml) were reacted under the condition of Step 3 of Example 7 to furnish the 2-amino-1 -(3,6-dimethyl-2-pyridinyl)ethanone dihydrochloride (840 mg, 99%). White solid. MS (ESI) m/z 165 (M + H)⁺.

Step 3 2-(4-te/-f-Butylphenoxy)-Λ/-r2-(3,6-dimethyl-2-pyridinyl)-2-oxoethvπacetamide

(4-terf-Butylphenoxy)acetyl chloride (127 mg, 0.55 mmol), 2-amino-1-(6-methyl-2- pyridinyl)ethanone dihydrochloride (Step 2, 118 mg, 0.50 mmol) and triethylamine (0.5 ml) were reacted under the condition of Example 2 to furnish the 2-(4-tert-butylphenoxy)-Λ/-[2-(3,6-dimethyl-2-pyridinyl)-2- oxoethyl]acetamide (82 mg, 46%).

¹H-NMR (CDCI₃) δ 1.31 (9H, s), 2.55 (3H, s), 2.59 (3H, s), 4.57 (2H, s), 5.06 (2H, d, J = 5.4 Hz), 6.95 (2H, d, J = 10.8 Hz), 7.24 (1 H, d, J = 8.1 Hz), 7.36 (1 H, d, J = 10.8 Hz), 7.50 (1 H, d, J = 8.1 Hz), 7.60 (1 H, s,

NH).

White solid.

MS (ESI) m/z 355 (M + H)⁺.

Experimental Example

Human VR1 antagonist assay was conducted using the method described above. The results of these studies are summarized in Table 1.

Table 1. Results of Human VR1 anta onist assa

,2+

IC₅₀: the concentration of the individual compound required to reduce Ca influx capsaicin-evoked by 50%.

Claims

1. A compound of the formula (I):

wherein

R¹, R², R³ and R⁴ each independently represent hydrogen, (Ci-C₆)alkyl, halogen, cyano, hydroxy, (C₁-

C₆)alkoxy, hydroxy(C_rC₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁ -C₆JaIkOXy(C₁ -C₆)alkoxy, halo(C_r C₆)alkyl, (C_rC₆)alkylthio, (d-C^alkylsulfinyl, (d-C_fOalkylsulfonyl, [(d-CeJalkyljNH- or [(C₁-C₆) alkyl]₂N-; or R^ and R² groups together form (CrC₃)alkylene chain in which one or two non-adjacent carbon atoms are optionally replaced by oxygen or NH; or R³ and R⁴ together form alkenyl; n represents 1 or 2;

R⁵ and R⁶ each independently represent halogen, (C₁-C₆)alkyl, cyano, hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆JaIkOXy, halo(C_rC₆)alkyl, (CrC₆)alkylthio, (CrC^alkylsulfinyl and (d-C^alkylsulfonyl;

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_rC₆)alkyl, cyano, hydroxy, hydroxy(CrC₆)alkyl, (CrC₆)alkoxy, ha!o(C₁-C₆)alkyl, (C₁- C₆)alkylthio, (C_rC₆)alkylsulfinyl and (C_rC₆)alkylsulfonyl; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.

2. A compound according to Claim 1 , wherein:

R¹, R², R³ and R⁴ each independently represent hydrogen, (CrC₆)alkyl or halogen; or R³ and R⁴ together form alkenyl

R⁵ and R⁶ each independently represent halogen, (C_rC₆)alkyl or halo(CrC₆)alkyl; n represents 1 ;

A represents phenyl or a monocyclic 5- or 6-membered heteroaryl; said monocyclic heteroaryl containing 1 or 2 nitrogen and/or 1 oxygen or sulfur; said A is unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, (CrCβJalkyI, hydroxy, (C₁-C₆JaIkOXy, halo(C_rC₆)alkyl; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.

3. A compound according to Claim 1 , wherein R¹ and R² each independently represent hydrogen; R³ and R⁴ each independently represent hydrogen, (Ci-C₃)alkyl or halogen; or R³ and R⁴ groups together form alkenyl; R⁵ and R⁶ each independently represent halogen, (C₁-C₆)BlKyI or halo(C₁-C₆)alkyl; n represents 1 ; A represents phenyl, pyridine group or imidazole group; said A is unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, (C₁-C₆JaIlCyI, hydroxy, (CrC₆)alkoxy, halo(C₁-C₆)alkyl.

4.A compound according to any one of Claims 1 to 3, wherein

R³ and R⁴ each independently represent hydrogen, fluoro or methyl; or R³ and R⁴ together form methylen group.

6. A compound according to any one of Claims 1 to 3, wherein

A represents phenyl, pyridine or imidazole group; said A is unsubstituted or substituted by at least one substituent selected from the group consisting of fluoro, chloro, methyl, methoxy, hydroxy, trifluoromethyl, ethyl.

7. A compound according to any one of Claims 1 to 3, wherein

R⁵ and R⁶ each independently represent fluoro, trifluoromethyl, tert-butyl, 2,2,2-trifluoro-1 ,1-dimethylethyl.

8. A compound selected from claim 1 :

2-(4-terf-butylphenoxy)-Λ/-[2-(2-methylphenyl)-2-oxoethyl]acetamide;

Λ/-[2-(2-chlorophenyl)-2-oxoethyl]-2-(4-te/t-butylphenoxy)acetamide;

2-(4-terf-butylphenoxy)-Λ/-[2-oxo-2-(2-pyridinyl)ethyl]acetamide;

Λ/-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-fert-butylphenoxy)acetamide; 2-(4-fe/f-butylphenoxy)-N-[2-(3-methyl-2-pyridinyl)-2-oxoethyl]acetamide;

N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-tert-butylphenoxy)-2,2-difluoroacetamide;

N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-fert-butylphenoxy)propanamide;

N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-[4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetoamide;

2-(4-terf-butylphenoxy)-/V-[2-(6-methyl-2-pyridinyl)-2-oxoethyl]acetamide; N-[2-(3-chloro-2-pyridinyl)-2-oxoethyl]-2-(4-ferf-butylphenoxy)-2-methylpropanamide;

2-(4-ferf-butyIphenoxy)-N-[2-(3-ethyl-2-pyridinyl)-2-oxoethyl]acetamide;

2-(4-tert-butyl-3-fluorophenoxy)-N-(2-oxo-2-pyridin-2-ylethyl)acetamide;

2-[4-(1 ,1-dimethylethyl)phenoxy]-2-(2-methyl-5-hydroxyphenyl)oxoethylacetamide;

2-(4-fert-butylphenoxy)-2,2-dimethyl-Λ/-[2-(3-methylpyridin-2-yl)-2-oxoethyl]propanamide; N-[2-(3-methyl-2-pyridinyl)-2-oxoethyl]-2-(4-tert-butylphenoxy)-2,2-difluoroacetamide;

2-(4-butyl-3-fluorophenoxy)-N-[2-(3-methylpyridin-2-yl)-2-oxo-ethyl]acetamide;

2-(4-tert-butylphenoxy)-N-[2-(3-methyl-2-pyridinyl)-2-oxoethyl]-2-propenamide;

Λ/-[2-(3-methylpyridin-2-yl)-2-oxoethyl]-2-[4-(2,2,2-trifluoro-1 ,1-dimethylethyl)phenoxy]acetamide;

2-(4-te/t-butylphenoxy)-A/-{2-oxo-2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}acetamide; 2-(4-ferf-butylphenoxy)-Λ/-[2-oxo-2-(1 ,3-thiazol-2-yl)ethyl]acetamide; and 2-(4-tert-butylphenoxy)-Λ/-[2-(3,6-dimethyl-2-pyridinyl)-2-oxoethyl]acetamide; or a pharmaceutically acceptable ester thereof;or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition including a compound of any one of claims 1 to 8 or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable carrier.

10. A pharmaceutical composition according to Claim 9, for the treatment of a disease caused by overactivation of VR1 receptor, in a mammalian subject, which comprises a therapeutically effective amount of a compound of any one of Claims 1 to 8 or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable carrier.

11. A pharmaceutical composition according to Claim 10 where the disease is selected from acute cerebral ischemia, pain, chronic 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, gastrointestinal, such as gastroesophageal reflux disease (GERD), dysphagia, ulcer.irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis and Crohn's disease, ischemia, such as cerebrovascular ischemia, emesis, such as cancer chemotherapy- induced emesis, and obesity.

12. A method for the treatment of a disease caused by overactivation of VR1 receptor, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of any one of claims 1 to 8 or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.

13. A method according to Claim 12 where the disease is selected from acute cerebral ischemia, pain, chronic 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, gastrointestinal, such as gastroesophageal reflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis and Crohn's disease, ischemia, such as cerebrovascular ischemia, emesis, such as cancer chemotherapy-induced emesis, and obesity.

14. Use of a compound of any one of claims 1 to 8 or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease caused by overactivation of VR1 receptor in a mammalian subject.

15. A pharmaceutical formulation comprising a compound of formula (I) according to any one of Claims 1-8, a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active agents. .