WO2005095329A1

WO2005095329A1 - Substituted benzamide compounds as vr1 receptor antagonists

Info

Publication number: WO2005095329A1
Application number: PCT/IB2005/000728
Authority: WO
Inventors: Satoshi Nagayama; Yuji Shishido; Madoka Jinno; Kazunari Nakao
Original assignee: Pfizer Japan Inc.; Pfizer Inc.
Priority date: 2004-03-31
Filing date: 2005-03-21
Publication date: 2005-10-13

Abstract

This invention provides a compound of the formula (I): wherein R1 represents a (C1-C6)alkoxy group, a halo(C1-C6)alkoxy group, R2 represents a hydrogen atom or a (C1-C6)alkyl group, and R3 represents a hydrogen atom, a (C1-C6)alkoxy group or a hydroxy group; 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

SUBSTITUTED BENZAMIDE COMPOUNDS AS NRl RECEPTOR ANTAGONISTS Technical Field This invention relates to novel substituted benzamide compounds. These compounds are useful as antagonists of NRl (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 Nanilloid 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 NRl 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 NRl exists in bladder, kidney, brain, pancreas, and various kinds of organs. A body of studies using NRl agonists, e.g., capsaicin or resiniferatoxin, have suggested that NRl positive nerves are thought to participate in a variety of physiological responses, including nociception. Based on both the tissue distribution and the roles of NRl, VR1 antagonists would have good therapeutic potentials. International Patent Application Number WO 03095420 discloses a variety of tetrahydro-naphthalenylurea derivatives, which are NRl antagonists, for example,

Compound A below:

Compound A

It would be desirable if there were provided a novel NRl selective antagonist with potent binding activity by systemic administration with good absorption.

Brief Disclosure of the Invention It has now been found that substituted benzamide compounds are VR1 selective 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. In particular, the compounds of the present invention may display improved solubility and absorption over the compounds represented by A above. The present invention provides a compound of the following formula (I):

(I) wherein R¹ represents a halogen atom, a (d-C^alkyl group, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxy group, a (CrC₆)alkoxy group, a halo(Cι-C₆)alkoxy group, a (Cι-C₆)alkylthio group , a (CrC₆)alkylsulfinyl group, a ( -C^alkylsulfonyl group, a halo(Cι-C₆)alkylthio group, a

group, a halo(Cι- C₆)alkylsulfonyl group, a (C₁-C₆)alkylsulfonylamino group, a mono- or di-(Cr C₆)alkylaminosulfonyl group or or a heterocyclic group having from 4 to 7 ring atoms; said (CrC₆)alkyl group, said ( -C^alkoxy group, said cycloalkyl group having from 3 to 8 carbon atoms and said heterocyclic group having from 4 to 7 ring atoms are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituent α; said substituent α are selected from the group consisting of halogen atoms, (d- C₆)alkyl groups, cycloalkyl groups having from 3 to 8 carbon atoms, hydroxy groups, (d-C₆)alkoxy groups, hydroxy(C -C₆)alkyl groups, hydroxy(CrC₆)alkoxy groups, (C₁-C₆)alkoxy(C₁-C₆)alkyl groups, (C₁-C₆)alkoxy(C₁-C₆)alkoxy groups, halo(d- C₆)alkyl groups, (d-C₆)alkanoyl groups, cyano groups, carboxy groups, (d- C₆)alkoxycarbonyl groups, amino groups, aminocarbonyl groups, mono- or di-(d- C₆)alkylamino groups, mono- or di-(Cι-C₆)alkylaminocarbonyl groups, mono- or di- (d-C₆)alkylamino(Cι-C₆)alkoxy groups in each alkyl and alkoxy part, heterocyclic groups having from 4 to 7 ring atoms and heterocyclic groups having from 4 to 7 ring atoms substituted by one or two (d-C₆)alkyl groups; R² represents a hydrogen atom or a (d-C₆)alkyl group; and R³ represents a hydrogen atom, a (C₁-C₆)alkoxy group or a hydroxy group; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are antagonists of NRl receptor, and are thus useful in therapeutics, particularly for the treatment of 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, 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, hi 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 intervertabral 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, HIN 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: S 141 -S 147; 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; - Musculo-skeletal disorders including but not limited to myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, Glycogenolysis, 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 (GI) disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases QBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including FBD, gastro- esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), EBD, 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 NRl 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 term "alkyl" means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, π-propyl, z_?opropyl, w-butyl, iso- butyl, secondary-butyl, tert/ary-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, π-propoxy, wøpropoxy, n-butoxy, iso-butoxy, secondary-butoxy, tertiatγ-butoxy. As used herein, the term " alkanoyl" means a group having carbonyl such as R'-C(O)- wherein R' is H, Cι-₅ alkyl, phenyl or C₃-₆ cycloalkyl, including, but not limited to formyl, acetyl, ethyl-C(O)-, -propyl-C(O)-, t_?øpropyl-C(O)-, rc-butyl-C(O)-, z'_?o-butyl-C(O)-, secondary-butyl-C(0)-, tertiary-butyl-C(0)-, cyclopropyl-C(O)-, cyclobutyl-C(O)-, cyclopentyl-C(O)-, cyclohexyl-C(O)-, and the like. As used herein, the term "hydroxyalkoxy" means an alkoxy radical as defined above which is substituted by hydroxy group including, but not limited to, hydroxymethoxy, hydroxyethoxy, hydroxy rø-propoxy, hydroxy/sopropoxy, hydroxy π-butoxy, hydroxy t_rø-butoxy, hydroxy secondary-butoxy, hydroxy tertz^'α?χbutoxy. Preferable hydroxyalkoxy groups are hydroxymethoxy, hydroxyethoxy, hydroxy n- propoxy, hydroxy rc-butoxy. As used herein, the term "alkylthio" means alkyl-S- wherein alkyl is defined above, including, but not limited to methylthio, ethylthio, rc-propylthio, tso-propylthio, «-butylthio, tso-butylthio, secondary-buiy\ϊ άo, tertt r -butylthio. Preferable alkylthio groups are methylthio, ethylthio, w-propylthio, w-butylthio. As used herein, the term "alkylsulfinyl" means alkyl-SO- wherein alkyl is defined above, including, but not limited to methylsulfinyl, ethylsulfinyl, n- propylsulfinyl, tsσ-propylsulfinyl, /z-butylsulfmyl, zso-butylsulfinyl, secondary- butylsulfinyl, tertzαry-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, wo-propylsulfonyl, n-butylsulfonyl, zsø-butylsulfonyl, secondary- butylsulfonyl, terttαry-butylsulfonyl. Preferable alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl, H-propylsulfonyl, w-butylsulfonyl. As used herein the term "heterocyclic" means a 4-7 membered cycloalkyl ring in which one or two non-adjacent carbon atoms are optionally replaced by oxygen, sulfur or NH group. Examples of such heterocycles include, but are not limited to, piperidine, morpholine, 4-piperidone, pyrrolidine, 2-pyrrolidone, tetrahydrofiiran, , tetrahydroquinoline, tetrahydropyran, pyrrolidine, piperidine or piperazine. As used herein the term "haloalkyl", 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. As used herein the term "ordinary protecting group" means a protecting group, which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. Where the compounds of formula (I) contain hydroxy groups, they may form esters. Examples of such esters include esters with a hydroxy group. As used herein 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 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-methylhexadecanoyl, 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, α-naphthoyl and -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-trichloroethoxymethyl and bis(2- chloroethoxy)methyl groups; (7) substituted ethyl groups, for example: alkoxylated ethyl groups such as the 1-ethoxyethyl and l-(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, /3-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 benzyl oxycarbonyl, 4-methoxybenzyl oxycarbonyl, 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. According to formula (1), R¹ suitably represents a halogen atom, a (d-C₆)alkyl group, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxy group, a (Ci- C₆)alkoxy group, a halo(d-C₆)alkoxy group, a (Cι-C₆)alkylthio group , a (Ci- C₆)alkylsulfmyl group, a (d-C₆)alkylsulfonyl group, a halo(d-C₆)alkylthio group, a halo(d-C₆)alkylsulfmyl group, a halo(d-C₆)alkylsulfonyl group, a (Ci- C₆)alkylsulfonylamino group, a mono- or di-(Cι-C₆)alkylaminosulfonyl group or or a heterocyclic group having from 4 to 7 ring atoms; said (d-C₆)alkyl group, said (Cι-C₆)alkoxy group, said cycloalkyl group having from 3 to 8 carbon atoms and said heterocyclic group having from 4 to 7 ring atoms are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituent α; said substituent α are selected from the group consisting of halogen atoms, (d- C₆)alkyl groups, cycloalkyl groups having from 3 to 8 carbon atoms, hydroxy groups, (d-C₆)alkoxy groups, hydroxy(Cι-C₆)alkyl groups, hydroxy(C₁-C₆)alkoxy groups, (d-C₆)alkoxy(Cι-C₆)alkyl groups, (d-C₆)alkoxy(d-C₆)alkoxy groups, halo(C C₆)alkyl groups, (d-C₆)alkanoyl groups, cyano groups, carboxy groups, (d-

C₆)alkoxycarbonyl groups,, amino groups, aminocarbonyl groups, mono- or di-(d- C₆)alkylamino groups, mono- or di-(d-C₆)alkylaminocarbonyl groups, mono- or di- (d-C₆)alkylamino(d-C₆)alkoxy groups in each alkyl and alkoxy part, heterocyclic groups having from 4 to 7 ring atoms and heterocyclic groups having from 4 to 7 ring atoms substituted by one or two (Cι-C₆)alkyl groups; R¹ represents preferably a (Ci- C₆)alkyl group, a halo(d-C₆)alkoxy group. R¹ represents more preferably trifluoromethoxy OCF₃ or tert-butyl group.

According to formula (I), R² represent suitably a hydrogen atom or a methyl group; more preferably R² represent a hydrogen atom. According to formula (I), R³ suitably represents a hydrogen atom, a (Ci-

C₆)alkoxy group or a hydroxy group. R³ preferably represents a hydroxy group, a hydrogen atom, or metoxy group. 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 N-[2-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl)ethyl]-4- (trifluoromethoxy)benzamide;

N-[2-(7-methoxy-5,6,7,8-tetrahydronaphthalen-l-yl)propyl]-4- (trifluoromethoxy)benzamide; and

N-[2-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl)propyl]-4- (trifluoromethoxy)benzamide; 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 R through R in the reaction Schemes and discussion that follow are defined as above. The term "protecting group", as used hereinafter, means a hydroxy protecting group which is selected from typical hydroxy protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (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 (la).

1-6 1-7

In the above formula, PG represents a protecting group. Example of suitable protecting groups include t-butoxycarbonyl group (Boc) or benzyloxycarbonyl group (Z).

Step 1A In this Step, a compound of formula 1-2 may be prepared by nucleophilic addition of acetonitrile in the presence of a base in an inert solvent. Examples of suitable solvents include: ethers, such as di ethyl ether, diisopropyl ether, 1,2- dimethoxyethane (DME), tetrahydrofuran and dioxane. Examples of suitable bases include: alkyl lithiums, such as n-butyllithium, sec-butyllithium or tert-butyllithium; aryllithiums, such as phenyllithium or lithium naphtilide; metal amide such as sodium amide or lithium diisopropylamide; and metal hydride, such as potassium hydride or sodium hydride. This reaction may be carried out at a temperature in the range from -78 °C to 200 °C, usually from -10°C to 100 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step IB In this Step, a compound of formula 1-3 may be prepared by oxidation of the compound of formula 1-2 in the presence of an oxidizing agent in an inert solvent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride. Examples of suitable oxidizing agents include: 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) or NaIO4 or HC1O4. This reaction may be carried out at a temperature in the range from -50°C to 100 °C, usually from -10°C to 50 °C for 5 minutes to 72 hours, usually 30 minutes to 36 hours.

Step 1C In this Step, a compound of formula 1-4 may be prepared by dehydration of the compound of formula 1-3 in the presence of an acid in an inert solvent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, toluene or carbon tetrachloride. Examples of suitable acids include: 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. This reaction may be carried out at a temperature in the range from -20 to 150 °C, usually from 0°C to 130 °C for 30 minutes to 24 hours, usually 60 minutes to 10 hours.

Step ID In this Step, a. compound of formula 1-5 may be prepared by reduction of the nitrile compound of formula 1-4 with a reducing agent. This reaction may be carried out in the presence of a suitable reducing agent such as diboran, boran-methyl sulfide complex, or lithium aluminum hydride in a reaction inert solvent selected form, tetrahydrofuran or diethyl ether. Reaction temperatures are generally in the range of -100 to 250 °C, preferably in the range of 0 °C to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The reduction may also be carried out under known hydrogenation conditions such as in the presence of a metal catalyst such as Raney nickel catalysts in the presence or absence of hydrazine, palladium catalysts or platinum catalysts under hydrogen atmosphere. This reaction may be carried out in a reaction inert solvent such as methanol, ethanol, and tetrahydrofuran in the presence or absence of hydrogen chloride. If necessary, this reduction may be carried out under the adequate pressure in the range from about 0.5 to 10 kg/cm², preferably in the range from 1 to 6 kg/cm². Reaction temperatures are generally in the range of -100 °C to 250 °C, preferably in the range of 0 °C to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours.

Step IE In this Step, a compound of formula 1-6 may be prepared by Birch reduction of the compound of formula 1-5 under conditions known to those skilled in the art. This reduction carried out in the presence of an active metal and liquid ammonia in a solvent. Examples of suitable solvents include: alcohols such as methanol, ethanol, propanol, butanol, t-butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME). Examples of suitable active metals include sodium, lithium, potassium, and calcium. This reaction may be carried out at a temperature in the range from -100 to 100°C, usually from -80°C to 80°C for 30 minutes to 24 hours, usually 60 minutes to 10 hours.

Step IF In this Step, a compound of formula 1-7 may be prepared by reduction of the olefin compound of formula 1-6. 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 100°C, usually from 0°C to 50°C for 30 minutes to 24 hours, usually 60 minutes to 10 hours.

Step 1G In this Step, a compound of formula 1-8 may be prepared by coupling of the amine compound of formula 1-7 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

100 °C, more preferably from about 0 C to 60 C for 5 minutes to 1 week, more preferably 30 minutes to 24 hours, will usually suffice. Suitable coupling reagents are those typically used in peptide synthesis including, for example, diimides (e.g., dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC)), O-behzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-ethoxy-N-ethoxycarbonyl-l,2-dihydroquinoline, 2- bromo-1-ethylpyridinium tetrafluoroborate (BEP), 2-chloro-l,3- dimethylimidazolinium chloride, benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylate-triphenylphosphine, diethylcyanophosphate, diethylphosphorylazide, 2-chloro-l-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 1-12 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 1-10 under the similar conditions as described in this Step.

Step 1H In this Step, a compound of formula (la) may be prepared by the deprotection of the compound of formula 1-8 according to known procedures such as those described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). This reaction may be carried out a number of standard procedures known to those skilled in the art (e.g., "Protection of Phenols", in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P.G. M. Wuts, Ed., John Wiley and Sons, Inc. 1999). For example, the compound of formula 3-7 may be treated with a proton and/or Lewis acid such as hydrogen bromide, boron tribromide or aluminum chloride in a suitable solvent such as water, acetic acid or dichloromethane. Reaction temperatures are generally in the range of -100 °C to 250 °C, preferably in the range of 0 °C to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The reaction may also carried out in the presence of a thioalkoxide such as sodium thiomethoxide, lithium thiomethoxide, sodium thioethoxide in the presence or absence of a reaction inert solvent such as DMSO, DMF or HMPA.

Scheme 2 This illustrates the preparation of compounds of formula (lb).

2-1 2-2

2-3 2-4

(lb)

In the above formula, Rx represents (d-C₆)alkyl group.

Step 2A In this Step, a compound of formula 2-1 may be prepared by alkylation of the compound of formula 1-4 in the presence of a metallic reagent and an alkylating agent in an inert solvent. The deprotonation is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.

Examples of suitable solvents include: tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ether, toluene, ethyleneglycol dimethylethergenerally or dioxane. The deprotonation can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -50 C to 70 C, more preferably from about 0 °C to 50 °C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the prefened conditions outlined above, a period of 5 minutes to 12 hours, more preferably 30 minutes to 3 hours, will usually suffice. Examples of suitable metallic reagents include, for example, 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. The alkylation may be carried out by using, for example, appropriate alkylhalide, such as methyliodide and ethyliodide. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from 0 C to 120 C, more preferably from 0 C to 70 °C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction may be effected under the preferred conditions outlined above, a period of from 5 minutes to 48 hours, more preferably from 30 minutes to 24 hours, will usually suffice.

Step 2B In this Step, a compound of formula 2-2 may be prepared by reduction of the nitrile compound of formula 2-1 with a reducing agent. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step ID in Scheme 1

Step 2C In this Step, a compound of formula 2-3 may be prepared by Birch reduction of the compound of formula 2-2 under conditions known to those skilled in the art.

This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step IE in Scheme 1.

Step 2D In this Step, a compound of formula 2-4 may be prepared by reduction of the olefin compound of formula 2-3. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step IF in Scheme 1.

Step 2E In this Step, a compound of formula 2-5 may be prepared by coupling of the amine compound of formula 2-4 with the acid compound of formula 1-8 in the presence or absence of a coupling reagent in an inert solvent. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1G in Scheme 1.

Scheme 3 This illustrates the preparation of compounds of formula (Ic).

2-3 3..,

(Ic) In the above formula, Rx represents (d-C₆)alkyl group.

Step 3A In this Step, a compound of formula 3-1 may be prepared by coupling of the amine compound of formula 2-3 with the acid compound of formula 1-8 in the presence or absence of a coupling reagent in an inert solvent. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1G in Scheme 1. Step 3B In this Step, a compound of formula 3-2 may be prepared by the deprotection of the compound of formula 3-1. This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step 1H in Scheme 1.

Step 3C In this Step, an acid compound of formula (Ic) can be prepared by hydrolysis of the vinyl ester compound of formula 3-2 in a solvent. The hydrolysis can 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 N,N-dimethylformamide (DMF) and hexamethylphosphohctriamide; and sulfoxides such as dimethyl sulfoxide (DMSO). Preferable solvents are methanol, ethanol, propanol, tetrahydrofuran (THF), dimethoxyethane (DME), 1,4-dioxane, NN-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). This reaction can be carried out at a temperature in the range from -20 to 100°C, usually from 20°C to 65 °C for 30 minutes to 24 hours, usually 60 minutes to 10 hour. The hydrolysis can 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 hexamethylphosphohctriamide; and sulfoxides such as dimethyl sulfoxide (DMSO). Preferable solvents are methanol, ethanol, propanol, tetrahydrofuran (THF), dimethoxyethane (DME), 1,4-dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). This reaction can be carried out at a temperature in the range from -20 to 100°C, usually from 20°C to 65°C for 30 minutes to 24 hours, usually 60 minutes to 10 hours. 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 from 1 to 7, 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 VRl antagonist assay VRl antagonistic activity can be determined by the Ca²⁺ imaging assay using human VRl highly expressing cells. The cells that highly express human VRl receptors are obtainable from several different conventional • methods. The one standard method is cloning from human DRG or kidney according to the methods such as described in the journal article; Nature, 389, pp816-824, 1997. Alternatively VRl receptors highly expressing human keratinocytes are also known and published in the journal article (Biochemical and Biophysical Research Communications, 291, pp 124-129, 2002). In this article, human keratinocytes demonstrated VRl mediated intracellular Ca²⁺ increase by addition of capsaicin. Further more, the method to up regulate human VRl gene, which is usually a silent gene or don't produce detectable level of NRl 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 VRl 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 VRl 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 VRl receptors were detached from the flask follow by washing with PBS(-) and resuspended in Krebs-Ringer HEPES (KRH) buffer (115 mM NaCl, 5.4 mM KC1, 1 mM MgSO₄, 1.8 mM CaCl₂, 11 mM D-Glucose, 25 mM HEPES, 0.96 mM Na₂HPO₄, pH 7.3). The 80 μl of aliquot of cell suspension (3.75xl0⁵ cells/ml) was added to the assay plate and the cells were spun down by centrifuge (950 rpm, 20 °C, 3 minutes). The capsaicin-induced changes in the intracellular calcium concentration were monitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometric imaging system. The cells were pre-incubated with 20 μl of varying concentrations of the test compounds or KRH buffer (buffer control) for 15 minutes at room temperature under the dark condition. Then 20 μl of capsaicin solution, which gives 300 nM in assay mixture, was automatically added to the assay plate by the FDSS 6000. 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 and continued for 5 minute. The IC₅o values of VRl antagonists were determined from the half of the increase demonstrated by buffer control samples after addition of capsaicin.

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 CaCl₂ and 0.5 mM MgCl₂ (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 CaCl₂ and 0.^'5 mM MgCl₂ (pH 7.4). At the end of the preincubation, the media was removed and test compound solution (lOμM) in buffer was added to the apical compartment. The inserts were moved to wells containing fresh basolateral buffer and incubated for 1 hr. 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 cm ), VD is the donor volume (0.3ml), MD is the total 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 HC1 containing 1 mM MgCl₂, 10 mM KC1. The cells were homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,000g 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 -80°C until use. An aliquot was used for protein concentration determination using a Protein Assay Rapid Kit and ARVO SX plate reader (Wallac). All the manipulation, stock solution and equipment were kept on ice at all time. For saturation assays, experiments were conducted in a total volume of 200 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 25 °C).

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 25 °C) containing 1 mM MgCl₂, 10 mM KC1 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. gπ 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% Fatal Calf Serum (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 15-28hrs 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); NaCl, 130; KC1, 4; CaCl₂, 2; MgCl₂, 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- 3MOhm when filled with the standard internal solution of the following composition (mM); KC1, 130; MgATP, 5; MgCl₂, 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 -80mV to +40mV for 1000ms. This was followed by a descending voltage ramp (rate 0.5mV 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 -40m V 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, lOμM 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 (5μM), a specific . IKr blocker, to evaluate the insensitive endogenous current. All experiments were performed at room temperature (23 ± 1°C). Evoked membrane currents were recorded on-line on a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at l-2KHz using the patch clamp amplifier and a specific data analyzing software. Peak current amplitude, which occurred at around -40mV, 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- I_D/I_C )X100, where I_D is the mean current value in the presence of drug and Ic 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 MgCl₂, 6.2 mM DL-Isocitric acid and 0.5 U/ml Isocitric 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 {( _o - Vj) / 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 MgCl₂ 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, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate 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. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties. Selection, and Use by Stahl and Wermuth (Wiley- VCH, 2002). Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also ■ exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point'). The compounds of the invention may also exist in 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. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. When the solvent or water is tightly bound, the complex will have a well- defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975). The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form' lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COOTSfa⁺, - COO^"K⁺, or -SO₃ ^"Na⁺) or non-ionic (such as -N^"N⁺(CH₃)₃) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4^th Edition (Edward Arnold, 1970). Hereinafter all references to compounds of formula (I) include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi -component complexes and liquid crystals of salts thereof. The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I). As indicated, so-called 'prodrugs' of the compounds of formula (I) are also within the scope of the invention. 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, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (d- C₈)alkyl; .

(ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (I) is replaced by (d- C₆)alkanoyloxymethyl; and

(iii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH₂ or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (I) is/are replaced by (C -Cι₀)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. Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I). Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include

(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH -> -CH₂OH):

(ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR^!R² -> -NHR¹ or -NHR²);

(iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂);

(v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH₂ -> COOH).

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 cisltrans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the foim of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. 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, -lactate or /-lysine, or racemic, for example, ^/-tartrate or /-arginine. Cisltrans 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, a base or acid such as 1- phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (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% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 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 which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ⁿC, ¹³C and ¹⁴C, chlorine, such as ³⁶C1, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ^{1 5}I, nitrogen, such as N and N, oxygen, such as O, O and O, phosphorus, such as P, and sulphur, such as ³⁵S.

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 for his 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 as ⁿC, ¹⁸F, ¹⁵O and ¹³N, 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 reagent 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. Also within the scope of the invention are intermediate compounds as hereinbefore defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I). The invention includes all polymorphs of the aforementioned species and crystal habits thereof. When preparing compounds of formula (I) in accordance with the invention, it is open to a person skilled in the art to routinely select the form of intermediate compound which provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation. 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, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

(ii) nonsteroidal antiinflammatory drugs (NSADDs), 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) Hi 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- methylmo hinan) 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-l,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, ( R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9, 10,11- tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[ 1 ,4]diazocino[2, 1 - g][l,7]naphthridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]- l,2-dihydro-3H-l,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 GI 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; c(xxvii) mixed serotonin-noradrenaline reuptake inhibitors, e.g. milnacipran, venlafaxine and duloxetine; (xxviii) o2δ ligand, e.g., gabapentin, 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)-(xxviii), 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 VRl antagonist is implicated.

DRUG PRODUCT The compounds of formula (I) should be assessed for their biophannaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication. 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, 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. 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, and/or buccal, lingual, or sub lingual administration by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano- particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001). For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. 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, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant. will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. 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 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants- such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80% drag, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms:

Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). Consumable oral films for human or veterinary use are typically pliable water- soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. The compound of fonnula (I) may be water-soluble or insoluble. A water- soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocoUoids and is typically present in the range 0.01 to 99_. weight %, more typically in the range 30 to 80 weight %. Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co- solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

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, intrasynovial 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 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 parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a suspension or 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 semi-solids and suspensions comprising drug-loaded poly( /-lactic-coglycolic)acid (PGLA) microspheres.

TOPICAL ADMINISTRATION The compounds of the invention may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). 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 release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

INHALED/INTRANAS AL 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, 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, or as nasal drops. 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 hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-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 trehalos^'e. A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from lμg to 20mg of the compound of the invention per actuation and the actuation volume may vary from lμl to 1 OOμl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, 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 10 mg 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.

RECTAL/1NTRAVAGINAL 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 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 fonnulations suitable for ocular and aural administration include ointments, gels, 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 methylcellulose, 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 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 Inasmuch 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 forni of a kit suitable for co administration 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 (ϊ) in accordance with the invention, and means for separately retaining said compositions, such as acontainer, 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 O.lmg to 3000mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from O.lmg to 3000mg, while an intravenous dose may only require from O.lmg to lOOOmg. The total daily dose maybe administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. 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 18-25 °C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 °C; reactions were monitored by thin layer chromatography (TLC); melting points (mp) given are uncorrected (polymorphism may result in different melting points); the structure of all isolated compounds were assured by at least one of the following techniques: TLC (Merck silica gel 60 F₂₅ precoated TLC plates), mass spectrometry, nuclear magnetic resonance spectra (NMR) or infrared red 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 (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), 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; L (liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), quant, (quantitative yield), liq.(liquid), sat.(saturated), aq.(aqua).

Example 1 N-r2-(7-HYDROXY-5.6.7.8-TETRAHYDRONAPHTHALEN-l-YL)ETHYLl-4- (TRJFLUOROMETHOXY)BENZAMIDE

STEP 1: 2-(7-METHOXY-5.8-DlHYDRONAPHTHALEN-l-YL)ETHANAMINE

To a tetrahydrofuran (10 ml) solution of 2-(7-methoxy-l-naphthyl)ethanamine (0.9 g, 4.47 mmol) (prepared according to Synthetic Communications, 31 (4), p 621- 629 (2001)) and t-buthanol (1.0 g, 13.4 mmol) were added liq. NH3 (100 ml) at - 78 °C. To the mixture was added Li wire (93.0 mg, 13.4 mmol) over 30 min. at - 78 °C and stirred for lh at -78 °C. Methanol/water (3:1) co-solvent (30ml) was added to this mixture to stop the reaction and additional stirring was allowed for 16h to evaporate ammonia. The obtained residue was partitioned with ethylacetate and water. Then organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(7-methoxy-5,8- dihydronaphthalen-1-yl)- ethanamine (crude 0.83 g) which was used for next reaction without further purification. Yellow colored oil. MS (ESI) m z 204 (M + H)⁺.

STEP 2; 2-(7-METHOXY-5.6.7.8-TETRAHYDRONAPHTHALEN-l- YDETHANAMINE

To a methanol (5.0 ml) solution of 2-(7-methoxy-5,8-dihydronaphthalen-l- yl)ethanamine (0.13 g, 0.64 mmol) was added 10% Pd/C (5.0 mg) and the mixture was stirred for 48 hours at room temperature under hydrogen pressure (5.0 kgf/cm2). Then, filtration, evaporation gave 2-(7-methoxy-5,6,7,8-tetrahydronaphthalen-l- yl)ethanamine (0.12g) which was used for next reaction without further purification. Yellow colored oil. MS (ESI) m z 206 (M + H)⁺.

STEP3 : N-β-f 7-METHOXY-5.6.7.8-TETRAHYDRONAPHTHALEN- 1 - YL ETHYLl-4-fTRIFLUOROMETHOXY BENZAMIDE

To a CH2CI2 (1.0 ml) and pyridine (2.0 ml) solution of 2-(7-methoxy-5,6,7,8- tetrahydronaphthalen-l-yl)ethanamine (0.12g, 0.6 mmol) was added 4- (trifluoromethoxy)benzoyl chloride (0.13g, 0.6 mmol) and the mixture was stirred for 4 hours at room temperature. The reaction mixture was partitioned with sat.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 (3:1) to furnish the N-[2-(7-methoxy-5,6,7,8-tetrahydronaphthalen -l-yl)ethyl]-4- (trifluoromethoxy)benzamide (150.0 mg, 64 %).

Η-NMR (CDC1₃) δ 1.67-2.03 (6H, m), 2.68 (2H, d, , J=5.5 Hz), 2.86-2.87 (1H, m), 3.50-3.59 (2H, m), 3.74 (3H, s), 6.53 (1H, NH) 6.66-7.25 (5H, m), 7.74 (2H, d, J=7.9 Hz ). Colorless oil.

MS (ESI) m/z 394 (M + H)⁺.

STEP4: N-r2-(7-HYDROXY-5.6,7,8-TETRAHYDRONAPHTHALEN-l - YL)ETHYLl-4-(TRIFLUOROMETHOXY)BENZAMIDE

To a CH2CI2 (1.0 ml) solution of N-[2-(7-methoxy-5, 6,7,8- tetrahydronaphthalen-l-yl)ethyl]-4-(trifluoromethoxy)benzamide (0.15g, 0.38 mmol) was added BBr3-CH2Cl2 (1.0M, 1.0 ml, 1.Ommol) at 0 °C and the mixture was stirred for 2h. The reaction mixture was partitioned with sat. 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 (3:1) to furnish the N-[2-(7- hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl)ethyl]-4-(trifluoromethoxy)benzamide (104.9mg, 75 %). ^!H-NMR (CDCI3) δ 1.43-1.94 (6H, m), 2.65 (2H, t, J = 5.5 Hz), 2.76-2.81 (1H, m), 3.28 (1H, OH), 3.45-3.60 (m, 2H), 6.42 (1H, NH), 6.63-6.75 (2H, m), 6.92 (1H, d, J = 8.3 Hz), 7.20-7.26 (2H, m), 7.74 (2H, d, J = 8.6 Hz). ^' White amorphous .

MS (ESI) m/z 380 (M + H)⁺.

Example 2

N-r2-⁽7-METHOXY-5.6.7.8-TETRAHYDRONAPHTHALEN-l-YL)PROPYLl-4- (TRIFLUOROMETHOXY)BENZAMIDE

STEP 1 : f2-(7-METHOXY-5.8-DIHYDRONAPHTHALEN- 1 - YDPROPYL1AMINE

To a THF (10 ml) solution of [2-(7-methoxy-l-naphthyl) ρroρyl]amine (1.35 g, 6.27 mmol) (prepared according to Bioorg & medicinal Chemistry, 7 (12), p 2945- 2952 (1999)) and t-butanol (1.4 g, 18.8 mmol) were added liq. NH3 (250 ml) at - 78 °C. To the mixture was added Li wire (130 mg, 18.8 mmol) over 30 min. at - 78 °C and stirred at -78 °C for lhour. Methanol/water co-solvent (60 ml, 3:1) was added to this mixture to stop the reaction and additional stirring was allowed for 16 hours to evaporate ammonia. The obtained residue was partitioned with ethylacetate and water. Then organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford [2-(7-methoxy-5,8- dihydronaphthalen- 1 -yl)propyl] amine (crude 1.22 g) which was used for next reaction without further purification: Yellow colored oil. MS (ESI) m/z 218 (M + H)⁺.

STEP 2: r2-f7-METHOXY-5,6,7,8-TETRAHYDRONAPHTHALEN-l- YDPROPYLl AMINE

To a methanol (5.0 ml) solution of [2-(7-methoxy-5,8-dihydronaphthalen-l-yl) propyljamine (1.22 g, crude) was added 10% Pd/C (5.0 mg) and the mixture was stirred for 48h at room temperature under hydrogen pressure (5.0 kgf/cm²). Then, filtration, evaporation gave [2-(7-methoxy-5,6,7,8-tetrahydronaphthalen-l- yl)propyl] amine (1.21 g) which was used for next reaction without further purification. Yellow colored oil. MS (ESI) m z 220 (M + H)⁺.

STEP 3 : N-r2-(7-METHOXY-5,6,7,8-TETRAHYDRONAPHTHALEN- 1 - YL PROPYLl-4-rTRIFLUOROMETHOXY BENZAMIDE

To a CH2CI2 (1.0 ml) and pylidine (1.0 ml) solution of [2-(7-methόxy-5,6,7,8- tetrahydronaphthalen-l-yl)propyl] amine (0.6 g, crude) was added 4- (trifluoromethoxy)benzoyl chloride (0.62 g, 2.8 mmol) and the mixture was stirred for 4 hours at room temperature. The reaction mixture was partitioned with sat. 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 (3:1) to furnish the N-[2-(7-methoxy-5,6,7,8-tetrahydronaphthalen-l-yl)propyl]-4- (trifluoromethoxy)benzamide (177 mg). ^-NMR (CDC1₃) δ 0.86 (3H, d, J-6.9 Hz), 1.26-1.31 (2H, m), 1.82-2.05 (2H, m), 2.33-2.40 (1H, m), 3.28-3.79 (5H, m), 6.68-6.77 (2H, m), 7.01 (1H, d, J=8.2 Hz), 7.22-7.30 (2H, m), 7.73 (2H, d, J=8.6 Hz ). Colorless oil. MS (ESI) m/z 408 (M + H)⁺.

Example 3

N-r2-(7-HYDROXY-5,6.7.8-TETRAHYDRONAPHTHALEN-l-YL PROPYLl-4- ( RIFLUOROMETHOXY)BENZAMIDE

STEP 1: N-Γ2-(7-METHOXY-5.8-DIHYDRONAPHTHALEN-1-YDPROPYL1-4- (TRIFLUOROMETHOXY)BENZAMIDE

To a CH2CI2 (1.0 ml) and pyridine (1.0 ml) solution of [2-(7-methoxy-5,8- dihydronaphthalen- 1-yl) propyljamine (0.6 g, crude) was added 4-(trifluoromethoxy)- benzoyl chloride (0.62 g, 2.8 mmol) and the mixture was stirred for 4h at room temperature. The reaction mixture was partitioned with sat. 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 (3:1) to furnish the N-[2-(7-methoxy-5,8-dihydronaphthalen-l-yl)propyl]-4- (trifluoromethoxy)benzamide (685 mg). Colorless oil.

MS (ESI) m/z 406 (M + H)⁺.

STEP 2: Ν-r2-(7-OXO-5,6,7,8-TETRAHYDROΝAPHTHALEΝ- 1 -YDPROPYL]- 4-(TR__FLUOROMETHOXY)BENZAMIDE

To a 1,4-dioxane solution of N-[2-(7-methoxy-5,8-dihydronaphthalen-l- yl)propyl]-4-(trifluoromethoxy)benzamide (673 mg, 1.66 mmol), 2Ν HC1 was added and the mixture was stirred for 5 hours at room temperature. The reaction mixture was partitioned with ethylacetate and sat. NaHCO3 aq. and the organic layer was separated, dried over NaSO4. Then, filtration, evaporation gave the crude residue, which was recrystalized from ethylacetate/hexane to afford the N-[2-(7-oxo-5, 6,7,8- tetrahydronaphthalen-1 -yl)propyl]-4-(trifluoromethoxy)benzamide (384 mg). White solid. MS (ESI) m/z 392 (M + H)⁺.

STEP 3; N-r2-f7-HYDROXY-5.6.7.8-TETRAHYDROΝAPHTHALEΝ-l- YL)PROPYLl-4-(TRIFLUOROMETHOXY)BENZAMIDE

To a methanol solution of N-[2-(7-oxo-5,6,7,8-tetrahydronaphthalen-l- yl)propyl]-4-(trifluoromethoxy)benzamide (370 mg, 0.95 mmol), 0.5 eq. of ΝaBH4 was added and the mixture was stirred for 3 hours at 0 °C. Then, the reaction was quenched with H2O, extracted with ethylacetate, dried over Na2SO4. After filtration, evaporation, crude residue was purified through silica gel column chromatography eluting with ethylacetate/hexane (1:2) to furnish the N-[2-(7-hydroxy-5,6,7,8- tetrahydronaphthalen-l-yl)propyl]-4-(trifluoromethoxy)benzamide (295 mg, 79%). 'H-NMR (CDC1₃) δ 1.25-1.29 (3H, m), 1.71-1.80 (IH, m), 1.97-2.20 (2H, m), 2.60- 3.67 (6H, m), 4.07-4.13 (2H, m), 6.43 (IH, s), 6.99-7.26 (5H, m), 7.70 (2H, d, J = 8.8 Hz ). White amorphous. MS (ESI) m/z 394 (M + H)⁺.

Experimental Example NRl Binding Assay were conducted using the method described above. The results of these studies are summarized in Table 1.

Table 1. Results of NRl Binding Assay

IC₅₀: the concentration of the individual compound required to reduce the amount of ligand by 50%.

Claims

1. A compound of the formula (I) :

(I) wherein

R¹ represents a halogen atom, a (C₁-C₆)alkyl group, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxy group, a (Cι-C₆)alkoxy group, a halo(C₁-C₆)alkoxy group, a (d-C₆)alkylthio group , a (d-C₆)alkylsulfmyl group, a (d-C₆)alkylsulfonyl group, a halo(d-C₆)alkylthio group, a halo(d-C₆)alkylsulfinyl group, a halo(d- C₆)alkylsulfonyl group, a (d-C₆)alkylsulfonylamino group, a mono- or di-(d- C₆)alkylaminosulfonyl group or or a heterocyclic group having from 4 to 7 ring atoms; said (C]-C₆)alkyl group, said (Cι-C₆)alkoxy group, said cycloalkyl group having from 3 to 8 carbon atoms and said heterocyclic group having from 4 to 7 ring atoms are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituent ; said substituent α are selected from the group consisting of halogen atoms, (Ci- C₆)alkyl groups, cycloalkyl groups having from 3 to 8 carbon atoms, hydroxy groups, (Cι-C₆)alkoxy groups, hydroxy(d-C₆)alkyl groups, hydroxy(d-C₆)alkoxy groups, (C]-C₆)alkoxy(d-C₆)alkyl groups, (C₁-C₆)alkoxy(C₁-C₆)alkoxy groups, halo(Cι- C₆)alkyl groups, (C₁-C₆)alkanoyl groups, cyano groups, carboxy groups, (Ci- C₆)alkoxycarbonyl groups,, amino groups, aminocarbonyl groups, mono- or di-(Cι- C₆)alkylamino groups, mono- or di-(d-C₆)alkylaminocarbonyl groups, mono- or di- (Cι-C₆)alkylamino(d-C₆)alkoxy groups in each alkyl and alkoxy part, heterocyclic groups having from 4 to 7 ring atoms and heterocyclic groups having from 4 to 7 ring atoms substituted by one or two (d-C₆)alkyl groups; R² represents a hydrogen atom or a (Cι-Ce)alkyl group; and R³ represents a hydrogen atom, a (CrC₆)alkoxy group or a hydroxy group; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.

2. A compound of the formula (I):

(I) wherein

R¹ represents a (d-C₆)alkoxy group, a halo(Cι-C₆)alkoxy group,

R² represents a hydrogen atom or a (Cι-C₆)alkyl group;

R³ represents a hydrogen atom, a (Cι-C₆)alkoxy group or a hydroxy group; or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof.

3. A compound according to Claim 1 or Claim 2 wherein, R¹ represents a (d- C₃)alkoxy group, a halo(d-C₃)alkoxy group,

4. A compound according to any one of Claims 1 to 3 wherein, R¹ represents OCF₃ or tert-butyl group.

5. A compound according to any one of Claims 1 to 4, wherein R² represents a hydrogen atom or a methyl group.

6. A compound according to any one of Claims 1 to 5, wherein R³ represents a hydroxy group, a hydrogen atom, or methoxy group.

7. A compound according to Claim ,1 selected from N-[2-(7-hydroxy-5,6,7,8-tetrahydronaphthalen- 1 -yl)ethyl]-4- (trifluoromethoxy)benzamide; N-[2-(7-methoxy-5,6,7,8-tetrahydronaphthalen-l-yl)propyl]-4- (trifluoromethoxy)benzamide; and N-[2-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl)propyl]-4- (trifluoromethoxy)benzamide or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 7, together with a pharmaceutically acceptable excipient.

9. A compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 7, for use as a medicament.

10. The use of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as defined in any one of claims 1 to 7 and 8, respectively, for the manufacture of a medicament to treat a disease for which a NRl antagonist is indicated.

11. A use 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, HIN-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, bums, 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 bums, 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 of treatment of a mammal, including a human being, to treat a disease for which an NRl antagonist is indicated, including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof, as defined in any one of claims 1 to 6 and 7, respectively.

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, HIN-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 bums, 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 (EBD), colitis and Crohn's disease, ischemia, such as cerebrovascular ischemia, emesis, such as cancer chemotherapy-induced emesis, and obesity.

14. A combination of a compound of the formula (I), as defined in any one of claims 1-7, and another pharmacologically active agent.