WO2005016922A1

WO2005016922A1 - Carbazole-2-carboxamide derivatives having vanilloid receptor antagonist activity

Info

Publication number: WO2005016922A1
Application number: PCT/EP2004/009082
Authority: WO
Inventors: Harshad Kantilal Rami; Mervyn Thompson; Susan Marie Westaway
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2003-08-14
Filing date: 2004-08-12
Publication date: 2005-02-24
Anticipated expiration: 2006-02-14
Also published as: GB0319151D0

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4 and R5 are as defined in the specification, a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds and composition in medicine.

Description

CARBAZOLE-2-CARBOXAMIDE DERIVATIVES HAVING VANILLOID RECEPTOR ANTAGONIST ACTIVITY This invention relates to novel amide derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in medicine, especially in the treatment of various disorders. Vanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. Vanilloid Receptor (VR-1 ), whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and

Experimental Therapeutics, 1999, Vol. 51 , No. 2.). A wide variety of Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers,

EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Applications, Publication Numbers WO 92/09285, WO

02/100819 and WO 02/076946. Particularly notable examples of vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N- vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine

(Tetrahedron, 53, 1997, 4791 ) and olvanil or - N-(4-hydroxy-3- methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595). International Patent Application, Publication Number WO 02/08221 discloses diaryl piperazine and related compounds which bind with high selectivity and high affinity to vanilloid receptors, especially Type I Vanilloid receptors, also known as capsaicin or VR1 receptors. The compounds are said to be useful in the treatment of chronic and acute pain conditions, itch and urinary incontinence. International Patent Applications, Publication Numbers WO 02/16317, WO 02/16318 and WO 02/16319 suggest that compounds having a high affinity for the vanilloid receptor are useful for treating stomach-duodenal ulcers. International Patent Applications, Publication Numbers WO 02/072536,

WO 02/090326, WO 03/022809, WO 03/053945, WO 03/068749 and WO 04/024710; and co-pending International Patent Application Numbers PCT/GB2004/000543, PCT/EP2004/002377, PCT/GB2004/000978 and PCT/EP2004/002376 also describe a variety of compounds having activity as vanilloid receptor antagonists. According to a first aspect of the present invention, there is provided a compound of formula (I),

(I)

or a pharmaceutically acceptable salt or solvate thereof, wherein,

R1 and R2 may be the same or different and represent -H, alkyl, alkoxy, halo, -

CF3, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, - (CH2)χOR⁶ or -

(CH2)χNR6R7; or R1 and R2 together with the carbon atoms to which they are attached form a heteroaryl ring which may be optionally substituted by one or more alkyl, alkoxy, halo, -CF3, -OH or -NO2 groups;

R³ and R5, which may be the same or different, represent -H, halo, alkyl, alkoxy, cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, -CN, -NO2, -OH, -

OCF₃, -CF3, -NR6R7, -S(O)_mR⁸, -S(O)₂NR6R7, -OS(O)₂R⁸, -OS(O)₂CF₃₎ -

O(CH₂)_XNR6R7 -O(CH₂)_xOR⁶, -C(O)CF₃, -C(O)alkyl, -C(O)cycloalkyl, -

C(O)aralkyl, -C(O)Ar, -C(O)(CH2)χOR⁸, -C(O)(CH₂)_xNR⁶R7, -C(O)alkoxy, -

C(O)NR6R7, -(CH₂)_xC(O)alkoxy, -(CH₂)χOC(O)R⁸, -(CH₂)_xOR⁸ -(CH₂)_XR⁶R⁷,

-(CH₂)_XC(O)NR6R7, -(CH₂)_χN(R6)C(O)R⁸, -(CH₂)_XS(O)₂NR6R7, -

(CH₂)_XN(R6)S(O)₂R⁸ -ZAr, -(CH₂)χS(O)₂R⁸, -(OCH₂)_xS(O)₂R⁸, -

N(R⁶)S(O)₂R⁸, -N(R⁸)C(O)R⁸, or -(CH₂)_xC(O)alkyl;

R4 represents -H, alkyl, -(CH2)_xOR⁸ or-(CH₂)_xNR6R7;

R6 and R may be the same or different and represent H or alkyl or R and R together with the atoms to which they are attached form a Ca-eazacycloalkane, C₃_₆(2-oxo)azacycloalkane ring or C₅.₈ polymethylene chain optionally interrupted by heteroatoms such as O or -NR⁸; R⁸ represents -H, alkyl or aryl; Ar represents aryl or heteroaryl; x represents an integer 0, 1 , 2, 3, 4, 5 or 6; and Z represents a bond, O, S, NR⁸ or CH2.

Preferably, R1 and R2 may be the same or different and represent -H, alkyl such as methyl, alkoxy such as methoxy or-CFβ. Preferably, R^"! and R2 together with the carbon atoms to which they are attached form a benzothiazole group (when taken together with the phenyl ring), which benzothiazole group may be optionally substituted by an alkyl group, such as methyl. Preferably, R⁸ and R each represent -H. Preferably, R⁴ represents -H, -(CH2)2θMe or -(CH2)2-NR⁶R⁷. Preferably, x represents 0, 1 , 2 or 3. Preferably, R⁸ represents hydrogen, methyl or ethyl. Preferably, R represents hydrogen, methyl or ethyl. Examples of the C₃.₆ ring that R⁶ and R⁷ may independently represent, when taken together with the atoms to which they are attached, include pyrrolidine, morpholine and piperidine. Preferably, R⁸ represents methyl. Preferably, Z represents a bond. Preferably, Ar represents phenyl.

According to a further aspect of the present invention, there is provided a subset of compounds of formula (I), of formula (IA),

(IA)

or a pharmaceutically acceptable salt or solvate thereof, wherein,

R1 and R2 may be the same or different and represent -H, alkyl, alkoxy or -CF3; or R1 and R2 together with the carbon atoms to which they are attached form a benzothiazole group (when taken together with the phenyl ring), which benzothiazole group may be optionally substituted by one or more groups selected from alkyl, such as methyl, alkoxy, halo, -CF3, -OH or -NO2; R³ represents -H, alkyl, -(CH2)χOR⁶ or -(CH₂)_XNR⁴R5; R⁴ and R^ may be the same or different and represent H or alkyl or R⁴ and R together with the atoms to which they are attached form a C₃-eazacycloalkane, C3-6.2-oxo)azacycloalkane ring or C₅.₈ polymethylene chain optionally interrupted by heteroatoms such as O or -NR⁶; R6 represents -H, alkyl or aryl; and x represents an integer 0, 1 , 2, 3, 4, 5 or 6.

Preferred compounds according to this invention include Examples 1 - 9 or pharmaceutically acceptable salts or solvates thereof. Particularly preferred compounds according to this invention include Examples 1 - 4 or pharmaceutically acceptable salts or solvates thereof. Certain of the carbon atoms of formula (I) are chirai carbon atoms, and therefore compounds of formula (I) may exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses. As indicated above, the compounds of formula (I) can form salts, especially pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are those used conventionally in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts. Suitable pharmaceutically acceptable salts include acid addition salts. Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid. The salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention. The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally hydrated or solvated. This invention includes in its scope stoichiometric hydrates as well as compounds containing variable amounts of water. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates. Solvates include stoichiometric solvates and non-stoichiometric solvates. As used herein the term "alkyl" as a group or part of a group refers to a straight or branched chain saturated aliphatic hydrocarbon radical containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms. Such alkyl groups in particular include methyl ("Me"), ethyl ("Et"), n-propyi ("Pr""), /so-propyl ("Pr""), n-butyl ("Bun"), _Sec-butyl ("Bu^S"), terf-butyl ("But"), pentyl and hexyl. The term "cycloalkyl" as part of a group refers to a saturated alicyclic hydrocarbon radical containing 3 to 12 carbon atoms, suitably 3 to 6 carbon atoms. Where appropriate, such alkyl groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C2- 6 alkenyl, C3_ alkynyl, C-j.g alkoxy, aryl and di-C-).ρ alkylamino. Alkyl is preferably unsubstituted. As used herein, the term "alkoxy" as a group or part of a group refers to an alkyl ether radical, wherein the term "alkyl" is defined above. Such alkoxy groups in particular include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, /so-butoxy, sec-butoxy and tet -butoxy. Where appropriate, such alkoxy groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C-j.g alkyl, C2-6 alkenyl, C3-.5 alkynyl, aryl and di-Cι_ρ alkylamino. Alkoxy is preferably unsubstituted. As used herein, the term "aryl" as a group or part of a group refers to a carbocyclic aromatic radical ("Ar"). Suitably such aryl groups are 6 membered monocyclic groups or 8-10 membered fused bicyclic groups (including aromatic systems fused with non-aromatic systems), especially phenyl ("Ph"), biphenyl, indene and naphthyl, particularly phenyl. Aryl and heteroaryl groups contained within moieties R or Ar may optionally be substituted with one or more substituents selected from the list consisting of halo, hydroxy, carbonyl, alkoxy, alkyl, -CF³, NR⁶R⁷ and -SO₂R⁸. The term "naphthyl" is used herein to denote, unless otherwise stated, both naphth-1-yl and naphth-2-yl groups. As used herein, the term "heteroaryl" as a group or part of a group refers to a stable 5- 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring (including an aromatic ring system fused with a non- aromatic ring system) which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of suitable heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 ,5,2-dithiazinyl, _„-- --_*. PCT/EP2004/009082

dihydrobenzofuranyl, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazoiyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1 ,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,5- triazolyl, 1 ,3,4-triazolyl and xanthenyl. As used herein, the terms "heterocyclyl" and "heterocyclic" as a group or part of a group refer to stable heterocyclic non-aromatic single and fused rings containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. A fused heterocyclyl ring system may include carbocyclic rings and need include only one heterocyclic ring. Examples of suitable heterocyclyl groups include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl, pyrrolidinyl and morpholinyl. The term "halo" is used herein to describe, unless otherwise stated, a group selected from fluorine ("fluoro"), chlorine ("chloro"), bromine ("bromo") or iodine ("iodo"). The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which process comprises: (a) reacting a compound of formula (II),

(II)

wherein, R^and R2 are as defined in relation to formula (I), with a compound of formula (III),

(III)

wherein, R³, R⁴ and R^ are as defined in relation to formula (I) and thereafter, as necessary, carrying out one or more of the following reactions: (i) converting one compound of formula (I) into another compound of formula (I); (ii) removing any protecting group; (iii) preparing a salt or a solvate of the compound so formed. The reaction between a compound of formula (II) and a compound of formula (III) may be effected using conventional methods for the formation of an amide bond, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 419-421. Typically, the reaction may be carried out in a solvent such as DCM in the presence of a suitable diimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Compounds of formula (II) are either commercially available, or may be prepared by the reaction of a compound of formula (IV),

(IV)

wherein, Rl and R are as defined in relation to formula (I), with a suitable reducing agent. The reaction of a compound of formula (IV) with a reducing agent may be effected by methods well known in the art, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 1216-1218. Suitable reducing agents include (a) iron or zinc metal in hydrochloric acid, or (b) hydrogen in the presence of a suitable catalyst, such as, 5% palladium on charcoal. Reduction using hydrogen may conveniently be performed in a solvent such as methanol or ethanol. Compounds of formula (IV) are commercially available or may be prepared according to literature methods. Compounds of formula (III) may be prepared by hydrolysis of a compound of formula (V),

(V)

wherein, R³, R⁴ and R§ are as defined in relation to formula (I), in the presence of a suitable base. A suitable base is aqueous sodium hydroxide. A suitable hydrolysis agent is methanol. Compounds of formula (V) may be prepared by reaction of a compound of formula (VI),

(VI)

wherein, R³ and R⁵ are as defined in relation to formula (I), with a suitable alkylating agent. The reaction between a compound of formula (VI) with a suitable alkylating agent may be effected by methods well known in the art, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p411. A suitable alkylating reagent is an alkyl halide. Typically, the reaction is performed in the presence of a suitable base, such as, potassium carbonate or caesium carbonate, in a suitable solvent, such as, dimethylformamide. Compounds of formula (VI) may be prepared from a compound of formula (VII),

(VII)

using methods similar to those described in D. Patrick et al., Eur. J. Med. Chem. Chim.Ther., 1997, 32, 781 ; V.Percec et al, J. Polymer Sci., 2002, 40, 3509. The above-mentioned conversions of a compound of formula (I) into another compound of formula (I) include any conversion, which may be effected using conventional procedures, but in particular the said conversions include any combination of:

(i) converting one group R^ nto another group R1 (ii) converting one group R2 nto another group R2

(Hi) converting one group R³ nto another group R³ (iv) converting one group R⁴ nto another group R⁴ and

(v) converting one group R5 nto another group Rβ The above-mentioned conversions (i) - (v) may be performed using any appropriate method under conditions determined by the particular groups chosen. It will be appreciated by those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques, such as those described in Greene T.W. ' Protective groups in organic synthesis', New York, Wiley (1981), can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures known in the art. Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative. Compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof have Vanilloid receptor antagonist (VR1) activity and are believed to be of potential use for the treatment or prophylaxis of certain disorders, or treatment of the pain associated with them, such as: pain, chronic pain, neuropathic pain, postoperative pain, postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart burn, Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder (GERD), stomach and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn's disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, burns, itch, psoriasis, pruritis, emesis (hereinafter referred to as the "Disorders of the Invention"). Accordingly, the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance, in particular, in the treatment and/or prophylaxis of the Disorders of the Invention. In particular, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of pain. The invention further provides a method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, in particular the Disorders of the Invention, in mammals including humans, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1 ) receptor is beneficial, particularly the Disorders of the Invention. In order to use the compounds of the invention in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient therefor. A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral, rectal administration or intravesical administration to the bladder and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions, suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.

Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1 % to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. For systemic administration, dosage levels from 0.01 mg to 100 mg per kilogramme of body weight are useful in the treatment of pain. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5 and 0.1 to 250 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 1000 mg; and such therapy may extend for a number of weeks or months. No unacceptable toxicological effects are indicated with compounds of the invention when administered in accordance with the invention. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The following Descriptions and Examples illustrate the preparation of the compounds of the invention.

Abbreviations

tβuOH = terf-butanol, DCM = dichloromethane, DMF = dimethylformamide, EtOAc = ethyl acetate, MeOH = methanol, MgSO₄ = magnesium sulfate, NaHCO₃ = saturated aqueous sodium bicarbonate, HCI = hydrochloric acid, tic = thin layer chromatography

Description 1

9-(2-Methoxyethyl)-9H-carbazole-2-carbonitrile (D1 )

To a solution of 9H-carbazole-2-carbonitrile (166 mg) in DMF (2 ml) was added caesium carbonate (675mg) followed by 2-bromoethyl methyl ether (106 mg) and the reaction heated at 80°C for 24h. On cooling to room temperature the mixture was diluted with DCM, washed with NaHCO₃, water and brine. The organic phase was dried (MgSO ) and concentrated in vacυo to give the title compound (187 mg), m/z (ES): MH⁺ 251.

Description 2

9-(2- ethoxyethyl)-9r/-carbazole-2-carboxylic acid (D2)

To a solution of D1 (187 mg) in MeOH (3 ml) was added 2M sodium hydroxide (2 ml) and the mixture heated at reflux until complete by tic. On cooling, the solvent was removed in vacuo, the residue taken up in EtOAc and extracted into NaHCO₃ and the pH adjusted to 3 with 2M HCI. Extraction with EtOAc/ tβuOH (1 :1) followed by drying (MgSO ) and evaporation in vacuo gave the title compound (161 mg), m/z (ES): (M-H)- 268. Description 3 9-[2-(4-Morpholino)ethyl]-9rY-carbazole-2-carboxylic acid (D3)

The title compound was prepared using procedures outlined for D1 and D2, from 9H-carbazole-2-carbonitrile (166 mg) and 4-(2-chloroethyl) morpholine hydrochloride (209 mg) as a white solid (369 mg), m/z (ES): (M-H)^" 323.

Description 4 9r/-Carbazole-2-carboxylic acid (D4)

Prepared according to the method of G.Rodger, J.Het.Chem., 1970, 2, 239.

Description 5 9H-Carbazole-2-carbonitrile (D5)

Prepared using methods similar to those of V.Percec et al., J. Polymer Sci., 2002, 40, 3509.

Example 1

W-(2-Methylbenzothiazol-5-yl)-9-[2-(methoxy)ethyl]-9H-carbazole-2- carboxamide (E1)

D2 (50 mg), 5-amino-2-methylbenzothiazole dihydrochloride (37 mg), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide (36 mg) and 4-dimethylaminopyridine (4 mg) in DCM (2 ml) were stirred at room temperature for 24h. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, brine, and dried (MgSO₄); concentration in vacuo gave crude product. Purification by column chromatography eluting with 5% MeOH/DCM gave the title compound as a white solid (40mg), m/z (ES): MH⁺ 416, (M-H)" 414

Example 2 ιV-(2-Methylbenzothiazol-5-yl)-9-[2-(4-morpholino)ethyl]-9H-carbazole-2- carboxamide (E2) Using a procedure similar to that of Example 1 , the title compound was prepared from 5-amino-2-methylbenzothiazole dihydrochloride (31 mg) and D3 (50 mg) as a brown gum (31 mg), m/z (ES): MH⁺ 471 , (M-H)" 469. Example 3 ιV-(3-Methoxyphenyl)-9-[2-(methoxy)ethyl]-9H-carbazole-2-carboxamide (E3) Using a procedure similar to that of Example 1 , the title compound was prepared from m-anisidine (38 mg) and D2 (100 mg) as a white solid (32 mg), m/z (ES): MH⁺ 375, (M-H)^" 373.

Example 4 Λ/-[4-Methyl-3-(trifluoromethyl)phenyl]-9-[2-(methoxy)ethyl]-9H-carbazole-2- carboxamide (E4) Using a procedure similar to that of Example 1 , the title compound was prepared from 4-methyl-3-trifluoromethylaniline (43 mg) and D2 (80 mg) as a white solid (96 mg), m/z (ES): MH⁺ 427, (M-H)" 425. Examples 5-9 presented in Table 1 were prepared in accordance with the procedures described herein and similar to those of E1 and E2.

Table 1

Pharmacological Data (a) In vitro assay As referenced above, the compounds of the invention are vanilloid receptor (VR1) antagonists and hence have useful pharmaceutical properties. Vanilloid receptor (VR1 ) antagonist activity can be confirmed and demonstrated for any particular compound by use of conventional methods, for example those disclosed in standard reference texts such as D. Le Bars, M. Gozarin and S. W. Cadden, Pharmacological Reviews, 2001 , 53(4), 597-652] or such other texts mentioned herein. The screen used for the compounds of this invention was based upon a FLIPR based calcium assay, similar to that described by Smart et al. (British Journal of Pharmacology, 2000, 129, 227-230). Transfected astrocytoma 1321 N1 cells, stably expressing human VR1 , were seeded into FLIPR plates at 25,000cells/well (96-well plate) and cultured overnight. The cells were subsequently loaded in medium containing 4μM Fluo-3 AM (Molecular Probes) for 2 hours, at room temperature, in the dark. The plates were then washed 4 times with Tyrode containing 1.5mM calcium, without probenecid.

The cells were pre-incubated with compound or buffer control at room temperature for 30 minutes. Capsaicin (Sigma) was then added to the cells. Compounds having antagonist activity against the human VR1 were identified by detecting differences in fluorescence when measured after capsaicin addition, compared with no compound buffer controls. Thus, for example, in the buffer control capsaicin addition results in an increase in intracellular calcium concentration resulting in fluorescence. A compound having antagonist activity blocks the capsaicin binding to the receptor, there is no signalling and therefore no increase in intracellular calcium levels and consequently lower fluorescence. pKb values are generated from the IC50 values using the Cheng-Prusoff equation.

All compounds tested by the above methodology had pKb > 5, preferred compounds (Examples 1 - 4) having a pKb > 7.0.

Claims

A compound of formula (I),

(I)

or a pharmaceutically acceptable salt or solvate thereof, wherein,

R1 and R2 may be the same or different and represent -H, alkyl, alkoxy, halo, - CF3, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, - (CH2)_xOR6 or - (CH2)_χNR-3R7; or R1 and R2 together with the carbon atoms to which they are attached form a heteroaryl ring which may be optionally substituted by one or more alkyl, alkoxy, halo, -CF3, -OH and -NO2 groups; R³ and Rβ, which may be the same or different, represent -H, halo, alkyl, alkoxy, cycloalkyl, aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylalkoxy, -CN, -NO2, -OH, - OCF3, -CF3, -NR6R7, -S(O)_mR⁸, -S(O)₂NR6R7, -OS(O)₂R⁸, -OS(O)₂CF₃, - O(CH₂)_xNR⁶R⁷, -O(CH₂)χOR⁸, -C(O)CF₃, -C(O)alkyl, -C(O)cycloalkyl, - C(O)aralkyl, -C(O)Ar, -C(O)(CH₂)_xOR⁸, -C(O)(CH₂)_xNR⁶R7, -C(O)alkoxy, - C(O)NR6R7, -(CH₂)_xC(O)alkoxy, -(CH₂)_xOC(O)R⁸, -(CH₂)_xOR⁸, -(CH₂)_XR⁶R⁷, -(CH₂)_xC(O)NR⁶R⁷, -(CH₂)_xN(R⁶)C(O)R⁸, -(CH₂)_XS(O)₂NR6R⁷, - (CH₂)χN(R6)S(O)₂R⁸, -ZAr, -(CH₂)_xS(O)₂R⁸, -(OCH₂)_xS(O)₂R⁸, - N(R6)S(O)₂R⁸, -N(R6)C(0)R⁸, -(CH₂)_XN(R6)S(O)₂R⁸, -(CH₂)_xN(R⁶)C(O)R⁸ or -(CH₂)_xC(O)alkyl; R⁴ represents -(CH₂)_xOR⁸ OΓ -(CH₂)_XNR6R⁷; R⁶ and R⁷ may be the same or different and represent -H or alkyl or R6 and R⁷ together with the nitrogen atom to which they are attached form a heterocyclic ring; R⁸ represents -H, alkyl or aryl; Ar represents aryl or heteroaryl; m represents an integer 1 or 2; x represents an integer 0, 1 , 2, 3, 4, 5 or 6; and Z represents a bond, O, S, NR⁸ or CH2.

2. A compound of formula (I), as claimed in claim 1 , wherein R^ and R2 may be the same or different and represent -H, alkyl, alkoxy or -CF3.

3. A compound of formula (I), as claimed in claim 1 , wherein R1 and R2 together with the carbon atoms to which they are attached form a benzothiazole group (when taken together with the phenyl ring), which benzothiazole group may be optionally substituted by an alkyl group.

4. A compound of formula (I), as claimed in claim 1 , wherein R³ and R§ represent -H.

A compound of formula (I), as claimed in claim 1 , of formula (IA),

(IA)

or a pharmaceutically acceptable salt or solvate thereof, wherein, Rl and R2 may be the same or different and represent -H, alkyl, alkoxy or -CF3; or R1 and R together with the carbon atoms to which they are attached form a benzothiazole group (when taken together with the phenyl ring), which benzothiazole group may be optionally substituted by one or more groups selected from alkyl, such as methyl, alkoxy, halo, -CF3, -OH or -NO2; R³ represents -H, alkyl, -(CH₂)_XOR6 OΓ -(CH₂)_XNR4R5; R⁴ and R⁵ may be the same or different and represent H or alkyl or R⁴ and R⁵ together with the atoms to which they are attached form a C₃-₆azacycloalkane, C₃-₆(2-oxo)azacycloalkane ring or C₅.₈ polymethylene chain optionally interrupted by heteroatoms such as O or -NR⁶; R⁶ represents -H, alkyl or aryl; and x represents an integer 0, 1 , 2, 3, 4,

5 or 6.

6. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 , substantially as hereinbefore described with reference to any one of the Examples.

7. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 , which process comprises: (a) reacting a compound of formula (II),

(il) wherein, R^and R2 are as defined in relation to formula (I), with a compound of formula (111),

(III) wherein, R³, R⁴ and R5 are as defined in relation to formula (I) and thereafter, as necessary, carrying out one or more of the following reactions: (i) converting one compound of formula (I) into another compound of formula (I); (ii) removing any protecting group; (iii) preparing a salt or a solvate of the compound so formed.

8. A pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 , and a pharmaceutically acceptable carrier or excipient therefor.

9. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 , for use as an active therapeutic substance.

10. A method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1 ) receptor is beneficial, in particular the Disorders of the Invention, in mammals including humans, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.

11. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 , in the manufacture of a medicament for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, particularly the Disorders of the Invention.