WO2005044825A1

WO2005044825A1 - Silicon compounds and their use

Info

Publication number: WO2005044825A1
Application number: PCT/GB2004/004240
Authority: WO
Inventors: John Gary Montana; Graham Andrew Showell; David Jonathan Otway
Original assignee: Amedis Pharmaceuticals Ltd.
Priority date: 2003-10-21
Filing date: 2004-10-07
Publication date: 2005-05-19

Abstract

A compound of formula (1) wherein R1, R2 and R3 are the same or different and are each alkyl, -alkyl-aryl or -alkyl-cycloalkyl; or R1-Si-R 2 taken together form heterocycloalkyl; R4 is aryl or heteroaryl, either of which is optionally substituted with -Y-R5; R5 is alkyl, cycloalkyl, heterocycloalkyl or heteroaryl; W is arylene, optionally substituted with one or more substituents selected from halogen, hydroxy, alkyl, -alkyl-aryl, -alkyl-cycloalkyl, aryl, heteroaryl, -alkylheteroaryl, -alkylheterocycloalkyl, -alkoxy-heterocycloalkyl, alkoxy, aryloxy, hydroxyalkyl, -NHC(O)-alkyl, -NHC(O)-aryl, -NHS(0)2-alkyl, -NH,9(0)2-aryl, cyano and -Si(R1)(R2)(R3); X is oxygen or sulphur; Y is a bond, -NH-, -0-, -S-, -Si(R6)(R7 )-, alkylene, -0-alkyl-, -S-alkyl-, -NH alkyl-, -Si(R6)(R7 )-alkyl-, heterocycloalkylene or -heterocycloalkyl-alkyl-; and R6 and R7 are the same or different and are each alkyl, -alkyl-aryl or -alkyl cycloalkyl; or R6-Si-R7 taken together form heterocycloalkyl; or a pharmaceutically acceptable salt thereof or a prodrug form that is oxidisable or hydrolysable to form a compound as defined above.

Description

SILICON COMPOUNDS AND THEIR USE

Field of the Invention This invention relates to silicon compounds and their use in therapy. Background to the Invention Tumour necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities collectively referred to as "proinflammatory cytokines". These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections. Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarelloef al, 1984, Rev. Infect. Disease, 6, 51 and Koch et al, 1995, J. Invest. Med. 43, 28- 38). An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNFα) and IL-1β (Rankin etal, 1997, British J. Rheum.35, 334-342; Stack et al, 1997, Lancet 349, 521-524; Brower et al, 1997, Nature Biotechnology 15, 1240; Renzefti et al, 1997, Inflamm. Res. 46, S143; Chevalier 1997, Biomed. Pharmacother. 51 , 58; and Evans et al, 1996, J. Bone Miner. Res. 11 , 300). Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (O'Banion etal, 1992, Proc. Natl. Acad. Sci. U.S.A. 89, 4888). Accordingly, inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorder currently treated with COX inhibitors, such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease. Elevation of several cytokines has been demonstrated during active inflammatory bowel disease (IBD) (Cominelli et al, 1996, Aliment. Pharmacol. Ther. 10, 49). Proinflammatory cytokines such as TNFα and IL-1 β are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. TNFα has also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al, 1988, Amer. J. Med. 85, 289). Compounds which modulate release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with release of these cytokines. For example, WO-A-98/52558, WO-A-00/43384, WO-A-01/04115 and WO-A-03/005999 disclose heteroaryl urea compounds, which are indicated to be useful in treating cytokine mediated diseases. WO-A-02/092576 describes diarylurea derivatives which may be useful as anti- inflammatory agents. Sila-substitution (C/Si-exchange) of drugs is a relatively recent approach for searching for organo-silicon compounds which have beneficial biological properties. The approach involves the replacement of specific carbon atoms in compounds by silicon, and monitoring how the biological properties of the compounds have changed. A review of this approach is provided in Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986). Summary of the Invention A first aspect of the invention is a compound of formula (I)

wherein R¹, R² and R³ are the same or different and are each alkyl, -alkyl-aryl or -alkyl-cycloalkyl; or R¹-Si-R² taken together form heterocycloalkyl; R⁴ is aryl or heteroaryl, either of which is optionally substituted with -Y-R⁵; R⁵ is alkyl, cycloalkyl, heterocycloalkyl or heteroaryl; W is arylene, optionally substituted with one or more substituents selected from halogen, hydroxy, alkyl, -alkyl-aryl, -alkyl-cycloalkyl, aryl, heteroaryl, -alkyl- heteroaryl, -alkyl-heterocycloalkyl, -alkoxy-heterocycloalkyl, alkoxy, aryloxy, hydroxyalkyl, -NHC(O)-alkyl, -NHC(0)-aryl, -NHS(0)₂-alkyl, -NHS(0)₂-aryl, cyano and -Si(R¹)(R²)(R³); X is oxygen or sulphur; Y is a bond, -NH-, -0-, -S-, -Si(R⁶)(R⁷)-, alkylene, -O-alkyl-, -S-alkyl-, -NH- alkyl-, -Si(R⁶)(R⁷)-alkyl-, heterocycloalkylene or -heterocycloalkyl-alkyl-; and R⁶ and R⁷ are the same or different and are each alkyl, -alkyl-aryl or -alkyl- cycloalkyl; or R⁶-Si-R⁷ taken together form heterocycloalkyl; or a pharmaceutically acceptable salt thereof or a prodrug form that is oxidisable or hydrolysable to form a compound as defined above. Compounds of the invention may act as inhibitors of cytokines and as a consequence may have utility in the therapy of diseases or conditions in which cytokines are implicated. Accordingly, another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of an inflammatory disease, an autoimmune disease, acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, a bone resorption disease, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising entrerocolitis, a syndrome associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease, congestive heart failure, Guillain- Barre syndrome, Crohn's disease, psoriasis or ulcerative colitis. Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.

Description of Preferred Embodiments Certain compounds and combinations of substituents are preferred; in particular see the subclaims. With regard to the formula (I), R¹, R² and R³ are preferably each alkyl, more preferably methyl. R⁴ is preferably naphthyl, indole or azaindole, any of which is optionally substituted with -Y-R⁵. Y is preferably alkylene (e.g. ethylene), -O-alkyl- (e.g. -OCH₂CH₂-) or -heterocycloalkyl-alkyl- (e.g. -piperidinyl- methyl-). R⁵ is preferably morpholin-4-yl, piperidinyl, piperazinyl or pyridinyl. W and X are preferably optionally substituted phenylene and oxygen respectively. The term "alkyl" as used herein refers to an optionally substituted straight or branched chain alkyl moiety having from one to six carbon atoms. This term includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "C,.₆ alkyl" has the same meaning. The group may be substituted with one or more substituents, the substituents being the same or different and selected from hydroxy and the like. "Alkylene" refers to a similar, divalent group. The term "alkoxy" as used herein refers to a straight or branched chain alkoxy group containing one to six carbon atoms. This term includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. "C_1-6 alkoxy" has the same meaning. The term "halogen" as used herein refers to F, CI, Br or I. The term "aryl" as used herein refers to an optionally substituted aromatic ring system having from six to fourteen ring carbon atoms. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes, for example, phenyl and naphthyl. The group may be substituted with one or more substituents, the substituents being the same or different and selected from alkyl, cycloalkyl, halogen, hydroxy, trifluoromethyl, cyano and the like. The term "cycloalkyl" as used herein refers to a saturated alicyclic moiety having from three to six carbon atoms. This term includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The group may be substituted with one or more substituents, the substituents being the same or different and selected from alkyl, alkoxy, hydroxy, oxo and the like. The term "heterocycloalkyl" as used herein refers to a saturated heterocyclic moiety having from three to seven ring carbon atoms and one or more heteroatoms selected from nitrogen, oxygen, phosphorus, sulphur and silicon. This term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. The group may be substituted with one or more substituents, the substituents being the same or different and selected from alkyl, alkoxy, hydroxy, oxo and the like. The term "heteroaryl" as used herein refers to an aromatic ring system having from five to ten ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes, for example, furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. The group may be substituted with one or more substituents, the substituents being the same or different and selected from alkyl, cycloalkyl, halogen, hydroxy, trifluoromethyl, cyano and the like. Preferred compounds of the invention include: 1-(2-tert-butyl-5-trimethylsilyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl- piperidin-1 -yl)-naphthalen-1 -yl]-urea; 1-(2-methyl-5-trimethylsilyl-phenyl)-3-[4-(4-piperidin-1-ylmethyl-piperidin- 1-yl)-naphthalen-1-yl]-urea; 1-(5-tert-butyl-2-trimethylsilyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl- piperidin-1 -yl)-naphthalen-1 -yl]-urea; 1-(2-methyl-5-trimethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea; 1-(2-methoxy-5-trimethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea; 1-(2,5-bis-thmethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-urea; 1 -(2-ethoxy-5-trimethylsilyl-phenyl)-3-[4-(2-morρholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea; 1 -(2-methoxy-5-trimethylsilyl-phenyl)-3-[4-(2-piperidin-1 -yl-ethoxy)- naphthalen-1 -yl]-urea; 1 -(2-methoxy-5-trimethylsilyl-phenyl)-3-{4-[2-(4-methyl-piperazin-1 -yl)- ethoxy]-naphthalen-1 -yl}-urea; 1-(2-methoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyridin-4-yl)ethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; 1-(2-methoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyhdin-4-yl)ethyl)-1H-indol- 5-yl)urea; 1 -(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyridin-4-yl)ethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; 1 -(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyridin^-yl)ethyI)-1 H-indol-5- yl)urea; 1-(2-methoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-morpholinoethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; 1 -(2-methoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-morpholinoethyl)-1 H-indol-5- yl)urea; 1 -(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-morpholinoethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; and 1-(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-morpholinoethyl)-1 H-indol-5- yl)urea; the corresponding structures of which are shown below, respectively:

35

25

Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate. The compounds may exist in isomeric or tautomeric form; such isomers or tautomers form part of the present invention. Similarly, it will be appreciated that compounds of the invention, such as those comprising a pyridyl or morpholinyl group, may be in the form of an N- oxide; such N-oxides also form part of the present invention. The compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base. Alternatively, the enantiomers of the novel compounds may be separated by HPLC using a chiral column. A compound of the invention may be in a protected amino or protected carboxy form. The terms "protected amino" and "protected carboxy" as used herein refer to amino and carboxy groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester. Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention. Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid and the like. It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid in a conventional manner. A compound of the invention may be prepared by any suitable method known in the art and/or by the following process (for suitable procedures see Regan et al, J. Med. Chem. 2002, 45, 2994; Shvedov et al, Zhumal Organicheskoi Khimii, 1969, 5, 2221; WO-A-03/087087; GB-A-0781390; and US3300506):

phosgene

It will be understood that the process detailed above is solely for the purpose of illustrating the invention and should not be construed as limiting. A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention. Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances. The activity and selectivity of the compounds may be determined by any suitable assay known in the art. The compounds of the invention may be used in the treatment of numerous ailments, conditions and diseases including, but not limited thereto, inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, Guillain- Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus, erythematosus or insulin-dependent diabetes mellitus), autoimmune diseases (e.g. toxic shock syndrome, osteoarthritis, diabetes or inflammatory bowel disease), acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, bone resorption diseases, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotisingentrerocolitis, syndromes associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease or congestive heart failure. The term "cancer" as used herein refers to any disease or condition characterised by uncontrolled, abnormal growth of cells and includes all known types of cancer, for example cancer of the bladder, breast, colon, brain, bone, head, blood, eye, neck, skin, lungs, ovaries, prostate and rectum; digestive, gastrointestinal, endometrial, hematological, AIDS-related, muscoskeletal, neurological and gynecological cancers; lympomas, melanomas and leukemia. In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Oral administration is preferred. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the art. Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment. Compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables. The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. The following Example illustrates the invention. Example: 1-(2-Methoxy-5-trimethylsilyl-phenyl)-3-r4-(2-nnorpholin-4-yl- ethoxy)-naphthalen-1 -yll-urea

Step 1: (4-Methoxyphenyl)trimethylsilane To a solution of 4-bromoanisole (3.3 ml, 26.7 mmol) in tetrahydrofuran (100ml) at -78 °C was added n-butyl lithium (16.7 ml, 1.6 M solution in hexanes, 26.7 mmol) dropwise and the reaction stirred at this temperature for 15 minutes. Trimethylsilyl chloride (3.4 ml, 26.7 mmol) was then added and the reaction allowed to warm to ambient temperature. The solution was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with water. The organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (silica; petroleum ether to 4: 1 petroleum ether/ethyl acetate) to give the title compound as a colourless oil (4.8g, 100%). R_f = 0.48 (95:5 petroleum ether/ethyl acetate on silica); ¹H NMR (CDCI₃, 400 MHz) δ_H 7.48 (2H, d, J = 8.1 Hz), 6.94 (2H, d, J = 8.1 Hz), 3.84 (3H, s), 0.27 (9H, s). Step 2: (4-Methoxy-3-nitrophenyl)trimethylsilane To a solution of (4-methoxyphenyl)trimethylsilane in acetonitrile at -30°C was added nitronium tetrafluoroborate (2.2 g, 16.8 mmol). The deep brown solution was stirred at this temperature for 20 minutes, water was added and the reaction extracted with ethyl acetate, dried (magnesium sulphate) and concentrated under reduced pressure to give the crude product. Purification by column chromatography (silica; petroleum ether to 85:15 petroleum ether/ethyl acetate) gave the title compound as a yellow crystalline solid (1.25 g, 34%). R_f = 0.35 (3:1 petroleum ether/ethyl acetate on silica); ¹H NMR (CDCI₃, 400 MHz) δ_H 7.93 (1 H, s), 7.67 (1 H, d, J = 8.3 Hz), 7.10 (1 H, d, 8.3 Hz), 3.98 (3H, s), 0.30 (9H, s). Step 3: 2- ethoxy-5-(trimethylsilyl)benzamine (4-Methoxy-3-nitrophenyl)trimethylsilane (1.25 g, 5.6 mmol) and 5% palladium on carbon (275 mg) were stirred in ethanol (40 ml) under an atmosphere of hydrogen for 20 hours. The mixture was filtered through Celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound as an orange oil which crystallised on standing overnight (765 mg, 71 %). R_f = 0.35 (3:1 petroleum ether/ethyl acetate); ¹H NMR (CDCI₃, 400 MHz) δ_H 6.92 (1 H, dd, J = 7.8, 1.5 Hz), 6.89 (1 H, d, J = 1.5 Hz), 6.83 (1H, d, 7.8 Hz), 3.88 (3H, s), 3.79 (2H, br s), 0.25 (9H, s); LCMS: DAD(254) 4.16 min, ES⁺: m/z 196 (MH⁺). Step 4: tert-Butyl 1-hydroxynaphthalen-4-ylcarbamate A mixture of 4-amino-1 -naphthol hydrochloride (5.3 g, 27.1 mmol), d\-tert- butyl dicarbonate (6.5 g, 29.8 mmol) and lithium hydroxide (0.65 g, 27.1 mmol) in tetrahydrofuran was stirred at ambient temperature overnight. The mixture was poured onto water and extracted with diethyl ether. The organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (silica; 2:1 petroleum ether/ethyl acetate to ethyl acetate) to give the title compound as a pink solid (6 g, 86%). R_f = 0.25 (2:1 petroleum ether/ethyl acetate on silica); ¹H NMR (CDCI₃, 400 MHz) δ_H 8.01 (1 H, d, J = 8.3 Hz), 7.77 (1 H, d, J = 8.3 Hz), 7.45 (1 H, td, J = 8.3, 1.3 Hz), 7.36 (1 H, t, J = 8.3 Hz), 7.24 (1 H, d, J = 7.8 Hz),

6.49-6.41 (2H, br m), 6.19 (1 H, br s), 1.50 (9H, s);

LCMS: DAD(254) 3.68 min, ES^": m/z 258 (M-1 ).

Step 5: tert-Butyl 1-(2-morpholinoethoxy)naphthalene-4-yI carbamate A mixture of the foregoing naphthol (4.2 g, 16.2 mmol), 4-(2- chloroethyl)morpholine hydrochloride (3.3 g, 17.8 mmol) and potassium carbonate (9 g, 64.9 mmol) in acetonitrile (150 ml) was heated at 80 °C for 16 hours, cooled to room temperature, and diluted with ethyl acetate and water. The organic layer was washed with brine, dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (silica; 9; 1 ethyl acetate/petroleum ether to ethyl acetate) to give the title compound as a light orange solid (4.8 g, 80%).

R_f = 0.10 (9:1 ethyl acetate/petroleum ether on silica); H NMR (CDCI₃, 400 MHz) δ_H 8.52 (1 H, d, J = 8.3 Hz), 8.10 (d, J = 8.3 Hz), 7.9- 7.7 (3H, m), 7.03 (1 H, d, J = 8.3 Hz), 6.79 (1 H, br s), 4.54 (2H, t, J = 5.6 Hz), 3.99

(4H, t, J = 4.7 Hz), 3.20 (2H, t, J = 5.6 Hz), 2.93-2.88 (4H, m), 1.78 (9H, s);

LCMS: DAD (254) 3.03 min, ES⁺: 373 (MH⁺).

Step 6: 4-(2-morpholinoethoxy)naphthalene-1-amine dihydrochloride tert-Butyl 1 -(2-morpholinoethoxy)naphthalene-4-yl carbamate (7.6 g, 20.4 mmol) was stirred with hydrochloric acid (75 ml, 4M solution in dioxane) at ambient temperature for 20 hours. The volatiles were removed under reduced pressure to give the title compound as a pink solid (7.8g).

¹H NMR (DMSO, 400 MHz) δ_H 10.65 (2H, br s), 8.41 (d, J = 8.1 Hz), 8.02 (2H, d,

J = 7.8 Hz), 7.79-7.72 (1 H, m), 7.72-7.63 (2H, m), 7.09 (1 H, d, J = 8.3 Hz), 4.66- 4.63 (2H, m), 4.03-3.95 (2H, m), 3.92-3.81 (2H, m), 3.75-3.69 (2H, m), 3.62-3.49

(2H, m), 3.37-3.24 (2H, m);

LCMS: DAD(254) 3.06 min, ES⁺: 273 (MH⁺ - 2HCI).

Step 7: 1 -(2-Methoxy-5-trimethylsilyl-phenyl)-3-[4-(2-mo olin-4-yl-ethoxy)- naphthalen-1 -yl]-urea To a solution of 2-methoxy-5-(trimethylsilyl)benzamine (242 mg, 1.2 mmol) in dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml) at 0 °C was added phosgene (2.6 ml of a 20% solution in toluene, 5 mmol) and the mixture stirred at this temperature for 30 minutes. Further phosgene was added (2.6 ml of a 20% solution in toluene, 5 mmol) and the reaction was warmed to room temperature and stirred for 2 hours. The organic layer was dried (magnesium sulphate) and concentrated under reduced pressure. A solution of this residue in tetrahydrofuran (2 ml) was added to a mixture of 4-(2- morpholinoethoxy)naphthalene-1-amine dihydrochloride and di-/so- propylethylamine (0.74 ml, 4.1 mmol) in tetrahydrofuran (20 ml) and the reaction stirred at ambient temperature for 40 hours. Water was added and the mixture extracted with ethyl acetate. The organic extracts were washed with brine, dried (magnesium sulphate) and concentrated under reduced pressure to give the crude product. Trituration from diethyl ether gave the title compound as a pink powder (426 mg, 70%). R_f = 0.22 (95:5 DCM/MeOH on silica); ¹H NMR (CDCIg, 400 MHz) δ_H 8.35-8.33 (2H, m), 8.08-8.05 (1H, m), 7.62-7.54 (2H, m), 7.53-7.50 (1H, m), 7.14 (1H, dd, J = 8.1 , 1.8 Hz), 7.06 (1 H, br s), 6.85 (1H, d, J = 8.1 Hz), 6.79 (1H, d, J= 7.8 Hz), 6.36 (1H, s), 4.36 (2H, t, J= 5.2 Hz), 3.81-3.77 (4H, m), 3.61 (3H. s), 3.05-2.99 (2H, m), 2.74-2.69 (4H, m), 0.27 (9H, s);

LCMS: DAD (254) 4.39 min, ES⁺: 494 (MH⁺).

Claims

1. A compound of formula (I)

wherein R¹, R² and R³ are the same or different and are each alkyl, -alkyl-aryl or -alkyl-cycloalkyl; or R¹-Si-R² taken together form heterocycloalkyl; R⁴ is aryl or heteroaryl, either of which is optionally substituted with -Y-R⁵; R⁵ is alkyl, cycloalkyl, heterocycloalkyl or heteroaryl; W is ar lene, optionally substituted with one or more substituents selected from halogen, hydroxy, alkyl, -alkyl-aryl, -alkyl-cycloalkyl, aryl, heteroaryl, -alkyl- heteroaryl, -alkyl-heterocycloalkyl, -alkoxy-heterocycloalkyl, alkoxy, aryloxy, hydroxyalkyl, -NHC(0)-alkyl, -NHC(0)-aryl, -NHS(0)₂-alkyl, -NHS(0)₂-aryl, cyano and -Si(R¹)(R²)(R³); X is oxygen or sulphur; Yis a bond, -NH-, -0-, -S-, -Si(R⁶)(R⁷)-, alkylene, -O-alkyl-, -S-alkyl-, -NH- alkyl-, -Si(R⁶)(R⁷)-alkyl- heterocycloalkylene or -heterocycloalkyl-alkyl-; and R⁶ and R⁷ are the same or different and are each alkyl, -alkyl-aryl or -alkyl- cycloalkyl; or R⁶-Si-R⁷ taken together form heterocycloalkyl; or a pharmaceutically acceptable salt thereof or a prodrug form that is oxidisable or hydrolysable to form a compound as defined above.

2. A compound according to claim 1 , wherein R¹, R² and R³ are each alkyl.

3. A compound according to claim 2, wherein R¹ , R² and R³ are each methyl.

4. A compound according to any preceding claim, wherein R⁴ is naphthyl, indole or azaindole.

5. A compound according to any preceding claim, wherein R⁴ is substituted with -Y-R⁵.

6. A compound according to claim 5, wherein Y is alkylene, -O-alkyl- or -heterocycloalkyl-alkyl-.

7. A compound according to claim 6, wherein Y is ethylene, -OCH₂CH₂- or -piperidinyl-methyl-.

8. A compound according to claim 6 or claim 7, wherein R⁵ is morpholin-4-yl, piperidinyl, piperazinyl or pyridinyl.

9. A compound according to any preceding claim, wherein W is optionally substituted phenylene.

10. A compound according to any preceding claim, wherein X is oxygen.

11. A compound according to claim 1 , selected from 1-(2-tert-butyl-5-trimethylsilyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl- piperidin-1 -yl)-naphthalen-1 -yl]-urea; 1-(2-methyl-5-trimethylsilyl-phenyl)-3-[4-(4-piperidin-1-ylmethyl-piperidin- 1 -yl)-naphthalen-1 -yl]-urea; 1-(5-tert-butyl-2-trimethylsilyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl- piperidin-1 -yl)-naphthalen-1 -yl]-urea; 1-(2-methyl-5-trimethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea; 1-(2-methoxy-5-trimethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea; 1-(2,5-bis-trimethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-urea; 1 -(2-ethoxy-5-trimethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea; 1-(2-methoxy-5-trimethylsilyl-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)- naphthalen-1 -yl]-urea; 1 -(2-methoxy-5-trimethylsilyl-phenyl)-3-{4-[2-(4-methyl-piperazin-1 -yl)- ethoxy]-naphthalen-1 -yl}-urea; 1-(2-methoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyridin-4-yl)ethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; 1-(2-methoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyridin-4-yl)ethyl)-1H-indol- 5-yl)urea; 1-(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyridin-4-yl)ethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; 1-(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-(pyridin-4-yl)ethyl)-1H-indol-5- yl)urea; 1 -(2-methoxy-5-(trimethylsilyl)ρhenyl)-3-(3-(2-morpholinoethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; 1 -(2-methoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-morpholinoethyl)-1 H-indol-5- yl)urea; 1 -(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-morpholinoethyl)-1 H- pyrrolo[2,3-b]pyridin-5-yl)urea; and 1-(2-ethoxy-5-(trimethylsilyl)phenyl)-3-(3-(2-morpholinoethyl)-1 H-indol-5- yl)urea.

12. A compound according to any preceding claim, which is in the form of a single enantiomer, diastereomer or tautomer.

13. A compound according to any preceding claim, for therapeutic use.

14. A pharmaceutical composition comprising a compound of any of claims 1 to 12 and a pharmaceutically acceptable diluent or carrier.

15. Use of a compound of any of claims 1 to 12, for the manufacture of a medicament for the treatment or prevention of an inflammatory disease.

16. Use according to claim 15, for the treatment or prevention of rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease ulcerative colitis, psoriasis, graft versus host disease, systemic lupus, erythematosus or insulin-dependent diabetes mellitus.

17. Use of a compound of any of claims 1 to 12, for the manufacture of a medicament for the treatment or prevention of an autoimmune disease.

18. Use according to claim 17, for the treatment or prevention of toxic shock syndrome, osteoarthritis, diabetes or inflammatory bowel disease.

19. Use of a compound of any of claims 1 to 12, for the manufacture of a medicament for the treatment or prevention of acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, a bone resorption disease, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising entrerocolitis, a syndrome associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease or congestive heart failure.

20. Use of a compound of any claims 1 to 12, for the manufacture of a medicament for the treatment or prevention of rheumatoid arthritis, psoriasis or chronic obstructive pulmonary disease.

21. Use according to claim 20, wherein the compound is 1 -(2-methoxy-5- trimethylsilyl-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea.