GB2269170A - Azatricyclic tachykinin antagonists - Google Patents

Abstract

Compounds of formula (I), and salts and prodrugs thereof: <IMAGE> wherein Q, together with the C-C-N skeleton depicted in the formula, is an optionally substituted azatricyclic ring system; X represents O, S, CH2 or =CH-; Y represents H, OH, =O or halo; R<1> represents phenyl (optionally substituted by halo or trifluoromethyl) or a group CWR<6>R<7>; R<3>, R<4> and R<5> independently represent H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR<a>, SCH3, SOCH3, SO2 CH3, -NR<a>R<b>, -NR<a>COR<b>, -NRaCo2 Rb, -CO2R<a> or -CONR<a>R<b>; R<a> and R<b> independently represent H, C1-6 alkyl, phenyl or trifluoromethyl; W represents H or hydroxy; R<6> represents furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl (each optionally substituted by one or two substituents selected from halo, trifluoromethyl, C1-3 alkyl, C1-3 alkoxy, and CO2R<c>, where R<c> is H, C1-3 alkyl or benzyl); R<7> represents thienyl or phenyl optionally substituted by halo or trifluoromethyl; with the proviso that when X is O or S, Y is H are tachykinin receptor antagonists useful in therapy.

Description

THERAPEUTIC AGENTS This invention relates to a class of azatricyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention comprise an azatricyclic ring system substituted by an arylmethyloxy, arylmethylthio, arylalkyl or arylalkenyl moiety and by an aryl moiety.

The tachykinins are a group of naturallyoccurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the peripheral nervous and circulatory systems.

The structures of three known mammalian tachykinins are as follows: Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Neurokinin A: His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 Neurokinin B: Asp-Met-His-Asp-Phe-Phe-Val -Gly-Leu-Met-NH2 For example, substance P is believed inter alia to be involved in the neurotransmission of pain sensations (Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (Dec. 1987) 8 506-510), specifically in the transmission of pain in migraine (B.E.B. Sandberg et al, J.Med Chem, (1982) 25 1009) and in arthritis (Levine et al in Science (1984) 226 547-549). These peptides have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract such as inflammatory bowel disease (Mantyh et al in Neuroscience (1988) 25 (3) 817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al, Elsevier Scientific Publishers, Amsterdam (1987) page 85)). It is also hypothesised that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Grönblad et al "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J.Rheumatol. (1988) 15(12) 1807-10). Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al in Arthritis and Rheumatism (1990) 33 1023-8). Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et al Can.

J. Pharmacol. Physiol. (1988) 66 1361-7), immunoregulation plotz et al Science (1988) 241 1218-21 and Kimball et al, J. Immunol. (1988) 141 (10) 3564-9) vasodilation, bronchospasm, reflex or neuronal control of the viscera tMantyh et al, PNAS (1988) 85 3235-9) and, possibly by arresting or slowing 8-amyloid-mediated neurodegenerative changes tYankner et al, Science (1990) 250, 279-82) in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.

Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (J. Luber-Narod et al, poster to be presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July 1992, in press), and in disorders of bladder function such as bladder detrusor hyper-reflexia (Lancet, 16th May, 1992, 1239).

It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (European patent application no. 0 436 334), opthalmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent application no. 0 394 989).

In view of their metabolic instability, peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that nonpeptide tachykinin antagonists are sought.

WO-A-90/05729 describes inter alia a class of cis-3-[cyclic]methylamino-2- -substituted)- arylmethyl)quinuclidine compounds which are stated to be useful as substance P antagonists for treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases and pain or migraine.

There is, however, no disclosure or suggestion in WO-A90/05729 of the arylmethyloxy- or arylmethylthiosubstituted azabicyclic derivatives provided by the present invention.

We have now found a further class of nonpeptides which are potent antagonists of tachykinin.

The present invention provides a compound of formula (I), or a salt or prodrug thereof:

wherein Q is the residue of an optionally substituted azatricyclic ring system; X represents 0, S, CH2 or CH; Y represents H, OH, =O or halo; R1 represents phenyl optionally substituted by halo or trifluoromethyl or a group CWR6R7; R3, R4 and R5 independently represent H, C16 alkyl, C26 alkenyl, C26 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -ORa, SCH3, SOCH3, SO2CH3, -NRaRb, -NRaCORb, -NRaCO2Rb, -CO2Ra or -CONRaRb; Ra and Rb independently represent H, C16 alkyl, phenyl or trifluoromethyl; W represents H or hydroxy;; R6 represents furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl optionally substituted by one or two substituents selected from halo, trifluoromethyl, C1-3alkyl, C1-3alkoxy, and CO2RC, where Rc is H, Cl,galkyl or benzyl; R7 represents thienyl or phenyl optionally substituted by halo or trifluoromethyl; with the proviso that when X is O or S, Y is H.

The azatricyclic ring system of which Q is the residue is a non-aromatic ring system optionally containing, in addition to the nitrogen atom indicated in formula (I) above, a further heteroatom selected from 0 and S, or a group NR8R, where R8 represents H or C16alkyl. Suitably the ring system contains from 7 to 15 ring atoms, preferably from 10 to 14 ring atoms.

Examples of such azatricyclic ring systems include:

where in It will be appreciated that the nitrogen atom in the azatricyclic ring system will carry a lone pair of electrons.

It will be appreciated that when X represents CH, there is a carbon-carbon double bond between X and the carbon atom of the azatricyclic ring system to which it is attached.

The alkyl, alkenyl and alkynyl groups referred to with respect to any of the formulae herein may represent straight, branched or cyclic groups or combinations thereof. Thus, for example, suitable alkyl groups include methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkyl groups such as cyclopropylmethyl; suitable alkenyl groups include vinyl and allyl; and suitable alkynyl groups include propargyl.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo.

In one preferred group of compounds according to the invention, X is O.

In a further preferred group of compounds of formula (I), X is CH. When X is CH or CH2, Y is preferably OH or halo, especially fluoro.

Preferably R1 represents unsubstituted phenyl or a group CWR6R7 wherein W is H and R6 and R7 each represent unsubstituted phenyl.

Suitably, R3, R4 and R5 independently represent H, C16 alkyl, C26 alkenyl, C26 alkynyl, halo, cyano, nitro, trifluoromethyl, -ORa, -NRaRb, -NRaCORb, NRaCOZRbl -C02Ra or -CONRaRb; and Ra and Rb independently represent H or C16 alkyl.

For example, suitable values for the groups R4 and R5 include H, amino, nitro, trifluoromethyl, trimethylsilyl, halo, cyano, methyl, ethyl, cyclopropyl, vinyl, carbonylmethoxy, methoxy and phenoxy, more suitably H, nitro, trifluoromethyl and halo, such as chloro.

Preferably, at least one of R3, R4 and R5 is other than H. More preferably, two of R3, R4 and R5 are other than H. The (non-H) substituents are preferably at the 3- and 5-positions of the phenyl ring. In a particularly preferred group of compounds of formula (I), two of R3, R4 and R5 are trifluoromethyl and the other is H.

The compounds according to the invention have at least two asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. In particular, the relative orientation of the substituents on the azatricylic ring system in formula (I) above may give rise to cis and trans diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

It is believed that of the cis diastereomers, tachykinin receptor antagonist activity preferentially resides in the 2S,3S diastereomer, whereas of the trans diastereomers, activity preferentially resides in the 2R,3S diastereomers. Thus, it is believed that S stereochemistry at the 3-position of the azatricyle is crucial to tachykinin receptor antagonist activity.

For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g.

sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.

The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H.

Bundgaard, Elsevier, 1985.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage form such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, or suppositories, for oral, parenteral or rectal administration. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a nontoxic pharmaceutically acceptable salt thereof.When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The present invention futher provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. These may include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example, diabetic and chemotherapy-induced neuropathy, and neuralgia; respiratory diseases such as chronic obstrucutive airways disease, bronchopneumonia, bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disorders of bladder function such as bladder detrusor hyper-reflexia; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine.

The compounds of formula (I) are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy, asthma, osteroarthritis, rheumatoid arthritis and especially migraine.

The present invention further provides a compound of formula (I) for use in therapy. According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P. The present invention also provides a method for the the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I).

In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day. For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

The compounds according to the invention wherein X is O or S may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):

wherein Q, R1, R3, R4 and R5 are as defined for formula (I) above, and one of R30 and R31 represents a leaving group and the other of R30 and R31 represents XH, where X is as defined for formula (I); in the presence of a base.

Suitably, R31 represents a leaving group and R30 represents XH.

Suitable leaving groups include halo, e.g.

chloro, bromo or iodo, or sulphonate derivatives such as tosylate or mesylate.

The reaction is conveniently carried out in a suitable organic solvent, such as an ether, e.g. 1,2dimethoxyethane, at a temperature in the range of -5 to 25"C, preferably about 00C. Favoured bases of use in the reaction include alkali metal amides and hydrides, such as potassium bis(trimethylsilyl)amide and potassium hydride. Suitably, potassium bis(trimethylsilyl)amide is used.

The compounds according to the invention wherein X is CH or CH2 and Y is OH may be prepared by a process which comprises reacting a compound of formula (V) with a compound of formula (VI):

wherein Q, R1, R3, R4 and R5 are as defined in formula (I) and the dotted line represents an optional double bond, A represents CHO (intermediates (VB)), and Z is a metal, such as aluminium or lithium, or metal halide.

The group Z in the reaction of (V) with (VI) suitably represents a metal such as aluminium or, preferably, the residue of a Grignard agent such as MgBr.

The reaction is preferably carried out in an inert organic solvent such as an ether such as diethyl ether, tetrahydrofuran or a mixture thereof.

The compounds according to the invention wherein X is CH and Y is =O may be prepared by a process which comprises hydrolysing a compound of formula (VII):

wherein Q, R1, R3, R4 and R5 are as defined in formula (I). The reaction may take place with dilute acid such as dilute mineral acid, for example, hydrochloric acid.

The compound of formula (VII) need not be isolated but may be hydrolized in situ after being prepared from the corresponding compound of formula (VA) wherein A represents CN by reaction with the corresponding compound of formula (VI) (wherein Z is preferably lithium) as described above in relation to preparing compounds of formula (I) wherein X is CH and Y is OH.

The compounds according to the invention wherein X is CH or CH2 and Y is H may be prepared by reducing the corresponding compound of formula (I) wherein Y is OH. The reduction may be effected by standard methods known to those skilled in the art such as catalytic reduction by hydrogen in the presence of a catalyst such as platinum or palladium, preferably palladium dihydroxide. Such reduction is preferably carried out in the presence of a polar solvent such as an alcohol such as ethanol or an acid such as an inorganic acid, for example, hydrochloric acid, or a mixture thereof.Alternatively, the reduction may be carried out by, for example, lithium aluminium hydride/aluminium trichloride in the presence of a solvent such as an ether such as diethyl ether or tetrahydrofuran or a mixture thereof, preferably at ambient temperature such as around 25"C.

The compounds according to the invention wherein Y is halo may be prepared from the corresponding compounds of formula (I) wherein Y is OH using conventional techniques, for example, by reaction with a suitable halogenating agent. Examples of halogenating agents,include thionyl halides, phosphorous trihalides and phosphorous pentahalides.

A preferred halogenating agent for use in the reaction is diethylaminosulphurtrifluoride. The reaction is preferably conducted at low temperature, for example, at about -15 to +5"C.

The intermediates of formula (III) above wherein R30 is SH may be prepared from the corresponding intermediates of formula (III) wherein R30 represents OH by treating the latter compound with Lawesson's reagent or phosphorus pentasulphide in a suitable solvent, e.g.

pyridine, at ambient or elevated temperatures, suitably at reflux temperature.

The intermediates of formula (III) above wherein R30 is OH may be prepared by procedures analogous to those described in J. Med. Chem., 1974, 17, 497, and J. Med. Chem., 1975, 18, 587.

Intermediates of formula (III) wherein R30 is OH having cis stereochemistry may preferably be prepared from the corresponding ketones via a selective reduction using a suitable reducing agent such as a lithium aluminium hydride or a substituted borohydride such as triethylborohydride, as described in the accompanying examples.

Intermediates of formula (III) wherein R30 is OH having trans sterochemistry may be obtained selectively via a procedure involving non-selective reduction of the corresponding ketone, for example using sodium in an aromatic hydrocarbon solvent, e.g. toluene, preferably in the presence of an alcohol, e.g. iso-propyl alcohol, to give a mixture of cis and trans isomers, followed by selective oxidation of the cis isomer using a ketone in the presence of a base (Oppenauer oxidation).

Suitable ketones include acetone, methyl ethyl ketone, cyclohexanone and, preferably, benzophenone. Suitable bases include alkali metal hydrides, e.g. potassium hydride.

Intermediates of formula (III) wherein R30 is a leaving group may be prepared from compounds of formula (III) wherein R30 is OH, for example, by reaction with a thionyl halide, a mesyl halide or a tosyl halide.

Where they are not commercially available, the intermediates of formula (IV) above may be prepared by conventional procedures which will be readily apparent to one skilled in the art.

The compounds of formula (VA) wherein the double bond is present and A represents CN may be prepared by reaction of a compound of formula (VIII) with a Wittig reagent:

wherein Q and R1 are as defined in formula (I).

Preferably, the compound of formula (VIII) is reacted with a reagent of formula (alkoxy)2PO(CH2CN), such as (EtO)2PO(CH2CN) or (iPrO)2PO(CH2CN) in the presence of an alkali or alkaline earth metal salt of an alcohol such as potassium t-butoxide in an inert organic solvent such as toluene at an elevated temperature in the range of from 25"C to 50or, preferably around 50 c.

The compounds of formula (VA) wherein the double bond is absent and A represents CN may be prepared from the corresponding compounds of formula (VA) wherein the double is present, by reduction. Suitable procedures and reagents will be readily apparent to one skilled in the art, and include dissolving metal reduction, for example, using magnesium in methanol.

The intermediates of formula (VB) above wherein A is CHO may be prepared by procedures analogous to those described in J. Med. Chem., 1974, 17, 497, and J. Med.

Chem., 1975, 18, 587. For example, from the corresponding intermediate of formula (VA) wherein A represents CN for example with a standard agent such as DIBAL-H (available from Aldrich).

Where they are not conmiercially available, the intermediates of formula (VI) above may be prepared by conventional procedures well known to those skilled in the art.

Where they are not commercially available, the intermediates of formula (VIII) above may be prepared from known starting materials by procedures analogous to those described in J. Med. Chem., 1974, 17, 497, and J.

Med. Chem., 1975, 18, 587, or by alternative procedures which will be readily apparent to those skilled in the art, for example, by Diekmann cyclisation of appropriate starting materials.

Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereo isomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. For example, intermediate alcohols of formula (III), wherein X is oxa, may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. The diastereomeric alcohols can then be used to prepare optically pure compounds of formula (I).

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wutts, Protective Groups in Organic Synthesis, John Wiley t Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Claims (2)

CLAIMS:

1. A compound of formula (I), or a salt or prodrug thereof:

where in Q is the residue of an optionally substituted azatricyclic ring system; X represents 0, S, CH2 or Y represents H, OH, rO or halo; R1 represents phenyl optionally substituted by halo or trifluoromethyl or a group CWR6R7; R3, R4 and R5 independently represent H, C16 alkyl, C26 alkenyl, C26 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -ORa, SCH3, SOCH3, SO2CH3, -NRaRb, -NRaCORb, -NRaCO2Rb, -Co2Ra or -CONRaRb; Ra and Rb independently represent H, C16 alkyl, phenyl or trifluoromethyl; W represents H or hydroxy; ; R6 represents furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl optionally substituted by one or two substituents selected from halo, trifluoromethyl, C1-3alkyl, C1-3alkoxy, and CO2RC, where Rc is H, C1-3alkyl or benzyl; R7 represents thienyl or phenyl optionally substituted by halo or trifluoromethyl; with the proviso that when X is O or S, Y is H.

2. A compound as claimed in claim 1 for use in therapy.