This invention relates to a class of aromatic compounds which are useful as tachykinin antagonists.

More particularly, the compounds of the invention contain a phenyl moiety and hydroxyl or ether moiety.

The tachykinins are a group of naturally occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in 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-NH 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-NH ₂ For example, substance P is believed inter alia to be involved in the neurotransmission of pain sensations [Otsuka et a , "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) 2 _. 5 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) _ _ (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 Grόnblad 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, and fibrositis [O'Byrne et al in Arthritis and Rheumatism (1990) 3J3 _. 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al Can. J. Pharmacol. Physiol.

(1988) 6j5 1361-7], immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball et a , J. Immunol. (1988) 141 (10) 3564-9] vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) J5 3235-9] and, possibly by arresting or slowing 3-amyloid-mediated neurodegenerative changes [Yankner et al Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Downs 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 detruεor 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 εcleroder a and eosinophillic fascioliaεiε, 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 eryth atosis (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) .

We have now found a class of non-peptides which are potent antagonists of tachykinin.

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

( I) wherein

R ¹ represents a nitrogen containing aromatic or non-aromatic heterocycle optionally subεtituted by one or more groupε selected from Cι_ ₆ lkyl, Ci-salkoxy, oxo, thioxo, halo, trifluoromethyl, nitro, NR ^a R ^b , NR ^a COR ^b , C0NR ^a R ^b , C0 ₂ R ^a , S0 ₂ R ^a and CH ₂ 0R ^a , where R ^a and R ^b each independently represent H, Ci-galkyl or phenyl optionally substituted by C^-galkyl, halo or trifluoromethyl;

R ² represents H, Ci-galkyl or C ₂ _ ₆ alkenyl;

R ³ represents C ₁ -. ₃ alkyl substituted by a phenyl group which may itself optionally be substituted by one or more of Cι_ ₆ alkyl, C ₂ _g alkenyl, C ₂ _ ₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, SR ^C , S0R ^c , S0 ₂ R ^c , 0R ^C , NR ^c R ^d , NR ^c C0R ^d , NR ^c C00R ^d , COOR ^c and CONR ^c R ^d ;

R ⁴ represents H, C^-galkyl or C _ ₆ alkenyl; each R independently represents Ci-galkyl, C^galkoxy, halo or trifluoromethyl; Z represents O or S; and m represents 0, 1, 2 or 3.

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.

For phenylalkyl substituents, the alkyl moiety may be straight or branched.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo. Aptly R represents an optionally substituted aromatic heterocycle.

The nitrogen containing aromatic heterocycle represented by R may be, for example, a 5- or 6-membered heterocycle and may contain, in addition to the nitrogen atom, one or more heteroatoms εelected from O, S and N, or groupε NR ⁸ , where R ⁸ is H or C^-galkyl.

Suitably R represents an optionally substituted 5-membered heteroaryl moiety selected from pyrrolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,

oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl and imidazolyl. Preferably R ¹ repreεents optionally substituted pyrrolyl or imidazolyl. More preferably R represents imidazolyl substituted by a nitro or an amino group.

Aptly R representε an optionally εubstituted non-aromatic heterocycle.

Suitably R ¹ represents a 4, 5, 6, 7 or 8 membered ring which may have one heteroatom in addition to the nitrogen atom, for example an oxygen atom. Apt groups include those of the formula

wherein Q is CH ₂ , NR where R is as hereinbefore defined, 0 or S, n ¹ is 1, 2 or 3 and m ¹ is 1 or 2 with the proviso that when Q is NR ⁸ , O or S neither n ¹ nor m ¹ is 1; which group can be optionally substituted by one or two oxo groups or C ₁ _ ₆ alkyl groups.

A favoured non-aromatic group R ¹ is orpholino. R is linked to carbon atom which also bears tthhee RR ²² ggrroouupp aanndd tthhee octher groups shown in formula (I) via the nitrogen atom.

Suitable values for the groups R ² and R ⁴ include H and methyl, preferably H. Suitably R represents a C^_ ₃ alkyl chain bearing a substituent which is a subεtituted phenyl group. Suitable phenyl εubεtituentε include methyl, methoxy, nitro, cyano, halo and trifluoromethyl.

Preferably R ³ repreεents methyl substituted by a

substituted phenyl group. Preferably one or two substituents will be preεent in the phenyl ring. More preferably R ³ represents methyl substituted by 3,5- disubstituted phenyl, such as 3,5-dimethylphenyl or 3,5- biεtrifluoromethylphenyl.

Preferably m represents zero.

A preferred sub-class of compounds according to the invention is represented by formula (Ia) :

( lα) wherein

X is N or CH; R and R each independently represent H,

Cι_ ₆ alkyl, C _g alkenyl, C^-galko y, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, hydroxy, phenoxy or amino;

R ²⁴ is N0 or NH ₂ , and may be located at any available ring position; and salts and prodrugs thereof.

Specific compounds within the scope of the present invention include:

(+)-l-[3,5-(biεtrifluoromethylphenyl)methyloxy]-2-N(2,5- dimethylpyrrole)-2-phenylethane;

1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-

N(imidazole)-2-phenylethane;

(+)-l-[3,5-(bistrifluoromethylphenyl) ethyloxy]-2-N(2- nitroimidazole)-2-phenylethane;

(±)-2-N(2-aminoimidazole)-1-[3,5-

(bistrifluoromethylphenyl)methyloxy]-2-phenylethane; (±)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-N(4- nitroimidazole)-2-phenylethane; (±)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]2-N- morpholino-2-phenylethane;

(±)-l-[3,5-(bistrifluoromethylphenyl)methyloxy]2-N- (piperidine-2,6-clione-2-phenylethane and salts and prodrugs thereof especially the pharmaceutically acceptable salts thereof.

For use in medicine, the saltε 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 acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic 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 saltε in which the amino nitrogen atom carrieε a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, εuitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potasεium εaltε; 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 prodrugε will be functional derivativeε 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 present invention includes within its scope solvates of the compounds of formula (I) and saltε thereof, for example, hydrates.

The compounds according to the invention have at least one asymmetric centre, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier. Preferably the compositionε according to the invention are in unit doεage formε εuch as tablets, pills, capsules, powders, granules, solutions or suεpenεions, or suppositorieε, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

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, εtearic acid, magneεium stearate, dicalciu 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 non-

toxic 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 capsuleε. Thiε εolid preformulation co poεition iε 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 pasε 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 formε in which the novel compoεitionε of the present invention may be incorporated for administration orally or by injection include aqueous solutionε, suitably flavoured syrupε, aqueous or oil suεpenεionε, and flavoured emulsions with edible oils such aε cottonεeed oil, εeεame oil, coconut oil or peanut oil, aε well as elixirs and εimilar pharmaceutical vehicleε. Suitable dispersing or suεpending agentε for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, εodiu

carboxymethylcelluloεe, methylcellulose, polyvinyl- pyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic εolventε, or mixtures thereof, and powders. The liquid or solid compositions may contain εuitable pharmaceutically acceptable excipientε aε set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solventε may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebuliεing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositionε may be adminiεtered, preferably orally or naεally, from devices which deliver the formulation in an appropriate manner.

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 syεtem εuch as anxiety, depression, psychoεiε and schizophrenia; neurodegenerative disorderε εuch aε dementia, including εenile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such

aε peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and poεtherpetic and other neuralgiaε; reεpiratory diεeases, particularly thoεe aεεociated with exceεε mucuε εecretion εuch as chronic obεtrucutive airwayε disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospaεm; inflammatory diseases such aε inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersenεitivity 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 disorderε εuch aε alcoholiε ; εtress related εomatic disorders; reflex sympathetic dystrophy such as shoulder/hand εyndrome; dyεthymic diεorderε; adverse immunological reactions εuch aε rejection of tranεplanted tissues and disorderε related to immune enhancement or εuppreεεion such as systemic lupus erythematosiε; gaεtrointeεtinal (GI) diεorderε and diseases of the GI tract such as disorderε aεεociated with the neuronal control of viεcera εuch aε ulcerative colitis, Crohn's diseaεe and incontinence; diεorderε of bladder function εuch aε bladder detruεor hyper-reflexia; fibrosing and collagen diseaseε εuch aε εcleroderma and eoεinophilic faεcioliaεiε; disorders of blood flow caused by vasodilation and vaεoεpaεtic diεeaεeε εuch aε angina, migraine and Reynaud'ε diεeaεe; and pain or nociception, for example, that attributable to or aεεociated with any of the foregoing conditions, especially the transmiεsion of pain in migraine.

The compounds of formula (I) are particularly useful in the treatment of pain or nociception and/or inflammation and disorders aεεociated therewith εuch as,

for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, poεtherpetic and other neuralgiaε, aεthma, osteroarthritis, rheumatoid arthritis and especially migraine. The present invention further provideε a compound of formula (I) for uεe in therapy. According to a further or alternative aεpect, the preεent invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological diεorderε aεsociated with an excesε of tachykininε, eεpecially εubstance P. The present invention also provides a method for the the treatment or prevention of physiological disorderε aεεociated with an excess of tachykinins, especially subεtance 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 compriεing a compound of formula (I) .

In the treatment of the conditionε aεεociated with an exceεε of tachykininε, a εuitable doεage level iε about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, εuch aε from about 0.05 to about 10 mg/kg per day. For example, in the treatment of conditionε involving the neurotrans isεion of pain εenεationε, a εuitable doεage 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 may be prepared from compounds of formula (II)

(ID wherein R ² , R ³ , R , R ⁵ , Z and m are aε defined for formula (I) above and R repreεentε a leaving group, by reation with a metallated aromatic heterocycle of formula R^-M wherein R lε aε defined for formula (I) and M repreεentε a metal, such as an alkai metal, for example sodium or lithium, or with an non-aromatic amine R ¹ -H, optionally in the presence of a tertiary amine base. Suitable leaving groups represented by R ³⁰ include aryl and alkyl sulphonate groupε, εuch aε toεylate and meεylate groupε. The reaction is conveniently effected in a suitable organic solvent, such as dimethyl formamide, or an ether, such as, for example, tetrahydrofuran, or a mixture thereof, suitably at room temperature.

Alternatively, compounds of formula (I) may be prepared from compounds of formula (III)

wherein R ² , R ³ , R , R ⁵ , Z and m are defined for formula (I) using conventional methods for the construction of the heteroaromatic ring. Suitable methods are described, for example, in Comprehensive Heterocyclic Chemistry, Katritzky and Rees, Pergamon Presε, 1984.

Compounds of formula (I) may also be prepared from other compounds of formula (I) by interconversion processes. Such procesεes are particularly useful for modifying substituents in the heteroaromatic ring. For example, compoundε of formula (I) wherein R represents a heteroaryl moiety substituted by an a ino group may be prepared from the corresponding compounds of formula (I) wherein R represents the same heteroaryl moiety substituted by a nitro group, by reduction. Further suitable interconversion procedures will be readily apparent to those skilled in the art.

Compounds of formula (II) may be prepared from intermediates of formula (IV)

H

(ιv) wherein R ² , R ³ , R ⁴ , R ⁵ , Z and are as defined for formula (I) , by conversion of the hydroxy group to a leaving group under conventional conditions, for example, by reaction with a compound of formula R ³⁰ -Hal, where Hal represents halo, such as chloro or bromo, in the presence of a base.

Suitable bases of use in the reaction include tertiary amines such as, for example, triethylamine.

The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, diethyl ether.

Intermediates of formula (IV) may be prepared by reaction of compounds of formula (V) with compounds of formula (VI)

(V) (VI)

wherein R ² , R ³ , R ⁴ , R ⁵ , Z, m and Hal are as previously defined.

The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, diethyl ether. Compoundε of formula (V) may be prepared by reaction of a compound of formula (VII) , or an appropriately protected derivative thereof, with a compound of formula (VIII)

R

(VI I ) ( I M )

Wherein R ² , R ³ and R ⁴ are aε previouεly defined, one of R ⁴⁰ and R ⁴¹ repreεentε ZH where Z iε as previously defined and the other of R ⁴⁰ and R ⁴¹

represents a leaving group, in the presence of a base, followed by deprotection, if required.

Suitably R represents ZH and R ⁴¹ representε a leaving group. 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 dimethylformamide, at a temperature in the region of 0*C. Favoured baseε of uεe in the reaction include alkali metal hydrideε, εuch aε sodium hydride.

The intermediates of formula (VII) above wherein R ⁴⁰ is SH may be prepared from the corresponding intermediates of formula (VII) wherein R ⁴⁰ represents OH by treating the latter compound with hydrogen sulphide in the presence of aluminium oxide, as described by Lucien et al.. Nouveau J. Chem.. 3_, 15 (1979) , or phosphoruε pentaεulphide in a εuitable εolvent, e.g. pyridine, at ambient or elevated temperatureε, εuitably at reflux temperature.

Intermediateε of formula (VII) wherein R ⁴⁰ iε a leaving group may be prepared form intermediateε of formula (VII) wherein R ⁴⁰ repreεentε OH aε deεcribed for the preparation of compounds of formula (II) from compounds of formula (IV) above.

Intermediates of formula (VII) wherein R ⁴⁰ is OH are commercially available or may be prepared from commercially available starting materials by conventional procedures which will be readily apparent to those skilled in the art.

Intermediates of formula (III) may be prepared from compounds of formula (IX)

( IX) wherein R ² , R , R , R ⁴⁰ adn m are as previouεly defined, by reaction with compounds of formula (VIII) as previously defined, in the presence of a base, as described for the preparation of compounds of formula (V) above.

Compounds of formula (IX) wherein R ⁴⁰ is SH or a leaving group may be prepared from compounds of formula (IX) wherein R ⁴⁰ iε OH analogously to the preparation of compounds of formula (VII) wherein R ⁴⁰ is SH or a leaving group.

Compounds of formula (IX) wherein R ⁴ is H and

R 40 is OH may be prepared from compounds of formula (X)

(x) wherein R ² , R and m are aε previously defined, or alkyl esterε thereof, by reduction.

Suitable reducing agentε include metal hydrideε, εuch as lithium aluminium hydride. The reaction is conveniently effected in a suitable organic εolvent, εuch aε ether, for example, tetrahydrofuran,

suitably at elevated temperature, such as the reflux temperature of the solvent.

Compounds of formula (X) are commercially available or may be prepared by conventional procedures for the preparation of amino acids which are well documented and are described, for example, in Chemistry and Biochemistry of the Amino Acids. ed. G. C. Barrett, Chapman and Hall, 1985.

Compounds of formula (IX) wherein R ° iε OH and R ⁴ iε other than H may be prepared from intermediateε of formula (XI)

(XI) wherein R^, R ^J and m are aε defined for formula (I) , by reaction with an organometallic reagent of formula MR , wherein R ⁴ is as previously defined and M represents a metal, such as lithium, or a metal halide, such as a magneεium halide, e.g. magneεium chloride or magnesium bromide.

The reaction is suitably effected in an inert organic εolvent such as an ether, for example, diethylether or tetrahydrofuran.

Aldehydes of formula (XI) may be prepared by reduction of esterε of compounds of formula (X) using diisobutylaluminium hydride.

Where the above-deεcribed proceεε for the preparation of the compoundε according to the invention giveε rise to mixtures of stereoisomers theεe iεomerε

may, if desired, be separated, suitably by conventional techniques εuch aε preparative chro atography.

The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. For example, compounds of formula (I) wherein R ¹ is H may be resolved into their component enantiomers by standard techniqueε, εuch as the formation of diastereo eric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. These compounds can then be used to make individual enantiomers of compounds of formula (I) wherein R ¹ is other than H.

During any of the above synthetic sequenceε it may be neceεεary 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 Preεε, 1973; and T.W. Greene and P.G.M. Wutts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent εtage using methods known from the art.

The following Examples illustrate the preparation of compounds according to the invention.

EXAMPLE 1

(+)-l-r(3.5-BistrifluoromethylDhenyl)methyloxyl-2-N(2.5- dimethyl pyrrole)-2-phenyl ethane

a) L-2-Phenylglycinol (5g) and di-t-butyldicarbonate (9.4g) was stirred in a dichloromethane solution (30ml) at room temperature for 3 hours. The precipitate which formed was filtered to give N-t-butoxycarbonyl-L-2-phenylgIvcinol. 4g.

b) To a solution of 2-N-t-butoxycarbonylamino- L-2-phenylglycinol (23.7g; Example la) and

3,5-bis(trifluoromethyl)benzyl bromide (33.8g) dissolved in dimethylformamide (75ml) was added sodium hydride (80% suspension in oil, 3.3g) in portions over 30 minutes. After stirring the solution at ambient temperature for lh, water (500ml) and ethyl acetate (500ml) were added. The organic phase was washed further with water (2 x 100ml), saturated brine and dried (MgSO ). After evaporation in υacuo the residue was chromatographed on silica (eluting with 5% ethyl acetate in petroleum ether bp 60-80°C) to give (S)-l-(3.5-bis(trifluoromethyl)phenyl)methyloxy)-2-N-t- butoxycarbonylamino-2-phenylethane. m.p. 53-54°C.

c) The product of Example lb (lOg) was allowed to stand in 250ml of diethyl ether saturated with gaseous HC1. The solvent was removed in υacuo and the residue recrystallised from diethyl ether-petroleum ether to give crystalline (+)-2-ammonium-l-(bistrifluoromethylphenyl)methyloxy-2- phenyl ethane, hvdrochloride salt.

d) To a solution of (+)-2-ammonium-l- (bistrifluoromethylphenyl)methyloxy-2-phenyl ethane, hydrochloride salt (lmmol) and 1.1 equivalents of 2,5-hexanedione in 5ml methanol was added potassium hydroxide (l.δmmol). The reaction was refluxed for 48h and partitioned between dichloromethane-water. The organic phase was separated, dried (MgSO ), concentrated in υacuo, and poured through a plug of silica using 5% ethyl acetate-pet. ether as eluent. The filtrate was concentrated to give the title compound as a clear oil: (CDCy δ 2.05 (6H, s), 4.1-4.15 (1H, m),

4.4-4.45 (1H, m), 4.5-4.7 (2H, m), 5.6-5.65 (1H, m), 5.8 (2H, s), 7.1-7.15 (2H, m), 7.2-7.4 (3H, m), 7.7 (2H, s), 7.8 (1H, s); Found: C, 62.43; H, 4.83; N, 3.32. C 23 H 21 NOF 6 requires: C, 62.58; H,

4.79; N, 3.17.

EXAMPLE 2

l-r(3.5-Bistrifluoromethylphenyl)methyloxyl-2-N (imidazole)-2-phenyl ethane

a) To a stirred solution of solketal (O.lδlmol) in DMF/THF (1:1, 300ml) under a nitrogen atmosphere was added sodium hydride (1.2 equivalents of an 80% dispersion in mineral oil). The anion was allowed to form over one hour prior to addition of 3,5-bistrifluoromethylbenzyl bromide. The reaction was partitioned between ethyl acetate-saturated ammonium chloride after lh and the organic phase separated, dried (MgSO 4 ), and concentrated to a yellow oil. Chromatography using pet. ether then 20% ethyl acetate-pet. ether as eluent gave 2,2-dimethyl-l,3-dioxolane-4-methanol-3,5-bistrifluoromethyl ben zyl ether as a yellow oil: (CDCy δ 1.4 (3H, s), 1.45 (3H, s),

3.6-3.65 (2H, m), 3.7-3.8 (1H, m), 4.1-4.15 (1H, m), 4.3-4.4 (1H, m), 4.7 (2H, s), 7.8 (3H, s).

b) The product from a) above was dissolved in 150ml THF and allowed to stand for 18h with 30ml 2N hydrochloric acid.

THF was removed in υacuo and the residue partitioned between ethyl acetate and saturated sodium carbonate solution. The organic phase was separated, dried (MgSO ) and concentrated to give l-glycerol-(3,5-bistrifluorobenzyl)ether as a yellow oil: (CDC1 ₃ ) δ 2.0 (1H, s), 2.6 (1H, s), 3.6-3.7 (3H, m), 3.7-3.8 (1H, m),

3.9-4.0 (1H, m), 4.7 (2H, s), 7.8 (2H, s), 7.85 (1H, s).

c) A solution of the diol from b) above in 200ml dichloromethane was cooled in an ice-water bath, and treated with a solution of 1.1 equivalents sodium metaperiodate in

100ml water. A further lg of sodium metaperiodate was added after 3h. The reaction was allowed to stand for 48h, the dichloromethane layer separated, dried (MgSO ), concentrated in υacuo and purified by chromatography using 20% ethyl acetate-pet. ether as eluent, to give

[(3,5-bistrifluoromethylphenyl)methyloxy] ethanol as a clear oil. Bp. 94°C/1.31 mBar.

d) To a stirred solution of the aldehyde (3.3mmol) from c) above in 5ml anhydrous diethyl ether under a nitrogen atmosphere was added phenylmagnesium bromide (3.0M solution in diethyl ether, 1.3ml). The reaction was partitioned between ethyl acetate-saturated ammonium chloride after 2h. The organic phase was separated, dried (MgSO ), concentrated and chromatographed using 20% ethyl acetate-pet. ether as eluent, to give l-[(3,5-bistrifluoromethylphenyl)methyloxy]-

2-hydroxy-2-phenyl ethane as a clear oil. (CDCy δ 3.6-3.8 (2H, m), 4.7 (2H, s), 4.95-5.05 (1H, m), 7.2-7.4 (5H, m), 7.7-7.8 (2H, m).

e) A solution of the alcohol (6.9mmol) from d) above in 5ml diethyl ether was treated with triethylamine (1.44ml) followed by methanesulphonyl chloride (0.8ml). The reaction was stirred for 2h then partitioned between ethyl acetate-water. The organic phase was separated, dried (MgSO ) and concentrated to a yellow oil. Purification by chromatography using 10% ethyl acetate-pet. ether as eluent gave the mesylate as a pale yellow oil.

f) A mixture of the mesylate (0.7mmol) from e) above and 1.2 equivalents of the sodium salt of imidazole in 4ml DMF/THF

(1:1) was allowed to stand overnight. The reaction was partitioned between diethyl ether-water, the organic phase separated, dried (MgSO ), concentrated in υacuo and purified by chromatography using 20% ethyl acetate-pet. ether as eluent to afford the title compound as a clear oil: (CDCy δ 4.1-4.15 (2H, m), 4.6-4.7 (2H, m), 5.4-5.45 (1H, m), 7.0 (1H, s), 7.1 (1H, s), 7.15-7.2 (2H, m), 7.3-7.4 (3H, m), 7.6-7.65 (3H, m), 7.8 (1H, s).

EXAMPLE 3

(±)-l-r(3.5-Bistrifluoromethylphenyl)methyloxyl-2-N(2- nitroimadazole-2-phenyl ethane

A suspension of 2-nitroimidazole (2.5mmol) in 3ml anhydrous THF was stirred under nitrogen and treated with sodium hydride (1.1 equivalents of an 80% dispersion in oil). The anion was allowed to form over 2h prior to being reacted in

an analogous manner described in Example 2 to give the title compound as a yellow oil. (CDCy δ 4.1-4.2 (2H, m), 4.6-4.8 (2H, m), 6.5-6.6 (IH, m), 7.1-7.4 (7H, m), 7.6 (2H, s), 7.8 (IH, s)

EXAMPLE 4

(±)-2-N(2-aminoimidazole)-l-r(3.5-bistrifluoromethylphen vI) methyloxyYl-2-phenyl ethane

l-[(3,5-bistrifluoromethylphenyl)methyloxy]-2-N(2-nitroim idazole)-2-phenyl ethane (Example 3) (60mg) was dissolved in 10ml methanol and was hydrogenolysed over lOOmg Pd C at 50 psi for 3h. The catalyst was removed by filtration, the filtrate concentrated in υacuo and purified by chromatography using methanol-ethyl acetate as eluent, to give the title compound as an oil. (CDCy δ 4.0-4.2 (4H, m), 4.6-4.7 (2H, m), 5.3-5.4 (IH, m), 6.6-6.7 (2H, m), 7.2-7.4 (5H, m), 7.7 (2H, s), 7.8 (IH, s).

EXAMPLE 5

(±)-l-r(3.5-Bistrifluoromethylphenyl)methyloxyl-2-N(4- nitroimidazole)-2-phenyl ethane

The title compound was prepared in an analogous manner to that described in Example 3 using 4-nitroimidazole (6.6mmol): (CDCy δ 4.1-4.2 (2H, m), 4.7 (2H, s), 5.2-5.3 (IH, m), 7.2-7.3 (2H, m), 7.4-7.45 (3H, m), 7.55 (IH, s), 7.6 (2H, s), 7.8 (2H, 2).

EXAMPLE 6

(±)-l-r(3.5-Bistrifluoromethylphenyl)methyloxyl-2-N- morpholino-2-phenyl ethane hvdrochloride salt

A solution of 2,5-dihydro uran (0.11ml) in methanol (10ml) was cooled to -78°C. Ozone gas was bubbled through the solution until a blue colouration developed. The mixture was flushed with nitrogen and then sodium cyanoborohydride (0.22g) was added. After stirring at -78°C for 10 minutes, a solution of l-[3,5-bistrifluoromethylphenyl)methyloxy-2-amino-2-phenyl ethane in methanol (8ml) was added dropwise and the reaction mixture stirred at 0°C for 3h. The reaction was quenched by addition of acetic acid, and solvent was removed in υacuo. 10% Sodium hydroxide solution was added to the residue and the product extracted into dichloromethane (x 3). The combined organics were washed with brine, dried (MgS0 ₄ ) and concentrated in υacuo. The product was purified by chromatography on silica using 20% → 30% — > 40% ethyl acetate in petrol as eluent. The product was dissolved in diethyl ether and a methanolic solution of hydrogen chloride was added. Solvent was removed in υacuo and the title compound obtained by trituration with diethyl ether. MS (CI ⁺ ) m/z 434 ((M+D+ 100%).

EXAMPLE 7

(±)-l-r(3.5-Bistrifluoromethylphenyl)methyloxyl-2-N- (piperidine-2.6-dione-2-phenyl ethane

A solution of l-[3,5-bistrifluoromethylphenyl)methyloxy-2- amino-2-phenyl ethane (0.28g) in toluene (5ml) was added to a solution of glutaric anhydride (0.088g) in toluene (10ml) and the reaction mixture heated at reflux for 20h. Solvent was removed in υacuo and the crude material purified by chromatography on silica using 15% ethyl acetate in petrol as eluent. The title

compound was recrystallised from ethyl acetate-petrol. MS (CI ⁺ ) m/z 460 ((M+l) ⁺ 80%).