This invention relates to a class of heterocyclic compounds, which are useful as tachykinin receptor antagonists.

The tachykinins are a group of naturally- occurring 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- ys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NHg Neurokinin A:

His-Lys-Thr-Asp-Ser-Phe-Val-Gly- eu-Met-NH2 Neurokinin B: Asρ-Met-His-Asρ-Phe-Phe-Val-Gly-Lβu-Met-NH ₂

Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer\'s disease, multiple sclerosis, attenuation of morphine withdrawal, cardivasσular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitus, inflammatory diseases of the gut including ulcerative colitis and Crohn disease , ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper- reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", CA. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.

Pharmacol. (1993) 3, 23-93- Tachykinin antagonists are also believed to be useful in allergic conditions (Ha elet ______ al Can. J. Pharmacol. Physiol. (1988) ££

1361-7], immunoregulation [Lotz et al Science (1988) 241 1218-21 and -Kin-ball et al, J. Immunol, (1988) (10) 3564-9] , and as anticonvulsants [Garant ≤ al.. Brain Research (1986) 382 372-8]. Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al,., Cancer Research (1992) ___2_, 4554-7],

It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthy ic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and

Reynauld\'ε disease, fibrosing and collagen diseases such as scleroder a 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), co uctivitis, vernal conjunctivitis, contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent application no. 0 394 989) and e esis (European patent application no, 0 533 280) . peptide tachykinin antagonists containing an indolyl or like moiety are disclosed in European patent applications nos. 0 394 989 and 0 482 539,

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

In essence, this invention provides a class of potent non-peptide tachykinin receptor antagonists.

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

( l ) wherein

Q ¹ represents a phenyl group substituted by one or more halo; optionally substituted naphthyl; optionally substituted indolyl; optionally substituted benzthiophenyl; optionally substituted benzofuranyl; optionally substituted benzyl; or optionally substituted fluorenyl; the dotted line represents an optional covalent bond? one of X and Y represents H and the other of X and Y represents hydroxy or Cj-galkoxy, or X and Y together form a group -0 or -NOR ⁵ where R ⁵ is H or Cι- ₆ alkyl;

R ¹ represents H or Cι_§alkyl.

R ² represents co- -R ⁶ where W represents a bond or a saturated or unsaturated hydrocarbon chain of l, 2, 3, 4, 5 or 6 carbon atoms and R ⁶ is an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group;

R ³ represents H, C _] __ ₆ alkyl or c ₂ - ₆ alkenyl; and

R ⁴ represents phenyl optionally substituted by 1, 2, or 3 groups selected from C^-galkyl, C ₂ -6alkenyl, c ₂ ~6alkynyl halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR ^a , SR ^a , SOR ^a , NR ^a R ^b , NR ^a COR ^b , NR ^a C0 ₂ R ^b , Cθ2R ^a or CONR ^a R ^b , where R and R ^b independently represent H, phenyl or trifluoromethyl.

For the avoidance of doubt, when the covalent bond represented by the dotted line is present, the compounds of formula (I) contain an olefinic double bond. AS used herein, the definition of each expression, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups referred to with respect to any of the above formulae may represent straight, branched or cyclic groups or combinations thereof. Thus, for example, suitable alkyl groups include methyl, ethyl, n- or iso-prαpyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl, eyclopentyl 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, especially chloro and fluoro. when W represents a hydrocarbon chain of 2 or more carbon atoms, it may be straight or branched.

Where ¹ represents optionally substituted fluorenyl, the fluorenyl group is linked through the bridgehead carbon atom, that is to say, C-9. Where Q ¹ represents optionally substituted naphthyl, indolyl, benzothiophenyl, benzofuranyl, benzyl or fluorenyl, suitable substituents include Cχ-galkyl, C2-6 ^alken y ¹ / ^c 2-6 ^allc y ⁿ y ¹ ■ halo, cyano, nitro, trifluoromethyl, trimethylsilyl, SR ^α , S0R ^α , S0 ₂ R ^α , OR

NR ^a R ^b , NR ^a COR ^b , NR ^a COOR ^b , COOR ^a or C0NR ^a R ^b , where R and R are as above defined, one or more substituents may be present and each may be located at any available ring position, except, where Q ¹ is optionally substituted indolyl, the nitrogen atom. Where Q ¹ is optionally substituted indolyl, suitable nitrogen substituents include C^-galkyl, optinally substituted phenyl(C ₁ _ alkyl) , COOR ^a or CONR ^a R ^b , wherein R ^a and R ^b are as above defined. Suitable values of the group Q ¹ include dihalophenyl such as 3,4-dichlorophenyl, indolyl such as 3-indolyl, naphthyl such as 2-naphthyl and 3-naphthyl, 9- fluorenyl, benzyl, benzothiophenyl such as 3- benzothiophenyl and benzofuranyl such as 3-benzofuranyl. Preferably ¹ is 3-indolyl, 3-benzothiophenyl or 3,4-dichlorophenyl, more preferably 3-indolyl. Preferably the double bond is absent. Preferably one of X and Y represents C -g lkoxy, such as ethoxy, or X and Y together represent =0. More preferably X and Y together represent =0.

Preferably R ¹ is H.

Suitable values for W include a bond, CH , CH ₂ CH ₂ , CH=CH, CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ CH2CH2. In one subgroup of compounds according to the invention, R ² represents CO(CH ₂ )qR ⁶ , where q is 0, 1, 2 , 3, 4, 5 or 6 and R ⁶ is as previously defined.

The aromatic or non-aromatic azacycle or azabicycle R ⁶ may contain one or more additional heteroatoms selected from N, 0 and S, or groups NR ⁷ , where R ⁷ is H or Cι-6 ^alk yl» ^{and OTa e} unsubstituted or substituted. Suitable substituents include Ci-^al yl, Ci-galkoxy, oxo, SK, =S, halo, trifluoromethyl, NR R ^b ,

NR ^a COR ^b , CONR ^a R , C0 ₂ R ^a and CH ₂ 0R ^a , where R ^a and R ^b are as previously defined.

When R ⁶ represents an aromatic azaσycle or azabicycle, suitable values of R ⁶ include imidassolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridyl, oxadiazolyl, thiadiazolyl, isoxazolyl, iεothiazolyl, benzimidazolyl, benzoxazolyl and indolyl, preferably imidazolyl, such as 2,4- i idazolyl, or pyridyl, more preferably pyridyl such as 4-, 3- or 2-pyridyl.

When R ⁶ represents a non-aromatic azacycle or azabicycle, suitable values of R ⁵ include mσrphαlinyl, piperdinyl, pyrrolidinyl, piperazinyl, methylpiperazinyl, azanorbornanyl, 3,4-pyridinecarboximido, azabicyclo[2.2.2]octanyl and azabicyclo[3.2.2]nonyl, preferably orpholinyl, piperazinyl, methylpiperazinyl, piperidinyl, pyrrolidinyl, 3,4-pyridinecarboximido, quinuclidinyl (azabicyclo[2.2.2] octanyl) or azabicyclo[3.2.2] onyl. Preferably R ⁴ represents substituted phenyl.

Suitable phenyl substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, methyl, ethyl, cyclopropyl, t-butyl, vinyl, methoxy, phenoxy and amino. Suitably R ⁴ represents monosubstituted phenyl, such as 3-substituted phenyl, or, preferably, disubstituted phenyl, such as 3,5- disubstituted phenyl. When R ⁴ is 3-substituted phenyl, a particularly suitable substituent is t-butyl. More preferably, R ⁴ represents phenyl substituted by 1 or 2 groups selected from Cι_4alkyl, halo and trifluoromethyl.

Particularly preferred are compounds wherein R ⁴ represents 3,5-bis(trifluoromethyl)phenyl.

A particular subgroup of compounds according to the invention is represented by compounds of formula (Ia) , and salts and prodrugs thereof:

(io)

wherein X and Y are as defined for formula (I) ; the dotted line represents an optional covalent bond;

Z represents o, S or NR ¹⁴ (where R ¹⁴ is H _r Ci-g l yl, optionally substituted phenyl(C1-4alkyl) , Cθ R ^a or CONR ^a R ^b , where R ^a and R ^b are as previously de ined), preferably s or NH, more preferably NH;

R ¹⁰ is CO-W-R ¹⁶ where R ¹⁶ is i idazolyl, triazolyl, tetrazolyl, oxazolyl, thia2θlyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, benzi idazolyl, benzoxazolyl, indolyl, orpholinyl, piperdinyl, pyrrolidinyl, pyridosuccini ido, piperazinyl, methylpiperazinyl, azanorboranyl, azabicyclo[2.2,2]octanyl or azabicyclo[3.2.2]nonyl, preferably imidazolyl, pyridyl, morpholinyl, methylpiperazinyl, azabicyclo[2.2.2]octanyl or azabicyclo[3.2.2]nonyl and W is as previously defined, preferably a bond or a hydrocarbon chain of 1, 2 or 3 carbon atoms;

R ¹¹ and R ¹² each independently represent H, c^-g lkyl, C _ _$ alkenyl, Cg-galkynyl, halo, cyanc, nitro,

trifluoromethyl, trimethylsilyl, 0R ^a , SR ^a , SOR ^a , KR R°, NR ^a cθR ^b , NR ^a C0 ₂ R ^b , C0 ₂ R ^a or C0NR ^a R ^b , where R ^a and R ^b are as previously defined; each R ¹³ may occupy any available carbon atom of the bicyclic ring system and independently represents C^-galkyl, C2-6al enyl, C ₂ - _$ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR ^a , SR ^a , SOR ^a , NR ^a R , NR ^a COR ^b , NR ^a C0 ₂ R ^b , C0 ₂ R ^a or CONR ^a R ^b , where R and R ^b are as previously defined; and n is o, i, 2 or 3, preferably 0.

Preferred are compounds of formula (Ia) wherein the optional covalent bond is absent.

A further subgroup of compounds according to the invention is represented by compounds of formula (lb) , and salts and prodrugs thereof:

(lb) wherein R ³ , R ¹⁰ , R ¹¹ , R ¹² , X and Y are as previously defined and the dotted line represents an optional covalent bond.

For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their 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, sulphuric acid, oxalic 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 salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Thus, for example, when both R ¹ and R ² are other than hydrogen, the nitrogen atom to which they are attached may be further substituted to give a quaternary ammonium salt. 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 accordingly provides compounds of formula (I) and their pharmaceutically acceptable 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 j-n 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 compounds according to the invention may exist both as enantiomers and as diastereoroers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

The substance P antagonising activity of the compounds described herein was evaluated using the human NKIR assay described in published European patent application no. 0 528 495. The method essentially involves determining the concentration of the test compound required to reduce by 50% the amount of radiolabelled substance P binding to human NKIR, thereby affording an IC50 value for the test compound. The compounds of Examples 1-10, for example, were found to have IC50 values less than lOOnM.

The invention also provides pharmaceutical compositions comprising a compound of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or topical administration including 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 table ing ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalσium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid prefor ulation 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

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 σarboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions

may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are adminsitered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly rom the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. For topical administration, for example as a cream, ointment or lotion, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylaikanols, vegetable oils, poiyalkylene glyσols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxy ethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 2QO, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuriσ salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan onolaurate, triethanolamine, oleate.

polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, onothioglycerol, thiosorbitol , ethylenedia ine tetraacetic acid, and the like.

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; epilepsy; neurodegene ative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer\'s disease and Down\'s syndrome; demyelinating diseases such as MS and A S and other neuropathological disorders such as peripheral neuropathy, including diabetic and chemotherapy-induced neuropathy, and postherpetic and other neuralgias; small cell carcinomas such as small cell lung cancer; respiratory diseases, particularly those associated with excess mucus secretion such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritiε 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 erythe atosis; - 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; emesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, surgery, migraine and variations in intercranial pressure; disorders of bladder function such as bladder detrusor hyper-reflexia? fibrosing and collagen diseases such as scleroder a and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reyhaud\'s disease; and pain or noσiception, 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 and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine, The present invention further provides a compound of formula (I) , or a salt or prodrug thereof, for uβe in therapy.

In the treatment of conditions involving actions of tachykinins released physiologically in

response to noxiouβ or other stimuli, a suitable dosage level is about 0.001 to 50 g/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 daily.

According to a further or alternative aspect, the present invention provides a method of treatment of a human or animal subject suffering from or susceptible to a condition characterised by the presence of an excess of tachykinin which method comprises administering to a human or animal subject in need of such treatment an effective amount of a compound of formula (I) , or a salt or prodrug thereof. The present invention also provides the use of a compound of formula (I) , or a salt or prodrug thereof, for the manufacture of a medicament for the treatment of conditions characterised by the presence of an excess of tachykinins. Compounds of formula (I) may be prepared from intermediates of formula (II) :

(ID wherein Q _# R ³ , R ⁴ , X, V and are as defined for formula (I) , by reaction with a reagent suitable to

— introduce the group R .

Suitable reagents will be readily apparent to those skilled in the art and include, for example, carboxylic acids of formula R*-OH, acyl halides of

formula R ² -Hal, here Hal is halo, such as chloro, bromo or iodo. The reaction is preferably conducted in the presence of a base, such as a tertiary a ine, for example, triethyla ine, conveniently in a suitable organic solvent, such as, for example, dimethyl formamide.

Acids and acyl halides of formulae R ² -0H and R ² -Hal are commercially available or may be prepared by conventional methods, for example, as described in the accompanying examples or in Helv. Chi . Acta. ≤2, 2332 (1974) . intermediates of formula (II) wherein X and Y together represent =0 and the double bond is present may be prepared by reaction of an aldehyde of formula R ⁴ CH0 with a compound of formula (III) :

⁽ Hi ⁾ wherein Q , R and R ³ are as defined for formula (I) and R ²⁰ represents a group PR ^X ₃ or P0(0R ^x ) , wherein R ^x represents phenyl or c^-io lkyl, in the presence of a base.

Suitable bases include alkali metal hydrides, such as, for example, sodium hydride, alkali metal carbonates, such as, for example, potassium carbonate, and strong orgainc bases such as, for example, 1,8- diazabicylo(5.4,0] undec-7-ene in the presence of anhydrous lithium chloride.

The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, or acetonitrile, suitably at ambient temperatur . Compounds of formula (II) wherein one of X and

Y represents H and the other represents hydroxy may be

^* prepared from the corresponding compounds of formula (II) wherein X and Y together represent =0, by reduction.

Suitable reducing agents include, for example, hydride reducing agents such as lithium aluminium hydride and sodium borohydride.

The reaction is conveniently carried out in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, suitably at ambient temperature. Compounds of formula (II) wherein one of X and

Y represents H and the other represents Ci-g lko y may be prepared from the corresponding compounds of formula (II) wherein one of X and Y represents H and the other represents hydroxy, by alkylation. suitable alkylation procedures include treatment of an alcohol of formula (II) with an alkali metal hydride, such as sodium hydride, and a Ci-galkylhalide. suitable halideε include, in particular, bromides and iodides. The reaction is conveniently effected in an anhydrous organic solvent, for example, an ether, e.g. dimethoxyethane, suitably at ambient temperature.

Compounds of formula (II) wherein X and Y together represent =NOR ⁵ may be prepared from the corresponding compounds of formula (II) wherein X and Y together represent =0 by the addition of hydroxylamine, or a derivative thereof. Compounds wherein R ⁵ is other than H may be prepared from the corresponding compounds wherein R ⁵ is H by alkylation, for example, using a diazo

- IB -

compound, such as diazo ethane, or an alkyl halide or sulphate.

Compounds of formula (II) wherein the double bond is absent may be prepared from the corresponding unsaturated compounds of formula (II) by reduction.

Suitable reduction procedures include catalytic hydrogena ion. Suitable hydrogenation catalysts include nobel metals, for example, platinum or palladium, or oxides thereof, which may be supported, for example, on charcoal. A preferred catalyst is Wilkinson\'s catalyst (tris(triphenylphosphine) hodiu (I)chloride) .

The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, an alcohol, e.g. ethanol, or an ester, e.g. ethyl acetate, suitably at ambient temperature.

Compounds of formula (III) may be prepared from compounds of formula (IV)

(IV) wherein Q , R ¹ and R ³ are as defined for formula (I) and R ²¹ represents an alkoxy or a suitably substituted amino group, such as a group NR ^v OR ² , where R ^y and R ^z represent alkyl, in particular a group NCH3(OCH ₃ ) , by reaction with a compound of formula CH ₃ PO(0R*) ₂ , where ^x is an alkyl group, in the presence of a base.

Suitable reaction procedures will be readily apparent to the skilled person and examples thereof are described in the accompanying Examples. suitable bases of use in the reaction include alkyl lithiums, such as butyl lithiums.

Compounds of formula (IV) are commercially ^" available or may be prepared using standard procedures well known to the skilled person in the art. The compounds of formula (IV) are amino acid derivatives. Syntheses of amino acids and derivatives thereof are well documented and are described, for example, in Chemistry and Biochemistry of_ he Amino Acids, ed. G. C. Barrett, Chapman and Hall, 1985.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomexs may 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. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereo eric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and/αr (+)-di-p-toluoyl-l-tartariσ acid followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

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 Chemistrv. ed. J.F.W. McOmie, Plenum Press, 1973; and T. , Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

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

EXAMPL-q \: g.f3 _f g.BiEtrifluorπτnet, yln enyl -l-f3-indo1yl)-2- ((N- morpholinyl) acetamJHnl -3-pf tannne Hydrochloride

(a) N-Methmcv-N-πifithvl2-t-butvloxvcarhonvlamintp3.r3- in olyl) propionamidfi N-δ-BOC-L-tryptophan (lOOg) was dissolved in dimethyl formamido (800ml) and tricthylaminc (lOlg) was added. The reaction was cooled to -30°C and isobutyl chloroformate (42,5ml) was added, maintaining the internal temperature to below -20°C. The reaction was stirred for 15 minutes before adding N,O-dimethyl hydroxylamine hydrochloride (64g) and then diluting the reaction with dichloromothan© (11), maintaining the internal temperature below 0 ^β C. Tho reaction was stirred for 15 minutes, poured into ethyl acetate (31) and washed with 10% citric acid (11), water (3x 11), saturated sodium bicarbonate (11) and water (11). The organic phase was dried (MgSO filtered, and evaporated until crystallisation ensued. The suspension was diluted with petroleum ether, filtered and dried to yield the title compound; mp -. 129-130°C; MR (360MHz, D- DMSO) δ 10.80 UH, β); 7.51 (1H, d, J « 7Hz); 7.33 (1H» d, J - 7Hz); 7.16 (1H, s); 7.08-6.97 (3H, m); 4.62-4,58 (1H, m); 3.72 (3H, s); 3.34

(3H, s); 3.02-2.81 (2H, m); 1.31 (9H, β).

(h) 2-t-Butvlojcvcarbonvlamino-l-(3-indolv1V4- di .ethylphQBP pnQ-a-bυtanQne

Dimethyl methane phosphonate (205g) was dissolved in tetrahydrofuran (800ml), cooled to -70°C; and then treated with n-buty lithium (1.6M in hexane, 900ml), maintaining the internal temperature of the reaction at below -55°C. The reaction was stirred for one hour before adding the product of part (a) (90g). The reaction was stirred at -70°C for 30 minutes before quenching with saturated ammonium chloride. The resulting mixture was extracted with ethyl acetate and the

organic extract was washed with water (5 x 500ml), dried (MgSO and evaporated. The residue was purified on silica (eluting with ethyl acetate) to yield the title compound as an oil; ^l NMR (360MHz, CDClg) 810.84 (IH, s), 7.56 (IH, d, J = 7Hz), 7.33 (IH, d, J ■ 7Hz), 6.98 (IH, t, J =» 7Hz), 4.34-4.31 (IH, m),

3.63 (6H, d, J _* 11Hz), 3.39 (2H, d, J - 22Hz), 3.19-3.11 (IH, m), 2.91-2.84 (IH, m); found: C, 55.73, H, 6.34; N, 6.80;

^C 19 ^H 27 ^N 2°6 ^{P re <} ϊ ^{uires C} > ^{55 6} °f ^H > ^{6 63» N} \' ^{6 82%} - (c) 5-(3.5-Bist.rifluoromethvlphenvl)-2-t-

A solution of the product of part (b) (69.0g) in acβtonitrile (600ml) was stirred with diisopropylcthylaminc (43.3g), and anhydrous lithium chlorido (14.13g) for 30 minutes before adding 3,5-bistrifluoromethylbenzaldehyde (55g) in acetonitrile (200ml), The reaction was stirred for two hours then the solvent was removed and the rosiduo partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid (500ml), water (500ml), saturated sodium bicarbonate (500ml) and water (500ml). The solution was dried (MgSO filtered and evaporated. The residue was purified by column chromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound as a pale yellow solid, mp = 137-138°C; found: C, 69.23; H, 4.79; N, 5.35; C26 ^H 24 ^F 6 ^N 2°3 requires C, 59.32; H, 4.60; N 5.32%. (d) 5-(3-5-Bifitrifluorom hvlnhenvn-2-t- butvloxvcflrhonvlaminn- 1- (3-indolvl)-3-nontanone

The product of part (c) was heated under reflux with tri-n-butyltin hydride (51.12g) in toluene for 20 hours. The reaction was cooled and purified by column chromatography on silica using ethyl acetate potroleum ether (1:4) to yield the title compound as a white solid (37. lg), mp = 138-140°C: found: C,

59.23; H,4.90; N, 5.28; C ₂₆ H ₂₄ F ₆ N ₂ O ₃ requires C, 69.09, H, 4.96; N, 5.30%.

(e) 2-Amiτιo-5-f3,6-bistrifi orom ^g thylp epyl)-l-(g-indQlyl ⁾ -3- pentanone Hydrochloride Tho product of part (d) was treated with ethereal hydrogen chloride for one hour. The precipitated white solid was filtered and dried, mp = 84-86°C; found: C,54.40; H, 4.25; N, 6.10; C ₂₁ H ₁₈ F ₆ N ₂ O. HCl requires C, 54.26; H, 4.12; N, 6.03%.

(f) fi-f3-fi-histrjfluoromethvlnhenvl)-1-(3-indo1v1 -2.((N- mπrp nliny nr_ tn idoV3-panfo one Hvdrochlnririf.

Potassium 2-(N-morpholinyI) acetate (0.2g) and triethylamine (O.lg) wore dissolved in dry dimethylformamide and cooled to -30°C before adding isobutylchloroformate (0.147g). The reaction was stirred for 20 minutes before adding the product of example 1(e). The reaction was stirred for 3 hours, poured into water and then partitioned between ethyl acetate and water. The organic phase was washed with water (100ml), sodium bicarbonate (100ml) and water (100ml). The organic extract was dried (MgSO , filtered and evaporated. The residue was purified by column chromatography on silica using ethyl acetate. The resulting oil was treated with ethereal hydrogen chloride to yield the title compound as a white solid, mp =- 83-86°C; found: C, 63.67; H, 4.89; N, 6.86 C^H^FgNgOg. HCl. 0.5 H ₂ O requires C, 53.96; H, 4.86; N, 6.99%.

EXAMPLE 2: 5-f3.5.Bi _g trif1uomm ₆ thvl henvn-1-(3-indnlv1V2. f(4-Pvridvnacetamido)-3-nenfcftnnne Hydrochloride

4-Pyridylacetic arid (210mg) was suspended in a solution of triethylamine (234mg) in dimethylformamide (4ml) and dichloromβthane (5ml). Carbonyl dii idaϋole (196mg) was added to the suspension and stirred for 0.5 hours before adding

the compound of Example 1(e) (500mg). The reaction was stirred for 12 hours, poured into ethyl acetate and washed with water. The organic layer was dried (MgSO^), evaporated and purified by silica chromatography using dichlorαmothane/methanol (98.2). The oil obtained was treated with ethereal hydrogen chloride to yield the title compound as a solid, mp = 88-90°C; found: C, 55.79; H, 4.40; N, 6.78 C ₂₈ H _{23 6} N ₃ O ₂ . HCl. H ₂ O requires C, 55.87; H, 4.35; N, 6.98%.

EXAMFI/B 3: 5-f3.fi.-Ri _H t.Hf1unrnmR hvlphenvlV2-((4-imidazQlvl> acetamidoVl-O- indolvl)-3-pentønone Hydrochloride

Prepared from tho compound of Example 1(e) in a similar manner to Example 2 using imidazole-4-acetic acid to give the title compound as a white solid, mp = 103-106°C; found: C, 51.95; H, 4.33; N, 9.29; C ₂ 6 ^H 22 ^F 6 ^N 4°2- HCl. 1.5 H ₂ O requires C,

52.05; H, 4.37; N, 9,34%.

EXAMPLE! 4: grf3,5-Pi8trifiuorQmethvlph ^« ?nylVi- ⁽ 3-indolyl)-2- ff - vri v]1aRβtamido 3-PGnta nne Hydrochloride Prepared from the compound of Example 1(e) in a similar manner to Example 2 using 3-pyridylacetic acid to give the title compound as a solid, mp = 90 - 92*C; found: C, 56.48; H, 4.47; N, 7.10; C _2δ H ₂₃ F ₆ N ₃ O ₂ . HCl. 0.5 H _g O requires C, 56.72; H, 4.26; N, 7.09%.

EXAMPLE.5: 5.f3.5^i _H trifluornτnethvlnhenv1 -l-(3-indnlvn-2- ((2-pvridvl) acetamidoVB-pentanone Hvdrochlnrido

Prepared from the compound of Example 1(e) in a similar manner to Example 2 using 2-pyridylacetic acid to give the title compound as a solid, mp = 92 - 94°C; found: C, 56.72; H, 4.35; N,

6.91; C ₂₈ H ₂₃ F ₆ N ₃ O ₂ . HCl. 0.5 H ₂ O requires C, 56.72; H, 4.25 N, 7.09%.

EXAMPLE β_ fi.(3-K.Ωi _w riflιιornmethvlphenv1Vl-r3^ndn1vl).2. ((4-methvl pi erazinvl)anRtamidnV3-nentanone Hvdroπhlnride

Prepared from the compound of Example Ke) in a similar manner to Example 1(f) using potassium 2-(4-methylpiperazinyl) acetate to give the title compound as a white solid, mp ^~ = 120 - 122°C; found: C, 49.35; H, 5.04; N, 8.09; C ₂₈ H ₃₀ F ₆ N ₄ O ₂ . 2 HCl. 2H ₂ O requires C, 49.64; H, 5.36; N, 8.27%.

EXAMPLE 7.: fi-(3.fi-Bififcriflιιnτr>met vlphenvlV1-(3-indΩlv1 2- (qtrimιclidine-4- c»rhnxnmidt_V3-pβntanone Hydrochloride

Quinuclidine-4-carboxylic acid (I-Ielv, Chim Acta. fil, 2332, ( 1974) ) ( llOmg) was heated with thionyl chloride (2ml) for 2 hours. The solvent was rcmovod and tho residue was azeotroped with toluono (3 x 10ml) and then dissolved in dichloromethane (10ml). The compound of Example Ke) (325ml) was dissolved in a mixture of dichloromethane (10ml) and triethylamine (200mg) and added to the above solution. The reaction was stirred for 1 hour, poured into ethyl acetate and washed with potassium carbonate solution. The organic solution was dried, evaporated and purified by alumina chromatography using dichloromethane methanol (99:1). The oil obtained was treated with ethereal hydrogen chloride to yield the title compound as a white solid mp = 183 - 184°C; found: C, 55.97; H, 5.25; N, 6.85;

^C 29 ^H 29 ^F 6 ^N 3°2- ^HC1 \' ^H 2° ^re( * ^{uireB C} \' ^{56 18« H} \' ⁵ - ²⁰ > ^N > ⁶ - ^8% -

EXAMPLE fi_ 5;(3,5-Bistriπuorvm$thylphenyl)-l-(3-indQlyl)-2- (3- (piperidin-1-vl) pronionamido)-3-Dontanone

Prepared from the compound of Example Ke) in a similar manner to Example 7 using 1-piporidinopropionic acid and obtained as a white solid, mp 141°C; found: C, 61.26; H, 5.46; N, 7.35. C ₂₉ H ₃₁ N ₃ O ₂ F ₆ requires C: 61.37; H, 6.50; N, 7.40.

EXAMPLE ft: ff-fff,frBiB riflwnrffπifit;hγ1phfflγl)-l-fa-indo1vl>2- (4-(3-(3 azahicvc1or3.2.21nnnvl))butvramidoV3-pentanone

HYdrochtoride ft) EthvM-f3-(3-azahiπvclor3.2.21nonvl))bαtvrate To a solution of 3 azabicyclo[3.2.2]nonano (0.5g) in tetrahydrofuran (5ml) was added triothylaminc (0.61ml) followed by ethyl 4-bromobutyrate (0.63ml). The solution was stirred for 16 hours under reflux, cooled and concentrated in vacuQ. The residue was partitioned botwoon othyl acetate and water and the organic solution soparated, dried (Na ₂ SO , ) and concentrated. The residue was purified by chromatography on silica gel eluting with diethyl ether-potrolcum other (1:9) to give the title compound. b) ■5-(3.5-BiBtrifluoromcthylphonyl)-l-(3-indolylV2-(4-(3-(3. azabityclQ rs.2.21 nonyfl) frμtyramidp) - 3 - pentanons Hydrochloride To a solution of the product of part a) (0.67g) in water (3ml) and ethanol (1.5ml) was added 2N sodium hydroxide solution (1.4ml). The solution was heated under reflux for 2 hours then cooled and adjusted to pH with dilute hydrochloric acid. The solution was freeze dried and the resulting solid added to dimethylformamide (15ml) containing l-(3-dimethylaιninopropyl)-3- ethylcaihodiimide hydrochloride (0.54g). After stirring for 30 minutes at 0°C, a solution of 6- (3, 5- bistrifluoiOmethylphcnyl) -l-(3- indolyl) -2-amino-3- pentanone hydrochloride and triethylamine (0.3ml) in dimethylfbrmamide (5ml) was added and stirred for 16 hours at 25°C.

Ethyl acetate was added and the solution washed with water (3x),

dried (NaoSO and concentrated. The residue was purified by chromatography on βilica gel eluting with methanol- dichloromcthano (1:19) then treated with ethereal hydrogen chlorido to give tho title compound, mp 101-104°C; found: C, 66.90; H, 6.95; N, 6.67, CggHgγFρNgO^ HCl. 2H ₂ O requires C,

57.09; H, 6.09; N, 6,05.

EXAMPLE 10: fi-(3,5-Big ritl oro e yl hepyl)-l-(3-b9P^fbl thienvl)-2- ((4-pvridvl) acetamidoV3-nentanone a) 3-(3-Benzofb1thienvI)-2-t-butvloxvcarbonvlamino propionic acid

2-Anώn_>3- (3-bcnzo[b] Ihiicnyl) propionic arid Qnt . Peptide Ptotein Bfi&,(1987), 2S, 118) (22.9g) and sodium carbonate (27.6g) were added to a mixture of water (350ml) and 1,4-dioxane (160ml). Di-t-butyldicarbonate (34. lg) was added to the mixture and the reaction was stirred for 16 hours and washed with ether (500ml). The reaction mixture was acidified to pH3 with solid citric acid and extracted with ethyl acetate to yield the title compound (31.5g). b) Methvl 3 - (3- benzo Tbl thicnvl) - 2-t - butvloxv carbonvl amino propionate

The product of Example 9(a) (31.5g) and Cesium carbonate (lδ.93g) were dissolved in mcthanol and the solvent was removed by evaporation. The residue was dissolved in dimethylformamide and iodomethane (27.8g) was added. The reaction was stirred for 16 hours then the solvent was removed and the residue partitioned between ethyl acetate and water. The organic extract was washed with sodium bicarbonate solution and water, dried (MgSO , and evaporated, The residue was purified by column cliromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound (27.3g),

c) fi-(3.5-Biatriflυoromethylphenyl)-l-(3-ben2θfb1thienyl)\' 2-((4-p t l)acetømτd )-3- gn a 9 e

Prepared by the methods of Examples Kb)-l(e) and 2 starting with the compound of Example 10(b) instead of the compound of Example 1(a). Mp 184-187°C; found: C, 56.06; H,

4.03; N, 4.77. C ₂₈ H ₂₂ F ₆ N ₂ O ₂ S. HCl requires O, 55.96; H, 3.86; N, 4.66.

EXAMPLE 11 : 5.f3.5-Bi _S trifluoromothvlphonvl)-l-(3.4- dichlorophenvl)-2- ((4-pvririvl . acetamido)-3-pentanone

Prepared by the method of Example 10 starting with

3,4-dichlorophenylalanine. Mp 142-144°C; found: C, 49.96; H,

3.63; N, 4.36. C ₂₆ H ₂₀ C1 ₂ F ₆ N ₂ O ₂ . HCl. 0.5 H ₂ O requires C,

50.14; H, 3.66; N, 4.50.

EXAMP E 18; g-(8^Biff ηfl _tt Qromftthγ1phfflγ1)-1-(fl.4- dichlorophβnvl)-2- (αιιimιriid β~4-carboxamido 3-pentanone

Hydrochloride.

Prepared by the methods of Examples 7 and 14. Mp 50-530C; found: C, 49.89; H, 4.53; N, 4.30.

^C 27 ^H 26 ^C1 2 ^F 6 ^N 2°2" ^HCl " ^H 2° ^rec l ^{uires c» 49} - ⁹ °J ^H» " ^50\' » N, 4.37.

EXAMPLE 13: 5-(3.5-Bi _S trifluoromcthylphcnyl)-l-(3-indolylV2. ((4-pyridyl)acetaπύdc)- p ^χ iminppentane,

The compound of Example 2 (l.Og) in methanol (20ml) was treated with hydroxylamine hydrochloride (0.5g) and sodium acetate (1.5g) for 16 hours. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate solution was separated, dried and concentrated and the residue crystallised from ethyl

acetate/petroloum other to give the title compound, mp 196-1980C. Found: C, 59.87; H, 4.39; N, 9.93. C ₂₈ H ₂₄ FgN ₄ O ₂ requires C, 59.79; H, 4.30; N, 9.96.

EXAMPLE 14: 5.f3 _r 5.Ηi triflιιnromethvlphenvl).l-(3.4-.

Hit.hlnmph_»nvn-.2-4-(3-(3-ngah_r.vc1or3.2.21nnτιvnib� �ιt_vraτrιidn -3- pentanone Hvrirnchlori o

Prepared by the methods of Examples 9 and 14. Mp 90-930C. Found: C, 51.58; H, 5.42; N, 3.83. C ₃₁ H ₃₄ Cl ₂ FgN ₂ O ₂ . HCl. 2H ₂ 0 requires C, 51.43; H, 5.43;

N, 3.87.

EXAMPLE Iff; 6-(3.5-Bistriflupromet,hylphenylH-(3- indolvlV2-((4- pvridvl\'.acetamido)-3-pentanol A solution of the compound of Example 2 (360mg) in ethanol (10ml) was treated with sodium borohydride (lOOmg) for 1 hour. The solution was concentrated jη yflcuo and the residue partitioned between ethyl acetate and ammonium chloride solution. The organic solution was dried and evaporated to give a white solid. Crystallisation from ethyl acetate-diethyl ether gave the title compound as a single diastereomer, mp 213-214 ^β C; found: C, 60.97; H, 4.58; N, 7.47. C ₂ gH ₂₅ F ₆ Ng0 ₂ requires C, 61.20; H, 4.59; N, 7.65.

Further crystallisation of the mother liquors from above gave the title compound as a mixture of diastereo ers.

EXAMPLE lβ: 5.(3.5-Bistrifluoromothvlphenvl)-l-(3-indolvI)-2- (4-(l-pyrrolidinyl)butyramido -3-pentanone

The title compound was prepared from pyrrolidine-1- butyric acid and the compound of Example lo) using l-(3- dimethylaminopropyl)-3-cthylcarbodiimido hydrochloride as

coupling agent by the method of Example 9. Mp 99-100°C; found: C, 61.70; H, 5.48; N, 7.36. C ₂₉ H _aι F ₆ N ₃ O. _J requires C, 61.37; H, 5.51; N, 7.40.

EXAMPLE 17_ fi.ffl.fi-Bi _a trifluorom _Q thvlphenvl)-l-(3-indolvl)-2- f4-(4-morphQli^^b^tyramido)-3-ρentanone Hydrochloride

Prepared by the method of Example 16 using 4- morpholine butyric acid. Mp 64-65°C; found: C, 53.84; H, 5.44; N, 6.32. C ₂₉ H ₈₁ F _β N _a O ₃ . HC1.1.5H ₂ O requires C, 53.83; H, 5.46; N, 6.49.

EXAMPLE 1 ft: fi.f3.B-Bi^rifluoromethvIphenvl .(3- dolv1)-2. f3-(a-pvririvnacrylamido)-3-pentanone

Prepared by the method of Example 16 using 3*(3- pyridyDacrylic add. Mp 138-139°C; found: C, 62.66; H, 4.01; N,

7.54. Ca^F _β NA requires C, 62.25; H, 4.14; N, 7.51.

EXAMPLE 19: S.f3.6.Biκ-_rifluoromet.hvlphenvl)-l-(3- dolvl)-2-

(3-(3-pyridyl)prQpiopam^do)-3-pentanone A solution of 3-pyridylacrylic acid (900mg) in ethanol

(30ml) was shaken under hydrogen gas at 30 psi for 2.5 hours ovor 10% Pd-C (lOOmg). The solution was filtered and concentrated under reduced pressure to give a colourless solid which was dried under high vacuum. The resulting solid with the compound of Example le), by the method of Example 7, gave the title compound, mp 123-124°C; found: C, 62.11; H, 4.16; N, 7.25. CagH _jj gFeN _jj O _j requires C, 62.03; H, 4.49; N, 7.48.

EXAMPLE 20; fi-(a.fi-BiBt,rifluQrym ^β th ^γ iphmγlM- ⁽ a-mdglγ1V2- (3-(4-pyridvnflffrv1amidn .-pentanone Hvdronhloridf. a) 4-pvridylacryitø ari

A mixture of potassium carbonate (22g), triethylphosphonoacetate (22.6ml) and 4-pyridylcarboxaldehydo (llg) in tetrahydrofuran ( 10ml) was heating under reflux for 3 hours under an atmosphere of argon. The reaction was cooled, diluted with ethyl acetate, washed with water, dried (K^COg) and concentrated in vacuo. The residue was diluted with - petroleum ether and the resulting solid filtered and dried in vacuo. A solution containing a portion of the foregoing solid (2. ig) in tetrahydrofuran (15ml) and 4N aqueous sodium hydroxide (20ml) was stirred for 16 hours. Ethyl acetate (30ml) was added followed by acetic acid until tho aqueous solution reached pH 7. The ethyl acetate solution was separated, dried (MgSO ₄ ) concentrated and the residue crystallised from diethyl ether-petroleum ether to give the title compound. b) B-(3.B-BiHtrifl«ornπnRt.hylphflnvl l-(3-indolvlV2-r3>

(4-pyridyl)acryla idQ)-3-pgntanono HvdrQchlQridfi

Prepared from 4-pyridylacrylic arid by the method of

Example 16. Mp 122-126°C; found C, 58.08; H, 3.92; N, 6.79 _,

Cs _B H^FeN _g O _j s. HCl requires C, 58.45; H, 4.06; N, 7.05.

EXAMPLE 21: 5-f3, ffistrifluoromethylphenyl)-l-(3-mdolyl)-2-

(3-.4vpvridvl)propionamido)-3-pantanono

4-Pyridylacrylic acid was hydrogenated by tho method of

Example 19 and reacted with the compound of Example le) by the method of Example 16 to give tho title compound, mp 108°C; found: C, 61.89; H, 4.31; N, 7.28. C, 62.03;

H, 4.49; N, 7.48.

EXAMPLE 22: 6-f3.6-Bis rifluoromethvlnhenvlVl-(3-indolviy.2- f3-(4-piperidinvl)propionamido)-3-Dcntønonfi Hvdroπhlnrififl a) 3-(4-f 1-iButvloxvparhonvl .iϋeridinvl) propionic acid

2 -

To a solution of ethyl isonipecotate (17. Ig) in dichloromethane (60ml) at 4°C was added di- ^fc butyldicarbonate (24g) with stirring, After 10 minutes the solvent was removed under reduced pressure and the residue dried under high vacuum, then dissolved in dichloromethane (lOOml). To this solution, under an atmosphere of argon, at -78 ^C \'C , was added diisobutyl aluminum hydride (110ml of a 1.0M solution in toluene). After stirring for 1 hour, 2N hydrochloric acid (55ml) was addod dropwise and the mixture allowed to warm to 20°C, then diluted with ethyl acetate. The othyl acetate solution was separated off, dried ( _j CO.,) and concentrated. Tho resulting rosidue was reacted with triethylphosphonoacetate and then sodium hydroxide by the method of Example 20a), then hydrogenated by the method of Example 19 to give the title compound which was crystallised from hot petroleum ether h ^β O-80°C). b) 5-(3.5-BistπflttQrQmcthyiphgnyl)-l-(3-indolyl?-2-(3-(l:

Tho compound of part a) (476mg) in dry benzene (5ml) was treated with oxalyϊ chloride (0.16ml) until evolution of gas ceased. Tho solution was concentrated in vacuo and dissolved in dichloromethane (10ml) with the compound of Example le) (740mg) and triethylamine (0.5Cml). After stirring 1 hour aqueous sodium bicarbonate was added and the mixture extracted with dichlororaothane which was then dried (Na ₂ S0 ₄ ) and concentrated. The residue was purified by chromatography on silica gel (eiuant ethyl acetate-petroleum ether 2;3) then treated with ethereal hydrogen chloride for 16 hours, After removal of the solvent undor reduced pressure, Irituration with diisopropyl ether gave the title compound, rap 124-126 ^C C; found:

- 3,

C, 57.31; H, 5.55; N, 6.53. C ₂₉ H _sl F ₆ N ₃ O ₂ . HCl requires C, 57.66; H, 5.34; N, 6.96.

EXAMPLE 23: 5-f3.5-Bistrifluoromethvl _D henvl)-l.(3-mdolvl)-2- (4-ρiperidingcarbQxamidQ)-3-pentanon$ HvdrvςhIoride

The compound of Example le) was reacted with N- ^fc butoxycarbonylnipecotic acid by the method of Example 2. The resulting material was treated with etheral hydrogen chloride for 16 hours then concentrated and crystallised from methanol- ethyl acetate to give the title compound, mp 209-213°C; found: C, 55.82; H, 4.76; N, 6.89. C ₂₇ H ₂₇ F _$ N ₃ O ₂ . HC1.0.25H ₂ O requires C, 55.87; H, 4.95; N, 7.24.

EXAMPLE 24: fi-(. 5-Bi__trifl orom ₆ thvlphenvl l-r3- rfolv1>-2- {3-f - iperflginyl)ttrfii fi)- - ^ntanQnft

The compound of Example 1(c) (400mg) in tetrahydrofuran (10ml) was treated with triethylamine (0.12ml) and 4- nitrophenylchloroformate (174mg) for 1 hour. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic solution was dried (N 2SO4) and concentrated to give a solid which was dissolved in dichloromethane (15ml). tButyl-l-piperarine carboxylate (156mg) was added and the solution stirred under an atmosphere of nitrogen overnighL The reaction was diluted with dichloromethane, washed with water, di-ied (Na2SO ) and concentrated to give an oil which was purified by chromatography on silica gel eluting with ethyl acetate- petroleum, ether (1:1). The resulting product was treated with ethereal hydrogen chloride for 16 hours then the solution was evaporated and the residue crystallised from diethyl ether- petroleum ethor to give tho title compound, mp 120-122°C;

found: C, 51.86; H, 4.97; N _v 8.85. C2GH2GF6 4O2.HCI.I.5H2O requires C, 51.70; H, 5.00; N, 9.27.

EXAMPLE 25. 5-(3-5-Bifitrifluoromet v]phcnyl)-l-(3-indolyl).2 (4-pvridinficarboxamido 3-p*ntan no,

Tho title compound was prepared using pyridine-4-carboxylic acid by the method of Example 9(b). Mpt 72-74°C; found: C,

59.63; H, 4.06; N, 7.62. C27H21 6 3O2 O.5H2O requires C,

59.78; H, 4.09; N, 7.75.

EXAMPLE 26: 5-(3-S-Bist.r_f1ιιoromet,hvtphenvI -(3-indolyl)-2-

(2-(N-(3.4-pvridmedicarboximido))acetamido)-3-nentannne The title compound was prepared using N-carboxymethyl-

3,4-pyridinedicarboxiτnide by the method of Example 9(b). Mpt 144-145°C; found: C, 58.64; H, 3.57; N, 8.69. C30H22F6N4O4 requires C, 58.45; H, 3.60; N, 9.09.

The following examples illustrate pharmaceutical compositions according to the invention.

EXAMPLE 27A Tablets containing i-25mct of compound

Compound of formula (I) - Microcrystalline cellulose Modified food corn starch Lactose Magnesium stearate

EXAMPLE 27g Tablets containing 26-lOOrocr of compound mou t

Compound of formula (I) Microcrystalline cellulose

Modified food corn starch

Lactose

Magnesium Stearate

The compound of formula (I), cellulose, lactose and a portion of the corn starch are mixed and granulated with

10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing l.O g, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet.

EXAMPLE 28 Parenteral injection

Amount mo Compound of formula (I) l to lOOmg Citric Acid Monohydrate o.75mg Sodium Phosphate 4.5mg

Sodium Chloride 9mg

Water for Injections to 1ml

Tho sodium phosphate, citric acid raonohydrate and sodium chloride are dissolved in a portion of the water. The compound of formula (I) is dissolved or suspended in the solution and made up to volume.

EXAMPLE 2 Topical formulation

Amount mg Compound of formula (I) 1-lOg Emulsifying Wax 30g Liquid paraffin 20g

White Soft Paraffin to lOOg

The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of formula (I) is added and stirring continued until dispersed. The mixture, is then cooled until solid.