Background to the Invention Alzheimer's disease (AD) is the most common form of dementia among older people, and affects parts of the brain that control thought, memory and language. Susceptibility to Alzheimer's disease increases with age, but the disease is not a normal part of the ageing process.

Alzheimer's disease is associated with regions of accumulated proteins in the brain. These dense regions, termed"amyloid plaques"and "neurofibrilliary tangles", contain ß-amyloid precursor protein (ß-APP). ß-APP is degraded by ß-amyloid converting enzyme (BACE, also known as secretase) to produce (3-amyloid peptide Ap 40/42, which accumulates in the plaques. Research has shown that the activity of BACE is an early step in the pathogenesis pathway common to all familial and sporadic forms of Alzheimer's disease; thus inhibitors of BACE may have therapeutic utility in the treatment of this disease.

Summary of the Invention A first aspect of the invention is a compound of formula (I) wherein RI is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, heteropolycyclyl or polycyclyl, any of which is optionally substituted with alkyl, heteroaryl, aryl or-O-aryl ;

RI is alkyl, alkenyl or aryl, any of which is optionally substituted with hydroxy, halogen, aryl, heteroaryl, cycloalkyl, cycloalkenyl,-C (O) NH-aryl, heterocycloalkyl, heterocycloalkenyl, heteropolycyclyl or polycyclyl ; R3 is hydrogen or aryl ; R4 is alkyl, alkenyl, alkoxy, alkylthio or aryl, any of which is optionally substituted with hydroxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, thioalkyl, heterocycloalkyl, heterocycloalkenyl, heteropolycyclyl or polycyclyl ; R5 is hydrogen or an alkyl or alkenyl group optionally substituted with hydroxy, aryl,-C (O) 0-alkyl or-C (O) NH-alkyl ; or R4-C-R5 taken together form cycloalkyl, cycloalkenyl or polycyclyl, any of which is optionally substituted with alkyl or hydroxyalkyl ; R6 is hydrogen, alkyl,-alkyl-aryl or-alkyl-heteroaryl ; or a pharmaceutically-acceptable salt thereof.

Compounds of the invention are inhibitors of BACE and as a consequence may have utility in the treatment or prevention of diseases or conditions in which BACE is implicated.

In particular, the compounds may be useful for the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (AP), for example Alzheimer's disease.

Accordingly, another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (AP).

Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutical acceptable carrier or diluent.

Description of the Invention With regard to formula (1), R'is preferably-alkyl-aryl, alkyl,-heteroaryl- aryl,-aryl-aryl, aryl,-heteroaryl-heteroaryl,-aryl-0-aryl or heteropolycyclyl. R2 is preferably-alkyl-aryl,-hydroxyalkyl-aryl,-alkyl-heteroaryl, trifluoroalkyl, alkyl, hydroxyalkyl, aryl or-alkyl-C (O) NH-aryl. R3 is preferably hydrogen or phenyl.

R4 is preferably aryl,-alkoxy-aryl,-hydroxyalkyl-aryl, hydroxyalkyl,-alkylthio-alkyl

or-alkyl-aryl ; RI is preferably hydrogen, hydroxyalkyl,-C (O) NH-alkyl, alkyl or aryl ; or R4-C-R5 taken together form polycyclyl or-cycloalkyl-hydroxyalkyl R6 is preferably hydrogen or methyl.

The term"alkyl"as used herein refers to a straight or branched chain alkyl moiety having from one to ten carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like."ci_,, alkyl" has the same meaning.

The term"alkenyl"as used herein refers to a straight or branched chain alkyl moiety having two to ten carbon atoms and having in addition at least one double bond, of either E or Z stereochemistry where applicable. This term includes for example, vinyl, 1-propenyl, 1-and 2-butenyl, 2-methyl-2-propenyl and the like."C2_o alkenyl"has the same meaning.

The term"alkoxy"as used herein refers to a straight or branched chain alkoxy group containing one to ten carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like."C1 10 alkoxy"has the same meaning.

The term"aryl"as used herein refers to optionally substituted aromatic ring systems comprising six to fourteen ring atoms, and optionally substituted polycyclic ring systems having two or more cyclic rings at least one of which is aromatic. This term includes for example, phenyl and naphthalenyl. The group may be optionally substituted, the substituents being the same or different in each occurrence and selected from halogen, alkyl, alkoxy, haloalkyl, trifluoromethyl and the like.

The term"cycloalkyl"as used herein refers to a saturated alicyclic moiety having from three to six carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term"cycloalkenyl"as used herein refers to an alicyclic moiety having from three to six carbon atoms and having in addition at least one double bond, and includes for example cyclopentenyl, cyclohexenyl and the like.

The term"heterocycloalkyl"as used herein refers to a saturated heterocyclic moiety having from four to seven carbon atoms and one or more

heteroatoms selected from the group N, O, S and P, and includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like.

The term"polycyclyl"as used herein refers to two or more optionally substituted rings in which two or more carbons are common to two adjoining rings, and includes for example fused rings such as fluorene or bridged rings such as bicyclo [2.2. 1] heptane.

The term"heteroaryl"as used herein refers to aromatic ring systems of five to fifteen atoms or which at least one atom is selected from 0, N and S and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.

The group may be optionally substituted, the substituents being the same or different in each occurrence and selected from halogen, alkyl, alkoxy, haloalkyl, trifluoromethyl and the like.

The term"halogen"as used herein refers to F, Cl, Br or 1.

Preferred compounds of the invention include : 3-benzo [b] thiophen-3-yl-N- [ (1 S, 2R)-2-hydroxy-indan-1-yl]-2 (R) - phenylmethanesulphonylamino-propionamide ; 3-benzo [b] thiophen-3-yl-N- (1 (S)-naphthyl-ethyl)-2 (R) - phenylmethanesulphonylamino-propionamide ; 3-benzo[b]thiophen-3-yl-N-[(1 S, 2R)-2-hydroxy-1, 2-diphenyl-ethyl]-2 (R) - phenylmethanesulphonylamino-propionamide ; 3-benzo [b] thiophen-3-yl-2 (R)-phenylmethane-sulphonylamino-N- (1, 3,3- trimethyl-bicyclo [2.2. 1] hept-2-yl)-propionamide ; N-benzhydryl-3- (3, 5-difluoro-phenyl)-2-phenylmethanesulphonylamino- propionamide; 3-(3, 5-difluoro-phenyl)-N-[(1 S, 2R)-2-hydroxy-1, 2-diphenyl-ethyl]-2- phenylmethanesulphonylamino-propionamide ; N-tert-butyl-2 (S)- (3-cyclohexyl-2 (S)-phenylmethane-sulphonylamino- propionylamino)-3-methyl-butyramide ; 2-phenylmethanesufphonylamino-decanoic acid [ (1 S, 2R)-2-hydroxy- indan-1-yl]-amide ; 2-phenylmethanesulphonylamino-decanoic acid [1 (S)-hydroxymethyl-2- (1 H-indol-3-yl)-ethyl]-amide ;

2-phenylmethanesulphonylamino-decanoic acid benzhydryl-amide ; 2-phenylmethanesulphonylamino-decanoic acid [1 (S)-naphthyl-ethyl]- amide; 2-phenylmethanesulphonylamino-decanoic acid [ (1 S, 2R) -2-hydroxy-1, 2- diphenyl-ethyl]-amide ; 2-phenylmethanesulphonylamino-decanoic acid [ (1 S, 2R)-2-benzyloxy-1- hydroxymethyl-propyl]-amide ; 2-phenylmethanesulphonylamino-decanoicacid (1 (S)-tert-butylcarbamoyl- 2-methyl-propyl)-amide ; 2-phenylmethanesulphonylamino-decanoicacid (trans-2-hydroxymethyl- cyclohexyl)-amide ; 2-(butane-1-sulphonylamino)-decanoic acid benzhydryl-amide ; 2-(butane-1-sulphonylamino)-decanoic acid [(1S, 2R) -2-hydroxy-1,2- diphenyl-ethyl]-amide ; 2- (butane-1-sulphonylamino)-decanoic acid (1,3, 3-trimethyl- bicyclo [2.2. 1] hept-2-yl)-amide ; N- [(1 S, 2R)-2-hydroxy-1, 2-diphenyl-ethyl)-2 (S)- phenylmethanesulphonylamino-3-m-tolyl-propionamide ; 2 (S)-phenylmethanesulphonylamino-3-m-tolyl-N-(1, 3, 3-trimethyl- bicyclo [2.2. 1] hept-2-yl)-propionamide ; 6,6, 6-trifluoro-2-phenylmethanesulphonylamino-hexanoic acid [1 (S)- naphthyl-ethyl]-amide ; 2-(butane-1-sulphonylamino)-6, 6, 6-trifluoro-hexanoic acid [1 (S)-naphthyl- ethyl]-amide ; 6,6, 6-trifluoro-2-phenylmethanesulphonylamino-hexanoic acid [(1S, 2R) -2- hydroxy-1, 2-diphenyl-ethyl]-amide ; N-benzhydryl-4-phenyl-2 (S)-phenylmethane-sulphonylamino-butyramide ; N-benzhydryl-2 (S)- (butane-1-sulphonylamino)-4-phenyl-butyramide ; 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 5- [ (4-methoxy- naphthalen-2-yl)-amide] 1- [ (4-phenyl-butyl)-amide] ; 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 5- [ (4-methoxy- naphthalen-2-yl)-amide] 1-[(1 (S)-methyl-3-phenyl-propyl)-amide] ;

N-benzhydryl-2- (biphenyl-4-sulphonylamino)-3- (3, 5-difluoro-phenyl)- propionamide; N-benzhydryl-3-benzo[b]thiophen-3-yl-2(R)-(4-methoxy- benzenesulphonylamino)-propionamide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- [5- (2-methyl-thiazol-4-yl)- thiophene-2-sulphonylamino]-propionamide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R) - phenylmethanesulphonylamino-propionamide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)-(2-naphthalen-1-yl- ethanesulphonylamino)-propionamide ; 6,6, 6-trifluoro-2- (4-phenoxy-benzenesulphonylamino)-hexanoic acid benzhydryl-amide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (naphthalene-2- sulphonylamino)-propionamide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2(R)-(naphthalene-1- sulphonylamino)-propionamide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (2, 3-dihydro-benzofuran-5- sulphonylamino)-propionamide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (3-methoxy- benzenesulphonylamino)-propionamide ; N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (4-phenoxy- benzenesulphonylamino)-propionamide ; 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 1- [ (2-hydroxy- 1 (S), 2 (R)-diphenyl-ethyl)-amide] 5- [ (4-methoxy-naphthalen-2-yl)-amide] ; 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 5- [ (4-methoxy- naphthalen-2-yl)-amide] 1- [ (1 (S)-naphthalen-1-yl-ethyl)-amide] ; 3- (4-methoxy-phenyl)-2 (S)- (methyl-phenylmethanesulphonyl-amino)-N- (1 (S)-naphthalen-1-yl-ethyl)-propionamide ; 3- (4-hydroxy-phenyl)-2 (S)- (methyl-phenylmethanesulphonyl-amino)-N- (1 (S)-naphthalen-1-yl-ethyl)-propionamide ; and N-benzhydryl-3-(4-methoxy-pehnyl)-2(S)-(methyl- phenylmethanesulphonyl-amino)-propionamide.

Compounds of the invention may be chirai. They may be in the form of a single enantiomer or diastereomer, or a racemate.

The compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base. Alternatively, the enantiomers of the compounds may be separated by HPLC using a chiral column.

A compound of the invention may be in a protected amino, protected hydroxy or protected carboxy form. The terms"protected amino","protected hydroxy"and"protected carboxy"as used herein refer to amino, hydroxy and carboxy groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group.

A carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or ter-butyl ester. A hydroxy group can be protected by an alkyl or like group.

Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention.

Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2- (4-chlorophenoxy)-2- methylpropionic acid, 1, 2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2- (4-hydroxybenzoyl) benzoic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl

sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ( (4-aminophenyl) phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid and the like.

Salts may also be formed with inorganic bases. Such inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, potassium, sodium, zinc and the like. Organic base salts include, for example, salts of N, N'-dibenzylethylenediamine, choline (as a counterion), diethanolamine, ethanolamine, ethylenediamine, N, N'- bis (dehydroabietyl) ethylenediamine, N-methylglucamine, procaine, tris (hydroxymethyl) aminoethane ("TRIS") and the like.

It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid or base in a conventional manner.

A compound of the invention may be prepared by any suitable method known in the art and/or by the following processes: Scheme 1 H R a N H Rs HN75 CO2H R1SO2a, 1, N CO2H R5 > R1/ , a R"r F R3 R2 R3 pDIV H

Coupling agent = HBTU or D) HOBT Scheme 2 R,'N H2 R6 0 I. Ha/dioxane 0 1 coupling agent NR5 R SQ N R DMF R3 H 2. RSOZCUDIEA/DMF R2 R H Coupling agent = HBTU or EDC/HOBT Scheme 3 _ I N2 H2N C02H H2N C02Me R'S02CI f H C02Me 2 R2R3 R R DIEA or NEt3/DMF R2R3 R6 Rs RtHal NR LiOH, RISON C02Me 30 R'SO-N C02H s-Rz R3 THFIMeOH/H20 R2 R3 (emitted when R-H) EDC, NEM orDIEA,, R6 O 14 HOBS' RNH2 R SO2 XH R5 R R R5

in which DMF N, N-Dimethylformamide ; D = Diisopropylcarbodiimide ; DIEA = N, N-Diisopropylethylamine ; EDC = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ; HBTU = 2-(1H-Benzotriazole-1-yl)-1,1, 3, 3-tetramethyluronium hexafluorophosphate ; HOBT = N-Hydroxybenzotriazole ; THF = Tetrahydrofuran

It will be appreciated that the processes detailed above are solely for the purposes of illustrating the invention and should not be construed as limiting.

A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used.

Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.

The activity and selectivity of the compounds may be determined by any suitable assay known in the art.

The compounds of the invention may be used in the treatment of numerous ailments, conditions and diseases including, but not limited thereto, Alzheimer's disease.

In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Oral administration is preferred. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutical acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.

Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight,

general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment.

Compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutical elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutical acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone ; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl

pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylen oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables.

The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compositions for topical administration may also be suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutical acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.

The following Examples illustrate the invention.

Unless stated otherwise, samples were purified with a Waters mass- directed purification system utilising a Waters 600 LC pump, Waters Xterra C18 column (5 um 19 mm x 50 mm) and Micromass ZQ mass spectrometer, operating in +ve ion electrospray ionisation mode. Mobile phases A (0. 1% formic acid in water) and B (0. 1% formic acid in acetonitrile) were used in a gradient; 5% B to 100% B over 7 minutes, held for 1 minute, at a flow rate of 20 ml/minute.

Analytical hplc was carried out with a Waters 600 LC pump and Supelco Discovery C18 column (5, um, 50 mm x 4.6 mm). Mobile phases A (0.1 % formic acid in water) and B (0.1 % formic acid in acetonitrile) were used in a gradient of 5% B rising to 98% B after 5 minutes, held for 4 minutes at a flow rate of 2 ml/minute. PDA detection was by a Waters 996, range 210-400 nm UV and ELS detection with a Polymer Laboratories PL-ELS 1000 (Nitrogen flow rate 1.3 I/minute. Nebulisertemp. 80°C, Evap. temp. 110°C). The Mass spectrometer was a Micromass ZQ operating in electrospray ionisation mode.

Intermediate 1 : (R) -3-Benzo [b] thiophen-3-yl-2-phenylmethane-sulphonylamino- propionic acid alpha-Toluene sulphonyl chloride (589 mg, 3.08 mmol) was added to a stirred solution of beta- (3-benzothienyl)-D-alanine (505 mg, 2.28 mmol) in 3M sodium hydroxide (2.28 ml). The mixture was stirred at room temperature and after 1 hour further 3M sodium hydroxide (0.5 ml) was added. The reaction was monitored by hplc/ms and after 4 hours it was acidified to pH 1-2 by addition of 5M hydrochloric acid. The mixture was extracted with ethyl acetate and washed with brine. Drying (MgS04) and evaporation gave the product, 325 mg (38%), hplc/ms (negative ion) Rt 4.37 min, m/z 374 (M-H-).

Intermediate 2: 3- (3, 5-Difluorophenyl)-2-phenylmethane-sulphonylamino- propionic acid alpha-Toluene sulphonyl chloride (569 mg, 2.98 mmol) was added to a stirred solution of DL-3, 5-difluorophenylalanine (445 mg, 2.21 mmol) in 3M sodium hydroxide (2. 21 ml). The mixture was stirred at room temperature and after 10 minutes further 3M sodium hydroxide (1 ml) was added. The reaction

was monitored by hplc/ms and after 4 hours it was acidified to pH 2 by addition of 5M hydrochloric acid.

The precipitated solid was filtered off and dried giving a crude product that was dissolved in ethyl acetate and washed with 5M hydrochloric acid and with brine. Drying (MgSO4) and evaporation gave the product, 190 mg (24%), hplc/ms (negative ion) Rt 4.20 min, m/z 354 (M-H-).

Intermediate 3: (S)-3-Cyclohexyl-2-phenylmethanesulphonylamino-propionic acid alpha-Toluene sulphonyl chloride (751 mg, 3.94 mmol) was added to a stirred solution of (S)-beta-cyclohexylalanine hydrochloride (606 mg, 2.92 mmol) in 3M sodium hydroxide (2.29 ml). The mixture was stirred at room temperature and during the next hour further 3M sodium hydroxide (2.92 ml) was added. The reaction mixture was then stirred overnight at room temperature. A precipitate formed and this was removed by filtration giving the product as a brown solid, 315 mg (33%), hplc/ms Rt 4.36 min m/z 324 (M-H-).

Intermediate 4: N-Boc-L-3-Methylphenylalanine A solution of L-3-methylphenylalanine (448 mg, 2.5 mmol) in a mixture of dioxane/water (2: 1,5 ml) and 1M sodium hydroxide (1.5 ml) was stirred and cooled in an ice-water bath. Di-tert-butyl dicarbonate (600 mg, 2.75 mmol) was added and stirring was continued at room temperature. The reaction was t monitored by tic (ethyl acetate/methanol/water 5: 1: 1).

After 18 hours, the solution was concentrated in vacuo, acidified with 10% citric acid solution to pH 2-3 and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to give the product as an oil, 680 mg (97%), hpic/ms Rt 4.18, m/z 204 (M-tBuOH-H').

Intermediate 5: N-Boc-trifluoronorleucine A solution of 6,6, 6-trifluoronorleucine (555 mg, 3 mmol) in a mixture of dioxane/water (2: 1,6 mi) and 1M sodium hydroxide (4.25 ml) was stirred and cooled in an ice-water bath. Di-tert-butyl dicarbonate (720 mg, 3.3 mmol) was added and stirring was continued at room temperature overnight. The reaction was monitored by tic (ethyl acetate/methanol/water 5: 1: 1) and the solution was concentrated in vacuo, acidified with 10% citric acid solution to pH 2-3 and

extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to give the product as a white solid, 710 mg (83%), hpic/ms Rt 4.00, m/z 284 (M-H-).

Intermediate 6: N-Boc-2-aminodecanoic acid 2-Aminodecanoic acid (1.00 g) was added to 1 M sodium hydroxide (5.86 ml) with stirring to give an off-white suspension. The mixture was diluted with 1,4-dioxane (15 mi) to furnish a turbid mixture to which di-tert-butyl dicarbonate (1.16 g) was added portionwise over 1 minute. Stirring was continued at room temperature for 2 hours and the reaction was monitored by TLC (ethyl acetate /methanol/water 5: 1: 1); Rf (SM) 0.01, Rf (product) ca 0.6).

The reaction mixture was concentrated under vacuum, ethyl acetate was added and the mixture was acidified to pH 3-4 with 0.5 M citric acid solution.

Some undissolved solid was removed by filtration and the organic phase separated. The aqueous phase was extracted with ethyl acetate (2 x 25 ml) and the combined organic phases were washed with water (2 x 25 mi) and dried (MgS04). Evaporation of solvent gave the product as a pale yellow oil, 1.39 g (90%), hpic/ms (ELS detection) Rt 4.85 m/z 288.

Intermediate 7: N-Boc-L-homophenylalanine L-Homophenylalanine (799 mg, 4.46 mmol) was added to a solution of sodium hydroxide (187 mg, 4.68 mmol) in water (15 ml). A solution of di-tert- butyl dicarbonate (1.022 g, 4.68 mmol) in THF (15 ml) was then added with stirring at 0°C. The reaction mixture was stirred overnight at room temperature and concentrated by evaporation under reduced pressure. The aqueous phase was acidified to pH 4-5 with 10% aqueous citric acid (5 ml) and extracted with ethyl acetate. The extract was washed with brine, dried (MgS04) and evaporated to give the crude product. Purification by silica gel chromatography eluting with ethyl acetate/hexane gave the product, 550 mg, hpic/ms Rt 4.28 m/z 278 (M-H-).

Example 1: 3-Benzo [b] thiophen-3-yl-N- [ (1S, 2R)-2-hydroxy-indan-1-yl]-2 (R) - phenylmethanesulphonylamino-propionamide A solution of HBTU in DMF (1 M, 0.048 ml) was added to a mixture of (R)- 3-benzo [b] thiophen-3-yl-2-phenylmethanesulphonylamino-propionic acid

(Intermediate 1,15 mg, 0.04 mmol) and (1S, 2R)-(-)-cis-1-amino-2-indanol (7.2 mg, 0.048 mol) in DMF (0.1 ml). The mixture was treated briefly in an ultrasonic bath to ensure complete solution of reagents and the solution was stored at room temperature for 3 days. Purification by preparative hplc (see Methods) gave the desired product, 1.3 mg (6%), hpic/ms Rt 5.59 min, m/z 507.

Example 2: 3-Benzo [b] thiophen-3-yl-N- (1 (S)-naphthyl-ethyl)-2 (R) - phenylmethanesulphonylamino-propionamide A solution of HBTU in DMF (1 M, 0.048 ml) was added to a mixture of (R)- 3-benzo [b] thiophen-3-yl-2-phenylmethanesulphonylamino-propionic acid (Intermediate 1,15 mg, 0.04 mmol) and (S)- (-)-1- (1-naphthyl) ethylamine (8.2 mg, 0.048 mmol) in DMF (0.1 ml). The mixture was treated briefly in an ultrasonic bath to ensure complete solution of reagents and the solution was stored at room temperature for 3 days. Purification by preparative hplc (see Methods) gave the desired product, 4.3 mg (20%), hplc/ms Rt 6.28 min, m/z 529.

Example 3 : 3-Benzo [b] thiophen-3-y !-N- [ (1 S, 2R) -2-hydroxy-1, 2-diphenyl- ethyl]-2 (R)-phenylmethanesulphonylamino-propionamide A solution of HBTU in DMF (1 M, 0.048 ml) was added to a mixture of (R)- 3-benzo [b] thiophen-3-yl-2-phenylmethanesulphonylamino-propionic acid (Intermediate 1,15 mg. 0.04 mmol) and (1 R, 2S)-(-)-2-amino-1, 2-diphenylethanol (10.2 mg, 0.048 mmol) in DMF (0.1 ml). The mixture was treated briefly in an ultrasonic bath to ensure complete solution of reagents and the solution was stored at room temperature for 3 days. Purification by preparative hplc (see Methods) gave the desired product, 7.3 mg (32%), hplc/ms Rt 5.89 min, m/z 571.

Example 4 : 3-Benzo [b] thiophen-3-yl-2 (R)-phenylmethane-sulphonylamino-N- (1,3, 3-trimethyl-bicyclo [2. 2. 1] hept-2-yl)-propionamide A solution of HBTU in DMF (1 M, 0.048 ml) was added to a mixture of (R)- 3-benzo [b] thiophen-3-yl-2-phenylmethanesulphonylamino-propionic acid (Intermediate 1,15 mg, 0.04 mmol) and 2-amino-exo-1,3, 3- trimethylbicyclo [2.2. 1] heptane hydrochloride (9.1 mg, 0.048 mmol) in DMF (0.1 ml). A solution of diisopropylethylamine in DMF (1 M, 0.048 ml) was added and the mixture was treated briefly in an ultrasonic bath to ensure complete solution of reagents. The solution was stored at room temperature for 3 days.

Purification by preparative hpic (see Methods) gave the desired product, 4.8 mg (23%), hpic/ms Rt 6.64 min, m/z 511.

Example 5 : N-Benzhydryl-3- (3, 5-difluoro-phenyl)-2-phenylmethane- sulphonylamino-propionamide A solution of HBTU in DMF (1 M, 0.048 ml) was added to a mixture of 3- (3, 5-difluorophenyl)-2-phenylmethanesulphonylamino-propionic acid (Intermediate 2,14 mg, 0.04 mmol) and aminodiphenylmethane (8.8 mg, 0.048 mmol) in DMF (0.1 ml). The mixture was treated briefly in an ultrasonic bath to ensure complete solution of reagents and the solution was stored at room temperature overnight. Purification by preparative hpic (see Methods) gave the desired product, 1.3 mg (6%), hpic/ms Rt 6.07 min, m/z 521.

Example 6: 3- (3, 5-Difluoro-phenyl)-N- [ (1S, 2R) -2-hydroxy-1, 2-diphenyl-ethyl]- 2-phenylmethanesulphonylamino-propionamide A solution of HBTU in DMF (1 M, 0.048 ml) was added to a mixture of 3- (3, 5-difluorophenyl)-2-phenylmethanesulphonylamino-propionic acid (Intermediate 2, 14 mg, 0.04 mmol) and (1 R, 2S)-(-)-2-amino-1, 2-diphenylethanol (10.2 mg, 0.048 mol) in DMF (0.1 ml). The mixture was treated briefly in an ultrasonic bath to ensure complete solution of reagents and the solution was stored at room temperature overnight. Purification by preparative hplc (see Methods) gave the desired product, 8.7 mg (39%), hpic/ms Rt 5.68 min, m/z 551.

Example 7: N-tert-Butyl-2 (S)- (3-cyclohexyl-2 (S)-phenyl methane- sulphonylamino-propionylamino)-3-methyl-butyramide A solution of diisopropylcarbodiimide in DMF (1 M, 0.048 ml) was added <BR> <BR> <BR> <BR> toamixtureof (S)-3-cyclohexyl-2-phenylmethanesulphonylamino-propionic acid (Intermediate 3, 13 mg, 0.04 mmol), N-hydroxybenzotriazole (54 mg, 0.04 mmol), N, N-diisopropylethylamine (0.015 ml, 0.08 mmol) and L-valine t-butylamide hydrochloride (10 mg, 0.048 mmol) in DMF (0.2 ml). The mixture was treated briefly in an ultrasonic bath to ensure complete solution of reagents and the solution was stored at room temperature overnight. The reaction was monitored by hpic/ms and a further portion of diisopropylcarbodiimide was added and

reaction left at room temperature for 1 day. Purification by preparative hpic (see Methods) gave the desired product, 1.3 mg (7%), hplc/ms Rt 5.97 min, m/z 480.

Example 8 : 2-Phenylmethanesulphonylamino-decanoic acid [ (1 S, 2R) -2- hydroxy-indan-1-yl]-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF (0. 1 ml) was mixed with a solution of HBTU in DMF (0.5M, 0.24 ml). <BR> <BR> <BR> <BR> <P>Solutions of (1S, 2R) -cis (-)-1-amino-2-indanol (0. 12 mmol) in DMF (0. 12 ml) and N, N-diisopropylethylamine (0.12 mmol) in DMF (0.12 mi) were then added and the reaction was stored overnight at room temperature. The reaction was monitored by hplc/ms and worked up by addition of ethyl acetate and water. The organic phase was washed with 1M hydrochloric acid, aqueous sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave the crude amide which showed one major component on tic (dichloromethane/methanol, 9: 1). The crude product was used in the next step without further purification.

Step 2 The crude product from Step 1 was dissolved in 4M hydrochloric acid in dioxane (2 mi) and the reaction divided into two portions of equal volume that were allowed to stand at room temperature. The reaction was monitored by tic (dichloromethane/methanol, 9: 1) until starting material disappeared. Both reaction mixtures were then evaporated to dryness under reduced pressure and the crude amine hydrochloride obtained was used in the next step.

Step 3 One portion of the crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) was added followed by a solution of alpha-toluenesulphonyl chloride (1 M, 0. 05 mmol, 1 eq). The reaction was allowed to stand overnight at room temperature and was monitored by hplc/ms.

When the reaction was complete*, purification by preparative hplc gave the desired product, 4.7 mg (20%), hplc/ms Rt 6.02 and 6.1 min, m/z 473.

* In subsequent reactions using this method, further portions of N, N- diisopropylethylamine and the appropriate sulphonyl chloride were added if the reaction had not gone to completion.

Example 9 : 2-Phenylmethanesulphonylamino-decanoic acid [1 (S) - <BR> <BR> <BR> hydroxymethyl-2- (1 H-indol-3-yl)-ethyl]-amide<BR> <BR> <BR> <BR> <BR> Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of L-tryptophanol (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and alpha-toluenesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3. Purification by preparative hpic gave the desired product, 4.2 mg (16%), hplc/ms Rt 5.82 min, m/z 514.

Example 10: 2-Phenylmethanesulphonylamino-decanoic acid benzhydryl- amide Step 1 A solution of N-Boc-2-aminodecanoic acid (intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of aminodiphenylmethane (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and

alpha-toluenesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3. Purification by preparative hplc gave the desired product, 4.2 mg (16%), hplc/ms Rt 6.65 min, m/z 507.

Example 11 : 2-Phenylmethanesulphonylamino-decanoic acid [1 (S)-naphthyl- ethyl]-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of (S)-1- (1-naphthyl) ethylamine (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and alpha-toluenesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3. Purification by preparative hpic gave the desired product, 3.6 mg (14%), hpic/ms Rt 6.65 min, m/z 495.

Example 12 : 2-Phenylmethanesulphonylamino-decanoic acid [(1S, 2R) -2- hydroxy-1, 2-diphenyl-ethyl]-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of (1 R, 2S)- (-)-2-amino-1, 2-diphenylethanol (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and

alpha-toluenesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3. Purification by preparative hpic gave the desired product, 3.0 mg (11 %), hpic/ms Rt 6.24 min, m/z 559 (MNa+).

Example 13: 2-Phenylmethanesulphonylamino-decanoic acid [(1S, 2R) -2- benzyloxy-1-hydroxymethyl-propyl]-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of 3-0-benzyl-L-threoninol (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and alpha-toluenesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3. Purification by preparative hplc gave the desired product, 4.8 mg (18%), hpic/ms Rt 6.11 and 6.21 min, m/z 519.

Example 14 : 2-Phenylmethanesulphonylamino-decanoic acid (1 (S)-tert- butylcarbamoyl-2-methyl-propyl)-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of L-valine t-butylamide hydrochloride (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.24 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 mi) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and

alpha-toluenesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3. Purification by preparative hpic gave the desired product, 3.7 mg (15%), hpic/ms Rt 6.32 min, m/z 496.

Example 15 : 2-Phenylmethanesulphonylamino-decanoic acid (trans-2- hydroxymethyl-cyclohexyl)-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of trans-2-hydroxymethyl-1- cyclohexylamine hydrochloride (0.12 mmol), HBTU (0.12 mmol) and N, N- diisopropylethylamine (0.24 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and alpha-toluenesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3. Purification by preparative hplc gave the desired product, 2.1 mg (9%), hplc/ms Rt 6.06 and 6.23 min, m/z 453.

Example 16 : 2-(Butane-1-sulphonylamino)-decanoic acid benzhydryl-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of aminodiphenylmethane (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and 1- butanesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3.

Purification by preparative hpic gave the desired product, 9 mg (38%), hplc/ms Rt 6.65 min, m/z 473.

Example 17 : 2- (Butane-1-sulphonylamino)-decanoicacid [ ( S, 2R) -2-hydroxy- 1, 2-diphenyl-ethyl]-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of (1 R, 2S)-(-)-2-amino-1, 2-diphenylethanol (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 mi) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and 1- butanesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3.

Purification by preparative hplc gave the desired product, 3.5 mg (14%), hplc/ms Rt 6.15 and 6.23 min, m/z 525 (MNa+).

Example 18 : 2-(Butane-1-sulphonylamino)-decanoic acid (1,3, 3-trimethyl- bicyclo [2. 2.1] hept-2-yl)-amide Step 1 A solution of N-Boc-2-aminodecanoic acid (Intermediate 6,0. 1 mmol) in DMF was treated with DMF solutions of 2-amino-exo-1,3, 3- trimethylbicyclo [2.2. 1] heptane hydrochloride (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.24 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxan as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (1 ml) and treated with N, N-diisopropylethylamine (0.034 ml, 0.2 mmol, 4 eq) and 1- butanesulphonyl chloride (0.05 mmol, 1 eq) as described in Example 8 Step 3.

Purification by preparative hp ! c gave the desired product, 5.7 mg (26%), hpic/ms Rt 7.06 min, m/z 443. <BR> <BR> <BR> <BR> <P>Example 19 : N- [ (1 S, 2R) -2-Hydroxy-1, 2-diphenyl-ethyl)-2 (S) - phenylmethanesulphonylamino-3-m-tolyl-propionamide Step 1 A solution of N-Boc-L-3-methylphenylalanine (Intermediate 4, 0. 1 mmol) in DMF was treated with DMF solutions of (1R, 2S)- (-)-2-amino-1, 2- diphenylethanol (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (0.2 mi) and treated with N, N-diisopropylethylamine and alpha-toluenesulphonyl chloride as described in Example 8 Step 3. Purification by preparative hplc gave the desired product, 2 mg (7%), hplc/ms Rt 5.66 min, m/z 529.

Example 20: 2 (S)-Phenylmethanesulphonylamino-3-m-tolyl-N- (1, 3, 3-trimethyl- bicyclo [2.2. 1] hept-2-yl)-propionamide Step 1 A solution of of N-Boc-L-3-methylphenylalanine (Intermediate 4,0. 1 mmol) in DMF was treated with DMF solutions of 2-amino-exo-1,3, 3- trimethylbicyclo [2.2. 11heptane hydrochloride (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.24 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (0.2 ml) and treated with N, N-diisopropylethylamine and alpha-toluenesulphonyl chloride as described in Example 8 Step 3. Purification by preparative hpic gave the desired product, 4.1 mg (17%), hplc/ms Rt 6.47 min, m/z 469.

Example 21: 6,6, 6-Trifluoro-2-phenylmethanesulphonylamino-hexanoic acid [1 (S)-naphthyl-ethyl]-amide Step 1 A solution of N-Boc-3,3, 3-trifluoronorleucine (Intermediate 5,0. 1 mmol) in DMF was treated with DMF solutions of (S)- (-)-1- (1-naphthyl) ethylamine (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (0.5 ml) and treated with N, N-diisopropylethylamine andalpha-toluenesulphonyl chloride as described in Example 8 Step 3. Purification by preparative hpic gave the desired product, 3.8 mg (15%), hpic/ms Rt 5.99 min, m/z 493.

Example 22 : 2-(Butane-1-sulphonylamino)-6, 6, 6-trifluoro-hexanoic acid [1 (S) - naphthyl-ethyl]-amide The crude amine hydrochloride from Example 21 Step 2 was dissolved in DMF (0.5 ml) and treated with N, N-diisopropylethylamine and 1- butanesulphonyl chloride as described in Example 8 Step 3. Purification by preparative hplc gave the desired product, 5.7 mg (25%), hplclms Rt 5.88 min, m/z 459.

Example 23: 6,6, 6-Trifluoro-2-phenylmethanesulphonylamino-hexanoic acid [ (1 S, 2R)-2-hydroxy-1, 2-diphenyl-ethyl]-amide Step 1 A solution of N-Boc-3,3, 3-trifluoronorleucine (Intermediate 5,0. 1 mmol) in DMF was treated with DMF solutions of (1 R, 2S)- (-)-2-amino-1, 2- diphenylethanol (0.12 mmol), HBTU (0.12 mmol) and N, N-diisopropylethylamine (0.12 mmol) as described in Example 8 Step 1.

Step 2 The crude product from Step 1 was treated with 4M hydrochloric acid in dioxane as described in Example 8 Step 2.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (0.5 ml) and treated with N, N-diisopropylethylamine and alpha-toluenesulphonyl chloride as described in Example 8 Step 3. Purification by preparative hplc gave the desired product, 4.6 mg (17%), hplc/ms Rt 5.48 min, m/z 535.

Example 24 : N-Benzhydryl-4-phenyl-2 (S)-phenylmethane-sulphonylamino- butyramide Step 1 A solution of N-Boc-L-homophenylalanine (Intermediate 7,0. 21 mmol), aminodiphenylmethane (0.25 mmol), N-hydroxybenzotriazole (0.25 mmol), N, N- diisopropylethylamine (0.84 mmol) and EDC (0.25 mmol) in DMF (0.6 mi) was allowed to stand overnight at room temperature. The reaction mixture was then worked up as described in Example 8 Step 1 to give a crude amide, 68 mg, tic Rf 0.59 (ethyl acetate/hexane 1: 1).

Step 2 The crude product from Step 1 (68 mg, 0.15 mmol) was treated with 4M hydrochloric acid in dioxane (2 ml) and the reaction divided into two portions of equal volume that were allowed to stand at room temperature for 2 hours. Both reaction mixtures were then evaporated to dryness under reduced pressure and the crude amine hydrochloride obtained was used in the next steps.

Step 3 The crude amine hydrochloride from Step 2 was dissolved in DMF (0.5 ml) and treated with N, N-diisopropylethylamine (0.3 mmol) and alpha- toluenesulphonyl chloride (0.076 mmol). Purification by preparative hpic gave the desired product, 8.3 mg (33%), hplclms Rt 4.87 min, m/z 499.

Example 25 : N-Benzhydryl-2 (S)-(butane-1-sulphonylamino)-4-phenyl- butyramide The crude amine hydrochloride from Example 24 Step 2 was dissolved in DMF (0.5 ml) and treated with N, N-diisopropylethylamine (0.3 mmol) and 1- butanesulphonyl chloride (0.076 mmol). Purification by preparative hplc gave the desired product, 2.9 mg (12%), hplc/ms Rt 4.87 min, m/z 465.

Example 26 : 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 5- [ (4- <BR> <BR> <BR> <BR> methoxy-naphthalen-2-yl)-amide] 1- [ (4-phenyl-butyl)-amide]<BR> <BR> <BR> <BR> <BR> <BR> Step 1<BR> <BR> <BR> <BR> <BR> A solution of 2 (S)-amino4-(4-methoxy-naphthalen-2-ylcarbamoyl)-butyric acid (250 mg, 0.83 mmol) in 10% methanol/dichloromethane (10 ml) was treated with a 2M solution of trimethylsilyl diazomethane in hexane (0-83 mol, 1.66 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was washed with aqueous sodium bicarbonate (10 ml) and the aqueous fraction extracted with dichloromethane (2 x 10 ml). The combined organic fractions were dried over anhydrous magnesium sulphate, filtered and evaporated to give 2 (S)-amino-4- (4-methoxy-naphthalen-2-ylcarbamoyl)-butyric acid methyl ester (235mg, 90%), m/z 317 (M+H+).

Step 2 A solution of 2 (S)-amino-4- (4-methoxy-naphthalen-2-ylcarbamoyl)-butyric acid methyl ester (235 mg, 0.74 mmol) and alpha-toluenesulphonyl chloride (170 mg, 0.89 mmol) in dichloromethane (3 ml) under nitrogen was treated with N, N- diisopropylethylamine (160 ul, 0.89 mmol). The solution was left at room temperature for 3 days then diluted with dichloromethane (10 ml) and stirred with aqueous sodium bicarbonate (5 ml) for 30 minutes. The layers were separated and the aqueous phase extracted with dichloromethane (2 x 10 ml). The combined organic fractions were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluted with 5% methanol/dichloromethane. Concentration of product containing fractions gave 4- (4-methoxy-naphthalen-2-ylcarbamoyl)-2 (S) - phenylmethanesulphonylamino-butyric acid methyl ester (210 mg, 60%), m/z 471 (M+H+).

Step 3 The product from Step 2 (210 mg, 0.45 mmol) in tetrahydrofuran (4 ml) containing methanol (0.2 ml) and water (0.2 mi) was stirred and treated with lithium hydroxide (13 mg, 0.53 mmol). After 17 hours, the mixture was treated with 1 M hydrochloric acid (5 ml) and stirred for 20 minutes. The reaction mixture was extracted with ethyl acetate (3 x 5 ml) and the combined organic fractions

dried over anhydrous sodium sulphate, filtered and evaporated to give 4- (4- <BR> <BR> <BR> <BR> methoxy-naphthalen-2-ylcarbamoyl)-2-phenylmethanesulphonylam ino-butyric acid (182 mg, 89%), m/z 457 (M+H+).

Step 4 A mixture of the product from Step 3 (25 mg, 55 pmol), 4-phenyl butylamine (12.3 mg, 82 umol) and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (16 mg, 82 pmol) was stirred in dichloromethane (1 ml) under nitrogen and treated with N, N-diisopropylethylamine (10.6 mg, 82 pmol). N-Hydroxybenzotriazole (5 mg, 37 umol) was added and the mixture stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane (2 ml), treated with 1 M hydrochloric acid (2 ml) and stirred for 30 minutes. The phases were separated and the aqueous phase extracted with dichloromethane (2 ml). The combined organic fractions were evaporated and the residue purified by preparative hpic (see methods) to give 2 (S)- <BR> <BR> <BR> <BR> phenylmethanesulphonylamino-pentanedioic acid 5- [ (4-methoxy-naphthalen-2- yl)-amide] 1- [ (4-phenyl-butyl)-amide] (2. 4 mg, 8%), hpic/ms Rt 4. 81 min, m/z 588 (M+H+).

Example 27 : 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 5- [ (4- methoxy-naphthalen-2-yl)-amide] 1- [ (1 (S)-methyl-3-phenyl-propyl)-amide] In a manner analogous to that of Example 26, replacing 4-phenyl butylamine in Step 4 with 1 (S)-methyl-3-phenyl-propylamine gave 2 (S)- <BR> <BR> <BR> <BR> phenylmethanesulphonylamino-pentanedioicacid 5- [ (4-methoxy-naphthalen-2- yl)-amide] 1- [ (1 (S)-methyl-3-phenyl-propyl)-amide], hplc/ms Rt4. 81 min, m/z588 (M+H+).

Example 28 : N-benzhydryl-2- (biphenyl-4-sulphonylamino)-3- (3, 5-difluoro- phenyl)-propionamide In a manner analogous to that of Example 10, using N-Boc-2-amino-3- (3, 5-difluoro-phenyl)-propionic acid in place of N-Boc-2-aminodecanoic acid and biphenyl-4-sulphonyl chloride in place of alpha-toluenesulphonyl chloride, was prepared N-benzhydryl-2- (biphenyl-4-sulphonylamino)-3- (3, 5-difluoro-phenyl)- propionamide. m/z 582.

Example 29: N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (4-methoxy- benzenesulphonylamino)-propionamide In a manner analogous to that of Example 10, using N-Boc-2 (R)-amino-3- benzo [b] thiophen-3-yl-propionic acid in place of N-Boc-2-aminodecanoic acid and 4-methoxy-benzene-sulphonyl chloride in place of alpha-toluenesulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (4-methoxy- benzenesulphonylamino)-propionamide. m/z 556.

Example 30 : N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- [5- (2-methyl-thiazol- 4-yl)-thiophene-2-sulphonylamino]-propionamide In a manner analogous to that of Example 29, using 5- (2-methyl-thiazol-4- yl)-thiophene-2-sulphonyl chloride in place of 4-methoxy-benzene-sulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- [5- (2-methyl- thiazol-4-yl)-thiophene-2-sulphonylamino]-propionamide. m/z 629.

Example31 : N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R) - phenylmethanesulphonylamino-propionamide In a manner analogous to that of Example 10, using N-Boc-2 (R) -amino-3- benzo [b] thiophen-3-yi-propionic acid in place of N-Boc-2-aminodecanoic acid, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R) - phenylmethanesulphonylamino-propionamide. m/z 540.

Example 32: N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (2-naphthalen-1-yl- ethanesulphonylamino)-propionamide In a manner analogous to that of Example 29, using 2-naphthalen-1-yl- ethanesulphonyl chloride in place of alpha-toluenesulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (2-naphthalen-1-yl- ethanesulphonylamino)-propionamide. m/z 604.

Example 33 : 6,6, 6-trifluoro-2- (4-phenoxy-benzenesulphonylamino)-hexanoic acid benzhydryl-amide In a manner analogous to that of Example 21, using benzhydrylamine in place of (S)- (-)-1- (1-naphthyl) ethylamine and 4-phenoxy-benzenesulphonyl chloride in place of alpha-toluenesulphonyl chloride, was prepared 6,6, 6- trifluoro-2- (4-phenoxy-benzenesulphonylamino)-hexanoic acid benzhydryl- amide. m/z 582.

Example 34: N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (naphthalene-2- sulphonylamino)-propionamide In a manner analogous to that of Example 29, using naphthalene-2- sulphonyl chloride in place of 4-methoxy-benzene-sulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (naphthalene-2- sulphonylamino)-propionamide. m/z 576.

Example 35: N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)-(naphthalene-1- sulphonylamino)-propionamide In a manner analogous to that of Example 29, using naphthalene-1- sulphonyl chloride in place of 4-methoxy-benzene-sulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)-(naphthalene-1- sulphonylamino)-propionamide. m/z 576.

Example 36 : N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (2, 3-dihydro- benzofuran-5-sulphonylamino)-propionamide In a manner analogous to that of Example 29, using 2,3-dihydro- benzofuran-5-sulphonyl chloride in place of 4-methoxy-benzene-sulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (2, 3-dihydro- benzofuran-5-sulphonylamino)-propionamide. m/z 569 [M+H] +.

Example 37 : N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (3-methoxy- benzenesulphonylamino)-propionamide In a manner analogous to that of Example 29, using 3-methoxy- benzenesulphonyl chloride in place of 4-methoxy-benzene-sulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (3-methoxy- benzenesulphonylamino)-propionamide. m/z 556.

Example 38: N-benzhydryl-3-benzo [b] thiophen-3-yi-2 (R)- (4-phenoxy- benzenesulphonylamino)-propionamide In a manner analogous to that of Example 29, using 4-phenoxy- benzenesulphonyl chloride in place of 4-methoxy-benzene-sulphonyl chloride, was prepared N-benzhydryl-3-benzo [b] thiophen-3-yl-2 (R)- (4-phenoxy- benzenesulphonylamino)-propionamide. m/z 618.

Example 39 : 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 1- [ (2- hydroxy-1 (S), 2 (R)-diphenyl-ethyl)-amide] 5- [ (4-methoxy-naphthalen-2-yl)-amide] In a manner analogous to that of Example 26, replacing 4-phenyl butylamine with 2-Amino-1 (R), 2 (S)-diphenyl-ethanol in Step 4, was prepared 2 (S)-phenylmethanesulphonylamino-pentanedioicacid 1-[(2-hydroxy-1 (S), 2 (R)- diphenyl-ethyl)-amide] 5- [ (4-methoxy-naphthalen-2-yl)-amide], hplc/ms Rt 4.47 min, m/z 652 (M+H+).

Example 40: 2 (S)-phenylmethanesulphonylamino-pentanedioic acid 5- [ (4- methoxy-naphthalen-2-yl)-amide] 1- [ (1 (S)-naphthalen-1-yl-ethyl)-amide] In a manner analogous to that of Example 26, replacing 4-phenyl butylamine with 1 (S)-naphthalen-1-yl-ethylamine in Step 4, was prepared 2 (S)- <BR> <BR> <BR> <BR> phenylmethanesulphonylamino-pentanedioic acid 5- [ (4-methoxy-naphthalen-2-<BR> <BR> <BR> <BR> <BR> <BR> yl)-amide] 1- [ (1 (S)-naphthalen-1-yl-ethyl)-amide], hpic/ms Rt 4. 86 min, m/z 610 (M+H+).

Example 41: 3- (4-methoxy-phenyl)-2 (S)- (methyl-phenylmethanesulphonyl- <BR> <BR> <BR> <BR> amino)-N- (1 (S)-naphthalen-1-yl-ethyl)-propionamide<BR> <BR> <BR> <BR> <BR> <BR> Step 1 A solution of (L)-tyrosine methyl ester (11.73 g, 0.06 mol) in dichloromethane (75 ml) under nitrogen was cooled to <5°C in an ice-salt bath.

Triethylamine (18.5 ml, 0.132 mol) was added followed by alpha- toluenesulphonyl chloride (25.5 g, 0.133 mol). The mixture was allowed to warm to room temperature overnight then diluted with dichloromethane (350 ml). The solution was washed with aqueous sodium bicarbonate (100 ml), 1 M hydrochloric acid (100 ml) and brine (100 ml), dried over anhydrous sodium sulphate, filtered and evaporated. Trituration of the residue with petroleum ether/diethyl ether gave 2 (S)-phenylmethanesulphonylamino-3- (4- phenylmethanesulphonyloxy-phenyl)-propionic acid methyl ester (25.2 g, 84%) as a yellow solid, m/z (negative ion) 502 (M-H-).

Step 2 The crude product from Step 1 (0.05 mol) was heated at 60°C in a solution of potassium hydroxide (12.6 g, 0.225 mol) in methanol (170 ml)/water (17 ml) for 6 hours. The reaction mixture was cooled, acidified with 1M

hydrochloric acid and extracted with ethyl acetate (3 x 150 ml). The combined extracts were dried over anhydrous sodium sulphate, concentrated under reduced pressure and the residue crystallised from ethanol. The solid, alpha- toluenesulphonic acid, was removed by filtration and the filtrate evaporated. The residue was partitioned between ethyl acetate (200 ml) and aqueous sodium bicarbonate (300 ml) and the aqueous fraction acidified with 1M hydrochloric acid. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml) and the combined extracts washed with brine (100 ml). The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated to give 3- (4-hydroxy- phenyl)-2 (S)-phenylmethanesulphonylamino-propionic acid (15.5 g, 92%) as an orange gum, m/z (negative ion) 334 (M-H-).

Step 3 The product from Step 2 (1 g, 3 mmol) in acetone (10 ml) was treated with potassium carbonate (0.86 g, 6.3 mmol) and iodomethane (0.4 mi, 6.3 mmol).

The mixture was heated at 100°C in a sealed tube in a microwave for 1 hour.

After cooling to room temperature a further portion of iodomethane (0.4 ml, 6.3 mmol) was added and heating continued for 1 hour. Solvent was evaporated and the residue partitioned between ethyl acetate (25 ml) and water (10 ml). The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated to give 3- (4-methoxy-phehyl)-2 (S)- (methyl-phenylmethanesulphonyl- amino) -propionic acid methyl ester (1.1 g, 97%) as a yellow gum, m/z 378 (M+H+).

Step 4 Crude product from Step 3 (340 mg, 0.9 mmol) was dissolved in THF (8 ml) and treated with water (0.5 ml) and methanol (0.5 ml). The solution was treated with lithium hydroxide (27 mg, 1.1 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (5 ml), acidified with 1 M hydrochloric acid and extracted with ethyl acetate (3 x 10 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and evaporated to give 3- (4-methoxy-phenyl)-2 (S)- (methyl-phenylmethanesulphonyl-amino)- propionic acid (300 mg, 92%) as an orange gum, m/z 364 (M+H+).

Step 5 The product from Step 4 (150 mg, 0.41 mmol) and 1 (S)-naphthalen-1-yl- ethylamin (70 mg, 0.41 mmol) were stirred in dichloromethane (10 mi) under nitrogen and cooled to <5°C in an ice-bath. N-Hydroxybenzotriazole (62 mg, 0.45 mmol) and N-ethyl morpholine (52 mg, 0.45 mmol) were added, followed by 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0. 45 mmol) after 15 minutes. The reaction mixture was allowed to warm to room temperature overnight then diluted with dichloromethane (10 ml) and washed with aqueous sodium bicarbonate (5 ml), 1M hydrochloric acid (5 ml) and brine (5 ml). The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. Flash chromatography of the residue on silica gel eluted with 20% ethyl acetate/hexane and concentration of product containing fractions gave 3- (4-methoxy-phenyl)-2 (S)- (methyl-phenylmethanesulphonyl-amino)-N- (1 (S) - naphthalen-1-yl-ethyl)-propionamide (55mg, 26%) as a pale yellow solid, m/z (negative ion) 515 (M-H-).

Example 42 : 3- (4-hydroxy-phenyl)-2 (S)- (methyl-phenylmethanesulphonyl- amino)-N- (1 (S)-naphthalen-1-yl-ethyl)-propionamide The title compound was obtained as a by-product from the synthesis of Example 41, m/z 503 (M+H').

Example 43 : N-benzhydryl-3- (4-methoxy-phenyl)-2 (S)- (methyl- phenylmethanesulphonyl-amino)-propionamide 3- (4-Methoxy-phenyl)-2 (S)- (methyl-phenylmethanesulphonyl-amino)- propionic acid (150 mg, 0.41 mmol), prepared in Example 41, Step 4, and amino- diphenylmethane hydrochloride (90 mg, 0.41 mmol) were stirred in dichloromethane (10 mi) under nitrogen and cooled to <5°C in an ice-bath. N- Hydroxybenzotriazole (62 mg, 0.45 mmol) and N-ethyl morpholine (100 mg, 0.87 mmol) were added followed by 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) after 15 minutes. The reaction mixture was allowed to warm to room temperature overnight then diluted with dichloromethane (10 ml) and washed with aqueous sodium bicarbonate (5 ml), 1 M hydrochloric acid (5 ml) and brine (5 ml). The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. Flash chromatography of

the residue on silica gel eluted with 20% ethyl acetate/hexane and concentration of product containing fractions gave N-benzhydryl-3- (4-methoxy-phenyl)-2 (S) - (methyl-phenylmethanesulphonyl-amino)-propionamide (40 mg, 18%) as a pale yellow solid, m/z 529 (M+H+).

The compounds of Examples 1 to 43 were shown to have desirable inhibitory activity towards BACE.

Example 44: activity assay The compounds of Examples 3,26, 39,41 and 43 were tested for their inhibitory activity towards BACE.

All enzyme assays were performed at 20°C on an AlphaFusion (Packard Instruments) using 384 well plates (Greiner Bio-One Ltd). The assay volume was 30 pl. Inhibitors were dissolved in dimethyl sulphoxide (DMSO) and added into a well with 50 mM sodium acetate buffer pH 4.5 and 10 uM EDANS- EVNLDAEFK-DABCYL peptide substrate. The DMSO concentration was set at 10% in the assay.

The reaction was started with the addition of 1 ug/ml recombinant human soluble BACE-1. After 3 hours the fluorescence increase was measured in the plate reader at 365ex/485em. The EDANS-DABCYL peptide substrate becomes slightly fluorescent upon enzymatic cleavage due to disruption of the resonance energy transfer between the EDANS donor and DABCYL quenching acceptor in the intact substrate.

The activities (IC50 values in, uM) of the Example compounds are shown in Table 1.

Table 1 Example No. IC5o (pM) 3 59 26 26 39 34 41 13 43 23