IE904522A1 - Pharmacologically Active Amide Carboxylate Derivatives - Google Patents

Abstract

This invention relates to compounds having pharmacological activity, processes for their preparation, compositions containing them and methods of treatment involving their use. In its broadest aspect, the invention is concerned with compounds, having general formula (I) in which R<1> represents an alkyl C1-18 group optionally substituted by an aryl group or hydroxy or a cycloalkyl C3-6 group, R<2> represents an alkyl C1-18 group optionally substituted by an aryl group, or R<2> represents a group -CH2-X-R4 wherein X represents O or S, and R4 represents hydrogen, an aryl group, or an alkyl or alkenyl C1-18 group optionally substituted by an aryl group, R<3> represents OH, alkoxy C1-6 or -NHR<31>, wherein R<31> represents hydrogen, alkyl C1-6, OH or alkoxy C1-6 optionally substituted by an aryl group, R<5> represents hydrogen, an aryl group or an alkyl or alkenyl C1-18 group optionally substituted by an aryl group, n represents 0, 1, 2 or 3, p represents 0, 1 or 2, q represents 0 or 1, Y represents -CHR<6>-, -CH=CH-, O or S, in which R<6> represents hydrogen, an aryl group or an alkyl or alkenyl C1-18 group optionally substituted by an aryl group, and pharmaceutically acceptable derivates thereof.

Description

Pharmacologically Active Amide Carboxylate Derivatives This invention relates to compounds having pharmacological activity, processes for their preparation, compositions containing them and methods of treatment involving their use.

In its broadest aspect, the invention is concerned with compounds having the general formula R2 I 3 10 RA“CON-CH-(CH2)n-[Y(CH2)p]q-COR3 R5 in which R1 represents an alkyl or alkenyl 0^_18 group 15 optionally substituted by an aryl group or hydroxy or a cycloalkyl C3_6 group, R2 represents an alkyl Ο1-18 group optionally substituted by an aryl group, or R2 represents a group -CH2~X-R4 wherein X represents O or S, and R4 2Q represents hydrogen, an aryl group, or an alkyl or alkenyl C1_18 group optionally substituted by an aryl group, R3 represents OH, alkoxy C3_6 or -NHR3wherein R31 represents hydrogen, alkyl 01-6, OH or 25 alkoxy C1_6 optionally substituted by an aryl group, - 2 R5 represents hydrogen, an aryl group or an alkyl or alkenyl ci-18 9rouP optionally substituted by an aryl group, n represents 0, 1, 2 or 3, p represents 0, 1 or 2, q represents 0 or 1, Y represents -CHR6-, -CH=CH-, O or S, in which R6 represents hydrogen, an aryl group or an alkyl or alkenyl Ci-18 9rouP optionally substituted by an aryl group, £0 and pharmaceutically acceptable derivatives thereof.

According to a first aspect of the invention, there is provided the use of a compound of formula I, as defined above, in the manufacture of a medicament for the treatment or prophylaxis of inflammation.

According to a second aspect of the invention, there is provided a method of treatment or prophylaxis of inflammation, which method comprises administering a therapeutically effective quantity of a compound of formula I, as defined above, to a patient suffering from or 2q susceptible to an inflammatory condition.

Certain of the compounds of formula I are known for use as pharmaceuticals, or to have pharmacological effects. For example: European Patent Application No 226304 (Sankyo) describes certain N-acyl amino acid derivatives which on concurrent administration with a penem or carbapenem antibiotic reduce the renal toxicity of the antibiotic.

European Patent Application No 136879 (Yamanouchi) describes carboxylic acid and amide derivatives which are orally administered fibrinolytic agents.

Japanese Patent Application No 54-119414 (Fuji) describes the synthesis of ^-aminoacid derivatives having antibiotic properties.

German Patent Application No 2252882 (Oreal) relates IQ to aminoacid-amine salts containing sulphur which are useful as hair and scalp conditioners.

Yao Hsueh Hsueh Pao 10(7), 418-435 (1963) discloses one compound falling within the scope of formula I which has anthelmintic activity.

A number of compounds active as cholecystographic agents are disclosed in Rec.Trav.Chim.Pays-Bas 87(4), 308-318 (1968).

In addition there have been a number of publications indicating that certain compounds of formula I may act as 2Q inhibitors of various enzymes, but without suggesting any particular utility for those compounds. Examples are J.Med.Chem. 29. 104-111 (1986), J.Med.Chem. 27, 711-712 (1984), Biochem. Pharmacol. 29.(16), 2205-2212 (1980), and Pept.,Proc.Am.Pept.Symp.,5th, 209-212 (1977).

None of these citations, however, discloses or suggests any utility of the compounds of formula I as anti-inflammatory agents.

With the above-mentioned exceptions, the pharmaceutical use of the compounds of formula I is novel.

As a further aspect of the invention, therefore, there are provided compounds of formula I, as first defined above, and pharmaceutically acceptable derivatives thereof, with the provisos that a) when R1 represents methyl, then R2 is other than IQ an alkyl group or benzyl, and b) when R2 represents methyl, then R1 is other than an alkyl group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl, and c) when R2 represents iso-propyl, n represents 1, q ο 1 , represents 0 and R represents hydroxy, then RA is other than an alkyl C1-6 group optionally substituted by phenyl, and d) when n represents 1, q represents 0, and R represents hydroxy or t-butoxy, then R1 and R2 do not 2q both represent CH3(CH2)14~, for use as pharmaceuticals.

In addition to those for which pharmacological effects have previously been described, a number of other compounds of formula I are known. The majority of the compounds are, however, novel and according to a further aspect of the invention there are provided compounds of formula I, as first defined above, and pharmaceutically acceptable derivatives thereof, with the provisos that i) when R1 represents methyl, then R2 is other than an alkyl ci_ig group or benzyl or 2-phenylethyl or -CH2OH or -CH2SCH3, and ii) when R2 represents methyl, then R1 is other than an alkyl 01-18 group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl or 2-(3-phthalimido)propyl 10 or CH2=CH- or CH3CH=CH-, and iii) when R2 represents iso-propyl or ethyl, n represents 1, q represents 0, and R3 represents hydroxy, then R1 is other than an alkyl C3_6 group optionally substituted by phenyl, and iv) when R2 represents benzyl, n represents 0, Y represents -CH=CH-, p represents 1, q represents 1, and R1 represents 2-methylpropyl, then R3 is other than hydroxy or methoxy, and v) when R1 represents heptadec-8-enyl, n represents 1, q 2 · 2Q q represents 0 and R represents hydroxy, then R is other than n-propyl, and vi) when n represents 1, q represents 0, and R represents hydroxy or t-butoxy, then R and R do not both represent CH3(CH2)i4“, and vii) when R1 represents n-hexyl, . (CH2^ntY(CH2^p1q represents (CH2)4, and R3 represents hydroxy, then R2 is other than n-pentyl.

According to the invention there is also provided a process for the preparation of compounds of formula I and pharmaceutically acceptable derivatives thereof, with provisos i) - vii) above, which process comprises: a) producing a compound of formula I in which R3 represents hydroxy by hydrolysis of a corresponding compound of formula I in which R3 represents alkyl C1_6, or b) producing a compound of formula I m which R represents alkoxy Cj.g by condensation of an acid of formula II: R^-COOH II with an amine of formula III: NH -CH-(CH2)n-[Y(CH2)p]q-CORIII wherein R3 represents alkoxy C^.g, or c) producing a compound of formula I in which R3 represents NHR31 by reacting the corresponding compound IE 904572 - 7 in which R3 represents COOH with a compound of formula IV H2NR31 IV in which R31 is as defined above, or d) producing a compound of formula I in which R3 represents hydroxy or alkoxy C^_g by reacting a compound of formula III in which R3 represents hydroxy or alkoxy cl-6 a compound of formula V R1-CO-L V in which L represents a leaving group, • · 31 e) producing a compound of formula I in which R represents hydroxy by hydrolysis of the corresponding compound in which R31 represents alkoxyCi_6 optionally substituted by an aryl group, or f) producing a compound of formula I in which the chain (CH2)n[Y(CH2)p]q contains a group -CH2CH2- by 2θ hydrogenation of the corresponding compound of formula I in which Y represents -CH=CH-, or and where desired or necessary, converting the compound of formula I so obtained to a pharmaceutically acceptable derivative thereof.

The hydrolysis of process a) may be carried out under - 8 acid or, preferably, base catalysis. Reagents which may be used for the base catalysed hydrolysis include lithium hydroxide and potassium hydroxide. The reaction may be carried out in the presence of a co-solvent such as tetrahydrofuran.

The reaction of process b) is preferably carried out in an inert solvent such as dichloromethane in the presence of a coupling reagent such as dicyclohexylcarbodiimide with or without 1-hydroxybenzotriazole or other additives. Ιθ The reaction of process c) is preferably carried out in an inert solvent or mixture of solvents. A coupling reagent such as dicyclohexylcarbodiimide may be employed.

Leaving groups which L may represent in process d) include halide, notably chloride. Acid chlorides of 15 formula V may be prepared by treatment of the corresponding acid with for example, thionyl chloride or oxalyl chloride. The acid chloride is then treated with the amine of formula III in the presence of an inert solvent such as dichloromethane. 2q The reaction of process e) may be carried out in the presence of a suitable catalyst, eg 10% palladium on carbon. Alternatively, the reaction may be carried out by hydrolysis using an inorganic base.

The hydrogenation of process f) may also be carried 2g out over a suitable catalyst, eg 10% palladium on charcoal. - 9 Certain compounds of formula III are novel and useful as intermediates in the preparation of the compounds of formula I. According to another aspect of the invention, therefore, there are provided compounds of formula III R2 NH-CH-(CH2)n-[Y(CH2)p]q-COR3 III Ιθ in which R3, R5, Y, n, p and q are as first defined above and R2 represents CH2-X-R4. A preferred group of such compounds are those in which R4 represents an aryl group, or an alkyl or alkenyl Ο3_18 group optionally substituted by an aryl group.

These novel compounds of formula III may be prepared by reacting a compound of formula VI R4-X-H VI with the corresponding compound of formula III in which R2 represents -CH2-L in which L is a leaving group, eg a halogen such as iodine.

Other compounds of formula III, as well as compounds of formulae II, IV, V and VI are either commercially __ available or may be obtained from commercially available - 10 compounds by known processes which will be apparent to those skilled in the art.

Preferred groups that R^ may represents are alkyl or alkenyl ci_ig, optionally substituted by hydroxy, phenyl or cycloalkyl C3_6.

Alkyl groups which R1 may represent include both straight and branched chain groups. Straight chain alkyl groups include both relatively short chains, eg methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, and longer chains, eg pentadecyl, hexadecyl and heptadecyl.

Similarly, branched chains include both relatively simple groups such as i-propyl, i-butyl, s-butyl and t-butyl, and groups containing larger numbers of carbon atoms, eg 6-ethyl-octyl.

Alkenyl groups which R3 may represent may contain up to 3 double bonds. Where there is more than 1 double bond, they may be conjugated or non-conjugated. Examples of such alkenyl groups include 7-heptadecenyl, 9-pentadecenyl and 2-nonenyl. 2θ Cycloalkyl groups with which the group R1 may be substituted include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Aryl groups with which the group R3 may be substituted include both carbocyclic and heterocyclic groups. The groups may contain rings of various numbers of 9θ*522 -llC-atoms and may be fused ring structures. Examples of carbocyclic aryl groups are phenyl and naphthyl.

Heteroaryl groups include nitrogen, oxygen or sulphur heterocycles and may contain one or more heteroatoms.

Examples of heterocycles containing only one heteroatom include pyrrole, furan, thiophen and pyridine. Groups containing more than one heteroatom include pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole etc. The aryl group may be substituted by a range of IQ substituents including halogen, nitro, alkyl phenyl and phenyl(alkyl Ci_6).

Particularly preferred aryl groups with which R1 may be substituted are carbocyclic groups, especially phenyl.

When R2 represents alkyl Ci_18, it may be substituted by a similar range of aryl groups to R1.

Again, the preferred aryl groups with which R2 may be substituted are carbocyclic groups, especially phenyl.

Preferred groups which R2 may represent include alkyl Ci_18, more preferably alkyl Cj.g, optionally substituted by phenyl, and, more preferably, groups of the formula —ch2—x—r4 in which X represents S or 0, and R4 represents alkyl 18, an aryl group or alkyl Cx_i8 substituted by an aryl group. - 12 β ο Alkyl groups which R may represent include similar groups to those which R1 may represent. Similarly, when R2 represents the group -CH2-X-R4, R4 may represent a similar range of long and short, straight or branched 5 alkyl groups.

When R2 represents -CH2-X-R4, then R4 preferably represents an aryl group.

Aryl groups which R4 may represent include carbocyclic groups, notably phenyl, optionally substituted IQ by, for example, phenyl and phenylmethyl, and fused ring structures such as naphthyl. Other aryl groups which R4 may represent include heterocyclic structures. Such heteroaryl groups include nitrogen, oxygen or sulphur heterocycles and may contain one or more heteroatoms.

Examples of heterocycles containing only one heteroatom include pyrrole, furan, thiophen and pyridine. Groups containing more than one heteroatom include pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole etc. The aryl group may be substituted by a range of substituents including halogen, nitro, alkyl C-^.g, phenyl and phenyl(alkyl C1-6).

Alkoxy groups which R3 may represent include methoxy, ethoxy and propoxy.

When R3 represents NHR31, R31 preferably represents hydrogen, alkyl Ci_6, hydroxy or alkoxy Έ904522 - 13 optionally substituted by aryl. Aryl groups with which R4 may be substituted include both carbocyclic and heterocyclic groups. It is particularly preferred that R31 be substituted by a carbocyclic group, especially phenyl.

Most preferably, R31 represents alkoxy C1-6 or, especially, hydroxy.

R5 is preferably lower alkyl, say alkyl Cj.g, or, more preferably, hydrogen.

We prefer compounds in which q is zero.

We also prefer compounds in which n represents 0, 1 or 2, q represents 1 and p represents zero. In such compounds, Y is preferably CHR6 in which R6 is preferably hydrogen or alkyl We particularly prefer compounds in which n is 1 or 2.

Alkyl groups which R6 may represent include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.

Aryl groups with which R6 may be substituted include 20 both carbocyclic and heterocyclic groups. It is particularly preferred that R6 be substituted by a carbocyclic group, especially phenyl.

A particularly preferred group of compounds are those in which 25 R^ represents alkyl or alkenyl C^-ig, optionally - 14 substituted by hydroxy, phenyl or cycloalkyl C3_6, R2 represents alkyl C3_18, optionally substituted by phenyl, or a group -ch2-x-r4 wherein X represents S or 0, and R4 represents alkyl ci-i8, an aryl group or alkyl ci_i8 substituted by an aryl group, 31 R represents hydroxy, alkoxy Ο1-6 or NHR wherein R31 represents hydrogen, alkyl C3_6, hydroxy or alkoxy C3_g optionally substituted by phenyl, and n represents 0, 1 or 2, q represents 1, and Y represents -CHR6-, in which R6 represents hydrogen or alkyl C3_6, and pharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable derivatives of the compounds of formula I include esters, amides and salts. Salts of the compounds of formula I include metal ion salts, eg alkali metal and alkaline earth metal salts, and addition salts with suitable bases, eg suitable amines such as dicyclohexylamine and 1-adamantanamine.

The compounds of formula I, and pharmaceutically acceptable derivatives thereof, are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as broad spectrum - 15 anti-inflanunatory agents as demonstrated in one or more of the following in vitro assay systems: 1. Porcine pancreatic PLA2 induced release of 14C-arachidonic acid from mixed micelles: Mixed micelles of l-stearoyl-2-[1-14C]-2-arachidonyl-L-3-phosphatidyl choline and deoxycholate are added to a mixture of porcine pancreatic PLA2 and test compound in buffer solution.

After 8 minutes the reaction is quenched and 14C-arachidonic acid is extracted by the method of IQ Katsumata et al: Anal. Biochem., 154♦ 676, (1986), then assayed by scintillation counting techniques. 2. PLA2 induced cleavage of a thioester: porcine pancreatic PLA2 is incubated with 4-hydroxy-3,5-dioxa4,9-dioxo-8-thia-4-phosphahexadecan-l-ammonium hydroxide in buffer solution containing the test compound. Cleavage of the thio ester is assayed photometrically after reaction with DTNB (5,5'-dithiobis[2-nitrobenzoic acid]). 3. Human platelet cystolic PLA2 induced release of 14C-arachidonic acid from liposomes of l-stearoyl-2-14C-arachidonyl phosphatidylcholine in buffer containing 10% DMSO: Assays were carried out as in system 1, but human platelet cystolic PLA2 was used in place of porcine pancreatic PLA2. 4. Assay of PLA2 in intact HL60 cells and polymorphonuclear leucocytes (PMN): In the presence of the - 16 test compound and a 5-lipoxygenase inhibitor, HL60 or PMN cells in which the arachidonate moieties of the phospholipids have been equilibrated with tritium-labelled arachidonic acid are challenged with ionophore A23187.

After 1 minute (N-formyl-methionyl-leucyl-phenylalanine) or 2 minutes (A23187) the reaction is quenched, the mixture centrifuged and the supernatent assayed by scintillation techniques.

The compounds are indicated for use in the treatment IQ or prophylaxis of inflammatory conditions in mammals including man. Conditions that may be specifically mentioned are: osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, inflamed joints; eczema, psoriasis, dermatitis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including uveitis and conjunctivitis; lung disorders in which inflammation is involved, eg asthma, bronchitis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, bacteraemia, endotoxaemia (septic shock) and pancreatitis; conditions of the gastrointestinal tract including aphthous ulcers, gingivitis, Crohn's disease (a condition of the small and sometimes also of the large intestine), atrophic gastritis and gastritis varialoforme (conditions of the stomach), ulcerative colitis (a condition of the large and sometimes of the small intestine), coeliac disease (a condition of the small intestine), regional ileitis (a regional inflammatory condition of the terminal ileum), peptic ulceration (a condition of the stomach and duodenum) and irritable bowel syndrome; pyresis, pain; and other conditions associated with inflammation, particularly IQ those in which phospholipid, lipoxygenase and cyclooxygenase products are a factor.

For the above mentioned uses the doses administered will, of course, vary with compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compound is administered at a daily dosage of from about O.lmg to about 20mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form. For man the total daily dose is in 2q the range of from 7.0mg to l,400mg and unit dosage forms suitable for oral administration comprise from 2.Omg to l,400mg of the compound admixed with a solid or liquid pharmaceutical diluent or carrier.

The compounds of formula I may be used on their own or in the form of appropriate medicinal preparations for - 18 enteral, parenteral or topical administration.

According to the invention there is also provided a pharmaceutical composition comprising preferably less than 80% and more preferably less than 50% by weight of a compound of formula I, or a pharmaceutically acceptable derivative thereof, with the provisos that a) when R1 represents methyl, then R2 is other than an alkyl group or benzyl, and b) when R2 represents methyl, then R1 is other than IQ an alkyl Ci_i8 group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl, and c) when R2 represents iso-propyl, n represents 1, q represents 0 and R3 represents hydroxy, then R1 is other than an alkyl C1-6 group optionally substituted by phenyl, and d) when n represents l, q represents 0, and R represents hydroxy or t-butoxy, then R1 and R2 do not both represent CH3(CH2)i4“» in admixture with a pharmaceutically acceptable 20 adjuvant, diluent or carrier.

Examples of such adjuvants, diluents and carriers are for tablets and dragees - lactose, starch, talc, stearic acid; for capsules - tartaric acid or lactose; for injectable solutions - water, alcohols, glycerin, - 19 vegatable oils; for suppositories - natural or hardened oils or waxes Compositions in a form suitable for oesophageal administration include tablets, capsules and dragees; compositions in a form suitable for administration to the lung include aerosols, particularly pressurised aerosols; compositions in a form suitable for administration to the skin include creams, eg oil-in-water emulsions or 2q water-in-oil emulsions; compositions in a form suitable for administration to the eye include drops amd ointments.

The compounds of formula I have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds of similar structure.

The invention is illustrated but in no way limited by the following examples.

Example 1 -Methvl-3-r(1-oxohexadecvl)aminolhexanoic acid, dicyclohexylamine salt.

A mixture of 3-amino-5-methylhexanoic acid (0.23g), hexadecanoyl chloride (0.44g) and pyridine (14ml) in - 20 dichloromethane (20ml) was heated under reflux for 4 hours. The solution was poured into water and separated. The organic solution was washed with dilute hydrochloric acid and water, then dried and the solvents removed by rotary evaporation. Purification of the residue by chromatography gave a white solid (0.18g). A solution of the white solid in dichloromethane was treated with dicyclohexylamine to yield the product salt (0.15g) as a white solid after recrystallisation from acetonitrile.

M.p.: 100-101.5’C C23H45NO3 recIuires: C 74.41, H 12.13, N 4.96% found: C 74.78, H 11.58, N 4.98%.

Example 2 Ethvl 4(R)-r(1-oxohexadecvl) amino1-6-methvlheptanoate a) Ethvl 4(R)-rt-butoxvcarbonvlaminol-6-methvlhept-2-enoate To a solution of potassium t-butoxide (1.06g) in dry tetrahydrofuran (30ml) stirred at room temperature under nitrogen was added dropwise over 5 minutes a solution of triethyl phosphonoacetate (2.25ml) in dry tetrahydrofuran (15ml). After 30 minutes a solution of N-t-butoxycarbonyl(R)-leucinal in dry tetrahydrofuran (9.48ml of 1M solution) was added and the solution stirred at room temperature for hours then heated under reflux for 3 hours.

The mixture was evaporated, partitioned between dilute hydrochloric acid and ethyl acetate, the organic extract - 21 washed with brine, dried over magnesium sulphate and the solvent removed by rotary evaporation. Chromatography of the residue over silica with 20% ethyl acetate/hexane gave a colourless oil which crystallised on scratching to give the title compound as a white solid (0.41g, 30%).

Mass spectrum: m/e = 286 (m+l). b) Ethyl 4fR)-r(1-oxohexadecvl)aminoT-6-methvlhept-2-enoate A solution of the BOC-protected amine (as prepared above, 1.23mmol, 0.35g) in dichloromethane (20ml) was 2Q stirred, cooled to 0°C and treated with trifluoroacetic acid (4ml). After 19 hours the mixture was evaporated, co-evaporated with toluene and the residue dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulphate and evaporated to give the crude free amine as a yellow oil. The oil was dissolved in dichloromethane (100ml), treated with triethylamine (0.172ml) followed by hexadecanoyl chloride (0.338g) and the mixture was stirred for 19 hours. The solution was washed with dilute 2q hydrochloric acid, brine, dried over magnesium sulphate and evaporated. Chromatography of the residue with 20% ethyl acetate/hexane over silica gave the title compound as a white crystalline solid (0.32g, 62%).

M.p.: 52-54eC.

Mass spectrum: m/e = 423 (M) . - 22 c) Ethyl 4fR)-r fl-oxohexadecvl)aminol-6-methvlheptanoate A solution of the a,β-unsaturated ester as prepared in step b) (0.29g) in methanol (50ml) was treated with 10% palladium on charcoal and hydrogenated at atmospheric pressure for 4 hours. The mixture was filtered through hyflo and evaporated to a white solid. Flash chromatography of the solid using ethyl acetate/hexane mixtures afforded the sub-titled compound as a white solid (0.27g, 93%).

M.p.: 55-57’C IQ Mass spectrum: m/e = 425 (M) Example 3 4(R)-r(1-Oxohexadecvl)aminol-6-methvlheptanoic acid A solution of ethyl 4(R)-[(1-oxohexadecyl)amino]-6methylheptanoate (0.23g)in tetrahydrofuran (20ml) was mixed with a solution of lithium hydroxide hydrate (0.023g) in water (8ml) and stirred at room temperature for 16 hours. After evaporation the residue was partitioned between dilute hydrochloric acid and ethyl acetate and the organic layer was separated, dried over magnesium sulphate and evaporated to give the title compound as a white solid (0.22g, 100%).

M.p.: 67-69’C Mass spectrum: m/e = 398 (M + 1), 420 (M + Na) Example 4 Methyl (E)-5-methvl-3(Rl-Γ(l-oxodec-3-envl)aminoIhexanoate - 23 A solution of methyl 3(R)-amino-5-methylhexanoate (0.56g) in dichloromethane (10ml) was added over 10 min. to a stirred solution of trans 3-decenoic acid (0.6g) and dicyclohexylcarbodiimide (0.72g) in dichloromethane (20ml).

The mixture was stirred for 16 hours at room temperature when the precipitated solids were removed by filtration.

The filtrate was evaporated and the residual oil was purified by flash chromatography on silica to give the title compound as a yellow oil (0.65g). 2q Mass spectrum (Plasma spray): m/e = 312 (M + H)+ Example 5 (E)-5-Methvl-3(R)-Γ(l-oxodec-3-envl)aminolhexanoic acid dicyclohexylamine salt A solution of the compound from Example 5 (0.53g) in tetrahydrofuran (5ml) was added to a solution of lithium hydroxide monohydrate (O.llg) in water (5ml) and the reaction mixture was stirred for 2 hours at room temperature. The solution was acidified with dilute hydrochloric acid and extracted with ether. The combined ether extracts were washed with water, dried and evaporated. The residual oil was purified by flash chromatography on silica to give a colourless oil (0.35g).

A solution of this oil in ethanol (50ml) was treated with dicyclohexylamine to yield the product salt as a white solid (0.4g). - 24 M.p.: 126-127’C C17H31NO3,C12H23N requires: C 72.75%, found: C 72.75%, H 11.37%, H 11.66%, Mass spectrum: (plasma spray) (M + H)+ N 5.85% N 5.87% m/e = 298 (M + H)+ 182 The following compounds were prepared by analogous procedures: ii) (2)-5-methvl-3(R)-Γ(l-oxooctadec-6-envl)aminolhexanoic 2Q acid dicyclohexylamine salt M.p.: 88-89’C C25H47NO3‘C12H23N requires: C 75.20%, H 11.94%, N 4.74% found: C 75.02%, H 12.06%, N 4.81% iii) (Z)-5-methvl-3(R)-Γ(l-oxohexadec-9-envl)aminolhexanoic acid adamantanamine salt M.p.: 107-108’C C23H43NO3 ’ ^12^23N· 0 · 6H2O requires: C 72.90%, H 11.34%, N 5.15%, H2O 2.0% found: C 73.14%, H 10.90%, N 5.51%, H20 2.1% Example 6 Ethyl 2,6-dimethvl-4(R)-Γ(1-oxooctvllaminolheptanoate a) Ethvl 4(R)-rt-butoxvcarbonvlaminol-2,6-dimethyl hept-2-enoate A solution of N-t-butoxycarbonyl-(R)-leucinal (2.15g) - 25 in dry dichloromethane (50ml) was stirred under nitrogen at room temperature and treated with a solution of ethyl 2-(triphenylphosphoranylidene)propionate (5.44g). After 17 hours the mixture was evaporated, treated with hexane-ethyl acetate (10:1, 100ml) and filtered to remove the triphenylphosphine oxide. The filtrate was evaporated and the residue chromatographed over silica with ethyl acetatehexane (10:1) to give a colourless crystalline solid identified as the sub-titled compound (2.23g).

M.p.: 47-48'C Mass spectrum: (FAB) m/e = 384 (M + Rb)+ aD= +5.62[C = 0.53, MeOH] b) Ethvl 2,6-dimethvl-4(R)-Γ(1-oxooctvl)aminolhept-2-enoate A solution of the product from step a) (1.78g) in dichloromethane (30ml) was stirred at room temperature and treated with trifluoroacetic acid (5ml). After 19 hours the mixture was evaporated, co-evaporated with toluene and the residue dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate, dried over 2q magnesium sulphate and evaporated to give the crude free amine as a yellow oil. The oil was dissolved in dichloromethane (20ml), treated with triethylamine (0.83ml) followed by octanoyl chloride (1.02ml) and stirred at room temperature for 20 hours. The resulting solution was washed with dilute hydrochloric acid, brine, dried over magnesium It 904522 - 26 sulphate and evaporated. Chromatography of the residue with % ethyl acetate/hexane over silica gave the sub-titled compound as a colourless oil.

Mass spectrum: (FAB) m/e = 326 (M + H)+ c) Ethvl 2.6-dimethvl-4(R)-Γ(1-oxooctvl) amino1heptanoate A solution of the product from step b) (1.3g) was dissolved in methanol (50ml), treated with 10% palladium on charcoal (0.13g) and hydrogenated at atmospheric pressure for 5 hours. The mixture was filtered through hyflo and evaporated. The mixture of diastereomers was separated by flash chromatography on silica to give the less polar isomer as an oil (0.57g), and the more polar isomer as an oil (0.65g).

Mass spectrum less polar isomer: (plasma spray) m/e = 328 15 (M + H) + Mass spectrum more polar isomer: (plasma spray) m/e = 328 (M + H) + Example 7 2.6-Dimethvl-4(Rl-Γ(1-oxooctvl) amino1heptanoic acid 1-adamantanamine salt A solution of the less polar isomer of the product from Example 6 (0.47g) was dissolved in tetrahydrofuran (30ml), stirred at room temperature and treated with a solution of lithium hydroxide hydrate (O.lg) in water (12ml). After 16 hours the mixture was evaporated and the - 27 residue partitioned between dilute hydrochloric acid and ethyl acetate and the organic layer separated, washed with brine and dried over magnesium sulphate. The solvent was evaporated and the residue purified by chromatography on silica with 30% ethyl acetate/hexane to give the free acid as a colourless oil (0.38g). The oil was dissolved in dichloromethane (10ml), treated with 1-adamantanamine (0.177g) and evaporated to give the title salt as a cream foam (0.5g).

Mass spectrum: (FAB) m/e = 451 (M + H)+C17H33N03*C10H17N-°*33H20 requires: C 71.04%, H 11.18%, N 6.14%, H2O 1.27% found: C 71.34%, H 11.25%, N 6.01%, H2O 1.27% The more polar diastereomer of the product from Example 6 was treated analogously to give a white foam (0.58g).

Mass spectrum: (FAB) m/e = 451 (M + H)+ Elemental analysis: ε37Η33ΝΟ3.C1QH17N. 0.36H20 requires: C 70.94%, H 11.18%, N 6.13%, H2O 1.40% found: C 70.95%, H 10.96%, N 6.04%, H2O 1.40% Example 8 Methyl 5-methvl-3(R)-Γ(1-oxododecvl)aminoIhexanoate A solution of methyl 3(R)-amino-5-methylhexanoate (0.55g) and triethylamine (0.35g) in dichloromethane (20ml) was treated with a solution of dodecanoyl chloride (0.76g) - 28 in dichloromethane (10ml) and the resulting mixture was stirred at room temperature for 16 hours. The organic solution was washed with water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, dried and evaporated. The residual oil was purified by flash chromatography on silica to give white crystals (l.lg). M.p.: 49-50’C Mass spectrum: (electron impact) m/e = 341 M+ Example 9 2Q 5-Methvl-3(R)-Γ(1-oxododecvl)aminolhexanoic acid A solution of the product from Example 8 (l.lg) in tetrahydrofuran (10ml) was added to a solution of lithium hydroxide monohydrate (0.2g) in water (10ml) and the reaction mixture was stirred for 16 hours at room temperature. The solution was acidified with dilute hydrochloric acid and extracted with ether. The combined ether extracts were washed with water, dried and evaporated. The residual solid was purified by flash chromatography on silica to give the title compound as a white solid.

M.p.: 57-58‘C Mass spectrum: (electron impact) m/e = 399 (M - H + TMS) + C19H37NO3 requires: C 69.68%, H 11.39%, N 4.28% found: C 69.99%, H 11.20%, N 4.07% The following compounds were prepared by analogous - 29 procedures. ii) 5-Methvl-3(R)-Γ(l-oxo-10-phenvldecvl)aminolhexanoic acid dicyclohexylamine salt M.p.: 112-113°C c23H37NO3,C12H23N requires: C 75.49%, H 10.86%, N 5.03% found: C 75.55%, H 10.72%, N 4.49% iii) 3(R)-r(1-Oxohexadecyl)aminolhexanoic acid M.p.: 96-97’C C22H43NO3 ΤθΦ1!1·®3! c 71.50%, H 11.73%, N 3.79% found: C 71.39%, H 11.52%, N 3.67% iv) fR)-ff-r f1-Oxooctyl)aminoIbenzenebutanoic acid M.p.: 100-102’C C18H27NO3 re(5uires: C 70.82%, H 8.85%, N 4.59% 15 found: C 70.70%, H 8.94%, N 4.27% v) fRl-6-Γ(1-Oxohexadecvl)aminolbenzenebutanoic acid M.p.: 113-114’C C26H43NO3 requires: C 74.82%, H 10.31%, N 3.36% found: C 74.75%, H 10.42%, N 3.25% 2Q vi) 5-Methvl-3(R)-Γ(1-oxooctvl)aminolhexanoic acid dicyclohexylamine salt M.p.: 134-135’C C15H29NO3,C12H23N requires: C 71.68% found: C 71.70% H 11.50% H 11.48% N 6.19% N 6.54% ΙΕ 904522 - 30 vii) 5-Methvl-3(R)-Γ(l-oxo-8-phenvloctvl)aminolhexanoic acid dicyclohexylamine salt M.p.: 109—110’C C21H3 3NO3 *C12H23N requires: C 74.95%, H 10.67% found: C 74.93%, H 10.48% N 5.30% N 5.27% viii) 5-Methvl-3(R)-Γ(1-oxohexadecvl)aminolhexanoic acid M.p.: 78-79’C C23H45NO3 requires: C 72.01%, H 11.82%, N 3.65% found: C 72.21%, H 11.44%, N 3.56% ix) (El-5-Methvl-3(R)-Γ(l-oxodec-4-envllaminolhexanoic acid dicyclohexylamine salt M.p.: 124-125’C C17H31NO3,C12H23N15 requires: C72.75: H 11.37; N 5.85% found: C72.41; H 11.25; N 5.81% x) (E)-g(R)-r(l-Oxodec-3-enyl1 aminolbenzenebutanoic acid dicyclohexylamine salt M.p.: 141-142’C C20H29NO3*C12H23N requires: C74.95; H10.22; N4.56% found: C75.05; H9.83; N5.32% xi) (R)-5-Methvl-3Γ(l-oxo-7-phenvlheptvl)aminolhexanoic acid dicyclohexylamine salt 25 M.p.: 200-202’C - 31 . C20H31NO3,C12H23N requires: C74.66; H10.57; N5.44% found: C74.45, H10.64; N5.07% Example 10 Methyl 3(R)-r(2-hydroxy-1-oxohexadecvl)aminol-5-methvlhexanoate 2-Hydroxyhexadecanoic acid (1.3g), followed by 1-hydroxybenzotriazole (0.63g) were added to a stirred solution of methyl 3(R)-amino-5-methylhexanoate (0.74g) in 2Q dichloromethane (75ml). A solution of dicyclohexylcarbodiimide (0.96g) in dichloromethane (25ml) was added and the mixture was stirred for 5 hours. The precipitated solids were removed by filtration and the filtrate evaporated. The residue was taken up in a mixture of diethyl ether and ethyl acetate which was washed with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, water, dried and evaporated to give a white solid. The mixture of diastereomers was separated by flash chromatography on silica to give the less polar isomer as a white solid. Recrystallisation from hexane gave the title compound as white crystals (0.42g).

M.p.: 76-77eC Mass spectrum: m/e = 414 (M + H)+ The more polar diastereomer was isolated as a white solid (0.55g) - 32 M.p. 87-88’C Mass spectrum: m/e = 414 (M + H)+ Example 11 3(R)-f2-Hydroxv-l-oxohexadecvl)aminol-5-methvlhexanoic acid The less polar isomer from Example 10 (0.4g) in tetrahydrofuran (10ml) was treated with a solution of potassium hydroxide (O.llg) in water (5ml). After stirring for 4 hours the tetrahydrofuran was evaporated. The aqueous residue was washed with ether and acidified with dilute IQ hydrochloric acid. The product was extracted with ether which was washed with water, dried and evaporated. Recrystallisation of the residue from ethyl acetate gave the title compound as white crystals (O.llg).

M.p.: 76-77'C Mass spectrum: (plasma spray) m/e = 400 (M + H)+C23H45NO4 requires: C 69.13%, H 11.35%, N 3.51% found: 68.83%, H 11.33%, N 3.59% The more polar product from Example 10 (0.54g) was treated analogously to give the other diastereomer as white 2q crystals (0.32g).

M.p.: 93’C Mass spectrum: (plasma spray) m/e = 400 (M + H)+C23H45NO4 requires: C 69.13%, H 11.35%, N 3.51% found: C 69.32%, H 11.04%, N 3.60% Example 12 - 33 Methvl (4S)-5-r (3-(1.11-Biphenyl)vl) thiol-4-Γ(1-oxodec -3-enyl) amino1pentanoate a) Methyl 4 (S1 - Γ(1,1-dimethylethoxy1 carbonyl1amino-5iodopentanoate A solution of methyl (S)-4-[(1,1-dimethylethoxy) carbonyl]-amino-5-hydroxypentanoate (11.8g) [prepared by the method of Shimamoto and Ohfune : Tet Lett 30 (29), 3803-3804 (1989)] in dry tetrahydrofuran (600ml) was treated with N,Ν'-dicyclohexylcarbodiimide methiodide 2q (31.5g) under nitrogen and heated at 50°C for 5 hours. The mixture was cooled, the solvent evaporated and the residual red oil was taken up in ethyl acetate. The organic solution was washed with saturated aqueous sodium metabisulphite and water then dried (MgSO4) and the solvent removed by rotary evaporation. Purification of the residue by chromatography gave a white solid (10.73g).

M.p. 93-95’C Mass spectrum: m/e = 358 (m+H) b) Methvl 5-Γ3-(1.11-biphenvllvl1 thiol-4(SI -Γ Γ(1.120 dimethylethoxy1 carbonyl1aminolpentanoate A solution of 3-phenylthiophenol (1.58) in dry dimethylformamide (25ml) was stirred under nitrogen and treated, batchwise, with sodium hydride (0.25g of 80% dispersion in oil) at room temperature. After a further ^-hour, a solution of the product of step a) (2.24g) in dry - 34 dimethylformamide (15ml) was added over 1 minute. The mixture was stirred for 3 hours, poured onto dilute hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with water, 50% aqueous sodium metabisulphite solution, water and saturated brine, then dried (MgS04) and the solvent removed by rotary evaporation. Purification of the residue by chromatography gave the sub-title product as an oil (2.29g) which slowly solidified.

M.p. 57-59’C Mass spectrum: m/e = 500 (M+Rb) c) Methyl (Ε1-5-Γ(3-(1.1’-biphenyl)vl)thiol-4(S)-r(1oxodec-3-env1) amino1pentanoate A solution of the product of part b), (1.43g) in dichloromethane (50ml) was treated with trifluoracetic acid (12ml) and stirred at room temperature for 18 hours. The excess trifluoracetic acid was evaporated and the residue taken up in dichloromethane. The organic solution was washed with 10% aqueous sodium bicarbonate solution and brine then dried (MgSO4) and the solvent evaporated to yield a gum (l.lg).

A solution of the gum (0.55g) in dichloromethane (25ml) was treated with 3-decenoic acid (0.3g), followed by N-hydroxybenzotriazole (0.23g) and then a solution of dicyclohexylcarbodiimide (0.36g) in dichloromethane - 35 (5ml). The mixture was stirred at room temperature for 18 hours, filtered and the filtrate evaporated. The residue was taken up in ethyl acetate, filtered, and the filtrate washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution, water then dried (MgSO4) and the solvent removed by rotary evaporation. Purification of the residue by chromatography gave a white solid which was recrystallised from a mixture of hexane and ethyl acetate to give the title product as a white solid (0.13g). !0 M.p.: 61-62’C Mass spectrum: = m/e = 468 (M+H) C28H37NO3S ΓθφΊίΓθ15·· C71.91; H7.97; N3.00; S6.86% found: C71.87; H8.07; N2.67; S6.36% The following compounds were prepared by analogous 15 procedures: ii) Methyl 5-Γ(3-(1,11-biphenyl)vl)thiol-4(S)-Γ(1-oxo5-phenvlpentvl)aminoIpentanoate M.p.: 96-97’C C29H33NO3S requires: C73.24; H6.99; N2.94; S6.7% found: C73.28; H7.20; N2.71; S6.59% iii) Methyl 5-Γ(3-(1,I1-biphenyl)vl)thio)l-4(S)-r(4cvclohexvl-l-oxobutvl)aminolpentanoate M.p.: 101-102’C C28H37NO3S requires: C71.91,; H7.97; N3.00; S6?86% found: C72.05; H8.27; N3.04; S6.48% - 36 iv) Methvl (Ε)-5-Γ(2,3.5,6-tetrafluorophenyl)thiol4(S)-Γ(1-oxodec-3-envl)aminolpentanoate M.p.: 67-68°C C22H29NO3F4S requires: C57.00; H6.31; N3.02% 5 found: C57.ll; H6.56; N2.94% Example 13 (Ε1-5-Γ(3-(1.lt-Biphenyl)vl)thiol-4(S)-r(1-oxodec -3-envl)-aminolpentanoic acid dicyclohexylamine salt A solution of the compound from Example 12 (0.35g) in 2Q tetrahydrofuran (5ml) was added to a solution of lithium hydroxide monohydrate (0.063g) in water (5ml) and the reaction mixture was stirred for 3 hours at room temperature. The tetrahydrofuran was evaporated and the aqueous residue was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water, dried (MgSO4) and evaporated.

The residual oil was taken up in dichloromethane (10ml), treated with dicyclohexylamine (O.llg) and the solvents removed by rotary evaporation. Recrystallisation of the residue from a mixture of ethyl acetate and hexane gave the title product as a white crystalline solid (0.17g) M.p.: 114-115’C Mass spectrum: m/e = 454 (M+H) C27H35NO3S,C12H23N requires: C73.77; H9.21; N4.41; S5.05* found: C73.50; H8.ll; N4.19; S4.99% The following compounds were prepared by analogous procedures. ii) 5-Γ3-(1.l'-Biphenyl)vl)thio1-4(S) -Γ(l-oxo-5-phenvlpentvl)aminolpentanoic acid.

M.p. 94-97’C C28H31NO3S requires: C72.85; H6.77; N3.03; S6.95% found: C73.15; H7.13; N3.12; S7.22% IQ iii) 5-Γ(3-(1.1'-Biphenyl1vl)thiol-4(S) -Γ(4-cvclohexvl -1-oxobutvl)aminolpentanoic acid.

M.p.: 134-135’C c27h35N°3s requires: C71.49; H7.78; N3.09; S7.07% found: C71.09; H.7.99; N3.04; S6.89% iv) 5-Γ(3—(l,1'—Biphenyl)vl)thio]—4(S)—Γ(l-oxo-7phenvlheptvl)aminolpentanoic acid M.p.: 95-96.5’C c30H35NO3s requires: C73.59; H7.20; N2.86; S6.55% found: C73.30; H7.34; N2.81; S6.70% v) 5-Γ(3-(1.1'-Biphenyl)vl)thiol-4(S) - Γ(l-oxo-8phenvl-octvl)aminolpentanoic acid dicvclohexvlamine salt M.p.: 142-143’C C31H37NO3S-C12H23N· °·65Μ h2° requires: C74.12; H8.87; N4.02; S4.60% 25 found: C74.39; H8.80; N3.93; S4.76% IE 90*522 vi) 5-Γ (3-(1,11-Biphenyl)vl)thio)-4(S)-[ (l-oxo-6phenvlhexvl)-aminolpentanoic acid M.p.: 99.5-100’C C29H33NO3S requires·· C73.23; H6.99; N2.94; S6.74% found: C73.48; H6.79; N3.02; S6.95% vii) (E)-4(S)-(l-Oxodec-3-envl)aminol-5-Γ Γ2-(4-phenyl) thiazolyl1 thiolpentanoic acid dicyclohexylamine salt M.p.: 141-144’C C24H32N2°3S2 *C12H33N 2q requires: C67.35; H8.64? N6.55% found: C67.23; H8.44; N6.54% viii) (E)-5-Γ(4-(1-Methvl-l-phenvl)ethvl)phenylthio)-4(S) Γ(l-oxodec-3-envl)aminolpentanoic acid M.p.: 99-102’C c30H41NO3S requires: C74.51; H9.53; N4.15% found: C74.55; H9.53; N4.11% ix) (Ε)-5-Γ(2,4-Di(1.1-dimethylethvl)phenvl)thiol-4(S)f(1-oxo-dec-3-envl)amino]pentanoic acid dicyclohexylamine salt 20 M.p.: 121-124’C C23H46NO3S·C12H23N requires: C73.49; H10.38; N4.18% found: C72.83. H10.18; N4.02% x) (E)-5-[(2,3.5,6-Tetrafluorophenyl)thiol-4(S)-T(125 oxodec-3-envl)aminolpentanoic acid dicyclohexylamine salt - 39 M.p.: 130-133’C C21H27NO3F4S·C12H23N requires: C62.93; H7.85; N4.45% found: C62.62; H7.85; N4.09% xi) (E)-4(S)-r(l-Oxodec-3-enyllaminol-5-Γ(2-thiadiazolvllthiolpentanoic acid M.p.: 90-91’C C18H28^2°3S2 requires: C56.22; H7.34; N7.28% found: C56.24; H7.40; N7.29% xii) (E)-5-(2-Naphthalenvlthio)-4(S)-Γ(l-oxodec-3-enyl)aminolpentanoic acid M.p. 85-87’C C25H33NO3S requires: C70.26; H7.73; N3.28% found: C70.44; H7.76; N2.98% xiii) 5-(2-Naphthalenvlthiol-4(SI -Γ(1-oxododecyll aminol-pentanoic acid M.p. 74-76’C C27H39NO3S requires: C70.90; H8.53; N3.06% found: C70.04; H8.43; N3.06% xiv) (Ε1-5-Γ(5-Methvl-1.3.4-thiadia2ol-2-vllthiol-4(Slfl-oxo-dec-3-envllaminolpentanoic acid M.p.: 83-84’C C18H29N3S2 requires: C54.ll; H7.32; NIO.52% found: C54.ll. H7.56; N10.40% xv) (E)-4(Sl-((l-Oxodec-3-envllaminol-5-Γ (4-pyridinyl1 IE 904522 - 40 thiolpentanoic acid M.p.: 146-148'C Mass spectrum m/e = 379 (M+H) xvi) 5-r(3-(1.11-Biphenyl1vl1 thiol-4(S) -Γ(7-ethvl-l5 oxononvl)aminolpentanoic acid M.p. 77-79’C C28H39NO3S requires: C71.60; H8.37; N2.98; S6.83% found: C71.72; H8.52; N2.87; S6.99% xvii) (E)-4(S)-r(l-0xodec-3-envllaminol-5-Γ(2-pyrimidinvl) 20 thiopentanoic acid M.p.: 96-98’C C19H29N3°3S requires: C60.08; H7.64; Nil.07% found: C60.16; H7.37; NIO.96% xv i i i) (Ε)-5-Γ(4-(1.11-Biphenyl1yllthiol-4(SI-Γ(l-oxodec-325 envl)aminolpentanoic acid M.p.: 120-122’C C23H35NO3S requires: C71.52; H7.73; N3.09% found: C71.67; H7.88; N3.13% xix) (El-4(S1-r(l-Oxo-7-phenvlheptvl)amino)-5-Γ(4-phenvl 20 methyllohenvlthiolpentanoic acid M.p.: 85-88’C C31H37NO3S requires: C73.87; H7.35; N2.78% found: C74.10; H7.61; N2.47% xx) (El-4(Sl-i(l-0xodec-3-envl)aminol-5-Γ(5-phenyl-l,2,425 triazol-2-yl)thiolpentanoic acid - 41 M.p.: 139-141’C c23h32n4°3s requires: C62.13; H7.25; N12.60% found: C61.89; H7.30; N12.33% xxi) (E)-5-[4.5-Diphenvl-2(1H)-imidazolyl)thiol-4(S)5 Γ(l-oxodec-3-envl)aminolpentanoic acid M.p.: 135-139’C C30H37N3O3S·0·67H2O requires: C67.76; H7.27; N7.90% 2.3% H2O found: C68.ll; H7.07; N7.80% 2.3% H2O xxii) f Ε)-5-Γ Γ1.1’-Biphenyl)-3-vllthiol-4 fS) — Γ(1-oxodec-4-envl)aminolpentanoic acid M.p.: 91-93’C C27H35NO3S requires: C71.49; H7.78; N3.09% found: C71.54; H7.71; N3.12% Example 14 Methyl (E)-3(S)-Γ(l-oxodec-3-envl)aminol-4(phenylthio)butanoate a) Methyl 3 (S) - Γ(1. Ι-dimethylethoxy) carbonyl1amino-4hvdroxvbutanoate A solution of N-[(1,1-dimethylethoxy)carbonyl]aspartic acid 4-methyl ester (24.6g) in ethyl acetate (400ml) was treated with N-hydroxysuccinimide (11.47g) and cooled to O’C. A solution of dicyclohexylcarbodiimide (20.57g) in ethyl acetate (250ml) was added slowly and the resulting mixture was stirred at room temperature for 18 hours. The 45# suspended solids were removed by filtration and the filtrate was evaporated. The residue was dissolved in dry tetrahydrofuran (250ml) and dry ethanol (50ml), cooled to -5’C and treated batchwise with sodium borohydride (11.31g) over 40 minutes. The mixture was stirred at O’C for a further 3 hours, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and the solvent evaporated. Purification of the residue by 2Q chromatography gave the sub-title product as a colourless oil (3.6g) Mass spectrum m/e = 318 (M+Rb) b) Methvl 3(S)-Γ(1.1-dimethvlethoxv)carbonyl1 amino-4iodobutanoate The sub-title product was obtained as a yellow solid by treatment of the product of step a) by a procedure analogous to that described in Example 12a).

Mass spectrum m/e = 428 (M+Rb) c) Methvl 3(S)-ΓΓ(1.1-dimethvlethoxv)carbonyl]amino-12Q 4-(phenylthio)butanoate The sub-title product was obtained as a gum from the product of step b) by a procedure analogous to that described in Example 12b).

Mass spectrum m/e = 325 d) Methvl (E)-3(S)-r(l-oxodec-3-envl)amino1-4-(phenvlthio)IE 904522 - 43 butanoate • The title product was obtained as an oil by treatment of the product of step c) by a procedure analogous to that described in Example 12c).

Mass spectrum m/e = 377 The following compounds were prepared by analogous procedures. ii) Methyl (E)-4-r4-nitrophenvl)thiol-3(S)-Γ(l-oxodec-3enyl)-aminolbutanoate 10 M.p.: 72-76’C <“21^30^2θ58 requires: C59.69; H7.16; N6.63% found: C59.90; H7.27; N6.38* iii) Methyl 3(S)-Γ(1-oxooctyl)aminol-4-(phenylthio)butanoate M.p.: 54-44’C C19H29NO3S requires: C64.92; H8.32; N3.98% found: C64.48; H8.13; N3.99% Example 15 (E)-3(S)-Γ(l-Oxodec-3-envl)aminol-4-(phenylthio)2Q butanoic acid dicyclohexylamine salt The title product was obtained as a colourless solid by treatment of the product of Example 14d) by the procedure of Example 13a).

M.p.: 127-130’C 25 C20H29NO3S’C12H33N* o,17H2° 9045# requires: C7O.O8; H9.63; N5.11% found: C69.83; H9.55; N5.26% The following compounds were prepared by analogous procedures: ii) (E)-3(S)-r(l-Oxodec-3-envl)aminol-4-Γ(2-dibenzofuran) thiolbutanoic acid dicyclohexylamine salt M.p. 101-103’C C26H31NO4S,C12H23N requires: C71.89; H8.57; N4.41% 2Q found: C71.83; H8.44; N4.38% iii) (Ε)-4-Γ(4-Nitrophenvl)thlo1-3(S)-Γ(l-oxodec-3-envl)aminolbutanoic acid M.p.: 113-116’C C20H28N2°5S requires: C58.80; H6.90; N6.86% 15 found: C58.56; H6.76; N6.60% iv) (E)-3(S)-r(l-Oxodec-3-envl)aminol-4-(phenvlmethvlthio) butanoic acid dicyclohexylamine salt M.p. 110-112’C C21H31NO3S,C12H23N 2θ requires: C70.92; H9.74; N5.01% found: C70.81; H9.92; N4.73% v) (E)—4—Γ(l-Naphthalenvlthiol-3(S)-Γd-oxodec-3-enyl) aminolbutanoic acid M.p.: 119-120’C c24H3lNO3s requires: C69.70; H7.56; N3.39* Αδ# found: C69.12; H7.85? Ν3.26% vi) (Ε)—4—Γ(2-(1.11-Biphenyl)vl)thiol-3(S)-Γ(1-oxodec-3-enyl)aminolbutanoic acid M.p.: 79-81eC C26H33NO3S requires: C71.04; H7.57; N3.19% found: C70.62; H7.64; N2.93% vii) 3 (S)-(Acetylamino)-4-(hexadecvlthio)butanoic acid M.p.: 91-92’C C22H43NO3S requires: C65.79; H10.79; N3.49% θ found: C65.84; H10.40; N3/48* viii) 4-Γ(4-(1.11-Biphenyl)vl)thiol-3(S)-Γ(1-oxooctvl)aminolbutanoic acid M.p.: 156-158’C C23H31NO3S requires: C69.70; H7.55; N3.39% 5 found: C69.60; H7.89; N3.36% ix) 4-Γ(Hexadecvl)thiol-3(S)-Γ(1-oxooctvl)aminol butanoic acid M.p.: 77-78’C C28H55NO3S requires: C69.23; H11.41; N2.88% ¢0 found: C69.07; H11.89; N2.90% x) (Ε1-4-Γ(4-Benzvl)phenylthio)1-3(S)-r(1-oxodecen3-envl)aminolbutanoic acid M.p.: 71-72’C C27H35N03S requires: C71.49; H7.78; N3.09% found: C71.27; H7.63; N2.92* - 46 xi) (Ε)-4-Γ(3-(1.1*-Biphenyllyl)thio1-3(S) -Γ(1-oxodec3-envl)aminolbutanoic acid M.p.: 94-96’C C26H33NO33S re<5uires: C71.04; H7.57; N3.19% found: C70.55; H7.41; N3.08% xii) 3(S)-Γ(1-Oxooctvl)aminol-4-Γ(2-phenylethyl)thiolbutanoic acid dicyclohexylamine salt M.p.: 120-121°C C20H31NO3S*C12H23H2 2q requires: C70.28; H9.95? N5.12% found: C70.56; H9.77; N5.20% xiii) 4-Γ(3-(1,11-Biphenyl)vl)thiol-3(S)-Γ(1-oxooctvl) aminolbutanoic acid M.p.: 78-80’C C24H31NO3S requires: C69.70; H7.55; N3.39% found: C69.48; H7/37; N3.38% xiv) 4-Octvlthio-3(S)-Γ(1-oxooctvl)aminolbutanoic acid M.p.: 71-72’C C20H39NO3S requir®535 C64.34; H10.45; N3.78% found: C64.59; H10.12; N3.93% xv) (E)-4-r2-Naphthalenvlthiol-3(S)-Γ(l-oxodec-3-envl) aminolbutanoic acid M.p.: 70-74’C C24H31NO3S requires: C69.70; H7.55; N3.39; S7.75% - 47 found: C70.03; H7.72; N3.57; S8.01% xvi) 4-r2-Naphthalenvlthio1-3(S)-Γ(1-oxooctvl)amino1butanoic acid M.p.: 99-100’C C22H29NO3S requires: C68.18; H7.54; N3.61% found: C68.53; H7.66; N3.66% Example 16 Methvl (Ε)-5-Γ(3-(1.11-Biphenyl)yl)oxvl-4(S)Γ(l-oxodec-3-envl)aminolpentanoate 2Q a) Methvl 5-Γ(3-(1,11-biphenyl)vl)oxvl-4(S)-Γ Γ(1.1dimethvlethoxv)carbonyl1aminolpentanoate A solution of methyl(S)-4-[(1,1-dimethylethoxy) carbonyl]amino-5-hydroxypentanoate (0.25g) in dry benzene (10ml) was treated with 3-phenylphenol (0.17g) and triphenylphosphine (0.26g). A solution of diisopropyl azodicarboxylate (0.20g) in dry benzene (10ml) was added over -hour. The mixture was stirred for 72 hours and then the solvent was evaporated. The residue was purified by chromatography to give the sub-title product as a 2q colourless oil (0.13g) Mass spectrum m/e = 400 (M+H) b) Methvl (Ε)-5-Γ(3-(1.11-biphenvl)vl)oxvl-4(S)-Γ(1oxodec-3-envl) amino1pentanoic acid The title product was obtained as a white solid by treatment of the product of step a) by a procedure - 48 analogous to that described in Example 12c).

M.p.: 65-66’C C28H37NO4 requires: C74.47; H8.26; N3.10% found: C74.40; H8.54; N3.17% Example 17 (E)-5-(3-(1.11-Biphenyl)vl)oxv1-4(S)-f(l-oxodec-3envl)aminolpentanoic acid The title product was obtained as a white solid from methyl (E)-5-[(3-(1,1’-biphenyl)yl)oxy]-4(S)-[(1-oxodec3-enyl)amino]pentanoic acid by a procedure analogous to that described in Example 13a).

M.p. 88-90’C C27H36NO4 requires: C73.94; H8.27; N3.19% found: C73.83; H7.96; N3.25% Example 18 (R)-N-Phenvlmethoxv-fl-((1-oxooctvl)aminobenzenebutanamide A solution of the compound of Example 9vi) (0.61g, 0.002 moles), benzyl hydroxylamine hydrochloride (0.32g, 0.002 moles), hydroxybenzotriazole (0.33, 0.002 moles) and triethylamine (0.2g, 0.002 moles) in a mixture of tetrahydrofuran and dichloromethane (20ml, 1:1) was stirred at room temperature for ij-hour. The mixture was cooled to 5’C and treated with dicyclohexylcarbodiimide (0.45g, 0.022 moles). The resulting solution was allowed to warm to room - 49 temperature, stirred for a further 16 hours and then acetic acid (2 drops) added. The mixture was filtered and the filtrate evaporated to a solid. A solution of the residue in ethyl acetate was washed with dilute hydrochloric acid, water, sodium bicarbonate solution and water. The dried organic solution was evaporated to low volume whereupon crystallisation commenced. The white solid recrystallised from a small volume of methanol to give the product, (650mg, 80%).

M.p.: 152-3’C c25H34N2°3 requires: C73.17; H8.29; N6.82% found: C73.17; H8.32; N6.49% Example 19 (R)-N-Hvdroxv-B-((1-oxooctvl)amino)benzenebutanamide 25 A solution of the compound of Example 18 (400mg) in ethanol (20ml) was stirred over 10% palladium on carbon for 3 hours at room temperature. The solution was filtered and the filtrate evaporated to a solid. The residue was recrystallised from ethyl acetate to give the title product (200mg, 64%) as colourless needles.

M.p.: 140-145’C.

C18H28N2°3 requires: C67.50; H8.75; N8.75% found: C67.52; H8.87; N8.79% Example 20 (E)-N-i4(S)-Γl-Amino-l-oxo-5-(2-naphthalenvlthio)1IE 904522 - 50 pentyl1dec-3-enamide a) 4(S)-Γ(1,1-Dimethvlethoxv)carbonyl)amino-5-(2naphthalenvlthio)pentanamide A solution of 4(S)-[(1,1-dimethylethoxy)carbonyl] amino-5-(2-naphthalenylthio)pentanoic acid (0.5g) in tetrahydrofuran (50ml) was treated with N-hydroxybenzotriazole (0.22g) followed by dicyclohexylcarboddiimide (0.33g). After stirring for 15 minutes ammonia (5ml) was added and the mixture was stirred 2Q for a further 20 minutes. The solvents were removed by evaporation and the residue was purified by chromatography to give the sub-titled product as a gum (0.4g).

Mass spectrum m/e = 375 (M+H) b) (E)-N-r4(S)-ri-Amino-l-oxo-5-(2-naphthalenvlthio)125 pentyl1dec-3-enamide The title product was obtained as a white solid by treatment of the product of step a) by a procedure analogous to that described in Example 12c).

M.p. 144-146’C C25^34N2°2S requires: C70.42; H7.98; N6.57 found: C69.61; H7.82; N6.38 Example 21 (E)-(R)-N-Hvdroxv-fl-Γ(l-oxodec-3-envl)aminolbenzene butanamide a) (E)-(R)-N-(l,1-Dimethylethoxy)-β-Γ(l-oxodec-3-envl) - 51 aminoIbenzenebutanamide A solution of the product of Example 9x) (1.2g), hydroxybenzotriazole (0.48g), triethylamine (0.36g) and 0-(t-butyl)hydroxylamine hydrochloride (0.45g) in dichloromethane (20ml) and tetrahydrofuran (20ml) was stirred at room temperature for hour. The solution was cooled to 10°C, treated with dicylohexylcarbodiimide (0.74g) and stirred at room temperature with acetic acid (0.1ml), filtered and the filtrated evaporated. The 2q residue was purified by flash chromatography on silica to give the sub-title product as a white solid (l.lg).

M.p.: 92-94’C Mass spectrum (FAB): m/e = 403 (M+H)+ b) (E)-(R)-N-Hvdroxv-fl-r(l-oxodec-3-envl)aminolbenzene butanamide A solution of the product (0.83g) of part a) in triflouroacetic acid (40ml) was stirred at room temperature for 16 hours. The solution was made alkaline (pH8) with saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate which was dried (MgSO4) and evaporated. Partial purification of the residue by flash chromatography gave a solid which was purified by recrystallisation from ethyl acetate to give the title product as a white solid (0.17g) M.p.: 134-136’C - 52 . c20H30N2°3 requires: C69.33? H8.75; N8.09% found: C69.25; H8.86: N8.28% The following compound was prepared by an analogous procedure: ii) (Ε)-Ν-Γ (4S)-Γl-Hvdroxvamino-5—Γ (3-(1,1'-biphenyl)yl) thiol-l-oxo1pentvl1dec-3-enamide M.p.: 102-103°C c27h36n2°3s requires: C69.20; H7.74; N5.98% found: C69.49; H7.66; N5.99% Example 22 Methyl (E)-5-(2-naphthalenvlthio)-4(S)-Γ(l-oxodec-3envl)aminol-2-(phenylmethyl)pentanoate a) Methyl 5-(2-naphthalenvlthio)-4(S)-triphenylmethyl amino)pentanoate A solution of methyl 4(S)-[(1-dimethylethoxy)carbonyl] amino-5-(2-naphthalenylthio)pentanoate (8.7g) (prepared by a procedure analogous to that described in Example 12b)) in dichloromethane (100ml) was stirred and treated with trifluoroacetic acid (10ml). After 20 hours the mixture was evaporated. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulphate and evaporated to give the crude free amine as a light brown oil. The oil was dissolved in dichloromethane (100ml), treated with triethylamine (4.2ml) followed by triphenylmethyl chloride - 53 (7.0g) and the mixture was stirred for 20 hours. The solution was washed with water, dried over magnesium sulphate and evaporated. Chromatography of the residue with 10% ethyl acetate/hexane over neutral alumina gave the title compound as a colourless gum (8.4g).

Mass spectrum: m/e = 532 (M+l). b) Methyl 5-(2-naphthalenylthio)-2-(phenylmethyl)-4(S) -(triphenylmethvlamino)pentanoate A solution of the product of part a) (2.0g) was dissolved in dry tetrahydrofuran (50ml) and cooled to -78’C under a nitrogen atmosphere. A 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.7ml) was added dropwise and stirred for 30 minutes. Benzyl bromide (0.6ml) was added and stirred at -78’C for 5 hours.

Aqueous citric acid was added and the mixture extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated. The residue oil was purified by flash chromatography on neutral alumina to give a colourless gum (1.2g).

Mass spectrum: m/e = 622 (M+l) c) Methyl 4(S)-amino-5-(2-naphthalenvlthio)-2(phenylmethyl) pentanoate A solution of the product of part b) (1.2g) in acetone (50ml) was treated with 2M hydrochloric acid (20ml). After hours the mixture was evaporated to a small volume. The - 54 residue was partitioned between ether and water and the ethereal layer discarded. The aqueous phase was neutralised with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried and evaporated leaving a light brown oil (0.6g).

Mass spectrum: m/e = 380 (M+l). d) Methvl (E)-5-(2-naphthalenvlthio)-4(S)-Γ(l-oxodec-3envl)amino1-2-(phenylmethyl)-pentanoate The sub-title product was obtained as an oil by treatment of the product of step c) (0.7g) by a procedure analogous to that described in Example 12c). The mixture of diastereomers was separated by flash chromatography on silica to give the less polar isomer as an oil (0.21g).

Mass spectrum: (FAB) m/e = 532 (M+l).

The more polar isomer was isolated as an oil (0.25g) Mass spectrum: (FAB) m/e = 532 (M+l).

Example 23 (E)-5-(2-Naphthalenvlthio)-4(S)-r(l-oxodec-3-envl) aminol-2-(phenylmethyl)pentanoic acid The title product was obtained as an oil (O.lg) by treatment of the less polar product of Example 23d) (0.26g) by a procedure analogous to that described in Example 11. Mass spectrum (FAB): m/e = 518 (M+l)+ The more polar product of Example 23d) (0.31g) was treated analogously to give the other diastereomer as an - 55 oil (0.03g).

Mass spectrum (FAB): m/e = 518 (M+l)+.

Example 24 (R) -Β-ΓΝ-Methvl-N-(1-oxooctvl)aminolbenzenebutanoic acid Prepared by method analogous to Example 11.

M.p. 107-9’C C19H29NO3 requires: C 71.47; H 9.09; N 4.39 % found: C 70.90; H 8.50; N 4.40 %

Claims (17)

Claims

1. The use of a compound of formula I, R 2 1 I 3 5 R J --CON-CH-(CH 2 ) n -[Y(CH 2 ) p ] q -COR J I i 5 in which R 1 represents an alkyl or alkenyl ε 1-18 group 20 optionally substituted by an aryl group or hydroxy or a cycloalkyl C 3 _g group, R 2 represents an alkyl C3_18 group optionally substituted by an aryl group, or R 2 represents a group -CH2-X-R 4 wherein X represents O or S, and R 4 25 represents hydrogen, an aryl group, or an alkyl or alkenyl C 1-18 group optionally substituted by an aryl group, R 3 represents OH, alkoxy C2_g or -NHR 31 , wherein R 31 represents hydrogen, alkyl ^i-g, OH or 20 alkoxy C^.g optionally substituted by an aryl group, R 5 represents hydrogen, an aryl group or an alkyl or alkenyl C2„ 18 group optionally substituted by an aryl group, n represents 0, 1, 2 or 3, p represents 0, 1 or 2, - 57 q represents 0 or 1, Y represents -CHR 6 -, -CH=CH-, 0 or S, in which R 6 represents hydrogen, an aryl group or an alkyl or alkenyl C^-xg group optionally substituted by an aryl group, 5 or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of inflammation.

2. A method of treatment or prophylaxis of inflammation, which method comprises administering a therapeutically 2θ effective quantity of a compound of formula I, as defined in Claim 1, to a patient suffering from or susceptible to an inflammatory condition.

3. A compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable derivative thereof, with the 25 provisos that a) when R 1 represents methyl, then R 2 is other than an alkyl C2_28 9 rou P or benzyl, and b) when R 2 represents methyl, then R 1 is other than an alkyl c i_ig group, optionally substituted by phenyl, 2θ or 2-(5-nitro-2-furyl)ethylenyl, and c) when R 2 represents iso-propyl, n represents 1, q 3 1 represents 0 and R represents hydroxy, then R is other than an alkyl C2_ 6 group optionally substituted by phenyl, and 25 d) when n represents 1, q represents 0, and R 3 - 58 represents hydroxy or t-butoxy, then R 1 and R 2 do not both represent CH 3 (CH 2 )24”, for use as a pharmaceutical.

4. A compound of formula I, as defined in Claim 1, or a 5. Pharmaceutically acceptable derivative thereof, with the provisos that i) when R 1 represents methyl, then R 2 is other than an alkyl C 3 _ 18 group or benzyl or 2-phenylethyl or -CH 2 OH or -CH 2 SCH 3 , and 20 ii) when R 2 represents methyl, then R 1 is other than an alkyl group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl or 2-(3-phthalimido)propyl or CH 2 =CH- or CH 3 CH=CH-, and iii) when R 2 represents iso-propyl or ethyl, n represents 25 1, q represents 0, and R J represents hydroxy, then R is other than an alkyl C 3 _ 6 group optionally substituted by phenyl, and iv) when R 2 represents benzyl, n represents 0, Y represents -CH=CH-, p represents 1, q represents 1, and 20 R 1 represents 2-methylpropyl, then R 3 is other than hydroxy or methoxy, and v) when R 1 represents heptadec-8-enyl, n represents 1, q represents 0 and R represents hydroxy, then R is other than n-propyl, and 25 vi) when n represents 1, q represents 0, and R 3 - 59 represents hydroxy or t-butoxy, then R 1 and R 2 do not both represent CH 3 (CH 2 ) 14 -, and vii) when R 1 represents n-hexyl, (CH 2 ) n [Y(CH 2 ) p ] q represents (CH 2 ) 4 , and R 3 5 represents hydroxy, then R 2 is other than n-pentyl.

5. A compound according to Claim 4, in which R 2 represents alkyl ΰ 1-18 , optionally substituted by phenyl, or a group of the formula -ch 2 -x-r 4 20 in which R 4 represents alkyl C2_ 18 , an aryl group or alkyl substituted by an aryl group.

6. A compound according to Claim 5, wherein R 4 represents an aryl group.

7. A compound according to Claim 4, wherein 25 R 3 represents alkyl or alkenyl C 3 _ 18 , optionally substituted by hydroxy, phenyl or cycloalkyl C 3 _ 6 , R 2 represents alkyl C2_ 18 , optionally substituted by phenyl, or a group -ch 2 -x-r 4 20 wherein X represents S or O, and R 4 represents alkyl C 1-18 , an aryl group or alkyl ΰ 3 _ 18 substituted by an aryl group, R 3 represents hydroxy, alkoxy C2_g or NHR 31 wherein R 31 represents hydrogen, alkyl Ci_g, hydroxy or 25 alkoxy C 1-6 optionally substituted by phenyl, and - 60 n represents 0, 1 or 2, q represents 1, and Y represents -CHR 6 -, in which R 6 represents hydrogen or alkyl Cj_ 6 , 5 or a pharmaceutically acceptable derivative thereof.

8. A compound according to Claim 4, which is 5-Methyl-3-[(1-oxohexadecyl)amino]hexanoic acid; Ethyl 4(R)-[(1-oxohexadecyl)amino]-6-methylheptanoate; 4(R)-[(1-Oxohexadecyl) amino]-6-methylheptanoic acid; IQ Methyl (E)-5-methyl-3(R)-[(l-oxodec-3-enyl)amino]hexanoate; (E)-5-Methyl-3(R)-[(l-oxodec-3-enyl)amino]hexanoic acid; (Z)-5-methyl-3(R)-[(l-oxooctadec-6-enyl)amino]hexanoic acid; (Z)-5-methyl-3(R)-[(l-oxohexadec-

9. -enyl)amino]hexanoic 25 acid; Ethyl 2,6-dimethyl-4(R)-[(1-oxooctyl)amino]heptanoate; Ethyl 2,6-dimethyl-4(R)-[(1-oxooctyl)amino]hept-2-enoate; 2,6-Dimethyl-4(R)-[(1-oxooctyl)amino]heptanoic acid; Methyl 5-methyl-3(R)-[(1-oxododecyl)aminojhexanoate; 2Q 5-Methyl-3(R)-[(1-oxododecyl) amino]hexanoic acid; 5-Methyl-3(R)-[(l-oxo-10-phenyldecyl)amino]hexanoic acid; 3(R)-[(l-Oxohexadecyl)amino]hexanoic acid; (R)-/J-[ (l-Oxooctyl) amino]benzenebutanoic acid; (R)-β-((l-Oxohexadecyl) amino]benzenebutanoic acid; 25 5-Methyl-3(R)-[(1-oxooctyl)amino)hexanoic acid; -615-Methyl-3(R)-[(l-oxo-8-phenyloctyl)amino]hexanoic acid; 5-Methyl-3(R)-[(1-oxohexadecyl)amino]hexanoic acid; (E)-5-Methyl-3(R)-[(l-oxodec-4-enyl)amino]hexanoic acid; (E)-j8(R)-[ (l-Oxodec-3-enyl)amino]benzenebutanoic acid; 5 (R)-5-Methyl-3[(l-oxo-7-phenylheptyl)amino]hexanoic acid; Methyl 3(R)-[(2-hydroxy-l-oxohexadecyl)amino]-5-methylhexanoate; 3(R)-[2-Hydroxy-1-oxohexadecyl)amino]-5-methylhexanoic acid; 2Q Methyl (4S)-5-[(3-(1,1'-Biphenyl)yl)thio]-4-[(1-oxodec -3-enyl)amino]pentanoate; Methyl 5-[(3-(1,1'-biphenyl)yl)thio]-4(S)-[(1-oxo5-phenylpenty1) amino]pentanoate; Methyl 5-[(3-(1,1'-biphenyl)yl)thio)]-4(S)-[(425 cyclohexyl-l-oxobutyl)amino]pentanoate; Methyl (E)-5-((2,3,5,6-tetrafluorophenyl)thio]4(S)-[(l-oxodec-3-enyl)amino]pentanoate; (E)-5-((3-(1,1 1 -Biphenyl)yl)thio]-4(S)-[(1-oxodec -3-enyl)-amino]pentanoic acid; 20 5-[3-(1,1'-Biphenyl)yl) thio]-4(S)-[(1-oxo-5-phenylpentyl) amino] pentanoic acid; 5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)—[(4-cyclohexyl -1-oxobuty1) amino]pentanoic acid; 5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(l-oxo-725 phenylheptyl)amino]pentanoic acid; - 62 5-((3-(1,1'-Biphenyl)yl)thio]-4(S)-[(l-oxo-8phenyl-octyl) amino]pentanoic acid; 5-[(3-(1,1’-Biphenyl)yl)thio)-4(S)-((l-oxo-6phenylhexyl)-amino]pentanoic acid; 5 (E)-4(S)-(l-Oxodec-3-enyl)amino]-5-([2-(4-phenyl) thiazolyl]thio]pentanoic acid; (E)-5-[(4-(1-Methyl-l-phenyl)ethyl)phenylthio]-4(S) — [(l-oxodec-3-enyl)amino]pentanoic acid; (E)-5-((2,4-Di(1,1-dimethylethyl)phenyl)thio]-4(S)20 [(l-oxo-dec-3-enyl)amino]pentanoic acid; (E)-5-((2,3,5,6-Tetrafluorophenyl)thio]-4(S)-((1oxodec-3-enyl)amino]pentanoic acid; (E)-4(S)-[(l-Oxodec-3-enyl)amino]-5-((2-thiadiazolyl) thio]pentanoic acid; 25 (E)-5-(2-Naphthalenylthio)-4(S)-[(l-oxodec-3-enyl)amino)pentanoic acid; 5-(2-Naphthalenylthio)-4(S)-[(1-oxododecyl) amino]-pentanoic acid; (E)-5-((5-Methyl-l,3,4-thiadiazol-2-yl)thio]-4(S)2Q [l-oxo-dec-3-enyl)amino]pentanoic acid; (E)-4(S)-[(l-0xodec-3-enyl)amino]-5-((4-pyridinyl)thio]pentanoic acid; 5-((3-(1,l'-Biphenyl)yl)thio]-4(S)-((7-ethyl-loxononyl)amino]pentanoic acid; 25 (E)-4(S)-[(l-Oxodec-3-enyl)amino]-5-((2-pyrimidinyl) - 63 thiopentanoic acid? (E)-5-[(4-(1,1'-Biphenyl)yl)thio]-4(S) -[(l-oxodec-3enyl)amino]pentanoic acid? (E)-4(S)-[(l-Oxo-7-phenylheptyl)amino]-5-[(4-phenyl 5 methyl)phenylthio]pentanoic acid; (E)-4(S)-[(l-Oxodec-3-enyl)amino]-5-[(5-phenyl-l,2,4triazol-2-yl)thio]pentanoic acid; (E)-5-[4,5-Diphenyl-2(1H)-imidazolyl)thio]-4(S)[(l-oxodec-3-enyl)amino]pentanoic acid; 2Q (E)-5-[[1,1'-Biphenyl)-3-yl]thio]-4(S)-[(1-oxodec-4-enyl)amino]pentanoic acid; Methyl (E)-3(S)-((l-oxodec-3-enyl)amino]-4(phenylthio)butanoate; Methyl (E)-4-[4-nitrophenyl)thio]-3(S)-[(l-oxodec-325 enyl)-amino]butanoate; Methyl 3(S)-[(1-oxooctyl)amino]-4-(phenylthio)butanoate; (E)-3(S)-[(l-Oxodec-3-enyl)amino]-4-(phenylthio)butanoic acid; 20 (E)-3(S)-[(1-Oxodec-3-enyl)amino]-4-[(2-dibenzofuran) thio]butanoic acid; (E)-4-((4-Nitrophenyl)thio]-3(S)-[(l-oxodec-3-enyl) amino]butanoic acid; (E)-3(S)-[(l-Oxodec-3-enyl)amino]-4-(phenylmethylthio) 25 butanoic acid; - 64 . (E)-4-((l-Naphthalenylthio]-3(S)-((l-oxodec-3-enyl) amino]butanoic acid; (E)-4-((2-(1,1’-Biphenyl)yl)thio]-3(S)-[(1-oxodec-3-enyl)amino]butanoic acid; 5 3(S)-(Acetylamino)-4-(hexadecylthio)butanoic acid; 4-[(4-(1,1'-Biphenyl)yl)thio]-3(S)-[(1-oxooctyl)amino]butanoic acid; 4-((Hexadecyl)thio]-3(S)-((1-oxooctyl)amino] butanoic acid; 2Q (E)-4-((4-Benzyl)phenylthio)]-3(S)-[(1-oxodecen3-enyl)amino]butanoic acid; (E)-4-((3-(1,1'-Biphenyl)yl)thio]-3(S)-[(1-oxodec3- enyl)amino]butanoic acid; 3(S)-[(1-Oxooctyl)amino]-4-((2-phenylethyl)thio]25 butanoic acid; 4- ((3-(1,1'-Biphenyl)yl)thio]-3(S)-[(1-oxooctyl)amino]butanoic acid; 4-Octylthio-3(S)-[(1-oxooctyl)amino]butanoic acid; (E)-4-[2-Naphthalenylthio]-3(S)-[(l-oxodec-3-enyl)2q amino]butanoic acid; 4-[2-Naphthalenylthio]-3(S)-[(1-oxooctyl)amino]butanoic acid; Methyl (E)-5-[(3-(1,1'-Biphenyl)yl)oxy]-4(S)[(l-oxodec-3-enyl)amino]pentanoate; 25 (E)-5-(3-(1,1'-Biphenyl)yl)oxy]-4(S)-[(l-oxodec-3IE 904522 enyl)amino]pentanoic acid; (R)-N-Phenylmethoxy-)3-((1-oxooctyl)aminobenzenebutanamide; (R) -N-Hydroxy-/?- ((1-oxooctyl) amino) benzenebutanamide; 5 (E)-N-[4(S)-[l-Amino-l-oxo-5-(2-naphthalenylthio)]pentyl]dec-3-enamide; (E)-(R)-N-(1,1-Dimethylethoxy)-β-[(l-oxodec-3-enyl) amino]benzenebutanamide; (E)-(R)-N-Hydroxy-0-[(l-oxodec-3-enyl)amino]benzene 2Q butanamide; (E)-N-[(4S) -[l-Hydroxyamino-5-[(3-(1,1 1 -biphenyl)yl) thio]-l-oxo]pentyl]dec-3-enamide; Methyl (E)-5-(2-naphthalenylthio)-4(S)-[(l-oxodec-3enyl)amino]-2-(phenylmethyl)pentanoate; 25 (E)-5-(2-Naphthalenylthio)-4(S)-[(l-oxodec-3-enyl) amino]-2-(phenylmethyl)pentanoic acid; (R)-)3-[N-Methyl-N-( 1-oxooctyl)amino]benzenebutanoic acid; or a pharmaceutically acceptable derivative of any one thereof. 2q 9. A pharmaceutical composition comprising a compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable derivative thereof, with the provisos that a) when R 1 represents methyl, then R 2 is other than an alkyl C2_ 18 group or benzyl, and 25 b) when R 2 represents methyl, then R 1 is other than an alkyl Ο 3 _ 18 group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl, and c) when R 2 represents iso-propyl, n represents 1, q represents 0 and R 3 represents hydroxy, then R 1 is 5 other than an alkyl C 1 ” 6 group optionally substituted by phenyl, and d) when n represents 1, q represents 0, and R 3 represents hydroxy or t-butoxy, then R and R do not both represent CH 3 (CH 2 )24r 2q in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A process for the preparation of a compound according to Claim 4, or a pharmaceutically acceptable derivative thereof, which process comprises t 3 25 a) producing a compound of formula I in which R represents hydroxy by hydrolysis of a corresponding compound of formula I in which R 3 represents alkyl C2_g, or , 3 b) producing a compound of formula I in which R 2q represents alkoxy ϋ 3 _ 6 by condensation of an acid of formula II: R 1 COOH II 25 with an amine of formula III: - 67 NH-CH-(CH 2 ) n -[Y(CH 2 ) p ] q -COR 3 III R 5 wherein R 3 represents alkoxy or c) producing a compound of formula I in which R J represents NHR 31 by reacting the corresponding compound in which R 3 represents COOH with a compound of formula IV H 2 NR 31 IV in which R 31 is as defined above, or d) producing a compound of formula I m which R 25 represents hydroxy or alkoxy C 3 _ 6 by reacting a compound of formula III in which R 3 represents hydroxy or alkoxy with a compound of formula V R 1 -CO-L v in which L represents a leaving group, . · 31 e) producing a compound of formula I in which R represents hydroxy by hydrolysis of the corresponding compound in which R 31 represents alkoxyC2_g optionally 25 substituted by an aryl group, or •Ε 904522 - 68 f) producing a compound of formula I in which the chain (CH 2 ) n [Y(CH 2 )p]q contains a group -CH 2 CH 2 - by hydrogenation of the corresponding compound of formula I in which Y represents -CH=CH-, or 5 and where desired or necessary, converting the compound of formula I so obtained to a pharmaceutically acceptable derivative thereof.

11. A compound of formula III η 2 NH-CH-(CH 2 ) n -[Y(CH 2 ) p ]g-COR 3 III R 5 in which R 3 , R 5 , Y, n, p and q are as defined in 25 Claim 1 and R 2 represents CH 2 -X-R 4 .

12. Use according to Claim 1, substantially as hereinbefore described.

13. A compound as claimed in Claim 3, substantially as hereinbefore described and exemplified.

14. A pharmaceutical composition according to Claim 9, substantially as hereinbefore described.

15. A process for the preparation of a compound as claimed in Claim 3, substantially as hereinbefore described and exemplified.

16. A compound as claimed in Claim 3, whenever prepared by a process claimed in Claim 10 or 15.

17. A compound according to Claim 11, substantially as hereinbefore described and exemplified.