WO1991008737A2

WO1991008737A2 - Pharmacologically active amide carboxylate derivatives

Info

Publication number: WO1991008737A2
Application number: PCT/GB1990/001941
Authority: WO
Inventors: Colin Bennion; Stephen Connolly; David Hulme Robinson
Original assignee: Fisons Plc
Priority date: 1989-12-16
Filing date: 1990-12-12
Publication date: 1991-06-27
Also published as: CA2072018A1; WO1991008737A3; EP0505467A1; JPH05502233A; IE904522A1; PT96210A; FI922720A0

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 R1 represents an alkyl C¿1-18? group optionally substituted by an aryl group or hydroxy or a cycloalkyl C3-6 group, R?2¿ represents an alkyl C¿1-18? group optionally substituted by an aryl group, or R?2¿ represents a group -CH¿2¿-X-R4 wherein X represents O or S, and R4 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 C¿1-6? or -NHR?31¿, wherein R31 represents hydrogen, alkyl C¿1-6?, OH or alkoxy C1-6 optionally substituted by an aryl group, R?5¿ represents hydrogen, an aryl group or an alkyl or alkenyl C¿1-18? 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 R6 represents hydrogen, an aryl group or an alkyl or alkenyl C¿1-18? 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

(CH₂)_n-[Y(CH₂)_p]_q-COR³

in which

R¹ represents an alkyl or alkenyl C_1-18 group

optionally substituted by an aryl group or hydroxy or a cycloalkyl C_3-6 group,

R² represents an alkyl C_1-18 group optionally

substituted by an aryl group, or R² represents a group -CH₂-X-R⁴ wherein X represents O or S, and R⁴

represents hydrogen, an aryl group, or an alkyl or

alkenyl C_1-18 group optionally substituted by an aryl group,

R³ represents OH, alkoxy C_1-6 or -NHR³¹, wherein R³¹ represents hydrogen, alkyl C_1-6, OH or

alkoxy C_1-6 optionally substituted by an aryl group, R⁵ represents hydrogen, an aryl group or an alkyl or alkenyl C_1-18 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 -CHR⁶-, -CH=CH-, O or S, in which R⁶ represents hydrogen, an aryl group or an alkyl or alkenyl C_1-18 group optionally substituted by an aryl group,

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 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 ß-aminoacid derivatives having antibiotic properties.

German Patent Application No 2252882 (Oreal) relates 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 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 an alkyl C_1-18 group or benzyl, and

b) when R² represents methyl, then R¹ is other than an alkyl C_1-18 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 C_{1- 6} group optionally substituted by phenyl, and

d) when n represents 1, q represents 0, and R³

represents hydroxy or t-butoxy, then R¹ and R² do not 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 C_1-18 group or benzyl or 2-phenylethyl or

-CH₂OH or -CH₂SCH₃, and

ii) when R² represents methyl, then R¹ is other than an alkyl C_1-18 group, optionally substituted by phenyl, or 2-(5-nitro-2-furyl)ethylenyl or 2-(3-phthalimido) propyl 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 C_1-6group 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 represents 0 and R³ represents hydroxy, then R² is other than n-propyl, and

vi) when n represents 1, q represents 0, and R³

represents hydroxy or t-butoxy, then R¹ and R² do not both represent CH₃(CH₂)₁₄-, and

vii) when R¹ represents n-hexyl. (CH₂)_n[Y(CH₂)_p]_q 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 C_1-6,or

b) producing a compound of formula I in which R³

represents alkoxy C_1-6 by condensation of an acid of formula II:

R¹COOH II with an amine of formula III: -(CH₂)_n-[Y(CH₂)_p]_q- COR³ III

wherein R³ represents alkoxy C_1-6, or

c) producing a compound of formula I in which R³ represents NHR³¹ by reacting the corresponding compound in which R³ represents COOH with a compound of formula IV

H₂NR ³¹ IV in which R³¹ is as defined above, or

d) producing a compound of formula I in which R³

represents hydroxy or alkoxy C_1-6 by reacting a compound of formula III in which R³ represents hydroxy or alkoxy

C_1-6 with a compound of formula V

R¹-CO-L V in which L represents a leaving group,

e) producing a compound of formula I in which R³¹ represents hydroxy by hydrolysis of the corresponding compound in which R³¹ represents alkoxy C_1-6 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

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 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.

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 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.

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 out over a suitable catalyst, eg 10% palladium on charcoal. 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

(CH₂) _n-[Y(CH₂)_p]_q-COR³ III

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 C_1-18 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 compounds by known processes which will be apparent to those skilled in the art.

Preferred groups that R₁ may represents are alkyl or alkenyl C_1-18, optionally substituted by hydroxy, phenyl or cycloalkyl C_3-6.

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 R¹ 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.

Cycloalkyl groups with which the group R¹ may be substituted include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Aryl groups with which the group R¹ may be

substituted include both carbocyclic and heterocyclic groups. The groups may contain rings of various numbers of C-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

substituents including halogen, nitro, alkyl C_1-6, phenyl and phenyl (alkyl C_1-6).

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

When R² represents alkyl C_1-18, 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 C_1-18, more preferably alkyl C_1-6, optionally substituted by phenyl, and, more preferably, groups of the formula

-CH₂-X-R⁴

in which X represents S or O, and R⁴ represents

alkyl C_1-18, an aryl group or alkyl C_1-18 substituted by an aryl group. Alkyl groups which R² 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 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 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

Alkoxy groups which R³ may represent include

methoxy, ethoxy and propoxy.

When R³ represents NHR³¹, R³¹ preferably

represents hydrogen, alkyl C_1-6, hydroxy or alkoxy C_1-6 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 C_1-6 or, especially, hydroxy.

R⁵ is preferably lower alkyl, say alkyl C_1-6, 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 C_1-6.

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 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

R₁ represents alkyl or alkenyl C_1-18, optionally substituted by hydroxy, phenyl or cycloalkyl C_3-6,

R₂ represents alkyl C_1-18, optionally substituted by phenyl, or a group

-CH₂-X-R⁴

wherein X represents S or O, and R⁴ represents

alkyl C_1-18, an aryl group or alkyl C_1-18 substituted by an aryl group,

R³ represents hydroxy, alkoxy C_1-6 or NHR³¹

wherein R³¹ represents hydrogen, alkyl C_1-6, hydroxy or alkoxy C_1-6 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 C_1-6,

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 anti-inflammatory 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 1-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

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-dioxa- 4,9-dioxo-8-thia-4-phosphahexadecan-1-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

1-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 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 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 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 0.1mg 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 the range of from 7.0mg to 1,400mg and unit dosage forms suitable for oral administration comprise from 2.0mg to 1,400mg 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 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 C_{1-1 8} group or benzyl, and

other than an alkyl C^1-6 group optionally substituted by phenyl, and

d) when n represents 1, q represents 0, and R³

represents hydroxy or t-butoxy, then R¹ and R² do not both represent CH₃(CH₂)₁₄-,

in admixture with a pharmaceutically acceptable 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, 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 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

5-Methyl-3-r(1-oxohexadecyl)aminolhexanoic acid,

dicyclohexylamine salt.

A mixture of 3-amino-5-methylhexanoic acid (0.23g), hexadecanoyl chloride (0.44g) and pyridine (14ml) in 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.: 100-101.5ºC

C₂₃H₄₅NO₃ requires: C 74.41, H 12.13, N 4.96%

found: C 74.78, H 11.58, N 4.98%.

Example 2

Ethyl 4(R)-[(1-oxohexadecyl)amino]-6-methylheptanoate

a) Ethyl 4 (R) -[t-butoxycarbonylamino]-6-methylhept-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 2 hours then heated under reflux for 3 hours.

The mixture was evaporated, partitioned between dilute hydrochloric acid and ethyl acetate, the organic extract 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+1).

b) Ethyl 4 (R)-[(1-oxohexadecyl)aminol-6-methylhept-2-enoate

A solution of the BOC-protected amine (as prepared above, 1.23mmol, 0.35g) in dichloromethane (20ml) was 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

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.: 52-54ºC.

Mass spectrum: m/e = 423 (M). c) Ethyl 4(R)-[(1-oxohexadecyl)amino]-6-methylheptanoate

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

Mass spectrum: m/e = 425 (M)

Example 3

4 (R)-[(1-Oxohexadecyl)amino]-6-methylheptanoic acid

A solution of ethyl 4 (R)-[(1-oxohexadecyl)amino]-6- methylheptanoate (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.: 67-69ºC

Mass spectrum: m/e = 398 (M + 1), 420 (M + Na)

Example 4

Methyl (E)-5-methyl-3(R)-[(1-oxodec-3-enyl)amino]hexanoate 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).

Mass spectrum (Plasma spray): m/e = 312 (M + H)⁺

Example 5

(E)-5-Methyl-3 (R)-[(1-oxodec-3-enyl)amino]hexanoic 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 (0.11g) 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). M. p . : 126-127 º C

C₁₇H₃₁NO₃.C₁₂H₂₃N

requires: C 72.75%, H 11.37%, N 5.85%

found: C 72.75%, H 11.66%, N 5.87%

Mass spectrum: (plasma spray) m/e = 298 (M + H)⁺, 182

(M + H)⁺

The following compounds were prepared by analogous procedures:

ii) (Z)-5-methyl-3(R)-[(1-oxooctadec-6-enyl) aminolhexanoic acid dicyclohexylamine salt

M.p.: 88-89ºC

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-methyl-3(R)-[(1-oxohexadec-9-enyl)amino]hexanoic acid adamantanamine salt

M.p.: 107-108ºC

C₂₃H₄₃NO₃.C₁₂H₂₃N.O.₆H₂O

requires: C 72.90%, H 11.34%, N 5.15%, H₂O 2.0%

found: C 73.14%, H 10.90%, N 5.51%, H₂O 2.1%

Example 6

Ethyl 2,6-dimethyl-4(R)-[(1-oxooctyl)amino]heptanoate a) Ethyl 4 (R)-[t-butoxycarbonylamino]-2,6-dimethyl

hept-2-enoate

A solution of N-t-butoxycarbonyl-(R)-leucinal (2.15g) 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 acetate- hexane (10:1) to give a colourless crystalline solid identified as the sub-titled compound (2.23g).

M.p.: 47-48ºC

Mass spectrum: (FAB) m/e = 384 (M + Rb)⁺

α_D= +5.62[C = 0.53, MeOH]

b) Ethyl 2,6-dimethyl-4(R)-[(1-oxooctyl)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 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 sulphate and evaporated. Chromatography of the residue with 20% ethyl acetate/hexane over silica gave the sub-titled compound as a colourless oil.

Mass spectrum: (FAB) m/e = 326 (M + H)⁺

c) Ethyl 2,6-dimethyl-4(R)-[(1-oxooctyl)amino]heptanoate 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 (M + H)⁺

Mass spectrum more polar isomer: (plasma spray) m/e = 328

(M + H)⁺

Example 7

26 , 6-Dimethyl-4(R)-[(1-oxooctyl)amino]heptanoic 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 (0.1g) in water

(12ml). After 16 hours the mixture was evaporated and the 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)⁺

C₁₇H₃₃NO₃. C₁₀H₁₇N.0.33H₂O

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: C₁₇H₃₃NO₃.C₁₀H₁₇N. 0.36H₂O

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-methyl-3(R)-[(1-oxododecyl)amino]hexanoate

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) 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 (1.1g). M.p.: 49-50ºC

Mass spectrum: (electron impact) m/e = 341 M⁺

Example 9

5-Methyl-3(R)-[(1-oxododecyl)amino]hexanoic acid

A solution of the product from Example 8 (1.1g) 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

evaporated. The residual solid was purified by flash chromatography on silica to give the title compound as a white solid.

M.p.: 57-58ºC

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 procedures.

ii) 5-Methyl-3(R)-[(1-oxo-10-phenyldecyl)amino]hexanoic acid dicyclohexylamine salt

M.p.: 112-113ºC

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) -[(1-Oxohexadecyl)amino]hexanoic acid

M.p.: 96-97ºC

C₂₂H₄₃NO₃ requ ires: C 71.50%, H 11.73%, N 3.79%

found: C 71.39%, H 11.52%, N 3.67% iv) (R)-ß-[(1-Oxooctyl) amino]benzenebutanoic acid

M.p.: 100-102ºC

C₁₈H₂₇NO₃ requires: C 70.82%, H 8.85%, N 4.59%

found: C 70.70%, H 8.94%, N 4.27% v) (R)-β-[(1-Oxohexadecyl)amino]benzenebutanoic acid M.p.: 113-114ºC

C₂₆H₄₃NO₃ requires: C 74.82%, H 10.31%, N 3.36%

found: C 74.75%, H 10.42%, N 3.25% vi) 5-Methyl-3(R)-[(1-oxooctyl)amino]hexanoic acid dicyclohexylamine salt

M.p.: 134-135ºC

C₁₅H₂₉NO₃.C₁₂H₂₃N

requires: C 71.68%, H 11.50%, N 6.19%

found: C 71.70%, H 11.48%, N 6.54% vii) 5-Methyl-3(R)-[(1-oxo-8-phenyloctyl)amino]hexanoic acid dicyclohexylamine salt

M.p.: 109-110ºC

C₂₁H₃₃NO₃.C₁₂H₂₃N

requires: C 74.95%, H 10.67%, N 5.30%

found: C 74.93%, H 10.48%, N 5.27%

viii) 5-Methyl-3(R)-[(1-oxohexadecyl)amino]hexanoic 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) (E)-5-Methyl-3(R)-((1-oxodec-4-enyl)amino]hexanoic acid dicyclohexylamine salt

M.p.: 124-125ºC

C₁₇H₃₁NO₃.C₁₂H₂₃N

requires: C72.75: H 11.37; N 5.85%

found: C72.41; H 11.25; N 5.81%

x) (E)-ß(R)-[(1-Oxodec-3-enyl)amino]benzenebutanoic acid dicyclohexylamine salt

M.p.: 141-142ºC C₂₀H₂₉NO₃.C₁₂H₂₃N

requires: C74.95; H10.22; N4.56%

found: C75.05; H9.83; N5.32%

xi) (R)-5-Methyl-3[(1-oxo-7-phenylheptyl)amino]hexanoic acid dicyclohexylamine salt

M.p.: 200-202ºC C₂₀H₃₁NO₃. C₁₂H₂₃N

requires: C74.66; H10.57; N5.44%

found: C74.45, H10.64; N5.07%

Example 10

Methyl 3(R)-[(2-hydroxy-1-oxohexadecyl) amino1-5-methyl- hexanoate

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 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.: 76-77ºC

Mass spectrum: m/e = 414 (M + H)⁺

The more polar diastereomer was isolated as a white solid (0.55g) M. p . 87-88 º C

Mass spectrum: m/e = 414 (M + H)⁺

Example 11

3(R)-[2-Hydroxy-1-oxohexadecyl)amino]-5-methylhexanoic acid The less polar isomer from Example 10 (0.4g) in tetrahydrofuran (10ml) was treated with a solution of potassium hydroxide (0.11g) in water (5ml). After stirring for 4 hours the tetrahydrofuran was evaporated. The aqueous residue was washed with ether and acidified with dilute 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 (0.11g).

M.p.: 76-77ºC

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

crystals (0.32g).

M.p.: 93ºC

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 Methyl (4S)-5-[(3-(1,1'-Biphenyl)yl)thiol-4-[(1-oxodec -3-enyl) aminoIpentanoate

a) Methyl 4 (S)-[(1,1-dimethylethoxy)carbonyl]amino-5- iodopentanoate

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,N'-dicyclohexylcarbodiimide methiodide

(31.5g) under nitrogen and heated at 50ºC 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. 93-95ºC

Mass spectrum: m/e = 358 (m+H)

b) Methyl 5-[3-(1,1'-biphenyl)yl)thio]-4(S)-[[(1,1- dimethylethoxy)carbonyl]amino! pentanoate

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 ½-hour, a solution of the product of step a) (2.24g) in dry 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 (MgSO₄) 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. 57-59ºC

Mass spectrum: m/e = 500 (M+Rb)

c) Methyl (E)-5-[(3-(1,1'-biphenyl)yl)thio]-4(S)-[(1- oxodec-3-enyl) amino]pentanoate

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 (1.1g).

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 (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).

M.p.: 61-62ºC

Mass spectrum: = m/e = 468 (M+H)

C₂₈H₃₇NO₃S requires: C71.91; H7.97; N3.00; S6.86%

found: C71.87; H8.07; N2.67; S6.36% The following compounds were prepared by analogous procedures:

ii) Methyl 5-[(3-(1,1'-biphenyl)yl)thiot-4(S)-[(1-oxo-

5-phenylpentyl) amino]pentanoate

M.p.: 96-97ºC

C₂₉H₃₃NO₃S requires: C73.24; H6.99; N2.94; S6.7%

found: C73.28; H7.20; N2.71; S6.59% iii) Methyl 5-[(3-(1,1'-biphenyl)yl)thio)1-4(S)-[(4- cyclohexyl-1-oxobutyl) amino]pentanoate

M.p.: 101-102ºC

C₂₈H₃₇NO₃S requires: C71.91,; H7.97; N3.00; S6;86%

found: C72.05; H8.27; N3.04; S6.48% iv) Methyl (E)-5-[(2,3,5-6-tetrafluorophenyl)thiol-

4 (S)-[(1-oxodec-3-enyl) amino]pentanoate

M.p.: 67-68°C

C₂₂H₂₉NO₃F₄S requires: C57.00; H6.31; N3.02%

found: C57.11; H6.56; N2.94%

Example 13

(E)-5-[(3-(1,1'-Biphenyl)yl)thiol-4(S)-[(1-oxodec

-3-enyl)-aminolpentanoic acid dicyclohexylamine salt

A solution of the compound from Example 12 (0.35g) in 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 (0.11g) 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.: 114-115ºC

Mass spectrum: m/e = 454 (M+H)

C₂₇H₃₅NO₃S.C₁₂H₂₃N requires: C73.77; H9.21; N4.41; S5.05%

found: C73.50; H8.11; N4.19; S4.99%

The following compounds were prepared by analogous procedures.

ii) 5-[3-(1,1'-Biphenyl)yl)thiol-4(S)-[(1-oxo-5-phenyl- pentyl) amino]pentanoic acid.

M.p. 94-97ºC

C₂₈H₃₁NO₃S requires: C72.85; H6.77; N3.03; S6.95%

found: C73.15; H7.13; N3.12; S7.22% iii) 5-[(3-(1,1'-Biphenyl)yl)thiol-4(S)-[(4-cyclohexyl -1-oxobutyl) amino]pentanoic acid.

M.p.: 134-135ºC

C₂₇H₃₅NO₃S requires: C71.49; H7.78; N3.09; S7.07%

found: C71.09; H.7.99; N3.04; S6.89% iv) 5-[(3-(1,1'-Biphenyl)yl)thiol-4(S)-[(1-oxo-7- phenylheptyl) amino]pentanoic acid

M.p.: 95-96.5ºC

C₃₀H₃₅NO₃S requires: C73.59; H7.20; N2.86; S6.55%

found: C73.30; H7.34; N2.81; S6.70% v) 5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(1-oxo-8- phenyl-octyl)amino]pentanoic acid dicyclohexylamine salt M.p.: 142-143ºC

C₃₁H₃₇NO₃S.C₁₂H₂₃N. 0.65M H₂O

requires: C74.12; H8.87; N4.02; S4.60%

found: C74.39; H8.80; N3.93; S4.76% vi) 5-[(3-(1,1'-Biphenyl)y)thio)-4(S)-[(1-oxo-6- phenylhexyl)-amino]pentanoic acid

M.p.: 99.5-100ºC

C₂₉H₃₃NO₃S requires: C73.23; H6.99; N2.94; S6.74%

found: C73.48; H6.79; N3.02; S6.95%

vii) (E)-4(S)-(1-Oxodec-3-enyl)amino]-5-[[2-(4-Phenyl) thiazolyl]thiolpentanoic acid dicyclohexylamine salt

M.p.: 141-144ºC

C₂₄H₃₂N₂O₃S₂. C₁₂H₃₃N

requires: C67.35; H8.64; N6.55%

found: C67.23; H8.44; N6.54%

viii) (E)-5-[(4-(1-Methyl-1-phenyl)ethyl)phenylthiol-4(S)-

[(1-oxodec-3-enyl)amino]pentanoic acid

M.p.: 99-102ºC

C₃₀H₄₁NO₃S requires: C74.51; H9.53; N4.15%

found: C74.55; H9.53; N4.11%

ix) (E)-5-[(2,4-Di(1,1-dimethylethyl)phenyl)thiol-4(S)-

[(1-oxo-dec-3-enyl)amino]pentanoic acid dicyclohexylamine salt

M.p.: 121-124ºC

C₂₃H₄₆NO₃S.C₁₂H₂₃N

requires: C73.49; H10.38; N4.18%

found: C72.83. H10.18; N4.02%

x) (E)-5-[(2,3,5,6-Tetrafluorophenyl)thio]-4(S)-[(1- oxodec-3-enyl)amino]pentanoic acid dicyclohexylamine salt M.p. : 130-133 º C

C₂₁H₂₇NO₃F₄S.C₁₂H₂₃N

requires: C62.93; H7.85; N4.45%

found: C62.62; H7.85; N4.09%

xi) (E)-4(S)-[(1-Oxodec-3-enyl)amino]-5-[(2-thiadiazolyl)- thio]pentanoic acid

M.p.: 90-91°C

C₁₈H₂₈N₂O₃S₂ requires: C56.22; H7.34; N7.28%

found: C56.24; H7.40; N7.29% xii) (E)-5-(2-Naphthalenylthio)-4(S)-[(1-oxodec-3-enyl)- amino)pentanoic acid

M.p. 85-87ºC

C₂₅H₃₃NO₃S requires: C70.26; H7.73; N3.28%

found: C70.44; H7.76; N2.98%

xiii) 5-(2-Naphthalenylthio)-4(S)-[(1-oxododecyl)

amino]-pentanoic acid

M.p. 74-76ºC

C₂₇H₃₉NO₃S requires: C70.90; H8.53; N3.06%

found: C70.04; H8.43; N3.06%

xiv) (E)-5-[(5-Methyl-1,3,4-thiadiazol-2-yl)thiol-4(S)-

[1-oxo-dec-3-enyl)amino]pentanoic acid

M.p.: 83-84ºC

C₁₈H₂₉N₃S₂ requires: C54.11; H7.32; N10.52%

found: C54.11. H7.56; N10.40% xv) (E)-4(S)-[(1-Oxodec-3-enyl)amino]-5-[(4-pyridinyl)- thiolpentanoic acid

M.p.: 146-148ºC

Mass spectrum m/e = 379 (M+H)

xvi) 5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(7-ethyl-1- oxononyl)amino]pentanoic acid

M.p. 77-79ºC

C₂₈H₃₉NO₃S requires: C71.60; H8.37; N2.98; S6.83%

found: C71.72; H8.52; N2.87; S6.99% xvii) (E)-4(S)-[(1-Oxodec-3-enyl)amino]-5-[(2-pyrimidinyl) thiopentanoic acid

M.p.: 96-98ºC

C₁₉H₂₉N₃O₃S requires: C60.08; H7.64; N11.07%

found: C60.16; H7.37; N10.96% xviii) (E)-5-[(4-(1,1'-Biphenyl)yl)thiol-4(S)-[(1-oxodec-3- enyl) amino]pentanoic acid

M.p.: 120-122ºC

C₂₃H₃₅NO₃S requires: C71.52; H7.73; N3.09%

found: C71.67; H7.88; N3.13%

xix) (E)-4(S)-[(1-Oxo-7-phenylheptyl)amino]-5-[(4-phenyl methyl)phenylthiolpentanoic acid

M.p.: 85-88ºC

C₃₁H₃₇NO₃S requires: C73.87; H7.35; N2.78%

found: C74.10; H7.61; N2.47%

xx) (E)-4(S)-[(1-Oxodec-3-enyl)aminol-5-[(5-phenyl-1,2,4- triazol-2-yl)thio]pentanoic acid M. p . : 139-141 º C

C₂₃H₃₂N₄O₃S requires: C62.13; H7.25; N12.60%

found: C61.89; H7.30; N12.33% xxi) (E)-5-[4,5-Diphenyl-2(1H)-imidazolyl)thiol-4(S)- [ (1-oxodec-3-enyl) amino]pentanoic acid

M.p.: 135-139ºC

C₃₀H₃₇N₃O₃S.O.67H₂O

requires: C67.76; H7.27; N7.90% 2.3% H₂O

found: C68.11; H7.07; N7.80% 2.3% H₂O

xxii) 9E)-5-[[1,1'-Biphenyl)-3-yl]thio]-4(S)-[(1-oxodec-

-4-enyl) amino]pentanoic acid

M.p.: 91-93ºC

C₂₇H₃₅NO₃S requires: C71.49; H7.78; N3.09%

found: C71.54; H7.71; N3.12%

Example 14

Methyl (E)-3(S)-[(1-oxodec-3-enyl)aminol-4-

(phenylthio)butanoate

a) Methyl 3(S)-[(1,1-dimethylethoxy) carbonyl]amino-4- hydroxybutanoate

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

0ºC. 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 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 0ºC 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 chromatography gave the sub-title product as a colourless oil (3.6g)

Mass spectrum m/e = 318 (M+Rb)

b) Methyl 3 (S)-[(1,1-dimethylethoxy)carbonyl]amino-4- iodobutanoate

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) Methyl 3(S)-[[(1,1-dimethylethoxy)carbonyl]amino-1- 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) Methyl (E)-3(S)-[(1-oxodec-3-enyl)amino]-4-(phenylthio)- 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-[4-nitrophenyl)thio]-3(S)-[(1-oxodec-3- enyl)-amino] butanoate

M.p.: 72-76'C

C₂₁H₃₀N₂O₅S requires: C59.69; H7.16; N6.63%

found: C59.90; H7.27; N6.38%

iii) Methyl 3(S)-[(1-oxooctyl)amino]-4-(phenylthio)- butanoate

M.p.: 54-44ºC

C₁₉H₂₉NO₃S requires: C64.92; H8.32; N3.98%

found: C64.48; H8.13; N3.99%

Example 15

(E)-3(S)-[(1-Oxodec-3-enyl)amino]-4-(phenylthio)- 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.: 127-130ºC

C₂₀H₂₉NO₃S.C₁₂H₃₃N. 0.17H₂O requires: C70.08; H9.63; N5.11%

found: C69.83; H9.55; N5.26%

The following compounds were prepared by analogous procedures:

ii) (E)-3(S)-[(1-Oxodec-3-enyl)amino1-4-[(2-dibenzofuran) thiolbutanoic acid dicyclohexylamine salt

M.p. 101-103ºC

C₂₆H₃₁NO₄S.C₁₂H₂₃N

requires: C71.89; H8.57; N4.41%

found: C71.83; H8.44; N4.38%

iii) (E)-4-[(4-Nitrophenyl)thio]-3(S)-[(1-oxodec-3-enyl)- aminolbutanoic acid

M.p.: 113-116ºC

C₂₀H₂₈N₂O₅S requires: C58.80; H6.90; N6.86%

found: C58.56; H6.76; N6.60%

iv) (E)-3(S)-[(1-Oxodec-3-enyl)amino]-4-(phenylmethylthio)- butanoic acid dicyclohexylamine salt

M.p. 110-112ºC

C₂₁H₃₁NO₃S.C₁₂H₂₃N

requires: C70.92; H9.74; N5.01%

found: C70.81; H9.92; N4.73%

v) (E)-4-[(1-Naphthalenylthio]-3(S)-[(1-oxodec-3-enyl)- amino]butanoic acid

M.p.: 119-120ºC

C₂₄H₃₁NO₃S requires: C69.70; H7.56; N3.39% found: C69.12; H7.85; N3.26%

vi) (E)-4-[(2-(1,1'-Biphenyl)yl)thiol-3(S)-[(1-oxodec- -3-enyl)amino]butanoic acid

M.p.: 79-81ºC

C₂₆H₃₃NO₃S requires: C71.04; H7.57; N3.19%

found: C70.62; H7.64; N2.93%

vii) 3(S)S(Acetylamino)-4-(hexadecylthio)butanoic acid

M.p.: 91-92ºC

C₂₂H₄₃NO₃S requires: C65.79; H10.79; N3.49%

found: C65.84; H10.40; N3/48% viii) 4-[(4-(1,1'-Biphenyl)yl)thiol-3(S)-[(1-oxooctyl)- amino]butanoic acid

M.p.: 156-158ºC

C₂₃H₃₁NO₃S requires: C69.70; H7.55; N3.39%

found: C69.60; H7.89; N3.36% ix) 4-[(Hexadecyl)thio]-3(S)-[(1-oxooctyl)amino] butanoic acid

M.p.: 77-78ºC

C₂₈H₅₅NO₃S requires: C69.23; H11.41; N2.88%

found: C69.07; H11.89; N2.90% x) (E)-4-[(4-Benzyl)phenylthio)1-3(S)(1-oxodecen-

3-enyl) amino]butanoic acid

M.p.: 71-72ºC

C₂₇H₃₅NO₃S requires: C71.49; H7.78; N3.09%

found: C71.27; H7.63; N2.92% xi) (E)-4-[(3-(1,1'-Biphenyl)yl)thiol-3(S)-[(1-oxodec- 3-enyl) amino]butanoic acid

M.p.: 94-96ºC

C₂₆H₃₃NO₃₃S requires: C71.04; H7.57; N3.19%

found: C70.55; H7.41; N3.08% xii) 3(S)-[(1-Oxooctyl)amino]-4-[(2-phenylethyl)thiol- butanoic acid dicyclohexylamine salt

M.p.: 120-121ºC

C₂₀H₃₁NO₃S.C₁₂H₂₃H₂

requires: C70.28; H9.95; N5.12%

found: C70.56; H9.77; N5.20%

xiii) 4-[(3-(1,1'-Biphenyl)yl)thiol-3(S)-[(1-oxooctyl)- amino]butanoic acid

M.p.: 78-80°C

C₂₄H₃₁NO₃S requires: C69.70; H7.55; N3.39%

found: C69.48; H7/37; N3.38%

xiv) 4-Octylthio-3(S)-[(1-oxooctyl)amino]butanoic acid

M.p.: 71-72ºC

C₂₀H₃₉NO₃S requires: C64.34; H10.45; N3.78%

found: C64.59; H10.12; N3.93% xv) (E) -4-[2-Naphthalenylthio]-3(S)-[(1-oxodec-3-enyl)- amino]butanoic acid

M.p.: 70-74ºC

C₂₄H₃₁NO₃S

requires: C69.70; H7.55; N3.39; S7.75% found: C70.03; H7.72; N3.57; S8.01%

xvi) 4-[2-Naphthalenylthio]-3(S)-[(1-oxooctyl)amino]- butanoic acid

M.p.: 99-100ºC

C₂₂H₂₉NO₃S requires: C68.18; H7.54; N3.61%

found: C68.53; H7.66; N3.66%

Example 16

Methyl (E)-5-[(3-(1,1'-Biphenyl)y)oxyl-4(S)-

[(1-oxodec-3-enyl)amino]pentanoate

a) Methyl 5-[(3-(1,1'-biphenyl)yl)oxy]-4(S)- [[(1,1- dimethylethoxy) carbonyl]amino]pentanoate

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 ½-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

colourless oil (0.13g)

Mass spectrum m/e = 400 (M+H)

b) Methyl (E)-5-[(3-(1,1'-biphenyl)yl)oxyl-4(S)-[(1- oxodec-3-enyl) amino]pentanoic acid

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.: 65-66ºC

C₂₈H₃₇NO₄ requires: C74.47; H8.26; N3.10%

found: C74.40; H8.54; N3.17%

Example 17

(E)-5-(3-(1,1'-Biphenyl)yl)oxyl-4(S)-[(1-oxodec-3- enyl) amino]pentanoic acid

The title product was obtained as a white solid from methyl (E)-5-[(3-(1,1'-biphenyl)yl)oxy]-4(S)-[(1-oxodec- 3-enyl) amino]pentanoic acid by a procedure analogous to that described in Example 13a).

M.p. 88-90ºC

C₂₇H₃₆NO₄ requires: C73.94; H8.27; N3.19%

found: C73.83; H7.96; N3.25%

Example 18

(R)-N-Phenylmethoxy-β-((1-oxooctyl)amino- benzenebutanamide

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 ½-hour. The mixture was cooled to

5ºC and treated with dicyclohexylcarbodiimide (0.45g, 0.022 moles). The resulting solution was allowed to warm to room 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.: 152-3ºC

C₂₅H₃₄N₂O₃ requires: C73.17; H8.29; N6.82%

found: C73.17; H8.32; N6.49%

Example 19

(R)-N-Hydroxy-β-((1-oxooctyl)amino)benzenebutanamide

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.: 140-145ºC.

C₁₈H₂₈N₂O₃ requires: C67.50; H8.75; N8.75%

found: C67.52; H8.87; N8.79%

Example 20

(E)-N-[4(S)-[1-Amino-1-oxo-5-(2-naphthalenylthiy)]- pentyl]dec-3-enamide

a) 4 (S) -[(1,1-Dimethylethoxy)carbonyl]amino-5-(2- naphthalenylthio)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 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-[4(S)-[1-Amino-1-oxo-5-(2-naphthalenylthio)]- pentyl]dec-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. 144-146ºC

C₂₅H₃₄N₂O₂S requires: C70.42; H7.98; N6.57

found: C69.61; H7.82; N6.38

Example 21

(E)-(R)-N-Hydroxy-β-[(1-oxodec-3-enyl)amino]benzene butanamide

a) (E)-(R)-N-(1,1-Dimethylethoxy)-β-[(1-oxodec-3-enyl) aminoIbenzenebutanamide

A solution of the product of Example 9x) (1.2g), hydroxybenzotriazole (0.48g), triethylamine (0.36g) and O-(t-butyl)hydroxylamine hydrochloride (0.45g) in

dichloromethane (20ml) and tetrahydrofuran (20ml) was stirred at room temperature for ½ hour. The solution was cooled to 10ºC, treated with dicylohexylcarbodiimide

(0.74g) and stirred at room temperature with acetic acid (0.1ml), filtered and the filtrated evaporated. The residue was purified by flash chromatography on silica to give the sub-title product as a white solid (1.1g).

M.p.: 92-94ºC

Mass spectrum (FAB): m/e = 403 (M+H)⁺

b) (E)-(R)-N-Hydroxy-ß-[(1-oxodec-3-enyl)amino]benzene 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.: 134-136ºC C₂₀H₃₀N₂O₃ requires: C69.33; H8.75; N8.09%

found: C69.25; H8.86: N8.28%

The following compound was prepared by an analogous procedure:

ii) (E)-N-[(4S)-[1-Hydroxyamino-5-[(3-(1,1'-biphenyl)yl) thio]-1-oxolpentyl]dec-3-enamide

M.p.: 102-103°C

C₂₇H₃₆N₂O₃S requires: C69.20; H7.74; N5.98%

found: C69.49; H7.66; N5.99%

Example 22

Methyl (E)-5-(2-naphthalenylthio)-4(S)-[(1-oxodec-3- enyl) amino]-2-(phenylmethyl)pentanoate

a) Methyl 5-(2-naphthalenylthio)-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 (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+1).

b) Methyl 5-(2-naphthalenylthio)-2-(phenylmethyl)-4(S) -(triphenylmethylamino)pentanoate

A solution of the product of part a) (2.0g) was dissolved in dry tetrahydrofuran (50ml) and cooled to -78ºC 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 -78ºC 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+1)

c) Methyl 4 (S)-amino-5-(2-naphthalenylthio)-2- (phenylmethyl) pentanoate

A solution of the product of part b) (1.2g) in acetone (50ml) was treated with 2M hydrochloric acid (20ml). After 5 hours the mixture was evaporated to a small volume. The 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+1).

d) Methyl (E)-5-(2-naphthalenylthio)-4(S)-[(1-oxodec-3- enyl) 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+1).

The more polar isomer was isolated as an oil (0.25g) Mass spectrum: (FAB) m/e = 532 (M+1).

Example 23

(E)-5-(2-Naphthalenylthio)-4(S)-[(1-oxodec-3-enyl) aminol-2-(phenylmethyl)pentanoic acid

The title product was obtained as an oil (0.1g) 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+1)⁺

The more polar product of Example 23d) (0.31g) was treated analogously to give the other diastereomer as an oil (0. 03g) .

Mass spectrum (FAB): m/e = 518 (M+1)⁺.

Example 24

(R)-β-[N-Methyl-N-(1-oxooctyl)aminoIbenzenebutanoic acid Prepared by method analogous to Example 11.

M.p. 107-9ºC

C₁₉H₂₉NO₃ requires: C 71.47; H 9.09; N 4.39 %

found: C 70.90; H 8.50; N 4.40 %

Claims

1. The use of a compound of formula I,

(CH₂) _n-[Y(CH₂)_p]_q-COR³

in which

R¹ represents an alkyl or alkenyl C_1-18 group optionally substituted by an aryl group or hydroxy or a cycloalkyl C_3-6 group,

R² represents an alkyl C_1-18 group optionally substituted by an aryl group, or R² represents a group -CH₂-X-R⁴ wherein X represents O or S, and R⁴

represents hydrogen, an aryl group, or an alkyl or alkenyl C_1-18 group optionally substituted by an aryl group,

alkoxy C_1-6 optionally substituted by an aryl group,

R⁵ represents hydrogen, an aryl group or an alkyl or alkenyl C_1-18 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,

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 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 provisos that

other than an alkyl C_1-6 group optionally substituted by phenyl, and

d) when n represents 1, q represents 0, and R³ represents hydroxy or t-butoxy, then R¹ and R² do not both represent CH₃(CH₂)₁₄-,

for use as a pharmaceutical.

4. A compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable derivative thereof, with the provisos that

-CH₂OH or -CH₂SCH₃, 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 C_1-6 group optionally substituted by phenyl, and

iv) when R² represents benzyl, n represents 0, Y

vi) when n represents 1, q represents 0, and R³ represents hydroxy or t-butoxy, then R¹ and R² do not both represent CH₃(CH₂)₁₄-, and

vii) when R¹ represents n-hexyl,

(CH₂)_n[Y(CH₂)_p]_q represents (CH₂)₄, and R³

represents hydroxy, then R₂ is other than n-pentyl.

5. A compound according to Claim 4, in which R²

represents alkyl C_1-18, optionally substituted by phenyl, or a group of the formula

-CH₂-X-R⁴

in which R⁴ represents alkyl C_1-18, an aryl group or alkyl C_1-18 substituted by an aryl group.

6. A compound according to Claim 5, wherein R⁴

represents an aryl group.

7. A compound according to Claim 4, wherein

R₂ represents alkyl C_1-18, optionally substituted by phenyl, or a group

-CH₂-X-R⁴

wherein X represents S or O, and R⁴ represents

alkyl C_1-18, an aryl group or alkyl C_1-18 substituted by an aryl group,

R³ represents hydroxy, alkoxy C_1-6 or NHR³¹

wherein R³¹ represents hydrogen, alkyl C_1-6, hydroxy or alkoxy C_1-6 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 C_1-6,

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;

Methyl (E)-5-methyl-3(R)-[(1-oxodec-3-enyl)amino]hexanoate; (E)-5-Methyl-3(R)-[(1-oxodec-3-enyl)amino]hexanoic acid; (Z)-5-methyl-3(R)-[(1-oxooctadec-6-enyl)amino]hexanoic acid;

(Z)-5-methyl-3(R)-[(1-oxohexadec-9-enyl)amino]hexanoic 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)amino]hexanoate;

5-Methyl-3(R)-[(1-oxododecyl)amino]hexanoic acid;

5-Methyl-3(R)-[(1-oxo-10-phenyldecyl)amino]hexanoic acid; 3 (R) -[(1-Oxohexadecyl)amino]hexanoic acid;

(R)-β-[(1-Oxooctyl)amino]benzenebutanoic acid;

(R)-β-[(1-Oxohexadecyl)amino]benzenebutanoic acid;

5-Methyl-3(R)-[(1-oxooctyl)amino]hexanoic acid; 5-Methyl-3(R)-[(1-oxo-8-phenyloctyl)amino]hexanoic acid;

5-Methyl-3(R)-[(1-oxohexadecyl)amino]hexanoic acid;

(E)-5-Methyl-3(R)-[(1-oxodec-4-enyl)amino]hexanoic acid;

(E)-β(R)-[(1-Oxodec-3-enyl)aminoIbenzenebutanoic acid; (R)-5-Methyl-3[(1-oxo-7-phenylheptyl)amino]hexanoic acid;

Methyl 3(R)-[(2-hydroxy-1-oxohexadecyl)amino]-5-methyl- hexanoate;

3 (R)-[2-Hydroxy-1-oxohexadecyl)amino]-5-methylhexanoic acid;

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-oxo-

5-phenylpentyl)amino]pentanoate;

Methyl 5-[(3-(1,1'-biphenyl)yl)thio)]-4(S)-[(4- cyclohexyl-1-oxobutyl)amino]pentanoate;

Methyl (E)-5-[(2,3,5,6-tetrafluorophenyl)thio]-

4 (S)-[(1-oxodec-3-enyl)amino]pentanoate;

(E)-5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(1-oxodec

-3-enyl)-amino]pentanoic acid;

5-[3-(1,1'-Biphenyl)yl)thio]-4(S)-[(1-oxo-5-phenyl- pentyl)amino]pentanoic acid;

5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(4-cyclohexyl

-1-oxobutyl)amino]pentanoic acid;

5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(1-oxo-7- phenylheptyl) amino]pentanoic acid; 5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(1-oxo-8- phenyl-octyl) amino]pentanoic acid;

5-[(3-(1,1'-Biphenyl)yl)thio)-4(S)-[(1-oxo-6- phenylhexyl)-amino]pentanoic acid;

(E)-4(S)-(1-Oxodec-3-enyl)amino]-5-[[2-(4-phenyl) thiazolyl]thio]pentanoic acid;

(E)-5-[(4-(1-Methyl-1-phenyl)ethyl)phenylthio]-4(S)-

[(1-oxodec-3-enyl)amino]pentanoic acid;

(E)-5-[(2,4-Di(1,1-dimethylethyl)phenyl)thio]-4(S)- [(1-oxo-dec-3-enyl)amino]pentanoic acid;

(E)-5-[(2,3,5,6-Tetrafluorophenyl)thio]-4(S)-[(1- oxodec-3-enyl)amino]pentanoic acid;

(E)-4(S)-[(1-Oxodec-3-enyl)amino]-5-[(2-thiadiazolyl)- thio]pentanoic acid;

(E)-5-(2-Naphthalenylthio)-4(S)-[(1-oxodec-3-enyl)- amino)pentanoic acid;

5-(2-Naphthalenylthio)-4(S)-[(1-oxododecyl)

amino]-pentanoic acid;

(E)-5-[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]-4(S)- [1-oxo-dec-3-enyl)amino]pentanoic acid;

(E)-4(S)-[(1-Oxodec-3-enyl)amino]-5-[(4-pyridinyl)- thio]pentanoic acid;

5-[(3-(1,1'-Biphenyl)yl)thio]-4(S)-[(7-ethyl-1- oxononyl)amino]pentanoic acid;

(E)-4(S)-[(1-Oxodec-3-enyl)amino]-5-[(2-pyrimidinyl) thiopentanoic acid;

(E)-5-[(4-(1,1'-Biphenyl)yl)thio]-4(S)-[(1-oxodec-3- enyl)amino]pentanoic acid;

(E)-4(S)-[(1-Oxo-7-phenylheptyl)amino]-5-[(4-phenyl methyl)phenylthio]pentanoic acid;

(E)-4(S)-[(1-Oxodec-3-enyl)amino]-5-[(5-phenyl-1,2,4- triazol-2-yl)thio]pentanoic acid;

(E)-5-[4,5-Diphenyl-2(1H)-imidazolyl)thio]-4(S)-

[(1-oxodec-3-enyl)amino]pentanoic acid;

(E)-5-[[1,1'-Biphenyl)-3-yl]thio]-4(S)-[(1-oxodec-

-4-enyl)amino]pentanoic acid;

Methyl (E)-3(S)-[(1-oxodec-3-enyl)amino]-4-

(phenylthio)butanoate;

Methyl (E)-4-[4-nitrophenyl)thio]-3(S)-[(1-oxodec-3- enyl)-amino]butanoate;

Methyl 3(S)-[(1-oxooctyl)amino]-4-(phenylthio)- butanoate;

(E)-3(S)-[(1-Oxodec-3-enyl)amino]-4-(phenylthio)- butanoic acid;

(E)-3(S)-[(1-Oxodec-3-enyl)amino]-4-[(2-dibenzofuran) thio]butanoic acid;

(E)-4-[(4-Nitrophenyl)thio]-3(S)-[(1-oxodec-3-enyl)- amino]butanoic acid;

(E)-3(S)-[(1-Oxodec-3-enyl)amino]-4-(phenylmethylthio)- butanoic acid; (E) -4- [ ( 1-Naphthalenylthio]-3(S)-[(1-oxodec-3-enyl) - amino]butanoic acid;

(E)-4-[(2-(1,1'-Biphenyl)yl)thio]-3(S)-[(1-oxodec-

-3-enyl)amino]butanoic acid;

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;

(E)-4-[(4-Benzyl)phenylthio)]-3(S)-[(1-oxodecen-

3-enyl)amino]butanoic acid;

(E)-4-[(3-(1,1'-Biphenyl)yl)thio]-3(S)-[(1-oxodec-

3-enyl) amino]butanoic acid;

3(S)-[(1-Oxooctyl)amino]-4-[(2-phenylethyl)thio]- 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)-[(1-oxodec-3-enyl)- amino]butanoic acid;

4-[2-Naphthalenylthio]-3(S)-[(1-oxooctyl)amino]- butanoic acid;

Methyl (E)-5-[(3-(1,1'-Biphenyl)yl)oxy]-4(S)-

[(1-oxodec-3-enyl)amino]pentanoate;

(E)-5-(3-(1,1'-Biphenyl)yl)oxy]-4(S)-[(1-oxodec-3- enyl) amino]pentanoic acid;

(R)-N-Phenylmethoxy-ß-((1-oxooctyl)amino- benzenebutanamide;

(R)-N-Hydroxy-ß-((1-oxooctyl)amino)benzenebutanamide;

(E)-N-[4(S)-[1-Amino-1-oxo-5-(2-naphthalenylthio)]- pentyl]dec-3-enamide;

(E)-(R)-N-(1,1-Dimethylethoxy)-ß-[(1-oxodec-3-enyl) amino]benzenebutanamide;

(E)-(R)-N-Hydroxy-ß-[(1-oxodec-3-enyl)amino]benzene

butanamide;

(E)-N-[(4S)-[1-Hydroxyamino-5-[(3-(1,1'-biphenyl)yl) thio]-1-oxo]pentyl]dec-3-enamide;

Methyl (E)-5-(2-naphthalenylthio)-4(S)-[(1-oxodec-3- enyl) amino]-2-(phenylmethyl)pentanoate;

(E)-5-(2-Naphthalenylthio)-4(S)-[(1-oxodec-3-enyl)

amino]-2-(phenylmethyl)pentanoic acid;

(R)-ß-[N-Methyl-N-(1-oxooctyl)aminoIbenzenebutanoic acid; or a pharmaceutically acceptable derivative of any one thereof.

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 R¹ represents methyl, then R² is other than an alkyl C_1-18 group or benzyl, and

c) when R² represents iso-propyl, n represents 1, q represents 0 and R³ represents hydroxy, then R¹ is other than an alkyl C^1-6 group optionally substituted by phenyl, and

d) when n represents 1, q represents 0, and R³

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

alkyl C_1-6 , or

b) producing a compound of formula I in which R³

represents alkoxy C_1-6 by condensation of an acid of formula II:

R¹COOH II with an amine of formula III: (CH₂)_n-[Y(CH₂)_p]_q-COR³ III

wherein R³ represents alkoxy C_1-6 or

c) producing a compound of formula I in which R³

represents NHR³¹ by reacting the corresponding compound 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_1-6 by reacting a compound of formula III in which R³ represents hydroxy or alkoxy C_1-6 with a compound of formula V

R¹-CO-L V in which L represents a leaving group,

e) producing a compound of formula I in which R³¹ represents hydroxy by hydrolysis of the corresponding compound in which R³¹ represents alkoxyC_1-6 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

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

(CH₂)_n-[Y(CH₂)_p]_q-COR³ III

in which R³, R⁵, Y, n, p and q are as defined in

Claim 1 and R² represents CH₂-X-R⁴.