CA2072018A1 - 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 R1 represents an alkyl C1-18 group optionally substituted by an aryl group or hydroxy or a cycloalkyl C3-6 group, R2 represents an alkyl C1-18 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 C1-18 group optionally substituted by an aryl group, R3 represents OH, alkoxy C1-6 or -NHR31, wherein R31 represents hydrogen, alkyl C1-6, OH or alkoxy C1-6 optionally substituted by an aryl group, R5 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 -CHR6-, -CH=CH-, O or S, in which R6 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

~ ~: WO91~08737 2;~ 7;~ ~ ~ PCT/¢~ 4~

Pharmacolo~ically Active Amide Carboxvlate Derivatives This invention relates to compound;`having pharmacological activity, processes for their preparati.on~
compositions containing them and method~ of treatment involving their use.
In its broadest aspect, the inventi.on is concerned ~; with compounds having the general formula Rl-col-cH-(cH23n-[y(cH2)p]q-coR3 .
in which R1 represents an alkyl or alkenyl Cl_l8 group 15 optionally substituted by an aryl group or hydroxy or a cycloalkyl C3_6 group, . . ',~ A J,, ~2~represents-an alkyl C1_18.group-optionally substituted by an aryl group, or R2 represents a group CH2-X-R4 wherain X represents O or S, and R4 20 represents hydrogen, an aryl group, or an alkyl or . alkenyl C1 18 group optionally substituted ~y an aryl group, R3 represents OH, alkoxy Cl_6 or -NHR31,-wherein R31 represents hydrogen, alkyl C~_6, OH or 25 alkoxy Cl_6 optionally sub~tituted by an aryl group, WO9l/08737 -2 0 ~ 2 0~ ~ -PCT/GB90~01 ~ `

R5 represents hydrogen, an aryl group or an alkyl or alkenyl Cl_l8 group;:optionally substituted by an aryl group, -. n represents 0, 1, 2 or 3, p represents 0, 1 or 2, . .
: q represents O or l, Y represents -CHR6-, -CH=CH-, o or S, in which R5 represents hydrogen, an aryl group or an alkyl or alkenyl Cl_18 group optionally substituted by an aryl group, and pharmaceutically acceptable derivatives thereofO
According to a first aspect of the invention, there is provided the use o~ a compound of formula I, as defined above, in the manufacture of a medicament for the treatment or pr~phylaxis of inflammation.
According to a second aspect o~ the invention, there is provided a method of treatment or prophylaxis of inflammation,:-which method.comprises a~ministering a therapeutically effective quantity of a compound of formula I, as de~ined above, to a patient suffering from or 20 susceptible to an inflammatory condi~ion.
- - Certaln of:the compounds of ~ormula I are known for use as pharmaceuticals, or to have pharmacological effects. For-example:-European Patent Application No 226304 (Sankyo) 25 describes certain N-acyl amino acid deriva~ives which on . . . . . : :: , , ~

WO9l/U8737 ~ ~ 72~ `. PcT/GB90/

concurrent administration with a penem.or carbapenem antibiotic reduce the renal toxicity of the antibioticO
European Patent Application No 13~879 ~amanouchi~
describes carboxylic acid and amide derivatives which a:re .
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 lQ to aminoacid-amine salts containing sulphur which are useful as hair and ~calp 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 ~hat certain compounds of formula I may act as 20 inhibitors of various enzymesj but without suggesting any particular utility..for those-compounds. Examples are J.Med.Chem. 29, 104-111 (1986), J.M~d.Chem. 27, 711-712 (1984), Biochem.Pharmacol. 29(16), 2205-2212 ~1980), and Pept.,Proc.Am.Pept.Symp.,5th, 209-212 (1977~.
None o~ these citations, however, discloses or - , .:: . . .,. :~

: :: ,,, : , . ,, ,:, ::. : .,.: ,. - : . .; . ::1 ~ :

` WO91/08737~. 2~291~ - P~T~ ~
-- 4 -- .

, suggests any utility of the compounds of formula I as anti-inflammatory agents.
:~ With the above-mentioned exceptions, the . pharmaceutical use of:the compounds o~ formula I is no~elO
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 Cl_l8 group or ~enzyl, and b) when R2 represents methyl, then Rl is other than an alkyl C1_18 group, optionally substituted by phenyl~
or 2-t5-nitro-2-furyl)ethylenyl, and c) when R2 represents iso-propyl, n represents 1, q 15 represents O and R3 represents hydroxy, then Rl is other-.than an alkyl Cl_6 group optionally substituted ~y phenyl, and d) when n represents 1, q represents O, and R3 represents hydroxy ox t-butoxy, then R1 and R2 do not 20 both represenk CH3(CH2)14-~
for use as pharmaceuticals.
In addition to those for which pharmacological effeetshave previously been described, a number of other compounds of formula I are known. The ma~ority of the compounds are, however, novel and according to a further aspect of the ~ ~. WO91/0~737 ~0~2~1$ pCT/~g~ 941 ~

invention there ars provided compounds of formula I, as first defined above, and pharmaceutically acceptable derivatives thereofl with the provisos that t i) when Rl represents methyl, then R2 is other than 5 an alkyl C1_18 group or benzyl or 2-phenylethyl or -CH2OH or -CH2SCH3, and ii) when R2 represents methyl, then R1 is other than an alkyl Cl_l8 group, optionally substituted by phenyl~
or 2-(5-nitro-2-furyl)ethylenyl or 2-(3-phthalimido~propyl lO or CH2-CH- or C~3CH=CH-, and iii) when R2 represents iso-propyl or ethyl, n represents 1, q represents O, and R3 represents hydroxy, then Rl is other than an alkyl Cl_6 group optionally substituted by phenyl, and 15 i~ when R2 represents benzyl, n represents 0, Y
represents -CH=CH-, p represents l, q represents 1~ and R1 represents 2-methylpropyl, then R3 is other than hydroxy or methoxy, and v) when Rl represents heptadec-8-enyl, n represents t

2~ q represents 0 and R3 represents hydroxy, then R2 i5 other than n-propyl, and .
vi) when n represents 1, q represents 0, and R3 represents hydroxy or t-butoxy, then Rl and R2 do not both represent CH3(CH2)14-~ and 25 Yii ) when Rl represents n-hexyl, ::
WO9l/~8737 ~-2 O 7 2 0 1 ~ ~ Pcr/~go/ol~

(CH2)n[Y(~H2)p]q repre5ents (CH2)4~ and R
represents hydroxy, then R2 is other than n-pëntylO .
According to the invention there is also provided a process for the preparation of compounds of formula ~ and pharmaceutically acceptable derivatives thereof, with provisos i) vii) above, which process comprisesO
a) producing a compound of ~ormula I in which R3 represents hydroxy by hydrolysis of a corresponding compound of formula I in which R3 represents alkYl Cl_6, or b) producing a compound of formula I in which R3 ~`
represents alkoxy Cl_6 by condensation of an acid of formula II:

RlCOOH X~

with-an amine of:formula III:

~-CN-(C~2)n-lY(cH2)pjq-cox3 III

~ .
wherein R3 represents alkoxy Cl_6, or c) producing a compound of formula I in which R3 25 represents NHR31 by reacting the corresponding compound ,,: . :' ' . ' , : ; ' ' . ; .', '': :'. . " ' ,: ' . . ,:' ' ; `, ,': ,. , ', , .: ', , ~ , WO91/0~737 ~ 0 7 2 ~ i8 . PCT/GB90/0194 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 Cl_6 by reacting a compound of formula III in which R3 represents hydroxy or alkoxy ~1-6 with a compound of formula V ~ .
ln _co_L V

in which L represents a leaving group, e) producing a compound of formula I in which R31 15 represents hydroxy by hydroly~is of the corresponding compound in which R3l..represents alkoxyCl_6 optionally . substituted by an aryl group, or . -- -~) producing a compound of formula I in which the chain (CH2)n~YtCH~)p]~ contains a group -CH2CH2- by 2~ hydrogenation of the corresponding compound of formula I in which-Y represents -CH=CH-,-or - - - -and where desired or necessaxy, converting the compound of formula I so obtained to a pharmaceutically acceptable derivative thereof.

The hydrolysis of proces~ a) may be carried out under . ~
207,~,2,0,~8 W091/08737~ - PCT/GB90/01 ~ 1, : - 8 -acid or, preferably, base catalysis. Reagents which may be ;
used for the base catalysed hydrolysis i~?clude lithium hydroxide and potassium hydroxide. The reaction may ba carried out in tha presence of a co-sol~ent such as tetrahydrofuran.
The reactio~ 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 l-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 employedO
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 wi~h the amine of formula III in the presence of an inert solvent such as dichlorome~hane.

The reaction of process e) may be carried out in the presence o~ a suitable catalyst, eg 10% palladium on carbon. Alternatively, the reaction ~ay be carried out by hydroly~is using an inorganic base.
The hydroge~ation o~ process f~ ~ay also be carried 25 out over a suitable catalyst, eg 10% palladium on charcoal.

W O 91/08737 20`7~ PCr/GB90/0l941 ~ ~

Certain compounds of formula III are novel and useful as intermediates in the preparation of the compounds of formula I. Accoxding to another aspect o~ the invention, therefore, there are provided compounds of formula III !
s ,. .
R2 ' NH-l~-(CH2)n-[Y(cH2)p]q COR III ~ .
~5 , ~
'' ~' .,.
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 alXenyl C1_18 group optionally substituted by an aryl group.

These no~el compounds of formula III may be prepared by reacting a compound of ~ormula VI.
-, . . .: . . . ....... . . . . . .
. R4-X H VI

20 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 25 available or may be obtained from commercially aYailable ... WO91/08737 2 0 7 2 ~ 1~ - - PCT/GB90/01 ~

compounds by known processes which will be apparent to those skilled in the art.
. Preferred groups that Rl may represents-are alkyl or alkenyl Cl_l8, 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 lO chains, eg pentadecyl, hexadecyl and heptadecyl.
Simil~rly, 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-~ctyl.

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.

~ycloalkyl groups with which the group Rl may be substituted include cyclopropyl, cyclobu~yl,-cyclopentyl and cyclohexyl.
Aryl groups with which the group R1 may be substitut~d include both carbocyclic and heterocyc~ic 25 groups. The groups may contain rings of various numbers of ,~

~: WO91/08737 :~ ~ 7~ - PCT/GB~0/0194l 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 heteroatomsO 3 5 Examples of heterocycles containing only one heteroatom include pyrrole, furan,~thiophen and pyridineO Groups containing more than one h~teroatom include pyrazole, I
oxazole, thiazole, triazole, oxadiazole, thiadiazole etc.
The aryl group may be substituted by a range of 10 substituents including halogen, nitro, alkyl Cl_6, phenyl and phenyl~alkyl ~1-6)-Particularly preferred aryl groups with which R1 may be substituted are carbocyclic groups, especially phenyl.
When R2 represents alkyl Cl_l8, it may be 15 substituted by a similar range of aryl groups to Rl. :
Again, the pref~rred aryl groups with which R2 may be substituted are carbocyclic groups,-especially-phenylO
Preferred groups which R2 may represent include alkyl C1_18, more pre~erably alkyl Cl_6, optionally 20 substituted by phenyl, and, more preferably, groups of the formula - - -in which X represents S or O, and R4 represents alkyl Cl_l8~ an aryl group or alkyl C1_18 substituted 25 by an aryl group.

: :. . .::: :::, ::: , , ': :: ' . : ' ' ' , .. -; `~ WO91/08737 2 0 7 2 0 1`~ ~ PCT/GB90~01~

Alkyl groups which R2 may represent include similar groups to those ~hich R1 may represent. Similarly, ~hen R2 represents the group -CH2-X-R4, R4 may rëpresent a ~imilar range of long and short, straight or branched 5 ~alkyl groups. - -When R2 represents -CH2-X-~4, then R4 preferably represents an aryl group.
- Aryl groups which R4 may represent include carbocyclic groups, notably phenyl, optionally substituted 10 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.
15 Examples of heterocycles containing only one heteroatom include pyrrole, furan, thiophen and jyridine. Groups containing more than`~one heteroàtom includë pyrazole~
oxazole, thiazole, triazole, oxadiazole, thiadiazole etoO
The aryl group may be substituted by a range o~
20 subs~ituents including halogen, nitro, alkyl Cl_6, phenyl and phenyl(alkYl Cl_6).
Alkoxy groups which R3 may represent include methoxy, ethoxy and propoxy.
When R3 represents NHR31, R31 preferably 25 represents hydrogen, alkyl Cl_6, hydroxy or alkoxy Cl_6 ~ WO91/08737 ,i s20~7~ ~ `-P~/~Bg~'g4D

optionally substituted by aryl. Aryl groups with which R4 may be substituted include both carbocyclic and heterocyclic groups. It is particularly preferred ~hat R31 be substituted by a carbocyclic-group, especially phenyl.
Mo~t preferably, R31 represents alkoxy Cl_6 OE~
especially, hydroxy.
R5 is preferably lower alkyl, say alkyl Cl_6, or, more preferably, hydrogen.

We prefer compounds in which q is zero.
We also prefer compounds in which n represents 00 1 or 2, q represents 1 and p represents zero. In such compounds, Y is preferably CHR6 in which ~6 is preferably hydrogen or alkyl Cl_6.

We particularly prefer compounds in which n i5 1 or 20 Alkyl groups which R6 may represent include methyl~
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, 9 butyl and t-butyl.
Aryl groups with which R6 may be substituted include 20 both carbocyclic and heterocyclic groups. It is particularly preferred that ~6 be substituted by a carbocyclic group, especially phenyl. ;
A particularly preferred group of compounds are tho~e in which Rl represents alkyl or alkenyl C1_18, optionally ` WO91/08737 2 0 7 2 0 ~ 8 - PCT/GBgo/~

substituted by hydroxy, phenyl or cycloalkyl C3_6, R2 represents alkyl Cl_l8, optional]Ly substituted . by phenyl, or a group ;

wherein X represents S or O, and R4 represents alkyl Cl_l8, an aryl group or alkyl Cl_l8 substituted by an aryl group, R3 xepresents hydroxy, alkoxy Cl_6 or NHR31 wherein R31 represents hydrogen, alkyl Cl_6, hydroxy or ~;
alkoxy Cl_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 Cl_6, and pharmaceutically acceptable derivatives thereof.
; Pharmaceutically acceptable derivatives of the -compounds of formula I include ssters, amides and saltsO
Salts of the compounds o~ formula I include metal ion salts, eg a}kali metal and alkaline earth metal salts, and 20 addition salts with suitable bases, eg suitable amines such as dicyclohexylamine and l-adamantanamine.- ~
The compounds o~ formula I, and pharmaceutically acceptable derivati~es thereof, are useful because they possess pharmacological activity in animals. In 25 particular, the compounds are useful as broad spectrum .. .: . : : . -;: . .

^ WO91/08737 2 0 ~ 8 ~PCT/GB90/0~941 anti-inflammatory ayents as demonstrated in one or more of the ~ollowing in vitro assay systems:
- 1. Porcine pancreatic PLA2 induced'release of 14C-arachidonic acid from mixed micelles: Mixed micelles of 1-stearoyl-2-~ 4C~-2-arachidonyl-L-3-phosphatidyl choline and-deoxycholate'are'addèd to a mixture ~f porcine pancreatic PLA2 and test~compound in buf~er solutionO
After 8 minutes the reaction is quenched and 14C-arachidonic acid is extracted hy the method of 10 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-phosphahexad~can-1-ammonium hydroxide in 15 buffer solution containing the test compound. Cleavage of ,, the thio estsr is assayed photometrically after reaction with DTNB ~5,5'-dithiobis~2-nitr'obenzoic acid]). -

3. Human platelet cystolic PLA2 induced release of 14C-arachidonic acid from liposomes of 20 l~stearoyl-2-14C-arachidonyl phosphatidylcholine in buffer containing 10~-DMS0: Assays were carried out as in system 1, but hu~an platelet cystolic PLA2 was used in place o~ porcine,pancreatic PLA2.

4. Assay of PL~z in intact HL60 cells and 25 polymorphonuclear leucocytes (PMN): In the presence of the A .W09~/fl8737 . 2 ~ 7 2 oi ~ PCT~GB90~01 ~

test compound and a 5-lipoxygenase inhibitor,. HL60 or PMN
cells in which the arachidonate moieties of the phospholipids have been equil.ibrated with tri~ium-label~d arachidonic acid are:challenged with ionophore A231870

5 After 1 minute (N-formyl-methionyl-laucyl-phenylalanine3 or 2 minutes (A23187) the reaction is quench~d, the mixtur2 centri.fuged and the supernatent assayed by scintillation technigues~
The compounds are indicated for use in the treatment 10 or prophylaxis of inflammatory conditions in mammals including man. Conditions that may be specifically mentioned are: :
osteoarthritis, rheumatoid arthritis, rheumatold spondylitis, youty arthritis and okher ar~hritio 15 conditions, inflamed joint ; .
. . eczema, psoriasis/ dermatitis or other in~lammato~y skin conditions such as sunburn; ~ .
inflammatory eye conditions including uvei.tis and conjunctivitis: :
lung disorders in which in1ammation is involved/ eg -asth~a, bronchitis,-pigeon fancier's disease, farmerls lung, acute respiratory distress-syndrome, bacteraemia~
endotoxaemia ~septic shock) and pancreatitis;
conditions of the gastrointestinal tract including 25 aphthous ulcers, gi~givitis, Crohn's disease (a condition ..W091/OX737 ~ 2 Q 7 ~, Q ~ PCT/G~9~D~4 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 tha small. intestine), coeliao 5 disease (a condition of the small intestine),iregional ileitis ~a regional inflammatory condition of the te~minal ileum), peptic.ulceration (a condition of the stomach ax1d duodenum) and irritable bowel syndrome; pyresis, pain, and other conditions associated with inflammation, particularly those in which phospholipid, lipoxyqenase 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 15 general, satisfactory resul~s are obtained when the compound is administered at a daily dosage of from about O.lmg to about-.20mg per kg o~-animal body weight, prefexably given in divided doses l to 4 times a day or in sustained release form. For man the total daily dose is in the range of from 7.Omg to 1,400~g and unit dosage forms .
. . ..~ suitable for oral administration comprise-from 2.Omg to 1,400mg of the compound admixed~with a solid or li~uid pharmaceutical diluent or carrier.
The compounds of formula I may be used on their own or 25.in the fo~m o~ appropriate medicinal preparations for ;, , . . . . . ........ : .. . . :. . , .. ,,: .. .. .. - ,. .. . ..... . ...
, . , , -.. . i . : : :. : ~ . .:: : .. ..

WO91/C8737 ~'~ `` PCT/GB90/0l ~

.., i .
enteral, parenteral or topical administration.
;Accordin~ 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 Rl-represents methyl, then R2 is othèr than an alkyl Cl_18 group or benzyl, and ~ .
b) when R2 represents methyl, then R1 is other than an alkyl Cl_l8 group, optionally substituted by phe~yl, or 2-(5-ni~ro 2-furyl)ethylenyl, and c) when R2 represents iso-propyl, n represents 1, q represents 0 and R3 represents hydroxy, then Rl is other than an alkyl cl~6 group optionally substituted by 15 phenyl, and :::
-d) when n:representa l; q represents 0, and R3 :
represents-hydroxy.or-t-butoxy,:then R1 and R2 do not both represent C~3~CH2)14 , . in admixture with a pharmaceutically acceptable 20 adjuvant, diluent or carrier.
-- - Examples of such adjuvants,~diluents and carriers are for tabl~ts and dragees - lactose, starch, talc, stearic acid;
for capsules - tartaric acid or lac~ose;
25 for injectable solutions: water, alcohols, glycerin, :: " : `

~ WO91/08737 ~J '~ $ PCT/GB90/01941 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 ~or administration to the lung include aerosols, particul~rly pressurised aerosols; - `
compositions in a form suitable for administr~tion to the skin include creams, eg oil-in-water emulsions or 10 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, 15 have a broader range of activity, are more potent, produce fewer side ef~ects, are more easily absorbed or have other - .useful pharm cological properties, than compounds~ of similar structure.
The invention is illustrated but in no way limited by 20 the following examples.

5-Methvl-3- r ! 1-oxohexadecyl~amino1hexanoic acid._ dicvclohexy~lamine_salt.
A mixture of 3-amino-5-methylhexanoic acid (0.23g), 25 hexadecanoyl chloride (0.44g) and pyridine (14ml) in - ~ . . . . , : , - .;, :: .:

~ wo gl/08737 ~ ~ 2 ~ 7, ~ PCT/GBYO/OI ~ ~
. - 20 -dichloromethane ~iOml) was heated under reflux ~or 4 hours.
The solution was poured.into water and separated. The . organic solution was.washed:.with dilute hydrochloric acid and w~ter, then dried and the solvents removed by rotary evaporation. Purification of the residue ~y 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.

10 M.p. 1oo-lol.5-c C23H45N03 requires: C 74.41, H 12.13, N 4.96~
found: C 74.7~, H 11.58, N 4.98%.
Exam~le 2 Ethvl 4(R)-t(l-oxohexadecvllaminoL~6-methylheptanoate 15 a) EthYl_4(R~-rt-butoxYcarbonylaminol-6-methylhept-2-enoate . ~ . To a solution of potassium t-butoxide (1.06g) in dry ~- tetrahydrofuran (3Oml) stirred at room temperature under nitrogen was added dropwise over 5 minutes a solution of triethyl phosphonoacetate (2.25ml) in dry tetrahydrofuran 20 (15ml). ~fter 30 minutes a solution of N-t-butoxycarbonyl-(R)-leucinal in dry tetrahydrofuran (9.48ml of lM solution) was added and the solution stirred at room temperature for 2 hours ~hen heated under reflux for 3 hours.
The mixture was evaporated, partition~d between dilute 25 hydrochloric acid and ethyl acetate, the organic extract ~ WO91/08737 ~ `2~7:~1 8 : PCT/GB~o/01941 washed with brine, dried over magnesium sulphate and the solvent removed ~y rotary evaporation. Chromatography of the-residue over silica with 20% ethyl acetate/hexane gave a colourless oil which crystalIised on scratching to give the-title compound as a whike solid (0.41g, 30%).
Mass spectrum: m/e = 286 (m+l).
b) Ethyl 4(R~-r(l-oxohexadecYl]aminol-6-methvlhept-2-enoate - A solution of the BOC-protected amine~(as prepared above, 1.23mmol, 0.35g) in dichloromethane t20ml) was stirred, cooled to 0C 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 15 and evaporated to give the crude free amine as a yellow oil. The oil was dissolved in dichloromethane (l00ml), ; treated:with triethylamine (0.172ml~` followed by hexadecanoyl ohloride:(~.338g) and the mixture was stirred for 19 hours. The solution was washed with dilute 20 hydrochloric acid, brine, dried over magnesium sulphate and evaporated. Chromatography of the residue with 20% ethyl--a~etate/hexane over silica gave the title compound as a white crystalline solid (0.32g, 62%).
M.p.: 52-54~C~
25 Mass spectrum: m/e = 423 (~).

.. .. . : ... .. .. - ... .... ,.. .. , .,., ~ ...... . .. :..... . - .

: ` :

: WO91/08737 ~ jO~ ~ PCTt~B90tOI

c) Eth~l 4(R~-rll-oxohexadecyl)aminol-6-methylheptanoate . A solution of the a,~-unsaturated ester as prepared in ., . . step b) (0.29g) in ~athanol (50ml) was treated with 10%
palladium on charcoal and hydrogenated at atmospheric 5 pres~ure 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 :
10 Mass spectrum: m/e = 425 (M) Examnle 3 4(R~-r(1-Oxohexadecvl~aminol-6-methYlheDtanoic acid A solution of ethyl 4(R)-[(l-oxohexadecyl)amino~-6-methylheptanoate (0.23g)in tetrahydrofuran (20ml) was mixed 15 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 l~yer was separated, dried over magnesium sulphate and 20 evaporated to give the title compound as a white solid (0.22g, 100%). - - -M.p.: 67-69-C
~ass spectrum: m~e = 398 ~M + 1), 420 (~ ~ Na) Exam~le 4 25 Methyl (EL~5-methyl-3(Rl-r~l-oxodec-3-enyl~aminolhexanoate ~ WO91/08737 2 0~7 2 p.~ 8 PCTiGB90/01941 . - 23 -A solution of methyl 3(R)-amino-5-methylhexanoate (0.56g) in dichloromethane (lOml) was added.over 10 min. to a stirred solution of trans 3-decenoic acid (0.6g) and dicyclohexylcarbodiimide (0.72g) in dichloromethane (20ml)0 5~ The mixture was stirred for 16 hours at room temperature when the precipitated solids were remov~d by filtrationO
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). ~
10 Mass spectrum ~Plasma spray): m/e = 312 (M ~ H)+ ~;
Exam~le 5 ~E)-5-MethYl-3~R)- r (- -oxodec-3-envl)aminolhexanoic acid_ .
dicyclohexYlamine salt A solution of the compound from Example 5 (0.53g) in ~.
15 tetrahydrofuran (Sml) 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 ex~racted with ether. Th~ combined 2~ 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-(50~1) was treat~d with dicyclohexylamine to yie}d the product salt as a white 25 solid ~0.4g)~

.Wo9l/o8737 '" 2 0 7 2 a î ~ PC~/~B90/01 M.p.: 126-127C ~
cl7H3 1N03 C12H23N
... requires: C~72.75%, H 11.37%, N 5.85% . ~ r found:.... C 72.75~, H 11. 66%,-N. 5.B7% -Mass spectrum: (plasma spray) m/e =:298:(M + H)+, 182 ~M + H)+
The following compounds were prepared by analogous procedures~
ii) (Zl-5-methvl-3(R) r (l-oxooctadec-6 eny~? aminvlhexarlolc acid dic~clohexYlamine salt M.p.: 88-89-C

requires: C 75.20%, H 11~94%, N 4.74 found: C 75.02~, H 12.06%, N 4.81 15 iii) (Z)-5-methyl-3(R~rfl-oxohexadec-9-enyl)aminolhexanoic acid adamantanamine salt M.p.:.107-108-C --~

requlres: C 72.90%, H 11.34~, N 5.15%, H20 2.0%
zO found: C 73.14%, H 10.90%, N 5.51%, H20 2.1%
Example 6 -EthYl 2~6-dimethyl-4(R)-r(l-oxooctyl~amino~hePtanoate a) EthYl 4(RL-~t-butox~carbonylaminol-2,6-dimethY
hept-2~Loa~e A solution of N-t-butoxycarbonyl-(R~-leucinal (2~15g~

' ,' , " ' ',, " . J .; ', ~ . ' ' ' '' ' ' ' " " ' .~ : 1~' ' ' " ' ' ;; . ,' .' ' '. '' .' .' ' . ' ' , " ' , ' " " . ' " ' ' ; W091/08737 2 0 7~ ~ i 8 PCT/GB90/01g4 in dry dichloromethane (50ml) was stirred under nitrogen at room temperature and treated with a solut.ion of ethyl 2-(triphenylphosphoranylidene)propionate (5.44g). After 17 hours the mixture was evaporated, treated with hexane-ethyl 5~ acetate (lO 1,:lOOml~ and ~iltered to remove the .
triphenylphosphine oxide. The ~iltrate 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 oompound (2.23g).

10 M.p. 47-480C
Mass spectrum: (FAB) m/e = 384 (M + Rb)+
aD= +5.62[C = 0.53, MeOH]
b) Ethyl 2.6-dimethyl-4tR)-r~l-oxooctvl)aminolhept-?-enoate ~ .
A solution of the product from step a) (1.78g) in 15 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 rasidue dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate, dried over 20 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 chloridè ~1.02ml) and stirred at room temperature for 20 hours. The resulting solution was washed 25 with dilute hydrochloric acid, brine, dried over magnesium .
WO91/08737 2 0 7 2 0 ~ ~ PCTIGBgO/~I~

sulphate and evaporated. Chromatography of the residue with 20% ethyl acetate/hèxane over silica gave the sub-titled compound as a colourless.oil.. : -Mass spectrum: (FAB) m/e = 326 (M + H)+

c) Ethvl 2,6-dimethyl-41~) -r ll-Oxooctvl~aminolheDtanoate A solution of the product from step b) (1.3g) was ~issolved 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 (0O57g), and the more polar isomer as an oil (0.65g).
~ass spectrum less polar isomer (plasma spray) m/e = 328 (M + H)~
- Mass spectrum more:polar isomer: (plasma spray) m/e = 328 -/ ~M + H)+
Exam~le 7 2,6-Dimethyl-4(R~- r (1-oxooctyllaminolhePtanoic acid ;~ .
20 l-adam~ntanamine salt A-solution of the less polar lsomer of.the product from Example 6 (0.47g) was dissolved in tetrahydro~uran (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 "` WO91/08737 ~ J X . PCT~GB90/01941 : - 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 puri~ied ~y chromatography on silica with 30~.ethyl aretate/hexane to give the~free acid as a colourless oil ~0.38g). The oil was dissolved in dichloromethane (lOml), treated with l-adamantanamine (0~177g) and evaporated to give the title salt as a cream foam ~0.5g). :
10 Mass spectrum: (FAB) m/e = 451 (M ~ H)+ .~
Cl7H33No3CloH17N.33H20 requires: C 71.04~, ~ 11.18%, N 6.14%l H20 1.27%
found: C 71.34%, H 11.25%, N 6.01%, H20 1.27%

lS The more polar diastereomer of the product from Example 6 ; was treated analogously to give a white foam (0.58g)0 Mass spectrum: (FAB) m/e = 451 ~M + H)~-Elemental analysis: C17H33No3.C~oH17N. 0.36H20 requires: C 70.94%, H 11.18%/ N 6.13~, H20 1.40%
20 found: C 70.95~, H 10.96%, N 6.04%, H20 1.40 ExamPle 8 ~~
Methyl 5-methYl-3(R~ -r (1-oxododec~l~aminolhexanoate A solution of methyl 3(R)-amino-5-methylhexanoate (0.55g) and triethylamine (0.35g) in dichloromethane (20ml) 2~ was treated with a solution of dodecanoyl chloride (0.76g) .. .. . .. . .

r~ I ~ r. t;
WO gl/08737 2 0 7 2 0 ~ ~ Pcr/GBgo/ol~.

in dichloromethane (lOml) and the resulting mixture was stirred at room temperature ~or 16 hours. The organic solution was washed ~it~ water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, dried and evaporated~ The residual oil was:puri~ied by flash chromatography on siliaa to give white crystals (l.lg)O
M.p.: 4g-50-c Mass spectrum (electron impact) m/e = 341 M+
Example_9 5-MethYl-3(R)-rrl-oxododecyl)amino1hexanoic acid A solution of the product from Example 8 (l.lg) in tetrahydrofuran (lOml) was added to a solution o~ lithium hydroxide monohydrate (0.2g) in water (lOml) and the reaction mixture was stirred for 16 hours at room 15 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 20 white solid.
M.p.: 57-58-C
~ass spectrum: (electron impact~ m/e = 399 (M - H ~ TMS~+
ClgH37N03 requires: C 69.68~, ~ 11.39%, N 4.28%
- found: C 69.99%, H 11.20%, N 4.07%

The following compoun~s were prepared by analogous ~ ~ W091/08737 ~ 7'~0 1 8 ` PCTiGBgo/01941 procedures.
ii) 5-Methy1-3(R)-r(l-oxo-10-~henyldecyl?aminolhexano c -acid dicvclohexylamine salt M.p.: 112-113-C

requires: C 75.49%, H 10.86%, N 5.03 : found: C 75.55%, ~ 10.72%, N 4.49%
iii) 3(R)- Ul-Oxohexa-decyl)amino~hexanoic acid M.p.: 96-97~C.
C22H43N03 requires: C 71.50%, H 11.73%, N 3.79%
. ~ound: C 71.39%, H 11.52~, N 3.67~ :
iv) (R)-~- r tl-Oxooctyl~aminolbenzenebutanoic acid M.p.: 100-102~C
C18H27N03 requires: C 70.82%, H 8.85%, N 4.59%

found: C 70.70%, H 8.94~, N 4.27%
v) ~R)-~-rfl-OxohexadecYl)am nolbenzenebutanoic acid `- ~ M.p.:-~13-lï4-C - ~
C26H43N03 requires. C 74.82%, H 10.31%, N 3.36%
found: C 74.75%, H 10.42%, N 3.25%
20 vi) 5-Methyl-3(R)-r~l-oxoocty:L)aminolhexanoic acid a~,~ . , ~.p.: 134-135-C

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

25 found: C 71.70%, H 11.48%, N 6.54%

: . wo ?I/08737 r3 ~ 7~18 PCT/GB90/0 ~

vii) 5-Methyl-3(R)~ oxo-8-phenvlocty~lamino1hexanoic acid dicyclohexylamine salt M.p.: 109-llO-C

C21H33N3 C12H23N ~ ~
requires: C 74.95%, H 1~.67%, N 5.30%

found: C 74.93%, H 10.48%, N 5.27%
.. .. ;
viii) 5-MethYl-3(R~ oxohexadecYl)aminolhexanoic acid M.p.: 78-79C

C23H45N03 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(RL-LU-oxodec-4-enyl~amino~hexanoic acid dic~clohexYlamine salt M.p.: 124-125-C

15 requires: C72.75: H 11.37, N 5.85%

found: C72,41; H 11.25; N 5.81%
x) ~E)-~tR),~L(l-Oxodec-3-enyl~aminolbenzenebutanoic,~aeid dicYclohex~lamine salt M.p.: 141-142-C
20 C20H29N03.C12H23N
reguires: C74.95; H10.22; N4.56~ -found: C75.05; ~9.83; N5.32%

xi) rRL-5-Methyl-3r(1-oxo-7-~henylhe~tyl~a~elinolhexanoic acid dicvclohexYlamine salt 25 ~-P- 2Go-2o2oc .. .. . ~

.1 8 .; ! . . WO 91/OX737 '~ PCT/GB90/01941 C20H3lNo3-cl2H23N
requires: C74.6~; H10.57; N5.44%
found: C74.~5, H10.64; N5.07%
Examel~ l~
Methyl 3fR~- r (2-hvdroxY l-oxohexadecyl)aminol-5-methYl-~h~xanoate 2-Hydroxyhexadecanoic acid (1.3g), followed by l-hydroxybenzotriazole (0.63g) were added to a stlrr~d solution of methyl 3~R)-amino-5-methylhexanoate (0.74g) in 10 dichloromethane ~75ml). A solution o~ dicyclohexylcarbodi-imide (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 15 ethyl acetate which was washed with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, water,-dried and evaporated to give a whit~ solid. The mixture of diastereomers was separated by flash chromatography on silica to give the less polar isomer as a 20 white solid. Recrystallisation from hexane gave the title co=pound as white crystals (O.42g).
~.p.: 76 77-C
Mass spectrum: m/e = 414 (~ + H~
The more polar diastereomer was isolated as a white solid 25 (~SSg) :
o,~2~ 2,0~8 ... . W091/~8737 PCT/~90/019 ~ !

M.p. 87-88-C

Mass spectrum: m/e = 414 (M ~ H)+
ExamPle 11 : -3 (~-r2-Hydrox~ oxohexadëc~amino~-5-methylhexanoic acid The less polar i5C er from Example 10 (0.4g) in tetrahydrofuran (lOml) was treated wi~h 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 10 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
15 Mass spectrum: (plasma spray) m/e = 400 (M + H)~
C23H45NO~ 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 20 ~rystals (0.32g).
M.p.: 93-C --Mass spectrum: (plasma spray) m/e = 400 (M + H)+
C23H45N04 requires: C 69.13%, H 11.35%, N 3.51%
found: C 69.32%, H 11.04%, N 3.60%
25 Example 12 " : . . . ~ .. .,. , :, ... , . . , . .. :

~: ~
`~21~.~2Q18 ;; W091~08737 ~ PCT/GB90/01941 ~ - 33 -Methvl f4S)-5-r(3-(l,l'-Bi~henYl-L~l!thioJ-4-rrl-oxodec -3-en~l)aminol~ tanoate a) MethYl 4(S)-l(1~1-dimeth~lethoxY)carbonyllamino-5-iodo~entanoate -5 ? A solution of methyl (S]-4-~(l,l-dimethylethoxy) carbonyl]-amino-5-hydroxypen~anoate (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 50C 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 (MgS04) and the 15 solvent removed by rotary evaporation. Purification of the ; residue by chromatography gave a white solid (10.73g~0 M.p. 93 95-C - -Mass spectrum: m/e - 358 (m+~) b) Methyl 5-r3~ biphenyl)yl~thiol-4(S) -r r 20 dimethvlethoxylcarbonYl~aminol~entanoate A solution o~ 3-phenylthiophenol (1.58~ in dry dimethylforma~ide (25ml) was stirred under nitrogen and treated, batchwise, with sodium hydride (0.25g of 80~
dispersion in oil) at room temperature After a further 25 ~-hour, a solution of the product of step a) (2.24g) in dry . . ,, , ,, . : .~.

; ,: ., . ..:
.: : . - , . ,. . ~. .- . ~:

. W09l/08737 ~ 2 0 ~ X ~ ~ 8 PCT/GB90/0l ~

dimethylformamide (15ml) was added over 1 minute. The mixture was stirred for 3 hours, poured onto dilute hydrochloric acid and extracted with ethy:L acetate. The .... . .
organic ~olution 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-titlè product as an oil (2.29g) which slowly solidified.

10 M.p. 57-59 C
Mass spectrum: m~e = 500 (M~Rb) c) MethYl (~)-5- U3-(~ b~phenyl)YlLthiol-4fS)-~L
oxodec-3-en~l)aminolpentanoate A solution of the product of part b), (1.43g) in lS dichloromethane (SOml) 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 dichloromet~ane. The organic solution was washed with lO~ aqueous sodium bicarbonate solution and 20 brine then dried (MgSO4) and t~e solvent evaporated to yield a gum (l.lg).
A solutio~ of the gum (0.55g) in dichloromethane (25ml) was ~reated with 3-decenoic acid (0.3g), followed by N-hydro~ybenzotriazole (O.23g) and ~hen a solution of 25 dicyclohexylcarbodiimide (O.36g) in dichloromethane ~` wo gl/08737 ~ PCT/GB90/01941 (5ml). Tha mixture was stirred at room temperature ~or 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 ~gSo4) and the solvent removed by rotary evaporation. - Purification o~ the resid~e by chromatography gave a white solid-which wa~
recrystallised from a mixture of hexane and ethyl acetate to give the title product as a white solid tO.13g).

10 Mop~- 6l-62-c Mass spectrum: = m/e = 468 (M+H) C28H37N03S r~quires: 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-r f3~ '-bIphenvl~yl~thiol-4fs~-rf 5-~henvlPentYl)aminol~entan ate .p.::96-97-C
CigH33N03S requires: C73.24; H6.99; N2.94; S6.7%
2~ found: C73O28; H7,20; N2.71; S6.59%
iii) Meth~1 5~il3~ bi~henyl)yl~thio)l-4fs~-rf4 cyclohexYl-l_ oxobutvl~aminolPentanoate Mop~ 101-102-C
C28H37N03S requir~s: C71.91,; H7.97; N3.00: S6;86%

found: C72.05; H8.27; N3.04; S6.48%

: . . - , : : :: . : ,,, , . . . ,: , , , :, .,,:::: , ,:: ::, : . :

. WO9l/~8737~ b2~ 1 8 PCT/&B90/01 ~: - 36 -iv) Meth~l ~E)-5-r(2,3l5,h-tetrafluorophen~l)thio~
4fS)- r ( 1-oxodec-3-envl)aminol~entanoate . M.p.: 67-68-C . . . :
C22H29N03F4S requires: C57.00; H6.31: N3.02%
found: . C57.11; H6~!5;6; N2.94%
ExamDle l3 :~.
(E3 -5-r L3-(1,l'-BiPhenyl)~l)thlo~-4(S)~L~l-oxodec -3-envl)-aminolpentanoic acid dicYclohexvlamine salt A solution of the compound from Example 12 (0.35g) in 10 tetrahydrofuran (5ml) was added to a solution of lithium hydxoxide 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 15 and extracted with ethyl acetate. The combined organic extracts were washed with~water, dried (MgS04) and evaporated.
The residual oil was taken up in dichloromethane (lOml), treated with dicyclohexylamine (O.llg) and the 20 solvents removed by rotary evaporation. Recrystallisation of the residue from a mixture o~ 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) 25 C27H35N03S.C12H23N

: . . . - . ". :~ ,, : - ;. . ,::: . :.

WO91/08737 ' ~ 'PCTIGB90/01941 ~ - 37 -requires: C73.77; H9.21; N4.41; 55.05%
found: C73.50; H8.11; N4.19; S4.99%

...... . . .
The following compounds were prepared by analogous procedures .
5 ii ) 5- r 3-fl.1~-8i~henvl~yl~thiol-4(S)- r ( l_oxo-5-phenyl-entyl~ 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%
iii) 5~r(3-fl,l'-BiphenYllvl)thiol-4LS)-r_(4-cYclohexyl -l-oxobutyl ) aminol ~entanoic ac~ .
M.p.: 134-135-C
C27H35N03S requires: C71.49: H7.78: N3.09; S7.07%
found: C71.09: H.7.99; N3.04: S6.89%
15 iv) 5-r(3-f1.1'-BiphenylL~l)thiol-4~S~-rtl-oxo-7-phenylheptY12aminol~entanoic acid M.p.: 95-96.5-C
,. . .
C30H35NO3S reguires: C73.59; H7.20; N2.86; S6.55%
found: C73.30; H7.34; N2.81; S6.70%
20 v) s-r t3-(~ Biphenvl)YlLthiol-4 (s2~ oxo-8-phenYl-octyl~ no1~entanoic acid dicyclohe~y~ ne salt --.p.: 142-143-C

C31H37N3S-C12H23No ~.65~ H20 reguires: C74.12; H8.87; N4.02; S4.60~
25 found: C74.39; H8.~0; N3.93; S4076%

~ ..WO9l/08737 ~p~ 8~ - PCT/GB90/0l9 ~
; - 38 -vi ~ 5- r (3~ 1'.-Bi~henyl~yl)thio)-4(S~-r~l-oxo-6-Pheny~ yl)-amlnol~entanolc aid .N.p.: 99.5-lOO-C ~
C29H33N03S requires: C73.23; ~6.99; N2~94; 56.74%
~ . found:. C73.48; H6.79; N3.02; S6.95%
vii) (E)-4~S~(l-Oxodec-3-envl~aminol-5-r:r2-L4-~henvl~
thiazolvllthiolpentanoic acid dicYclohe~ylamine salt .p.: 141-144C
C24~32N203S2C12H33N
10 requires: C67.35; H8.64: N6.55 found: C67.23; H8.44: N6.54%
viii) (E~-5-r~4-(l-Meth~ Phenvl)ethyl)T2~envlthiol-4(S~- , rtl-oxodec-3-envl Laminol~entancic acid - ~.p.: 99-102-C
15 C30H41N03S requires: C74.51; H9.53; N4.15%
found: . C74.55; H9.53; N4.11%-ix,~ (E~ -5- r r 2 . 4-D~ -dimeth~eth~l ) Phen~ll ) thiQ ~ -4 (-s ~
r (l-Qxo-dec-3-envlLaminolpentanoic_acid dlc clohex~lam ne salt 20 M-p- 12l-l24-c Ci3H46N03S ~ ~ 12~323N '--requires: C73.49; H10.38: N4.1~
found: C72.83. Hl0018: N4.02%
x) (E~-5-r (~3 . 5,6-Tetra~luoroeke~l).thio~_4(S~L~l-25 oxodec-3-enYl)amino-~entanoic acid dicy~lohexY_amine salt WO91/08737 ~Q,~2'aI`,8 ~ P~r/~0/01941 _ 39 - i M.p.: 130-133C
C21H27N03F4s ~ C12H23N
requires: C62.93; H7.85; N4.45~
found: C6~.62; H7.85; N4.09%
xi) (E)-4(Sl-r(l-Oxodec-3-envl~3~inol-5-r(2-thiadiazoly~=
thio1pentanoic acid M.p.: 90-91C
C18H28N23S2 requires: C56.22; H7.34; N7.28%
found: C56.24; H7.40; N7.29%
10 xii) (E)-5-(2-Naphthalenvlthio~-4~-L~l-oxodec-3-enYl)~
amino)pentanoic acid M.p. 85-87-C ;~
C2~H33N03S requires: C70.26; H7.73; N3.28 found: C70.44; H7076; N2.98%
15 xiii) ~5-L2-Naphthalenvlthio!-4(s)- r fl-oxododecYlL
aminol-pentanoic acid ~ -M.p. 74-76-C
C27H39N03S reguires: C70.90; H8.53; ~3.06%
found: C70.04; H8.43; N3.06%
20 xiv) (EL-5-r~ eth~l-l 3,4-thiadiazol-2-~l Lt_iol-4~S~-r l-oxo-dec-3-enyl~aminol~entanoic acid - -M.p.: 83-S4~C
C18H29N3S2 requires: C54.11; H7.32; N10~52%
~ found: C54.11. ~7.56; Nl0040~
25 xv) (~4(S~-r~l-Oxodec-3-envllaminol-5-L~4-~yridinyl~-:~
WO91~08737~ PCr/GB90/019 thiolPentanoic acid M.p.: 146-148C
Mass spectrum m/e = 379 fM~H) xvi) 5-r~3 L~ BiphenYl~vl)thiol-4fS)-r(7-~th oxononvl)aminoiPentanoic 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% i xvii) fE~-4(S2-rfl-Oxodec-3-enyl~aminol-5-rf2-~yrimidinYll 10 thiopentanoic _cid M.p.: 96-98 C
ClgH29N303S requires: C60.08; H7.64; N11.07~
found: C60.16; H7.37; N10.96%
xviii~ (El-5-~l4-fl,l~-Biphenyl)~l)thiol~4fS)-r(l-oxodec-3-15 en~l)aminolpentanoic acidM.p.: 120-122-C
C23H35NO3S requires: C71.52; H7.73; N3.09%
found: C71.67; H7.88; N3.13%
xix) fE~4(~ r fl-Oxo-7-Phenylhe~tyl~aminoL-5-~t4-~hen~l 20 methYl)~henvlthio~pentanQic acid .
M.p.: 85-88-C
C31H37N03S requires: C73.87; H7.35: N2.78%
found: C74.10; H7.61; N2.47%
xx~ (El-4f~l-L(l-Oxodec-3-en~l~aminol-5- r (-phenxl-l,2.4-25 triazol-2-yl~thiolpentanoic acid , ~ i , . :: . , , . : :

,- WO9lJ08737 !~ ; PCT/GBgO/OY941 .p.: 139-141C
C23H32N4O3S reguir~s: C62.13; ~7.25; N1;2.60%
~ . found: C61.89: H7.30; N12O33~ !
xxi) . (E~-5-r4.5-Di~henYl-2(1H)-imidazolvl)thio1-4 :5 r Ll-oxodec-3-en~l)aminol~entanoic acid ~ M.p.: 135-139 C
~ j :
C3oH37N3o3s-O-67H2 requires: C67.76; H7.27; N7.90% 2.3% H2O
found: C68.11; H7.07; N7.80% 2.3% H2O
10 xxii) ~E)-s-rrl l'-BiPhenYl~-3-yllthiol-4(s~-r~l-oxode -4-enyllamino1~entanoic acid M.p.: 91-93-C
C27H35N03S requires: C71.49; H7.78; N3.09 found: C71.54; H7.71; N3.12 Exam~le 14 .... Meth~l (E)-3(Si-~L1-oxodec-3-enyl~aminol-4-~phenylt~ioLbutanoate ~ ; - ~;
a) Methvl 3(Sl-r~1.1-dimethyl~thox~)carbonvllamino 4_ - hydroxybutanoate .
A solution of N-[(1,1-dimethylethoxy)carbonyl]aspartic acid 4-methyl-ester (2~.6g)~in ethyl acetate (400ml) was treated.with N-hydroxysuccinimide (11O47g) and cooled to 0C. A solutio~ of dicyclohexylcarbodiimide (20.57g) in ethyl acetate (250ml) was added slowly and the resu}ting 25 mixture was stirred at roo~ temperature for 18 hours. The , .: ' , ' , , : ` ,', " ; '., ,, "' :" . ' , ", ' .' "' . ' , :
.' ' ' " ' ~ , ' ', ' '" '' ' '` " ", ' ' ''' ' ' " '.,~" '''' ' 'I ' WO91/08737~ 18 - P~TJ~g~

su~pended 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 borohydrida (llo 31.g) over 40 minutes. The mixture was-stirred at o~C for a further 3 hours, quenched with saturated aqueous a~monlum '.
chloride solution and extracted with ethyl acetate~ The organic extract was washed with brine, dried (MgS04) and the solvent evaporated. Purification of the residue ~y chromatography gave the sub-title product as a colourless oil (3.6g) Mass spectrum m/e = 31~ (M+Rb) b) Methvl 3(S)-!(l.l dimethy~Lethoxy~carbonyllamino-4-iOdobutanoate I5The sub-title product was obtained as a yellow so.lid by treatment of the product of step a) by a procedure analogous to that described in Example 12a)0 Mass spectrum m/e = 428 (M+Rb) c) MethYl 3!~)-r r fl.1-dimethylethoxylcarbonyllamino-1-20 4~(phenYlthiolbutanoate 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).
~ass spectrum m/e = 325 25 d) Methyl rE)-3($)-tLl-oxodec-3-enyl~aminol-4-Lphenylthio)-, .~ . . - , ... . ,.: .: : , .... ... .

~ WO91/08737 ~ ~$~?,~72~18 PCT/GBgo/olg4~
. - 43 -butanoate The title product was obtained as an oil by treatment of the pxoduct 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) Methy~_fE~-4-r4-nitro~henYl)thiol-3(S)-~f1-oxodec-3 envl)-aminoIbutanoate 10 M.p.: 72-76C
C21H30N2O5S requires: C59.69; H7.16; N6.63%
found: C59.90; H7.27; N6.38%
iii) MethYl 3fS)-rfl-oxooctvl)amino~ 4-Lehenylthio~-butanoate 15 M.p. 54-44-C
ClgH29NO3S requires: C64.92; H8.32; N3.98%
found- -C64.48; H8.13; N3.99%
Exam~le 15 fE)-3tSL-rfl-Oxodec 3-enyl)aminol-4-f~henYlthio)_ 20 butan~ic acid dicvclohexvlamine salt The title product was obtained as a colourless solid by treatment of the product of Example 14d) by the .. . ..
procedure of Example 13a).

Mop~ 127-130~C

25 C20H29NO3S-C12H33N. O.17H2O

WO9l/08737p)l 9 ~ !2~0~ 2 ~18 PC~/GB90/U1g~

requires: C70.08; H9.63; N5.11%
found: C69.83; H9~55; N5.26%
The following compounds were prepared by analogous procedures~
ii~ (E ? - 3fSl- r ~l-Oxodec-3-envl~aminol-4-L(2~dibenzoPura 1 - thiolbutanoic acid dicyclohexYlamine salt M.p. 101-103-C

-' C26H31N04S-C12H23N
requires: C71.89; H8.57; N4.41%
1~ found: C71.83; H8.44; N~.38%
iii) (E!-4-t(4-Nitrophenyl~thiol~LS~-r(l-oxodec-3~enY
aminolbutanoic acid M.p.: 113-116-C
C20H28N205S requires: C58.80; H6.90; N6.86%

fou~d- C58.56; H6.76; N6.60%
iv) (E)-3(S) -r (l-Oxodec-3-enyl~LaminQ~-4-(phen~lmeth~lth~
butanoic-acid dicvcloh~xylamine salt M.p. 110-112-C
C21H31N03s-cl2H23N
20 requires: C70.92; H9.74; N5.01%
- - found: C70.81; H9.92; N4.73% ----vl (El-4-Lfl~Naphthalen~lthiol~3(s) -r (l-oxode~3 eny aminolbutanoic acid M.p.: 119-120~C
25 C24H31N03S requires: C69.70; ~7.56; N3.39%

WO91/08737 ~ 3 ~ 2~ PCT~GB90/0l943 found: C69.12; H7.B5; N3.26%
vi) lEl-4-r ~-rl,l'-Biphenvl~yl)thi~-3(S~LL1~oxodec--3-enyl~aminolbutanoic acid M.p.: 79-81-C
C26H33N03S requires: C71.04; H7.57; N3.19%
fou~d: C70.62; H7.64; N2.93%
vii) 3~S)-(Acetylamino)-4~(hexadecYlthio~butanoic acld M.p.: 91-92C
C22H43N03S requires: C65.79; H10.79; N3.49%

found: C65.84; H10.40; N3/4a%
viii) 4-r f4-f1.1'-Biphenvl)vl~thio1-3fS) -r f l-oxooctY
aminolbutanoic acid M.p.: 156-158~C
C23H31N03S requires: C69.70; H7.55; N3.39~
found: C69.60; H7.89; N3.36%
ix) 4-r(Hexadecvl)thio]-31S~-r(l-oxooctylLamin butanoic acid M.p.: 77-78 C
C2~H55N03S requires: C69.23; H11.41; N2.88%

found: C69.07; H11.89; N2.90~
x) ! 4-L~4-BenzYl)phenylthio~L-3~s)- ~ l-oxodecen-3-envl~aminolbutanoic acid M.p.: 71-72-C
C27H35N03S requires: C71.49; H7.78; N3.09%
found: C71~27; H7.63; N2.92%

;

W091/08737 ~ a~ 201 ~ PCT/~B90/019 xi) fE)~4-r(3-(lLl'-B~iEhenyl~vl)thiol-3(S)-r(l-oxodec-3-enylLami~s~lbutanoic acid M.p.: 94-96'C .
C26H33N033S requires: C71.04; H7~57; N3.19%
found: C70.55; H7.41~ N3.0~%
xii) 3ts)-r(1-OxooctYl~ aminol-4-r(2-~hen~lethvlLthio butanoic acid dicvclohexvlamine salt M.p.: 120-121C
C2 0H3 1N03S . C12~I23H2 lQ requires: C70.28; H9.95; N5.12%
found: C70.56; H9.77; N5.20~ .
xiii) 4-r (3-~l.l'-Bi~henYl)vl)thiol-3 fs)-r (l~oxooctYl)-amino1butanoiC acid M.p.: 78-80-C
15 C24H31N03S requires: C6~.70; H7.55; N3.39%
found: C69.48; H7/37; N3.38~
xiv) 4-Octvlthio-3LS~-r(1-oxooct~lL~minolbutanoic acid M.p.: 71-72-C
C20H39N03S requires: C64.34; ~10,45; N3.78%

found: C64~59; H10.12; N3.93%
xv) (E)-4-~2-Naehthalenvlthio~-3(S)-r(l-oxodec-3-~.nY
aminolbutanoic acid M.p.: 70-74-C
C2 4H3 l~03S
2~ requires: C69.70; H7.55; N3.39; S7O75%

WO9l/08737 ~ 2 ~ 8 PCT/GB90/0194l ound: C70.03; H7.72; N3.57; S8.01%
x~i) 4-r2-NaPhthalen~rlthiol-3(sl-ul--oxooc-tyl~aminol=
butanoic acid -M~po 99-100C
C22H29N03S requires: C68.18; H7.54; N3.61%
~ found: --C68.53; ~7~66; N3.66%
Exam~le 16 Meth~l (E)-5- r ~3-L~ Biphenyl~yl~o~yl-4 ~ oxodec-3-enylL~minolpentanoate a) Methvl 5-r(3-ll,1'-bi~henYll~l)oxvl-4(S)-rr(l.1-dimeth~lethoxvlcarbonyllaminolpentanoate A solution of methyl(S)-4-[(l,l-dimethylethoxy) carbonyl]amino-5-hydroxypentanoate (O.25g) in dry benzene (lOml) was treated wit~ 3-phenylphenol (0.17g) and 15 triphenylphosphine (0.26g). A ~olution of diisopropyl azodicarboxylate (0.20g) in dry benzene -~lOml) was added over ~-hour. The m~xture 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 20 colourless oil (0.13g) Mass spectrum~m/e = 400 (M+H) - -b) ~ethYl lEl-s~L~3~ henvl~yl)o~y~--4(sl-r( oxodec-3-en~l~amin~pentano c acid The title product was obtained as a white solid by 25 treatment of the product o~ step a) by a procedure . WO91/08737 ~ ~ Q ~ 7 2 01; 8 ` PCT/GB90/01 ~ I
- 48 ~ s analogous to that described in Example 12c).
M.p.: 65-66-C
C28H37N04 requires: C74.47: H8.26; N3.10~ .
found: C74.40; H8.54; N3.17%
5 Example 17 .
__-(3-(1.1'-~iPhenyls~l)oxyl-4fS2- r (1-oxodec-3-enyl)aminol~entanoic acid The title product was obtained as a white solid from methyl (E)-5~[(3-(1,1'-biphenyl)yl)oxy]-4(S)~ oxodec-3-enyl~amino]pentanoic acid by a procedure analogous to that described in Example 13a).
M.p. 88-90-C
C27H36N04 requires: C73.94; H8.27; N3.19~
~ound: C73.83; H7.96; N3.25%
15 Bxam~le 18 (Rl-N-Pheny~methoxY-~-t(1-oxooctYlLamino-. ~benzenebutanami~e . ^ . .--A solution-of the compound of Example 9vi) (0.61g~
0.002 moles~, benzyl hydroxylamine hydrochloride (0.32g, 20 0.002 moles), hydroxybenzotriazole (0.33, 0.002 mole~) and triethylamine (0.2g, 0.002 moles) in a mixture of tetrahydrofuran and dichloromethane-(20ml, 1:1) was stirred at xoom temperature for ~-hour. The mixture was cooled to 5 C and treated with dicyclohexylcarbodiimide ~.45g, 0.022 25 moles). The resulting solution was allowed to warm to room ~ WO91/08737 i 2 t~ 7 2 018 PCT/GB90~01941 . _ ~9 _ 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 ~olutlon of the residue .in ethyl acetate was washed wikh dilute :hydrochloric acid, :5 water, sodium bicarbonate solution~and water. The dried organic solution was evaporated to low volume whereupon crystalli~ation commenced. The white solid recrystallised - from a small volume of methanol to give the product, - (650mg, 80%).

M-p, 152-3-C
C25H34N203 requires: C73.17, H8.29; N6.82%
found: C73.17; H8.32; N6.49%
Example 19 (R)-N-Hydro~y~ oxooctvl~amino)benzsnebutanamide A soluti~n of the compound of Example lB (400mg) in .. ethanol (20ml) was stirred over lO~:palladium on carbon for :-3:hours at room temperature. The solution was;filtered and .
the filtratQ evaporated to a solid. The residue was recrystallised from ethyl acetate to give the title product 20 (200mg, 64%) as colourless needles. ..
- M.p.: 140-145-C. -~
C18H28N203 requires: C67.50: HB.75; N8.75%
: found: C67.52; H8.87; N8.79%
a~L~ ' ' 25 ~E~-N-f4~S~ ~mino-1-oxo-5-(2-naphthalenYlthio1l-.

~j WO91/08737 2 8 7 2 0 1 8 PCT/GBgo/o~

.

~en~ylldec-3-enamide a) 41s2~r ~l.L~_methylethoxY~carbon~llamino-5-(2-na~hthalen~lthio)~entanamide . ::
. A solutlon of 4(S)-[~l,l-dimethylethoxy)carbonyl]
5~ amino-5-(2-naphthalenylthio)pentanoic acid (0.5g) in tetrahydrofuran (50ml~ was treated with N-hydroxybenzotriazole (0.22g) followed by dicyclohexylcarboddiimide (O.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 (O.4g).
Mass spectrum m/e = 375 (M+H) b) (El-N-r4ts)-rl-~mino-l-oxo-5-(2-na~hthal~n~lthio)L=

15 pentylLd-ec-3-enamide The title product was obtained as a white solid by . rtreatment-o~ the product of step~a),by a procedure analogous to that described in Example 12c~.
M . p . 144-146-C

0 C25H34N202S re~uires: C70.42; H7.98; N6.57 found: C69.61; H7.82; N6.38 Exam~le 21 (E)-~R)-N-Hydroxv-~-L(l-oxodec-3-enyl)aminolbenzene --butanamide 25 a) LEL-tRL-N~ Dimeth~lethox~L-~- L( 1-oxodec-3-enyll ~ , WO91~08737 ~ ~3 ~ O ~ ~ 018 PCT/GB90~0~94~

aminol~enzenebutanamide A solution of the product o~ Example 9x) (1.2g)~
hydroxybenzotriazole (0.48g), triethylamine (0.36g) and 0-(t-butyl)h~droxylamine hydrochloride ~O.45y) in dichloromethane (20ml) and tetrahydrofuran (20ml) was stirred at room temperature for ~ hour. The solution was cooled to lO C, treated with dicylohexylcarbodiimide (0.74g) and stirred at room temperature wit~ acetic acid (O.lml), filtered and the filtrated evaporated. The residue was puri~ied by flash chromatography on silica to give the sub-title product as a white solid (l.lg).
M.p.: 92-94C
Mass spectrum (FAB): m/e = 403 (M+H)+
b) (E)-(R)-N-Hvdroxy-~- r (l-oxodec-3-enYl~aminolbenzene -~`
15 butanami-de A solution of the product (0.83g) of part a) in triflouroacetic acid (40ml3 was stirred at room temperatur for 16 hours. The solution was made alkaline ~pH8) with saturated aqueous sodium bicarbonate solution. The product 20 was extracted with ethyl acetate which was dried (MgS04) and evaporated.- Partial purification of the-residue by flash chromatography gave a solid which was purified by recrystallisation from ethyl acetate to gi~e the title product as a white solid (0.17g) 25 ~-P- 13~-136~
.

',, ' ; ` ;; .. , ,-: , .;

: : : " :~
. ~

: ` WO91/08737 ~1 ~i 2 b7 ~018 PCT/GB90/0l ~
-- 52 -- !

o C20H30N203 requires: C69.33; H8.75; N8.t)9 found: . C69.25; H8.86: N8.2~
The following compound was prepared by an analogous procedure:
5 ii) (E~-N~C(4~ ydrox~am no-5 ~ ~ L.1'-bi~henvl)Yl) thiol-1-oxo1pentylldec-3-enamide M.p.: 102-103-C
C27H36N203S requires: C69.20; H7.74; N5.98%
found: C69.49; H7.66; N5.99%

EXample 22 Methyl (E~-5-(2-na~hthalen lthio)-~S)-rtl-oxodec-3-enYllaminol-2-t~henYlmethyl)pentanoate a) Methyl~ L2-naPhthalenYlthio)-4(S)-triphenylmethyl amin~ ntanoate A solution of methyl 4(S)-[(}-dimethylethoxy)carbonyl]
amino-5-(2-naphthalenylthio)pentanoate ~8.7g) (prepared by a proce~ure analogous to that described in Example 12b)) in dichloromethane (lOOml~ was stirred and treated with trifluoroacetic acid (lOml). After 20 hours the mixture 20 w~s evaporated. The residue was dissolved in dichloro~ethane, washed-with-saturated aqueous sodium bi arbonate, dried over magnesium sulphate and evaporated to give the crude free amine as a light brown oil. The oil was dissolved in dichioromethane ~lOOml), treated with 25 triethylamine (4.2ml) followed by triphenylmethyl chloride .

.... ,. . : . . . .. . :.,.; . ... ::.. , . : . . : . ~. , ~r-~ W091~8737 ~ f~ j7 2 0 1 8 ~ pcT/GB9o/

(7.0g~ and the mixture was stirred for 20 hours. Thesolution was washed with water, dried over magnesium ~ulphate and evaporated. Chromatography of the residue . with 10~ ethyl acetate/hexane over neutral alumina gave the S title compound as a colourless yum (8.4g)~,- . ' ' Mass sp~ctrum: m/e = 532 (M~
b) Methyl 5-(2-naphthalenYlthio~-2-(phenYlmethyl)-4 .
-(tri~henylmethylamino)pentanoate A solution of the product of part a) (2.0g) was dissolved in dry tetrahydrofuran (50ml) and cooled to -78C
under a nitrogen atmosphereO A l.OM solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.7ml~ was added dropwise and stirred for 30 minutes. B nzyl bromide ~ :
(0.6ml) was added and stirred at -78C for 5 hours.
1~ 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).
20 Mass spectrum: m/e = 622 (~+1) c) - Methvl-4~) amino-5-(2-naPhthalenvlthioL-2 (Phenylme~hyl~ pentanoate A solution of the product of part b) (1.2g) in asetone (50ml) was treated with 2M hydrochloric acid (20ml). After 25 5 hours the mixture was evapora~ed ~o a small volume. The :~

- . : : . , :

WO91/08737 3 ~ O 8 PCT/GB90/01 ~ 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) MethYl rE)-5-(2-na~hthalenvlthio)-4(S) r(1-oxodec3- ~.
enyl)aminol-2-(Phenvlmethvl)-p_ntanoate 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 tQ.21g).
Mass spectrum: (FAB) m/e = 532 (M+l).

The more polar iso~er was isolated as an oil (0O25g) -Mass spectrumo (FAB) m/e = 532 (M+l).
- .Example 23~
(E)-5-(2-Na~hthalenYlthio)~4~S)-rLl--oxodec-3-enylL
aminol-2-~henylmethyl)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 Ex~mple ll.
- ~ass spectrum (FAB): m/e = 518 (~+1)+
The more polar product of Example 23d) (0.31g) was 25 treated analogously to give the other diastereomer as an ~VO 91/08737 ~ ~r/~g~ 4 .
oil ( 0 . 03g) .
~5ass spectrum (FAB): m/e = 518 (M+l) + .
ExamPle 24 (R)-~-rN-Methyl-N~ oxooctyl~aminolbenzerlebutanoio~ at-iid Prepared by method analogous to Example 11~ ;
M . p . 107-9 C
ClgH29N03 requires: C 71.47; H 9.09; N 4.39 %
found: C 70.90; H 8.50; N 4.40 9c "

15 , . .

. r . . ~
~. "- ' ~

.

- : .. : : . :.... - : . . , :

Claims (11)

Claims

1. The use of a compound of formula I, I

in which R1 represents an alkyl or alkenyl C1-18 group optionally substituted by an aryl group or hydroxy or a cycloalkyl C3-6 group, R2 represents an alkyl C1-18 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 C1-18 group optionally substituted by an aryl group, R3 represents OH, alkoxy C1-6 or -NHR31, wherein R31 represents hydrogen, alkyl C1-6, OH or alkoxy C1-6 optionally substituted by an aryl group, R5 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 -CHR6-, -CH=CH-, O or S, in which R6 represents hydrogen, an aryl group or an alkyl or alkenyl C1-18 group optionally substituted by an aryl group, 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 a) when R1 represents methyl, then R2 is other than an alkyl C1-18 group or benzyl, and b) when R2 represents methyl, then R1 is other than an alkyl C1-18 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 C1-6 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 i) when R1 represents methyl, then R1 is other than an alkyl C1-18 group or benzyl or 2-phenylethyl or -CH2OH or -CH2SCH3, and ii) when R2 represents methyl, then R1 is other than an alkyl C1-18 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 C1-6 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 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 nok both repre5ent 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 C1-18, optionally substituted by phenyl, or a group of the formula in which R4 represents alkyl C1-18, an aryl group or alkyl C1-18 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 R1 represents alkyl or alkenyl C1-18, optionally substituted by hydroxy, phenyl or cycloalkyl C3-6, R2 represents alkyl C1-18, optionally substituted by phenyl, or a group wherein X represents S or O, and R4 represents alkyl C1-18, an aryl-group or alkyl C1-18 substituted by an aryl group, R3 represents hydroxy, alkoxy C1-6 or NHR31 wherein R31 represents hydrogen, alkyl C1-6, hydroxy or alkoxy C1-6 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 C1-6, 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)-.beta.-[(1-Oxooctyl)amino]benzenebutanoic acid;
(R)-.beta.-[(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)-.beta.(R)-[(1-Oxodec-3-enyl)amino]benzenebutanoic 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-.beta.-((1-oxooctyl)amino-benzenebutanamide;
(R)-N-Hydroxy-.beta.-((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)-.beta.-[(1-oxodec-3-enyl) amino]benzenebutanamide;
(E)-(R)-N-Hydroxy-.beta.-[(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)-.beta.-[N-Methyl-N-(1-oxooctyl)amino]benzenebutanoic 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 C1-18 group or benzyl, and b) when R2 represents methyl, then R1 is other than an alkyl C1-18 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 C1-6 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.

10. A process for the preparation of a compound according to Claim 4, or a pharmaceutically acceptable derivative thereof, 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 in which R3 represents alkoxy C1-6 by condensation of an acid of formula II:

with an amine of formula III:

wherein R3 represents alkoxy C1-6, 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

in which R31 is as defined above, or d) producing a compound of formula I in which R3 represents hydroxy or alkoxy C1-6 by reacting a compound of formula III in which R3 represents hydroxy or alkoxy C1-6 with a compound of formula 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 alkoxyC1-6 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.

11. A compound of formula III

III

in which R3, R5, Y, n, p and q are as defined in Claim 1 and R2 represents CH2-X-R4.