GB2292149A - Peptide inhibitors of pro-interleukin-1beta converting enzyme - Google Patents

Peptide inhibitors of pro-interleukin-1beta converting enzyme Download PDF

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GB2292149A
GB2292149A GB9416078A GB9416078A GB2292149A GB 2292149 A GB2292149 A GB 2292149A GB 9416078 A GB9416078 A GB 9416078A GB 9416078 A GB9416078 A GB 9416078A GB 2292149 A GB2292149 A GB 2292149A
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amino
oxo
alkyl
pentanoic acid
alanyl
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GB9416078D0 (en
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Graeme Semple
Graham Baker
Michael Szelke
Hamish Ryder
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Ferring Research Ltd
Yamanouchi Pharmaceutical Co Ltd
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Ferring Research Ltd
Yamanouchi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

Compounds of the formula I: <IMAGE> or a pharmaceutically acceptable salt thereof, wherein R<1>, R<2>, R<3>, R<4>, R<5>, A<1>, A<2>, A<3> and X<2>, are as defined in the specification, together with pharmaceutical compositions for treatment of interleukin-1 mediated disorders or diseases comprising the compounds, are disclosed.

Description

Background to the Invention This invention relates to peptidic derivatives which are useful in the treatment of diseases in which IL-1 plays a central role. Interleukin-l (IL-i) is a pro-inflammatory protein produced mainly by stimulated monocytes, although many other cell types have been shown to produce measurable quantities (Devine & Duff, Immunology Today, 1990, 11, 13). IL-1 exists in two structurally distinct forms, IL-la and IL-IS, each of mass 17,500 daltons but which show only 26% homology (March et al. Nanue, 1985, 315, 641). Each protein is synthesised in 31 kDa pro-form, and these are subsequently processed to their respective mature forms.Most IL-la remains cell associated whereas 60 - 70% of IL-lss is released within 6 h of synthesis (di Giovine et al. Lymphokine Res. 1988, 7, 271, and Hazuda et al. J.
Biol. Chem. 1988, 263, 8473). Both polypeptides interact with the same receptors giving rise to responses which are species- and tissue-dependant (Dinarello, Blood, 1991, 77 1627). However, whereas both pro-L-a and its mature form are fully active, pro-IL-lss is completely inactive and processing to the mature form is required before the protein will bind to its receptor (Mosley et al. J. Biol. Chem. 1987, 262, 2941). It is now known that a cytoplasmic enzyme, termed pro-IL-1ss converting enzyme (ICE) is responsible for generating lL-lss in its mature form. This enzyme has been isolated from THP-1 human monocytic cells (Cenetti et al. Science, 1992, 256, 97; Miller et al. J. Biol. Chem. 1993, 268, 18062) and its gene has been cloned Crhornberry et al.Nature, 1992, 356, 768).
It has been shown that ICE is a cysteine protease which shows little homology to any known protein, including cellular cysteine and serine proteases (Thornberry et aL 1992).
ICE cleaves pro-lL-lss at two sites, Asp27 - Gly28 and Asp116 - Ala117, thus exhibiting a unique specificity. Other enzymes present in synovial fluid of patients with inflammatory disorders have been shown to cleave pro-IL-1ss to give active forms with an additional 3 or 13 amino acids (Hazuda et al. J. Biol. Chem. 1990, 265? 6318), but these events can only occur after secretion of pro-lL-lss from cells.
It is evident then, that compounds which are capable of inhibiting ICE activity would have the ability to prevent processing of pro-IL-1ss to its active pro-inflammatory form, and thus would be useful in the treatment of diseases which are mediated or exacerbated by IL-1.
Examples of such disease states include but are not limited to rheumatoid arthritis, encephalitis, inflammatory bowel disease, pancreatitis, psoriasis, hypotensive shock, Alzheimer's disease, sepsis, diabetes, immune complex glomerulonephritis, hepatitis, Crohn's disease, periodonitis, conditions involving T-cells, autoimmune diseases and reperfusion injury.
Description of the Invention Novel peptidyl derivatives of formula I are potent inhibitors of ICE and are useful for treating diseases in which IL-1 plays a central role. The compounds differ for example from those of EP 0 519 748 A2, EP 0 529 713 Al, EP 0 547 699 Al, WO 93/16710, WO 93/09135 and WO 93/14777 in that they contain novel functionality at their C-terminus which act as powerful recognition and binding sites for the enzyme, making them significantly more potent inhibitors than those previously described The present invention provides compounds of formula I:
or a pharmaceutically acceptable salt thereof wherein:: R1 is (a) substituted (saturated or unsaturated) alkyl C1 - C12, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1 - C6 alkoxy, C1 - C6 alkylcarbonyl and phenyl; (b) aryl or aryl C1 - C6 (saturated or unsaturated) alkyl wherein the aryl group is selected from phenyl, napthyl, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, purinyl, isoxazolyl, oxazolyl, quinoxalinyl, triazolyl and triazinyl, and mono and di-substituted aryl as defined above wherein the substituents are independently C1 - C6 alkyl, halo, hydroxy, NR6R7, C1 - 6 alkoxy, C1 6 alkylthio, C1 6 alkylcarbonyl, carboxy or phenyl;
(c) AryI-X II;; wherein aryl is defined as in (b) above, and may be substituted as defined in (b) above.
R2 is hydrogen, alkyl C1-4, benzyl; R3 is hydrogen, alkyl C1 4 or phenyl; R4 is hydrogen, fluorine, C1 -4 alkyl, -(CH2)a-CO2H; R5 is (a) substituted (saturated or unsaturated) alkyl C1 . 10, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1.6 alkoxy; (b) aryl alkyl C1 6 (saturated or unsaturated) wherein the alkyl groups may be substituted by hydrogen, halogen or hydroxy and the aryl group is selected from phenyl, pyridyl, napthyl, furtyl, thienyl, pyrazinyl or pyrimidinyl, and is optionally mono or di-substituted with the substituents being selected independently from C1 6 alkyl, halo, hydroxy, C1 6 6 alkoxy, C1 -6 alkylthio, C1.6 alkylcarbonyl, carboxy or phenyl;; (c) aryl or substituted aryl as defined in (b) above, subject to R4 not being hydrogen and/or at least two of A1, A2 and A3 being absent, and/or X2 being -OCONH- or -NHCONH-; R6 and R7 are independently hydrogen or C1.4 alkyl; R8, R10 and R12 are each independently selected from hydrogen or alkyl C1 - R9, R11 and R13 are each independently selected from (a) hydrogen (b) substituted saturated or unsaturated alkyl C1 -6, wherein the substituent is selected from hydrogen, hydroxy, halo, -SH, -S-C1 4 alkyl, C1 6 alkylcarbonyl, carboxy, -CONH2, amino, C1-4 alkylamino, guanidino, -O-C1-4 alkyl;; (c) aryl or aryl C1 -6 alkyl, wherein aryl is defined as above for R1 and wherein the aryl is optionally mono and di-substituted, the substituents being each independently C1.4 alkyl, halo, hydroxy, CO2H, Me2N-, NH2, C1. 4 alkylamino, C1 - 4 alkoxy, C1 .4 alkylthio, C1 - 4 alkyl carbonyl, NO2, -SH or -CN; A1 is selected from (a) a single bond; (b) an amino acid residue or analogue of formula L1T;
(c) an imino acid residue or analogue of formula IV;
A2 is selected from (a) a single bond; (b) an amino acid residue or analogue of formula V;
(c) an imino acid residue or analogue of formula VI;
A3 is selected from (a) a single bond; ; (b) an amino acid residue or analogue of formula VII;
(c) an imino acid residue or analogue of formula VIII
X1 is absent, -0- or -NH-; X2 is -O-, -S-, -OCONH-, -NHCO2- or -NHCONH-; X3 is absent, -NH-, -(CH2)e-, -(CH2)eO-, -O(CH2)e-, -CH=CH-, -CO(CH2)e-, -(CH2)eCO-, -(CH2)eNHCO-, -NHCO(CH2)e-, -(CH2)eCONH-, -CONH(CH2)e-, -(CH2)eNHSO2-, -NHSO2(CH2)e-, -SO2NH(CH2)e-, -(CH2)eSO2NH-, -(CH2)eNH-, -NH(CH2)e-; X4, X5 and X6 are each independently 0 or H2; aisO-3 bis 0 - 4 cis0-4 d is 0-4 eis 0 - 3 fis 0 - 2 Preferably A1 is a residue of tyrosine, phenylalanine, homophenylalanine, phenylglycine, tryptophan or histidine; R1 is unsubstituted C1-6 alkyl; X1 is absent, and other substituents are as described above;; Or more preferably R4 is hydrogen; R5 is substituted alkyl C1 10, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1 -6 alkoxy or phenyl; X2 is O or S, and the other substituents are as described above.
Another preferred embodiment of the invention is when R1 is aryl or aryl C1 6 (saturated or unsaturated) alkyl wherein the aryl group is selected from phenyl, napthyl, pyridyl, frryl, thienyl, pyrazinyl, pyrimidinyl, pyrazolyl and indolyl, and mono and disubstituted aryl as defined above wherein the substituents are independently C1 6 alkyl, halo, hydroxy, NR6R7, C1 6 alkoxy, C1 - 6 alkylthio, C1- 6 alkyl carbonyl, carboxy or phenyl; A1 is absent; Or more preferably R4 is hydrogen; R5 is substituted alkyl C1 10, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1 -6 alkoxy, or phenyl; X2isOorS.
Amongst preferred compounds according to the invention are those listed below and salts thereof: (3S)-3-(Acetyl-tyrosinyl-valyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Acetyl-typosinyl-valyl-alanyl)amino-4-oxo-5-npropyloxy pentanoic acid; (3S)-3-(Acetyl-tyrosinyl-valyl-alanyl)amino-5-ethoxy4-oxo pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-alanyl)amino-5-methoxy-4-oxo pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-alanyl)amin > 5-nbutyloxywoxo pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-alanyl)amino-5-ethoxy-4-oxo pentanoic acid; (3S)-3-(Benzyloxycarbonyl-phenylalanyl-alanyl)amino-4-oxo-5(2',2',2'trifluoroethoxy) pentanoic acid;; (3S)-3-(Benzyloxycarbonyl-homophenylalanyl-alanyl)amino-4-oxo-5-(2',2',2'trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-norleucinyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (35)- 3-(Benzyloxycarbonyl-pwlyl-alanyl)aniinooxoS-(2',2',2'-tiifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-phenylglycinyl-alanyl)amino-soxo-5-(2',2',2'- trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-leucinyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3- (Benzyloxycarbonyl-isoleucinyl- alanyl)amino-4-oxo-5 - (2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-cyclohexylglycinyl-alanyl)amino-4-oxo-5-(2',2',2'trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-isolcucyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid;; (3S)-3-(Benzyloxycarbonyl-valyl-norleucyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-homophenylalanyl)amino-4-oxo-5-(2',2',2'trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-valyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-propyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S )-5-Methoxy-4-oxo-3- (3 '-phenylpropanoyl-valyl-alanyl) amino pentanoic acid; (3S)-5-Ethoxy-4-oxo-3-(3'-phenylpropanoyl-valyl-alanyl)amino pentanoic acid; (3S)-3-(Benzoyl-valyl-alanyl)arnino-5-nbutyloxy-4-oxo pentanoic acid; (3S)-3-(Benzoyl-valyl-alanyl)amino-5-benzyloxyXoxo pentanoic acid; (3S)-3-(Benzoyl-valyl-alanyl)amino-4-oxo-5-(3'-hydroxypropyloxy) pentanoic acid.
The compounds of the invention can be prepared using general methods outlined in the schemes below, and further illustrated with specific, non-limiting examples.
Scheme 1
o 0 R PG 2 R4 PG2 PG '-N OH step (i) PG '--N/ 2 R2 o R2 I R2 0 1A 1B (ji) step (ii) O 0 /PGZ R4OPG2 12 2 3 step (iv) PG -NX- PG PG 1 Br R2 0 R2 o 1E 1C step (vi) t(v) l step (iii) O 0 R Ao R )4 < PG'-N step (vii) PGI X2RS I 1F 1D in which R2, R4, R5 and X2 are as defined previously;; PG' is an amine protecting group (for example benzyloxycarbonyl or t-butyloxycarbonyl); PG2 is a carboxylic acid protecting group (for example an alkyl group which forms a readily hydrolysable ester), provided that PG2 is stable under conditions used to remove PG'; and PG3 is a group chosen such that it facilitates the introduction of X2 and it can either be removed under conditions that leave PG' and PG2 intact or it can be directly transformed into R5.
In step (i) an aspartic acid analogue 1A is converted into a diazomethyl ketone 1B. This is accomplished in two steps. The acid is first converted into a more active acylating species; for example an acyl chloride (by reaction with eg. oxalyl chloride or thionyl chloride) or a mixed anhydride (by reaction with eg. isobutyl chloroformate). This acylating species is then reacted with diazomethane to give 1B.
In step (ii) the diazoketone 1B is converted into the bromomethyl ketone 1C. This is conveniently accomplished by treating 1B with an anhydrous solution of hydrogen bromide in a convenient solvent (for example ethyl acetate or diethyl ether).
Elaboration of 1C into 1D depends on the precise nature of the group R5X2-. In some cases a single step is sufficient. In these cases the route followed is via step (iii). This involves the reaction of 1C with the chemical entity R5X2-H, usually in the presence of a base. One example of this is the case where R5 = CF3CH2- and X2 = -O-. The chemical entity R5X2-H is then 2,2,2-trifluoroethanol, which reacts with bromomethyl ketones in the presence of bases such as cesium fluoride and sodium hydride.
If direct reaction of 1C with R5X2-H is not a viable process then a less direct scheme is adopted. In step (iv) the bromomethyl ketone 1C is reacted with a species PG3-X2-H which introduces the group X2 into 1E but which requires further manipulation to elaborate R5. For example in many cases where X2 = -0- the direct route of step (iii) is inappropriate due to the high basicity or low nucleophilicity of R5-X2, the anion corresponding to R5X2-H. The use of a more nucleophilic, less basic, carboxylate anion is often better. Benzoylformate (PhCOCO2-) is one prefered option. This would give 1E in which PG3- is PhCOCO-.
Another example is the case where X2 is -NHCONH-. Displacement of the bromide from 1C with a nitrogen nucleophile requires the careful selection of reagents. It can be achieved by reagents such as, for example, sodium azide and potassium cyanate when the group -X2PG3 would be -N3 and -NCO respectively.
Conversion of 1E to 1D will require either one or two further operations. Step (v) represents the one step procedure. This requires that -X2PG3 be able to be transformed directly into -X2R5. One example of this is the case discussed above in which -X2PG3 is -NCO. This compound is capable of reacting with an amine R5NH2 to give a urea 1D in which X2 is -NHCONH-.
More frequendy two operations are required. In step (vi) the group -PG3 is removed. This can be achieved by the application of a number of different treatments. For example when X2 is -0- and PG3- is PhCOCO- the use of alkaline hydrolysis is a prefered method. This liberates an alcohol. When -X2PG3 is -N3 a seductive method, for example hydrogenolysis over a catalyst, can be used to liberate an amine 1F in which -X2-H is -NH2. Step (vii) represents the final elaboration of 1D from 1F. Again the reagents and conditions chosen depend on the precise nature of R5 and X2.Continuing with the two examples above, when 1F is an alcohol (i.e. when -X2-H is OH) it can be treated with an alkylating agent, for example an alkyl iodide or alkyl bromide, in the presence of a base to give an ether 1D in which X2-R5 is -O-alkyl. When 1F is an amine (i.e. when -X2-H is NH2) it will react with an isocyanate R5 NCO to give a urea 1D in which -X2-R5 is -NHCONH-R5.
Scheme 2
0 0 R /J4O R XJ4O PG-N X2R5 step (viii) PG 1-NX2R5 R2 O R2 OH 1D / 2A step (xi) / I step (ix) O 0 R4J PG2 step (x) 0PG R'-XCo-A'-A2-A3- Ck^ xZDS PGeA? 2R5 2 N 2C 2B step (xii) O 0 R4 PG2 R4OR3 OR3 1112325 R'-XCO-A'-AA3-N step (xiii) R12O XR 2D 2E in which A', A2, A3, R1, R2 R3 R4, R5, X1, X2, PGl and PG2 are as defined previously and PG4 is an amine protecting group as defined for (but not necessarily identical with) PG'. It is usually found that elaboration of 1D proceeds better if the ketone is temporarily masked by reduction to the secondary alcohol 2A. This is represented in step (viii). The reagent used is chosen from any of the reagents known to achieve this conversion. Complex metal hydrides are examples of such reagents. One prefered reagent is sodium borohydride.
The further elaboration of 2A can either be a stepwise process or a single operation. Most often the stepwise protocol is prefered. In step (ix) PG' is removed from the amino group of 2A. The amine is then coupled to a protected amino acid corresponding to A3. Any incompatible functionality in A3 is suitably protected prior to this coupling. The reagents chosen for the removal of PG1 and the coupling of A3 can be any of those known to achieve these conversions. Step (x) represents the iterative addition of further residues to the growing chain by the repetition of the transformations of step (ix). Step (xi) represents the single-step alternative to steps (ix) and (x).The preformed fragment corresponding to Rl-Xl-Co-Al-A2-A3 with any incompatible functionality protected, is coupled directly onto the amine obtained by the deprotection of 2A. In the final steps in the sequence 2C is elaborated into 2E by oxidation to restore the ketone and by deprotection. Step (xii) is the oxidation of alcohol 2C to give the ketone 2D. The reagent used is selected from any of the usual oxidising agents which achieve this transformation. A prefered reagent is an iodine (m) species derived from ortho-iodobenzoic acid and commonly called the Dess-Martin periodinane. Step (xiii) involves the removal of all remaining protecting groups. These include PG2 and any groups used to protect, for example, the residues A', A2 and A3.
Preferably these will have been chosen such that their removal requires only one operation.
For example, when Al is tyrosine the hydroxyl group has to be protected during the couplings. If it is protected as a tert-butyl ether then choosing PG2 to be tert-butyl allows both protecting groups to be removed by a single acid treatment.
The preceding general methods are further illustrated in the following non-limiting Examples.
GENERAL METHODS NMR: Proton nuclear magnetic resonance spectra were recorded at 270 MHz. Samples were dissolved in deuterochloroform unless otherwise stated. Chemical shifts are reported relative to Me4Si ( > 0).
MS: Mass spectra were recorded in positive ion mode using fast atom bombardment ionization. The peak reported corresponds to [M+H]+ unless otherwise stated.
HPLC: High pressure liquid chromatographic analysis of products was carried out on a Spherisorb C18 column; particle size 5 ; column dimensions 4.6 x 100 mm.
Eluant A: 0.1% TFA in water, Eluant B: 0.1% TFA in acetonitrile In the Tables: Gradient A: 20% to 80% B into A in 25 mins at 0.8 cumin Gradient B: 40% to 9/o B into A in 25 mins at 0.8 mLlmin Gradient C: 30% to 90% B into A in 25 mins at 0.8 mL/min Gradient D: 10% to 70% B into A in 25 mins at 0.8 mL/min MPLC: Medium pressure liquid chromatographic purification of products was carried out on a Vydac C18 column using the eluants A and B described above. In the Tables the figures give the initial and final proportion (%) of B in the eluant.
Column: In the Tables this refers to flash chromatography on silica gel. The following abbreviations are used: A acetic acid C chloroform E ethyl acetate H hexane fraction M methanol P petroleum ether AAA: Aminoacid analysis: peptides were hydrolyzed for 90 min at 1500C in 6N HCI + phenol; PC is the peptide content.
Example 1: (3 SS3 (BenzvloxycarbonylvalvlalanylaminoWSoxaXoxo-8,8,8- trifluorooctanoic acid 1A: tert-Butyl (3S)-3-(benzyloxycarbonylamino)-5-diazo-4-oxo-pentanoate (1) To a cold (-20 C) stirred solution of Z-Asp(O-t-Bu)OH (29.1 g, 90 mmol) in ethyl acetate (100 mL) was added N-methylmorpholine (10.4 mL, 95 mmol) and isobutyl chloroformate (12.25 mL, 95 mmol). Stirring was continued for 40 min while the temperature of the reaction mixture was maintained between -20 C and -15 C.The mixture was filtered and the filtrate was added to an ice-cold ethereal solution of diazomethane (generated from 38.7 g, 180 mmol of Diazald. The resulting solution was allowed to warm to room temperature and stirred for 2 hr before the excess diazomethane was destroyed by the dropwise addition of acetic acid. The mixture was washed with 5% aqueous KHCO3, water and brine, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 25:75 EtOAc:hexane.
Because of its potential thermal instability no attempt was made to remove all traces of solvent from the diazoketone, hence no meaningful yield could be recorded.
1B: tert-Butvl (3 S3-(benzvloxyearbonylamino)-5-bromoA-oxo-pentanoate (2) To an ice-cold stirred solution of diazoketone 1 in ethyl acetate (250 mL) was added dropwise a saturated solution of HBr in ethyl acetate until the yellow coloration had disappeared and evolution of N2 had ceased. The solution was washed with 5% aqueous KHC03, water and brine, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 25:75 EtOAc:hexane, to give the title bromomethyl ketone as a colourless oil which crystallises on standing (28.0 g, 78% over 2 steps).
1C: tert-Butyl (3S)-3-(benzyloxycarbonylamino)-6-oxa-4-oxo-8,8,8-trifluorooctanoate (3) To a stirred solution of bromomethyl ketone 2 (6.0 g, 15 mmol) in DMF (25 mL) was added 2,2,2-trifluoroethanol (1.31 mL, 18 mmol) and cesium fluoride (3.42 g, 22.5 mmol). The mixture was stirred at room temperature for 18 hr then the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and brine. The organic layer was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 20:80 EtOAc:hexane to give the title ketone as a colourless oil (3.2 g, 51%).
1HNMR (CDCl3) 54.55 and 4.40 (isolated AB), 4.10(s), 3.85 (q), 2.95 and 2.85 (ABXn).
The NMR spectrum of this compound is complex and indicates that a mixture of at least two components is present, presumably ketone and hydrate. Only selected peaks are reported.
1 D: tert-Butyl (3 S 4RSS3-(benzyloxycarbonylamino)4hydroxv-6-oxa-8.8.8- trifluorooctanoate (4) To a cold (-20 C) stirred solution of the ketone 3 (3.20 & 7.6 mmol) in methanol (25 mL) was added NaBH4 (290 mg, 7.6 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hr then quenched by the addition of 2 M aqueous NH4Cl (75 mL). The mixture was extracted 3 times with EtOAc. The combined extracts were washed with brine, filtered and concentrated in vacua. The residue was purified by flash chromatography on silica gel eluting with 30:70 EtOAc:hexane to give the title compound as a white amorphous solid (1.95 & 61%).
@HNMR (CDCl3) 54.15 - 4.00 (2H, m); 3.65 - 3.50 (2H, m).
1E: tert-Butyl (3S, 4RS)-3-(benzyloxycarbonylalanylamino)-4-hydroxy-6-oxa-8,8,8 trifluorooctanoate (5a) This was prepared from the protected aminoalcohol 4 on a 1.47 mmol scale using standard solution phase peptide coupling techniques. 4 was deprotected by catalytic hydrogenolysis over 10% Pd-on-C in methanol. The resultant amine was isolated by filtration and evaporation of the solvent, then coupled to Z-Ala-OH using the hydroxybenzotriazole/watersoluble carbodiimide methodology. The product was purified by flash chromatography on silica gel eluting with 55:45 EtOAc:hexane and isolated in 66% yield.
1 F: tert-Butyl (3 S. 4RS)-3-(benzyloxycarbonylvalylalanylamino)-4-hydroxy-6-oxa-8,8,8- trifluorooctanoate (6aa! This was prepared from 5a on a 0.96 mmol scale by deprotection and subsequent coupling to Z-Val-OH following the method outlined in Example 1E. The product was isolated in 48% yield after flash chromatography on silica gel eluting with 75:25 EtOAc:hexane.
1 G: tert-Butyl (3 SS3-(benzyloxyzarbonylvalylalanylaminoWSoxaXoxo-8.8.8- trifluorooctanoate (7aa) To a stirred solution ofthe alcohol 6aa (280 mg, 0.47 mmol) in dichloromethane (10 mL) was added 1,1,1 -tris(acetoxy)-l -ioda-3-oxoisobenzofUran (Dess-Martin periodinane, 400 mg, 0.95 mmol). The mixture was stirred at room temperature for 3 days then diluted with EtOAc (20 mL). To this mixture was added a solution of sodium thiosulphate in saturated aqueous sodium hydrogencarbonate (15 mL). Stirring was continued for 20 min then the phases were separated and the aqueous layer was extracted twice with EtOAc.The organic layers were combined and washed once with the sodium thiosulphate/sodium hydrogencarbonate mixture, then with water and brine, filtered and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel eluting with 65:35 EtOAc:hexane to give the title compound as an amorphous solid (215 mg, 77%).
1H: (3S)-3-(Benzyloxycarbonylvalylalanylamino)-6-oxa-4-oxo-8,8,8-trifluorooctanoic acid (8aa) To a stirred solution of 7aa (215 mg, 0.36 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The mixture was stirred for 1 hr then concentrated in vacuo.
The residue was purified by repeated MPLC on a Vydac C18 column eluting first with a gradient of 30:70:0.1 to 90:10:0.1 MeCN:H2O:TFA and subsequently with a gradient of 20:80:0.1 to 80:20:0.1 MeCN:H2O:TFA, to give the title compound as an amorphous solid (94 mg, 49%).
HPLC: Gradient 20 to 80% B into A in 25 min at 0.8 mLlmin.
Peak detected at 17.9'.
A.A.A.: Found: Ala 0.96; Val 1.04.
P.C. =87%.
M.S. [M+H]+ =534.3.
Example 2: (3S)-3-(Acetyltyrosinylvalylalanylamino)-6-oxa-4-oxo-8,8,8-trifluorooctanoic acid 2 A: tert-Butyloxycarbonylvalylalanine methyl ester (9) This was prepared from Boc-Val-OH and H-Ala-OMe on a 8.7 mmol scale using the standard hydroxybenzotriazole/water-soluble carbodiimide methodology. The product was used without purification, assuming a quantitative yield.
2B: Benzylcarbonvl (O-tert-butyltyrosinyl)valylalanine methvl ester (10) This was prepared from 9 on a 8.7 mmol scale by deprotection with 4N HCVdioxan followed by coupling to Z-Tyr(t-Bu)-OH using the standard hydroxybenzotriazole/water-soluble carbodiimide methodology. The product was isolated in 65% yield after flash chromatography on silica gel eluting with 65:35 EtOAc:hexane.
2C: Benzvloxvcarbonyl (O-tert-butyltyrosinyl)valylalanine (11) This was prepared from 10 on a 5.7 mmol scale by lithium hydroxide hydrolysis in a dioxan/water mixture. The product isolated in 96% yield following flash chromatography on silica gel eluting with 60:2:1 CHCl3:MeOH:AcOH.
2D: tert-Butvl (3 S. 4RS)-3-(benzyloxycarbonyl(O-tert-butyltyrosinyl)valylalanylamino)-4- hydroxy-6-oxa-8,8,8-trifluorooctanoate (12a) This was prepared from 4 and 11 on a 0.25 mmol scale following the method of Example 1E.
The product was isolated in 66% yield after flash chromatography on silica gel eluting with 80:20 EtOAc:hexane.
2E: ten-Butyl (3 S)-3-(benzyloxycarbonyl(O-tert-butyltyrosinyl)valylalanylamino)-6-oxa-4- oxo-8,8,8-trifluorooctanoate (13a) This was prepared from 12a on a 0.17 mmol scale following the method of Example 1G. The product was isolated in 58% yield after flash chromatography on silica gel eluting with 80:20 EtOAc:hexane.
2F: tert-Butyl (3S)-3-(acetyl(O-tert-butyltyrosinyl)valylalanylamino)-6-oxa-4-oxo-8,8,8 trifluorooctanoate (1 4a) This was prepared from 13a on a 0.099 mmol scale by hydrogenolysis over 10% Pd-on-C in methanol and subsequent acetylation with acetic anhydride in a mixture of dichloromethane and DMF. The product was isolated in 70% yield after flash chromatography on silica gel eluting with 100:2 EtOAc:AcOH.
2G: (3S)-3-(Acetyltyrosinylvalylalanylamino)-6-oxa-4-oxo-8,8,8-trifluorooctanoic acid (iSa) This was prepared from 14a on a 0.07 mmol scale following the method of Example 1H. The product was purified by MPLC on a Vydac Cis column using a gradient of 10:90:0.1 to 60:40:0.1 MeCN:H2O:TFA to give the title compound as an amorphous solid (6 mg, 14%).
HPLC: Gradient 10 to 70% B into A in 2S min at 0.8 mL/min.
Peak detected at 11.6'.
A.AA.: Found: Ala 1.00; Tyr 0.99; Val 1.01.
P.C. =74%.
MS.: [M+H]+= 605.3.
ExamDles 3- 15 Following the route described in Example 1 the following compounds were prepared.
Table A: Analogues of 5a prepared following the method of Example 1E.
Product Xaa Scale (mmol) Yield (%) Column 5b Ile 0.7 43 60:40 E:P Sc Hph 0.7 34 55:45 E:P 5d Val 0.75 45 55:45 E:P 5e Aha 0.75 49 55:45 E:P 5f Pro 0.70 50 65:35 E:P Table B: Analogues of 6aa prepared following the method of Example 1F.
Starting Product Yaa Xaa Scale (mmol) Yield (%) Column Material Sa 6ab Phe Ala 0.3 78 80:20 E:P 6ac Hph 0.36 85 65:35 E:P 6ad Aha 0.40 79 75:25 E:P 6ae Pro 0.40 85 95:5 E:P 6af Phg 0.45 69 65:35 E:P 6ag Leu 0.45 73 70:30 E:P 6ah Ile 0.45 85 70:30 E:P 6ai Chg 0.45 77 70:30 E:P 5b 6ba Val Ile 0.30 74 70:30 E:P Sc 6ca Hph 0.24 73 70:30 E:P 5d 6da Val 0.34 89 65:35 E:P 5e 6ea Aha 0.37 91 65:35 E:P 5f 6fa Pro 0.70 50 65:35 E:P Table C: Analogues of 7aa prepared following the method of Example 1G.
Product Yaa Xaa Scale (mmol) Yield (%) Column 7ab Phe Ala 0.23 72 65:35 E:P 7ac Hph 0.36 85 65:35 E:P 7ad Aha 0.31 80 65:35 E:P 7ae Pro 0.34 63 80:20 E:P 7af Phg 0.31 67 60:40 E:P 7ag Leu 0.33 68 60:40 E:P 7ah Ile 0.38 72 60:40 E:P 7ai Chg 0.35 73 60:40 E:P 7ba Val lie 0.22 79 55:45 E:P 7ca Hph 0.18 57 50:50 E:P 7da Val 0.30 50 50:50 E:P 7ea Aha 0.34 50 45:55 E:P 7fa Pro 0.32 85 60:40 E:P Table D: Analogues of8aa prepared following the method of Example 1H.
Table DI Example Product Yaa Xaa Scale (mmol) Yield(%) 3 8ab Phe Ala 0.16 16 4 8ac Hph 0.31 53 5 8ad Aha 0.25 52 6 8ae Pro 0.21 82 7 8af Phg 0.21 69 8 8ag Leu 0.22 88 9 8ah Ile 0.27 68 10 8ai Chg 0.26 62 11 8ba Val ne 0.17 47 12 8ca Hph 0.10 61 13 8da Val 0.15 52 14 8ea Aha 0.17 50 15 8fa Pro 0.27 74 Table D2 Example Column MPLC HPLC AAA: PC (%) M.S.
Found 3 60:2:1 30% to 70% A 15.6' Ala 0.99 87 582.1 C:M:A Phe 1.01 4 60:2:1 30% to 70% A 16.5' Ala 1.00 86 596.2 C:M:A Hph 1.00 5 60:2:1 25% to 75% A 15.0' Ala 0.98 88 548.3 C:M:A Aha 1.02 6 30:2:1 20% to 70% A 12.0' Ala 1.00 83 532.2 C:M:A Pro 1.00 7 50:2:1 25% to 75% A 15.0' Ala 0.99 84 568.2 C:M:A Phg 1.01 8 50:2:1 25%to70% A 15.3' Ala 0.97 77 548.2 C:M:A Leu 1.03 9 50:2:1 25% to 70% A 15.0' Ala 1.01 82 548.2 C:M:A ne 0.99 10 50:2:1 30% to 70% A 16.5' Ala 0.99 82 574.2 C:M:A Chg 1.01 11 70:2:1 30% to 70% A 16.4' Ile 0.94 81 576.4 C:M:A Val 1.06 12 70:2:1 30%to75% B 10.5' Hph0.99 77 624.4 C:M:A Val 1.01 13 70:2:1 30% to 70% A 15.6' 83 562.3 C:M:A 14 70:2::1 30% to 70% A 17.0' Aha 1.00 84 576.2 C:M:A Val 1.00 15 50:2:1 25% to 70% A 14.6' Pro 1.01 83 560.3 C:M:A Val 0.99 Examples 16- 18
16A: tert-Butyl (3S)-3-(benzyloxycarbonylamino)-5-hydroxy-4-oxopentanoate (16) To a stirred solution of the bromomethyl ketone 2 (4.3 g, 10.8 mmol) in DMF (30 mL) was added benzoylformic acid (1.94 & 12.9 mmol) and cesium fluoride (2.45 g, 16.1 mmol). The mixture was stirred at room temperature for 16 hr then diluted with EtOAc (100 mL) and washed with 1M hydrochloric acid (3 x 75 mL) and brine, filtered and concentrated in vacuo.
The residue was taken up in THF (40 mL), aqueous KOH (10.8 mL, 1M, 10.8 mmol) was added, and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated in vacuo and the residue was partitioned between EtOAc (70 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2 x 70 mL) and the combined organic phases were washed with brine, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 45:55 EtOAc:hexane to give the title compound as a colourless oil (3.14 & 86%).
16B: tert-Butvl (3S)-3-(benzyloxycarbonylamino)-4-oxo-5-methoxy-pentanoate (1 7a) To a stirred solution of the alcohol 16 (lg, 2.96 mmol) was added iodomethane (1.38 mL, 22.2 mmol) and silver (I) oxide (1.37 g, 5.92 mmol). The mixture was heated at reflux in the dark for 18 hr then allowed to cool and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with 30:70 EtOAc:hexane to give the title compound as a colourless oil (670 mg, 64%).
'H NMR (CDCl3): 5 4.69 - 4.28 (2R isolated AB); 3.45 (3H, s).
Table E: Analogues of 17a prepared following the method of Example 16B.
Product R Scale (mmol) Yield (%) Column NMR b Et Et 2.95 39 30:70 E:H 4.25 (2H, ABq), 3.55(2H,q) 17c Bu 2.95 20 15:85 E:H 4.22(2H,ABq), 3.47 (2X t) 17d Pr 1.50 25 20:80 E:H 4.28 (2H, ABq), 3.42 (2H, E) Table F: Analogues of4 prepared following the method of Example 1D.
Product R Scale (mmol) Yield (%) Column NMR 18a Me 1.91 84 45:55 E:H 3.45(2H,m), 3.36 and 3.35 (3H, 2 x s) 18b Et 1.16 94 45:55 E:H 4.06(2H,m), 3.50 (2X q) 18c Bu 0.58 70 35:65 E:H 4.06 (2H, m), 3.42 (2H, t) 18d Pr 0.37 67 30:70 E:H 3.54-3.32 (4X m) Table G: Analogues of 5a prepared following the method of Example 1E.
Product R Scale (mmol) Yield (%) Column NMR 19a Me 1.28 61 90:10 E:H 3.46-3.28(2H,m), 3.35 and 3.33 (3H, 2 x s) 19b Et 1.09 68 90:10 E:H 4.22(2H,m), 3.46 (2H, q) 19c Bu 0.40 75 80:20 E:H 4.13 (2H, m), 3.43 (2H, t) Table H: Analogues of 6aa prepared following the method of Example 1F.
Product R Scale (mmol) Yield (%) Column 20a Me 1.28 61 90:10 E:H 20b Et 0.74 92 100:1.2 C:M 20c Bu 0.30 84 100:0.75 C:M Table I: Analogues of 7aa prepared following the method of Example 1G.
Product R Scale (mmol) Yield (%) Column NMR 21a Me 0.78 61 75:25 E:H 4.23 (2H, ABq), 3.40 (3H, s) 21b Et 0.68 63 70:30 E:H 4.25 (2X ABq), 3.54 (2H, q) 21c Bu 0.25 85 60:40 E:H 4.21 (2H, ABq), 3.47 (2H, t) Table J: Analogues of 8aa prepared following the method of Example 1H.
Table JI Example Product R Scale (mmol) Yield (%) 16 22a Me 0.14 37 17 22b Et 0.13 40 18 22c Bu 0.21 17 Table J2 Example MPLC HPLC AAA: Found PC (%) M.S.
16 15% to 60% D 4.0' Ala 1.15 84 464.2 Val 0.85 17 15% to 60% D 5.0' Ala 0.88 81 478.2 Val 1.12 18 20%to80% C 9.6' Ala 1.00 83 508.2 Val 1.00 Example 19: (3S)-5-Methoxy-4-oxo-3-(3-phenylpropionylvalylalanylamino)pentanoic acid
19A: tert-Butyl (3S)-5-methoxy-4-oxo-3-(3-phenylpropionylvalylalanylamino)pentanoate (23a) This was prepared from 21a on a 0.24 mmol scale by sequential hydrogenolysis and hydroxybenzotriazole-mediated coupling to phenylpropionic acid following the method of Example 1E. The product was isolated in 56% yield after flash chromatography on silica gel eluting with ethyl acetate.
19B: (3S)-5-Methoxy-4-oxo-3-(3-phenylpropionylvalylalanylamino)pentanoic acid (24a) This was prepared from 23a on a 0.14 mmol scale following the method of Example 1H. The product was purified by MPLC on a Vydac Cis column eluting with a gradient of 15:85:0.1 to 60:40:0.1 MeCN:H2O:TFA and isolated as an amorphous solid (24 mg, 37%).
HPLC: Gradient 30 to 90% B into A in 25 min at 0.8 mLlmin.
Peak detected at 4.0'.
A.A.A.: Found: Ala 0.85; Val 1.15.
P.C. = 84%.
M.S. [M+H]+=464.2.
Example 20: (3S)-5-Ethoxy-4-oxo-3-(3-phenylpropionylvalylalanylamino)pentanoic acid
23b R = t-Bu 24b R = H Following the methods of Example 19, 21b was converted on a 0.21 mmol scale into 23b in 62% yield (column eluant EtOAc) which was then converted on a 0.13 ,nmol scale into 24b which was isolated in 40% yield after MPLC on a Vydac C18 column eluting with a gradient of 15:85:0.1 to 60:40:0.1 MeCN:H2O:TFA.
HPLC: Gradient: 30 to 90% B into A in 25 min at 0.8 mL/min.
Peak detected at 5.0'.
A.A.A.: Found: Ala 0.88; Val 1.12.
P.C. = 81%.
M.S.: [M+H1+ = 478.2.
Examples 21-22 Following the route described in Example 2 the following compounds were prepared.
Table K: Analogues of 12a prepared following the method of Example 2D.
Starting Product R Scale (mmol) Yield (%) Column Material 18b 12b Et 0.65 67 100:2 E:A 18d 12c Pr 0.25 65 85:15 E:H Table L: Analogues of 13a prepared following the method of Example 2E.
Product R Scale (mmol) Yield (%) Column 13b Et 0.44 55 75:25 E:H 13c Pr 0.16 88 80:20 E:H Table M: Analogues of 14a prepared following the method of Example 2F.
Product R Scale (mmol) Yield (%) Column 14b Et 0.24 60 100:2 E:A 14c Pr 0.14 81 100:1 E:A Table N: Analogues of 15a prepared following the method of Example 2G.
Table NI Example Product R Scale (mmol) Yield (%) 21 15b Et 0.15 15 22 l5c Pr 0.11 19 Table N1 Example MPLC HPLC AAA: Found PC (%) M.S.
21 15% to 70% D 8.4' Ala 1.00, Tyr 1.01, 84 551.8 Val 0.99 22 15% to 70% D 10.1' Ala 1.00, Tyr 0.95, 76 565.2 Val 1.05 The Compounds of the present Invention reversibly inhibit the proteolytic action of interleukin-1ss converting enzyme (ICE) with high potency. This activity can be demonstrated and quantified as follows.
Determination of K@ Compounds were assayed using a COBAS FARA II centrifugal analyser (Roche Diagnostics).
All substrate and inhibitor solutions were made by diluting a iOmM DMF stock into standard assay buffer 10mM HEPES NaOH pH 7.5, 10% sucrose, 0.1% CHAPS, lmM EDTA.
Ac-Tyr-Val-Ala-Asp-AFC substrate concentrations used in the assay were 10, 20 and 30 pM and inhibitor concentrations used in the assay were varied from O.5xKi to 20xKi. Enzyme solution was prepared by reactivating 50 L ICE-glutathione conjugate [N. A. Thornberry et al. Nature 356, 768-774 (1992)] (5,000 unit/mL) in 2.3 mL assay buffer containing 50 mM DTT, where 1 unit of activity#1 pmole AFC min-1 30 pL Inhibitor (x10 conc.), 30 L substrate (x10 conc.) and 180 L assay buffer were mixed together by centrifugal vortexing. Then 60pL freshly prepared enzyme solution (6 unit) was added and this was mixed with the substrate and inhibitor by centrifugal vortexing. The assay was then incubated at 37 C and fluorimetric readings (excitation 395nm, emission 515nm) were taken after 2 min and every 2 min thereafter for 20 min.
The rate of AFC production was determined for several inhibitor concentrations at each of three substrate concentrations, and the steady state Ki value was determined by the method of Dixon [Dixon H.B.F. Biochem. J. 55, 170-171(1953)] using the ENZFITTER program (Biosoft, Camb. UK).
Typical values for the dissociation constant Ki are as follows: Compound of Example Ki (nM) 1 64 2 38 3 180 4 450 5 370 6 19000 7 1500 8 530 9 470 10 770 11 180 12 100 13 200 14 92 15 57 16 790 17 330 18 41 19 1500 20 630 21 115 22 55 As described above, this inhibition of ICE in vitro can be expected to translate into an antiinflammatory activity in vivo. Thus a further aspect of the present Invention is the treatment of a disease in which interleukin-lp is a causative factor. Examples of such diseases include, but are not limited to, rheumatoid arthritis, encephalitis, inflammatory bowel disease, pancreatitis, psoriasis, hypotensive shock and reperfusion injury following myocardial infarction.
The compounds of the present Invention can be administered in ways which are well known in the Art. For example they may be administered orally as tablets or capsules, by intravenous or intramuscular injection, or by topical, transdermal or rectal application.
Depending on the route of administration the compounds will be formulated in an appropriate manner. The dosage required will be determined by the physician taking into account all the relevant factors and will typically be between lmg and 1000mg either once per day or in repeated doses.

Claims (9)

Claims
1. A compound of formula I
or a pharmaceutically acceptable salt thereof wherein: R' is (a) substituted alkyl C1 - C6, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1 - C6 aLkoxy, C1 - C6 alkylcarbonyl and phenyl; (b) aryl or aryl C1 - C6 alkyl wherein the aryl group is selected from phenyl, napthyl, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, purinyl, isoxazolyl, oxazolyl, quinoxalinyl, triazolyl and triazinyl, and mono and di-substituted aryl as defined above wherein the substituents are independently C1 - C6 alkyl, halo, hydroxy, NR6R7, C1 - 6 alkoxy, C1 -6 alkylthio, C1 - 6 alkylcarbonyl, carboxy or phenyl;;
wherein aryl is defined as in (b) above, and may be substituted as defined in (b) above.
R2 is hydrogen, alkyl C1 4, benzyl; R3 is hydrogen, alkyl C1-4 or phenyl; R4 is hydrogen, fluorine, C1 -4 alkyl, -(C:H2)a-CO2H; R5is (a) substituted alkyl C1 - 10, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1-6 alkoxy; (b) aryl alkyl C1 6 wherein the alkyl groups may be substituted by hydrogen, halogen or hydroxy and the aryl group is selected from phenyl, pyridyl or napthyl, and is optionally mono or di-substituted with the substituents being selected independently from C1 - 6 alkyl, halo, hydroxy, C1 - 6 alkoxy, C1 - 6 alkylthio, C1-6 alkylcarbonyl, carboxy or phenyl;; (c) aryl or substituted aryl as defined in (b) above, subject to R4 not being hydrogen andlor at least two of A1, A2 and A3 being absent, and/or X2 being -OCONH-, -NHCO2- or -NHCONH-; R6 and R7 are independently hydrogen or C1 -4 alkyl; R8, R10 and R12 are each independently selected from hydrogen or alkyl C1 - R9, R11 and R13 are each independently selected from (a) hydrogen (b) substituted saturated or unsaturated alkyl C1 6. wherein the substituent is selected from hydrogen, hydroxy, halo, -SH, -S-C1.4 alkyl, C1- 6 alkylcarbonyl, carboxy, -CONH2, amino, C1 4 4 alkylamino, guanidino, -C-C1 - 4 alkyl, phenylcarbonylamino;; (c) aryl or aryl C1.6 alkyl, wherein aryl is phenyl, pyridyl, indolyl or imidazolyl and wherein the aryl is optionally mono and di-substituted, the substituents being each independently C1 4 alkyl, halo, hydroxy, CO2H, Me2N-, NH2, C1- 4 alkylamino, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkyl carbonyl, NO2, -SH or -CN; A1 is selected from (a) a single bond; (b) an amino acid residue or analogue of formula m;
(c) an imino acid residue or analogue of formula IV;
A2 is selected from (a) a single bond; (b) an amino acid residue or analogue of formula V;
(c) an imino acid residue or analogue of formula VI;
A3 is selected from (a) a single bond; (b) an amino acid residue or analogue of formula VII;;
(c) an imino acid residue or analogue of formula vm
X' is absent, -0- or -NH-; X2 is -O-, -S-, -OCONH-, -NHCO2- or -NHCONH-; X3 is absent, -NH-, -(CH2)e-, -(CH2)eO-, -O(CH2)e-, -CH=CH-, -CO(CH2)e-, -(CH2)eCO-, -(CH2)eNHCO-, -NHCO(CH2)e-, -(CH2)eCONH-, -CONH(CH2)e-, -(CH2)eNHSO2-, -NHSO2(CH2)e-, -SO2NH(CH2)e-, -(CH2)eSO2NH-, -(CH2)eNH-, -NH(CH2)e-; X4, X5 and X6 are each independently 0 or H2; ais 0 - 3 bis0-4 c is 0- 4 dis0-4 eis 0 - 3 fis0-
2 2. A compound according to claim 1 wherein: A1 is a residue of tyrosine, phenylalanine, homophenylalanine, phenylglycine, tryptophan or histidine; R1 is unsubstituted C1.6 alkyl; X1 is absent.
3. A compound according to claim 2 wherein: R4 is hydrogen; R5 is substituted aLkyl C1 ro, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1 -6 alkoxy or phenyl; X2isOorS.
4. A compound of claim 1 wherein: R1 is aryl or aryl C1 6 (saturated or unsaturated) alkyl wherein the aryl group is selected from phenyl, napthyl, pyridyl, furyl, thienyl, pyrazinyl, pyrimidinyl, pyrazolyl and indolyl, and mono and disubstituted aryl as defined above wherein the substituents are independently C1-6 alkyl, halo, hydroxy, NR6R7, C1 .6 alkoxy, C1 - 6 alkylthio, C1 -6 alkyl carbonyl, carboxy or phenyl; A1 is absent;
5. A compound of claim 4 wherein: R4 is hydrogen; R5 is substituted alkyl C1 ,o, wherein the substituents are selected from hydrogen, halogen, hydroxy, C1 6 alkoxy, or phenyl; X2isOorS.
6. A compound of claim 1 where both A1 and A2 are absent.
7. A compound of claim 1 where R4 is methyl.
8. At least one compound selected from the following compounds according to claim 1 and pharmaceutically acceptable salts thereof: (3S)-3-(Acetyl-tyrosinyl-valyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Acetyl-tyrosinyl-valyl-alanyl)amino-4-oxo-5-npropyloxy pentanoic acid; (3S}3-(Acetyl-tyrosinyl-valyl-alanyl)amino-5-ethoxywoxo pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-alanyl)amino-5-methoxy-4-oxo pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-alanyl)amino-5-nbutyloxy-4-oxo pentanoic acid; (3S)-3- (Benzyloxycarbonyl-valyl-alanyl)amino-5-ethoxy-4-oxo pentanoic acid; (3S)-3-(Benzyloxycarbonyl-phenylalanyl-alanyl)amino-4-oxo-5-(2',2',2' trifluoroethoxy) pentanoic acid;; (3S)-3-(Benzyloxycarbonyl-homophenylalanyl-alanyl)-amino-4-oxo-5-(2',2',2' trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-norieucinyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-prolyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-phenylglycinyl-alanyl)amino-4-oxo-5-(2',2',2' trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-leucinyl-alanyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-isoleucinyl-alanyl)arnino-soxo-5- (2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-cyclohexylglycinyl-alanyl)amino-4-oxo-5-(2',2',2' trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-isoleucyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid;; (3S)-3-(Benzyloxycarbonyl-valyl-norleucyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-homophenylalanyl)amino-4-oxo-5-(2',2',2' trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-valyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-3-(Benzyloxycarbonyl-valyl-propyl)amino-4-oxo-5-(2',2',2'-trifluoroethoxy) pentanoic acid; (3S)-5 -Methoxy-4-oxo-3- (3 '-phenylpropanoyl-valyl-alanyl)amino pentanoic acid; (3S)-5-Ethoxy-4-oxo-3-(3'-phenylpropanoyl-valyl-alanyl)amino pentanoic acid; (3S)-3-(Benzoyl-valyl-alanyl)amino-5-nbutyloxy-4Oxo pentanoic acid; (3S)-3-(Benzoyl-valyl-alanyl)amino-5-benzyloxy4-oxo pentanoic acid, (3S)-3-(Benzoyl-valyl-alanyl)amino-4-oxo-5-(3'-hydroxypropyloxy) pentanoic acid.
9. A pharmaceutical composition for treatment of interleukin-1 mediated disorders or diseases in a patient in need of such treatment comprising of a compound according to claim 1 as the active constituent.
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