METHOD OF INHIBITING SERINE PROTEASE ENZYMES

Abstract: According to the invention there is provided an inhibitor of a serine protease enzyme which is a substituted derivative of trans-hexahydropyrrolo[3,2-b]pyrrol-2-one save that it is not a compound of formula IA and IB (as defined in Annex 1).

Description: Method of inhibiting serine protease enzymes This invention relates to a new class of chemical compounds and their use as inhibitors of serine protease enzymes. These compounds are useful as pharmaceuticals and we provide processes for preparing them and formulations containing them. Serine proteases are a class of proteolytic enzymes characterised by having at the active site a serine residue which interacts with the carbonyl carbon of a peptide bond to cleave the peptide bond via an acyl enzyme intermediate. Under the conventional residue numbering based on homology with the serine protease enzyme chymotrypsin, the active site serine is generally numbered Ser-195. Most members of the family of serine proteases have a histidine and an aspartic acid residue in the active site (numbered His-57 and Asp-102 based on chymotrypsin) which activate the serine hydroxyl group to attack the scissile peptide carbonyl. In a small number of enzymes (notably Herpes virus proteases) the role of Asp-102 is taken by a further histidine residue (which is His-157 in cytomegalovirus protease). Residue mutation studies have shown these three residues to be essential for activity and they are conventionally referred to as the "catalytic triad". Although the mechanism of hydrolysis of peptide bonds by serine proteases is believed to be similar for all enzymes in the family, it is well known that their substrate specificities differ dramatically. In general, specificity is shown for peptide bonds which have a particular moiety α to the scissile peptide carbonyl which in conventional nomenclature is said to be in the P- t position and to occupy the S Ϊ specificity subsite (see Schlecter and Berger (1967) Biochem Biophys Res Common 27 157). For example, the preferred substrate for thrombin is a peptide containing a basic residue (e.g. arginine i.e. the moiety (CH 2 ) 3 NHC(=NH)NH 2 ) is in the P., position) whereas the preferred substrate for elastase is a peptide containing a valine residue (i.e. the moiety CH(CH 3 ) 2 is in the P* position). The X-ray crystal structures of a substantial number of serine protease enzymes have become available in recent years. It can be concluded in explanation of the above observations, that the "catalytic triad" is generally highly conserved in terms of its spacial orientation at the active site and that a major factor in the difference in substrate specificity comes from the shape and character of the S 1 specificity subsite. Serine proteases are widespread in the human body and abnormal or excessive activity of serine proteases is implicated in a diverse range of diseases and conditions (see "Proteinase Inhibitors", Barrett and Salveson (1986), Elsevier, p56; Drugs Future (1996), 21(8), 811-816; Exp. Opin. Ther. Patents (1997) 7(1) 17-28). The following enzymes and associated conditions are exemplary: Neutrophil elastase is found in neutrophil azurophilic granules associated with tissue inflammation and is associated with a number of inflammatory diseases including emphysema, chronic bronchitis and adult respiratory distress syndrome (ARDS). Members of the blood coagulation cascade (e.g. thrombin, Factor Vila, Factor Xa, Factor Xla, Factor Xlla) and members of the fibrinolytic cascade (e.g. tissue plasminogen activator and plasmin) are potential targets for treatment of diseases of the vascular system. For example, thrombin is a potential target for the treatment of thrombosis. Tissue plasminogen activator and plasmin may also be implicated in tumour metastasis. Tryptase is present in mast cells and inhibitors of tryptase have shown efficacy in models of asthma. Pancreatic elastase, trypsin and chymotrypsin are associated with digestive disorders such as pancreatitis. Cathepsin G is associated with emphysema. Serine proteases are also widespread in human pathogens especially viruses and these provide an attractive target for the treatment of pathogenic diseases and conditions. For example Herpes viruses encode a serine protease which is crucial for viral replication and is therefore a target for the treatment of conditions caused by these viruses. The Herpes family of viruses is responsible for a wide range of human infectious diseases including chicken pox and shingles (varicella and Herpes zoster viruses, respectively), cold sores and genital herpes (herpes simplex virus), retinitis, pneumonitis and keratitis (human cytomegalovirus, hCMV), as well as diseases caused by Epstein Barr Virus (EBV), human herpes virus 6 (HHV 6), HHV 7 and HHV 8. Hepatitis C virus also encodes a serine protease (known as the NS3 serine protease) which is a target for treatment of Hepatitis C virus infection and associated hepatic damage. It will be appreciated that aside from the enzymes and conditions mentioned above many other serine protease enzymes are known to be suitable targets for pharmaceutical therapy and indeed it can be expected that many more will be identified in the future. We have now invented a novel chemical class of molecules which are capable of inhibiting a wide range of serine protease enzymes. As such they are of potential value in the treatment of diseases as discussed above. More particularly, according to the invention, we provide inhibitors of serine protease enzymes which are substituted derivatives of trans- hexahydropyrrolo[3,2-b]pyrrol-2-one (save that we exclude the compounds of formula IA and IB as defined in Annex 1). Most particularly, this invention relates to inhibitors of serine protease enzymes which are compounds of formula I: (relative stereochemistry indicated) wherein R 1 is a moiety adapted to fit in the S specificity subsite of the enzyme; R 2 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the inhibitor; R 3 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the inhibitor; and physiologically acceptable salts and solvates thereof save that we exclude compounds of formula IA and IB (as defined in Annex 1). Without being limited by theory, we believe that the translactam template of formula I is highly complementary to the active site of serine proteases and the lactam carbonyl mimics the peptide carbonyl of the enzyme's natural substrate. Inhibition of serine proteases by compounds of the invention has been found to be either competitive (reversible) or time-dependent (acylating) depending on the precise enzyme and particular substitution pattern on the translactam template. Time-dependent (acylating) inhibition is believed to occur when attack of the enzyme active site serine on the translactam carbonyl causes opening of the strained lactam ring generating an enzyme acylated at the serine sidechain. The advantages of our invention reside inter alia in that (a) the trans- hexahydropyrrolo[3,2-b]pyrrol-2-one template is completely new and therefore highly desirable in a medicament especially for the treatment of pathogenic conditions which are prone to drug resistance, (b) the trans- hexahydropyrrolo[3,2-b]pyrrol-2-one template may be highly functionalised and is therefore ideal for the specific and selective inhibition of a wide range of different enzymes, (c) the trans-hexahydropyrrolo[3,2-b]pyrrol-2-one template may potentially be functionalised to give (i) high or low metabolic stability and (ii) competitive or time-dependent inhibition as desired. The determination of the optimum substitution of the derivatives of trans- hexahydropyrrolo[3,2-b]pyrrol-2-one, especially regarding selection of groups R 1 , R 2 and R 3 for a particular serine protease enzyme can be made in a conventional manner, namely: (a) by preparation of a number of compounds having sufficient diversity especially in groups R 1 , R 2 and R 3 , (b) treatment of a sample of the enzyme in question with a sample of each of the compounds so prepared and (c) determining the extent to which inhibition of the enzyme has occurred. Assays for enzyme inhibition will generally be well known and in any event will be capable of being performed by a person skilled in the art. More particularly: Suitable R 1 groups will fit appropriately in the S ! specificity subsite of the target enzyme. Choice of group R 1 may be made having regard to the known substrate specificity preferences of the target enzyme, crystallographic information concerning the geometry of the S 1 specificity subsite of the target enzyme and/or empirical determination based on screening data (see for example "Proteinase Inhibitors" Barrett and Salveson (1986), Elsevier, p9 and p59). When classified by their primary substrate specificity, there are three major types of serine proteinases: elastase-like, trypsin-like and chymotrypsin-like. The differences between these types can be understood in structural terms - see Kraut J (1977) Am. Rev.Biochem. 46 331-358). We find, for example that for inhibition of neutrophil elastase and elastase-like enzymes, the group R 1 is preferably small and hydrophobic, e.g. C 2-4 alkyl or C 2-4 alkenyl, especially propyl or isopropyl, particularly isopropyl. For inhibition of chymotrypsin-like enzymes (including chymotrypsin and cathepsin G) the group R 1 is preferably large and hydrophobic, e.g. (CH 2 ) 1-2 Ph, (CH 2 ) 0-2 cyclohexyl, t-butyl. Ph represents phenyl or substituted phenyl (e.g. phenyl substituted by C 1-6 alkyl, halogen). Planar aromatic sidechains (e.g. benzyl) are especially preferred. For inhibition of trypsin-like enzymes (including trypsin, thrombin, tryptase, Factor Vila, Factor Xa, Factor Xla, Factor Xlla) the group R 1 is preferably basic e.g.(CH 2 ) 2 ^NHC(=NH)NH 2 , (CH 2 ) 1-2 PhC(=NH)NH 2 , (CH 2 ) 3 . 5 C(=NH)NH 2 , CH 2 (cyclohexyl)NH 2 , (CH 2 ) 1-3 (NH) 0-1 Het ( wherein Het represents a 5 or 6 membered aromatic ring containing 1 or more nitrogen atoms and optionally substituted by amine) or (CH 2 ) 3-5 NH 2 especially (CH 2 ) 4 C(=NH)NH 2 or (CH 2 ) 3 NHC(=NH)NH 2 , particularly (CH 2 ) 4 C(=NH)NH 2 . For inhibition of Herpes virus proteases, group R 1 is preferably methyl. R 2 will be a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the serine protease inhibitor. Preferably, R 2 will be lactam activating moiety. Suitable activating groups include electron withdrawing groups which may typically (but not exclusively) comprise a SO 2 or CO moiety attached to the lactam nitrogen. For inhibition of neutrophil elastase, we have found that R 2 may represent CHO or SO 2 C 1-6 alkyl and is preferably a group -SO 2 Me. For inhibition of thrombin we have found that R 2 is preferably a group CONH(CH 2 ) 1-4 Ph, SO 2 (CH 2 ) 0-1 Ph, -COOC 1-4 alkyl (e.g. -COOMe), CONH 2 or -CONHC 1-4 alkyl (e.g. -CONHMe). These may also be the preferred R 2 for other trypsin-like enzymes. For inhibition of herpes virus proteases group R 2 is preferably -COC 1-6 alkyl (e.g - CO-cyclopropyl). For inhibition of herpes virus proteases an electron wwiitthhddrraawwiiing heteroaryl group (e.g. 2- benzothiazolyl) for R 2 may also be preferred. When R 2 is highly activating we find that the inhibitors act through a time- dependent (acylating) mechanism whereas when R 2 is less activating, the inhibitors may act through a reversible (competitive) mechanism. When R 2 comprises an SO 2 moiety attached to the lactam nitrogen, the inhibitor is generally time-dependent (acylating). When R 2 comprises a CO moiety attached to the lactam nitrogen, the inhibitor may be time-dependent (acylating) or not depending on the exact nature of R 2 . When R 2 represents COOC 1-4 alkyl it is more likely to be time-dependent (acylating) than when R 2 represents CONHC^alkyi. R 3 will be a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the serine protease inhibitor. It may also be adapted to optimise other pharmacological properties such as water solubility and oral activity (if desired). In general, R 3 can vary quite widely and a person skilled in the art would be able to determine from suitable testing if a given R 3 is suitable for the aforementioned purposes or not. Frequently, an increase in potency is achieved when the R 3 moiety binds at a remote specificity subsite such as S 3 , S 4 , or S 5 (see "Proteinase Inhibitors", Barrett and Salveson (1986) Elsevier, p6, 69). We have found that it is often preferred that R 3 comprises a CO, SO 2 or CO.O (especially a CO or SO 2 ) moiety attached directly to the pyrrolidine nitrogen and is, for example, a group of formula R 30 CO, R 30 SO 2 or R 30 OCO (especially R 30 CO or R 30 SO 2 ). R 30 will also be a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the serine protease inhibitor and may represent, for example, alkyl (e.g. C 1-8 alkyl), alkenyl (e.g. C 1-8 alkenyl), aryl, alkylaryl (e.g. C 1-8 alkyiaryl), or alkenylaryl (e.g. C-,_ 8 alkenylaryl). Where used herein, alkyl includes branched and cyclic alkyl. Alkenyl includes branched and cyclic alkenyl. Aryl includes mono and bicyclic aromatic rings optionally containing heteroatoms, e.g. O, N and S atoms (for example 1 to 4 heteroatoms) and biaryl. Alkyl, alkenyl, aryl, alkylaryl and alkenylaryl groups may be optionally substituted, e.g. by amine and halogen and optionally interrupted by a heteroatom (e.g. nitrogen or oxygen) or otherwise functionalised. Amine groups include primary, secondary and tertiary amine groups including cyclic amine. Thus according to the invention we also provide a method of inhibiting a serine protease enzyme which comprises treating it with a compound of the invention. We also provide a method of screening for inhibitors of serine proteases which comprises treating a serine protease enzyme with a compound of the invention and determining the extent to which inhibition has occurred. We also provide a method of identifying an inhibitor of a serine protease enzyme which comprises: (a) preparation of a number of substituted derivatives of trans- hexahydropyrrolo[3,2-b]pyrroI-2-one; (b) treatment of a sample of the enzyme in question with a sample of each of the derivatives so prepared; and (c) determining the extent to which inhibition of the enzyme has occurred. The extent to which inhibition has occurred may be determined by conventional assay techniques including (but not limited to) chromogenic assays, fluorogenic assays, HPLC and scintillation proximity assays. In one particularly advantageous method of drug discovery, a library comprising a plurality of substituted derivatives of trans-hexahydropyrrolo[3,2-b]pyrrolo-2- one will be prepared. Preferably the library will comprise a plurality of compounds of formula I wherein R 1 is a moiety adapted to fit in the S 1 specificity subsite of the enzyme; R 2 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the inhibitor; R 3 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the inhibitor; and physiologically acceptable salts and solvates thereof. The library will, ideally comprise at least 10 (e.g. 10, 100, 1000 or more) different compounds. A library of compounds of formula I wherein R 1 represents a small and hydrophobic group e.g. C 2-4 alkyl or C -4 alkenyl, especially propyl or isopropyl, particularly isopropyl may be particularly useful for screening for an inhibitor of elastase-like enzymes e.g. neutrophil elastase. A library of compounds of formula I wherein R 1 represents methyl may be especially useful for screening for an inhibitor of Herpes virus proteases. A library of compounds of formula I wherein R 1 represents a basic group e.g. (CH 2 ) 2-4 NHC(=NH)NH 2 , (CH 2 ) 1-2 PhC(=NH)NH 2 , (CH 2 ) 3-5 C(=NH)NH 2 , CH 2 (cyclohexyl)NH 2 , (CH 2 ) 1-3 (NH) 0 . 1 Het ( wherein Het represents a 5 or 6 membered aromatic ring containing 1 or more nitrogen atoms and optionally substituted by amine) or (CH 2 ) 3-5 NH 2 especially (CH 2 ) 4 C(=NH)NH 2 or (CH 2 ) 3 NHC(=NH)NH 2 , particularly (CH 2 ) 4 C(=NH)NH 2 may be especially useful for screening for an inhibitor of a trypsin-like enzyme (e.g. thrombin or tryptase). A library of compounds of formula I wherein R 1 represents a large and hydrophobic group e.g. (CH 2 ) 1-2 Ph, (CH 2 ) 0-2 cyclohexyl or t-butyl may be useful for screening for an inhibitor of a chymotrypsin-like enzyme e.g. chymotrypsin or cathepsin G. Library technology will be known to a person skilled in the art and is reviewed in Drug Discovery Today (1996) 1(4) 134-144 and Annual Reports in Combinatorial Chemistry and Molecular Diversity 1. Ed. Moos Walter H, Pavia Michael R, Kay Brian K, Ellington Andy D. The library may be a solid phase or a solution phase library. It may be a discrete library or a pooled library. We also provide a method of treatment of a disease in which serine protease activity is implicated which comprises administering to a patient an effective amount of compound of the invention; and use of a compound of the invention in the manufacture of a medicament for the treatment of a disease in which serine protease activity is implicated. It will be appreciated that references herein to treatment extend to prophylaxis as well as the treatment of established conditions. A particularly preferred embodiment of the invention relates to the application of compounds of the invention in the inhibition of neutrophil elastase, thrombin, herpes virus proteases and tryptase. Compounds of the invention may be prepared from compounds of formula II (relative stereochemistry indicated) wherein R 1 is a moiety adapted to fit in the S 1 specificity subsite of the enzyme; or a protected derivative thereof, by sequential reaction to introduce the desired R 2 and R 3 substituent. The following intermediates are also useful: Conditions for such sequential reactions will be known to a person skilled in the art. Generally these reactions will consist of alkylations (usually with an alkyl halide), sulphonylations (with a sulphonyl halide), acylations (reaction with a carboxylic acid, acid halide or anhydride) or conversion into a urea (eg by reaction with an isocyanate) or conversion into a carbamate (eg by reaction with a haloformate ester). As an illustrative example, when R 2 represents -SO 2 Me, the compound of formula II (or a protected derivative thereof) may be reacted with MeS0 2 CI. Compounds of formula II may be prepared following Scheme 1 below: Scheme 1 methionine (III) (IV) (C) (VIII) (h) rel-(2S,3R) (j) (I) Step (a) This is a conventional protection reaction which, in the case when P 2 represents BOC, may be performed by reacting with (BOC) 2 O in the presence of base (e.g. NaOH) in a polar solvent system such as dioxan/water. Step (b) This conversion may be performed on treatment with ammonium bicarbonate in the presence of a suitable solvent such as pyridine/DMF and in the presence of (BOC) 2 0 or suitable equivalent. Step (c) This is a conventional protection reaction which, in the case when P 1 represents CBZ, may be performed by reaction with nBuLi followed by CBZ-CI in the presence of an inert solvent such as THF below -50°C. Step (d) This reaction may be performed by treatment with RX where RX is a compound (e.g. Mel, benzyliodide or Me 2 S0 4 ) capable of converting sulphur in the SMe moiety to sulphonium in a suitable solvent, e.g. propanone or acetonitrile. Generally R will represent alkyl or aralkyl and X will represent halide, especially iodide, or sulphate. Protection of the amide is convenient, although not essential, for this reaction. Step (e) This ring closure reaction may be performed by treatment with Dowex 2 x 8 400 mesh OH " resin in a suitable solvent, e.g. MeCN. Alternatively, the ring closure may be performed by treatment with potassium carbonate in a suitable solvent e.g. MeCN. Step (f) Deprotection may be performed in a conventional manner, for example, a BOC protecting group may be removed by treatment with HCI, e.g. in dioxan. Step (g) This reaction may be performed by treatment with a trifluoroacetic acid alkyl ester (e.g. the methyl ester) or anhydride in the presence of a suitable base e.g. N-methylmorpholine. Step (h) This conversion will take place on treating the compound of formula (IX) with a reducing agent eg sodium borohydride, followed by treatment with concentrated sulphuric acid in the presence of an alkyl alcohol e.g. ethanol solvent. Step (i) The reaction of compounds of formula (X) and (XI) takes place in the presence of a Lewis acid and an inert solvent. The group "alkyl" in Oalkyl and OSi(alkyl) 3 generally represents C 1-6 alkyl. In the compound of formula (XI), suitable alkyl groups in the silyl alkyl moiety include methyl, isopropyl and t-butyl. The preferred Oalkyl is OEt and the preferred OSi(alkyl) 3 is OSi(i-Pr) 3 or OSi(Me) 2 (t- Bu). The use of variants of compounds of formula (XI) in which Oalkyl is replaced by OSi(alkyl) 3 is also envisaged. By judicious choice of reaction conditions particularly the selection of the Lewis acid, the relative proportions of the rel-(2S,3R,1S) and rel-(2S,3R,1R) diastereoisomers can be varied. Use of boron trifluoride dietherate in DCM or preferably MeCN leads primarily to the rel-(2S,3R,1S) diastereoisomer. Use of TMSOTf in DCM leads primarily to the rel-(2S,3R,1 R) diastereoisomer. Compounds of formula (XI) may be prepared by treatment of the corresponding carboxylic acid ester (R 1 CH 2 COOEt or another alkyl ester, which compounds are either known or may be prepared by known methods) with a strong base (eg LHMDS) followed by a trialkylsilylchloride (such as trimethylsilylchloride) or a trialkylsilyltriflate. Typically the reaction will be performed at low temperature (less than 0°C) in an inert solvent (such as THF) in the presence of DMPU. Step (j) This deprotection reaction will take place on treatment with base, such as potassium carbonate. Step (k) This ring closure reaction may be performed on treatment with an alkyl Grignard reagent (e.g. t-butylmagnesium chloride) in an inert solvent such as THF in the presence of tetramethylethylenediamine at a temperature of -20°C to 25°C. Ring closure of the rel-(2S,3R,1S) diastereoisomer of the compound of formula (XIII) should lead to the rel-(3S,3aS,6aR) diastereoisomer of the compound of formula (XIV). Ring closure of the rel-(2S,3R,1 R) diastereoisomer of the compound of formula (XIII) should lead to the rel-(3R,3aS,6aR) diastereoisomer of the compound of formula (XIV). Step (I) This is a standard deprotection reaction. When P^ represents CBZ, the protecting group can be removed by catalytic hydrogenation, e.g. hydrogen over Pd/C. in a suitable solvent (e.g. ethanol) optionally in the presence of acid (e.g. acetic acid). Compounds of formula (IX) may also be prepared by following a route described in Scheme 2: Scheme 2 (XV) (b) o ■ -5- NHCOCF, (IX) Step (a) The reaction will proceed under standard conditions for forming alkyl esters, for example by treatment with an alcohol eg methanol in the presence of SOCI 2 . R 13 is suitably a C 1-6 alkyl group, preferably methyl. Step (b) The cyclisation reaction will take place on stirring in water with Dowex 2X8 (preferably 400 mesh). Step (c) The TFA protected amine is formed by treating the compound of formula (XVII) with methyl trifluoroacetate in a polar protic solvent, eg MeOH. Step (d) Suitable protecting groups P., include CBZ. In this case, the compound of formula (XVIII) may be treated with a strong base such as LHMDS or nBuLi in an inert solvent such as THF, followed by treatment with CBZ-CI. An alternative route for preparation of certain compounds of formula (XIV) from Scheme 1 is given in Scheme 3: Scheme 3 Scheme 3 continued (XXVIII) (XIV) Step (a) The compounds of formula (XIX) are either known compounds or may be made in analogous manner to known compounds. P 1 is a N-protecting group, preferably CBZ (benzyloxycarbonyl). Step (a) is a further N-protection reaction. P 2 in formula (XX) is a different N-protecting group, preferably BOC (t-butyloxy carbonyl). When P 2 is BOC, the reaction is suitably carried out using BOC 2 0. Suitably the reaction is carried out in the presence of a base such as triethylamine or 4-dimethylaminopyridine in a solvent such as ethyl acetate, at a temperature of suitably 0°-25° C. Step (b) This conversion is suitably carried out with pyridinium p-toluenesulfonate, in a solvent such as acetone/water, at a temperature suitably between 25°-75° C. Step (c) This is a condensation rearrangement reaction suitably carried out using a 2- phenylsulfinyl acetic acid ester (PhSOCH 2 CO 2 R 13 ) and piperidine, in a solvent such as acetonitrile, suitably at ambient temperature. R 13 is suitably a C 1-6 alkyl group, preferably methyl. Step (d) This is a Mitsunobu substitution reaction, using phthalimide, PPh 3 and a dialkylazodicarboxylate such as DEAD in the presence of a solvent such as THF, at a temperature of suitably 0°-40° C. Step (e) This is a deprotection reaction, e.g. when P 2 represents BOC using a strong acid such as TFA in a solvent such as DCM, at a temperature of suitably 0°-40°C. Step (f) This is a cyclisation reaction, suitably carried out as an intramolecular Michael reaction. Suitably NaH is used, in a solvent such as THF, at a temperature such as O° - 25° C. Step (g) In this step two reactions occur: N-deprotection and re-protection. The phthalimido group is removed suitably with hydrazine hydrate in a solvent such as ethanol at a temperature between 0°C and reflux. Protecting group P 3 is incorporated in a conventional manner. When P 3 is BOC, this is suitably achieved with BOC 2 O. Step (h) Generally, the R 1 side chain may be introduced by alkylation, using as reactant R Y, wherein Y is a reactive group such as bromo or iodo. Thus the reaction is carried out using a base, preferably a strong base such as LHMDS. With LHMDS suitably a cosolvent DMPU in THF is used. Suitable reaction temperatures are -78° to 50°C. Under these conditions the reaction generally takes place with good stereochemical control preferably producing the isomer as illustrated. Other R 1 side chains may be introduced by conventional processes. Step (i) This is an ester hydrolysis reaction, followed by a N-deprotection reaction. The former is carried out in a conventional manner, for example by using KOH in aqueous ethanol, at a temperature of suitably 25°-80°C . The latter is carried out in a conventional manner, for example by using HCI in dioxan, at a temperature of suitably 0°-50°C if the protecting group is BOC. If the protecting group is trifluoroacetate, this may be achieved by treatment with base. Step (j) This is a cyclocondensation reaction, suitably carried out in the presence of a cyclising agent such as diphenylphosphorylazide or 2-chloro-1- methylpyridinium iodide and a suitable base such as triethylamine or N, N- diisopropyl ethylamine in a solvent such as dichloromethane, at a temperature of suitably O°C-reflux. We have also found that it is possible to use the compound of formula (XXVIII) as a carboxylic acid ester in which case the ester hydrolysis of step (i) is not necessary. In this case the preferred conditions for the cyclocondensation reaction involve the use of an alkyl Grignard reagent eg t-BuMgCI in THF at a temperature between -20°C and 25°C. An alternative process for preparation of compounds of formula (XXVI) is shown in Scheme 4: Scheme 4 diaminobutyric acid Step (a) The compounds of formula (XXIX) are either known compounds or may be prepared in analogous manner to known compounds. P 3 is a protecting group as discussed above, and is suitably BOC. The reaction is suitably carried out using PIFA (phenyl iodosylbis(trifluoroacetate) and a base such as pyridine in an aqueous solvent, such as aqueous THF, dioxan or acetonitrile. This is the method of Stansfield, CF. Organic Preparations and Procedures Int., 1990, 22(5), 593-603. Step (b) P., is a protecting group eg CBZ. This protection reaction may be carried out in a conventional manner. For instance it is suitably carried out in a water miscible solvent such as THF, DMF or dioxan using N- (benzyloxycarbonyloxy)succinamide, benzyloxycarbonyl chloride, or any suitable source of the benzyloxycarbonyl group, with pH adjustment to alkaline with sodium carbonate. As an alternative step (b 1 ), the compound of formula (XXXI) can be prepared in conventional manner from diaminobutyric acid. Step (c) This reaction is suitably carried out in two stages. The first stage involves reacting the compound of formula (XXXI) at reduced temperature with N- methylmorpholine and then an alkyl chloroformate such as ethyl chloroformate, in an organic solvent such as DCM, dioxan or THF. In the second stage the product is reduced, suitably with sodium borohydride at reduced temperature, such as -20° to 10°C, in a solvent such as THF. Step (d) This oxidation reaction may be carried out in any suitable manner, for instance using oxalyl chloride in DMSO and methylene dichloride under nitrogen at reduced temperature, such as -30° to -70°C, followed by triethylamine. The intermediate (XXXIII) suitably is not isolated. Step (e) This reaction is suitably carried out using a Wittig reagent such as a triphenylphosphorane R 13 0 2 CCH=PPh 3 , or may also be carried out using a phosphonate in a Wadsworth-Emmons reaction. R 13 is suitably C 1-6 alkyl, preferably ethyl. Step (f) This Michael addition reaction is suitably carried out using LHMDS or other suitable strong base in a suitable organic solvent such as THF, ether or toluene, and preferably a complexing agent such as TMEDA is also present. Other compounds of formula II may be prepared from compounds of formula X in Scheme 1 following Scheme 5: Scheme 5 Oalkyl " OSi(alkyl) 3 Oalkyl ' . NHCOCF, (XXXV) (XXXVI) ► rel-(2S,3R) (X) (a) (b) (XXXVII) (d) The reaction conditions for steps (a) to (c) are analogous to those described above for Scheme 1 , steps (i) to (k). When step (d) is an alkylation it may be performed by treating with a base (e.g. LHMDS) and then with a compound R 1 Y wherein Y is a leaving group such as halogen. Other R 1 may be introduced by conventional processes. Step (e) may be performed under conditions analogous to Scheme 1 , step (I). It will be apparent that Schemes 1 , 2, 3, 4 and 5 may be modified to produce homochiral products by using homochiral starting materials (e.g. S-methionine in Scheme 1 or S-diaminobutyric acid in Scheme 4) or by performing an additional chiral resolution step. If compounds of formula (VIM) in racemic form are prepared following Scheme 1 from racemic methionine, we have found that the isomers of the compounds of formula (VII) may be resolved by a dynamic resolution procedure. Thus a racemic compound of formula (VII) may be treated with homochiral di-p-toluoyl tartaric acid in the presence of 3,5-dichloro-2-hydroxybenzaldehyde as catalyst in an inert solvent, e.g. THF. A homochiral salt of the compound of formula (VIII) results. A compound of formula (IX) may then be produced by subsequent treatment with trifluoroacetic acid methyl ester in the presence of N- methylmorpholine. Both enantiomers of the compound of formula (VIII) may also be produced from a synthesis based on S-methionine or R-methionine following similar procedures. Compounds of formula (I) may also be prepared from another compound of formula (I) following one or more conventional chemical transformations. It will be apparent to a person skilled in the art that the above synthetic processes for the preparation of compounds of formula (I) may be modified so as to include or omit protecting groups or so as to use alternative protecting groups (for example those described in T W Greene "Protective Groups in Organic Synthesis", 2nd Ed (1991) J Wiley & Sons) in the course of routine optimisation of experimental conditions. For example, when R 1 contains an amidine moiety, it may be preferred to introduce substituent R 1 (e.g. as in Scheme 1 or 3) as the oxadiazolinone derivative. This may be suitably O or N protected in subsequent chemical processes. Treatment of this derivative with hydrogen over Pd/C yields the free amidine. The invention embraces compounds of the invention in racemic form as well as in a form in which one enantiomer predominates or is present exclusively. Generally, we prefer to provide a compound of formula (I) in diastereoisomerically and enantiomerically pure form. For inhibition of elastase we prefer the diastereoisomers having relative stereochemistry shown in formula (1a) Enantiomers having the absolute stereochemistry shown in formula (la) are especially preferred. For inhibition of thrombin and tryptase we also prefer the diastereoisomers having relative stereochemistry shown in formula (la). For inhibition of herpes virus proteases, we prefer the diastereoisomers having relative stereo chemistry shown in formula (lb) Enantiomers having the absolute stereochemistry shown in formula (lb) are especially preferred. The present invention also covers the physiologically acceptable salts of the compounds of the invention. Suitable physiologically acceptable salts include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts. Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts). Suitable inorganic and organic acid salts include the hydrochloride, trifluoroacetate and tartrate. The compounds of the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in therapy, comprising a compound of the invention or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers. There is also provided according to the invention a process for preparation of such a pharmaceutical composition which comprises mixing the ingredients as considered appropriate for the indication. The compounds of the invention may, for example, be formulated for oral, buccal, parenteral, topical or rectal administration. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p_- hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate. For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner. The compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. The compounds of the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre- filled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or toxicity adjusting agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying. By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol. Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents. Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents. Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1 ,1 ,1 ,2- tetrafluorethane, carbon dioxide or other suitable gas. Capsules and cartridges for use in an inhaler or insufflator, of for example gelatin, may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. Compounds of the invention may also be used in purification and diagnostic applications involving serine protease enzymes. For example, an immobilised compound of the invention may allow a serine protease capable of binding that compound to be isolated. A tagged compound of the invention may enable a serine protease capable of binding that compound to be identified. ABBREVIATIONS BOC t-butyloxycarbonyl CBZ Benzyloxycarbonyl (BOC) 2 O Di-tert-butyldicarbonate THF Tetrahydrofuran LHMDS Lithium bis (trimethylsilyl)amide DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro 2 (1H)- pyrimidinone DMAP 4-dimethylaminopyridine DMF Dimethylformamide EDC 1-(3-N,N-dimethylaminopropyl)-3- ethylcarbodiimide DEAD diethylazodicarboxylate DCM dichloromethane TMEDA tetramethylethylenediamine DMSO dimethylsulphoxide HOBT 1 -hydroxybenzotnazole TBTU O-(1 H-Benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate DIPEA N,N-Diisopropylethylamine Moz 4-Methoxybenzyloxycarbonyl TDA-1 Tris[2-(2-methoxyethoxy)ethyl]amine IMS Industrial methylated spirit Dansyl 5-dimethylamino-naphthalene-1-sulfonyl The invention will be illustrated by reference to the following examples: Assay Examples In the foregoing, enzyme activity is generally determined at a 15 minute timepoint. Enzyme kinetics may be investigated by determining enzyme activity at other timepoints (e.g. 0, 30 minutes). Assay Example 1 In vitro assay for inhibition of human neutrophil elastase Assay contents: 50mM Tris/HCI (pH 8.6) 150mM NaCI 11.8nM purified human neutrophil elastase Suitable concentrations of compound under test diluted with water from a 10mM stock solution in dimethylsulphoxide. Values above are final concentrations after the addition of substrate solution (see below). The mixture above is incubated for 15 minutes at 30°C at which time the remaining elastase activity is measured for 10 minutes in a BioTek 340i plate- reader, after the addition of 0.6mM MeO-succinyl-Ala-Ala-Pro-Val-p-nitroanilide. The rate of increase in absorbance at 405nm is proportional to elastase activity. Enzyme activity is plotted against concentration of inhibitor and an IC50 determined using curve fitting software. Assay Example 2 In vitro assay for inhibition of human thrombin Compounds of the invention may be tested for their thrombin inhibitory activity as determined in vitro by their ability to inhibit human α-thrombin in a chromogenic assay, using N-p-tosyl-Gly-Pro-Lys p-nitroanilide as the chromogenic substrate. All dilutions were made in a buffer consisting of: 50mM HEPES, 150 mM NaCl, 5mM CaCI 2 , 0.1% PEG and at pH7.4. Briefly, the substrate (final cone, of 100μM) was added to thrombin (final cone, of 1 nM) and the reaction monitored for 10mins at 405nm using a Biotek EL340 plate reader; the assay was performed at room temperature. To obtain IC 50 values the data were analysed using Kineticalc ® with a 4-parameter curve fitting procedure to obtain the IC 50 value. To determine the IC 50 at 15mins, the compounds were preincubated with thrombin for these times prior to adding the chromogenic substrate. Assay Example 3 In vitro pNA assay of viral serine protease inhibitor activity The hCMV serine protease used is a mutant of the 30K protease lacking the internal cleavage site (Ala142/Ala143) and which has been cloned in E.coli to produce active enzyme (hCMV δAla protease). IC 50 data for test compounds are determined after preincubation of the enzyme with test inhibitor compound for 15 minutes. Test compounds are dissolved in DMSO, serially diluted and added at a range of concentrations (from 100μM - 0.195μM) to a reaction containing 0.5μM CMV δAla protease, 100mM HEPES pH7.5, 0.2mM EDTA, 10mM NaCl, 1mM DTT, and 30% glycerol. The reaction mixture is pre-incubated at 32°C for 15 minutes prior to addition of 4mM oligopeptide substrate (Arg-Glu-Ser-Tyr-Val- Lys-Ala-pNA), and then analysed at 32°C in a BIO-TEK Bio Kinetics Reader EL340L The plate reader monitors production of pNA and calculates the reaction rates over 30 minutes. The rates are plotted against inhibitor concentration and IC 50 values determined. Assay Example 4 In vitro assay for inhibition of human mast cell tryptase Compounds of the invention may be tested for their tryptase inhibitory activity as determined in vitro by their ability to inhibit human lung mast cell tryptase in a chromogenic assay, using N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 10mM Tris- HCI, 120mM NaCl, pH 7.4. Briefly, the substrate (final cone, of 400μM) was added to tryptase (final cone, of 0.1 Iμg.ml "1 ) and compound at appropriate concentrations and the reaction monitored for 30 minutes at 405nm using a Molecular Devices Thermomax microplate reader; the assay was performed at room temperature. To obtain IC 50 values the data were analyzed using curve fitting software. To determine the IC 50 at 30 mins the compounds were preincubated with tryptase for this time prior to addition of the chromogenic substrate. Assay Example 5 In vitro assay for inhibition of trypsin Compounds of the invention may be tested for their trypsin inhibitory activity as determined in vitro by their ability to inhibit bovine trypsin in a chromogenic assay, using N-Benzoyl-lle-Glu-Gly-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris- HCI, 15mM CaCI 2 , pH 8.4. Briefly, the substrate (final cone, of 160μM) was added to trypsin (final cone, of 25ng.ml "1 ) and compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 37°C. To obtain IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve-fitting procedure. Assay Example 6 In vitro assay for inhibition of Factor Xa Compounds of the invention may be tested for their Factor Xa inhibitory activity as determined in vitro by their ability to inhibit human Factor Xa in a chromogenic assay, using N-α-Benzyloxycarbonyl-D-Arg-Gly-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris-HCI, 150mM NaCl, 5mM CaCI 2 , pH 7.4. Briefly, the substrate (final cone, of 200μM) was added to Factor Xa (final cone, of 0.02 U.ml "1 ) and compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 37°C. To obtain IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve fitting procedure. Assay Example 7 In vitro assay for inhibition of Factor Xla Compounds of the invention may be tested for their Factor Xla inhibitory activity as determined in vitro by their ability to inhibit human Factor Xla in a chromogenic assay, using L-Pyroglutamyl-Pro-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 8.1mM NaH 2 P0 4 , 147mM KH 2 PO 4 , 2.7mM KCI, 137mM NaCl, pH 7.2. Briefly, the substrate (final cone, of 400μM) was added to Factor Xla (final cone, of 0.25μg.ml "1 ) and compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 25°C. To obtain IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve fitting procedure. Assay Example 8 In vitro assay for inhibition of Factor Xlla Compounds of the invention may be tested for their Factor Xlla inhibitory activity as determined in vitro by their ability to inhibit human Factor Xlla in a chromogenic assay, using H-D-Pro-Phe-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 28mM NaBarbitone, 125mM NaCl, 1mM EDTA, pH 7.35. Briefly, the substrate (final cone, of 200μM) was added to Factor Xlla (final cone, of 1.25μg.ml "1 ) and compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 25°C. Assay Example 9 In vitro assay for inhibition of tPA Compounds of the invention may be tested for their tissue plasminogen activator inhibitory activity as determined in vitro by their ability to inhibit human tissue plasminogen activator in a chromogenic assay, using MeSO 2 -D-CHT-Gly-Arg-p- nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris-HCI, 150mM NaCl, pH 8.4. Briefly, the substrate (final cone, of 750μM) was added to tissue plasminogen activator (final cone, of I .Oμg.ml "1 ) and compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 30°C. To obtain IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve-fitting procedure. Assay Example 10 In vitro assay for inhibition of plasmin Compounds of the invention may be tested for their plasmin inhibitory activity as determined in vitro by their ability to inhibit human plasmin in a chromogenic assay, using H-D-Val-Leu-Lys-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris-HCI, 150mM NaCl, 5mM CaCI 2 , pH 7.4. Briefly, the substrate (final cone, of 363μM) was added to plasmin (final cone, of 0.02 U.ml "1 ) and compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 37°C. To obtain IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve fitting procedure. Assay Example 11 In vitro assay for inhibition of Factor Vila Compounds of the invention may be tested for their Factor Vila inhibitory activity as determined in vitro by their ability to inhibit human Factor Vila in a chromogenic assay, using H-D-lle-Pro-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 20mM Tris- HCI, 150mM NaCl, 5mM CaCI 2 , 0.1% bovine serum albumin, pH 7.5. Briefly, the substrate (final cone, of 400μM) was added to Factor Vila (final cone, of 10nM in the presence of recombinant soluble tissue factor at optimal concentration) and compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 30 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 37°C. To obtain IC 50 values the data were analyzed using. Kineticalc ® with a 4-parameter curve fitting procedure. Assay Example 12 In vitro assay for inhibition of chymotrypsin Compounds of the invention may be tested for their chymotrypsin inhibitory activity as determined in-vitro by their ability to inhibit human pancreatic chymotrypsin in a chromogenic assay, using MeO-Succ-Arg-Pro-Tyr-pNA hydrochloride as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of 50mM Tris-HCI, 150mM NaCl, 25mM CaCI 2 , pH 8.4. Briefly, the substrate (final cone, of 178μM) was added to chymotrypsin (final cone, of 0.2μg/mL) and compound at appropriate concentrations and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader: the assay was performed at 30°C. To obtain IC 50 values the data were analysed using Kineticalc ® with a 4-parameter curve fitting procedure. To determine the IC 50 at 15 mins the compounds were preincubated with chymotrypsin for these times prior to addition of the chromogenic substrate. Assay Example 13 In vitro assay for inhibition of cathepsin G Compounds of the invention may be tested for their Cathepsin G inhibitory activity as determined in vitro by their ability to inhibit human neutrophil Cathepsin G in a chromogenic assay, using N-succinyl-Ala-Ala-Pro-Phe-p- nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 100mM HEPES, 300mM NaCl, pH 7.2. Briefly, the enzyme (1.25ug/mL final ), buffer and compound at appropriate concentrations were incubated for 15 mins at 30°C. Substrate (7.25mM final ) was added and the reaction monitored at 30°C for 30 minutes at 405nm using a BioTek EL340 plate reader. To obtain IC 50 values the data were analyzed using Microsoft Excel® within ActivityBase® with a 4-parameter curve fitting procedure (XLFIT®). Assay Example 14 In vitro assay for plasma stability Stability of the compounds of the invention to exposure to undefined esterolytic (and other) activity was assessed in rat plasma and blood. Briefly, compounds were mixed with fresh rat plasma or rat blood, then incubated at 37°C and at various times after mixing were extracted by precipitation with acetonitrile. Reverse phase high performance liquid chromatography was used to quantify compounds at each time point. Half-lives for the compounds were calculated from the time-course data by log-linear regression. Compounds were considered to be unstable if the half life was less than 10 minutes. Assay Example 15 Tests for acylating enzyme inhibitors The mechanism of binding of the compounds was determined using biophysical techniques such as mass spectrometry and X-ray crystallography. Briefly, crystal structures were prepared in complex with thrombin by soaking and co- crystallisation. X-ray data was collected using a FAST area detector system and difference fourier analysis identified the binding modes of the inhibitors. The bound conformations for each inhibitor were obtained after subsequent refinement cycles which often identified an acylation event. Active thrombin, after incubation with the compounds, was examined by liquid chromatography coupled in-line to a mass spectrometer. If the measured mass of the thrombin bearing the active site serine residue was increased by the mass of the inhibitor this indicated the formation of a covalent bond between the two. Compound Examples Compound Example 1 rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4-(3-piperidin-1yl-propionyl)- hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride (a) 2,4-Diamino-butyric acid methyl ester dihydrochloride To D,L-diaminobutyric acid dihydrochloride (350g) in methanol (1.6L) at 0°C was added thionyl chloride (200ml) over Vz . After reflux for 3h, the solvent was removed in vacuo and the residue triturated with toluene (650ml) to give the title compound as a white solid (385g). Mass spec, of free base MH + (found) 133 MH + (calculated) 133 (b) 3-Amino-pyrrolidin-2-one The product of step (a), (1g), water (70ml) and Dowex 2x8-400 mesh (16.4ml) were stirred for 1h. The resin was then filtered and the filtrate concentrated in vacuo to give the title compound as a white solid (0.40g), T.l.c silica (18:3 ethyl acetate: methanol) Rf 0.07. (c) 2,2,2-Trifluoro-N-(2-oxo-pyrrolidin-3-yl)-acetamide A suspension of the product of step (b), (181g), methyl trifluoroacetate (218ml) and methanol (2.6L) was stirred for 2h. The solvent was then removed in vacuo to afford the title compound as a cream solid (355g). Mass spec. MNH 4 + (found) 214 MNH 4 + (calculated) 214 (d) 2-Oxo-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1 -carboxylic acid benzyl ester To the product of step (c) (3.5g) and tetrahydrofuran (100ml) at -70°C was added lithium hexamethyldisilazide (20ml). After IΛh, benzyl chloroformate (2.8ml) was added. The mixture was warmed to room temperature for 1 h and 1M hydrochloric acid (25ml) added. After extraction with ethyl acetate (3x25ml), the combined extracts were washed with 2% ammonia solution, 2M hydrochloric acid and brine, then dried (MgSO 4 ). After solvent removal, the white solid was recrystallised from ethyl acetate: hexane 5:1 to give the title compound (4.2g). T.l.c. (18:2 ethyl acetate: methanol) Rf 0.7 (e) 2-Ethoxy-3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1 -carboxylic acid benzyl ester To the product of step (d) (34g) in ethanol (1070ml) at -5°C was added sodium borohydride (9.86g). A solution of 4M hydrogen chloride in 1 ,4-dioxan (20ml) was then added dropwise. Periodically further portions of 4M hydrogen chloride in 1 ,4-dioxan (2x5ml, 1x10ml) and sodium borohydride (2g) were added. After 3h, concentrated sulphuric acid (11ml) was added and the mixture warmed to room temperature for 2h. Saturated aqueous sodium bicarbonate (300ml) was then added and the ethanol and dioxan removed in vacuo. The residue was diluted with water (500ml) and the mixture extracted with ethyl acetate (3x500ml). The combined extracts were washed with brine and dried (MgS0 ). The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel 9385 eluting with ether, to give the title compound (21 g). Mass spec. MNH 4 + (found) 378 MNH 4 + (calculated) 378 (f) trans-2-(1-Ethoxycarbonyl-2-methyl-propyl)-3-(2,2,2-trifluoro-acetylamino)- pyrrolidine-1 -carboxylic acid benzyl ester The product of step (e) (10g), ethyl trimethylsilyl isopropylketene acetal (11ml) and dichloromethane (250ml) were cooled to 5°C and boron trifiuoride dietherate (17ml) added over h. After 1h, further boron trifiuoride dietherate (3.4ml) and ketene acetal (11ml) were added. After a further 1h, 1 M hydrochloric acid (200ml) was added and the organic layer separated and washed with brine and dried (MgS0 4 ). Solvent removal in vacuo gave the title compound (16.7g). T.l.c. silica (2:1 ether: cyclohexane) Rf 0.18 and 0.27 (g) trans-3-Amino-2-(1-ethoxycarbonyl-2-methyl-propyl)-pyrrolidine-1 -carboxylic acid benzyl ester The product of step (f) (31g), potassium carbonate (71g), water (930ml) and ethanol (930ml) were warmed at 60°C for 3h. The ethanol was removed in vacuo and the aqueous residue extracted with ethyl acetate (3x300ml). The combined extracts were washed with brine and dried (MgSO 4 ) and concentrated in vacuo to give the title compound as a brown oil (17.5g). Mass spec. MH + (found) 349 MH + (calculated) 349 (h) rel-(3R,3aR,6aS)-6-lsopropyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1- carboxylic acid benzyl ester The product of step (g) (17.5g) in tetrahydrofuran (1,800ml) was cooled to -5°C and 1M t-butylmagnesium chloride in tetrahydrofuran(204ml) was added over Vah. After 2h, 1 M hydrochloric acid (250ml) and brine (300ml) were added and then extracted with ethyl acetate (250ml). After concentrating the extracts to half the volume in vacuo, the extracts were washed with brine and dried (MgS0 4 ). Solvent removal in vacuo followed by trituration with diethyl ether (60ml) gave a white solid. This was recrystallised from ethyl acetate to give the title compound (3.4g). Mass spec. MH + (found) 303 MH + (calculated) 303 (i) rel-(3R,3aR,6aS)-6-lsopropyl-4-methanesulfonyl-5-oxo-hexahydro- pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester To a stirred solution of the product of step (h) (15.01g) in anhydrous tetrahydrofuran (950ml) at -74°C under nitrogen, was added 1.0M lithium hexamethyldisilylazide in tetrahydrofuran (69.5ml) dropwise. After stirring at - 74°C for 10 min, the mixture was allowed to warm up to 0°C over 45 min, then left at this temperature for 20 min. It was then cooled to -76°C, treated dropwise with methanesulfonyl chloride (9.61ml) and left to stir at this temperature for 1.5h. It was then warmed to -50°C, quenched with saturated ammonium chloride solution (480ml) and allowed to warm up to room temperature. The mixture was partitioned between water (300ml) and ethyl acetate (750ml), the aqueous layer extracted with further ethyl acetate (750ml), then the combined organic extracts washed with brine (450ml), dried (Na 2 SO 4 ) and concentrated in vacuo to a cream solid. Purification by flash column chromatography on silica (Merck 9385) eluting with ethyl acetate: cyclohexane (1 :3, 1 :2, 1 :1 then 3:1) gave the title compound as a white crystalline solid (13.65g). T.l.c. silica (dichloromethane) Rf 0.22 Mass spec MNH 4 + (found) 398 MNH 4 + (calculated) 398 (j) rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2- b]pyrrol-2-one A suspension of the product of step (i) (13.63g) in ethyl acetate (900ml) was added to 20% palladium hydroxide (moist) on carbon (3.16g) and the resulting black suspension stirred vigorously under hydrogen at room temperature for 90 min. The mixture was then filtered through Harborlite J2 and concentrated in vacuo to give the title compound as a fine white powder (8.63g). Tic (methano dichloromethane 1 :9) Rf 0.50 Mass spec MH + (found) 247 MH + (calculated) 247 (k) rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4-(3-piperidin-1yl- propionyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride The product of step G) (0.04g), piperidinepropanoic acid (0.028g), di- isopropylethylamine (0.085ml), bromo-tris-pyrrolidine-phosphonium hexafluorophosphate (0.083g) and dichloromethane (3ml) were mixed for 4h. The mixture was diluted with ethyl acetate and washed with water and brine and dried (MgS0 4 ). Solvent removal in vacuo followed by flash chromatography on silica 9385 eluting with ethyl acetate: methanol gave an oil (41 mg). This material was dissolved in dichloromethane (3ml) and 1 M hydrogen chloride in ether (0.5ml) added. The solvents were removed and the solid triturated in diethyl ether to give the title compound (0.045g) as a cream solid. Data for free base T.l.c. silica (7:3 ethyl acetate : methanol + trace ammonia) Rf 0.31 Mass spec MH + (found) 386 MH + (calculated) 386 Compound Example 2 rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4-{4-[(methyl-propyl-amino)- methyl]-benzoyl}-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride (a) rel-4-(6R-lsopropyl-4-methanesulfonyl-5-oxo-hexahydro-(3aS,6aR)- pyrrolo[3,2-b]pyrrole-1-carbonyl)-benzaldehyde A stirred solution of the product of Compound Example 1 , step (j) (100mg) in acetonitrile (5ml) under nitrogen had 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (156mg), 1-hydroxybenzotriazole (110mg) and 4-carboxybenzaldehyde (79mg) added before stirring at 22°C for 22 hours. The solvent was removed from the mixture in vacuo and the gummy residue partitioned between 2N Na 2 CO 3 (15ml) and dichloromethane (15ml). The organic phase was separated, washed with 2N Na 2 CO 3 (10ml), water (10ml) saturated brine (10ml), dried (MgSO 4 ), filtered and the solvent removed in vacuo to give a yellow gum. The gum was purified by flash column chromatography using Merck 9385 silica and eluted with 2% MeOH/DCM. The required fractions were combined and the solvent removed in vacuo to give the title compound, as a white foam (148mg). T.l.c. Silica (9:1 DCM/MeOH) Rf = 0.60, visualised by UV, KMn0 4 Mass Spec. MH + (found) = 379; MH + (calc.)= 379 (b) rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4-{4-[(methyl-propyl- amino)-methyl]-benzoyl}-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride A solution of the product of step (a) (30mg) in dry dichloromethane (3ml) was stirred with N-methylpropylamine (9.8μl). Sodium triacetoxyborohydride (25.2mg) was added and the reaction was stirred for 48 hours. NaHCO 3 solution (1ml) and water (2ml) was added to the reaction before stirring vigorously for 10 mins. The product was isolated from the organic phase by pipetting it equally onto two varian silica cartridges (500mgSi) which had DCM filtered through them until the solvent reached the top of the silica. Each pair of columns were then filtered under vacuum to remove the load volume of solvent, before eluting the following solvent quantities into collection tubes by vacuum filtration; dichloromethane (2xcol.vol), chloroform (2xcol.vol), ether (2xcol.vol), ethyl acetate (2xcol.vol), acetonitrile (2xcol.vol), methanol (4xcol vol) (each col.vol. being ~2.5ml). The product containing fractions were combined and the solvent removed in vacuo to give the free base. The free base was dissolved in DCM (2ml) and treated with 1.0M HCI in ether (1ml). The solvent was removed in vacuo to give a solid which was triturated in ether, filtered and dried; giving the title compound as a white solid (26.7mg). Tic Silica (9:1 ; DCM:MeOH), Rf 0.23 Mass spec MH + (found) 436; MH + (calc) 436 Compound Example 3 (3S,3aR,6aS)-1 -Cyclopropanecarbonyl-4-[1 -(5-dimethylamino-naphthalene-1 - sulfonyl)-pyrrolidine-2S-carbonyl]-3-methyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one a 1-{3-[(Benzyloxy-carbonyl)-amino]-1-hydroxymethyl-propyl}-carbamic acid, tert-butyl ester A solution of compound Nα-BOC,Nγ-CBZ-2,4-Diaminobutyric acid (3.198g) in tetrahydrofuran (44ml, dry) was cooled to -10°C under nitrogen, 4- methylmorpholine (1.0ml) was added followed by ethylchloroformate (0.868ml). After stirring for 8 mins sodium borohydride (1.03g) was added in one portion followed by methanol (88ml) over a period of 11 mins at 0°C. The mixture was stirred at ca 0°C for an additional 11 mins before 1 M hydrochloric acid (18ml) was added. The mixture was evaporated under reduced pressure and the aqueous residue was extracted with ethyl acetate. The organic layer was separated and washed with 1 M hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water, then dried (magnesium sulphate), evaporated under reduced pressure and some of the residue (1.8g from 2.87g) was purified by chromatography (Merck 7734) using cyclohexane:ethylacetate (3:2) as eluent to give the title compound (1.6g) : t.l.c. (1 :1 cyclohexane : ethyl acetate) Rf 0.23 ir (CHBr3) 3432, 1704cm "1 . (b) 6-Benzyloxycarbonylamino-4-fe/f-butoxycarbonylamino-hex-2E-enoic acid ethyl ester A solution of dimethyl sulfoxide (6.82ml) in dry dichloromethane (135ml) was stirred under N2 and cooled (dry ice/acetone) to - 72°C. Oxalyl chloride (7.4ml) was added dropwise over 10 minutes (temp kept in the range - 60 → 65°C) and the reaction was stirred for 15 minutes. A solution of the product of step (a) (12.6g) in dry dichloromethane (135ml) was added over 20 minutes (temp kept in the range -60→-63°C) and the reaction mixture then stirred for 20 minutes by which time the temperature had risen to -52°C. Triethylamine (53.7ml) was added dropwise over 10 minutes followed by the immediate addition of the Wittig reagent (19.3g). The cooling bath was removed and the internal temperature allowed to rise to 17°C. The reaction mixture was poured into ether (400ml) and brine (400ml). The organic phase was separated and the aqueous phase extracted with ether (2x100ml). The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to give a tan oil (36.22g). This was purified by flash column chromatography (Merck 9385 silica eluting with 40% ethyl acetate in cyclohexane) to give the product (15.71g) as an oil: 1H NMR (CDCI 3 ); 7.40-7.30 (5H, m), 6.86 (1 H, dd), 5.93 (1 H, dd), 5.42-5.28 (1 H, br), 5.12 (2H, ABq), 4.72-4.60 (1 H, m), 4.50-4.32 (1 H, m), 4.19 (2H, q), 3.60-3.30 (1 H, m), 3.15-2.98 (1 H, m), 2.00-1.80 (1 H, m), 1.65-1.50 (1 H, m), 1.45 (9H, s) and 1.28 (3H, t), Rf 0.45 (2:3 ethyl acetate /cyclohexane) (c) rel-(2R,3S)-3-tert-Butoxycarbonylamino-2-ethoxycarbonylmethyl-pyrrolidine- 1 -carboxylic acid benzyl ester The product of step (b) (12.2g) was suspended in dry toluene (175ml) with stirring under N2. Tetramethylethylenediamine (1.1ml) was added followed by lithium bis-(trimethylsilyl)amide (1.0M in hexanes, 7.6ml). On completion of the addition a solution had formed. The reaction mixture was stirred for 15 minutes and then poured into ethyl acetate (300ml) and saturated aqueous ammonium chloride (300ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2x50ml). The combined organic extracts were washed with brine (150ml) and the aqueous phase extracted with ethyl acetate (2x25ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to give a tan oil (12.86g) which was filtered through a plug of silica gel using ethyl acetate/cyclohexane (2/3) as eluant to give a crude mixture including title compound (10.74g) as an oil. This oil was purified further by flash column chromatography on silica gel. Elution with ethyl acetate/cyclohexane (2/3) gave the title compound, as a solid (8.49g, 69.7%). A small sample of the title compound was crystallised from ether to give a white solid: 1 H NMR (CDCI3); 7.40-7.30 (5H, m), 5.12 (2H, s), 4.72-4.53 (1 H, m), 4.20-3.95 (4H, m), 3.65-3.40 (2H, m), 2.95-2.65 (1 H, m), 2.60-2.40 (1 H, m), 2.25-2.10 (1 H, m), 1.92-1.75 (1 H, m), 1.40 (9H, s) and 1.30-1.15 (3H, m). Rf 0.8 (1 :1 , ethyl acetate/cyclohexane) (d) trans-3-Amino-2-ethoxycarbonylmethyl-pyrrolidine-1 -carboxylic acid benzyl ester To the product of step (c) 246.6gm, 1eq, 0.607mol) was added trifluoroacetic acid (25eq, 15.18mol, 1731gm, 1169ml) at room temperature. After stirring for one hour the solution was evaporated and the residue azeotroped twice with toluene (300ml). The resulting oil was dissolved in ethyl acetate (2500ml) and washed with 2M sodium hydroxide (1x800ml + 3x300ml), water and brine, dried (MgS0 4 ) and evaporated to give the title compound as a golden oil, 168.9gm, after high vacuum. Mass spec 613 [2M+H] + , 307 [MHf. (e) (2R,3S)-3-amino-2-ethoxycarbonylmethyl-pyrrolidine-1 -carboxylic acid benzyl ester (2S,3S)-bis-(4-methyl-O-benzyloxy)-succinate salt. A solution of the product of step (d) (168.9gm, 0.55mol) was dissolved in ethanol (2500ml) and was added to a solution of (+) di-O-para-toluyl-D-tartaric acid (ex Fluka) (213gm, 0.55mol) in ethanol (2500ml) and the solution allowed to stand overnight. The resulting solid was collected by filtration and washed with ethanol and then recrystallised from boiling ethanol (~3500ml) to give the title compound as a white solid, 93.7gm. A further recrystallisation gave a white solid, mp 184-185°C. Chiral HPLC (Chiracel OJ column, eluent system ethanohheptane; 3:7; flow rate = 1ml/min, , λ = 215nm). Retention time = 7.7 min, 97.5 %ee. (f) (2R,3S)-3-amino-2-ethoxycarbonylmethyl-pyrrolidine-1 -carboxylic acid benzyl ester. The product of step (e) (131.8 gm, 190mmol) was suspended in an 1 :1 mixture of water: ethyl acetate (1500ml), and solid potassium carbonate added (63gm, 457mmol). After fifteen minutes the phases were separated and the aqueous phase extracted with ethyl acetate (3x200ml). The organic portions were combined and washed with water and brine, dried (MgSO 4 ) and evaporated to give the title compound as a colourless oil, 57.8gm. Mass spec 613 (100%) [2M+H] + , 307(83%) [MH] + . [α] D = -11.3° (c=1.33, MeOH) (g) (3aS,6aR)-5-Oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester To the product of step (f)(52.9gm, 173mmol) in tetrahydrofuran (550ml) in an ice-salt bath was added a solution of tert butyl magnesium chloride (554ml of a 1M solution in tetrahydrofuran, 554mmol), keeping the temperature <1°C. The mixture was warmed to room temperature over 1 hr 15min, then quenched with saturated ammonium chloride whilst cooling in an ice bath. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organics were washed with water and brine, dried (MgSO 4 ) and evaporated and to give the title compound as a cream solid, 43.5gm. A portion of the solid was purified by flash column chromatography over silica gel ( Merck 9385) using ethyl acetate as the eluting solvent, to give the title compound as a white solid, mp 157-159°C. [α] D = -68.4° (c=1.28, MeOH) (h) (3aR,6aS)-2-Oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1 ,4-dicarboxylic acid 4- benzyl ester 1-tert-butyl ester To the product of step (g) (43.2gm, 166mmol) in tetrahydrofuran (1200ml) at - 72°C under a nitrogen blanket was added lithium bis (trimethylsilyl)amide (216ml of a 1 M solution in tetrahydrofuran, 216mmol) dropwise, keeping the temperature <-71°C. After ten minutes a solution of di-tert-butyldicarbonate (54.3 gm, 249mmol) in tetrahydrofuran (350ml) was added, keeping the temperature <-71°C. The reaction was stirred at -73°C for two and a half hours and then quenched with saturated ammonium chloride. Then the mixture was allowed to warm to room temperature, water was added and the phases separated. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with water and brine, dried (MgSO 4 ) and evaporated to give the title compound as an orange-red semi solid. Pure material could be obtained as a pale cream solid by trituration under diethyl ether. Yield 42.5gm. A portion of the solid was recrystallised from boiling diethyl ether to give the title compound as a white solid, mp 101-103°C. [α] D = -45.6° (c=1.13, MeOH). (i) (3S,3aR,6aS)-3-Methyl-2-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1 ,4- dicarboxylic acid 4-benzyl ester 1-tert-butyl ester The product of step (h) (606mg, 1eq, 1.68mmol) was dissolved in tetrahydrofuran (6ml) and cooled, under nitrogen, to -75°C. Lithium hexamethyldisilazide (1.3 eq, 2.2ml of a 1 M solution in tetrahydrofuran) was added, keeping the temperature below -70°C. After 10 minutes methyl iodide was added (17eq, 28.9mmol, 1.8ml). After stirring for a further 45 minutes the reaction was quenched with saturated aqueous ammonium chloride and then allowed to warm to room temperature. Water was added and then the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and brine, dried (MgSO 4 ) and evaporated to give a golden oil. Purification by flash column chromatography over silica gel ( Merck 9385) using cyclohexane:ethyl acetate (3:1)as the eluting solvent system, afforded the title compound as a white foam, 526mg. Mass spec 275 [M-100+H] + [α] D = -88.6° (c=1.1 , MeOH). (j) (3aS,6S,6aR)-6-Methyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester To the product of step (i) (486mg, 1eq, 1.3mmol) was added trifluoroacetic acid (60eq, 6ml) and the mixture stirred at room temperature for 40 minutes, then evaporated to give a brown oil. This was dissolved in ethyl acetate (6ml) and washed with saturated sodium bicarbonate solution (2x3ml), water (3ml) and brine (3ml), dried (MgSO 4 ) and evaporated to give the title compound as a pale beige solid 340mg. The solid was recrystallised from boiling diethyl ether to give a white solid (202mg), mp 112-113°C. Chiral HPLC (Chiral Pak464 column, eluent system propan-2-ol:heptane; 2:25; flow rate = 1ml/min). Retention time = 20.91 min, 96.00 %ee. (k) (3aS,6S,6aR)-4-Cyclopropanecarbonyl-6-methyl-5-oxo-hexahydro- pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester To a solution of the product of step (j) (992mg, 1eq, 2.75mmol) in dry THF (7ml) at -78°C under nitrogen was added lithium hexamethyldisilazide (3.3ml of a 1 M solution in tetrahydrofuran, 1.2eq, 3.3mmol), keeping the temperature below - 70°C. The solution was kept at -78°C. for 10 mins, then at 0°C for 10 mins, recooled to -78°C and cyclopropanecarbonyl chloride (0.75ml, 3eq, 8.25mmol) was added and the reaction mixture was the stirred at -78°C. for 55 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride (25ml) and then allowed to warm to room temperature. Water was added (20ml) and then the aqueous phase was extracted with ethyl acetate (100ml), and the combined organic phase was washed with water (30ml) and brine(30ml), dried (MgSO 4 ) and evaporated to give a yellow oil. Purification by flash column chromatography over silica gel ( Merck 9385) using cyclohexane:ethyl acetate (4:1)as the eluting solvent system afforded the title compound as a pale yellow gum, 334mg. Mass Spec: 343 [MH] + (I) (3aS,6S,6aR)-1-Cyclopropanecarbonyl-3-methyl-hexahydro-pyrrolo[3,2- b]pyrrol-2-one hydrochloride A solution of the product of step (k) (330mg, 0.96mmol) in isopropanol (30ml) was added to the catalyst (119mg, 10% palladium on activated carbon with 50% water, Degussa type E101 NE/W) under nitrogen and the resulting mixture stirred vigorously under an atmosphere of hydrogen for 2.75hours. The catalyst was filtered off under an atmosphere of nitrogen and a 1M solution of hydrogen chloride in diethyl ether (1ml, 1eq, 1mmol) was added to the filtrate. Evaporation of the solvent gave the title compound as a colourless gum, 175mg. Mass Spec: 209 [MH] + (m) 2S-(4-Cyclopropanecarbonyl-6S-methyl-5-oxo-hexahydro-(3aS,6aR)- pyrrolo[3,2-b]pyrrole-1-carbonyl)-pyrrolidine-1 -carboxylic acid benzyl ester and 2S-(4-Cyclopropanecarbonyl-6R-methyl-5-oxo-hexahydro-(3aR,6aS)- pyrrolo[3,2-b]pyrrole-1-carbonyl)-pyrrolidine-1 -carboxylic acid benzyl ester To a solution of carbobenzyloxy-L-proline (0.171g,0.69mmol,1.1eq.) in DMF (3mL), stirred at room temperature, was added a solution of TBTU (0.221g, 0.69mmol, 1.1 eq.) in DMF:MeCN (0.5mL:0.5mL) and a solution of HOBT (0.094g, 0.70mmol,1.1 eq.) in DMF: MeCN (0.5mL:0.5mL). After 15 min. the product of step (I) (racemic) (0.152g,0.62mmol,1 eq.) in DMF (0.5mL) and diisopropylethylamine (0.215mL,1.23 mmol, 2 eq.) were added. The reaction mixture was allowed to stir at room temperature for 16 hours and was then diluted with dichloromethane (15mL) and water (15mL). The aqueous layer was re-extracted with dichloromethane (15mL) and the combined organic extracts were then washed with 2N HCI (15mL) , water (15mL) and sat. NaHCO 3 solution (15mL). After drying over MgSO the solvent was evaporated in vacuo to give an orange oil. The product was purified by flash column chromatography over silica gel (Merck 9385) using ethyl acetate: cyclohexane to give as the less polar(6S,3aS,6af? diastereoismer) the title compound, as a white solid (89mg). Mass Spec: 440 [MHf Circular dichroism λ max 199.8 nm, dE 4.82; λ max 216.6 nm, dE -15.8; λ max 238.6 nm, dE 17.8; HPLC (Intersil M column ODS2, eluent system A (H 2 O, 0.1% H 3 PO 4 ) B (95% MeCN/H 2 O, 0.1% H 3 PO 4 ):Gradient 0%B 2mins, 0%-100% B 40mins,100% B 10mins; flow rate = 1ml/min, , λ = 215nm). Retention time =24.9 min., 100%. The more polar 6R,3aR,6aS diastereoismer, was obtained as a white foam (61mg,22%). Mass Spec: 440 [MH] + Circular dichroism λ max 214.6 nm, dE 26.8; λ max 238.6 nm, dE -17.0; HPLC (Same system as less polar isomer) : Retention time = 24.1 min. ,92%, 24.9 min., 4.5%. (n) (3S,3aR,6aS)-1-Cyclopropanecarbonyl-3-methyl-4-(pyrrolidine-2S-carbonyl)- hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride The product of step (m) (0.893g,2.03mmol) was added to the catalyst (0.419g, 10% palladium on activated carbon with 50% water, Degussa type E101 NE/W) as a solution in isopropanol (160mL). Warming was required for all material to dissolve. A 1.0M solution of HCI in ether (2.3mL,2.3mmol) was also added. The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 5 hours with further catalyst (0.4g) added after 1.5 hours to complete the reaction. The catalyst was filtered off and a 1.0M solution of HCI in ether (0.2 mL) was added to the filtrate. Evaporation of the filtrate in vacuo afforded the title compound, as a white foam (0.721 g). It was used in step (o) without further purification. Mass Spec: 306 [MH] + (o) (3S,3aR,6aS)-1-Cyclopropanecarbonyl-4-[1-(5-dimethylamino-naphthalene- 1-sulfonyl)-pyrrolidine-2S-carbonyl]-3-methyl-hexahydro-pyrrolo[3,2-b]pyrrol-2- one The product of step (n) (57mg,233μmol,1eq.) was dissolved in MeCN (4 mL). To the clear solution was added triethylamine (80mL,574μmol,2.5eq.) and a solution of dansyl chloride (69mg,256μmol,1.1eq.) in MeCN (1mL). The reaction mixture was stirred at room temperature for 1.5 hours. Isopropanol (10mL, 128μmol) was added and the solution was evaporated to dryness. The residue was purified by flash column chromatography silica gel (Merck 9385) and eluted with cyclohexane:ethyl acetate to give the title compound as a yellow/ green foam (15.4mg). 1 H nmr (CDCI3): δ 8.54 (1 H,d), 8.42 (1H,d), 8.29 (1H,d), 7.55 (2H,dd), 7.18 (1 H,d), 4.75 (1 H,dd), 4.26 (1 H,t), 3.89-3.20 (6H,m), 3.00-2.84 (7H,m), 2.83-2.68 (1 H,m), 2.32-1.80 (5H,m), 1.28-0.94 (7H,m) ppm. Mass Spec. 539 [MH] + ' 471 [M-COcyclopropyI] + Circular dichroism λ max 200.8 nm, dE 0.01 ; λ max 217.8 nm, dE -23.80; λ max 238.4 nm, dE 15.10. Compound Example 4 2S-(4-Benzothiazol-2-yl-6S-methyl-5-oxo-hexahydro-(3aS,6aR)-pyrrolo[3,2- b]pyrrole-1 -carbonyl)-pyrrolidine-1 -carboxylic acid (4-isopropyl-phenyl)-amide (a) (3S,3aR,6aS)-3-Methyl-2-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester hydrochloride Prepared in a similar manner to the product of Compound Example 3, step (n) from the product of Compound Example 3, step (i). The title compound , was obtained as a white solid in 93% yield and was used in the next reaction without further purification. Mass Spec. : 141[M-Boc] + , 241 [MH] + , 481 [2MH] + (b) (3S,3aR,6aS)-3-Methyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride To the product of step (a) (8.61g, 31.1 mmol) in dry dichloromethane (20mL) was added trifluoroacetic acid (20mL, 260mmol, 8 eq.). The solution was stirred at room temperature for 2 hours. The solvents were then evaporated and the resulting brown gum was azeotroped with toluene (4X 50 mL). The title compound , was obtained in quantitative yield as a brown gum which was used in the next reaction without further purification. Mass Spec: 141 [MH] + parent amine. 1 H nmr (d 6 -DMSO) : δ 9.18-8.80 (2H,brd.), 7.30-7.08 (1H,m), 3.92-3.20 (4H,m), 2.60 (1 H,m), 2.26-2.10 (1 H,m), 1.75 (1 H,m), 1.09 (3H,d) ppm. (c) (3aS,6S,6aR)-6-Methyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid 4-methoxy-benzyl ester The product of step (b) (12.01g, 31.1 mmol of trans-lactam + 57 mmol TFA) and triethylamine (11.2 mL, 80.43 mmol, 2.6 eq. w.r.t. trans-lactam) were dissolved in water (40mL). A solution of 2-(4-methoxybenzyloxycarbonyloxyimino)-2- phenylacetonitrile (MOZ-ON) (7.45g,31 mmol, 0.8 eq.) in 1 ,4-dioxane (60mL) was added to the stirred mixture. After 18 hours it was diluted with water (140mL) and extracted with ethyl acetate (2 X 100mL). The aqueous phase was acidified to pH2 with solid citric acid and then saturated with solid sodium chloride. It was then further extracted with ethyl acetate (3 X 60mL). The combined organic extracts were washed with water (50mL) and sat. brine (50mL), dried over MgSO 4 and the solvent was evaporated to give a brown oil. Trituration under ether caused precipitation of a white solid which was collected by filtration washed with ether and dried in vacuo at room temperature to give the title compound (5.37g). LCMS: 305.2 [MH] + , Retention time = 3.76 min (Gilson Supelcosil LC ABZ plus column; elutant system A: water, 0.1% formic acid, 10mM ammonium acetate, B: MeCN, 0.1% formic acid; gradient 100%A 0.7 min, 100%A-100%B 3.5 min, 100%B 3.5 min, 100%B-0%B 0.3min; flow rate 1ml/min) (d) (3aS,6S,6aR)-4-Benzothiazol-2-yl-6-methyl-5-oxo-hexahydro-pyrrolo[3,2- b]pyrrole-1 -carboxylic acid 4-methoxy-benzyl ester To the product of step (c) (1.04g,3.42mmol,1eq.) was added 2- bromobenzothiazole 1 (1.17g,5.47mmol,1.6eq.), potassium carbonate (0.768g,5.56 mmol, 1.6 eq.), copper (I) chloride (0.345g,3.49mmol,1eq.), TDA-1 (0.330mL,1.03 mmol,0.3eq.) and xylene (55mL). The reaction mixture was refluxed under a Dean-Stark head for 7.5 hours. After leaving to cool, the brown solids were filtered off and washed with ethyl acetate (30mL). The combined filtrate and washings were washed with water (100mL) and brine (100mL) and dried over MgS0 4 . The solvent was evaporated to give a brown gum (1.99g). The title compound, was purified by flash column chromatography over silica gel (Merck 9385) using cyclohexane:ether and was obtained as a white solid (0.95g). Mass Spec. : 438 [MH] + Ref 1. M.P. Doyle, J.F. Dellaria, B.J.Siegfried, J. Org. Chem., 42, 1977, 2426- 2430. (e) (3S,3aR,6aS)-1-Benzothiazol-2-yl-3-methyl-hexahydro-pyrrolo[3,2-b]pyrrol- 2-one trifluoroacetate To the product of step (d) (850mg, 2.194mmol) was added trifluoroacetic acid (20mL) at room temperature. After 20 minutes the solvent was evaporated in vacuo to give, after trituration under diethyl ether, the title compound as a tan solid, (643 mg). Mass spec 274 [MH] + . (f) 2S-(4-Benzothiazol-2-yl-6S-methyl-5-oxo-hexahydro-(3aS,6aR)-pyrrolo[3,2- b]pyrrole-1-carbonyl)-pyrrolidine-1 -carboxylic acid tert-butyl ester and 2S-(4- Benzothiazol-2-yl-6R-methyl-5-oxo-hexahydro-(3aR,6aS)-pyrrolo[3,2-b]pyrrole- 1-carbonyl)-pyrrolidine-1 -carboxylic acid tert-butyl ester. To a stirred mixture of N-tert Boc-L-proline (165mg, 0.77mmol, 2eq) in acetonitrile (3mL) and dimethylformamide (0.6mL) were added TBTU (246mg, 0.77mmol, 2eq) and HOBT (104mg, 0.77mmol 2eq) at room temperature. After 40 minutes a solution of the racemic form of the product of step (e) (230mg, 1eq) and di-isopropylethylamine (0.267mL, 1.53mmol, 4eq) in dimethylformamide (0.8mL) was added. The mixture was stirred for 2 hours and then left to stand overnight (14.75hr) before it was poured into ethyl acetate (30mL) and washed with water (2 x 15mL) and brine (15mL), dried (MgSO 4 ) and evaporated to leave a pale yellow gum. Purification by flash column chromatography over silica gel( Merck 9385) using cyclohexane:ethyl acetate (2:1)as the eluting solvent system gave 52mg of the title compound (3aS,6aR,6S diastereoismer) as a white solid. Mass spec 471 [MH]\ 371 [M-Boc] + . Circular dichroism λ max 197.4 nm, dE 6.72; λ max 208.0 nm, dE -2.39; λ max 215.0 nm, dE 3.67; λ max 230.6 nm, dE -5.72; λ max 2.48.2 nm, dE 3.44; HPLC (Intersil M column ODS2, eluent system A (H 2 O, 0.1 % H 3 P0 4 ) B (95% MeCN/H 2 0, 0.1% H 3 P0 4 ):Gradient 0%B 2mins, 0%-100% B 40mins,100% B 10mins; flow rate = 1ml/min, , λ = 215nm). Retention time =31.44min 100%. contains none of the other isomer, checked by spiking the sample with the 3aR,6aS,6R diastereoismer). and 49mg of the (3aR,6aS,6R diastereoismer) as a pale yellow solid. Mass spec 471 [MH] + , 371 [M-Bocf. Circular dichroism λ max 205.0 nm, dE 18.90; λ max 216.4nm, dE 3.24; λ max 228.4 nm, dE 7.48; λ max 247.8 nm, dE -3.40; HPLC (Same system as less polar isomer) : Retention time = 31.03min 98% (the peak has a small shoulder at 31.4min, which when spiked with the 3aS,6aR,6S diastereoismer becomes more marked, so probably contains a small amount of the other isomer). (g) 2S-(4-Benzothiazol-2-yl-6S-methyl-5-oxo-hexahydro-(3aS,6aR)-pyrrolo[3,2- b]pyrrole-1 -carbonyl)-pyrrolidine-1 -carboxylic acid (4-isopropyl-phenyl)-amide To the product of step (f) (64mg, 136μmol) was added trifluoroacetic acid (315μL, 4.09mmol, 30eq) at room temperature. After 10 minutes the solution was azeotroped with toluene (1mL x 2) to leave a yellow gum (78mg). The gum was dissolved in acetonitrile (2mL) and 4-(isopropyl)phenyl isocyanate (30μL, 188μmol, 1.37eq) added, followed by triethylamine (47.5μL, 341μmol, 2.5eq). The mixture was left to stand at room temperature for 4 hours before it was directly purified using preparative plate chromatography (WhatmanPK6F silica gel 60A plate) eluting with ethyl acetate to give the title compound as an off- white solid, 62mg. Circular dichroism λ max 198.0 nm, dE -11.0; λ max 212.4 nm, dE 8.47; λ max 228.0 nm, dE -4.01 ; λ max 239.0 nm, dE 2.94; λ max 248.2 nm, dE 0.47; λ max 257.2 nm, dE 4.78. 1 H nmr (CDCI 3 ): δ 7.80 (2H, m); 7.44 (1 H, td); 7.31 (1 H, td); 7.25 (2H, m); 7.14 (2H, m); 6.23 (1 H, s); 4.70 (1 H, m); 4.62 (1H, t); 4.13 (1 H, td); 3.93 (1 H, m); 3.80 (1 H, dd); 3.70 (1 H, m); 3.54 (1 H, q); 3.45 (1H, m); 3.14 (1H, m); 2.86 (1 H, m); 2.39 (2H, m); 2.25 (1 H, m); 2.11 (1H, m); 2.00 (1 H, m); 1.21 (9H, d). Mass spec 532 [MH] + , 371 [M-4-(isopropyl)phenyl isocyanate group] 4 . Compound Example 5 rel-(3R,3aR,6aS)-3-(4-Carbamimidoyl-butyl)-4-(1H-indole-2-carbonyl)-2-oxo- hexahydro-pyrrolo[3,2-b]-pyrrole-1 -carboxylic acid methyl ester trifluoroacetate (a) 4-Benzyloxycarbonylamino-2-terf-butoxycarbonylamino-butyric acid This compound was prepared from diaminobutyric acid following conventional processes known per se. (b) (3-Benzyloxycarbonylamino-1-hydroxymethyl-propyl)-carbamic acid tert- butyl ester A solution of the product of step (a) (3.198g) in tetrahydrofuran (44ml, dry) was cooled to -10°C under nitrogen, 4-methylmorpholine (1.0ml) was added followed by ethylchloroformate (0.868ml). After stirring for 8 mins sodium borohydride (1 03g) was added in one portion followed by methanol (88ml) over a period of 11 mins at 0°C. The mixture was stirred at ca 0°C for an additional 11 mins before 1 M hydrochloric acid (18ml) was added. The mixture was evaporated under reduced pressure and the aqueous residue was extracted with ethyl acetate. The organic layer was separated and washed with 1 M hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water, then dried (magnesium sulphate), evaporated under reduced pressure and some of the residue (1.8g from 2.87g) was purified by chromatography (Merck 7734) using cyclohexane:ethylacetate (3:2) as eluent to give the title compound (1.6g) : t.l.c (1 :1 cyclohexane : ethyl acetate) Rf 0.23 ir (CHBr 3 ) 3432, 1704cm- "1 . (c) 6-Benzyloxycarbonylamino-4-fetf-butoxycarbonylamino-hex-2E-enoic acid ethyl ester A solution of dimethyl sulfoxide (6.82ml) in dry dichloromethane (135ml) was stirred under N2 and cooled (dry ice/acetone) to - 72°C. Oxalyl chloride (7.4ml) was added dropwise over 10 minutes (temp kept in the range - 60 -» 65°C) and the reaction was stirred for 15 minutes. A solution of the alcohol, the product of step (b), (12.6g) in dry dichloromethane (135ml) was added over 20 minutes (temp kept in the range -60-»-63°C) and the reaction mixture then stirred for 20 minutes by which time the temperature had risen to -52°C. Triethylamine (53.7ml) was added dropwise over 10 minutes followed by the immediate addition of the Wittig reagent (19.3g). The cooling bath was removed and the internal temperature allowed to rise to 17°C. The reaction mixture was poured into ether (400ml) and brine (400ml). The organic phase was separated and the aqueous phase extracted with ether (2x100ml). The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to give a tan oil (36.22g). This was purified by flash column chromatography (Merck 9385 silica eluting with 40% ethyl acetate in cyclohexane) to give the product (15.71g) as an oil: 1 H NMR (CDCI3); 7.40-7.30 (5H, m), 6.86 (1H, dd), 5.93 (1 H, dd), 5.42-5.28 (1 H, br), 5.12 (2H, ABq), 4.72-4.60 (1 H, m), 4.50-4.32 (1 H, m), 4.19 (2H, q), 3.60-3.30 (1 H, m), 3.15-2.98 (1 H, m), 2.00-1.80 (1 H, m), 1.65-1.50 (1 H, m), 1.45 (9H, s) and 1.28 (3H, t), Rf 0.45 (2:3 ethyl acetate /cyclohexane) (d) rel-(2ff,3S)-3-ferf-Butoxycarbonylamino-2-ethoxycarbonylmethyl-pyrrolidine- 1 -carboxylic acid benzyl ester The product of step (c) (12.2g) was suspended in dry toluene (175ml) with stirring under N2- Tetramethylethylenediamine (1.1ml) was added followed by lithium bis-(trimethylsilyl)amide (1.0M in hexanes, 7.6ml). On completion of the addition a solution had formed. The reaction mixture was stirred for 15 minutes and then poured into ethyl acetate (300ml) and saturated aqueous ammonium chloride (300ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2x50ml). The combined organic extracts were washed with brine (150ml) and the aqueous phase extracted with ethyl acetate (2x25ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to give a tan oil (12.86g) which was filtered through a plug of silica gel using ethyl acetate/cyclohexane (2/3) as eluant to give a crude mixture including title compound (10.74g) as an oil. This oil was purified further by flash column chromatography on silica gel. Elution with ethyl acetate/cyclohexane (2/3) gave the title compound, as a solid (8.49g, 69.7%). A small sample of the title compound was crystallised from ether to give a white solid: 1 H NMR (CDCI3); 7.40-7.30 (5H, m), 5.12 (2H, s), 4.72-4.53 (1H, m), 4.20-3.95 (4H, m), 3.65-3.40 (2H, m), 2.95-2.65 (1 H, m), 2.60-2.40 (1 H, m), 2.25-2.10 (1 H, m), 1.92-1.75 (1 H, m), 1.40 (9H, s) and 1.30-1.15 (3H, m). Rf 0.8 (1 :1, ethyl acetate/cyclohexane) (e) 3-(4-lodo-butyl)-5-trichloromethyl-[1 ,2,4]oxadiazole To a solution of 1-iodo-5-nitro-pentane (82g) in toluene (820ml) was added trichloroacetonitrile (34ml), triethylamine (3ml) and phenylisocyanate (74ml). The mixture was then placed in an ultrasound bath for 18h. Hexane was added to the reaction and the mixture filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography eluting with diethyl etheπhexane, (2:98), (4:98), to give the title compound (110g) as an orange oil. T.l.c. (Silica, hexane:diethyl ether, 9:1) Rf 0.5 (f) 3-(4-lodo-butyl)-4H-[1 ,2,4]oxadiazol-5-one To a solution of the product of step (e) (85g) in ethanol (1500ml) was added potassium hydroxide (15.3g). The resultant mixture was stirred at room temperature for 3.5h and then concentrated under reduced pressure. The residue was then partitioned between sodium carbonate (2N) and diethyl ether. The aqueous layer was acidified to pH2 with concentrated hydrochloric acid and then extracted with diethyl ether. The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure to give, after triturating in diethyl ether, the title compound (37g) as a white solid. Analysis: Found: C.27.0; H,3.4; N,10.35% C 6 H 9 IN 2 O 2 requires C.26.9; H.3.4; N, 10.45% (g) trans-3-tert-Butoxycarbonylamino-2-[1-ethoxycarbonyl-5-(5-oxo-4,5-dihydro- [1 ,2,4]oxadiazol-3-yl)-pentyl]-pyrrolidine-1 -carboxylic acid benzyl ester A solution of the product of step (d) (3.5g) in THF (70ml) at -75°C was treated with a hexane solution of lithium hexamethyldisilazide (1 M, 38.5ml) over 15 min. After 2h at -78°C, the product of step (f) (2.31 g) in THF/HMPA (10ml/21ml) was added over 10 min and the resultant solution was maintained at -70°C for 1h. After reaching 0°C (over 1h), the reaction was quenched with ammonium chloride solution. The resultant solution was extracted with ethyl acetate and the combined organic extracts were washed with water, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was subjected to flash column chromatography eluting with ethyl acetate:ether: hexane [(0:1 :2), (0:1 :0) and (1 :0:0)], to give the title compound (2.6g) as a white foam. Analysis: Found: C,58.8; H,7.2; N,10.1% C 27 H 38 N 4 O 8 .0.37H 2 O requires C,58.6; H.7.1 ; N.10.1% (h) trans-3-Amino-2-[1-ethoxycarbonyl-5-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3- yl)-pentyl]-pyrrolidine-1 -carboxylic acid benzyl ester trifluoroacetate The product of step (g) (2.77g) was dissolved in trifluoroacetic acid (11ml) and dichloromethane (100ml). After 2h, the solvents were removed under reduced pressure to give the title compound (2.8g) as a yellow oil. Mass spectrum: Found: MH + 447 {i) trans-3-Amino-2-[1-carboxy-5-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)- pentyl]-pyrrolidine-1 -carboxylic acid benzyl ester hydrochloride A mixture of the product of step (h) (3.3g), potassium carbonate (4.1g), ethanol (60ml) and water (60ml) was stirred at reflux under nitrogen for 5 days. The cooled mixture was concentrated under reduced pressure and the residue treated with hydrochloric acid (2N) and concentrated under reduced pressure. The residue was stirred in hot ethanol, filtered and the filtrate concentrated under reduced pressure to give the title compound (1.8g) (mixture of isomers 2:1) as a yellow gum. Mass spectrum: Found: MNa + 441 (j) rel-(3aS,6R,6aR)-5-Oxo-6-[4-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-butyl]- hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester A mixture of the product of step (i) (1.6g), diphenylphosphorylazide (1.5ml) and triethylamine (2.5ml) in DMF (80ml) was stirred at room temperature for 48h. The mixture was concentrated under reduced pressure and the residue subjected to preparative h.p.l.c(gradient profile 10-90% (ii) in 25min). The title compound (0.547g) was obtained as a white solid by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH + 401 (k) rel-(3aS,6R,6aR)- 6-[4-(4-tert-Butoxycarbonyl-5-oxo-4,5-dihydro- [1 ,2,4]oxadiazol-3-yl)-butyl]-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester Triethylamine (0.1ml) was added to a stirred solution of the product of step (j) (0.1g) and di-tert-butylcarbonate (0.109g) in dry DMF (5ml) at room temperature. After 18h, further di-tert-butylcarbonate (0.055g) was added and stirring continued for 8h. The solution was poured into phosphate buffer (pH6.5) and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated under reduced pressure. The residue was triturated with ethyl acetate: hexane (1 :11) to give the title compound (0.094g) as a colourless gum. T.l.c. Silica (ethyl acetate) Rf 0.45 (I) rel-(3R,3aR,6aS)-2-Oxo-3-[4-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-butyl] hexahydro-pyrrolo[3,2-b]pyrrole-1 ,4-dicarboxylic acid 4-benzyl ester 1 -methyl ester A solution of the product of step (k) (0.093g) in DMF (5ml) was added to sodium hydride (0.018g, 60% dispersion in oil) at room temperature. After 30 min, methyl chloroformate (0.043ml) was added and stirring continued for 18h. Further sodium hydride (0.018g) followed by methyl chloroformate (0.043ml) was added and stirring continued for 24h. The mixture was poured into phosphate buffer (pH6.5) and extracted with ethyl acetate. The combined, dried (sodium sulfate) organic extracts were concentrated under reduced pressure and the residue was treated with dichloromethane (5ml) and trifluoroacetic acid (1ml). After stirring at room temperature for 1h, the solution was concentrated under reduced pressure and the residue subjected to preparative h.p.l.c (gradient profile 10-90% (ii) in 25min). The title compound (0.042g) was obtained as a yellow gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH + 459 (m) rel-(3R,3aR,6aS)-3-(4-Carbamimidoyl-butyl)-2-oxo-hexahydro-pyrrolo[3,2- b]pyrrole-1 -carboxylic acid methyl ester bis(trifluoroacetate) A mixture of the product of step (I) (0.136g), trifluoroacetic acid (45μl), 10% palladium on carbon (0.136g) and ethyl acetate (100ml) was stirred under an atmosphere of hydrogen for 24h. The reaction mixture was filtered through Harborlite™ and the filtrate evaporated under reduced pressure to give the title compound (0.15g) as an oil. Mass spectrum: Found: MH + 283 (n) rel-(3R,3aR,6aS)-3-(4-Carbamimidoyl-butyl)-4-(1H-indole-2-carbonyl)-2-oxo- hexahydro-pyrrolo[3,2-b]-pyrrole-1 -carboxylic acid methyl ester trifluoroacetate A solution of triethylamine (3.3μl) in acetonitrile (1 ml) was added dropwise to a stirred solution of the product of step (m) (0.012g) and 1 H-indole-2-carbonyl chloride*(0.004g) in acetonitrile (1ml) and stirred at room temperature for 20h. The reaction was concentrated under reduced pressure and the residue subjected to preparative h.p.l.c (gradient profile 10-70% (ii) in 15min) to give the title compound (0.004g) as a white foam by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. AnalyticalH.P.L.C. (gradient profile 10-90% (ii) in 25min) Rt 21.5min. Mass spectrum: Found: MH + 426 *W. H. Parsons et al., J. Med. Chem., 1989, 32, 1681. H.P.L.C. Conditions used: Preparative high performance liquid chromatography (h.p.l.c.) was carried out using a Dynamax 60A C18 8μM 25cm x 41.4mm i.d. column eluted with a mixture of solvents (i) 0.1% trifluoroacetic acid in water and (ii) 0.05% trifluoroacetic acid in acetonitrile, at a flow rate of 45ml/minute. Analytical h.p.l.c. was carried out using a Dynamax 60A C18 8μM 25cm x 4.6mm i.d. column using eluants as for preparative h.p.l.c. at a flow rate of 1 ml/minute. Compound Example 6 rel-(3R,3aR,6aS)-(3-(4-Carbamimidoyl-butyl)-4-(1 H-indole-2-carbonyl)-2-oxo- hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid methylamide trifluoroacetate (a) rel-(3aS,6R,6aS)-6-{4-[4-(2-Nitro-benzyl)-5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol- 3-yl]-butyl}-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester A mixture of the product of Compound Example 5, step (j) (56g), o- nitrobenzylbromide (27.2g) and trietruylamine (50ml) in DMF (1250ml) was stirred at room temperature for 16h. The solution was concentrated under reduced pressure and the residue was treated with phosphate buffer (pH6.5) and water. The mixture was extracted with ethyl acetate and the combined, dried (sodium sulfate) organic extracts were concentrated under reduced pressure, to give an oil which partially solidified after 24h. Trituration with ethyl acetate: cyclohexane (1 :1) gave the title compound (6.24g) as a white amorphous solid. Mass spectrum: Found: MH + 536 (b) rel-(3aS,6R,6aR)-4-Methylcarbamoyl-6-{4-[4-(2-nitro-benzyl)-5-oxo-4,5- dihydro-[1 ,2,4]oxadiazol-3-yl]-butyl}-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1- carboxylic acid benzyl ester A mixture of the product of step (a) (5g), sodium hydride (1.9g, 60% dispersion in oil) and methyl isocyanate (2.7ml) in THF (500ml) was stirred at room temperature for 64h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with ethyl acetate:hexane, (2:1) and (3:1), to give the title compound (0.564g) as a white solid. T.l.c. Silica (ethyl acetate: hexane, 2:1) Rf 0.3 (c) rel-(3aS,6R,6aR)-4-Methylcarbamoyl-5-oxo-6-[4-(5-oxo-4,5-dihydro [1 ,2,4] oxadiazol-3-yl)-butyl]-hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester A solution of the product of step (b) (0.250g) in anhydrous dioxan (200ml) was photolysed for 6h, and then concentrated under reduced pressure. The residue was subjected to preparative h.p.l.c. (gradient profile 10-90% (ii) in 25min) . The title compound (0.170g) was obtained as a beige foam by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH + 458 (d) rel-(3R,3aR,6aS)-3-(4-Carbamimidoyl-butyl)-2-oxo-hexahydro-pyrrolo[3,2-b] pyrrole-1 -carboxylic acid methylamide bis(trifluoroacetate) A mixture the product of step (c) (0.22g), trifluoroacetic acid (0.110ml), and 10% palladium on carbon (0.24g) in ethyl acetate (11ml) was hydrogenated at atmospheric pressure for 16h. The reaction mixture was filtered through Harborlite™ and the filtrate concentrated under reduced pressure to give the title compound (0.244g) as a brown foam. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 18.3min (for conditions see Compound Example 5). (e) rel-(3R,3aR,6aS)-(3-(4-Carbamimidoyl-butyl)-4-(1H-indole-2-carbonyl)-2-oxo- hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid methylamide trifluoroacetate A solution of triethylamine (15μl) in acetonitrile (1.2ml) was added dropwise to a stirred solution of the product of step (d) (0.055g) and 1 H-indole-2- carbonylchloride (0.019g) in acetonitrile (15ml) and stirred at room temperature for 24h. The reaction was concentrated under reduced pressure and the residue subjected to preparative h.p.l.c. (gradient profile 10-90% (ii) in 25min) to give the title compound (0.034g) as a white solid by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 20.2min (for H.P.L.C. conditions see Compound Example 5) Mass spectrum: Found: MH + 415 Compound Example 7 rel-(3R,3aR,6aS)-4-(Benzofuran-2-carbonyl)-3-(4-carbamimidoyl-butyl)-2-oxo- hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid methylamide trifluoroacetate This compound was prepared by an analogous method to Compound Example 6. Analytical h.p.l.c. (gradient profile 10-70% (ii) in 15min) Rt 14.1 min Mass spectrum: Found: MH + 426. Compound Example 8 rel-(3R,3aR,6aS)-5-[1-Benzenesulfonyl-4-(1 H-indole-2-carbonyl)-2-oxo- octahydro-pyrrolo[3,2-b]pyrrol-3-yl]-pentanamidine trifluoroacetate (a) rel-(3aS,6R,6aR)-4-Benzenesulfonyl-5-oxo-6-[4-(5-oxo-4,5-dihydro-[1 ,2,4] oxadiazol-3-yl)-butyl]-hexahydro-pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester A solution of the product of Compound Example 5, step (k) (0.250g) in THF (5ml) was added to sodium hydride (0.060g, 60% dispersion in oil) at room temperature. After 10 min, benzenesulfonyl chloride (0.195ml) was added and stirring continued for 24h. Further sodium hydride (0.060g) followed by benzenesulfonyl chloride (0.195ml) was added and stirring continued for 24h. The mixture was poured into phosphate buffer (pH6.5) and extracted with ethyl acetate. The combined, dried (sodium sulfate) organic extracts were concentrated under reduced pressure and the residue was treated with dichloromethane (30ml) and trifluoroacetic acid (3ml). After stirring at room temperature for 8h, the solution was concentrated under reduced pressure and the residue subjected to preparative h.p.l.c. (gradient profile 40-90% (ii) in 15min). The title compound (0.065g) was obtained as a white solid by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH + 541 (b) rel-(3R,3aR,6aS)-5-(1-Benzenesulfonyl-2-oxo-octahydro-pyrrolo[3,2-b]pyrrol- 3-yl)-pentanamidine trifluoroacetate A mixture of the product of step (a) (0.060g), trifluoroacetic acid (16μl), 10% palladium on carbon (0.060g) and ethyl acetate (60ml) was stirred under an atmosphere of hydrogen for 19h. The reaction mixture was filtered through Harborlite™ and the filtrate evaporated under reduced pressure to give the title compound (0.059g) as a white solid. Mass spectrum: Found: MH + 365 (c) rel-(3R,3aR,6aS)-5-[1 -Benzenesulfonyl-4-(1 H-indole-2-carbonyl)-2-oxo- octahydro-pyrrolo[3,2-b]pyrrol-3-yl]-pentanamidine trifluoroacetate A solution of triethylamine (13μl) in acetonitrile (1.5ml) was added dropwise to a stirred solution of the product of step (b) (0.052g) and 1 H-indole-2-carbonyl chloride (0.016g) in acetonitrile (3ml) and stirred at room temperature for 24h. The reaction was concentrated under reduced pressure and the residue subjected to preparative h.p.l.c. (gradient profile 10-70% (ii) in 15min) to give the title compound (0.042g) as a cream coloured solid) by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Analytical h.p.l.c. (gradient profile 10-70% (ii) in 15min) Rt 16.3min (for HPLC conditions see Compound Example 5). Mass spectrum: Found: MH + 508 Biological Data The results obtained by testing example compounds in the example assays are indicated below: -vl CJ) Data in columns 1-13 is indicated at IC 50 (μM) Data in column 14 is indicated as t 2 Annex 1 Compounds of formula IA ( of the invention) are defined as follows: (relative stereochemistry ind wherein: R 1 represents C 2- alkyl, C 2-4 alkylthio; R 2a represents C 1-6 alkyl; - heteroaryl, which aryl or heteroaryl are mono-ring, gs one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C 1-4 alkyl, halo, -NR 7 R 8 , -SO 2 NR 7 R 8 , -CONR 7 R 8 , -C 1-6 alkyl ester, -CN, -CH 2 OH, -O-C 1-6 alkyl, -CF 3 , or nitro groups; aryl-C 1-4 alkyl, aryl-C 1-4 alkyl-NH- or -(CH 2 ) n -NR 4 R 5 ; C 2-8 alkenyl-NR 4 R 5 ; -(CH 2 ) n CONR 4 R 5 ; -(CH 2 ) n NR 9 CO-C 1-6 alkyl; C 2-8 alkenyl-COOR 9 ; (CH 2 ) n COOR 9 ; and C 2-8 alkenyl CONR 4 R 5 ; X represents II o 0 || _ _ 7 Q 7 or - c- o— (where carbonyl is bound to the ring nitrogen) ; R 4 and R 5 independently represent hydrogen, C 1- alkyl, C 1-4 alkoxy, -(CH^^CONR^R^, -CO-C 1-4 alkyl or phenyl optionally substituted by one or more C 1-4 alkyl or halogen groups or R 4 and R 5 may be joined such that NR 4 R 5 represents a mono, bi- or tri-cyclic ring system containing 4-15 ring carbon atoms, wherein one or more rings may be optionally interrupted by one or more heteroatoms selected from O, N and S and wherein one or more ring carbon atoms may have carbonyl functionality; or -(CH 2 ) n -NR 4 R 5 may represent a group of formula 1 a: wherein R 6 is hydrogen or a carboxy C 1-6 alkyl ester, n 1 is 0-6 and a and b independently represent an integer 0-3 provided a+b is in the range 3-5; R 7 , R 8 , R 9 , R 10 , R 11 ( R 12 independently represent hydrogen or C 1-4 alkyl; m represents an integer 0 to 8; n represents an integer 1 to 9; and salts and solvates thereof. Compounds of formula IB (which are not compounds of the invention) are defined as follows: (relative stereochemistry indicated) wherein: R 1 represents H, substituted or unsubstituted C 1-3 alkyl; R 2 represents optionally substituted heteroaryl or fused heteroaryl with one to four heteroatoms, R 5 CO or R 5 NHCO wherein R 5 may be substituted or unsubstituted and represents H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, aryl, arylC 1-3 alkyl or heteroaryl containing one or more heteroatoms; R 3 represents R 3a CO; wherein R 3a represents wherein R 4 represents the group R 6 -X- ; wherein R 6 represents wherein the aryl rings are optionally further substituted with one or more heteroatoms, Y represents a hetero atom such as O, S or N, wherein N is optionally further substituted, W represents hydrogen or C 1-3 alkyl and Z represents hydrogen, halogen, C 1-6 alkyl, aryl, C 1-6 alkoxy, C n H 2n+1 OC m H 2rn wherein n and m are independently selected integers 1-3, CF 3 , O-haloC 1-3 alkyl, S-C 1 . 3 alkyl, S-haloC 1-3 alkyl, O-aryl, C 2-4 alkenyl or N(A)B wherein A and B are independently selected from H and C 1-4 alkyl; X represents a linker group chosen from C=O, NHC=O, C(=O)C=O, CH 2 CO or SO 2 ; and salts and solvates thereof. Compounds of formula MA (which are not intermediate compounds of the invention) are defined as follows: (relative stereochemistry indicated) wherein R 1 represents C 2- alkyl, C 2-4 alkenyl, C 1-3 alkoxy or C 1-3 alkylthio. Compounds of formula HB (which are not intermediate compounds of the invention) are defined as follows: (relative stereochemistry indicated) wherein: R 1 represents H, substituted or unsubstituted C^ alkyl. Compounds of formula ll'A (which are not intermediate compounds of the invention) are defined as follows: (relative stereochemistry indicated) wherein: R 1 represents C 2- alkyl, C 2- alkenyl, C 1-3 alkoxy or C 1-3 alkylthio; R 2a represents C 1-6 alkyl; -CH 2 (CF 2 )o -4 CF 3 ; aryl or heteroaryl, which aryl or heteroaryl are mono-ring, or have two fused rings one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C 1-4 alkyl, halo, -NR 7 R 8 , -SO 2 NR 7 R 8 , -CONR 7 R 8 , -C 1-6 alkyl ester, -CN, -CH 2 OH, -O-C 1-6 alkyl, -CF 3 , or nitro groups; aryl-C 1-4 alkyl, aryl-C 1-4 alkyl-NH- or aryl-C 2 . 4 alkenyl, or such groups wherein aryl is substituted by one or more C 1- alkyl or halo groups; R 7 , R 8 independently represent hydrogen or C 1- alkyl. Compounds of formula ll'B (which are not intermediates compounds of the invention) are defined as follows: (relative stereochemistry indicated) wherein: R 1 represents H, substituted or unsubstituted C 1-3 alkyl; R 2 represents optionally substituted heteroaryl or fused heteroaryl with one to four heteroatoms, R 5 CO or R 5 NHCO wherein R 5 may be substituted or unsubstituted and represents H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, aryl, arylC 1 . 3 alkyl or heteroaryl containing one or more heteroatoms.

Claims: Claims: 1. An inhibitor of a serine protease enzyme which is a substituted derivative of trans-hexahydropyrrolo[3,2-b]pyrrol-2-one save that it is not a compound of formula IA and IB (as defined in Annex 1). 2. An inhibitor of a serine protease enzyme which is a compound of formula I: (relative stereochemistry indicated) wherein R 1 is a moiety adapted to fit in the S Ϊ specificity subsite of the enzyme; R 2 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the inhibitor; R 3 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physiocochemical properties of the inhibitor; and physiologically acceptable salts and solvates thereof save that it is not a compound of formula IA and IB (as defined in Annex 1). 3. An inhibitor of a serine protease enzyme according to claim 2, wherein R 2 represents a lactam activating moiety. 4. Use of a substituted derivative of trans-hexahydropyrrolo[3,2-b]pyrrol- 2-one save that it is not a compound of formula IA and IB (as defined in Annex 1) as an inhibitor of a serine protease enzyme. 5. An inhibitor according to any one of claims 1 to 3 for use as a pharmaceutical in the treatment of a disease associated with activity of a serine protease enzyme. 6. An inhibitor according to claim 2 or claim 3 wherein R 1 represents C 2-4 alkyl or C 2- alkenyl for use as an inhibitor of an elastase-like enzyme, e.g. human neutrophil elastase. 7. An inhibitor according to claim 6 wherein R 1 represents propyl or isopropyl. 8. An inhibitor according to claim 2 or claim 3 wherein R 1 represents methyl for use as an inhibitor of a Herpes virus protease. 9. An inhibitor according to claim 2 or claim 3 wherein R 1 represents (CH 2 ) M NHC(=NH)NH 2 , (CH 2 ) 1-2 PhC(=NH)NH 2ι (CH 2 ) 3-5 C(=NH)NH 2 , CH 2 (cyclohexyl)NH 2 , (CH 2 )ι -3 (NH) 0- Het ( wherein Het represents a 5 or 6 membered aromatic ring containing 1 or more nitrogen atoms and optionally substituted by amine) or (CH 2 ) 3-5 NH 2 for use as an inhibitor of a trypsin-like enzyme, e.g. thrombin or tryptase. 10. An inhibitor according to claim 2 or claim 3 wherein R 1 represents benzyl for use as an inhibitor of a chymotrypsin-like enzyme, e.g. Cathepsin G. 11. An inhibitor according to claim 2, 3, 6 or 7 wherein R 2 represents CHO or -SO 2 C 1-6 alkyl. 12. An inhibitor according to claim 2, 3, or 8 wherein R 2 represents COC^ 6 alkyl, CO-cyclopropyl or an electron withdrawing heteroaryl group. 13. An inhibitor according to claim 2, 3, or 9 wherein R 2 represents CONH(CH 2 ) 1-4 Ph, Sθ 2 (CH 2 ) 0- ιPh, COOC 1-4 alkyl, CONH 2 or CONHC 1-4 alkyl. 14. An inhibitor according to any one of claims 1 to 3, 5 to 7, 9, 11 and 13 in the form of a single diastereoisomer having relative stereochemistry as shown in formula (la) 15. An inhibitor according to any one of claims 1 to 3, 5, 8 and 12 in the form of a single diastereoisomer having relative sterechemistry as shown in formula (lb) 16. A compound of formula II (relative stereochemistry indicated) wherein R 1 is a moiety adapted to fit in the S Ϊ specificity subsite of the enzyme; save that it is not a compound of formula HA or HB (as defined in Annex 1). 17. A compound of formula II' (relative stereochemistry indicated) wherein R 1 is a moiety adapted to fit in the S Ϊ specificity subsite of the enzyme; R 2 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the inhibitor; save that it is not a compound of formula ll'A or H'B (as defined in Annex 1). 18. A compound according to claim 16 or 17 wherein R 1 represents (CH 2 ) 2-4 NHC(=NH)NH 2 , (CH 2 ) 1 . 2 PhC(=NH)NH 2 , (CH 2 ) 3-5 C(=NH)NH 2 , CH 2 (cyclohexyl)NH 2 , (CH 2 ) 1 . 3 (NH) 0-1 Het ( wherein Het represents a 5 or 6 membered aromatic ring containing 1 or more nitrogen atoms and optionally substituted by amine) or (CH 2 ) 3-5 NH 2 . 19. A compound according to claim 17 wherein R 2 represents CHO or SO 2 C 1-6 alkyl. 20. A compound according to claim 17 or 18 wherein R 2 represents CONH(CH 2 ) 1-4 Ph, SO 2 (CH 2 ) 0- ιPh, COOC 1-4 alkyl, CONH 2 or CONHC 1-4 alkyl. 21. A compound according to claim 17 wherein R 2 represents COC 1-6 alkyl, CO-cyclopropyl or an electron withdrawing heteroaryl group. 22. A method of treatment of chronic bronchitis or ARDS which comprises administering to a patient an effective amount of a neutrophil elastase inhibitor according to claim 6, 7 or 11. 23. A method of treatment of Herpes virus infection which comprises administering to a patient an effective amount of an inhibitor according to claim 8 or 12. 24. A method of treatment of diseases of the vascular system especially thrombosis which comprises administering to a patient an effective amount of a thrombin inhibitor according to claim 9 or 13. 25. A method of treatment of asthma which comprises administering to a patient an effective amount of a tryptase inhibitor according to claim 9 or 13. 26. A library comprising a plurality of substituted derivatives of trans- hexahydropyrrolo[3,2-b]pyrrol-2-one. 27. A library comprising a plurality of compounds of formula I (relative stereochemistry indicated) wherein R 1 is a moiety adapted to fit in the S.| specificity subsite of the enzyme; R 2 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the inhibitor; R 3 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physiocochemical properties of the inhibitor; and pharmaceutically acceptable salts and solvates thereof. 28. A library according to claim 26 or 27 comprising at least 10 different compounds. 29. A library according to claim 27 or claim 28 wherein R 1 represents C 2-4 alkyl or C 2-4 alkenyl. 30. A library according to claim 27 or claim 28 wherein R^ represents methyl. 31. A library according to claim 27 or claim 28 wherein R^ represents (CH 2 ) 2-4 NHC(=NH)NH 2 , (CH 2 ) 1-2 PhC(=NH)NH 2, (CH 2 ) 3-5 C(=NH)NH 2 , CH 2 (cyclohexyl)NH 2 , (CH 2 ) 1 . 3 (NH) 0-1 Het ( wherein Het represents a 5 or 6 membered aromatic ring containing 1 or more nitrogen atoms and optionally substituted by amine) or (CH 2 ) 3-5 NH 2 . 32. A library according to any one of claims 26 to 31 which is a solid phase library. 33. A library according to any one of claims 26 to 31 which is a solution phase library. 34. A library according to claim 32 or 33 which is a discrete library. 35. A library according to claim 32 or 33 which is a pooled library. 36. Use of a library according to any one of claims 26 to 29 for screening for an inhibitor of neutrophil elastase. 37. Use of a library according to any one of claims 26, 27, 28 and 30 for screening for an inhibitor of Herpes virus proteases. 38. Use of a library according to any one of claims 26, 27, 28 and 31 for screening for an inhibitor of thrombin or tryptase. 39. A method of screening for an inhibitor of a serine protease enzyme which comprises treating a serine protease enzyme with an inhibitor according to any one of claim 1 to 3 and determining the extent to which inhibition has occurred. 40. A method of identifying an inhibitor of a serine protease enzyme which comprises: (a) preparation of a number of substituted derivatives of trans- hexahydropyrrolo[3,2-b]pyrrol-2-one save that they are not compounds of formula IA and IB (as defined in Annex 1); (b) treatment of a sample of the enzyme in question with a sample of each of the derivatives so prepared; and (c) determining the extent to which inhibition of the enzyme has occurred.

Inventors: BORTHWICK ALAN DAVID, COOTE STEVEN JOHN, DOWLE MICHAEL DENNIS, EXALL ANNE MARJORIE, FINCH HARRY, HANN MICHAEL MENTEITH, KELLY HENRY ANDERSON, MACDONALD SIMON JOHN FAWCETT, MASON ANDREW MCMURTRIE, PEGG NEIL ANTHONY, PENNELL ANDREW MICHAEL KENNETH, RAMSDEN NIGEL GRAHAME, WATSON NIGEL STEPHEN, WEINGARTEN GORDON GAD, BORTHWICK, ALAN, DAVID, COOTE, STEVEN, JOHN, DOWLE, MICHAEL, DENNIS, EXALL, ANNE, MARJORIE, FINCH, HARRY, HANN, MICHAEL, MENTEITH, KELLY, HENRY, ANDERSON, MACDONALD, SIMON, JOHN, FAWCETT, MASON, ANDREW, MCMURTRIE, PEGG, NEIL, ANTHONY, PENNELL, ANDREW, MICHAEL, KENNETH, RAMSDEN, NIGEL, GRAHAME, WATSON, NIGEL, STEPHEN, WEINGARTEN, GORDON, GAD
Applicants: BORTHWICK ALAN DAVID, COOTE STEVEN JOHN, DOWLE MICHAEL DENNIS, EXALL ANNE MARJORIE, FINCH HARRY, GLAXO GROUP LTD, HANN MICHAEL MENTEITH, KELLY HENRY ANDERSON, MACDONALD SIMON JOHN FAWCETT, MASON ANDREW MCMURTRIE, PEGG NEIL ANTHONY, PENNELL ANDREW MICHAEL KENNETH, RAMSDEN NIGEL GRAHAME, WATSON NIGEL STEPHEN, WEINGARTEN GORDON GAD, BORTHWICK, ALAN, DAVID, COOTE, STEVEN, JOHN, DOWLE, MICHAEL, DENNIS, EXALL, ANNE, MARJORIE, FINCH, HARRY, GLAXO GROUP LIMITED, HANN, MICHAEL, MENTEITH, KELLY, HENRY, ANDERSON, MACDONALD, SIMON, JOHN, FAWCETT, MASON, ANDREW, MCMURTRIE, PEGG, NEIL, ANTHONY, PENNELL, ANDREW, MICHAEL, KENNETH, RAMSDEN, NIGEL, GRAHAME, WATSON, NIGEL, STEPHEN, WEINGARTEN, GORDON, GAD
Application year: 1998
Main classification: C07D487
IPC codes: A61K31, A61P7, A61P11, A61P31, A61P43, C07B61, C07D207, C07D487, G01N33