Background The enzyme dipeptidyl peptidase IV, herein abbreviated DP-IV (and elsewhere as DAP-IV or DPP-IV) and also known by the classification EC. 3. 4. 14. 5, is a serine protease that cleaves the N-terminal dipeptide from peptides that begin with the sequence H-Xaa-Pro (where Xaa is any amino acid, although preferably a lipophilic one, and Pro is proline). It will also accept as substrates peptides that begin with the sequence H-Xaa-Ala (where Ala is alanine). DP-IV was first identified as a membrane-bound protein. More recently a soluble form has been identified.

Initial interest in DP-IV focussed on its role in the activation of T lymphocytes. DP-IV is identical to the T cell protein CD26. It was proposed that inhibitors of DP-IV would be capable of modulating T cell responsiveness, and so could be developed as novel immunomodulators. It was further suggested that CD26 was a necessary co-receptor for HIV, and thus that DP-IV inhibitors could be useful in the treatment of AIDS.

Attention was given to the role of DP-IV outside the immune system. It was recognised that DP-IV has a key role in the degradation of several peptide hormones, including growth hormone releasing hormone (GHRH) and glucagon-like peptide-1 and-2 (GLP-1 and GLP-2). Since GLP-1 is known to have a potentiating effect on the action of insulin in the control of post-prandial blood glucose levels it is clear that DP-IV inhibitors might also be usefully employed in the treatment of type 11 diabetes and impaired glucose tolerance. At least two DP-IV inhibitors are currently undergoing clinical trials to explore this possibility.

Several groups have disclosed inhibitors of DP-IV. While some leads have been found from random screening programs, the majority of the work in this field has been directed towards the investigation of substrate analogs. Inhibitors of DP-IV that are substrate analogs are disclosed in, for example, US 5, 462, 928, US 5, 543, 396, W095/15309 (equivalent to US 5, 939, 560 and EP 0731789), W098/19998 (equivalent to US 6, 011, 155), W099/46272 and W099/61431. The most potent inhibitors are aminoacyl pyrrolidine boronic acids, but these are unstable and tend to cyclise, while the more stable pyrrolidine and thiazolidine derivatives have a lower affinity for the enzyme and so would require large doses in a clinical situation. Pyrrolidine nitriles appear to offer a good compromise since they have both a high affinity for the enzyme and a reasonably long half-life in solution as the free base. There remains, however, a need for inhibitors of DP-IV with improved properties.

Brief Description of the Invention The present invention relates to a series of inhibitors of DP-IV with improved affinity for the enzyme. The compounds can be used for the treatment of a number of human diseases, including impaired glucose tolerance and type 11 diabetes. Accordingly, the invention further relates to the use of the compounds in the preparation of pharmaceutical compositions, to such compositions perse, and to the use of such compositions in human therapy. The compounds of the invention are described by general formula 1.

In general formula 1, X1 is selected from-S-,-O-,-SO-,-SO2-and-CH2-; x2 is selected from-O-,-S-,-NH-and-CH2-; X3 is either-NR5-or a >C=O or >C=S group ; R'is either H or-CN ; R2 and R3 are independently selected from H and lower alkyl, or together may be -(CH2) p-; R4 is R4A when X3 is-NR5-and R4B when X3 is >C=O or >C=S ; R4A is selected from R6R7NC (=o), R6R7NC (=S) ; R8 (CH2) qC (=O), R8 (CH2) qC (=S), R8 (CH2) qSO2, R8 (CH2) qOC (=S) and R8 (CH2) qOC (=O) ; R 411 is WREN ; R5 is H or lower alkyl ; R6 and R7 are each independently R8 (CH2) q or together they are- (CH2) 2-Z- (CH2) 2- ; R8 is. selected from H, alkyl, optionally substituted aryl, optionally substituted aroyl, optionally substituted aryisulphonyl and optionally substituted heteroaryl ; Z is selected from a covalent bond, - (CH2) r,-0-,-SOr and-N ( (CH2) qR)- ; n is 0-4 ; p is 2-5 ; q is 0-3 ; r is 1 or 2 ; and t is 0 -2.

Detailed Description of the Invention In a first aspect, the present invention comprises a series of novel compounds that are inhibitors of the enzyme DP-IV and are useful for the treatment of certain human diseases.

The compounds are described by general formula 1.

In general formula 1, X1 is a divalent group selected from a sulphur atom (-S-), an oxygen atom (-O-), a sulphinyl group (-SO-), a sulphonyl group (-SOZ-) and a methylene group (-CH2-). X2 is a divalent group selected from an oxygen atom (-O-), a sulphur atom (-S-) and a methylene group (-CH2-). X3 is either a substituted imino group (-NR5-) or a carbonyl (>C=O) or thiocarbonyl (>C=S) group.

R1 is either a hydrogen atom (H) or a nitrile group (-CN).

R2 and R3 may each independently of the other be a hydrogen atom or a lower alkyl group, or together they may be a chain of between two and five methylene units (-(CH2)--where p is in the range 2-5) so as to form, with the carbon atom to which they are attached, a three, four, five or six-membered ring. The value of m may be 1, 2 or 3. When m is greater than 1 then each CR2R3 unit may be the same or different. For example, when m is 2 then (CR2R3) 2 may be CH2CH2, CHZC (Me) 2, C (Me) 2CH2 and the like.

The nature of R4 depends on the identity of X3, such that the two groups are linked by an amide (CO-N), thioamide (CS-N) or sulphonamide (SO2-N) bond. So, when X3 is a substituted imino group (-NR5-) then R4 is R4A, where R4A is selected from carbamoyl groups (R6R7NC (=O)), thiocarbamoyl groups (R6R7NC (=S)) ; optionally modified acyl groups (R5 (CH2) qC (=O)), optionally modified thioacyl groups (R3 (CH2) qC (=S)), sulphonyl groups (R8 (CH2) qSO2), optionally modified (alkyl or aryloxy) carbonyl groups (R8 (CH2) qOC (=O)) and optionally modified (alkyl or aryloxy) thiocarbonyl groups (R8 (CH2) qOC (=S)). As used herein, the term"optionally modified"is taken to indicate that some embodiments of R8 are beyond the scope of the terms"alkyl","acyl" and"aryl". The scope of the definition of R4A is determined by the scope of the definition of R8. Alternatively, when X3 is a carbonyl (>C=O) or thiocarbonyl (>C=S) group then R4 is R, where R4B is a substituted amino group (R6R7N).

R5 is a hydrogen atom (H) or a lower alkyl group. Preferably, R5 is H.

R6 and R7 may each independently of the other be R8 (CH2) q. Alternatively, they may together be a group-(CH2) 2-Z1-(CH2) 2-or-CHR9-Z2-CH2-CR1°-. Here Z1 is a covalent bond, a methylene or ethyliden group (-(CH2)r- where r is 1 or 2), an oxygen atom (-O-), a sulphur or oxidised sulphur atom (-SOt-where t is zero, 1 or 2) or a substituted imino group (-N ((CH2) qR8O, such that the group NR6R7 is a pyrrolidine, piperidine, perhydroazepine, morpholine, optionally oxidised thiomorpholine or substituted piperazine ring. f is an ortho-phenylene moiety (-C6H4-), such that the group NR6R 7is a tetrahydroisoquinoline.

R8 is selected from a hydrogen atom (H), a lower alkyl group, a benzo-fused lower cycloalkyl group (such as an indanyl group), an acyl (lower alkyl-CO) group, a di (lower alkyl) amino group, a di (lower alkyl) carbamoyl group, an N- (lower alkyl) piperidinyl group, an optionally substitiued a-alkylbenzyl group, an optionally substituted phenyl, naphthyl or heteroaryl group, and an optionally substituted aroyl (aryl-CO) or arylsulphonyl (aryl-SO2) group. In the foregoing, suitable optional substituents are lower alkyl, aryl which may be further substituted with one or more methyl or trifluoromethyl groups, hydroxy, lower alkyloxy, lower alkylsulphonyl, acyl, perfluoroacyl, amino, lower alkylamino, di (lower alkyl) amino, aminoalkylene, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, carbamoyl, carboxy and lower alkyloxycarbonyl groups. In addition, two adjacent substituents may be linked so as to form a ring fused to the parent aryl or heteroaryl ring.

R9 and R10 are independently selected from hydrogen, carbamoyl, hydroxymethyl and cyanomethyl groups.

The integer n is selected from the range zero to 4, and q is selected from the range zero to 3.

Certain compounds are specifically excluded from the scope of the present invention.

When X is methylene, X3 is NH and R4 is R8 (CH2) qO (CO), with q = 1, then 8 may not be unsubstituted phenyl or phenyl substituted with a nitro group. It is generally preferred that when X2 is methylene, X3 is NH, R4 is R$ (CH2) qO (CO), q is 1 and Ra is a substituted phenyl group then the substituent or substituents should be selected from chloro, methoxy and trifluoromethyl groups.

In the context of the present disclosure, the term lower alkyl, either by itself or in such combinations as lower alkyloxy, is intended to comprise linear, branched and cyclic saturated hydrocarbon groups of between one and six carbon atoms. Examples of lower alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, tert-butyl, neopentyl, cyclohexyl, cyclopentylmethyl, 2- (cyclopropyl) ethyl, 3, 3-dimethylcyclobutyl and bicyclo [3. 1. 0] hexyl.

The term heteroaryl includes monocyclic five-and six-membered ring aromatic groups with one or two heteroatoms, which are selected from nitrogen, oxygen and sulphur. Thus, heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl. Heteroaryl further includes the benzofused derivatives of these rings, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, indolyl, isoindolyl, benzothiazolyl and the like, and bicyclic groups formed by the fusion of two such monocyclic heteroaromatic groups.

The term aryl includes phenyl, naphthyl and heteroaryl.

The compounds of general formula 1 have at least one stereogenic centre and so can exhibit optical isomerism. All such isomers, including enantiomers, diastereomers and epimers are included within the scope of the invention. Furthermore, the invention includes such compounds as single isomers and as mixtures, including racemates. Certain compounds according to general formula 1, including those with a heteroaryl group which carries a hydroxy or amino substituent, can exist as tautomers. These tautomers, either separately or as mixtures, are also considered to be within the scope of the invention.

The compounds according to general formula 1 have at least one basic functional group. They can therefore form addition salts with acids. Those addition salts that are formed with pharmaceutical acceptable acids are included within the scope of the invention.

Examples of suitable acids include acetic acid, trifluoroacetic acid, citric acid, fumaric acid, benzoic acid, pamoic acid, methanesulphonic acid, hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid and the like.

Certain compounds according to general formula 1 have an acidic group and so are able to form salts with bases. Examples of such salts include the sodium, potassium and calcium salts, which are formed by the reaction of the acid with the corresponding metal hydroxide, oxide, carbonate or bicarbonate. Similarly, tetra-alkyl ammonium salts may be formed by the reaction of the acid with a tetra-alkyl ammonium hydroxide. Primary, secondary and tertiary amines, such as triethylamine, can form addition salts with the acid.

A particular case of this would be an internal addition salt formed between an acidic group and the primary amine group of the same molecule, which is also called a zwitterion. Insofar as they are pharmaceutically acceptable, all these salts are included within the scope of the invention.

In a preferred embodiment of the invention R'is a nitrile group. Within this embodiment, it is preferred that the stereochemistry of the nitrile group is as shown in general formula 2. According to the standard terminology, this is the S configuration when X'is methylene but the R configuration when X1 is sulphur, oxygen, sulphinyl or sulphonyl.

In another preferred embodiment, the stereochemistry at the centre adjacent to the primary amine is as shown in general formula 3. This is the S configuration when X2 is an oxygen atom or a methylene or imino group, and the R configuration when X2 is a sulphur atom. Within this embodiment, it is more preferred that R'should be a nitrile group, and more preferred still that it should have the absolute configuration depicted in general formula 4. In another preferred embodiment of the invention, m is 1. More preferably m is 1 and R2 and R3 are independently hydrogen atoms or methyl groups. When X2 is a methylene group, it is more preferred that R2 and R3 both be hydrogen. When X2 is an oxygen atom, it is more preferred that one of R2 and R3 be hydrogen and the other a methyl group.

When X2 is a sulphur atom, it is more preferred that both R2 and R3 be methyl groups.

In another preferred embodiment, X1 is either S or methylene. More preferably, X, is S and R'is H, or X'is methylene and R1 is CN.

In another preferred embodiment, X3 is NH. More preferably, X3 is NH, m is 1, R2 and R3 are both H, X2 is methylene and n is 1 or 2.

In another preferred embodiment, R4 is R8NHCO or R8CO and R8 is an optionally substituted heteroaryl group. More preferably, R8 is an unsubstituted heteroaryl group, or a heteroaryl group substituted with one or two groups chosen from lower alkyl, lower alkyloxy, fluoro, chloro and trifluoromethyl groups.

In another preferred embodiment, X3 is CO and R4 is R8NH. More preferably Ra is an optionally substituted heteroaryl group. More preferably still, R8 is an unsubstituted heteroaryl group, or a heteroaryl group substituted with one or two groups chosen from lower alkyl, lower alkyloxy, fluoro, chloro and trifluoromethyl groups.

In another preferred embodiment, X3 is NH and R4 is selected from R6R'N (CO), R8 (CH2) qCO and R8 (CH2) qSO2.

Particularly preferred compounds within the invention include : (2S)-1- [N#-(Pyrazinyl-2-carbgonyl)-L-ornithinyl]pyrrolidine-2-carbo nitrile, <BR> <BR> <BR> <BR> <BR> (2S)-1-[Ne-(Pyrazinyl-2-carbonyl)-L-lysinyl] pyrrolidine-2-carbonitrile,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (2S)-1-[(2'S)-2'-Amino-4'-(pyrazinyl-2"-carbonylåmino) butanoyl] pyrrolidine-2-carbonitrile, (4R)-3- [Nw- (Pyrazinyl-2-carbonyl)-L-lysinyl] thiazolidine-4-carbonitrile, <BR> <BR> <BR> <BR> <BR> (2S)-1-[N#-(Pyridyl-3-methyl)-L-glutaminyl]pyrrolidine-2-car bonitrile,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 1- [N°'- (Pyrazinyl-2-carbonyl)-L-ornithinyl] pyrrolidine, (2S)-1-[S-(Acetylaminomethyl)-L-cysteinyl]pyrrolidine-2-carb onitrile, 3- thiazolidine, 1- (IV°'- (2-Chloropyridyl-3-carbonyl)-L-ornithinyl] pyrrolidine, and <BR> <BR> <BR> (2S)-1-[N#-(2-Chloropyridyl-3-carbonyl)-L-ornithinyl]pyrroli dine-2-carbonitrile<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- [Nw- (Pyrazinyl-2-carbonyl)-L-ornithinyl] thiazolidine,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3-[N#-(2-quinoxaloyl)-L-lysinyl]thiazolidine, 3- [IVm- (2-Quinoxaloyl)-L-ornithinyl] thiazolidine,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (2S)-1- [IV°'- (2-Quinoxaloyi)-L-ornithinyl] pyrrolidine-2-carbonitrile,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- [N'- (6-Methylpyrazinyl-2-carbonyl)-L-ornithinyl] thiazolidine,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3-[N#-(lsoquinoline-3-carbonyl)-L-ornithinyl]thiazolidine,&l t;BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- [lV°'- (6-Trifluoromethyinicotinoyl)-L-ornithinyl] thiazolidine,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (2S)-1-[(2'R)-3'-(Acetylaminomethylthio)-2'-amino-3'-methylb utanoyl] pyrrolidine-2- carbonitrile, <BR> <BR> <BR> <BR> <BR> <BR> <BR> (2S)-1-[S-(3-Picolylcarbamoylmethyl)-L-cysteinyl] pyrrolidine-2-carbonitrile,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- [AW- (3-Pyridyloxycarbonyl)-L-ornithinyl] thiazolidine, 3- [0- (3-Chlorobenzylcarbamoyl) serinyl] thiazolidine, and <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- [ (2'S)-2'-Amino-5'-oxo-5'- (1'", 2", 3", 4"-tetrahydroisoquinolin-2"-yl) pentanoyl] thiazolidine.

In a second aspect, the present invention comprises a pharmaceutical composition for human therapeutic use. The composition is characterised in that it has, as an active agent, at least one of the compounds described above. Such a composition is useful in the treatment of human diseases. The composition will generally include one or more additional components selected from pharmaceutically acceptable excipients and pharmaceutically active agents other than those of the present invention.

The composition may be presented as a solid or liquid formulation, depending on the intended route of administration. Examples of solid formulations include pills, tablets, capsules and powders for oral administration, suppositories for rectal or vaginal administration, powders for nasal or pulmonary administration, and patches for transdermal or transmucosal (such as buccal) administration. Examples of liquid formulations include solutions and suspensions for intravenous, subcutaneous or intramuscular injection and oral, nasal or pulmonary administration. A particularly preferred presentation is a tablet for oral administration. Another preferred presentation, particularly for emergency and critical care, is a sterile solution for intravenous injection.

The composition comprises at least one compound according to the preceding description. The composition may contain more than one such compound, but in general it is preferred that it should comprise only one. The amount of the compound used in the composition will be such that the total daily dose of the active agent can be administered in one to four convenient dose units. For example, the composition can be a tablet containing an amount of compound equal to the total daily dose necessary, said tablet to be taken once per day. Alternatively, the tablet can contain half (or one third, or one quarter) of the daily dose, to be taken twice (or three or four times) per day. Such a tablet can also be scored to facilitate divided dosing, so that, for example, a tablet comprising a full daily dose can be broken into half and administered in two portions. Preferably, a tablet or other unit dosage form will contain between 0. 1mg and 1g of active compound. More preferably, it will contain between 1 mg and 250mg.

The composition will generally include one or more excipients selected from those that are recognised as being pharmaceutical acceptable. Suitable excipients include, but are not limited to, bulking agents, binding agents, diluents, solvents, preservatives and flavouring agents. Agents that modify the release characteristics of the composition, such as polymers that selectively dissolve in the intestine ("enteric coatings") are also considered in the context of the present invention, to be suitable excipients.

The composition may comprise, in addition to the compound of the invention, a second pharmaceutical active agent. For example, the composition may include an anti-diabetic agent, a growth-promoting agent, an anti-inflammatory agent or an antiviral agent.

However, it is generally preferred that the composition comprise only one active agent.

In a third aspect, the invention comprises a use for the compounds and compositions described above for the treatment of human diseases. This aspect can equally be considered to comprise a method of treatment for such diseases. The diseases susceptible to treatment are those wherein an inhibition of DP-IV or CD26 results in a clinical benefit either directly or indirectly. Direct effects include the blockade of T lymphocyte activation. Indirect effects include the potentiation of peptide hormone activity by preventing the degradation of these hormones. Examples of diseases include, but are not limited to, auto-immune and inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, growth hormone deficiency leading to short stature, polycystic ovary syndrome, impaired glucose tolerance and type 2 diabetes. Particularly preferred is the use of the compounds and compositions for the treatment of impaired glucose tolerance and type 2 diabetes, and equally a method of treatment of these diseases by the administration of an effective amount of a compound or composition as previously described.

The precise details of the treatment, including the dosing regimen, will be established by the attending physician taking into account the general profile of the patient and the severity of the disease. For diseases such as inflammatory bowel disease that have acute phases of active disease separated by quiescent periods, the physician may select a relatively high dose during the acute phase and a lower maintenance dose for the quiescent period. For chronic diseases such as type 2 diabetes and impaired glucose tolerance, the dosing may need to be maintained at the same level for an extended period.

A dosing schedule of one to four tablets per day, each comprising between 0. 1mg and 1g (and preferably between 1mg and 250mg) of active compound might be typical in such a case.

The compounds according to the invention can be prepared by methods known in the art.

The route chosen will depend on the particular nature of the substituents present in the target molecule. In the following general description the synthetic route is outlined for compounds wherein m is 1. Compounds with m = 2 or 3 can generally be prepared by analogous routes.

The starting material will usually be an a. co-diamino acid derivative 5 or an amino dicarboxylic acid derivative 6.

PG1 and pG2 are"orthogonal"protecting groups-groups that mask the reactivity of the amine groups and that can each be selectively removed in the presence of the other.

Suitable groups are well known in the literature. PG3 and PG4 are protecting groups for carboxylic acids. They are chosen such that they are orthogonal to each other and to the amino protecting groups. Suitable possibilities for PG3 and PG4 are also well known in the literature. Derivatives of diamino acids according to general formula 5 and derivatives of amino dicarboxylic acids according to general formula 6 are either items of commerce, or can be prepared following methods described in the literature. In practice, and depending on the strategy chosen, the starting material will have only two of the three protecting groups present. Either PG3 will be absent to allow the pyrrolidine (or thiazolidine or oxazolidine) residue to be introduced, or PG'or PG4 will be absent to allow the side chain to be elaborated.

Scheme A illustrates the introduction of the pyrrolidine (or thiazolidine or oxazolidine) group as the first step in the preparation of the compounds of the invention.

Scheme A Compounds SA and 6A correspond to 5 and 6 with PG3 as a hydrogen atom (i. e. without the protecting group). The free carboxylic acid can be reacted with a pyrrolidine derivative 7 to give the amide 8 or 9. Reaction conditions for achieving this transformation are well known in the literature. Suitable reagents include carbodiimides, phosphorus reagents and alkyl chloroformates, and the reaction is usually catalysed by a tertiary amine such as triethylamine or dimethylaminopyridine.

The reaction depicted in Scheme A is available for all combinations of R'and X'.

However, for the case where R'is a nitrile group, or where Xr is a sulphinyl or sulphonyl group, it may be advantageous to modify the strategy as depicted in Schemes B and C.

Scheme B Scheme C In Scheme B, the R'group is introduced as a primary amide and subsequently transformed into a nitrile by the action of a dehydrating agent such as trifluoroacetic anhydride. In Scheme C, the X group is introduced as a thioether and subsequently transformed into a sulphoxide (a=1) or sulphone (a=2) by the action of an oxidant such as sodium periodate. The modification to the strategy afforded by Scheme C is not possible if X2 is a sulphur atom.

Scheme D 15 16 In Scheme D, compound 5° is the diamino acid derivative 5 where the-protecting group is a hydrogen atom. The free amine group reacts readily with sulphonyl chlorides, acyl chlorides and thioacyl chlorides, usually in the presence of a tertiary amine, to produce sulphonamides 14, amides 15 and thioamides 16 respectively. The reagents are generally either available per se, or can be prepared from the corresponding acids. The reaction of scheme D is generally applicable to all the variations of the group RII (CH2) q, with the proviso that certain of the substituents contemplated for the phenyl and heteroaryl rings which are options for Ra may require protection. Such substituents and the appropriate protection will generally be obvious to those familiar with the art.

Scheme E 21 22 Reagents : i) COC12 ; ii) CSCl2 ; iii) R8 (CH2) qOH ; iv) R6R7NH ; v) R8 (CH2) qOCOCI ; vi) R8 (CH2) qOCSCI ; vii) R6R7NCOCI ; viii) R6R7NCSCI.

Scheme E illustrates the elaboration of 5° to give carbamates and ureas, and their thio analogues. When R5 is other than a hydrogen atom, compound 5° can be converted to the corresponding carbamoyl chloride 17 or thiocarbamoyl chloride 18 by reaction with phosgene or thiophosgene. Other reagents are known in the art to be functionally equivalent to these toxic reagents and they may also be used. When R5 is hydrogen, the intermediate formed is an isocyanate or isothiocyanate, but this behaves functionally as an equivalent of the corresponding chloride. Intermediates 17 and 18 are not normally isolated, but are treated directly with alcohols to give carbamates 19 and thiocarbamates 20. Treatment of these same intermediates with amines leads to the formation of ureas 21 and thioureas 22. Alternatively, 5° may be reacted directly with a chloroformate or chlorothioformate to give the carbamate or thiocarbamate, or, when neither R6 nor R7 is hydrogen, with a chloroformamide or chlorothioformamide to give the urea or thiourea.

When R6 or R7 is a hydrogen atom the chloroformamide or chlorothioformamide will tend to be unstable, in which case the isocyanate (e. g. R6-NCO) or isothiocyanate (e. g. R6-NCS) is used. As discussed previously for Scheme D, certain substituents within the embodiments of R8 may require appropriate protection.

Scheme F R6 1 HOO pG2 R6R7NH R7, N PG2 (cl,), 1 3w 1 (C) NH ' 12 12 2 2 2-3 2y-3 R2 R3 O R2 Ra O 6F 23 6 23 /MeO OMe MeO Ss ß S PvSsPvs Y I S'S S C. NH (Lawesson's reagent) 12 R'R' R R 0 24 Scheme F illustrates the elaboration of the side chain of the amino dicarboxylic acid series.

The-deprotected acid 6F can be reacted under a variety of conditions with an amine to give amide 23. The condensation may be promoted by a dehydrating reagent such as a carbodiimide or a phosphorus reagent. Alternatively the acid may be converted into a more reactive derivative, such as by treatment with oxalyl chloride or thionyl chloride to give the corresponding acid chloride, which will react directly with an amine. The thioamide 24 may be obtained by treating the amide 23 with Lawesson's reagent. When all the groups have been elaborated the final protecting group is removed and the product is isolated and purified using standard techniques.

These general methods are further illustrated in the following, non limiting examples.

EXAMPLES Abbreviations The following abbreviations have been used.

DMF N, N-Dimethyformamide h Hour (s) hpic High pressure liquid chromatography min Minute (s) pet. ether Petroleum ether fraction boiling at 60-80°C PyBOP (Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate PyBroPe Bromotripyrrolidinophosphonium hexafluorophosphate TFA Trifluoroacetic acid EXAMPLE 1 (2S)-(Pyrazinyl-2-carbonyl)-L-ornithinyl] pyrrolidine-2-carbonitrile trifluoroacetate A. N- (2-Nitrobenzenesulphenyl)-L-proline L-Proline (25g, 217mmol) was dissolved in 2M NaOH (110mL, 220mol) and dioxan (120mL). A solution of 2-nitrobenzenesulphenyl chioride (42g, 222mmof) in dioxan (60mL) was slowly added at the same time as 2M NaOH (110mL, 220mmol). After 2h at room temperature the reaction mixture was poured into water (500mL) and the solid filtered off. The pH of the filtrate was adjusted to pH3 with 2M HO and the solution was extracted with ethyl acetate (3 x 500mL). The combined organic extracts were washed with water (4 x 200mL) and brine (1 x 200mL), dried (Na2SO4) and evaporated in vacuo to give an orange solid identified as N- (2-nitrobenzenesulphenyl)-L-proline (58. 1g, 217mmol, 100%).

B. N- (2-Nitrobenzenesulphenyl)-L-proline succinimidyl ester N- (2-Nitrobenzenesulphenyl)-L-proline (57. 9g, 216mol) was dissolved in CH2CI2/DMF (9 : 1, 500mL). N-Hydroxysuccinimide (37. 3g, 324mol) and water-soluble carbodiimide (51. 8g, 260mol) were added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (1000mL). The solution was washed with water (4 x 200mL) and brine (1 x 200mL), dried (Na2SO4) and evaporated in vacuo to give a yellow solid identified as N (2-nitrobenzenesulphenyl)-L-proline succinimidyl ester (78. 9g, 216mol, 100%).

C. N- (2-Nitrobenzenesulphenyl)-L-prolinamide N- (2-Nitrobenzenesulphenyl)-L-proline succinimidyl ester (78. 5g, 215mmol) was dissolved in dioxan (500mL). Ammonia (35%, 100mL) was added. After stirring at room temperature for 2h the reaction mixture was poured into water (700mL). The precipitate was filtered off, washed with water (200rriL), dried over P205 and recrystallised from ethyl acetate/pet ether to give a yellow solid identified as N- (2-nitrobenzenesulphenyl)-L- prolinamide (49. 6g, 185mmol, 86%).

D. (2S)-N- (2-Nitrobenzenesulphenyl) pyrrolidine-2-carbonitrile N- (2-Nitrobenzenesulphenyl)-L-prolinamide (49g, 183mmol) was dissolved in dry THF (300mL). The solution was cooled to 0°C, triethylamine (36. 7g, 367mol) was added followed by the slow addition of trifluoroacetic anhydride (77g, 367mol). The pH was adjusted to pH9 with triethylamine. After 30min the reaction mixture was diluted with ethyl acetate (500mL), washed with water (1 x 200mL) and brine (1 x 200mL), dried (Na2SO4) and evaporated in vacuo to give an orange oil which was purified by flash chromatography (eluant : 80% pet ether, 20% ethyl acetate) to give a yellow solid identified as (2S)-N- (2- nitrobenzenesulphenyl) pyrrolidine-2-carbonitrile (38. 9g, 150mol, 82%).

E. (2S)-Pyrrolidine-2-carbonitrile hydrochloride (2S)-N- (2-Nitrobenzenesulphenyl) pyrrolidine-2-carbonitrile (38. 5g, 149mmol) was dissolved in diethyl ether (200mL). 4M HCI/Dioxan (150mL, 600mmol) was slowly added.

After 2h at room temperature the reaction mixture was poured into diethyl ether (1000mL).

The solid was filtered off, washed with diethyl ether (500mL) and recrystallised from methanol/diethyl ether to give a white solid identified as (2S)-pyrrolidine-2-carbonitrile hydrochloride (18. 9g, 142. 5mmol, 96%).

F. (2S)-1-[Nα-(tert-Butyloxycarbonyl)-N#-(pyrazinyl-2-carbonyl )-L-ornithinyl]- pyrrotidine-2-carbonitrile.

Nα-(tert-Butyloxycarbonyl)-N#-(pyraziny-2-carbonyl)-L-or nithine (2. 5g, 7. 4mmol) was dissolved in CH2CI2 (50mL). This solution was cooled to 0°C, (2S)-pyrrolidine-2- carbonitrile hydrochloride (1. 2g, 9. 1mmol) and PyBOP# (4. 3g, 8. 23mmol) were added, and the pH adjusted to pH9 with triethylamine.'After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200mL). This solution was washed with 0. 3M KHS04 (2 x 50mL), sat. NaHCO3 (2 x 50mL), water (2 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil.

This was purified by flash chromatography (eluant : 80% ethyl acetate, 20% pet. ether) to give a colourless oil identified as (2S)-1-[Nα-(tert-butyloxycarbonyl)-N#-(pyrazinyl-2- carbonyl)-L-ornithinyl] pyrrolidine-2-carbonitrile (2. 98g, 7. 16mmol, 97%).

G. (2S)-1- » (pyrazinyl-2-carbonyl)-L-ornithinylipyrrolidine-2-carbonitri le trifluoroacetate (2S)-1- pyrrolidine-2- carbonitrile (2. 8g, 6. 7mmol) was dissolved in trifluoroacetic acid (5mL). After 1h at room temperature the solvent was removed in vacuo. The residue was purified by preparative hplc (Vydac C18, 5 to 50% 0. 15 TFA/acetonitrile into 0. 1% TFA/water over 40min at 3mL/min). Fractions containing the product were lyophilised to give a colourless oil identified as (2S)-1-[NO-(pyrazinyl-2-carbonyl)-L-ornithinylgpyrrolidine-2 -carbonitrile trifluoroacetate (1. 5g, 3. 48mmol, 52%).

[M+H] + = 317. 3 EXAMPLE 2 (2S)-1- s (Pyrazinyl-2-carbonyl)-L-lysinyl] pyrrolidine-2-carbonitrile trifluoroacetate A. (Nα-(tert-Butyloxycarbonhyl)-N#-9-fluorenylmethyloxycarbony l)-L-lysinyl)-L- prolinamide W- (tert-Butyloxycarbonyl)-W- (9-fluorenylmethyloxycarbonyl)-L-lysine (5g, 10. 7mmol) was dissolved in CH2CI2 (1. OOmL). The solution was cooled to O°C, L-prolinamide (1. 78g, 11. 7mmol) and PYBOPO (6. 7g, 12. 8mmol) were added, and the pH adjusted to pH9 with triethylamine. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200mL). The solution was washed with 0. 3M KHS04 (2 x 50mL), sat. NaHCO3 (2 x 50mL), water (2 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (Nα-(tert-butyloxycarbonyl)-N#-(9-fluorenylmethyloxycarbony l)-L-lysinyl)-L-prolinamide (4. 05g, 7. 2mmol, 67%).

B. (2S)-'i- (Nα-(tert-Butyloxycarbonyl)-N#-(9-fluorenylmethyloxycarbony l)-L-lysinyl)- pyrrolidine-2-carbonitrile<BR> (AF- (tert-Butyloxycarbonyl)-/\r- (9-fluorenyimethyloxycarbonyl)-L-lysinyl)-L-prolinamide (3. 95g, 7. 02mmol) was dissolved in dry THF (100mL). The solution was cooled to 0°C, triethylamine (1. 4g, 14mmol) was added followed by the slow addition of trifluoroacetic anhydride (2. 97g, 14. 1mmol). The pH was adjusted to pH9 with triethylamine. After 30min the reaction mixture was diluted with ethyl acetate (100mL), washed with water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give an orange oil. The residue was purified by flash chromatography (eluant : 60% pet ether, 40% ethyl acetate) to give a colourless oil identified as (2S)-1- (Nα-(tert-butyloxycarbonyl)-N#-(9- fluorenylmethyloxycarbonyl)-L-lysinyl) pyrrolidine-2-carbonitrile (3. 3g, 6. 11mmol, 87%).

C. (2S)-1-(Nα-tert-Butyloxycarbonyl)-L-lysinyl)pyrrolidine-2-c arbonitrile <BR> <BR> <BR> (2S)-l- (N- (tert-Butyloxycarbonyl)-A/- (9-fluorenylmethyloxycarbonyl)-L-lysinyl) pyrrolidine- 2-carbonitrile (3. 1g, 5. 7mmol) was dissolved in THF (80mL). Diethylamine (20mL) was added. After 2h at room temperature the solvent was removed in vacuo. The residue was purified by flash chromatography (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a colourless oil identified as (2S)-1-(N-(tert-butyloxyearbonyl)-L- lysinyl) pyrrolidine-2-carbonitrile (1. 63g, 5. 03mmol, 89%). <BR> <BR> <BR> <BR> <BR> <BR> <P>D. (2S)-1-(Nα-(tert-Butyloxycarbonyl)-N#-(pyrazinyl-2-carbonyl )-L-lysinyl)pyrrolidine- 2-carbonitrile (2S)-1- (tert-Butyloxycarbonyl)-L-lysinyl) pyrrolidine-2-carbonitrile (100mg, 0. 31mmol) was dissolved in CH2CI2/DMF (9 : 1, 20mL). To this solution at 0°C was added 1-hydroxybenzotriazole hydrate (84mg, 0. 62mol), water-soluble carbodiimide (76mg, 0. 38mmol), 2-pyrazinecarboxylic acid (43mg, 0. 35mmol) and triethylamine (65mg, 0. 65mol). After 18 h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). This solution was washed with 0. 3M KHS04 (2 x 20mL), sat. NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (2S)--(tert-butyloxyCarbonyl)-NO-(pyrazinyl-2-carbonyl)-L-ly sinyl) pyrrolidine-2- carbonitrile (124mg, 0. 29mmol, 93%).

E. (2S)-1- [IV°'- (Pyrazinyl-2-carbonyl)-L-lysinyl] pyrrolidine-2-carbonitrile trifluoroacetate (2S)-1- (Nα-(tert-Butyloxycarbonyl)-N#-(pyrazinyl-2-carbonyl)-L-lys inyl)pyrrolidine-2- carbonitrile (110mg, 0. 26mmol) was dissolved in trifluoroacetic acid (5mL). After 1h at room temperature the solvent was removed in vacuo. The residue was purified by preparative hplc (Vydac C18, 5 to 50% 0. 1% TFA/acetonitrile into 0. 1% TFA/water over 40min at 3mL/min). Fractions containing the product were lyophilised to give a colourless oil identified as (2S)-l- [Ar- (pyrazinyl-2-carbonyl)-L-lysinyl] pyrrolidine-2-carbonitrile trifluoroacetate (66mg).

[M+H] + = 331. 1 EXAMPLE 3 (4R)-3-lNe-(Pyrazinyl-2-carbonyl)-L-lysinyl] thiazolidine-4-carbonitrile trifluoroacetate A. (4R)-3- (tert-Butyloxycarbonyl) thiazolidine-4-carboxamide (4R)-3- (tert-Butyloxycarbonyl) thiazolidine-4-carboxylic acid (12. 5g, 54. 1mmol) was dissolved in CH2CI2/DMF (9 : 1, 150mL). To this solution at 0°C was added 1-hydroxybenzotriazole hydrate (14. 6g, 108mol) and water-soluble carbodiimide (13. 0g, 65mol). After 1h at 0°C ammonia (35%, 50mL) was added. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (500mL). The solution was washed with 0. 3M KHS04 (2 x 100mL), sat. NaHCO3 (2 x 100mL), water (2 x 100mL) and brine (1 x 100mL), dried (Na2S04) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (4R)-3-(teff- butyloxycarbonyl) thiazolidine-4-carboxamide (8. 9g, 38. 4mmol, 71 %).

B. (4R)-Thiazolidine-4-carboxamide hydrochloride (4S)-3-(tert-Butyloxycarbonyl)thiazolidine-4-carboxamide (8. 6g, 37. 1mmol) was dissolved in 4M HCI/dioxan (50mL). After 1 h at room temperature the solvent was evaporated in vacuo to give a white solid identified as (4R)-thiazolidine-4-carboxamide hydrochloride (6. 2g, 36. 8mmol, 99%).

C. (4R)-3- [IW- (tert-Butyloxycarbonyl)-N- (9-fluorenylmethyloxycarbonyl)-L-lysinyl]- thiazoiidine-4-carboxamide Nα-(tert-Butyloxycarbonyl)-N#-(9-fluorenylmethyloxycarbonyl )-L-lysine (5g, 10.7mmol) was dissolved in CH2CI2 (100mL). This solution was cooled to 0°C, (4R)-thiazolidine-4- carboxamide hydrochloride (1. 78g, 11. 7mmol) and PyBOP# (6. 7g, 12. 8mmol) were added, and the pH was adjusted to pH9 with triethylamine. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200mL).

The solution was washed with 0. 3M KHS04 (2 x 50mL), sat. NaHCO3 (2 x 50mL), water (2 x 50mL) and brine (1 x 50mL), dried (Na2S04) and evaporated in vacuo to give a yellow oil.

The residue was purified by flash chromatography (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (4R)-3-[Nα-(tert-butyloxycarbonyl)-N#-(9-fluorenyl) methyloxycarbonyl)-L-lysinyl] thiazolidine-4-carboxamide (2.. 81g, 4. 8mmol, 44%).

D. (4R)-3- [Nα-(tert-Butyloxycarbonyl)-N#-(9-fluorenylmethyloxycarbony l)-L-lysinyl]- <BR> <BR> <BR> thiazolidine-4-carbonitrile<BR> <BR> <BR> <BR> <BR> <BR> (4R)-3- [IW- (terf-Butyloxycarbonyl)-IV°- (9-fluorenylmethyloxycarbonyl)-L-lysinyl] thiazolidine- 4-carboxamide (2. 7g, 4. 7mmol) was dissolved in dry THF (100mL). The solution was cooled to 0°C, triethylamine (1. 0g, 10mmol) was added followed by the slow addition of trifluoroacetic anhydride (2. 0g, 9. 5mmol). The pH was adjusted to pH9 with triethylamine.

After 30min the reaction mixture was diluted with ethyl acetate (100mL), washed with water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 60% pet ether, 40% ethyl acetate) to give a colourless oil identified as (4R)-3-[Nα-(tert-butyloxycarbonyl)-N#-(9-fluorenylmethyl- oxycarbonyl)-L-lysinyl] thiazolidine-4-carbonitrile (2. 14g, 3. 81 mmol, 82%).

E. (4R)-3- «-(tert-Butloxycarbonyl) L-lysinylithiazolidine 4-carbonitrile <BR> <BR> <BR> <BR> (4R)-3-[Nα-(tert-Butyloxycarbonyl)-N#-(9-fluorenylmethyloxy carbonyl)-L-lysinyl]thiazolidine- 4-carbonitrile (1. 9g, 3. 4mmol) was dissolved in THF (40mL). Diethylamine (10mL) was added. After 2h at room temperature the solvent was removed in vacuo. The residue was purified by flash chromatography (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a colourless oil identified as (4R)-3-[Nα-(tert-butyloxycarbonyl)-L- lysinyl] thiazolidine-4-carbonitrile (863mg, 2. 5mmol, 75%).

F. (4R)-3-(tert-But iloxywarbonyl)" (pyrazinyl-2-carbonyl)-L-lysinylithiazolidine- 4-carbonitrile (4R)-3-[Nα-(tert-Butyloxycarbonyl)-L-lysinyl]thiazolidine-4 -carbonitrile (100mg, 0. 29mmol) was dissolved in CH2CI2 (20mL). To this solution at 0°C 2-pyrazinecarboxylic acid (43mg, 0. 35mmol) and PyBOP# (170mg, 0. 33mmol) were added and the pH was adjusted to pH9 with triethylamine. After 18 h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0. 3M KHS04 (2 x 20mL), sat. NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (4R)-3- [N"- (tert-butyloxycarbonyl)-A'- (pyrazinyl-2-carbonyl)-L-lysinyl] thiazolidine-4- carbonitrile (112mg, 0. 25mmol, 86%).

G. (4R)-3-lNe-(Pyrazinyl-2-carbonyl)-L-lysinyl] thiazoíidine-4-carbonitrile trifluoroacetate (4R)-3-[Nα-(tert-Butyloxycarbonyl)-N#-(pyrazinyl-2-carbonyl )-L-lysinyl]thiazolidine-4- carbonitrile (110mg, 0. 26mmol) was dissolved in trifluoroacetic acid (5mL). After 1h at room temperature the solvent was removed in vacuo. The residue was purified by preparative hplc (Vydac C18, 5 to 50% 0. 1% TFA/acetonitriie into 0. 1% TFA/water over 40min at 3mUmin). Fractions containing the product were lyophilised to give a colourless oil identified as (4R)-3- [N'- (pyrazinyl-2-carbonyl)-L-lysinyl] thiazolidine-4-carbonitrile trifluoroacetate (57mg).

[M+H]"* = 349.

EXAMPLE 4 <BR> <BR> (2S}-(Pyridyl-3-methyl)-L-glutaminylipyrrolidine-2-carbonitr ile dihydrochloride A. (2S)-1-[N-(tert-Butyloxycarbonyl)-O#-methyl-L-glutamyl]pyrro lidine-2-carbonitrile N-(teff-Butyloxycarbonyl)-O@-methyl-L-glutamic acid (1. 0g, 3. 83mmol) was dissolved in CH2CI2/DMF (9 : 1, 20mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (788mg, 5. 84mmol), water-soluble carbodiimide (877mg, 4. 38mmol), (2S)- pyrrolidine-2-carbonitrile hydrochloride (609mg, 4. 6mmol) and triethylamine (65mg, 0. 65mol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL), this solution was washed with 0. 3M KHS04 (2 x 20mL), sat. NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Nå2SO4) and evaporated in vacuo. The residue was purified by flash chromatography.

(eluant : 50% ethyl acetate, 50% pet. ether) to give a brown oil identified as (2S)-1-[N-(teff- butylOxyCarbonyl)-ON-methyl-L-glutamyl] pyrrolidine-2-carbonitrile (290mg, 0. 86mmol, 22%).

B. (2S)-1- [N- (tert-Butyloxycarbonyl)-L-glutamyl] pyrrolidine-2-carbonitrile (2S)-1- [N-(tert-Butyloxycarbonyl)-D°'-methyl-L-glutamyl] pyrrolidine-2-carbonitrile (250mg, 0. 74mmol) was dissolved in dioxan (5mL). 1M Lithium hydroxide (1. 1 mL, 1. 1mmol) was added. After 1h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). This solution was washed with 1 M KHSO4 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as (2S)-1-[N-(tert-butyloxycarbonyl)-L-glutamyl] pyrrolidine-2- carbonitrile (200mg, 0. 61 mmol, 83%).

C. (2S)-1- [Nα-(tert-Butyloxycarbonyl)-N#-(pyridyl-3-methyl)-L-glutami nyl]pyrrolidine- 2-carbonitrile (2S)-1- [N-(tert-Butyloxycarbonyl)-L-glutamyl] pyrrolidine-2-carbonitrile (30mg, 0. 093mmol) was dissolved in CH2CI2/DMF (9 : 1, 10mL). To this solution at 0°C was added 1-hydroxy- benzotriazole hydrate (21mg, 0. 16mol), water-soluble carbodiimide (21mg, 0. 105mmol), 3- (aminomethyl) pyridine (11mg, 0.1mmol) and triethylamine (20mg, 0. 2mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0. 3M KHS04 (2 x 20mL), sat.

NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (NaSO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (eluant : 5% methano, 97% chloroform) to give a colourless oil identified as (2S)-1-[Nα-(tert-butyloxycarbonyl)-N#-(pyridyl-3-methyl)-L- glutaminyl]pyrrolidine-2- carbonitrile (16. 6mg, 0. 04mmol, 44%).

D. (2S)-1-w-{Pyridyl-3-methyl)-L-glutaminylipyrrolidine-2-carbo nitrile dihydrochloride (2S)-1- [°- (tert-Butyloxycarbonyl)-N°'- (pyridyl-3-methyl)-L-glutaminyl] pyrrolidine-2- carbonitrile (17mg, 0. 04mmol) was dissolved in 4M HCl/dioxan (5mL). After 1h at room temperature the solvent was removed in vacuo to give a white solid identified as (2S)-1- [I\P-(pyridyl-3-methyl)-L-glutaminyl] pyrrolidine-2-carbonitrile dihydrochloride (17mg, 0. 04mmol, 100%).

[M+H]+ = 3.16. 2 EXAMPLE 5 1- [N- (Pyrazinyl-2-carbonyl)-L-ornithinyl] pyrrolidine trifluoroacetate A. 1-[N#-(Benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-orni thinyl]pyrrolidine N#-(Benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-ornithi ne (5. 49g, 15mmol) was dissolved in CH2CI2/DMF (9 : 1, 100mL). To this solution at 0°C was added 1-hydroxybenzotriazole hydrate (3. 37g, 22mmol), water-soluble carbodiimide (3. 46g, 18mmol), pyrrolidine (1. 28g, 18mmol) and triethylamine (200mg, 20mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200mL). The solution was washed with 0. 3M KHS04 (2 x 50mL), sat.

NaHCO3 (2 x 50mL), water (2 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 90% ethyl acetate, 10% pet. ether) to give a colour (ess oil identified as 1-je- (benzyloxycarbonyl)-N (tert-butyloxycarbonyl)-L-ornithinyl] pyrrolidine (5. 15g, 12. 3mmol, 82%).

B. 1- [Nα-(tert-Butyloxycarbonyl)-L-ornuithinyl]pyrrolidine <BR> <BR> <BR> <BR> 1- [I\r- (Benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-ornithinyl ]pyrrolidine (2.15g, 5. 13mmol) was dissolved in methanol (80mL). This solution was hydrogenated over 10% Pd/C (400mg). After 2h the catalyst was filtered off and washed with methanol (50mL).

The combined filtrates were evaporated in vacuo to give an off white solid identified as 1- [N°- (tert-butyloxycarbonyl)-L-ornithinyl] pyrrolidine (1. 35g, 4. 74mmol, 94%).

C. 1- [N- (tert-Butyloxycarbonyl)-N- (pyrazinyl-2-carbonyl)-L-ornithinyl] pyrrolidine 1-[Nα-(tert-Butyloxycarbonyl)-L-ornithinyl]pyrrolidine (100mg, 0. 35mmol) was dissolved in CH2CI2 (20mL). To this solution at 0°C were added PyBroPe (195mg, 0. 4mmol), 2- pyrazinecarboxylic acid (50mg, 0. 4mmol) and triethylamine (100mg, 1. Ommol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0. 3M KHS04 (2 x 20mL), sat.

NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 3% methanol, 97% chloroform) to give a sticky white solid identified as 1-[N-(tert- <BR> <BR> <BR> <BR> butyloxycarbonyl)-lW- (pyrazinyl-2-carbonyl)-L-ornithinyl] pyrrolidine (90mg, 0. 25mmol, 66%).

D. 1-[N#-(Pyrazinyl-2-carbonyl)-L-ornithinyl]pyrrolidine trifluroacetate <BR> <BR> <BR> <BR> 1- [N"- (tert-Butyloxycarbonyl)-11W- (pyrazinyl-2-carbonyl)-L-ornithinyl] pyrrolidine (90mg, 0. 23mmol) was dissolved in 4M HCI/dioxan (15mL). After 45min at room temperature the solvent was removed in vacuo. The residue was purified by preparative hplc (Vydac C18, 5 to 50% 0. 1% TFA/acetonitrile into 0. 1% TFA/water over 40min at 3mL/min). Fractions containing the product were lyophilised to give a colourless oil identified as 1- [Ar- (pyrazinyl-2-carbonyl)-L-ornithinyl] pyrrolidine trifluoroacetate (51 mg).

[M+H] + = 292. 1 EXAMPLE 6 3-lN'D-(Pyrazinyl-2-carbonyl)-L-ornithinylithiazolidine trifluoroacetate A. 3- [W- (tert-Butyloxycarbonyl)-N- (9-fluorenylmethyloxycarbonyl)-L- ornithinyqthiazolidine N (tert-Butyloxycarbonyl)-N#-(9-fluroentylmethloxycarbonyl)-L- ornithine (2. 73g, 6mmol) was dissolved in CHsCtz/DMF (9 : 1, 100mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (1. 53g, 10mmol), water-soluble carbodiimide (1. 34g, 7mmol), thiazolidine (1. 28g, 18mmol) and triethylamine (80mg, 8mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0. 3M KHS04 (2 x 25mL), sat.

NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 3-[Nα-(tert- butyloxycarbonyl)-N-fluorenylmethyloxycarbonyl)-L-ornithinyl ] thiazolidine (2. 55g, 4. 85mmol, 81%).

B. 3- (teff-Butyloxycarbonyl) ^L-ornithinylithiazolidine 3- [N"- (tert-Butyloxycarbonyl)-AJ- (9-fluorenylmethyloxycarbonyl)-L-ornithinyl] thiazolidine (1. 15g, 2. 13mmol) was dissolved in acetonitrile (20mL). Diethylamine (5mL) was added.

After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 3- [N- (tert-butyloxycarbonyl)-L-ornithinyl] thiazolidine (530mg, 1. 67mmol, 78%).

C. 3- [W- (tert-Butyloxycarbonyl)-Ar- (pyrazinyl-2-carbonyl)-L-ornithinyl] thiazolidine 3- [N = (tert-Butyloxycarbonyl)-L-omithinyl] thiazolidine (80mg, 0. 27mmol) was dissolved in CH2CI2 (20mL). To this solution at 0°C were added PyBroPe (146mg, 0. 3mmol), 2-pyrazinecarboxylic acid (37mg, 0. 3mmol) and triethylamine (90mg, 0. 9mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0. 3M KHS04 (2 x 20mL), sat.

NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 3% methanol, 97% chloroform) to give a sticky white solid identified as 3-[N-(teff- butylOxyzarbonyl)-Ne-(pyrazinyl-2-carbonyl)-L-ornithinyl] thiazolidine (45mg, 0. 11mmol, 41%).

D. 3-[N#-(Pyrazinyl-2-carbonyl)-L-ornithinyl]thiazolidine trifluroacetate 3-[Nα-(tert-Butyloxycarbonyl)-N#-(pyraznyl-2-carbonyl)-L-or nithinyl]thiazolidine (45mg, 0. 11mmol) was dissolved in 4M HCI/dioxan (1 OmL). After 45min at room temperature the solvent was removed in vacuo. The residue was purified by preparative hpic (Vydac C18, 5 to 50% 0. 1% TFA/acetonitrile into 0. 1% TFA/water over 40min at 3mL/min). Fractions containing the product were lyophilised to give a colourless oil identified as 3-[N@- (pyrazinyl-2-carbonyl)-L-ornithinyl] thiazolidine trifluoroacetate (14mg).

[M+H] + = 310. 0 EXAMPLE 7 (2S)-1-lS-(Acetylaminomethyl) *L-cysteinylipyrrolidine-2-carbonitrile trifluoroacetate A. (2S)-1- [S- (Acetylaminomethyl)-N- (tert-butyloxycarbonyl)-L-cysteinyl] pyrrolidine-2- carbonitrile S-(Acetylaminomethyl)-N-(tert-butyloxycarbonyl)-L-cysteine (660mg, 2. 26mmol) was dissolved in CH2CI2 (30mL). To this solution at 0°C were added (2S)-pyrrolidine-2- carbonitrile hydrochloride (250mg, 1. 89mmol) and PyBOP# (1. 3g, 2. 49mmol), and the pH adjusted to pH9 with triethylamine. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150mL). The solution was washed with 0. 3M KHS04 (2 x 30mL), sat. NaHCO3 (2 x 30mL), water (2 x 30mL) and brine (1 x 30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 75% ethyl acetate, 25% pet. ether) to give a colourless oil identified as (2S)-1- [S- (acetylaminomethyl)-N-(tert-butyloxycarbonyl)-L-cysteinyl]- pyrrolidine-2-carbonitrile (650mg, 1. 76mmol, 78%).

B. {2S)-S-(Acetylaminomethyl)-L-cysteinylipyrrolidine-2-carboni trile trifluoroacetate (2S)-1-[S-(Acetylaminomethyl)-N-(tert-butyloxycarbonyl)-L-cy steinyl]pyrrolidine-2- carbonitrile (610mg, 1. 65mmol) was dissolved in trifluoroacetic acid (30mL). After 1h at room temperature the solvent was removed in vacuo to give a colourless oil identified as (2S)-1- [S- (acetylaminomethyl)-L-cysteinyl] pyrrolidine-2-carbonitrile trifluoroacetate (620mg, 1. 61mmol. 98%).

[M+H]+ = 271. 0 EXAMPLE 8 (2S)-1- [ (2'R)-3'-(Acetylaminomethylthio)-2'-amino-3'-methylbutanoyll pyrrolidine-2- carbonitrile trifluoroacetate A. (2S)-1- [ (2'R)-3'- (Acetylaminomethylthio)-2'- (tert-butyloxycarbonylamino)-3'- methylbutanoyllpyrrolidine-2-carbonitrile S- (Acetylaminomethyl)-N-(tert-butyloxycarbonyl) penicillamine (720mg, 2. 25mmol) was dissolved in CH2Cl2 (30mL). To this solution at 0°C were added (2S)-pyrrolidine-2- carbonitrile hydrochloride (270mg, 2. 04mmol) and PyBOP# (1. 3g, 2. 49mmol), and the pH adjusted to pH9 with triethylamine. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethy acetate (150mL). The solution was washed with 0. 3M KHS04 (2 x 30mL), sat. NaHCO3 (2 x 30mL), water (2 x 30mL) and brine (1 x 30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 75% ethyl acetate, 25% pet. ether) to give a colourless oil identified as (2S)-1-[(2'R)-3'-(acetylaminomethylthio)-2'-(tert-butylOxyca rbonylamino)-3'- methylbutanoyl] pyrrolidine-2-carbonitrile (742mg, 1. 86mmol, 83%).

B. (2S)-1-t (2'R)-3'-(Acetylaminomethylthio)-2'-amino-3'-methylbutanoyll pyrrolidine-2- carbonitrile trifluoroacetate (2S)-1-[(2'R)-3'-(Acetylaminomethylthio)-2'-(tert-butylOxywa rbonylamino)-3'-methyl- butanoyl] pyrrolidine-2-carbonitrile (710mg, 1. 78mmol) was dissolved in trifluoroacetic acid (30mL). After 1h at room temperature the solvent was removed in vacuo to give a colourless oil identified as (2S)-1-[(2'R)-3'-(acetylaminomethylthio)-2'-amino-3'-methyl- butanoyl] pyrrolidine-2-carbonitrile trifluoroacetate (560mg, 1. 36mmol, 76%).

[M+H] + = 299. 1 EXAMPLE 9 (2S)-1- pyrrolidine-2-carbonitrile trifluoroacetate A. (2S)-1-(NW-(tert-Butyloxywarbonyl)-L-ornithyl) pyrrolidine-2-carbonitrile (2S)-1- (N°- (tert-Butyloxycarbonyl)-L-ornithyl) pyrrolidine-2-carbonitrile was prepared by the method described for the lysine derivative in Example 2.

B. (2S)-1-(Ng-(tert-Butyloxywarbonyl)-N-(2-chloropyridyl-3-carb onyl)-L-ornithyl)- pyrrolidine-2-carbonitrile (2S)-1- (Nα-(tert-Butyloxycarbonyl)-L-ornithyl)pyrrolidine-2-carbon itrile (80mg, 0. 26mmol) was dissolved in CH2CI2 (20mL). To this solution was added 2-chloropyridine-3-carbonyl chloride (55mg, 0. 32mmol) and the pH adjusted to pH9 with triethylamine. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0. 3M KHS04 (2 x 20mL), sat. NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo.

The residue was purified by flash chromatography (eluant : 95% ethyl acetate, 5% pet. ether) to give a colourless oil identified as (2S)-1- (Nα-(tert-butyloxycarbonyl)-N#-(2- chloropyridyl-3-carbonyl)-L-ornithyl) pyrrolidine-2-carbonitrile (60mg, 0. 14mmol, 53%).

C. (2S)-1- « (2-Chloropyridyl-3-carbonyl)-L-ornithinyl] pyrrolidine-2-carbonitrile <BR> <BR> <BR> trifluoroacetate<BR> <BR> <BR> <BR> <BR> <BR> (2S)-1-[Nα-(tert-Butyloxycarbonyl)-N#-(2-chloropyridyl-3-ca rbonyl)-L-ornithinyl]pyrrolidine-2- carbonitrile (60mg, 0. 14mmol) was dissolved in trifluoroacetic acid (5mL). After 1h at room temperature the solvent was removed in vacuo. The residue was purified by preparative hpic (Vydac C18, 5 to 50% 0. 1% TFA/acetonitrile into 0. 1% TFA/water over 40min at 3mL/min). Fractions containing the product were lyophilised to give a white solid identified as (2S)-1- [N°- (2-chloropyridyl-3-carbonyl)-L-ornithinyl] pyrrolidine-2-carbonitrile trifluoroacetate (52mg).

[M+H] + = 350. 1 EXAMPLE 10 1- 2-Chloropyridyl-3-carbonyl)-L-ornithinylipyrrolidine hydrochloride A. 1- (N°- (tert-Butyloxycarbonyl)-N- (2-chloropyridyl-3-carbonyl)-L-ornithyl)- pyrrolidine 1-(Nα-(tert-Butyloxycarbonyl)-L-ornithyl)pyrrolidine (20mg, 0. 069mmol) was dissolved in CH2CI2 (5mL). To this solution was added 2-chloropyridine-3-carbonyl chloride (14mg, 0. 076mmol) and the pH adjusted to pH9 with triethylamine. After 1 h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL).

The solution was washed with 0. 3M KHS04 (2 x 20mL), sat. NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 10% methanol, 90% dichloromethane) to give a colourless oil identified as 1-(Na-(teff-butyloxycarbonyl)-N@-(2-chloropyridyl-3-carbonyl )-L- omithyl) pyrrolidine (19mg, 0. 045mmol, 63%).

B. 1- [W42-Chloropyridyl-3-carbonyl)-L-ornithinyllpyrrolidine hydrochloride 1-[Nα-(tert-Butyloxycarbonyl)-N#-(2-chloropyridyl-3-carbony l)-L-ornithinyl]pyrrolidine (19mg, 0. 045mmol) was dissolved in 4M HCI/dioxan (10mL). After 45min at room temperature the solvent was removed in vacuo to give a white solid identified as 1- [I\r- (2-chloropyridyl- 3-carbonyl)-L-ornithinyl]pyrrolidine hydrochloride (15mg).

[M+H] + = 325.

EXAMPLE 11<BR> 3- [N#-(2-Chloropyridyl-3-carbonyl)-L-ornithinyl]thiazolidine hydrochloride A. 3- (N°- (tert-Butyloxycarbonyl)-N"- (2-chloropyridyl-3-carbonyl)-L-ornithyl)- thiazolidine 3- (N"- (tert-Butyloxycarbonyl)-L-ornithyl) thiazolidine (136mg, 0. 45mmol) was dissolved in CH2CI2 (10mL). To this solution was added 2-chloropyridine-3-carbonyl chloride (88mg, 0. 5mmol) and the pH adjusted to pH9 with triethylamine. After 1h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL).

The solution was washed with 0. 3M KHS04 (2 x 20mL), sat. NaHCO3 (2 x 20mL), water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant : 1. 5% methanol, 98. 5% dichloromethane) to give a colourless oil identified as 3-(Nα-(tert-butyloxycarbonyl)-N#-(2-chloropyridyl-3-carbony l)- L-ornithyl) thiazolidine (30mg, 0. 068mol, 15%).

B. 3* (2-Chloropyridyl-3-carbonyl)-L-ornithinylithiazolidine hydrochloride 3-[Nα-(tert-Butyloxycarbonyl)-N#-(2-chloropyridyl-3-carbony l)-L-ornithinyl]thiazolidine (30mg, 0. 068mol) was dissolved in 4M HCl/dioxan (10mL). After 45min at room temperature the solvent was removed in vacuo to give a white solid identified as 1- [/V- (2- chloropyridyl-3-carbonyl)-L-ornithinyl] thiazolidine hydrochloride (25mg).

[M+H] + = 342.1 EXAMPLE 12 (2S)-1-[S-(3-PIcolylcarbamoylmethyl)-L-cysteinyl]pyrrolidine -2-carbonitrile trifluoroacetate A. S- (Benzyloxycarbonylmethyl)-N- (tert-butyloxycarbonyl)-L-cysteine N-(fert-Butyloxycarbonyl)-L-cysteine (3. 5g, 15. 8mmol), benzyl 2-bromoacetate (3. 7g, 16. 1mmol) and triethylamine (1. 8g, 18. Ommol) were dissolved in THF (100mL). After 18 hours at room temperature the reaction mixture was diluted with ethyl acetate (100mL), washed with 0. 3M KHS04, sat NaHCO3, water and brine, dried (Na2S04) and evaporated.

The residue was purified by flash chromatography (eluant 95% chloroform, 4% methanol, 1% acetic acid) yielding a colourless oil identified as S- (benzyloxycarbonylmethyl)-N- (tert- butyloxycarbonyl)-L-cysteine (5. 2g, 14. 1mmol, 89%).

B. (2S)-1- [S- (Benzyloxycarbonylmethyl)-N- (tert-butyloxycarbonyl)-L-cysteinyl]- pyrrolidine-2-carbonitrile S- (BenzyloxycarbonylmethylN- (tert-butyloxycarbonyl)-L-cysteine (5. 10g, 13. 8mmol) was dissolved in CH2CI2 t200mL). This solution was cooled to 0°C, (2S)-pyrrolidine-2- carbonitrile hydrochloride (2. 1 g, 15. 8mmol) and PyBOP (8. 0g, 15. 3mmol) were added, and the pH was adjusted to pH9 with triethylamine. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150mL).

This solution was washed with 0. 3M KHS04 (1 x 50mL), sat. NaHCO3 (1 x 50mL), water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil.

This was purified by flash chromatography (eluant : 40% ethy acetate, 60% pet. ether) to give a colourless oil identified as (2S)-1-[S-(benzyloxycarbonylmethyl)-N-(tert- butyloxycarbonyl)-L-cysteinyl] pyrrolidine-2-carbonitrile (5. 82g, 13. Ommol, 94%).

C. (2S)"N-{terf-Butyloxywarbonyl)-S-(carboxymethyl)-L-cysteinyl lpyrrolidîne-2- carbonitrile <BR> (2S)-1- [S- (Benzyloxycarbonylmethyl)-N- (tert-butyloxycarbonyl)-L-cysteinyl] pyrrolidine-2- carbonitrile (1. 31g, 2. 9mmol) was dissolved in THF (100mL). Aqueous lithium hydroxide (1M, 3. 5mL, 3. 5mmol) was added. After 3 hours at room temperature the reaction mixture was diluted with ethyl acetate (100mL), washed with 1 M citric acid, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil. This was purified by flash chromatography (eluant : 97% chloroform, 2% methanol, 1 % acetic acid) to give a colourless oil identified as (2S)-1-EN-(tert-butyloxycarbonyl)-S-(carboxymethyl)-L- cysteinyl] pyrrolidine-2-carbonitrile (860mg, 2. 4mmol, 82%).

D. (2S)-1- [N- (tert-Butyloxycarbonyl)-S- (3-picolylcarbamoylmethyl)-L-cysteinyl]- pyrrolidine-2-carbonitrile (2S)-1-[N-(tert-Butyloxycarbonyl)-S-(carboxymethyl)-L-cystei nyl] pyrrolidine-2-carbonitrile (150mg, 0. 42mmol) was dissolved in CH2CI2 (20mL). This solution was cooled to 0°C, 3- (aminomethyl) pyridine (53mg, 0. 5mmol) and PyBOP (270mg, 0. 52mmol) were added, and the pH adjusted to pH9 with triethylamine. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). This solution was washed with 0. 3M KHS04 (1 x 20mL), sat. NaHCO3 (1 x 20mL), water (1 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. This was purified by flash chromatography (eluant : 96% chloroform, 4% methanol) to give a colourless oil identified as (2S)-1-[N-(tert-butyloxycarbonyl)-S-(3- picolylcarbamoylmethyl)-L-cysteinyl] pyrrolidine-2-carbonitrile (170mg, 0. 38mmol, 91%).

E. (2S)-1-[S (3-Picolylcarbamoylmethyl)-L-cysteinyl] pyrrolidine-2-carbonitrile trifluoroacetate <BR> (2S)-1- [N- (tert-Butyloxycarbonyl)-S- (3-picolylcarbamoylmethyl)-L-cysteinyl] pyrrolidine-2- carbonitrile (130mg, 0. 29mmol) was dissolved in trifluoroacetic acid (10mL). After 1 hour at room temperature the solvent was removed in vacuo to give a white solid identified as (2S)-1- [S- (3-picolylcarbamoylmethyl)-L-cysteinyl] pyrrolidine-2-carbonitrile trifluoroacetate (116mg, 0. 25mmol, 86%).

[M+H] + = 348. 2 EXAMPLE 13 <BR> <BR> 3-[N#-(2-Quinoxaloyl)-L-lysinyl]thiazolidine hydrochloride A. 3-[Nα-(tert-Butyloxycarbonyl)-N#-(2-quinoxaloyl)-L-lysinyl] thiazolidine 3-[Nα-(tert-Butyloxycarbonyl)lysinyl]thiazolidine (128mg, 0. 4mmol) was dissolved in CH2CI2 (10mL). 2-Quinoxaloyl chloride (85mg, 0. 44mmol) and potassium carbonate (45. 8mg, 0. 3mmol) were added. The reaction mixture was stirred at room temperature for 18 hours and the solvent removed in vacuo. The residue was purified by flash chromatography (eluant : 99. 5% chloroform, 0. 5% methanol) to give a colourless oil identified as 3- [Al- (tert- butylOxywarbonyl)-N@-(2-quinoxaloyl)-L-lysinyl] thiazolidine (140mg, 0. 296mol, 74%).

B. 3- [W- (2-Quinoxaloyl)-L-lysinyl] thiazolidine hydrochloride 3-[Nα-(tert-Butyloxycarbonyl)-N#-(2-quinoxaloyl)-L-lysinyl] thiazolidine (140mg, 0. 296mmol) was dissolved in 4M HCI/dioxan (20mL). After 1 hour at room temperature the solvent was removed in vacuo to give a white solid identified as 3-[N-(2-quinoxaloyl)-L- lysinyl] thiazolidine hydrochloride (128mg, 0. 296mol, 100%).

[M+H] + = 374. 2 EXAMPLE 14 <BR> <BR> 3-[N#-(3-Pyridyloxycarbonyl)-L-ornithinyl]thiazolidine hydrochloride A. 3- [N- (tert-Butyloxycarbonyl)-W- (3-pyridyloxycarbonyl)-L-ornithinyllthiazolldine 3-Hydroxypyridine (14. 9mg, 0. 138mmol) was dissolved in CH2Cl2 (20mL). Phosgene (20% solution in toluene, 0. 335mL, 0. 685mmol) and pyridine (14mg, 0. 182mol) were added at 0°C. After 90 mins the solvent was removed in vacuo and the residue dissolved in CH2CI2 (20mL). 3- [- (ert-Butyloxycarbonyl) ornithinyl] thiazolidine (42mg, 0. 138mmol) and triethylamine (28mg, 0. 28mmol) were added. The reaction mixture was stirred at room temperature for 18 hours and the solvent removed in vacuo. The residue was purified by flash chromatography (eluant : 97% chloroform, 3% methanol) to give a colourless oil identified as 3-[Nα-(tert-butyloxycarbonyl)-N#-(3-pyridyloxycarbonyl)-L- ornithinyl] thiazolidine (16mg, 0. 038mmol, 27%).

B, 3- (3-Pyridyloxywarbonyl)-L-ornithinyqthiazolidine hydrochloride 3- [N'- (tert-Butyloxycarbonyl)-AP- (3-pyridyloxycarbonyl)-L-omithinyl] thiazolidine (I 6mg, 0. 038mmol) was dissolved in 4M HCI/dioxan (20mL). After 1 hour at room temperature the solvent was removed in vacuo to give a white solid identified as 3- [AF- (3- pyridyloxycarbonyl)-L-ornithinyl] thiazolidine hydrochloride (14mg, 0. 038mmol, 100%).

[M+HF = 325. 1 EXAMPLE 15 <BR> <BR> 3- [O- (3-Chlorobenzyicarbamoyl) serinyl] thiazolidine hydrochloride A. 3-lN-(tert-Butyloxywarbonyl)-L-serinyllthiazolidine N-(tert-Butyloxycarbonyl)-:l-serine (2. 1 g, 10. 2mmol) was dissolved in CH2CI2/DMF (9 : 1, 50mL). Thiazolidine (650mg, 11. 2mmol), hydroxybenzotriazole (2. 8g, 20. 7mmol) and water soluble carbodiimide (3. 9g, 19. 5mmol) were added at 0°C. The pH was adjusted to pH8 with N-methylmorpholine. The reaction mixture was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue was taken up in ethyl acetate (150mL). This solution was washed with 0. 3M KHS04 (1 x 50mL), sat. NaHCO3 (1 x 50mL), water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a white solid identified as 3- [N- (tert-butyloxycarbonyl)-L-serinyl] thiazolidine (2. 15g, 7. 78mmol, 76%).

B. 3- [N- (tert-Butyloxycarbonyl)-O- (3-chlorobenzylcarbamoyl)-L-serinylthiazolidine 3- [N- (tert-Butyloxycarbonyl)-L-serinylthiazolidine (110mg, 0. 48mmol) was dissolved in DMF (10mL) and 1, 1'-carbonyl-diimidazole (71mg, 0. 43mmol) was added. After 2 hours at room temperature 3-chlorobenzylamine (62mg, 0. 4mmol) was added. After a further 18 hours EtOAc (200mL) was added. This solution was washed with 0. 3M KHS04 (1 x 50mL), sat. NaHCO3 (1 x 50mL), water (4 x 50mL) and brine (1 x 50mL), dried (Na2S04) and evaporated in vacuo to give a yellow oil. This was purified by flash chromatography (eluant : 40% ethyl acetate, 60% pet. ether) to give a colourless oil identified as 3-[N-(tert- butyloxycarbonyl)-O- (3-chlorobenzylcarbamoyl)-L-serinyl] thiazolidine (158mg, 0. 36mmol, 90%).

C. 3-lO-(3-Chlorobenzylcarbamoyl)-L-serinylithiazolidine hydrochloride 3-[N-(tert-Butyloxycarbonyl)-O-(3-chlorobenzylcarbamoyl)-L-s erinyl]thiazolidine (140mg, 0. 32mmol) was dissolved in 4M HCI/dioxan (20mL). After 1 hour at room temperature the solvent was removed in vacuo to give a white solid identified as 3- [0- (3- chlorobenzylcarbamoyl)-L-serinyl] thiazolidine hydrochloride (115mg, 0. 3mmol, 94%).

[M+H] + = 344. 1 The Examples set out in the following Tables were prepared by analogous methods to the above.

TABLE 1-Examples 16-162 Example n R8 (CH2) q R1 X 16 1 CN CH2 N 17 2 (<1 CN CH 18 1 H s 19 2 H S 201cons 20 1 CN S N 22 1 H CH2 23 2 H CH 24 1 CN CH 25 2 C CN CH 26 1 < H S 27 2 H S 28 1, CN CH 29 2 N CN CH2 30 1 H s 31 2 H S 32 1 CN CH 33 2 Cl\NqzCF3 CN CH 34 1 H s 35 2 H S I 36 1 N CN CH2 37 2 CN CH2 38 H S Example n R8 (CH2) q R1 X' 39 1 CN CH2 N 40 2 CN CH2 41 1 42 2 H S 422HS 43 1 CN CH2 44 2 CN CH2 45 1 Br H S 46 2 H S 47 1 cl CN CH2 48 2 CN CH2 49 1 H s 50 2 H S 51 1 Cl CN CH2 52 2 N CN CH2 53 1 H s 54 2 H S 55 1 CN CH 56 2 < CN CH 57 1 SDI 58 2 H S 59 1 CN CH 60 2 CN CH2 "HS 61 1 H s 62 2 H S 63 1 CN CH 64 2 j CN CH2 65 1 \o 'H S 66 2 H S 67 1 CN CH 68 2 N< CN CH 69 1 O g H S 70 2 H S Example n R$ (CHZ) q R'X' 71 1 CN CH2 72 2 CN CH2 73 1 H s s 74 2 N/H S 75 1/% CN CH2 76 2 CN CH2 77 1 H s 6 78 2 N, H S 79 1 CN CH2 I A 78 2 79 1 CN CH2 80 2 CN CH2 81 1 cmi H S 822ho 83 1 CN CH 831CNCHs 85 1 ENJv H S 86 2 H S 87 1 CN CH 88 2 CN CH2 88 2 89 1 H s 90 2 H S 91 1 N CN CH2 92 2 CN CH2 93 1 H s 94 2 H S 95 1 CN CH N 96 2 CN CH2 97 1 H s 98 2 H S 99 CN CH2 100 2 CF CN CH2 100 2 101 1 H s 102 2 H S Example n R'I (CH2), q R'xl 103 1 N CN CH2 104 2 CN CH2 105 1 H s 106 2 H S 1071CNCH2 108 2 CN CH2 109 1 H s 110 2 H S 111 1 CN CH2 9 112 2 CN CH2 113 1 s H s 114 2 H S 115 1 CN CH2 116 2 CN CH2 117 1 H S 118 2 H S 119 1 CN CH2 120 2 CN CH2 121 1 H S 122 2 H S 123 1 CN CH2 124 2 CN CH2 125 1 H S 126 2 H S 127 1 H s HO Nez 128 1 c I H S X, I 129 2 HO NZ H S 130 1 H s I s 131 2 cl NJ Exampte n RCHqR'X' ci 132 1 !)) H S -"SON) 133 1 H s 133 1 CI N CI y 134 1 H S CE3 N 135 1 S s 136 1 J H S Br 137 1 X H S F 138 1 CN H S CN \ v 139 1 ; X H i Nez ci 140 1 Ccl H S "-0 141 1 Cx) H S i | I Example n R8 (CH2) q R1 X 142 1 t H S CL3 CF3 143 1 s H CF3 CL v 144 1 U H CH2 cl 4 . 145 1 H CH2 C)""N' 146 1 H CH2 I'N'Cl 147 1 clJ0Nlcl H CH cri cl ci 148 1 clt H S -"ORN-D 149 1 H s H S 150 2 N+CO2H H S ci 151 1 H S N, 1 N, I 152 2 N N H S 153 1 J) j ! H S MeO N ove < 154 1 H H S Example n R$ (CH2) q R'X' w, 155 1 WJ H S 156 1 H H S CF3 ci 157 1 s cl I 158 1 I w H S 159 1 FX H S F 160 1 NC40 H S NC 161 1 WF H S F CRI 162 1 ¢CI H CH2 cul TABLE 2-Examples 163-250 Example n R6RN R'Xr 163 1 CN CH2 163 1 N CN CH 166 N H s T 166 2 H S 167 1 CN S 168 2 I N CN S H 169 N H CH2 N 170 2 H CH2 i 171 1 CN CH 1722fjCNCHs H 173 1 N N H S 1742HS 175 1 CN CH 176 2 H H 177 1 H s T 178 2 H S 179 1 CN CH 1802N) CNGHz H 1822 HS 182 2 H S 183 1 CN CH 1842N. CNCHb H S 185 1 186 2 H S | 186 2 H S I Example n R6R7N R'X' 187 1 CN CH2 1882 CN CH2 189 1 N H S H 190 2 H S 191 1 CN CH2 192 2 CN CH2 193 1 H S 194 2 H S 195 1 CN CH2 1962 CN CH2 197 1 X H S 198 2 H S 1991 CN CH2 2002 CN CH2 201 1 Ny H S 202 2 H S 203 1 CN CH2 2042 N CN CH2 2061 H s 206 2 H S 207 1 CN CH2 2082 CN CH2 l H 2091 H s 210 2 H S 2111 CN CH2 2122 CN CH2 I 2131 H s 214 2 H S 215 1 CN CH2 A 2162 CN CH2 2171 H s o 218 2 H S Example n R6R7N R'X' 219 1 CN CH2 220 2 H 2211/HS o 222 2 H S 223 1 CN CH2 H 224 2 CN CH2 225 1 > H S 226 2 H S 227 1 CN CH H 228 2 N CN CH 229 1 W H S 230 2 H S 231 1 CN CH2 H 232 2 N CN CH2 233 1 MeO4J H S mye0 234 2 H S 235 1 CN CH 236 2 j H. CN CH 237 1 H s 238 2 H S 239 1 CN CH2 0 240 2 tN CN CH 241 1 IN H S 2422ho 243 1 CN CH 244 2 0 CN CH2 "HS 2462HS 246 2 H S 247 1 0 CN CH2 248 2 AN CN CH2 2491kHS 2502HS TABLE 3-Examples 251-266 Example n RsR7N R'X' 251 1. CN CH2 H 252 2 CN CH2 253 1 WJ H S 254 2 H S 255 1 CN CH2 256 2 CN CH2 257 H S 258 2 H S 259 1 H CN CH2 260 2 CN CH2 261 1 W H S 2622HS 263 1 CN S 264 2 CN s 265 1 WJ H CH2 266 2 H CH2 TABLE 4-Examples 267-318 Example n R8 (CH2) q R'X' 267 1 CN CH2 268 2 CN CH2 269 1 CN S w v 270 2 CN S 271 1 CN CH2 272 2 CN CH2 273 1 CN CH2 ll I 274 2 CN CH2 274 2 275 1 CN CH2 276 2 CN CH2 277 1 CN CH2 cri 278 2 s cl CN CH2 279 1 CN CH2 CF N cF3 N I i CN CH 280 2 0 281 1 c H CH2 CK- 282 2 CIX H CH2 Example n R8 (CH2) q R'X' 283 1 CH2 CL3 NU 284 2 H CH2 o 285 1 H CH2 286 2 H CH2 287 1 9 H S w v 288 2 W H S I 289 1 ci H S w v 290 2 H S 291 1 H s 292 2 MeO H S I 293 1 CN CH2 294 2 CN CH 295 1 CN CH2 296 2 CN CH2 I 297 1 ci CN CH2 f I 298 2 CN CH2 299 1 CN CH2 300 2 MeO CN CH2 301 1 CN CH2 o 302 2 H CN C H2 H 303 1 N/+ CN CH2 iy 304 2NCN CH2 Example n R8 (CH2) q R'xl 305 1 NCX CN CH2 306 2 CN CHz 307 1 cl H s 308 2 CI <J H S I 309 1 ç \ H S CF3 NX 310 2) r H s o 311 1\H S 0 311 1 \ H S | 312 2 NX H S I 313 1 nrX H S i 314 2 ci H s 315 1 cl H S 316 zu 317 II 2 WJ H S 318 1 J4HX H S n TABLE 5-Examples 319-378 Example R4B R1 X1 319 NH2 CN CH2 Example R4B R'X' 320 CN CH2 N 321 CN CH2 322 CN CH2 'N 323 H CN CH2 eN N 324 CN CH2 H 325 CN CH2 326 rN\ CN CH2 ou 327 H CH2 H 328 H H CH2 N 329 ¢ f NHts H S i 330 j \ H H S non 331 tf Ht H S i I I I I d Example R4B R'X' 332 NN H S ! 333 CN CH2 N 334 ~ Ht CN C H i 335 ~ CN S 336 H CN S ZON 337 CN CH2 338 N CN CH2 339 sNSJNX CN CH2 N 340 OYNC) CN CH2 341 iNN H S H 0 342 ~ H S M 343 ¢3f tNts H S i Example R4B R'X' 344 lCf Ht H S N 3 345 CNt H S 346 H s o cl 347 eH H S ce 348 Clv H S ce 349 \ H'H S ci F 350 H H S F N H 351 (3/H H S 0 o 352 NA H S 353 XH H S X Example R4B R'X' 354 H S I H ci cl J' \ 356 ci H S 356 ¢DGNA H S l 357 H S 357 H 358 /o H S NH2 CN 359 M H I 360 H S H NA 361 W)."o H CH2 NH2 362 H H CH2 Cl FIC H S Example R4s R'Xa 364 CF3 364 H S CF3 N H S CF3 caf3 366 H H S N" ( N-\ 367 a tJ'H S s NA 0 ex 368 H H S ci 369 ¢3f HNA H S H NA H S 0 / 0 371 Xf HA H S 372 S HNA H S H nua H S su 373 H H S Example R4B R'X' T NHZ 375 N. OH H s .., oH NH2 N-\ 376 N H H C H 2 NH 377 N H CH2 OH ci 378 N H CH2 / TABLE 6-Examples 379-418 I Example n R8 (CH2) q R1 Xr 379 1 N CN CHZ 380 2 W CN CH2 I 381 1 CN CH2 N J'CN CH2 382 2 wv Example n R8 (CH2) q R'Xr 383 1 CN CH2 w 384 2 CN CH2 385 1 CN CH2 11 386 2 N+. CN CH2 387 1 CN CH2 388 2 N a CN CH2 389 1 /CN CH2 con 2 s CN CH2 390 2 S 3902s-"CNCHz une 392 2 CN CH2 393 1 CN CH2 394 2 CN CH2 395 1 < H CH2 396 2 H CH2 397 1/y H S NJ'H S 398 2 399 1 No CN s 400 2 W CN S 401 1 N CN CH2 402 2 CN CH 403 1 N CN CH2 404 C N CH2 405 (N C N C H 1 1 2 406 2 CN CH2 407 1 C N CH2 408 2 ts CN CH2 Example n R8 (CH2) q R'X' 409 1 CN CH2 410 2 CN CH2 411 1 \NA CN CH2 412 2 CN CH2 413 1 H s 414 2 H s 415 1 H s 416 2 H S 417 1 H s 418 H s TABLE 7-Examples 419-438 Example m R6R7N CF3 419 1 j CI 420 1 H 421 1 H Cl s Example m R6R7N ci 422'1 zu w N 423 1 u s h 0 424 1 cp ,, v 425 2 426 3 427 1 428 2 H 429 3 430 1 CI < NA 430 1 C I A , 431 2 zu 432 3 cl 433 2) su 1 J 434 3 p" 435 2 N A 436 3'lu 437 2 H 438 3 MeOw Me0 TABLE 8 - Examples 439 - 450 I Example n R8 (CH2) q R1 X' 439 1 cl CN CH2 440 2 CN CH2 441 1 ClgH CN CH2 l l l 442 2 cl/CN CH2 443 1 H s 444 2 H S CL 4451fCNCH2 . H 446 2 CN CH2 447 1 A 8 CN CH2 448 2 CN CH2 449 1 CN CH2 450 2 MeOw CN CH2 EXAMPLE 451 Determination of activity Compounds were assayed as inhibitors of DP-IV according to the methods described in W095/15309. All the compounds described in the foregoing Examples were competitive inhibitors of DP-IV with N values less than 300nM.

EXAMPLE 452 Determination of activity in vivo The anti-diabetic action of selected compounds was demonstrated in Zucker obese rats using a standard oral glucose tolerance test. Control rats were given a solution of glucose by oral gavage, and plasma glucose levels were determined. These rats demonstrated a significant hyperglycaemia. Compounds according to the present invention were dissolved in glucose solution at various concentrations, such that the rats could be given varying doses of the compound simultaneously with the glucose challenge. The hyperglycaemic excursion was reduced in a dose-dependent manner in animals receiving between 0. 1 and 100 mg/kg of DP-IV inhibitor.

EXAMPLE 453 Pharmaceutical formulation Tablets containing 100mg of the compound of Example 1 as the active agent are prepared from the following : Compound of Example 1 200. Og Corn starch 71. Og Hydroxypropylcellulose 18. Og Carboxymethylcellulose calcium 13. Og Magnesium stearate 3. Og Lactose 195. Og Tota/500. 0g The materials are blended and then pressed to give 2000 tablets of 250mg, each containing 100mg of the compound of Example 1. The above demonstrates that the compounds according to the present invention are inhibitors of DP-IV and would accordingly be expected to be useful as therapeutic agents for the treatment of impaired glucose tolerance, type it diabetes, and other diseases where inhibition of this enzyme leads to an improvement in the underlying pathology or the symptoms.

The present invention is further defined in the following Claims.