HYDROXAMIC ACID BASED COLLAGENASE INHIBITORS

Abstract: Compounds of general formula (I), wherein R1 represents a hydrogen atom or a C1-C6 alkyl, C1-C6 alkenyl, phenyl, phenyl(C1-C6)alkyl, C1-C6 alkylthiomethyl, phenylthiomethyl, substituted phenylthiomethyl, phenyl(C1-C6)alkylthiomethyl or heterocyclylthiomethyl group; or R<1> represents -SR<X> wherein R<X> represents a group ( alpha ); R<2> represents a hydrogen atom or a C1-C6 alkyl, C1-C6 alkenyl, phenyl(C1-C6)alkyl, cycloalkyl(C1-C6)alkyl, or cycloalkenyl(C1-C6)alkyl; R<3> represents an amino acid residue with R or S stereochemistry or a C1-C6 alkyl, benzyl, (C1-C6)alkoxybenzyl or benzyloxy(C1-C6)alkyl group; R<4> represents a hydrogen atom or a methyl group; n is an integer from 1 to 6; and A represents the group -NH2, a substituted acyclic amine or a heterocyclic base; or a salt and/or N-oxide and/or (where the compound is a thio-compound) a sulphoxide or sulphone thereof have collagenase inhibition activity and are useful in the management of disease involving tissue degradation and/or the promotion of wound healing. Diseases involving tissue degradation include arthropathy (particularly rheumatoid arthritis), inflammation, dermatological diseases, bone resorption diseases and tumour invasion.

Description: E DROXAMIC ACID BASPD COLLAGENASE INHIBITORS This invention relates to pharmaceutically and veterinarily active compounds, which are derivatives of hydroxamic acid. The compounds of the present invention act as inhibitors of metalloproteases involved in tissue degradation, such as collagenase, which initiates collagen breakdown, stromelysin . (protoglycanase) , gelatinase and collagenase (IV) . There is evidence implicating collagenase as one of the key enzymes in the breakdown of articular cartilage and bone in rheumatoid arthritis (Arthritis and Rheumatism. 20, 1231 - 1239, 1977). Potent inhibitors of collagenase and other metalloproteases involved in tissue degradation are useful in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is important. Inhibitors of metalloproteases of this type can therefore be used in treating or preventing conditions which involve tissue breakdown; they are therefore useful in the treatment of arthropathy, dermatological conditions, bone resorption, inflammatory diseases and tumour invasion and in the promotion of wound healing. Specifically, compounds of the present invention may be useful in the treatment of osteopeniaε such as osteoporosis, rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration and tumour invasion. A number of small peptide like compounds which inhibit metalloproteases have been described. Perhaps the most notable of these are those relating to the angiotensin converting enzyme (ACE) where such agents act to block the conversion of the decapeptide angiotensin I to angiotensin II a potent pressor substance. Compounds of this type are described in EP-A-0012401. Certain hydroxamic acids have been suggested as collagenase inhibitors as in US-A-4599361 and EP-A-0236872. Other hydroxamic acids have been prepared as ACE inhibitors, for example in US-A-4105789, while still others have been described as enkephalinase inhibitors as in US-A-4496540. EP-A-0012401 discloses antihypertensive compounds of the formula: O R 1 R 3 R 4 R 5 0 n I , I I . π R-C-C-NH-CH-C-N—C—C-R 6 I " I R 2 O " R 7 wherein R and R 6 are the same or different and are hydroxy, alkoxy, alkenoxy, dialkylamino alkoxy, acylamino alkoxy, acyloxy alkoxy, aryloxy, alkyloxy, substituted aryloxy or substituted aralkoxy wherein the substituent is methyl, halo, or ethoxy, amino, alkylamino, dialkylamino, aralkylamino or hydroxyamino; R 1 is hydrogen, alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups ; substituted alkyl wherein the substituent is halo, hydroxy, alkoxy, aryloxy amino, alkylamino, dialkylamino, acrylamino, aryla ino, guanidino, imidazolyl, indolyl, mercapto, alkyl thio, arylthio, carboxy, carboxamido, carbalkoxy, phenyl, substituted phenyl wherein the substituent is alkyl, alkoxy or halo; aralkyl or heteroaralkyl , aralkenyl or heteroaralkenyl, substituted aralkyl, substituted heteroaralkyl , substituted aralkenyl or substituted hetereoaralkenyl, wherein the substituent is halor or dihalo, alkyl, hydroxy, alkoxy, amino, aminomethyl, acrylamino, dialkylamino, alkylamino, carboxyl, haloalkyl, cyano or sulphonamido , aralkyl or hetereoaralkyl substituted on the alkyl portion by amino or acylamino; R 2 and R 7 are hydrogen or alkyl; R 3 is hydrogen , alkyl , phenylalkyl , aminomethylphenylalky 1 , hydroxypheny 1 alky 1 , hydroxyalkyl , acetylaminoalkyl , acylaminoalkyl, acylaminoalkyl aminoalkyl, dimethylaminoalkyl , haloalkyl, guanidinoalkyl , imidaz oly lalky 1 ,- indolylalkyl, mercaptoalkyl and alkylthioalkyl ; R 4 is hydrogen or alkyl; EET R 5 is hydrogen, alkyl, phenyl, phenylalkyl, hydroxyphenylalkyl , hydroxyalkyl , aminoalkyl, guanidinoalkyl , i idazolylalkyl , indolylalkyl , mercaptoalkyl or alkyl thioalkyl ; R 4 and R 5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms " containing a double bond or an alkylene bridge as above, substituted with hydroxy, alkoxy or alkyl and the pharmaceutically acceptable salts thereof. US-A-4599361 discloses compounds of the formula: O O R 2 O II •I HOHNC-A-CNH-CH-CNHR , J 1 wherein R 1 is C-^-Cg alkyl; "> R- ~ is ^-C Q alkyl, benzyl, benzyloxybenzyl, ( c ι~ c 6 alkoxy) benzyl or benzyloxy (C^Cg alkyl) ; a is a chiral centre with optional R or stereochemistry ; A is a -(CHR 3 -CHR 4 )- group or a -(CR 3 =CR 4 )- group wherein b and c are chiral centres with optional R or S stereochemistry; R 3 is hydrogen, C 1 -C 6 alkyl, phenyl or phenyl(C 1 -C 6 alkyl) and R 4 is hydrogen, C- j^ -C 8 alkyl, phenyl(C^C g alkyl), cycloalkyl or cycloalkyl(C-^-Cg alkyl). EP-A-0236872 discloses generically compounds of the formula A R- R HC-CH-CO-NH-CH-CO-N-CH-R- < wherein A represents a group of the formula HN(OH)-CO- or HCO-N(OH)-; R 1 represents a C 2 -C 5 alkyl group; R 2 represents the characterising group of a natural alpha-amino acid in which the functional group can be protected, amino groups may be acylated and carboxyl groups can be amidated, with the proviso that R 2 can not represent hydrogen or a methyl group; R 3 represents hydrogen or an amino, hydroxy, mercapto c l~ c 6 alkyl, c ι~ c 6 alkoxy, c ι~ c 6 acylamino C - C 6 - a 1 ky 11h i o , aryl- fC^Cg alkyl) - amino- (C^ ^ -Cg-alkyl) -, hydroxy (C 1 -C 6 -alkyl) - mercapto alkyl) group wherein the amino, hydroxy, mercapto or carboxyl groups can be protected and the amino groups may be acylated or the carboxyl groups may be amidated; 1 R 4 represents hydrogen or a methyl group; 2 3 R 5 represents hydrogen or a C^-C 8 acyl, c ι~ c 6 4 alkoxy-C^-Cg alkyl, difC-^-Cg-alkoxy)methylene, carboxy, 5 ( c ι" c 6 alkyl) carbinyl, ( ι" *c 6 alkoxy) carbinyl, 6 aryl ethoxy carbinyl, (C-^-C 8 alkyl)amino carbinyl or 7 arylamino carbinyl group; and 8 9 R 6 represents hydroxy or a methylene group; or 0 1 R 2 and R 4 together represent a group-(CH 2 ) n -, wherein n 2 represents a number from 4 to 11; or 3 4 R 4 and R 5 together represent a trimethylene group; 5 6 and pharmaceutically acceptable salts o-f such 7 compounds, which are acid or basic. 8 9 US-A-4105789 generically discloses compounds which have 0 the general formula 1 * 2* *^**-*t "\ 3 R 4 -0C-(CH 2 ) n -C rH-CO-N-CH-COOH 4 5 and salts thereof, wherein 6 7 R-^ is hydrogen, lower alkyl , phenyl lower alkylene , 8 hydroxy-lower alkylene , hydroxyphenyl ' lower 9 alkylene , amino-lower alkylene , guanidine lower 0 a lkyl ene , mercapto -l ower al kyl ene , l ower 1 alkyl-mercapto-lower alkylene, imidazolyl lower 2 v alkylene , indolyl-lower alkylene or carbamoyl 3 lower alkylene; R 2 is hydrogen or lower alkyl; R 3 is lower alkyl or phenyl lower alkylene; R 4 is hydroxy, lower alkoxy or hydroxyamino; and n is 1 or 2. US-A-4496540 discloses compounds of the general formula: A-B-NHOH wherein A is one of the aromatic group-containing amino acid residues L-tryptophyl, D-tryptophyl, L-tyrosyl, D-tyrosyl, L-phenylalanyl, or D-phenylalanyl, and B is one of the amino acids glycine, L-alanine, D-alanine, L-leucine, D-leucine, L-isoleucine, or D-iεoleucine; and pharmaceutically acceptable salts thereof. It would be desirable to improve on the solubility of known collagenase inhibitors and/or stromelysin inhibitors (whether as the free base or the salt) and, furthermore, increases in activity have also been sought. It is not a simple matter, however, to predict what variations in known compounds would be desirable to increase or even retain activity; certain modifications of known hydroxamic acid derivatives have been found to lead to loss of activity. According to a first aspect of the invention, there is provided a compound of general formula I: wherein: represents a hydrogen atom or a C-^-Cg alkyl, C^Cg alkenyl, phenyl, phenyl (C^Cg) alkyl , c ι~Cg alkylthiomethyl, phenylthiomethyl, substituted phenylthiomethyl , phenyl ( C-^-Cg ) alkylthiomethyl or heterocyclylthiomethyl group; or R 1 represents -SR X wherein R x represents a group represents a hydrogen atom or a C^-C 8 alkyl, C η -C 8 a l kenyl , ph enyl ( C 1 - C g ) a lky l , c y c l o a l ky l ( C 1 - C g ) a l k y l , o r cycloalkenyl (C^-C 8 ) alkyl ; R- represents an amino acid side chain or a C l " 6 alkyl, benzyl, ( C- j^ -C 8 ) alkoxybenzyl , benzyloxy(C 1 -C 8 ) alkyl or benzyloxybenzyl group; represents a hydrogen atom or a methyl group; n is an integer from 1 to 6; and represents the group -NH 2 , a substituted acyclic amine or a heterocyclic base; or a salt and/or N-oxide and/or (where the compound is a thio-compound) a sulphoxide or sulphone thereof. Hereafter in this specification, the term "compound" includes "salt" unless the context requires otherwise. As used herein the term "^-C alkyl" refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl, and cognate terms (such as "C 1 -C 6 alkoxy") are to be construed accordingly. The term "C-^-Cg alkenyl" refers to a straight or branched chain alkyl moiety having one to six carbons and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include, for example, an alpha, beta-unsaturated methylene, vinyl, 1-propenyl, l- and 2-butenyl and 2-methyl-2-propenyl. The term "cycloalkyl" refers to a saturated alicyclic moiety having from 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkenyl" refers to an unsaturated alicyclic moiety having from 3 to 8 carbon atoms and includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. The term "substituted acyclic amine" refers to a group -N(R A )R B , wherein each of R A and R B independently represents a hydrogen atom or a C-^-Cg alkyl group, with the proviso that at least one of R ~~ and R B represents a c ι~ c 6 alkyl group. The term "heterocyclic base" refers to a group of general formula (II) : __^/ (II) which represents a five or six membered saturated or unsaturated ring with or without an extra heteroatom (such as nitrogen and/or sulphur and/or oxygen) which may be fused to a benzene ring, for example pyridyl, imidazolyl, oxazolyl, thiazolyl, benzthiazolyl , benzoxazolyl, morpholinyl, pyrrolidinyl or piperidinyl. Preferred heterocyclic bases include pridyl, morpholinyl, piperidinyl and pyrrolidinyl. The term "heterocyclylthiomethyl" refers to a methyl group substituted by a hetrocyclic thiol for example pyridine-2 -thiol , pyridine-4-thiol , thiophene-2-thiol or pyrimidine-2-thiol. The term "substituted", as applied to a phenyl or other aromatic ring, means substituted with up to four substituents each of which independently may be C-^-Cg alkyl, C- j^ -Cg alkoxy, hydroxy, thiol, C- j^ -Cg alkylthiol amino, halo (including fluoro, chloro, bromo and iodo) , triflouromethyl or nitro. The term "amino acid side chain" means a characteristic side chain attached to the -CH(NH 2 ) (COOH) moiety in the following R or S amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, gluta ic acid and aspartic acid. There are several chiral centres in the compounds according to the invention because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereomers with the appropriate R or S stereochemistry at each chiral centre. General formula I and, where appropriate, all other formulae in this specification are to be understood to include all such stereoiso ers and mixtures (for example racemic mixtures) thereof. Compounds in which the chiral centre adjacent the substituent R 3 has S stereochemistry are preferred. Further or other preferred compounds include those in which, independently or in any combination: R 1 represents a hydrogen atom or a C^^ alkyl (such as methyl ) , phenylthiomethyl or heterocyclylthiomethyl ( such as thiophenylthiomethyl) group; R 2 represents a C 3 -C 6 alkyl (such as isobutyl or n-pentyl) group; R 3 represents a benzyl, 4- (C 1 -C 6 ) alkoxyphenylmethyl ' or benzyloxy benzyl group; R 4 represents a hydrogen atom; n has the value 1, 2 or 3; and/or A represents a morpholinyl (eg 4-morpholinyl) , piperidinyl, 2-, 3- or 4-pyridyl or pyrrolidinyl group. Particularly preferred compounds include: 1. [4- (N-Hydroxyamino) -2R-isobutylsuccinyl ] -L-phenyl- alanine-N- [ ( 2 -aminoethyl ) - 2 (RS ) - ( 1 -methyl - pyrrolidine) ] amide, 2. [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenyl- alanine-N-[1-(2-aminoethyl)-piperidine]amide, 3. [4-(N-Hydroxyamino)-2R-iεobutylεuccinyl]-L-phenyl- alanine-N-[l-(2-aminoethyl)-pyrrolidine]amide, 4. [4-(N-Hydroxyamino)-2R-isobutylεuccinyl]-L-phenyl- alanine-N- [1-(3-aminopropyl) -2 (RS) -methy1- piperidine]amide, 5. [4-(N-Hydroxyamino)-2R-iεobutylsuccinyl]-L-phenyl- alanine-N-[2-(2-aminoethyl)-1-methylpyrrole]amide, 6. [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenyl- alanine-N-(3-aminomethylpyridine)amide, 7. [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenyl- alanine-N-(2-aminomethylpyridine)amide, 8. [4-(N-Hydroxyamino) -2 (RS) -isobutylεuccinyl]-L- ' phenylalanine-N-(4-aminomethylpyridine)amide, 9. [4- (N-Hydroxyamino) -2 (RS) -isobutylsuccinyl]-L- phenylalanine-N- (1- ( 3 -aminopropyl) -imdazole) amide, 10. [4- (N-Hydroxyamino) -2 (RS) -isobutylεuccinyl] -L- phenylalanine-N- (2-aminomethylbenzimdazole) amide , 11. [ 4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- succinyl ]-L-phenylalanine-N-[ 4- (2-aminoethyl) - morpholino] amide, 12. [4- (N-Hydroxyamino) -2R-isobutylsuccinyl ] -L-phenyl- alanine-N- [4- (2-aminoethyl) -morpholine] amide, 13. [4- (N-Hydroxyamino) -2 (R,S) -iεobutylεuccinyl ]-L- phenylalanine-N-[2-(2-aminoethyl)-pyridine]amide, 14. [4- (N-Hydroxyamino) -2 (R,S) -isobutylsuccinyl] -L- phenylalanine-N- [4- (2-aminopropyl) -morpholine] - amide, 15. [4- (N-Hydroxyamino) -2R-iεobutylsuccinyl]-L-phenyl- alanine-N- (3-aminomethylpyridine) amide hydro- chloride, 16. [ 4- (N-Hydroxyamino) -2R-isobutylsuccinyl ] -L- phenylalanine-N- [4- (2-aminoethyl) -morpholine] amide hydrochloride, 17. [4- (N-Hydroxyamino) -2 (RS) -iεobutylεuccinyl] -L- phenylalanine-N- (4-aminomethylpyridine) amide hydrochloride, ET 18. [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- succinyl] -L-phenylalanine-N- [4- (2-aminoethyl) - morpholine]amide hydrochloride and 19. [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- succinyl] -L-phenylalanine-N- [4- (2-aminoethyl) - morpholine] amide sodium salt, 20. [4- (N-Hydroxyamino) -2R-isobutylsuccinyl]-l-phenyl- alanine-N- [l-(3-aminopropyl)-imidazole] amide 21. [4- (N-Hydroxyamino) -2R-isobutylεuccinyl] -1-phenyl- alanine-N- [ 2- (3-aminopropyl) -pyridine] amide 22. [4- (N-Hydroxyamino) -2R- iεobutylεuccinyl] -1-phenyl- alanine-N- [2-aminoethyl) -N, N-diethylamine] amide 23. [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- succinyl] -1-phenylalanine-N- [3-aminomethyl- pyridine] amide 24. [4- (N-Hydroxyamino) -2R-iεobuty 1-3 S-methyl- εuccinyl] - 1 -phenylalanine-N- [4 -am inome thy 1- pyridine] amide 25. [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- εuccinyl] -1-phenylalanine-N- [2-aminomethyl* pyridine] amide 26. [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl* succinyl] -l-phenylalanine-N-[2- (2-aminoethyl) • pyridine] amide 27. [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -1-phenyl- alanine-N- [2- (2-aminoethyl) -pyridine] amide hydro- chloride 28. [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -1-phenyl- alanine-N- [4-aminomethyl-pyridine] amide hydrochloride 29. [4-(N-Hydroxyamino)-2R-iεobutylsuccinyl]-l-phenyl- alanine-N- [2-aminomethyl-pyridine] amide hydro- chloride 30. [4- (N-Hydroxyamino) -2R-isobutylsuccinyl]-l-phenyl- alanine-N- [2- (3-aminopropyl) -pyridine] amide hydro- chloride 31. [ 4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- εuccinyl ]-l- phenylalanine-N- [3- am in omethyl- pyridine] amide hydrochloride 32. [ 4- (N-Hydroxyamino) -2R-iεobutyl-3S-methyl- succinyl] -1-phenylalanine-N- [2- (2-aminoethyl) - pyridine] amide hydrochloride 33. [ 4- (N-Hydroxyamino) -2R-iεobutyl-3S-methyl- succinyl] -1-phenylalanine-N- [2- am in omethyl- pyridine] amide hydrochloride 34. [ 4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- succinyl ]-l-pheny lalanine-N-[ 4- am inomethyl- pyridine] amide sodium salt 35. [ 4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- succinyl] -1-phenylalanine-N- [2- (2-aminoethyl) - pyridine ] amide sodium salt 36. [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- succinyl] -1-phenylalanine-N- [3-aminomethyl- pyridine] amide sodium salt 37. [4- (N-Hydroxyamino) -2R-isobutylsuccinyl ]-l-phenyl- alanine-N- [2- (3-aminopropyl) -pyridine] amide sodium salt 38. [4- (N-Hydroxyamino) -2R-isobutyl-3S-(phenylthio- methyl) εuccinyl] -L-phenylalanine-N- (2-methyl- pyridyl) amide and the free bases, free acids and saltε thereof, where appropriate. Compoundε 6 and 11 are eεpecially preferred becauεe of their good collagenaεe-inhibiting and protoglycanaεe inhibiting activitieε and compound 6 iε the most preferred. Compounds of general formula I may be prepared by any suitable method known in the art and/or by the following process, which itself forms part of the invention. According to a second aspect of the invention, there is provided a process for preparing a compound of general formula I as defined above, the process comprising: (a) ' deprotecting (for example by hydrogenating) a compound of general formula III wherein: R 1 , R 2 , R 3 , R , n and A are aε defined in general formula I and Z repreεents a protective group, such as a benzyl group; or (b) reacting a compound of general formula IV wherein: R 1 , R 2 , R 3 , R 4 , n and A are aε defined in general formula I, with the proviso that R 1 represents a hydrogen atom, with hydroxylamine or a salt thereof; and (c) optionally after step (a) or step (b) converting a compound of general formula I into another compound of general formula I. Compounds of general formula I which are sulphoxides or sulphoneε can be derived from thiol compoundε of general formula I by oxidation. Alternatively, thiolε of general formula III or IV can be oxidised. Compoundε of general formula I which are diεulphideε (ie compounds wherein R 1 represents SR X ) may be derived from thiol compounds of general formula I by mild oxidation with, for example, iodine in methanol. A compound of general formula III can be obtained by coupling, for example by conventional coupling techniques, a compound of general formula IV with an O-protected (for example benzyl) hydroxylamine or by reacting a compound of general formula V (V) wherein: R- R 2 and R J are aε defined in general formula I and Z repreεentε a protective group εuch aε benzyl, with a compound of general formula VI NHR 4 (CH 2 ) n A (VI) A compound of general formula V may be prepared by hydrolyεis in the presence of a base such as sodium hydroxide of a compound of general formula VII wherein: R 1 , R and R 3 are as defined in general formula I, with the proviso that R 1 represents a hydrogen atom, R 6 represents a C j -Cg alkoxy, benzyloxy or substituted (eg 4-nitro) benzyloxy group, and Z represents a protective group. A compound of general formula VII may be prepared by coupling, for example by conventional coupling techniques, a compound of general formula VIII with an O-protected (for example benzyl) hydroxylamine wherein: R 1 , R 2 and R 3 are as defined in general formula I g and R repreεents a C-^-Cg alkoxy , benzyloxy or εubstituted benzyloxy group . A compound of general formula VIII may be prepared by hydrogenating and (eg thermally) decarboxylating a compound of general formula IX wherein: R 1 , R 2 and R 3 are aε defined in general formula I, R 5 represents a C 1 -C 8 alkyl or benzyl group, R 6 represents a C1-C6 alkoxy, benzyloxy or subεtituted benzyloxy group and R 7 repreεents a c l ~ c 6 alkoxycarbonyl or benzyloxycarbonyl group. A compound of general formula IX may be prepared by reacting a εubstituted acid of general formula X wherein: R 1 and R 2 are as defined in general formula I, R 5 represents a C^-C 8 alkyl or benzyl group and R' represents a c ι~ c 6 alkoxycarbonyl or benzyloxycarbonyl group, with an amino acid derivative of general formula (XI) (XI) wherein: R 3 is as defined in general formula I and R 6 represents a C- j^ -Cg alkoxy, benzyloxy or subεtituted benzyloxy group. Alternatively, a compound of general formula IV can be prepared by de-esterifying (for example hydrolysing, under acid or base catalysis) a compound of general formula XII wherein: R- R 2 , R 3 , 1 - n and A are as defined in general formula I and Re represents C l "C 6 alkyl or benzyl group. A compound of general formula XII can be prepared in a manner analogous to the preparation of a compound of formula IX by reacting a substituted acid of general formula XIII 1 6 7 wherein : 8 9 R 1 and R 2 are as defined in general formula I and 10 R 5 represents a C-^-C 8 alkyl or benzyl group, 11 12 with an amino acid derivative of general formula XIV 13 18 19 wherein: 20 21 R 3 , R 4 , n and A are as defined in general formula I. 22 23 In a further synthetic variant, a compound of general 24 formula X aε defined above wherein R 1 represents a 25 hydrogen atom can be reacted with a compound of general 26 formula XIV to produce a compound of general formula XV 32 33 wherein: R 2 , R 3 R 4 , n and A are as defined in general formula I, R 5 represents a C-^-Cg alkyl or benzyl group and R 7 represents a ^-Cg alkoxycarbonyl or benzyloxycarbonyl group. A compound of general formula XV wherein R 5 represents benzyl and R 1 represents benzyloxycarbonyl may be hydrogenated to the malonic acid, then treatment with aqueous formaldehyde and piperidine gives a compound of formula XVI R 2 0 wherein : R 2 , R 3 R 4 , n and A are as defined in general formula I . Compounds of general formula XVI, by treatment with the appropriate thiols give the acids of general formula IV where R 1 is a substituted thiomethyl derivative. Thiomethyl derivatives can be oxidised to sulphoxides and sulphones as appropriate. The starting materials (compounds of general formulae IX, X, XIII and XIV) and reagents described above are either commercially available or may be produced by conventional processes from commercially E available materials. For example, when R 1 represents a hydrogen atom, the substituted acid of general formula XIII may be prepared by reaction of an aldehyde XVII R 9 CHO (XVII) wherein R 9 representε a hydrogen atom or a C-^-Cg alkyl c ι~ c 5 alkenyl, phenyl (C- j^ -Cg) alkyl, cycloalkyl (C^Cg) alkyl or cycloalkenyl (C- j^ -Cg) alkyl group, with a εuccinate derivative of general formula XVIII, R 5 0 2 C \^- C0 2 R^ (XVIII) wherein: R 5 repreεentε a C-^-Cg alkyl or benzyl group under baεe catalysis to give a mixture of acids of general formulae XlXa and XlXb which by hydrogenation, eεterification and hydrolysis can be converted to the acids of the general formula XIII. Alternatively an ester of general formula XX may be reacted with an ester stabliεed phosphorane of general formula XXI to yield a compound of general formula XXII wherein R representε a C-^-C alkyl group, which can be further converted by hydrogenation to the acids of general formula XIII. In addition the substituted esters may be prepared by reacting an ester of the general formula XXIII (XXIII) wherein Y represents halo and R 5 is as defined above and R 10 is either R 1 or R as defined above, with a malonate derivative of the general formula XXIV R ll wherein R 11 is R 2 or R 1 as defined above, and the alternative to that substituent employed in the halo ester. Compounds of general formulae III and IV are valuable intermediates in the preparation of compounds of general formula I. According to a third aspect of the invention, there is therefore provided a compound of general formula III. According to a fourth aεpect of the invention, there iε provided a compound of general formula IV. Aε mentioned above, compounds of general formula I are useful in human or veterinary medicine as they are active inhibitors , of metalloproteases involved in tisεue degradation. According to a fifth aspect of the invention, there is provided a compound of general formula I for use in human or veterinary medicine , particularly in the management (by which iε meant treatment of prophylaxis) of disease involving tissue degradation, in particular rheumatoid arthritis , and/or in the promotion of wound healing. According to a sixth aspect of the invention, there is provided the use of a compound of general formula I in the preparation of an agent for the management of disease involving tisεue degradation, particularly rheumatoid arthritiε, and/or in the promotion of wound healing. Compounds of general formula I can therefore be 'used in a method of treating diseaεe involving tiεεue degradation, particularly rheumatoid arthritiε, and/or in a method of promoting wound healing, the method in either case comprising administering to a human or animal patient an effective amount of a compound of general formula I. The potency of compounds of general formula I to act as inhibitors of collagenase (a metalloprotease involved in tissue degradation) was determined by the procedure of Cawston and Barrett, (Anal. Biochem.. 99, 340-345, 1979) and their potency to act as inhibitors of stromelysin was determined using the procedure of Cawston et al (Biochem. J. , 195, 159-165 1981), both of which techniques are to be described more fully in the examples and, to the extent that the law allows, are incorporated by reference herein. According to a seventh aspect of the invention, there is provided a pharmaceutical or veterinary formulation comprising a compound of general formula I and a pharmaceutically and/or veterinarily acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically and/or veterinarily acceptible carriers and/or diluents and/or adjuvents and if desired other active ingredients. According to an eighth aspect of the invention, there is provided a process for the preparation of a pharmaceutical or veterinary formulation in accordance with the seventh aspect, the process comprising admixing a compound of general formula I and a pharmaceutically and/or veterinarily acceptable carrier. Compounds of general formula I may be formulated for administration by any route and would depend on the disease being treated. The may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparation , such as oral, topical, or εterile parenteral solutions or suspenεionε. Tablets and capsuleε for oral administration may be in unit dose presentation form, and may contain conventional excipients εuch aε binding agentε, for example εyrup, acacia, gelatin, εorbitol, tragacanth, or polyvinyl-pyrrollidone; fillers for example lactoεe, εugar, maize-εtarch, calcium phosphate, sorbitol or glycine; tableting lubricant, for example magnesium εterate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tabletε may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensionε, solutions, emulεions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other εuitable vehicle before uεe. Such liquid preparationε may contain conventional additives such as suεpending agents, for example εorbitol, syrup,- methyl cellulose, glucoεe εyrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqujeous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esterε such as glycerine, propylene glycol, or ethyl alcohol; preεervatives, for example methyl or propyl p-hydroxybenzoate or εorbic acid, and if deεired conventional flavouring or colouring agents. The dosage unit involved in oral administration may contain from about 1 to 250 mg, preferably from about 25 to 250 g, of a compound of general formula I. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and will ultimately depend on the judgement of the physician or veterinarian. However, a dose of a compound of general formula I of about 0.1 to 300mg/kg body weight, particularly from about 1 to 100 mg/kg body weight may be appropriate. For topical application to the skin the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, aε described in standard text books of pharmaceutics such as the British Pharmacopoeia. For topical applications to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edeate; preservativeε including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorohexidine, and thickening agents such as hypromellose may also be included. The dosage employed for the topical administration will, of course, depend on the size of the area beiiig treated. For the eyes each dose will be typically in the range from 10 to 100 mg of the compound of general formula I. The active ingredient may also be administered parenterally in a sterile medium. The drug depending on the vehicle and concentration used, can either be εuεpended or diεεolved in the vehicle. Advantageouεly, adjuvants such as a local anaesthetic, preservative and buffering agents can be disεolved in the vehicle. For use in the treatment of rheumatoid arthritis the compounds of this invention can be adminiεtered by the oral route or by injection intra-articularly into the affected joint. The daily doεage for a 70 kg mammal will be in the range of 10 mgε to 1 gram of a compound of general formula I. The following exampleε illuεtrate the invention, but are not intended to limit the εcope in any way. The following abbreviationε have been used in the Exampleε:- DCC - Dicyclohexylcarbodiimide DCM - Dichloromethane DCU - Dicyclohexylurea DIPE - Diiεopropyl ether DMΓ* - N,N-dimethylformamide HOBT - Hydroxybenztriazole NMM - N-Methylmorpholine TFA - Trifluoroacetic acid THF - Tetrahydrofuran WSCDI - N-(Dimethylaminoethyl)-N / -ethylcarbodiimide Example 1 [ -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalani- ne-N-[ (2-aminoethyl)-2(RS)-(l-methylpyrrolidine) ]amide (a) [4-Benzyloxy-3-benzyloxycarbonyl-2R-isobutyl- succinyl]-L-phenylalanine methyl ester Benzyl (2-benzyloxycarbonyl-5-methyl-3R-tert-butoxy- carbonyl)-hexanoate (52g, 115 mmol) was stirred at room temperature with 5% water in TFA (250 ml) for 1.5h. After this time the TFA was evaporated under reduced pressure then the residue was azeotroped with toluene (3 x 250 ml) . The crude acid from this reaction was dissolved in DCM/DMF (4:1), then HOBT (16g, 118 mmol), NMM (12g, 118 mmol) and WSCDI (22g, 115 mmol) were added at room temperature. After 20 minutes a further equivalent of NMM (12g, 118 mmol) was added followed by L-phenylalanine methyl ester hydrochloride (23g, 107 mmol) . This solution was stirred overnight and then concentrated under vacuum. The oily residue was dissolved in DCM then washed with 10% citric acid (2x250 ml) , with 10% sodium bicarbonate (2x250 ml) and once with saturated brine (250 ml) . The organic layer was dried (sodium sulphate) , filtered then the solvent removed under reduced pressure to give the title compound as an oil ( 50.9g, 79%) . delta H (250MHz, CDC13) 7.39-7.11 (15H,m) , 5.19 (2H, d, J=5Hz), 5.11 (2H, d, J=5Hz) , 3.15-2.90 (2H, ABX) , 0.79 (3H, d, J=6Hz) , and 0.77 (3H, d, J=6Hz) (b) Hydroxy-2R-isobutylεuccinyl]-L-phenylalanine methyl eεter The product from above (50.9g, 91mmol) waε diεεolved in ethanol (100ml) and εtirred at room temperature with activated charcoal pellets for lh. 10% Palladium on charcoal (20g) in ethyl acetate was slurried into the ethanolic solution. Cyclohexene (20ml) in ethanol (100ml) was added and the mixture was brought to reflux for 5h. The reaction mixture waε filtered to remove the catalyεt then the εolventε evaporated under reduced preεεure to leave a yellow oil (29.8g). Thiε oil waε taken up in xylene (500ml) and heated at reflux for 10 minuteε. The xylene waε removed under reduced pressure to leave the crude material as an oil (26.5g). (c) [4-(N-Benzyloxyamino) -2R-isobutylsuccinyl] -__.- phenylalanine methyl ester The crude acid (26.5g, 79mmol) was dissolved in DCM/DMF (4:1, 500ml), then NMM (9.6g, 95mmol) , HOBT (12.8g 95mmol) and WSCDI (18.2g, 95mmol) added and the mixture εtirred at room temperature until tic indicated complete conversion to the activated ester (about 10 minutes) . To this solution containing the active ester was added benzylhydroxy1amine hydrochloride (15.2g, 95mmol) and a further equivalent of NMM (9.6g, 95mmol) in the solvent mixture (80ml). After stirring at room temperature overnight DCM (250ml) was added then the mixture washed with citric acid (2x250ml) , 10% sodium bicarbonate solution (2x250ml) and brine (250ml) then finally dried over sodium sulphate. The solution was filtered and the solvent removed under reduced presεure to give an oil (27.2g) which was purified by column chromatography using ether as an eluant to give the title compound (llg, 23.7mmol, 30%). Delta H (250MHz, CDC13) 7.47-7.09 (10H, m) , 4.88 (2H, ε) , 3.11 (2H, d, J=6Hz) , and 0.87 (6H, m) (d) [4- (N-Benzyloxyamino) -2R-isobutylεuccinyl] -L- phenylalanine [4-(N-Benzyloxyamino) -2R-isobutylsuccinyl]-L-phenyl- alanine methyl ester (9.5g, 21mmol) was dissolved in methanol (200ml) and lithium hydroxide solution (0.5N, 84ml, 42mmol) was added with stirring at room temperature. When the reaction was complete, as judged from tic, the methanol was removed by evaporation and the remaining aqueous phase was acidified to pHl with citric acid. The precipitated solid was filtered off and dried, while the fitrate was extracted with DCM (500ml) and dried over sodium sulphate. Solvent removal from the organic phase left an oil (5.38g) which could be recryεtalliεed from diisopropyl ether and methanol to give material which was identical with the solid which precipitated during acidification. These two batcheε were combined to give the title compound (6.40g, 15mmol, 71%) m.p. 161-162°C nu maχ (KBr) 3300, 3020, 2980, 1710, 1650, 1630, 1550, 1265, 740, and 700 cm -1 Delta H (250MHz, CDC1 3 /Dg-DMS0) 7.36 - 7.18 (10H, m) , 4.77 (2H, ε) , 3.14 - 2.91 (2H, ABX) , 2.06 - 2.00 (2H, ABX), 1.50 (2H, b ) ,and 0.87 - 0.80 (6H, m) Delta c (62.9MHz, D6-DMSO) 174.1, 173.1, 167.7, 137.9, 129.2-126.4, 76.9, 53.3, 40.7, 39.9, 36.8, 35.8, 25.3, 23.5, and 22.1 (e) [4-(N-Hydroxyamino)-2R-iεobutylsuccinyl]-L-phenyl- alanine-N-[ (2-aminoethyl)-2 (RS)-(1-methylpyrrolidine) ]- amide [4- (N-Benzyloxyamino) -2R-isobutylεuccinyl]-L-phenyl- alanine (200mg, 0.47mmol) waε disεolved in THF (6ml) and cooled in ice. Triethylamine (52mg, 0.522mmol) was added together with ethylchloroformate (50mg, 0.47mmol) and after 10 minutes 2-(2-aminoethyl) -N-methylpyrrolidine (67mg, 0.522mmol) in THF (1ml) was added. After 3h at room temperature the reaction mixture was diluted with ethyl acetate then washed with sodium bicarbonate solution and brine, then dried over sodium sulphate. Solvent removal under reduced pressure gave the crude benzyl hydroxamate (220mg, 0. 1mmol) . The crude material from above was dissolved in cyclohexene/ethanol (10% solution, 5ml) , 10% palladium on charcoal (50mg) was added then the mixture refluxed until starting material had dissappeared by tic (ca 30 minutes) . The catalyst was removed by filtration, and the solvent removed under reduced pressure to leave an oil which could be crystallised by the addition of hexane. The required product (150mg, 0.34mmol, 72%) was collected by fitration. m.p. 156-158°C Analysis calculated for C 2 4H 38 N 4 0 4 .1/2H 2 0 Requires C 63.27 H 8.63 N 12.30 Found C 63.28 H 8.53 N 12.03 nu maχ (KBr) 3300, 2950, 1650, 1550, and 700cm "1 Delta H (250MHz, CDC1 3 ) 7.19 (5H, m) , 4.41 (IH, bm) , 2.99 (2H, m) , 2.01 (4H, m) , 1.61 (4H, m) , 1.30 (4H, m) , and 0.72 (6H, ) . Example 2 [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -L-phenyl¬ alanine-N- [1- (2-aminoethyl) -piperidine] amide Using the procedure described in Example le [4-(N-benzyloxyamino) -2R-isobutylsuccinyl] -L-phenyl¬ alanine (200mg, 0.47mmol) was coupled with l-( 2-aminoethyl) -piperidine (67mg, 0.522mmol) then the product hydrogenated to give the title compound (66mg, 0.15mmol, 31%) m.p. 154-6°C (DCM/hexane) nu_ a (KBr) 3300, 2950, 1640, 700cm -1 Delta H (250MHz, CDC1 3 /Dg-DMS0) 7.2 (5H, s) , 3.2 (IH, bm) , 2.4 (5H, bm) , 1.6 (3H, bd) , 0.85 (6H, m) Example 3 [4- (N-Hydroxyamino) -2R-iεobutylεuccinyl] -L-phenyl¬ alanine-N- [ 1- ( 2 -aminoethy 1 ) -pyrrol idine ] amide Using the procedure deεcribed in Example le [4-(N-benzyloxyamino) -2R-iεobutylεuccinyl]-L-phenyl- alanine (200mg, 0.47mmol) waε coupled with 1- (2-aminoethyl) -pyrrolidine (117mg, 0.75mmol) then the product hydrogenated to give the title compound. m.p; 105-110°C Analysis calculated for C 23 H 36 N 4 O 4 .0.4H 2 O Requires C 62.82 H 8.43 N 12.74 Found C 63.09 H 8.18 N 12.23 Delta H (250MHz, Dg-DMSO) 8.14 (IH, d, J=8Hz, CONHCH) , 7.78 (IH, t, J=5Hz, NHCH 2 ), 7.20 (5H, m, aromatic H) , 4.42 (IH, m, PhCH 2 CH) , 3.10 - 2.62 (7H, m, NHCH 2 CH 2 , PhCH 2 , and CHCH 2 CO) , 2.44 - 2.32 (6H, m, CH 2 CH 2 CH 2 CH 2 and NHCH 2 CH 2 N) , 1.62 (4H, m, CH 2 CH 2 CH 2 CH 2 ) , 1.30 (2H, m, CHCH 2 CH) , 0.98 (IH, m, (CH 3 ) 2 CH), 0.74 and 0.78 (6H, 2xd, J=6Hz, (CH 3 ) 2 CH). Example 4 [4- (N-Hydroxyamino) - 2 R-isobutyl succinyl ] -L-phenyl- alanine-N- [1- (3-aminopropyl) -2 (RS) -methylpiperidine] - amide Using the procedure described in Example le [4- (N-benzyloxyamino) -2R-isobutylsuccinyl] -L-phenyl¬ alanine (200mg, 0.47mmol) was coupled with 1- (2-aminoethyl) -2-methylpiperidine (70mg, 0.75mmol) then the product hydrogenated to give the title compound. m.p. 119-124°C Delta H (250MHz, Dg-DMSO) 8.10 (IH, d, J= 8Hz, CONHCH), 7.88 (5H, m, aromatic H) , 4.38 (IH, , PhCH 2 CH) , 3.10 - 2.58 (7H, m, NHCH 2 , PhCH 2 , and COCH 2 CHCO) , 2.42 - 2.22 (5H, m, NCHCH 2 CH 2 CH 2 CH 2 and NHCH 2 CH 2 CH 2 N) , 2.12 - 1.34 (8H, m, NCHCH 2 CH 2 CH 2 CH 2 and NHCH 2 CH 2 CH 2 N) , 1.24 - 1.16 (2H, m, CHCH 2 CH) , 1.00 (3H, d, J=4Hz, CH 3 CHN) , and 0.96 - 0.62 (7H, m, (CH 3 ) 2 CH). Example 5 [4- (N-Hydroxyamino) -2R-iεobutylεuccinyl] -L-phenyl¬ alanine-N- [2- (2-aminoethyl) -1-methylpyrrole] amide (a) Phenylalanine-N- [2- (2-aminoethyl) -1-methyl¬ pyrrole] amide To a solution of N- (benzyloxycarbonyl) -phenylalanine (δ!θOg, 26.7mmol), 2- (2-aminoethyl) -1-methylpyrrole (3.65g, 29.4mmol) , HOBT (3.98g, 29.4mmol) and NMM (2.97g, 29.4mmol) in DMF cooled to 0° was added a solution of DCC (6.07g, 29.4mmol) in THF. After addition was complete the reaction was left to stir at room temperature overnight. The solvents were removed under reduced presεure and the reεidual εolid was taken up in ethyl acetate and washed with water, 10% sodium bicarbonate and brine then dried over sodium sulphate. Filtration and solvent removal gave the crude benzyloxy protected material which was converted to the free amine by dissolving in ethanol/cyclohexene (10% solution, 150ml) adding 10% palladium on charcoal and refluxing for 2h. This mixture was filtered to remove the catalyst, the ethanol was removed under reduced presεure, the residue dissolved in ethyl acetate and extracted with citric acid. Basification of the aqueous layer to pH 12 with εodium hydroxide solution was followed by extraction with ethyl acetate to give the title compound (4.11g, 15 mmol, 57%) Delta H (250MHz, CDC13) 7.45 - 7.20 (7H, m, NH2 + aromatic H) , 6.57 (IH, d, J= 3Hz), 6.06 (IH, d, J= 4Hz) , 5.89 (IH, m) , 3.50 (5H, m) , 3.28 (IH, ) , 2.71 (2H, ) , and 1.26 (2H, t, J= 7Hz) . (b) [4-Benzyloxy-3-benzyloxycarbonyl-2R-isobutyl- succinyl]-L-phenylalanine-N-[2-(2-aminoethyl)-1-methy1- pyrrole] mide To a solution of phenylalanine-N-[2-(2-aminoethyl) - 1-methylpyrrole]amide (2.00g, 7.4mmol), 4-tert-butyl- 2R-isobutyl εuccinate (3.23g, S.lmmol), HOBT (1.09g, S.lmmol) and NMM (1.82g, S.lmmol) in DMF cooled to 0° was added DCC (1.67g, δ.lm ol) in THF. The resultant mixture waε allowed to warm to room temperature then εtirring continued for 72h. The precipitated DCU was collected by filtration then the solvents removed under reduced pressure. The residual oil waε diεεolved in ethyl acetate, washed with 1-0% sodium bicarbonate, water and brine then dried over sodium sulphate. Solvent removal under reduced presεure gave the crude product (5.48g) as an oil. Thiε material waε purified by column chromatography using 40% ethyl acetate in hexane as eluant to give the desired isomer (1.45g, 2.2mmol, 30%) c o m p l e t e l y s e p a r a t e d f r o m t h e [ 4 -benzyloxy -3 -benzyloxycarbonyl-2S-isobutyl- succinyl] -L-phenylalanine-N- [2- (2-aminoethyl ) - 1-methy 1 pyrrole]amide isomer (1.04g, 1.6mmol, 22%) . Delta H (250MHZ, CDC1 3 ) 7.27 (10H, m, aromatic H) , 7.19 (5H, m) , 6.54 (IH, m) , 6.02 (IH, t, J= 3Hz) , 5.17 - 5.01 (3H, m) , 3.56 (3H, ε) , 3.31 (IH, m) , 2.74 (2H, m) , 1.68 (IH, bm) , 0.97 - 0.74 (3H, bm) , 1.65 (3H, d, J= 6Hz) , and 1.60 (3H, d, J= 6Hz) . (c) [4-Hydroxy-2R-isobutylsuccinyl]-L-phenylalanine-N- [2- (2-aminoethyl) -1-methylpyrrole] amide [ 4 -Benzyl oxy-3-benzyloxycarbonyl-2R- iεobutylεuccinyl ]- L-phenylalanine-N- [2- (2-aminoethyl) -1-methylpyrrole] - amide (1.45g, 2.3mmol) was diεεolved in ethanol / cyclohexene (10% εolution) , 10% palladium on charcoal (0.14g) added and the mixture refluxed for 2h. After thiε time tic εhowed complete conεumption of starting material so the reaction was cooled, filtered through celite and solvent removed under vacuum. The resultant oil was taken up in toluene and refluxed for two hours, solvent removal then gave the crude material (1.09g, 2.6mmol) which was used without further purification. Delta H (250MHz, CDC1 3 ) 7.21 (5H, m) , 6.53 (IH, m) , 5.99 (IH, s) , 3.57 (IH, s) , 3.50 (3H, m) , 3.38 (IH, bm) , 2.59 (2H, m) , 2.37 (3H, s) , 1.54 (IH, m) , 1.30 (IH, m) , and 0.90 (6H, m) . (d) [4- (N-Benzyloxyamino) -2R-iεobutylεuccinyl]-L- phenylalanine-N-[2-(2-a inoethy1)-1-methylpyrrole]amide [4-Hydroxy-2R-iεobutylεuccinyl]-L-phenylalanine-N-[2- ( 2-aminoethy1 ) -1-methylpyrrole] amide (0.68g, 1.6mmol), benzylhydroxylamine (0.28g, l.δmmol), NMM (O.lδg, l.δmmol) amd HOBT (0.24g, 1.8 mmol) were dissolved in DMF and cooled to 0°. DCC (0.36g, l.δmmol) in THF was added dropwise and when the addition was complete the mixture was allowed to stir overnight. The precipitated DCU waε removed by filtration, the εolventε removed from the filtrate under reduced pressure, the residue dissolved in ethyl acetate (50ml) and washed with 10% sodium bicarbonate (2x50ml) , water (50ml) and brine (50ml) then dried over sodium sulphate. Filtration and removal of the ethyl acetate gave the crude product (1.25g) as an oil. Further purification was achieved by column chromatography using 2% methanol/DCM as eluant to give the title compound (0.71g, 1.34mmol, δ3%) Delta H (250MHz, CDCl 3 ) 7.47 - 7.16 (10H, bm) , 6.52 (IH, t, J= 2Hz) , 6.00 (IH, dd, J= 3,4Hz), 5.75 (IH, m) , 4.δ6 (2H, s) , 3.44 (3H, ε) , 3.08 (2H, d, J= 7Hz) , 2.50 (2H, m) , 1.46 (IH, m) , and 0.δ5 (6H, m) (e) [4-(N-Hydroxyamino)-2R-iεobutylsuccinyl]-L-phenyl- alanine-N-[2-(2-aminoethyl)-1-methylpyrrole]amide [4-(N-Benzyloxyamino)-2R-isobutylεuccinyl]-L-phenyl- alanine-N-[2-(2-aminoethyl) -1-methylpyrrole]amide (0.53g, I.Ommol) waε diεsolved in cyclohexene/ethanol (10% solution, 20ml) , 10% palladium on charcoal (50mg) was added then the mixture refluxed for lh. The catalyst waε removed by filtration, and the εolvent removed under reduced pressure to leave an oil which could be recryεtalliεed from ethanol and diiεopropyl ether. The required product (196mg, 0.45mmol, 45%) was collected by fitration. m.p. 157-158°C Delta H (250MHz, CDCl 3 /D g -DMSO) δ.06 (2H, d, J=2Hz) , 7.97 (IH, m) , 7.52 (5H, m, Ph) , 6.δ7 (IH, d, J= 1.8Hz, NH) , 6.28 (IH, t, J= 3Hz, NH) , 6.27 (IH, s, NH) , 3.89 (3H, ε, N-CH 3 ), 3.70 (2H, m) , 3.46 (3H, m) , 2.98 (2H, m) , 1.70 (2H, m) , 1.43 (IH, m) and 1.20 (6H, m, 2XCH 3 ) . Delta c (62.9MHz, Dg-DMSO) 168.8, 165.6, 162.7, 132.5, 124.5, 123.7, 122.4, 120.6, 115.7, 100.9, 100.2, 72.1, 72.8, 73.5, 49.2, 36.3, 35.6, 35.0, 34.8, 34.0, 33.2, 32.δ, 31.7, 30.4, 27.9, 23.9, 20.5, 19.7, 17.4, and 16.'5 1 Example 6 2 3 [ 4- (N-Hydroxyamino) -2R-isobutylsuccinyl ] -L-phenyl* 4 alanine-N- (3 -aminomethylpyridine) amide 0 1 The title compound was prepared by the method 2 described in Example 5 to give a compound with the 3 following characteristics 4 m. p . 184 - 185° [alpha] D = +2.1° (c=l, MeOH) nu maχ (KBr) 3300, 1650, 1550, and 700 cm "1 Analysis calculated for C 2 3H 30 N 4 O 4 Requires C 64.77 H 7.09 N 13.14 Found C 64.51 H 7.08 N 13.21 Delta H (250MHz, CDC1 3 /Dg-DMS0) 8.68 (IH, bs) , 8.41 (2H, m) , 7.95 (IH, d, J= 8Hz) , 7.49 (IH, d, J= 8Hz) , 7.15 (5H, m, aromatic H) , 4.46 (2H, m) , 4.27 (2H, d, J= 6HZ), 3.09 (IH, dd, J= 6, 14Hz) , 2.88 (IH, dd, J= 10, 14Hz) , 2.12 (IH, dd, J= 8, 16Hz) , 1.95 (IH, dd, J=15, 6Hz) , 1.30 (3H, m) , and 0.70 (6H,m) . 1 Example 7 2 3 [ 4 - (N-Hydroxyamino) -2R-isobutylsuccinyl ] -L-phenyl- 4 alanine-N- (2 -aminomethylpyridine) amide 0 1 The title compound was prepared by the method described 2 in Example 5 to give a compound with the following 3 characteristics 4 5 m.p. 165 - 167° (decomp.) 6 7 [alpha] D = +1.8° (c = 0.83, MeOH) 8 9 nu maχ (KBr) 3280, 2960, 2920, 1715, 1680, and 750 cm "1 0 1 Delta H (250MHz, CDC1 3 /Dg-DMS0, 1:3) 8.46 (2H, m) , 8.05 2 (IH, partially obscured by solvent), 7.64 (IH, dt, 3 J=2,δ Hz), 7.22 (7H, m) , 4.56 (IH, m) , 4.42 (IH, ε) , 4 4.40 (IH, s) , 3.17 (IH, dd, J=5, 14 Hz) , 2.96 (IH, dd, 5 J=9,14 Hz) , 2.67 (IH, m) , 2.16 (IH, dd, J=7,14 Hz), 6 2.00 (IH, dd, J=14,7 Hz), 1.37 (2H, m) , 1.03 (IH, m) , 7 0.79 (3H, d, J= 6Hz) , and 0.75 (3H, d, J=6 Hz) . δ 9 Delta c (62.9MHz, CDC1 3 /Dg-DMS0, 1:3) 174.2, 171.2, 0 167.9, 158.1, 148.4, 137.9, 136.3, 129.0, 127.9, 1 126.0, 121.7, 120.9, 78.7, 54.3, 44.3, 40.4, 37.0, 2 35.7, 25.2, 23.1, and 21.8. 3 Example 8 [4- (N-Hydroxyamino) -2 (RS) -isobutylsuccinyl]-L-phenyl* alanine-N- (4-aminomethylpyridine) amide The title compound was prepared by the method described in Example 5 to give a 2:1 mixture of isomers with the following characteristics m.p. 189 - 192° (decomp) nu maχ (KBr) 3320, 3250, 2960, 2925, 1655, 1640, 1610, 1540, 730, and 700 cm "1 Delta H (250MHz, Dg-DMSO) includes 10.4 (IH, bs) , 7.24 (5H, ) , 7.11 (2H, d, J=6 Hz), 4.51 (IH, m) , 4.28 (IH, s) , 4.26 (IH, ε) , 0.76 (3H, d, J=6 Hz, major diastereomer) , 0.72 (3H, d, J=6 Hz, major diastereomer) , 0.69 (3H, d, J=6 Hz, minor diastereomer), 0.58 (3H, d, J=5 Hz, minor diastereomer) Delta c (62.9MHz, Dg-DMSO) Major isomer 174.2, 171.5, 167.7., 149.4, 148.4, 138.2, 129.3, 128.2, 126.4, 122.1, 54.3, 41.2, 40.5, 40.1, 37.2, 35.8, 25.3, 23.5, and 22.0 :Minor isomer 174.6, 171.7, 168.4, 149.5, 148.5, 138.6, 129.2, 128.1, 126.2, 122.2, 54.7, 41.5, 41.4, 40.9, 37.2, 36.8, 24.8, 23.6, and 21.9. 1 Example 9 2 3 [4-(N-Hydroxyamino)-2 (RS) -isobutylsuccinyl]-L-phenyl- 4 alanine-N-(1-(3-aminopropyl) -imdazole)amide 0 1 The title compound waε prepared by the method described 2 in Example 5 to give the title compound with the 3 following characteristicε 4 5 m.p. 166-167 6 7 Delta H (250MHz, CDC13) 7.35 (IH, m) , 7.28 - 7.15 (5H, 8 m) , 7.14 (IH, m) , 7.00 (IH, s) , 6.8δ (IH, ε) , 4.97 (IH, 9 m) , 4.00 - 3.90 (2H, m) , 3.55 - 3.34 (2H, m) , 3.32 0 (IH, m) , 3.14 (IH, m) , 2.59 (2H, m) , 2.0δ (2H, m) , 1 1.94 (2H, m) , 1.52 (IH, εep, J=7Hz) , 1.29 (IH, m) , and 2 0.91 - 0.73 (6H, m) . 3 4 Delta c (62.9MHz, CDCl 3 ) 179. δ, 177.0, 168.7, 137.6, 5 137.0, 129.2, 128.6, 126.8, 118.6, 116.0, 77.6, 77.2, 6 76.6, 55.4, 44.5, 40.3, 38.1, 37.2, 34.6, 33.7, 30.6, 7 25.8, 22.δ, and 21.7. δ 9 Example 10 0 1 [4- (N-Hydroxyamino) -2 (RS) -iεobutylεuccinyl]-L-phenyl- 2 alanine-N-(2-aminomethylbenzimdazole)amide 3 The title compound was prepared by the method described in Example 5 to give the title compound with the following characteristics m. p . 217 c [ alpha] n = -77 . 4° (c=l , MeOH) numax (KBr) 3280, 2960, 2920, 2860, 1650, 1550, 1510, 1440, 1275, 1030, 740, and 700 cm -1 Delta H (250MHZ, CDC1 3 /D 4 Methanol) 8.4 (IH, s, NH) , 7.34 (2H, m) , 7.26 (IH, s) , 7.05 (5H, m) , 4.48 (2H, m) , 3.27 (IH, dd, J=10,4Hz), 3.17 (3H, m) , 2.67 - 2.48 (2H, m) , 2.20 - 1.92 (2H, m) , 1.18 (IH, m) , 0.73 (IH, m) , and 0.52 (6H, m, (CH 3 ) 2 CH) Delta c (62.9MHz, CDC1 3 /D 4 Methanol) 171.1, 167.4, 164.7, 143.8, 132.0, 123.4, 123.1, 121.3, 117.3, 49.3, 36.3, 35.5, 31.6, 31.4, 30.2, 19.8, 17.8, and 16.0 Example 11 [ 4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl ] -L- phenylalanine-N- [4- (2-aminoethyl) -morpholino] amide (a) Phenylalanine-N-[4-(2-aminoethyl)morpholino]amide To a solution of N-(Benzyloxycarbonyl) -phenylalanine (29.91g, lOOmmol) , 4-(2-aminoethyl) -morpholine (14.32g, llOmmol) , HOBT (14.δ6g, llOmmol) and NMM (11.13g, llOmmol) in DCM / DMF (4:1) and DCC (6.07g, 29.4mmol) added. After addition waε complete the reaction was left to stir at room temperature overnight. The solvents were removed under reduced presεure and the reεidual εolid waε taken up in ethyl acetate and waεhed with ' water, 10% aodium bicarbonate and brine. The ethyl acetate layer waε then extracted with 3% hydrochloric acid the aqueouε solution separated and basified to pH 11. This solution was extracted with ethyl acetate, dried over sodium sulphate then solvent removal gave the amine as a crude solid which was recrystallised from ethyl acetate/hexane (44.7δg, 109mmol, 100%). Delta H (250MHz, CDC1 3 ) 7.56 (IH, m) , 7.45 (5H, m) , 7.39 (5H, bs) , 7.15 (IH, d, J= δHz) , 5.17 (2H, ε) , 4.49 (IH, q, J= 7HZ) , 3.75 (3H, m) , 3.40 (2H, t, J= 6Hz) , 3.24 (IH, dd, J= 5.5,14Hz), 3.05 (IH, m) , and 2.51 (4H, bs) . Delta c (62.9MHz, CDCl 3 ) 170.6, 136.8, 136.3, 129.4, 128.7, 128.6, 128.3, 128.1, 127.0, 77.7, 77.2, 76.6, 67.0, 66.7, 56.7, 56.4, 53.1, 39.3, and 35.5. This material was converted to the free amine by dissolving in ethanol/cyclohexene (10% solution) , adding 10% palladium on charcoal and refluxing for 2h. The mixture was filtered to remove the catalyst, then the ethanol was removed under reduced pressure to give the title compound (19.16g, 69mmol, 69%). (b) [4-tert-Butoχy-2R-isobutyl-3S-methylsuccinyl1- L-pheny1alanine-N-[4-(2-aminoethy1) -morpholine]amide To a solution of phenylalanine-N-[4- (2-aminoethyl) - morpholine] amide (19.16g, 69mmol) , 4-tert-butyl-2R- isobutyl εuccinate (18.57g, 76mmol) , HOBT (10.27g, 76mmol) and NMM (7.69gg, 76mmol) in DMF cooled to 0° was added DCC (15.68g, 76mmol) in THF. The resultant mixture was allowed to warm to room temperature then stirring continued over the weekend. The precipitated DCU was collected by filtration then the solventε removed under reduced preεεure. The residual oil was diεεolved in ethyl acetate, washed with 10% sodium bicarbonate, water and brine then dried over sodium sulphate. Solvent removal under reduced pressure gave the crude product (36.5g) aε an oil. This material was purified and the diastereomers separated by careful column chromatography using 0 5% methanol in DCM as eluant to give the desired isomer slightly contaminated with a lower running isomer (7.86g, 15.6mmol, 23%) Delta H (250MHz, CDC1 3 ) 7.23 (5H, m) , 6.54 (IH, d, J= 6.5Hz), 6.04 (IH, m) , 3.60 (4H, m) , 3.22 - 3.0δ (2H, m) , 2.95 (IH, m) , 2.44 - 2.20 (8H, m) , 1.71 (IH, m) , 1.43 (9H, m) , 1.12 (IH, m) , 0.95 (2H, d, J=6Hz), and 0.83 (6H, t, J= 6Hz) . (c) [4- (N-Benzyloxyamino) -2R-isobutyl-3S-methyl- succinyl] -L-phenylalanine-N- [4- (2-aminoethyl) - morpholine]amide [4-tert-Butoxy-2R-isobuty1-3S-methylsuccinyl]-L-phenyl- alanine-N-[4-(2-aminoethyl)-morpholine]amide (2.37g, 4.7mmol) was dissolved in 5% water in TFA (15ml) with cooling and stirred for 90 minutes after which time tic indicated that deprotection was complete. Removal of the excess TFA was achieved by azeotroping with xylene to give the crude acid which was uεed without further purification. Thiε product was taken up in DCM / DMF (4:1, 20ml) and the pH adjusted to 7 by adding NMM. To this waε added HOBT (0.76g, 5.6 mmol) and NMM (0.57g, 5.6mmol), then after cooling to 0°, WSCDI (1.08g,5.6mmol) . This mixture was left to stir at room temperature for 45 minutes, cooled in an ice bath and benzylhydroxylamine (0.90g, 5.6mmol) added and finally stirred overnight. The precipitated product was filtered off and dried to yield the title compound as a single isomer (1.62g, 2.9mmol, 52%). Delta H (250MHz, D g -DMSO) 8.26 - δ.23 (IH, d, J= δHz) , 7.70 (IH, t, J=4HZ), 7.35 (5H, bs) , 7.29 - 7.23 (5H, m) , 4.74 (2H, s) , 4.56 (IH, m) , 3.55 (4H, t, J= 5Hz) , 3.3 * 4 (5H, bε) , 3.16 (2H, q, J= 6Hz) , 2.90 (IH, m) , 2.77 1 ( IH , m) , 2 . 33 ( 4H , t , J= 5Hz ) , 2 . 27 - 2 . 25 ( 2H , m) , 2 1. 94 (IH, m) , 1. 30 - 1. 26 (2H, m) , 0. 80 (3H, d , J=6Hz ) , 3 0. 72 (3H, d, J= 6HZ) , and 0. 42 (3H, d, J=7Hz) . 4 5 (d) [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]- 6 L-phenylalanine-N-[4-(2-aminoethyl)-morpholine]amide 7 δ [4-(N-Benzyloxyamino)-2R-isobutyl-3S-methylsuccinyl]-L- 9 phenylalanine-N-[4-(2-aminoethyl)-morpholine]amide 10 (δ.lg, 14.6mmol) was diεεolved in ethanol / 11 cyclohexene (10% solution, 100ml) , 10% palladium on 12 charcoal (1.5g, 20% wt/wt) added and the mixture 13 refluxed for 30 minutes. Filtratiion to remove 14 catalyst followed by solvent removal under reduced 15 pressure gave a white solid which was recrystallised 16 from 5% methanol in ethyl acetate. Drying gave the 17 title compound (5.3g, ll.δmmol, 7δ%) . lδ 19 m.p. 205-210°C 20 Analysis calculated for c 24 H 3δ N 4 °5 1 Requires C 62.32 H 8.2δ N 12.11 2 Found C 62.05 H δ.22 N 11.97 3 4 Delta H (250MHz, Dg-DMSO) 8.76 (IH, s, NHOH), δ.22 5 (IH, d, J= δHz, CONHCH), 7.72 (IH, bs, NHCH 2 ) , 7.3δ - 6 7.04 (5H, m, aromatic H) , 4.56 (IH, m, PhCH 2 CH) , 3.64 - 7 3.42 (4H, m, CH 2 OCH 2 ) , 3.lδ (2H, d, J= 5Hz, NHCH 2 ), δ 2.98 - 2.70 (2H, m, PhCH 2 ), 2.44 - 2.10 (8H, m, 9 NHCH 2 CH 2 and CH 2 NCH 2 ) , 1.31 (2H, m, CH 2 CH) , 0.δ7 - 0 0.71 (7H, m, (CH 3 ) 2 CH), and 0.41 (3H, d, J= 6Hz, 1 CH 3 CH) . 2 3 1 Delta c (62.9MHz, Dg-DMSO) 173.5 (CONHOH), 171.2 2 (C.ONHCONH) , 136.2 - 126.2 (Aromatic C) , 66.3 3 (CH 2 OCH 2 ) , 57.3 (PhCH 2 CH) , 54.1 (NHCH 2 CH_ 2 ) , 53.4 4 (CH 2 NC H 2) , 46.δ (NHCH 2 ) , 37.4 (PhCH 2 and CHCHCO) , 36.0 5 (CH 2 CH) , 25.4 (Me2CH) , 24.2, 21.7 ((CH 3 ) 2 CH), and 6 16.1 (CH 3 CH) . 7 δ Example 12 9 0 [4-(N-Hydroxyamino)-2R-isobutylεuccinyl]-L-phenyl- 1 alanine-N-[4-(2-aminoethyl)-morpholine]amide 7 δ (a) [4-tert-Butoxy-2(RS)-iεobutylεuccinyl]-L-phenyl- 9 alaninebenzyl eεter 0 1 To a εolution of phenylalanine benzyl eεter toεic acid 2 salt (6.74g 17.6 mmol), 4-tert-butyl-2(RS)-isobutyl 3 succinate (3.6δg, 16.0 mmol), HOBT (2.3δg, 17.6 mmol) 4 and NMM (1.78g, 17.6 mmol) in DMF (20 ml) at 0° was 5 added a solution of DCC (3.63g, 17.6 mmol) in THF 6 (20ml) . The resultant mixture waε allowed to warm to 7 room temperature then εtirred overnight. The δ precipitated DCU was removed by filtration then the 9 solution concentrated under reduced pressure. The 0 residual oil was taken up in ethyl acetate and waεhed 1 εequentitally with 10% εodium bicarbonate, dilute 2 hydrochloric acid, water and finally brine. The 3 solution waε dried over sodium sulphate and the ethyl 1 acetate removed under reduced presεure. The crude 2 material thus produced was purified by column 3 chromatography using gradient elution of ethyl acetate 4 in DCM (0 - 15%) to give the title compound (3.16g, 5 6.7mmol, 42%) 6 7 (b) [4-tert-Butoxy-2 (RS)-isobutylsuccinyl]-L-phenyl- δ alanine 9 0 [4-tert-Butoxy-2(RS)-isobutylsuccinyl]-L-phenylalanine 1 benzyl eεter (3.16g, 6.7mmol) waε dissolved in 2 cyclohexene / ethanol (10% solution, 50ml) , 10% 3 palladium on charcoal (2.0g) added and the mixture 4 refluxed for 10 minutes. The cooled solution was 5 filtered through celite and the εolvent removed to 6 leave the title compound (2.25g, 6.0 mmol, δ9%) . 7 8 Delta H (250MHz, CDC13) 7.27 - 7.16 (5H, m) , 6.32 (IH, 9 m) , 4.8δ (IH, m) , 3.1δ (2H, m) , 2.61 (2H, m) , 2.33 0 (IH, m) , 1.45 - 1.42 (9H, 2xs) , 1.27 - 1.21 (2H, m) , 1 and O.δδ - 0.δ2 (6H, m) . 2 3 (c) [4-tert-Butoxy-2 (RS)-isobutylsuccinyl]-L-phenyl- 4 aianine-N-[4-(2-aminoethyl)-morpholine]amide 5 6 [4-tert-Butoxy-2 (RS)-isobutylsuccinyl]-L-phenylalanine 7 (2.27g, 6.01mmol), HOBT (0.δ9g,6.62mmol) , NMM δ (0.67g, 6.62mmol) and 4-(2-aminoethyl) -morpholine 9 (0.δ6g, 6.62mmol) were disεolved in DCM / DMF (4:1, 0 50ml) and cooled to 0° while WSCDI (1.27g, 6.62mmol) 1 was added. After addition waε complete the reaction was allowed to warm to room temperature and then stirred overnight. Solvents were removed under reduced 1 pressure then the residual oil taken up in ethyl 2 acetate and washed with water (200ml) and brine 3 (200ml) . Drying the organic layer with sodium 4 sulphate, filtration and solvent removal gave desired 5 compound aε a mixture of diastereomers (l.δ5g, 6 3.δmmol) which was deprotected without further 7 purification, δ 9 Delta H (250MHz, CDC1 3 ) 7.1δ (5H, m) , 7.16 (IH, m) , 6.4δ 0 (IH, m) , 3.59 (4H, t, J= 4.5Hz), 3.44 (IH, m) , 3.24 - 1 3.02 (2H, m) , 2.43 (IH, m) , 2.36 (8H, m) , 2.11 (IH, 2 m) , 1.35 (9H, s) , 1.09 (IH, d, J=lHz) , 1.06 (IH, d, J= 3 1Hz) , and 0.72 - 0.69 (6H, m, 2xCH 3 ) 4 5 (d) [4-(N-Benzyloxyamino)-2 (RS)-isobutylεuccinyl]-l- 6 phenylalanine-N-[4-(2-aminoethyl)-morpholine]amide 7 8 f4-tert-Butoxy-2 (RS) -iεobutylεuccinyl] -L-phenyl- 9 alanine-N-[4-(2-aminoethyl) -morpholine]amide (1.84g, 0 3.5mmol) waε diεεolved in water in TFA (5% εolution, 1 20ml) and εtirred for 2h at room temperature. The 2 exceεε TFA waε removed by azeotroping with xylene to 3 give the crude acid. Thiε material waε mixed with HOBT 4 (0.57g, 4.15mmol), benzylhydroxylamine hydrochloride 5 (0.67g, 4.1δmmol) and NMM (0.42g, 4.1δmmol) and 6 diεεolved in DCM / DMF (4:1, 35ml) and cooled to Oo 7 while WSCDI (O.δOg, 4.1δmmol) waε added. The mixture δ waε warmed to room temperature and εtirred overnight 9 then εolvent removed under reduced pressure to leave an 0 oily residue. 1 2 3 Delta H (250MHz, Dg-DMSO) 8.00 (IH, m) , 7.53 (5H, m) , 7.38 (5H, bs) , 4.98 (IH, s) , 3.79 - 3.75 (4H, t, J= 5Hz) , 3.41 ((4H, s) , 2.54 (8H, m) , and 0.99 - 0.95 (6H, 2xd, J= 6HZ) . ( e ) [4-(N-Hydroxyamino)-2 (RS)-isobutylsuccinyl]-L-phenyl- alanine-N-[4-(2-aminoethyl)-morpholine]amide [4-(N-Benzyloxyamino) -2 (RS) -isobutylsuccinyl]-1-phenyl- alanine-N-[4- (2-aminoethyl) -morpholine]amide (250mg, 0.46 mmol) , was dissolved in cyclohexene / ethanol (10%, 5ml) and to it was added 10% palladium on charcoal (250mg) . The mixture was refluxed for 1 h at room temperature, then the cooled εolution fitered through glass wool. The solvent waε then removed under reduced pressure to leave an oily solid which was recrystallised from ethanol and DIPE (131mg, 0.30 mmol, 64%) m.p. 151-153°C Delta H (250MHz, CDCl 3 ) 8.02 (2H, m) , 7.55 (IH, m) , 7.39 (5H, bs) , 4.69 (IH, m) , 3.31 - 3.28 (4H, m) , 3.14 (IH, m) , 2.63 - 2.54 (8H, m) , 1.26 (IH, m) , and 1.01 - 0.97 (6H, m) . Delta c (62.9MHz, CDC1 3 ) 174.1, 171.0, 167.5, 138.3, 129.2, 128.1, 126.2, 66.3, 57.3, 54.1, 53.4, 37.4, 36.1, 25.3, 23.5, and 22.0 Example 13 [4-(N-Hydroxyamino) -2 (R,S) -isobutylsuccinyl]-L-phenyl- alanine-N-[2-(2-aminoethyl)-pyridine]amide The title compound was prepared by the method described in Example 12 to give a compound with the following characteristicε m. p . 174 -175° nu maχ ( Br) 3300, 2900, 1700, 1650, 1550,and 700 cm "1 Analysis calculated for C 24 H 32 N 4 0 4 .0.2H 2 O Requires C 64.90 H 7.35 N 12.61 Found C 64.90 H 7.35 N 12.76 Delta H (250MHz, Dg-DMSO) 8.68 (IH, bm) , 8.49 (2H, d, J= 4Hz) , 8.36 (IH, d, J= 9Hz) , 8.03 (2H, m) , 7.70 (IH, m) , 7.21 (5H, m) , 4.39 (IH, m) , 3.46 (4H, m) , 2.83 (4H, m) , 2.17 (IH, dd, J= 9,15 Hz) , 1.92 (IH, dd, J= 12,3 Hz), and 0.76 (6H, m) Example 14 [4-(N-Hydroxyamino)-2(R,S) -isobutylεuccinyl]-L-phenyl- alanine-N-[4-(2-aminopropyl)-morpholine]amide The title compound was prepared by the method described in Example 12 to give a compound with the following characteristics m.p. 140-142°C Delta H (250MHz, CDC1 3 / Dg-DMSO, 60 : 40) 8.15 (IH, d, J= 9HZ), 8.03 (IH, S) , 7.93 (IH, t, J= 4.5Hz), 7.58 - 7.56 (5H, m) , 6.92 (IH, t, J= 4Hz) , 4.02 (4H, m) , 3.73 (IH, dd, j= 4,14HZ), 3.50 - 3.44 (2H, m) , 2.85 (IH, m) , 2.78 - 2.66 (4H, m) , 2.42 (2H, dd, J= 5,15Hz) , 1.64 (IH, m) , 1.26 - 1.08 (2H, m) , 1.04 (3H, d, J= 5Hz) , and 0.95 (3H, d, J= 6HZ) . Example 15 [ 4 - ( N-Hydroxyamino ) -2R-isobutyl succinyl ] -L-phenyl ¬ alanine-N- ( 3 -aminomethylpyridine) amide hydrochloride . HEET [4-(N-Hydroxyamino) -2R-isobutylsuccinyl]-L-phenyl- alanine-N-(3-aminomethylpyridine) amide (lOO g, 0.23 mmol) was disεolved in hydrochloric acid (2.34ml, 0.1M) then the εolution freeze dried to leave the title compound aε a white solid (64mg, 0.14mmol, 60%). m.p; 87° [alpha] D = -32.2 (c = 1, MeOH) nu maχ (KBr) 3300 - 3200, 3060, 2955, 2860, 1650, 1530, 1470, 1385, 700 and 680 cm "1 Delta H (250MHz, CDC1 3 / D 4 -Methanol) 9.30 (IH, s) , 8.50 (IH, t, J=4HZ), 8.45 (IH, s) , 8.42 (IH, d, J= 3HZ) , 8.10 (IH, d, J= 6Hz) , 7.65 (IH, t, J= 4Hz) , 6.99 (5H, m) , 4.20 (2H, ) , 3.09 (2H, m) , 3.02 (IH, d, J= 4Hz) , 2.86 (IH, m) , 2.3δ (IH, m) , 2.13 (IH, m) , 1.93 (IH, dd, J= 3,10Hz), 1.08 - 1.02 (IH, m) , 1.02 - 0.81 (2H, m) and 0.45 (6H, 2xd, J= 7Hz) . Delta c (62.9MHz, CDCl 3 / D 4 -Methanol) 175.8, 172.0, 168.δ, 144.3, 140.7, 139.6, 136.9, 128.6, 128.0, 126.3, 55.3, 41.4, 41.0, 39.6, 35.8, 35.1, 24.9, 22.2, and 21.1. Example 16 [4- (N-Hydroxyamino) -2R-iεobutylεuccinyl]-L-phenyl- alanine-N-[4-(2-aminoethyl) -morpholine]amide hydro- chloride The title compound waε prepared by the method deεcribed in Example 15 to give a compound with the following characteristics [alpha] D = -37.5 (c = 1, MeOH) nu maχ (KBr) 3450 - 3250, 2960, 2870, 1650, 1525, 1450, and 1100 cm "1 Delta R (250MHz, CDCl 3 / D 4 ~Methanol) 7.33 (5H, m, Aromatic H) , 4.75 (IH, s) , 3.90 (2H, m) , 3.45 (2H, m) , 3.20 - 3.00 (4H, m) , 2.74 (IH, t, J= Hz) , 2.28 (2H, m) , 1.50 - 1.10 (3H, m) , and 0.82 (6H, m, 2xMe) . Example 17 [4-(N-Hydroxyamino)-2 (RS) -isobutylεuccinyl]-L-phenyl- alanine-N-(4-aminomethylpyridine)amide hydrochloride The title compound waε prepared by the method deεcribed in Example 15 to give a compound with the following characteriεticε [alpha] D = -22.7 (c = 1, MeOH) nu maχ (KBr) 3300 - 3200, 3160, 2960, 1640, 1550 - 1500, 1410, 1380, 1365, 1250, and 600 cm "1 Analyεiε calculated for C 23 H 3 -^O^l Requires C 59.67 H 6.75 N 12.10 Found C 57.01 H 6.59 N 11.27 Delta H (250MHz, D 4 ~Methanol) 8.74 (2H, dd, J= 10,3Hz), 7.96 (IH, d, J=7HZ) , 7.90 (2H, d, J= 7Hz) , 7.84 (2H, d, J= 7Hz) , 7.28 (5H, m) , 4.76 (IH, ε) , 4.65 (2H, ε) , 4.50 (IH, dd, J= 9,6Hz), 3.28 (IH, m) , 3.12 (IH, m)2.70 (IH, m) , 2.37 (IH, m) , 2.15 (IH, m) , 1.34 (2H,m) , 0.97 (IH, m) , and 0.82 (6H, m, 2xMe) . Delta c (62.9MHz, D 4 ~Methanol) 177.7, 174.4, 170.8, 162.3, 142.4, 130.2, 129.9, 129.5, 127.7, 126.5, 126.4, 56.8, 43.4, 42.7, 37.5, 36.6, 26.5, 23.4, and 22.2 Example 18 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylεuccinyl]-L- phenylalanine-N- [4- (2-aminoethyl) -morpholine]amide hydrochloride The title compound was prepared by the method described in Example 15 to give a compound with the following characteristicε Analysis calculated for C 24 H 3g N 4 0 5 Cl Requires C 55.75 H 7.99 N 10.84 Found C 55.65 H 7.81 N 10.81 Delta H (250MHz, Dg-DMSO) 10.52 (IH, m, OH) , 8.22 (2H, m, CONH and CONH) , 7.02 - 7.40 (5H, , Aromatic H) , 4.50 (IH, m, CHCH 2 Ph) , 4.04 - 3.82 (4H, m, CH 2 OCH 2 ), 3.46 - 2.72 (12H, m, NHCH 2 CH 2 , CH 2 NCH 2 , PhCH 2 , and NHCH 2 ) , 2.40 - 1.96 (2H, m, CHCHCO) , 1.38 (2H, m, CHCH 2 CH) , 1.00 - 0.84 (7H, m, CH(CH 3 ) 2 ), and 0.42 (3H, d, J+ 4HZ, CH 3 CH) . Example 19 [ 4- (N-Hydroxyamino) -2R-isobutyl-3S-methylεuccinyl ] -L- phenylalanine-N- [4- (2-aminoethyl) -morpholine] amide sodium salt. [4-(N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L- phenylalanine-N- [4- (2-aminoethyl) -morpholine] amide (92.4mg, 0.2mmol) was dissolved in methanol (20ml) and sodium hydroxide solution (0.1M, 2.0ml) added to give a homogeneous solution. The methanol was removed under reduced presεure then the reεidual aqueous εolution freeze dried to give the title compound (97mg, 0.2mmol, 100%). nu maχ (KBr) 3300, 2940, 1630, 1540, 1440, 1360, 1110, 860, and 700 cm "1 Analysis calculated for C 24 H 37 N 4 0 5 Na.1.5H 2 0 Requires C 56.37 H 7.88 N 10.95 ET 1 Found C 56.44 H 7.40 N 10.61 2 3 Delta H (250MHz, Dg-DMSO) 8.26 (IH, d, J= 9Hz, CONH) , 4 7.74 (IH, m, CONH), 7.34 - 7.10 (5H, m, Aromatic H) , 5 4.54 (IH, m, CHCH 2 Ph) , 3.58 (4H, m, CH 2 OCH 2 ) , 3.20 6 (2H, m, NHCH 2 ), 3.02 - 2.76 (2H, m, CH 2 Ph) , 2.38 - 2.20 η (10H, m, NHCH 2 CH 2 , CH 2 NCg 2 , amd CHCHCO) , 1.38 (2H, m, 8 CHCH 2 CH) , 0.98 - 0.82 (7H, m, CH(CH 3 ) 2 ), and 0.40 (3h, 9 d, CH 3 CH) . 10 - j - j Example 20 12 *, [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -1-phenyl- 1 4 alanine -N-[l-(3-aminopropyl) -imidazole]amide 15 21 22 «_ Prepared by the method described in Example 12 to give „. a compound with the following characteristics. 25 26 m ,p. 196-197°C 27 Analysis calculated for C 23 H 3 0 4 N 5 (0.2 mols H 2 0) Requires C 61.80 H 7.39 N 15.68 Found C 61.86 H 7.47 N 15.81 31 nu max (KBr) 3280, 2960, 2860, 1640, 1540, 1520, 1440, 1375, 1240, 1110, 1080, 730, and 700. Delta H (62.9MHz, Dg-DMSO) 0.70, (3H, d, J=6Hz) , 0.76, (3H, d, J=6Hz), 1.0 (IH, m) 1.29, (2H, m) , 1.76, (2H, J=7HZ) , 1.92 (IH, 2d, J=8, 8Hz) , 2.05 (IH, 2d, J=7 , 7Hz) , 2.59 (IH, m) , 2.85 (IH, dd, J=9, 14Hz) , 3.0 (3H, m) , 3.84 (2H, t, J=7HZ) , 4.39 (IH, m) , 6.97, (IH, s) , 7.13, (IH, ε) , 7.23 (5H, m) , 7.58 (IH, s) , 8.08 (IH, ) , 8.18 (IH, d, J=8Hz) , and 8.54 (IH, s) . Example 21 [ 4- (N-Hydroxyamino) -2R-isobutylsuccinyl ] -l-phenyl¬ alanine -N-[2-(3-aminopropyl) -pyridine]amide Prepared by the method described in Example 12 to give a compound with the following characteristics. m.p. 169-170 U C Analysis calculated for C25 H 34 N 4°4 1- mols H 2 0 Requires C 62.76 H 7.11 N 11.72 Found C 63.15 H 7.32 N 11.36 nu.max (KBr) 3280, 2950, 2920, 2860, 1660, 1535, 1435, 1000, 750, 700, and 635, Delta H (250MHz, Dg-DMSO) 0.68, (3H, d, J=6Hz) , 0.76 (3H, d, J=6Hz), 0.99 (IH, m) , 1.34 (2H, m) , 1.77, (2H, t, J=7Hz) , 2.03 (2H, m) , 2.65 (3H, m) , 2.86 (IH, m) , 3.08 (3H, m) , 4.44 (IH, m) , 7.20 (7H, m) , 7.49 ( IH , t, J=7HZ) , 8.00 (IH, t, J=5HZ) , 8.14 (IH, d, J=8Hz) , and 8.47 (IH, d, J=4Hz) . Delta c (62.9MHz, Dg-DMSO) 22.0, 23.4, 25.3, 29.0, 34.8, 35.8, 37.41, 38.4, 40.6, 40.8, 54.2, 121.3, 122.9, 126.3, 128.1, 129.2, 136.5, 149.1, 161.3, 167.7, 171.0, 174.0, and 175.3. Example 22 [4- (N-Hydroxyamino) -2R-isobutylsuccinyl ] -l-phenyl¬ alanine -N- [2-aminoethyl) -N, N-diethylamine ] amide Prepared by the method deεcribed in Example 12 to give a compound with the following characteristics. m.p. 62 -65°C nu-. sγ (KBr) 3260, 3060, 2960, 2640, 1380, 1060, 745, and 700. Delta H (250MHZ, Dg-DMSO) 0.76, (3H, d, J=6Hz) , 0.77 (3H, d, J=6Hz) , 0.96 (3H, d, J=7Hz), 1.24 (2H, m) , 1.92 (IH, ) , 2.14 (2H, m) , 2.50 (5H, bm) , 2.80 (IH, dd, J=13,10Hz), 2.99 (IH, d, J=5Hz), 3.10 (4H, bm) , 3.44 (5H, bm) , 4.40 (2H, m) , 7.21 (5H, m) , 7.78 - 7.91 (IH, ) , and 8.12 - 8.37 (IH/ d, J=8Hz) . Delta c (62.9MHz, Dg-DMSO) 11.6, 11.6, 22.0, 23.5, 25.3, 35.3, 36.7, 46.7, 51.3, 54.1, 126.2, 128.1, 129.2, 138.3, 167.3, 170.9, and 178.2. Example 23 [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl ] -1- phenylalanine-N-[3-aminomethyl-pyridine]amide Prepared by the method described in example 11 to give a compound with the following characteristics, m.p. 236-238°C Analysis calculated for C 24 H 32 N 4°4 (Contains 4% ash) Requires C 62.81 H 7.03 N 12.15 Found C 62.74 H 7.03 N 12.36 nu maχ (KBr) 3270, 3060, 2950, 2920, 1630, 1540, 1425, 1365, 1280, 1230, 1030, and 700. Delta H (250MHz Dg-DMSO) 8.53 (IH, t, J=6Hz) , 8.44 (2H, dd, J=2, 5Hz) , 8.34 (IH, d, J=8Hz) , 7.54 (IH, dt, J=2, 8Hz) , 7.31-7.14 (6H, m) , 4.61 (IH, m) , 4.28 (2H, t, J=5Hz) , 2.97 (IH, dd, J=5, 13Hz), 2.83 (IH, dd, J=13, 11Hz) , 2.50 (IH, m) , 1.95 (IH, dd, J=6, lOHz) , 1.27 (3H, m) , 0.84 (IH, m) , 0.74 (3H, d, J=6Hz) , 0.67 (3H, d, J=6Hz) , and 0.42 (3H, d, J=7Hz) . Delta c (62.9MHz, Dg-DMSO) 172.4, 171.6, 171.5, 148.9, 148.1, 137.9, 135.01, 34.9, 129.3, 128.1, 126.3, 123.5, 54.2, 46.6, 36.4, 25.4, 21.6, and 16.1. Example 24 [4-(N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl]-l- phenylalanine-N-[4-aminomethyl-pyridine]amide Prepared by the method described in Example 11 to give a compound with the following characteristics. m .p. 227-230°C Analysis calculated forC 24 H 32 N 4 0 4 - (Contains 5% ash) Requires C 62.16 H 6.95 N 12.08 Found C 62.13 H 7.06 N 11.96 nu.max (KBr) 3300, 2960, 2935, 1640, 1605, 1560, 1440, 1370, 1030, and 700. Delta H (250MHz, Dg-DMSO) 0.47 (3H, d, J=7Hz) , 0.69 (3H, d, J=6HZ) , 0.76 (3H, d, J=6Hz) , 0.83 (IH, m) , 1.29 (2H, ) , 1.36 (IH, m) , 1.98 (IH, dd, J=7 , 10Hz) , 2.39 (IH, td, J=10, 3Hz), 2.84 (IH, dd, J=10, 13Hz) , 2.99 (IH, dd, J=5, 14Hz), 4.27 (2H, q, J=3Hz), 4.65 (IH, m) , 7.13 (2H, dd, J=2, 4Hz), 7.28 (4H, m) , 8.35 (IH, d, J=8Hz) , 8.44 (2H, dd, J=2, 4Hz) , 8.54 (IH, t, J=6Hz) , and 8.53 (H, s) Delta c (62.9MHz, Dg-DMSO) , 16.2, 21.6, 24.2, 25.4, 37.5, 41.2, 46.7, 54.7, 122.0, 126.4, 128.2, 129.4, 138.1, 148.4, 149.5, 171.4, 171.7, and 173.6. Example 25 [4-(N-Hydroxyamino) -2R-isobutyl-3S-methylεuccinyl] -1- phenylalanine-N-[2-aminomethyl-pyridine]amide Prepared by the method described in Example 11 to give a compound with the following characteristics. m.p. 244-245 υ C Analysis calculated for C 24 H 32 N 4°4 Requires C 65.43 H 7.32 N 12.72 Found C 65.18 H 7.13 N 12.60 nu.max (KBR) 3260, 3060, 2950, 1630, 1430, 1280, 1230, 1005, 950, 745, 700, and 630. Delta H (250MHz, Dg-DMSO) 0.42 (3H, d, J=7Hz) , 0.68 (3H, d, J=6Hz) , 0.76 (3H, d, J=6Hz) , 0.84 m (IH, m) , 1.30 (2H, m) , 1.98 (IH, m) , 2.49 (IH, m) , 2.83 (IH, dd, J=ll, 13Hz) 3.03 (IH, dd, J=13 , 5Hz) , 4.35 (2H, d, J=6Hz) 4.66 (IH, m) , 7.22 (8H, m) , 7.67 (IH, dd, J=2, 8Hz) , 8.32 (IH, d, J=8Hz) , and 8.47 (2H, m) . Example 26 [ 4 - (N-Hydroxyamino ) -2R-isobutyl-3S-methylsuccinyl ] -1- phenylalanine-N- [2- (2-aminoethyl) -pyridine] amide Prepared by the method described in Example 11 to give a compound with the following characteristics. m.p. 224-226°C Analysis calculated for C 25 H 34°4 N 4 °' 4 H 2° Requires C 65.04 H 7.37 N 12.15 Found C 65.01 H 7.40 N 12.04 nu ffiaχ (KBr) 3295, 3060, 2960, 2915, 2865, 1655, 1630, 1530, 1435, 1370, 1385, 1240, 1210, 1035, 1005, 720, 690, and 635. Delta R (250MHz, Dg-DMSO) 0.43 (3H, d, J=7Hz) , 0.73 (3H, d, J=6Hz) , 0.82 (3H, d, J=6Hz) ,_ 1.28 (2H, m) , 1.94 (IH, m) , 2.36 (IH, m) , 2.73 (IH, m) , 2.84 (3H, m) , 3.37 (4H, m) , 4.58 (IH, m) , 7.19 (6H, m) , 7.68 (IH, dt, J=2 , 8Hz) 7.96 (IH, t, J=5Hz) , 8.24 ( IH , d, J=8Hz) , and 8.52 (lH,d, J=6Hz) . Delta c (62.9MHZ, Dg-DMSO) 16.1, 21.7, 24.2, 25.4, 37.4, 37.5, 38.5, 46.8, 54.2, 121.6, 123.2, 126.2, 128.1, 129.3, 136.6, 138.3, 149.2, 150.1, 171.3, 171.4, and 173.4. Example 27 [ * 4_ (N-Hydroxyamino) -2R-isobutylsuccinyl ] -1-phenyl- alanine-N- [ 2- ( 2-aminoethyl) -pyridine] amide hydro- chloride. Prepared by the method described in Example 15 to give a compound with the following characteristics. m.p. 88°C-92°C Analysis calculated for C 24 H 33 N 4°4 cl - ~ % Ash Requires C 58.61 H 6.76 N 11.39 Found C 58.41 H 6.90 N 11.42 nu max ( KBr ) 3120, 3040, 2445, 1635, 1535, 1435, 695, and 625. Delta H (250MHz, Dg-DMSO) 1.02, (3H, d) 1.14 (2H, m) , 1.23 (IH, m) , 1.67 (2H, m) , 2.42 (IH, 2d, J=15, 3Hz) , 2.73 (IH, m) , 2.90 (2H, m) , 3.12m (IH) , 3.63 (4H, m) , 3.98 (2H, m) , 4.10 (IH, m) , 4.83 (IH, t, J=8Hz) , 7.55 (IH, m, J=5Hz) , 8.02 (t, 2H, J=7Hz) , 8.08 (IH, s) , 8.11 (IH, ε) , 8.38 (IH, d, J=7Hz) , 8.34 (2H, m) , and 9.00 (IH, d, J=6Hz) . Delta c (62.9MHz, Dg-DMSO) 26.60, 26.71, 27.80, 28.18, 29.63, 29.93, 38.71, 39.35, 40.38, 40.80, 41.41, 43.44, 46.25, 46.90, 59.59, 59.77, 82.36, 82.88, 83.40, 128.40, 128.67, 130.91, 131.34, 131.87, 132.85, 133.73, 133".83, 142.97, 147.47, 148.52, 160.66, 161.08, 173.58, 174.07, 176.48, 176.79, and 180.01. Example 28 [ 4 - ( N-Hydroxyamino) - 2 R- is obutyl εuccinyl ] -1 -phenyl alanine-N- [ 4-aminomethyl-pyridine] amide hydrochloride . Prepared by the method described in Example 15 to give a compound with the following characteristics. Delta H (250MHz, Dg-DMSO) 0.47 (3H, d, J=7Hz) , 0.69 (3H, d, J=6HZ) , 0.76 (3H, d, J=6Hz) , 0.83 (IH, ) , 1.29 (2H, m) , 1.36 (IH, m) , 1.98 (IH, dd, J=7, 10Hz) , 2.39 (IH, td, J=10, 3Hz) , 2.84 (IH, dd, J=10, 13Hz), 2.99 (IH, dd, J=5, 14Hz), 4.27 (2H, q, J=3Hz), 4.65 (IH, m) , 7.13 (2H, dd, J=2, 4Hz) , 7.28 (4H, m) , 8.35 (IH, d, J=8Hz) , 8.44 (2H, dd, J=2, 4Hz) , 8.54 (IH, t, J=6Hz) , and 8.53 (H, s) Delta c (62.9MHZ, Dg-DMSO) , 16.2, 21.7, 24.2, 25.4, 37.5, 41.2, 46.7, 54.7, 122.0, 126.4, 128.2, 129.4, 138.1, 148.4, 149.5, 171.4, 171.7, and 173.6 Example 29 [4- (N-Hydroxyamino) -2R-iεobutylεuccinyl] -1-phenyl* alanine-N-[2-aminomethyl-pyridine]amide hydrochloride. Prepared by the method described in Example 15 to give a compound with the following characteristics. Analysis for C 23 H 31 4 0 4 C1 Requires C 59.67 H 6.73 N 12.10 Found C 53.98 H 6.39 N 11.12 Delta H (250MHz, CDC1 3 /Dg-DMS0, 1:3) 8.46 (2H, m) , 8.05 (IH, partially obscured by solvent) , 7.64 (IH, dt, J=2,8 Hz) , 7.22 (7H, m) , 4.56 (IH, m) , 4.42 (IH, s) , 4.40 (IH, s) , 3.17 (IH, dd, J=5,14 Hz) , 2.96 (IH, dd, J=9,14 Hz), 2.67 (IH, m) , 2.16 (IH, dd, J=7, 14 Hz) , 2.00 (IH, dd, J=14,7 Hz), 1.37 (2H, m) , 1.03 (IH, m) , 0.79 (3H, d, J= 6Hz) , and 0.75 (3H, d, J=6 Hz) . Delta c (62.9MHz, CDC1 3 /Dg-DMS0, 1:3) 174.2, 171.2, 167.9, 158.1, 148.4, 137.9, 136.3, 129.0, 127.9, 126.0, 121.7, 120.9, 78.7, 54.3, 44.3, 40.4, 37.0, 35.7, 25.2, 23.1, and 21.8. Example 30 [ 4- (N-Hydroxyamino) -2R- isobutyl succinyl ] - 1 -phenyl - alanine-N- [2- (3-aminopropyl) -pyridine] amide hydrochloride . Prepared by the method described in Example 15 to give a compound with the following characteristics. Delta H f250MHz, Dg-DMSO) 0.68, (3H, d, J=6Hz) , 0.76 (3H, d, J=6Hz) , 0.99 (IH, m) , 1.34 (2H, m) , 1.77, (2H, t, J=7Hz) , 2.03 (2H, m) , 2.65 (3H, m) , 2.86 (IH, m) , 3.08 (3H, m) , 4.44 (IH, m) , 7.20 (7H, m) , 7.86 (2H, m) , 8.13 (2H, m) , 8.42 (IH, t, J=7Hz) , and 8.75 ( IH , d, J=5HZ) . Delta c (62.9MHZ, Dg-DMSO) 22.0, 23.4, 25.3, 29.0, 34.8, 35.8, 37.41, 38.4, 40.6, 40.8, 54.2, 121.3, 122.9, 126.3, 128.1, 129.2, 136.5, 149.1, 161.3, 167.7, 171.0, 174.0, and 175.3. Example 31 [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl ] -1- phenylalanine-N- [3-aminomethyl -pyri ine] amide hydrochloride . Prepared by the method described in Example 15 to give a compound with the following characteristics. nu maχ (KBr) 3270, 3060, 2950, 2920, 1630, 1540, 1425, 1365, 1280, 1230, 1030, and 700. Delta H (250MHz D g -DMSO), 8.87 (IH, t, j= 6Hz) , 8.76 (2H, d, J=8Hz) , 8.39 (IH, d, J=8Hz) , 8.23 (IH, d, J=δHz), 7.91 (IH, dd, J=8,6Hz), 7.31-7.14 (6H, m) , 4.61 (IH, m) , 4.26 (2H, t, J=5HZ) , 2.97 (IH, dd, J=5, 13Hz) , 2.83 (IH, dd, J=13, 11Hz) , 2.50 (IH, m) , 1.95 (IH, dd, J=6, 10Hz) , 1.27 (3H, m) , 0.84 (IH, m) , 0.74 (3H, d, J=6Hz) , 0.67 (3H, d, J=6Hz) , and 0.42 (3H, d, J=7Hz) . Delta c (62.9MHz, Dg-DMSO) 172.4, 171.6, 171.5, 148.9, 14 ' 8.1, 137.9, 135.0, 34.9, 129.3, 128.1, 126.3, 123.5, 54.2, 46.6, 36.4, 25.4, 21.6, and 16.1. Example 32 [ 4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl ] -l- phenylalanine-N- [ 2 - ( 2 -aminoethyl ) -pyridine ] amide hydrochloride. Prepared by the method described in Example 15 to give a compound with the following characteristics. Delta H (250MHz, Dg-DMSO) 0.43 (3H, d, J=7Hz) , 0.73 (3H, d, J=6Hz) , 0.82 (3H, d, J=6Hz), 1.28 (2H, m) , 1.94 (IH, m) , 2.36 (IH, m) , 2.67 (IH, m) , 2.86 (IH, dd, J=14 , 4 HZ), 3.12 (2H, t, J= 6HZ) , 3.5δ (3H,m), 4.58 (IH, m) , 7.19 (6H, m) , 7.83 (2H, m) , 8.20 (2H, m) , 8.38 (IH, t, J=7HZ) , and 8.78 (lH,d, J=5Hz) . Delta c (62.9MHz, Dg-DMSO) 16.1, 21.7, 24.2, 25.4, 37.4, 37.5, 38.5, 46.8, 54.2, 121.6, 123.2, 126.2, 128.1, 129.3, 136.6, 138.3, 149.2, 150.1, 171.3, 171.4, and 173.4. Example 33 [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl]-l- phenylalanine-N- [2 -ami nomethyl -pyridine] amide hydrochloride . Prepared by the method described in Example 15 to give a compound with the following characteristics. Delta H (250MHz, Dg-DMSO) 0.42 (3H, d, J=7Hz) , 0.68 (3H, d, J=6Hz) , 0.76 (3H, d, J=6Hz) , 0.84 m (IH, ) , 1.30 (2H, m) , 1.98 (IH, m) , 2.49 (IH, ) , 2.83 (IH, dd, J=ll, 13Hz) 3.03 (IH, dd, J=13 , 5Hz) , 4.35 (2H, d, J=6Hz) 4.66 (IH, m) , 7.22 (8H, m) , 7.48 (lh, t, J=6Hz) , 7.96 (IH, dt, J=2,8Hz), 8.33 (IH, d, J=8Hz) , and 8.61 (2H, t, J=6Hz) . Example 34 [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl ] -1- phenylalanine-N- [ 4-aminomethyl-pyridine] amide sodium salt. Prepared by the method described in Example 19 to give a compound with the following characteristics. Delta H (250MHz, Dg-DMSO) 0.47 (3H, d, J=7Hz) , 0.69 (3H, d, J=6Hz) , 0.76 (3H, d, J=6Hz) , 0.83 (IH, m) , 1.29 (2H, m) , 1.36 (IH, m) , 1.98 (IH, dd, 3=1, 10Hz) , 2.39 (IH, td J=10, 3Hz) , 2.84 (IH, dd, J=10, 13Hz) , 2.99 (IH, dd, J=5, 14Hz), 4.27 (2H, q,- J=3Hz) , 4.65 (IH, m) , 7.13 (2H, dd, J=2, 4Hz), 7.28 (4H, m) , 8.35 (IH, d, J=8Hz) , 8.44 (2H, dd, J=2 , 4Hz), 8.54 (IH, t, J=6Hz) , and 8.53 (H, ε) Delta c (62.9MHz, Dg-DMSO) , 16.2, 21.6, 24.2, 25.4, 37.5, 41.2, 46.7, 54.7, 122.0, 126.4, 128.2, 129.4, 138.1, 148.4, 149.5, 171.4, 171.7, and 173.6. Example 35 [4-(N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -1- phenylalanine-N-[2-(2-a inoethyl) -pyridine]amide sodium salt. Prepared by the method described in Example 19 to give a compound with the following characteristics. Delta H (250MHz, Dg-DMSO) 0.43 (3H, d, J=7Hz) , 0.73 (3H, d, J=6Hz) , 0.82 (3H, d, J=6Hz) , 1.28 (2H, m) , 1.94 (IH, ) , 2.36 (IH, m) , 2.73 (IH, m) , 2.84 (3H, m) , 3.37 (4H, m) , 4.58 (IH, m) , 7.19 (6H, m) , 7.68 (IH, dt, J=2, 8Hz) 7.96 (IH, t, J=5Hz) , 8.36 (IH, d, J=8Hz) , and 8.52 (lH,d, J=6Hz) . Delta c (62.9MHz, Dg-DMSO) 16.1, 21.7, 24.2, 25.4, 37.4, 37.5, 38.5, 46.8, 54.2., .121.6, 123.2, 126.2, 128.1, 129.3, 136.6, 138.3, 149.2, 150.1, 171.3, 171.4, and 173.4. Example 36 [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl]-l- phenylalanine-N- [ 3 -aminomethyl-pyr idine ] amide sodium salt. Prepared by the method described in Example 19 to give a compound with the following characteristics. nu.max (KBr) 3270, 3060, 2950, 2920, 1630, 1540, 1425, 1365, 1280, 1230, 1030, and 700. Delta H (250MHz Dg-DMSO) 8.53 (IH, t, J=6Hz) , 8.44 (2H, dd, J=2, 5Hz) , 8.34 (IH, d, J=8Hz) , 7.54 (IH, dt, J=2, 8Hz) , 7.31-7.14 (6H, m) , 4.61 (IH, m) , 4.28 (2H, t, J=5Hz) , 2.97 (IH, dd, J=5, 13Hz) , 2.83 (IH, dd, J=13, 11Hz) , 2.50 (IH, m) , 1.95 (IH, dd, J=6, 10Hz), 1.27 (3H, m) , 0.84 (IH, m) , 0.74 (3H, d, J=6Hz) , 0.67 (3H, d, J=6Hz) , and 0.42 (3H, d, J=7Hz) . Delta c (62.9MHz, Dg-DMSO) 172.4, 171.6, 171.5, 148.9, 148.1, 137.9, 135.01, 34.9, 129.3, 128.1, 126.3, 123.5, 54.2, 46.6, 36.4, 25.4, 21.6, and 16.1. Example 37 [ 4 - (N-Hydroxyamino ) -2R-isobutylsuccinyl ] - 1 -pheny l ¬ al an ine-N- [ 2 - ( 3-aminopropyl ) -pyridine ] amide sodium salt . Prepared by the method deεcribed in Example 19 to give a compound with the following characteristics. Delta H (250MHz, Dg-DMSO) 0.68, (3H, d, J=6Hz) , 0.76 (3H, d, J=6Hz) , 0.99 (IH, m) , 1.34 (2H, m) , 1.77, (2H, t, J=7HZ) , 2.03 (2H, m) , 2.65 (3H, m) , 2.86 (IH, m) , 3.08 (3H, m) , 4.44 (IH, m) , 7.20 (7H, m) , 7.49 (IH, dt, J=2,7Hz), 8.14 (IH, d, J=8Hz), and 8.47 (IH, d, J=4Hz) . Delta c (62.9MHz, Dg-DMSO) 22.0, 23.4, 25.3, 29.0, 34.8, 35.8, 37.41, 38.4, 40.6, 40.8, 54.2, 121.3, 122.9, 126.3, 128.1, 129.2, 136.5, 149.1, 161.3, 167.7, 171.0, 174.0, and 175.3. Example 38 [4- (N-Hydroxyamino) -2R-isobutyl-3S-(phenylthiomethyl) εuccinyl]-L-phenylalanine-N-(2-methylpyridyl) amide. a) 2R-Bromo-5-methylpentanoic acid. D-Leucine (lOOg, 0.76 mol) and potassium bromide (317.5g, 2.67 mol) were dissolved in aqueous acid (150ml concentrated sulphuric acid in 500ml of water) . The solution was cooled to just below 0° and sodium nitrite (69.6g, 0.95 mol in water) was added over lh taking care to maintain the temperature between- -1 and -2°. After addition was complete the mixture was kept at 0° for a further hour, then DCM was added and the mixture stirred for a few minutes. The layers were separated and the aqeous phase was washed with further portions of DCM (5 x 250ml) . The combined organic layers were dried over magnesium sulphate then the solvent removed to give the acid as a pale yellow oil (123.ig, 0.63 mol, 83%) [alpha] D = +38.0° (c = 2, methanol) Delta H (250 MHz, CDC1 3 ) 4.29 (IH, t, J= 6.5Hz , BrCHC0 2 H) , 1.91 (2H, t, J= 7Hz, CHCH 2 CH) , 1.83 (IH, m, Me 2 CH) , and 0.94 (6H, 2xd, J= 7Hz, (CH 3 ) 2 CH) b) 'tert-Butyl-2R-Bromo-5-methylpentanoate. 81 2R-Bromo-5-methylpentanoic acid (123g, 0.63 mol) was dissolved in DCM (400ml) and the solution cooled to -40° while isobutene waε condensed in to roughly double the volume. Maintaining the temperature at -40° concentrated εulphuric acid (4ml) was added dropwise. When the addition was complete the reaction was allowed to warm to room temperature overnight. The resultant solution was concentrate to half the volume by removing the εolvent at reduced pressure, then the DCM was washed twice with an equal volume of 10% sodium bicarbonate solution. The organic layer waε dried over magnesium sulphate and the solvent removed under reduced pressure to leave the title compound aε a yellow oil (148.Og, 0.59 mol, 94%). [alpha] D = +23.0° (c = 2, methanol) Delta H (250 MHz, CDC1 3 ) 4.18 (IH, t, J= 6.5Hz, BrCHC0 2 H) , 1.89 (2H, m, CHCH 2 CH) , 1.78 (IH, m, Me 2 CH) , 1.49 (9H, ε, (CH 3 ) 3 C) and 0.94 (6H, 2xd, J= 7Hz, (CH 3 ) 2 CH) Delta c (63.9 MHz, CDCl 3 ) 167.0, 82.0, 46.3, 43.4, 27.6, 26.3, 22.2, and 21.6. c) Benzyl ( 2 -benzloxycarbonyl-3R- (tert-butoxy- carbonyl)-5-methylhexanoate. Dibenzyl malonate (124.5g, 0.44 mol) was taken up in dry DMF and potassium tert-butoxide (49.2g, 0.44 mol) was added portionwise with stirring and cooling. When a homogeneous solution had formed it was cooled to 0° then tert-butyl-2R-bromo-5-methylpentanoate (llo.Og, 1 0.44 mol) in DMF (200 ml) was added dropwise over lh. When addition waε complete the reaction was trans fered 3 to a cold room at <5° and left for 4 days. The 4 reaction mixture was partitioned between ethyl acetate 5 and saturated ammonium chloride then the aqueous layer 6 extracted with further ethyl acetate (4x500ml) , drying 7 and solvent removal left an oil (228g) heavily 8 contaminated with DMF. Thiε oil waε taken into ether (1 9 litre) and waεhed with brine (2x11) then the organic 0 layer dried (magneεium εulphate) , εolvent removed to 1 leave the desired material (179g) contaminated with a Λ 2 small amount of dibenzyl malonate. 3 4 [alpha] D = +22.5° (c = 2, methanol) 5 6 Delta H (250 MHz, CDCl 3 ) 7.40 - 7.25 (10H, m, Aromatic 7 H) , 5.14 (4H, 2xABq, CH 2 Ph) , 3.77 (IH, d, J= 13Hz, 8 Bn0 2 CCHC0 2 Bn) , 3.09 (IH, dt, J= 13,6Hz, CH 2 CHC0 2 tBu) , ' 9 1.50 (3H, m, CH 2 + CHMe 2 )1.41 (9H, ε, C(CH 3 ) 3 ) and 0 0.88 (6H, 2xd, J= 7Hz) . 1 d) [4 - Benzyloxy - 3 - benzyloxycarbonyl - 2R 3 - i s obutyl succinyl ] - L-phenylalanine-N- (3- 4 aminomethylpyridine) amide 5 ~ Benzyl (2 -benzyloxycarbonyl -5 -methyl -3R-tert-butoxy- 7 carbonyl ) hexanoate (40g) was taken up in 5% water in 8 TFA (105 ml) and allowed to stand at 5° overnight. 9 After this time the TFA was evaporated under reduced 0 pressure then the residue partitioned between DCM 1 (250ml) and brine (50ml) . Solvent removal left an oil which crystallised on standing (30g) . The crude acid from this reaction waε diεεolved in DMF (250ml), then HOBT (13.5g, 90 mmol), NMM (9.1g, 90mmoϊ) and phenylalanine-N-(3-aminomethylpyridine) amide (23g, 90mmol) were added at room temperature. The mixture was cooled to 0° before dropwise addition of DCC (18.5g, 90mmol) in THF (250ml). This solution was εtirred to room temperature over the weekend. The precipitated DCU waε removed by filtration then the εolventε were removed from the filtrate under reduced pressure to leave an oil. This oily residue was dissolved in ethyl acetate then washed with 10% citric acid, 10% sodium bicarbonate and saturated brine. The organic layer was dried (magnesium sulphate) , filtered then the solvent removed under reduced presεure to give the title compound as an oil (73g) . This material waε columned on silica using gradient elution (0 - 50% ethyl acetate in hexane) to remove impurities and separate a small amount of the minor diastereoiεomer. The material from the column (29. Og, 61%) was recrystallised from ethanol/DIPE to give the title compound as a white crystalline solid (17.Ig) e) [4-Hydroxy-2R-isobutyl-3-ethenylsuccinyl]-L-phenyl- alanine-N-(3-aminomethylpyridine) amide. [4-Benzyloxy-3-benzyloxycarbonyl-2R-iεobutylsuccinyl] - L-phenylalanine-N-(3-aminomethylpyridine) amide (5g, 7.9mmol) was taken up in ethanol, ammonium formate (2.5g, 40mmol) added followed by 10% palladium on charcoal (lg) as a slurry in iεopropyl alcohol. After 30 minutes at room temperature the catalyst was removed by' filtration, then washed with ethanol to give a solution of the crude diacid. To this was added 1 piperidine (lg) and the mixture stirred at room 2 temperature for 15 minutes before addition of aqueous 3 formaldehyde (40% solution, 5ml) . After lδ hours at 4 room temperature the mixture was refluxed for 1 h. 5 Solvents were removed by rotary evaporation and the 6 residue partitioned between ethyl acetate and citric 7 acid. The acid layer was extracted with further 8 portions of ethyl acetate (2x250ml) , the combined 9 organic layers were extracted with potaεεium carbonate 0 (3x200ml) . Theεe baεe extractε were acidified to pH 4 1 and re-extracted with DCM then the organic layer dried 2 over magneεium εulphate. Solvent removal under reduced 3 preεsure gave the desired product as a white solid 4 (2.55g, 77%) . 5 6 f) [4-Hydroxy-2R-isobutyl-3S- (phenylthiomethyl) - 7 εuccinyl]-L-phenylalanine-N-(3-aminomethylpyridine) 8 amide 9 0 [4-Hydroxy-2R-iεobuty-3-ethenylεuccinyl]-L-phenyl¬ 1 alanine-N-(3-aminomethylpyridine) amide (lg, 2.4mmol) 2 was dissolved in thiophenol (10ml) and the mixture 3 εtirred in the dark under nitrogen at 60° overnight. 4 Ether was added to the cooled reaction mixture and the 5 precipitated product collected by filtration. The ^ εolid waε washed with large volumes of ether and dried 7 under vacuum to give the title compound (650mg, 51%) . 8 9 g) [4-(N-Hydroxyamino) -2R-isobutyl-3S-(phenylthio- ° methyl) succinyl]-L-phenylalanine-N-(3-aminomethyl- 1 pyridine) amide 2 3 [4-Hydroxy-2R-isobutyl-3S-phenylthiomethyl εuccinyl]-L- phenylalanine-N- (2-methylpyridyl) amide (0,2g, 0.4 mmol) and HOBT (0.07g, 0.5 mmol) were dissolved in 1:1 DCM/DMF and the mixture cooled to 0°C before adding WSDCI (0.09g, 0.5mmol) and NMM (0.05g, 0.5mmol) . The mixture waε εtirred at 0°C for lh to ensure complete formation of the activated eεter. Hydroxylamine hydrochloride (0.04g, 0.6mmol) and NMM (0.06g, 0.6mmol) were disεolved in DMF then this mixture was added dropwise to the cooled solution of the activated ester. After lh the reaction was poured into ether/water (1:1) whereupon the desired product precipitated aε white cryεtals. These were collected by filtration, further washed with ether and water, then dried under vacuum at 50°C. This material was recrystallised from methanol/water (1:1) to remove a trace of the minor diastereomer (O.lg, 0.2mmol, 48%). m.p. 207°C [alpha] D = -63° (c=l, methanol) Analysis calculated for 3 Q H 36 N 4 0 5 S Requires: C65.67 H6.61 N10.21 Found: C65.72 H6.71 N10.02 delta H (250MHz, Dg-DMSO) 8.84 (IH, s, NHOH) , 8.57 - 8.41 (3H, d, CONH and aromatic H) , 7.57 (IH, d, J = 6Hz, CONHMe) , 7.45 - 6.96 (7H, m, aromatic H) , 4.71 (IH, m, CHCH 2 Ph) , 4.30 (2H, m, CH 2 CgH 5 N) , 2.98 (IH, dd, J = 14,4Hz, CHCH 2 Ph) , 2.82 (IH, dd, J = 14,10Hz, CHCH 2 Ph) , 2.50 (2H, m) , 2.17 (2H, m) , 1.33 (2H, m, CHCH 2 (CH 3 ) 2 ) , 0.85 (IH, m, CH 2 CH(CH 3 ) 2 ) , 0.77 (3H, d, J = 6Hz, CH(CH 3 ) 2 ) , and 0.70 (3H, d, J = 6Hz,CH(CH 3 ) 2 ) . EET Example 39 Collagenase inhibition activity The potency of compounds of general formula I to act as inhibitorε of collagenaεe (a metalloproteaε involved in tiεεue degradation) waε determined by the procedure of Cawεton and Barrett, (Anal. Biochem.. 99, 340-345, 1979) , hereby incorporated by reference, whereby a ImM εolution of the inhibitor being teεted or dilutionε thereof waε incubated at 37° for 16 hourε with collagen and collagenaεe (buffered with 25mM Hepeε, pH 7.5 containing 5mM CaCl 2 , 0.05% Brij 35 and 0.02% NaN 3 ) . The collagen waε acetylated 1 C collagen prepared by the method of Cawεton and Murphy (Methods in Enzymolocry, 80, 711, 1981), hereby incorporated by reference. The εampleε were centrifuged to εediment undigeεted collagen and an aliquot of the radioactive supernatant removed for asεay on a scintillation counter as a measure of hydrolyεiε. The collagenaεe activity in the preεence of 1 mM inhibitor, or " a dilution thereof, was compared to activity in a control devoid of inhibitor and the resultε reported below as that inhibitor concentration effecting 50% inhibition of the collagenase (IC 50 ) • Compound of Example No. IC 5Q 3 70 nM 6 20 nM 11 15 nM Example 40 Stromelysin inhibition activity The potency of compounds of general formula I to act as inhibitorε of stromelysin was determined using the procedure of Cawston et al (Biochem. J. , 195, 159-165 1981) , hereby incorporated by reference, whereby a ImM εolution of the inhibitor being tested or dilutions thereof waε incubated at 37°C for 16 hours with εtromelysin and 14 C acetylate casein (buffered with 25mM Hepes, pH 7.5 containing 5mM CaCl 2 , 0.05% Brij 35 and 0.02% NaN 3 . The casein waε 14 C acetylated according to the method deεcribed in Cawεton et a_l (Biochem. J. , 195, 159-165, 1981), hereby incorporated by reference. The εtromelyεin activity in the presence of ImM, or a dilution thereof, was compared to activity in a control devoid of inhibitor and the results reported below as that inhibitor concentration effecting 50% inhibition of the stromelysin (IC 50 ) . Compound of Example No. IC 5Q 11 50 nM Examples of unit dosage compoεitions are aε follows: Example 41 Capsules: Per 10,000 Ingredients Per Capsule Capsuleε 1. Active ingredient (Cpd of Formula I) 40.0 mg 400 g 2. Lactose 150.0 mg 1500 g 3. Magnesium stearate 4.0 mg 40 g 194.0 mg 1940 g Procedure for capsuleε: Step 1. Blend ingredientε No. 1 and No. 2 in a εuitable blender. Step 2. Paεε blend from Step 1 through a No. 30 meεh (0.59 mm) screen. Step 3. Place screened blend from Step 2 in a suitable blender with ingredient No. 3 and blend until the mixture is lubricated. Step 4. Fill into No. 1 hard gelatin capsule εhells on a capsule machine. Example 42 Tablets: Per 10,000 Ingredients Per Tablet Tablets 1. Active ingredient (Cpd of Form. I) 40.0 mg 400 g 2. Corn Starch 20.0 mg 200 g 3. Alginic acid 20.0 mg 200 g 4. Sodium alginate 20.0 mg 200 g 5. Magnesium stearate 1.3 mg 13 g 101.3 mg 1013 g Procedure for tablets: Step 1. Blend ingredientε No. 1, No. 2, No. 3 and No. 4 in a εuitable mixer/blender. Step 2. Add εufficient water portionwise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass iε of a conεiεtency to permit itε conversion to wet granules. Step 3. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38) screen. Step 4. The wet granules are then dried in an oven at 140°F (60°C) until dry. Step 5. The dry granules are lubricated with ingredient No. 5. Step 6. The lubricated granuleε are compresεed on a suitable tablet press. Example 43 Intramuscular Injection: Ingredient Per ml. Per liter 1. Formula I compound Active ingredient 10,0 mg 10 g 2. Istonic buffer solution pH 4.0. q.s. q.s. Procedure: Step 1. Diεεolve the active ingredient in the buffer εolution. Step 2. Aεeptically filter the εolution from Step 1. Step 3. The εterile εolution iε now aεeptically filled into εterile ampoules. Step 4. The ampoules are sealed under aεpetic . conditionε. Example 44 Suppositories: Per Ingredients Per Supp. 1,000 Supp Formula I compound Active ingredient 40.0 mg 40 g Polyethylene Glycol 1000 1350.0 mg 1,350 g 3. Polyethylene Glycol 4000 450.0 mg 450 g 1840.0 mg 1,840 g 1 Procedure: 2 Step 1. Melt ingredient No. 2 and No. 3 together and 3 stir until uniform. 4 Step 2. Dissolve ingredient No. 1 in the molten masε 5 from Step 1 and stir until uniform. 6 Step 3. Pour the molten mass from Step 2 into 7 suppository moulds and chill. 8 Step 4. Remove the suppositories from moulds and 9 wrap. 10 11 Example 45 12 13 Eye Ointment 14 15 An appropriate amount of a compound of general formula 16 I iε formulated into an eye ointment baεe having the 17 following composition: lδ 19 Liquid paraffin 10% 20 Wool fat 10% 21 Yellow εoft paraffin δ0% 22 3 Example 46 4 5 Topical skin ointment 6 7 An appropriate amount of a compound of general formula 8 I is formulated into a topical skin ointment base 9 having the following compoεition: 0 1 Emulsifying wax 30% 2 v White soft paraffin 50% 3 Liquid paraffin 20%

Claims: CLAIMS A compound of general formula I: HONHCO wherein : R x represents a hydrogen atom or a C^-C 8 alkyl, C-,-C 8 alkenyl, phenyl, phenyl (C-^-C 8 ) alkyl , C- j^ -C 8 alkylthiomethyl, phenylthiomethyl, subεtituted phenylthiomethyl , phenyl ( C- j^ -C 8 ) alkylthiomethyl or heterocyclylthiomethyl group; or R 1 repreεents -SR X wherein R x representε a group HONHCO repreεentε a hydrogen atom or a C^-Cg alkyl, C-,-c 6 a l k e n y l , p h e n y l ( C 1 - C 6 ) a l k y l , c y c l o a l k y l ( C - j^ - C g ) a l k y l , o r cycloalkenyl (C- j^ -Cg) alkyl ; R 3 represents an amino acid side chain or a C^-Cg alkyl, benzyl, (C-^-CgJ alkoxybenryl ' , benzyloxy(C- j^ -Cg)alkyl or benzyloxy benzyl group; R represents a hydrogen atom or a methyl group; n iε an integer from 1 to 6; and A represents the group -NH 2 , a substituted acyclic amine or a heterocyclic base; or a salt and/or N-oxide and/or (where the compound is a thio-compound) a sulphoxide or sulphone thereof. 2. A compound as claimed in claim 1, in which the chiral centre adjacent the substituent R 3 has S stereochemistry. 3. A compound as claimed in Claim 1 or 2, wherein R 1 representε a hydrogen atom or a c ι -c 4 alkyl, phenylthiomethyl or heterocyclylthiomethyl group. 4. A compound as claimed in Claim 1, 2 or 3, wherein R"' repreεents a C 3 -C alkyl group. 5. A compound as claimed in any one of Claims 1 to 4, w h e r e i n R 3 r e p r e s e n t ε a b e n z y l , 4-(C 1 ~Cg)alkoxyphenylmethyl or benzyloxy benzyl group. 6. A compound as claimed in any one of Claims 1 to 5, wherein R 4 representε a hydrogen atom. E 7. A compound as claimed in any one of Claimε l to 6, wherein n haε the value 1, 2 or 3. 8. A compound aε claimed in any one of Claimε l to 7, wherein A represents a morpholinyl, piperidinyl, 2-, 3- or 4-pyridyl or pyrrolidinyl group. 9. [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenyl- alanine-N-[ (2-aminoethyl)-2(RS)-(1-methyIpyrrolidine) ]- amide, [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenyl- alanine-N-[1-(2-aminoethyl)-piperidine]amide, [4-(N-Hydroxyamino)-2R-isobutylεuccinyl]-L-phenyl- alanine-N-[1-(2-aminoethyl)-pyrrolidine]amide, [4-(N-Hydroxyamino) -2R-iεobutylsuccinyl]-L-phenyl- alanine-N-[l-(3-aminopropyl)-2(RS)-methylpiperidine]- amide, [4-(N-Hydroxyamino) -2R-isobutylsuccinyl]-L-phenyl- alanine-N-[2-(2-aminoethyl)-1-methylpyrrole]amide, [4- (N-Hydroxyamino) -2R-isobutylsuccinyl]-L-phenyl- alanine-N-(3-aminomethylpyridine)amide, [4-(N-Hydroxyamino)-2R-isobutylεuccinyl]-L-phenyl- alanine-N-(2-aminomethylpyridine)amide, [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenyl- alanine-N-(4-aminomethylpyridine)amide, [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenyl- alanine-N-(1-(3-aminopropyl)-imdazole)amide, [4-(N-Hydroxyamino)-2(RS)-isobutylεuccinyl]-L-phenyl- alanine-N-(2-aminomethylbenzimdazole)amide, [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L- phenylalanine-N-[4-(2-aminoethy1)-morpholino]amide, [4- (N-Hydroxyamino) -2R-isobutylεuccinyl]-L-phenyl- alanine-N-[4-(2-aminoethyl)-morpholine]amide, [4-(N-Hydroxyamino)-2(R,S)-iεobutylεuccinyl]-L-phenyl- alanine-N-[2-(2-aminoethyl)-pyridine]amide, [4-(N-Hydroxyamino)-2(R,S)-isobutylsuccinyl]-L-phenyl- alanine-N-[4-(2-aminopropyl)-morpholine]amide, [4- (N-Hydroxyamino) -2R-isobutylsuccinyl]-L-phenyl- alanine-N-(3-aminomethylpyridine)amide hydrochloride, [4-(N-Hydroxyamino) -2R-isobutylsuccinyl]-L-phenyl- alanine-N-[4-(2-aminoethyl) -morpholine]amide hydrochloride, [4- (N-Hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-phenyl- alanine-N- (4-aminomethylpyridine) amide hydrochloride, [4- (N-Hydroxyamino) -2R-iεobutyl-3S-methylsuccinyl]-L- phenylalanine-N- [4- (2-aminoethyl) -morpholine] amide hydrochloride or [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L- phenylalanine-N- [ 4- (2-aminoethyl ) -morpholine] amide εodium εalt, [4- (N-Hydroxyamino) -2R-isobutylsuccinyl]-1-phenyl- alanine-N-[l-(3-aminopropyl)-imidazole]amide [4- (N-Hydroxyamino) -2R-isobutylsuccinyl]-l-phenyl- alanine-N-[2-(3-aminopropyl)-pyridine]amide [4- (N-Hydroxyamino) -2R-isobutylεuccinyl] -1-phenyl- alanine-N-[2-aminoethyl)-N,N-diethylamine]amide [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl]- 1-phenylalanine-N-[3-aminomethyl-pyridine]amide [4-(N-Hydroxyamino) -2R-isobutyl-3S-methylεuccinyl]- 1-phenylalanine-N-[4-aminomethyl-pyridine]amide [4-(N-Hydroxyamino) -2R-iεobutyl-3S-methylεuccinyl] - 1-phenylalanine-N-[2-aminomethyl-pyridine]amide [4- (N-Hydroxyamino) -2R-iεobutyl-3S-methylεuccinyl] - 1-phenylalanine-N-[2-(2-aminoethyl)-pyridine]amide [4-(N-Hydroxyamino) -2R-iεobutylεuccinyl] -1-phenyl- alanine-N- [2- (2-aminoethyl) -pyridine] amide hydro- chloride [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -1-phenyl- alanine-N-[4-aminomethyl-pyridine]amide hydrochloride [ 4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -1-phenyl- alanine-N- [2-aminomethyl-pyridine] amide hydrochloride [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-1-phenyl- alanine-N-[2-(3-aminopropyl)-pyridine]amide hydro- chloride [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl ] - 1-phenylalanine-N- [3-aminomethyl-pyridine] amide hydro- chloride [4- (N-Hydroxyamino) -2R-iεobutyl-3S-methylsuccinyl] - 1-phenylalanine-N- [2- (2-aminoethyl) -pyridine] amide hydrochloride [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuecinyl ] - 1-phenylalanine-N- [ 2-aminomethyl-pyridine] amide hydrochloride [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] - 1-phenylalanine-N- [4-aminomethyl-pyridine] amide sodium salt [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl ] - l-phenylalanine-N-[2- (2-aminoethyl) -pyridine] amide sodium salt [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylεuccinyl] - l-phenylalanine-N- [3-aminomethyl-pyridine] amide sodium salt [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -1-phenyl- alanine-N- [2- (3-aminopropyl) -pyridine] amide εodium εalt [4-(N-Hydroxyamino)-2R-iεobutyl-3S-(phenylthiomethyl) εuccinyl]-L-phenylalanine-N-(2-methylpyridyl) amide or the free base, free acid or salt thereof, where appropriate. 10. [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenyl- alanine-N-(3-aminomethylpyridine)amide or [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylεuccinyl] -L-p- henylalanine-N- [4- (2-aminoethyl) -morpholino] amide, or a εalt thereof. 11. [4- (N-Hydroxyamino) -2R-iεobutylεuccinyl] -L-phenyl- alanine-N- ( 3 -aminomethylpyridine) amide or a salt thereof. 12. A compound as claimed in any one of claimε 1 to 11 for uεe in human or veterinary medicine. 13. The uεe of a compound aε claimed in any one of claimε 1 to 11 in the preparation of an agent for uεe in the management of diεeaεe involving tiεεue degradation and/or in the promotion of wound healing. 14. A pharmaceutical or veterinary formulation compriεing a compound aε claimed in any one of claimε 1 to 11 and a pharmaceutically and/or veterinarily acceptable carrier. 15. A process for preparing a compound of general formula I as defined in claim 1, the process comprising: (a) deprotecting a compound of general formula III wherein: R 1 , R 2 , R 3 , R 4 , n and A are as defined in general formula I and Z repreεentε a protective group; or (b) reacting a compound of general formula IV wherein: R 1 , R 2 , R 3 , R 4 , n and A are as defined in general formula I, with the proviso that R 1 represents a hydrogen atom. with hydroxylamine or a salt thereof; and (c) optionally after step (a) or step (b) converting a compound of general formula I into another compound of general formula I. 16. A compound of general formula III wherein: R , R 2 , _ ~ _ r R , n and A are as defined in general formula I and Z representε a protective group; or 17. A compound of general formula IV wherein: R-'v'R 2 , R 3 , R 4 , n and A a e aε defined in general formula I, with the proviεo that R 1 represents a hydrogen atom.

Inventors: CRIMMIN MICHAEL JOHN, DAVIDSON ALAN HORNSBY, DICKENS JONATHAN PHILIP, CRIMMIN, MICHAEL, JOHN, DAVIDSON, ALAN, HORNSBY, DICKENS, JONATHAN, PHILIP
Applicants: BRITISH BIO TECHNOLOGY, BRITISH BIO-TECHNOLOGY LIMITED
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61P17, A61P29, A61P35, A61P43, C07C237, C07C259, C07C317, C07C323, C07D207, C07D211, C07D213, C07D233, C07D235, C07D295, C07D521