CA2265671A1 - Matrix metalloproteinase inhibitors - Google Patents

Matrix metalloproteinase inhibitors Download PDF

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CA2265671A1
CA2265671A1 CA002265671A CA2265671A CA2265671A1 CA 2265671 A1 CA2265671 A1 CA 2265671A1 CA 002265671 A CA002265671 A CA 002265671A CA 2265671 A CA2265671 A CA 2265671A CA 2265671 A1 CA2265671 A1 CA 2265671A1
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alkyl
group
methyl
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substituted
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Daniela Jabes
Riccardo Corigli
Francesca Abrate
Ettore Perrone
Pierluigi Bissolino
Marco Alpegiani
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Pfizer Italia SRL
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Priority claimed from GBGB9714548.6A external-priority patent/GB9714548D0/en
Priority claimed from GBGB9724395.0A external-priority patent/GB9724395D0/en
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Publication of CA2265671A1 publication Critical patent/CA2265671A1/en
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A compound which is an amine derivative of formula (I) wherein W is -CONHOH or -COOH; R1 and R2 are each hydrogen or an organic residue, R3 is an organic group, Q is a secondary or tertiary acyclic or cyclic amido group, and the pharmaceutically acceptable salts, solvates and hydrates thereof, are inhibitors of matrix metalloproteinases (MMPs) and of the release of tumor necrosis factor-alpha (TNF) from cells. They are therefore useful in the prevention, control and treatment of diseases in which MMPs or TNF are involved, especially tumoral and inflammatory diseases. Processes for their preparation and pharmaceutical compositions containing them are also described.

Description

1015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/04220MATRIX METALLOPROTEINASE INHIBITORSThe present invention relates to new inhibitors of matrix metalloproteinases(hereinafier MMPS), to a process for their preparation, to pharmaceutical compositionscontaining them, and to the use of such compounds in the prevention, control and treatmentof diseases in which the proteolytic action of MMPS is involved.Certain disease states are characterised by an imbalance of active M]VIPs and their naturalinhibitors, the tissue inhibitors of metalloproteinases (hereinafter TIlV[Ps). When THVIP levelsare insufficient, a progressive slow degradation of the extracellular matrix occurs, forexample cartilage matrix loss in rheumatoid arthritis (L.A. Walakovits et al., Arthritis Rheum.35:35-42, 1992) and osteoarthritis (D.D. Dean et al., J. Clin. Invest., 84:678-685, 1989), andbone matrix degradation in osteoporosis (p.A. Hill et al., Biochem. J ., 3082167-175, 1995).In other situations, such as congestive heart failure, rapid degradation of the heart’sextracellular matrix occurs (P.W. Armstrong et al., Canadian J. Cardiol. lO:2l4-220, 1994).Cancer cells use MNIPS, either expressed by themselves or by the surrounding tissues, toachieve rapid remodelling of the extracellular matrix. There is considerable evidence thatMMPs are involved in at least 3 aspects of the growth and spread of tumors (e.g., see A.H.Davidson et al., Chemistry & Industry, 258-261, 1997, and references therein). In the processof tumor metastasis, l\/lMPs are used to break down the extracellular matrix, allowingprimary tumor cancer cells to invade neighbouring blood vessels where they are transportedto difi“erent organs and establish secondary tumors. The invasive growth at these secondarysites also needs MMPs to help break down tissue. In addition, MMP activity contributes tothe invasive in-growth of new blood vessels (angiogenesis) which is required for tumors togrow above a certain size.Low molecular weight compounds able to inhibit one or more of the matrixmetalloproteinases, in particular stromelysin-1 (MMP-3; EC 3.4.24.l7), gelatinase A (MMP-2; EC 3.4.24.24), gelatinase B (MMP-9; EC 3.4.24.35), neutrophil collagenase orcollagenase-2 (M1VlP—8; EC 3.4.24.34), interstitial collagenase or collagenase-l (MMP-1; EC3.4.27.7), matrilysin (MMP-7; EC 3.4.24.23), collagenase-3 (MMP-l3), and the membrane-type metalloproteinase (MT-MMPS: MMP-14, MMP-15, MMP-16, MMP-17) are currentlyconsidered as promising therapeutic agents in degenerative, tumoral and autoimmune10152025CA 02265671 1999-03-09wo 99/02510 PCT/EP98/04220pathologies (e.g., P.D. Brown: “Matrix mcitalloproteinase inhibitors: A new class ofanticancer agent”, Curr. Opin. Invest. Drugs, 2:617-626, 1993; A. Krantz: “Proteinases inInflammation”, Annu. Rep. Med. Chem. 28:187-195, 1993). Many of such compoundsdescribed hitherto are peptide derivatives or pseudopeptides, bearing analogies to recognizedpeptide substrates of these enzymes, and characterized in addition by a fiinctional groupcapable of binding the Zn (II) atom present in the catalytic site of said enzymes. Knownclasses of MMP inhibitors include those in which the Zn binding group is a hydroxamic acid,and the skeleton, as represented in the general formula (A), mimicks the amino acid sequenceof collagen at the site cleaved by collagenasezo Rb oHH0\ N\/U\ /Rd (A)H i ua 0 RCwherein R3, Rb, RC, and Rd are hydrogen atoms or appropriate substituents (e.g., N.R.A.Beeley et al., “Inhibitors of matrix metalloproteinases (MMP’s)”, Curr. Opin. Ther. Patents437-16, 1994;inhibitors”, Exp. Opin. Ther. Patents 5:1287-1296, 1995;JR. Porter et al., “Recent developments in matrix metalloproteinaseJ.R. Morphy et al., “Matrixmetalloproteinase inhibitors: Current status”, Curr. Med. Chem. 2:743-762, 1995; R.P.DDT 1:16-26,1996). Said MMP inhibitors of the prior art can be described as “peptide-basedBeckett et al., “Recent advances in matrix metalloproteinase research”,hydroxamates” or “substrate—based” inhibitors (e.g., A.H. Davidson et al., “The inhibition ofmatrix metalloproteinase enzymes”, Chemistry & Industry, 258-261, 1997).Although MMPs have been recognized as drug targets for at least 20 years, and potent l\/IMPinhibitors described by formula (A) have been disclosed since 1986 or before (e.g., see J .P.Dickens et al., U.S. Patent 4,599,361), no drug of this type has arrived at the market yet.This is not because of questions about the therapeutic potential of MMP inhibitors, butbecause of problems of “peptide-based hydroxamates”, such as aqueous solubility, metabolicstability, and other desirable properties, oral bioavailability in particular (e.g., J.R. Porter,reference above; J. Hodgson, “Remodelling l\/1]\IIPIs”, Biotechnology 13:554-557, 1995). Forexample, it is well known that most “peptide-based hydroxamates” of general formula (A)10152025CA 02265671 1999-03-09wo 99/02510 PCT/EP98/04220are rapidly glucuronidated, oxidized to the caraboxylic acid, and excreted in the bile (e.g., seeJ. Singh et al., Bioorg. Med. Chem. Lett. 5:337-342, 1995, and other references above).Finally, another type of problem of the known inhibitors described by general formula (A)may be one of tolerability. This problem is emerging for the most advanced MMP inhibitor inthe clinic, marimastat (formula A; R,..= OH, R.,= CH2CHMe2, Re: CMe3, Rd= Me), which wasreported to give muscoloskeletal problems in humans. We have extended these observationsby developing an animal model of tolerability with MMP inhibitors (S. Castellino et al.,unpublished), involving intraperitoneal administration of the latter in rats for 10 consecutivedays, and histological evaluation of stifle joints at the end of treatment. In this model,peptide-based MMP inhibitors of the prior art, e.g. Roche R031-9790 (formula A; R,= H,R.,= CH2CHMe2, Rc= CMe3, Rd= Me), at daily doses of 150 mg/kg or less, elicitedhypertrophic fibrosis of stifle ligaments, interstitial hypertrophic fibrosis of skeletal muscles,hypertrophic fibroplasia of the periostium and synovium, and chondrosysplasia and decreasedendochondrial ossification of the ephyseal plate. Although the precise reasons for these side-effects are not known at present, they support a strong need for better and diversifiedmolecules, especially as far as the properties referred to above are concerned.The present invention is concerned with novel MMP inhibitors, specifically characterised bythe presence of a nitrogen atom as a sostituent at the carbon atom next to the zinc-bindinggroup, and with less or no peptidic character, as compared to substrate-based inhibitors ofthe prior art.The present invention provides a compound which is an amine derivative of formula (I)Q (I)whereinW is -CONHOH or -COOH;R, and R2 , which are the same or different, are each hydrogen or1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042204- a group G, which is methyl, C2-Cm alkyl, C2-Cm alkenyl, C3-C7 cycloalkyl, cycloalkyl-CyC1o- alkyl, aryl, aryl-C1-C10-alkyl, aryl-C2-C10-alkenyl, heterocyclyl, heterocyclyl-C1-Curalkyl or heterocyclyl-C2-C,0-alkenyl, the said methyl, alkyl, alkenyl, cycloalkyl, aryl andheterocyclyl groups being unsubstituted or substituted by one to three substituents; or-S02-G, wherein G is as defined above; or-SO-G, wherein G is as defined above; or-CO-G, wherein G is as defined above; or-COO-G, wherein G is as defined above; or-S02-NH2, -S02-NHG or -S02-NGG’, wherein G is as defined above and G’, which is thesame or different, is as defined above for G, or G and G’, together with the nitrogen atom towhich they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclicring, which may be fiised to a carbocyclic, heterocyclic, or aromatic ring, and may besubstituted at any carbon or additional nitrogen atom, or- a group -CONH2, -CONHG or -CO-NGG’ wherein G and G’ are as defined above, or Gand G’, together with the nitrogen atom to which they are attached, constitute a saturated orunsaturated 3- to 7—membered azaheterocyclic ring, which may be fused to a carbocyclic,heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogenatom, orR1 and R2, taken together with the nitrogen atom to which they are attached, form asaturated or unsaturated 3- to 7—membered azaheterocyclic ring, which may be fiised to acarbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon oradditional nitrogen atom;R3 is C1 -C15 alkyl, either unsubstituted or substituted by a C3 -C7 cycloalkyl group, the alkyland/or the cycloalkyl group being either unsubstituted, or substituted by one to threesubstituents selected from methyl, ethyl, C3 -C4 linear or branched alkyl, fluoro, chloro, C1-C4alkoxy, nitro, amino, dimethylamino, carboxy and carboxymethyl; orR3 is a group -R-X-R’ wherein R is a chemical bond, -CH2-, -(CH2),.,— wherein m is aninteger from 2 to 5, -CH=CH-, -CH2CH=CH-, phenylene (i.e., -C6H4-), -CH2CH=CH-C5H4-,-CH2CH2CH=CH-, -CH2-CC-, -CH2CH2-CC-, -CH2CH2CH=CH-CsH4- , -CH2-CC-C6H4-,or —CH2CH2-CC-C5H4-; X is a direct bond, an oxygen atom, a sulfiir atom, or a sulfinyl -S(O)-, sulfonyl -S(O)2 or carbamoyl group -CONH- or -NHCO-; and R1 is C. -C6 alkyl, C;phenyl-(C1 -C5)-alkyl, phenyl-(C2 -C5)-alkenyl, heterocyclyl, orheterocyclyl-(C1-C5)-alkyl, either unsubstituted or substituted by a group selected from F, Cl,-C.-, alkenyl, phenyl,1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042205Br, C1—C4alkyl, C1-C4 alkoxy, alkylthio, arylthio, alkylsulfonyl, and arylsulfonyl;Q, being a secondary or tertiary carboxyarnide, is:- a group -CONHG or -CONGG’, wherein G and G’ are as defined above; or- a group -CONH—CHGG’, wherein G and G’ are as defined above; or a group -CONG”—CHGG’, wherein G”, being the same or different, is defined as G above; or- a group -CONH—CH2-CHGG’ or a group —CONG”-CH2-CHGG’, wherein G, G’ and G”are as defined above; or- a group -CO-azaheterocyclyl, wherein azaheterocyclyl, which is either unsubstituted orsubstituted, is as defined below; with the proviso that when Q is -CONHG, and G is methyl,alkyl-methyl, cycloalkyl-methyl, aryl-methyl or hetherocyclyl—methyl, then such methyl orsubstituted methyl cannot be fiirther substituted by a group -(CH2) , -CO2H, wherein t is 0, oresters and amides thereof,and a pharmaceutically acceptable salt, solvate or hydrate thereof.As used herein the term “alkyl” refers to a straight or branched chain alkyl moiety havingfrom 1 to 10 carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl and so on.The term “alkenyl” as used herein refers to a straight or branched chain alkenyl moiety havingfrom 2 to 10 carbon atoms and having in addition one double bond of either E or Zstereochemistry where applicable. Examples of alkenyl groups are: vinyl, allyl, metallyl,butenyl, crotyl and so on.The term “cycloalky” as used herein refers to a saturated carbocyclic group of 3 to 7 carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.The term “any ” as used herein refers to a monocyclic or bicyclic aromatic hydrocarbon group of 6to 10 carbon atoms, such as phenyl, naphthyl, indanyl; furthermore, “ary” as used herein mayrefer to a diphenyl group (-C6H4-C5H5), a 4-pyridyl-phenyl group, and a methylenedioxyphenylgroup.The term “heterocyclyl” as used herein refers to a 3- to 7-membered, saturated or unsaturatedheterocyclyl ring, containing at least one heteroatom selected fiom O, S and N, wherein any ringnitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a carbonyl, and anyring sulfur may be oxidized as a sulfoxide or sulfone; and wherein said heterocyclyl ring may beoptionally fused to a second 5- or 6-membered , saturated or unsaturated heterocyclyl ring, or to aC3 -C7 cycloalkyl ring, or to a benzene or naphthalene ring. Examples of heterocyclyl groups arepyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/042206isothiazolyl, thiadiazolyl, thienyl, tetrahydrothienyl, fiiryl, tetrahydrofiiryl, aziiidinyl, oxiranyl,pyfidyl, pyrazinyl, pyridazinyl,hexahydropyridazinyl, pytimidinyl, pyranyl, tetrahydropyranyl, benzothienyl, benzothiazolyl,azetidinyl, succinimido, piperidinyl, piperazinyl,benzoxazolyl, isobenzofiiranyl, benzofuranyl, benzimidazolyl, indazolyl, chromenyl, indolyl,oxindolyl, phthalimido, 1-oxo-2-isoindolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, indolizinyl,isoindolyl, 2-oxoisoindolyl, quinuclidinyl, hydantoinyl, saccarinyl, cinnolinyl, purinyl, morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, azepinyl and so on.The term “azaheterocycly” as used herein includes any of the heterocyclyl groups, as definedabove, containing at least one nitrogen atom, said heterocyclyl group being linked to the rest ofthe molecule by a nitrogen atom.Substituents which may be present in the methyl, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyland azaheterocyclyl groups in any of the above specifications include the following ones:- a group -(CH2).-Hal, wherein Hal is halo (i.e., fluoro, bromo, chloro or iodo), and t is an integerfrom O to 3;- a group -(CH2),-CF3, or a group -(CH2)¢—CI-IF2, wherein t is as defined above;- a group -(CH2)t—OH, wherein t is as defined above;- a group -(CH2),-OR", wherein t is as defined above, and R" is straight or branched C1-C6 alkyl,aiyl, arylmethyl, heterocyclyl, or heterocyclylmethyl, optionally substituted by hydroxy, methoxy,methyl, amino, methylamino, dimethylamino, chloro and fluoro;— a group -(CH2),—OC(O)R", wherein t and R“ are as defined above;- a group -(CH2),-OC(O)OR", wherein t and R“ are as defined above;- a group -(CH2).-OC(O)NH2, or -(CH2),-OC(O)NHR", or -(CH2).-OC(0)NR“Rm, wherein t is asdefined above, R" is as defined above, and Rm, being the same or different, is defined as R" above;or R" and Rm taken together with the nitrogen atom form an azaheterocycl ring;- oxo;— a group -(CH2).-N02, wherein t is as defined above;- a group -(CH2).-N3, wherein t is as defined above;- a group -(CH2),-CN, wherein t is as defined above;- a group -(CH2).-SH, wherein t is as defined above, and acetyl or phenylacetyl esters thereof (i.e.,-(CH2).-SCOCH3 and -(CH2).—SCOCH2CoHs);— a group -(CH2).-NH2, or -(CH2),—NHR", or -(CH2).-NR"Rm, wherein t, R" and R” are as definedabove, or R“ and Rm taken together with the nitrogen atom form an azaheterocyclyl ring;1015202530CA 02265671 1999-03-09wo 99/02510 PCTlEP98/042207— a group -(CH2).-NHC(O)R", or —(CH2).-NR"C(O)Rm, or -(CH2).-NHC(O)OR", wherein r, R"and R III are as defined above;— a group -(CH2).-NH(CO)NH2 , or —(CH2).-NH(CO)NI-IR", or —(CH2).-NH(CO)NR"R"',wherein t, R“ and Rm are as defined above, including the special case wherein R" and Rm takentogether with the nitrogen atom form an azaheterocyclyl ring;- a group -(CH2).-NHSO2R", wherein t and R" are as defined above;— a group -(CH2).-NH(SO2)NH2 , or -(CH2).-NH(SO2)NHR", or -(CH2).-NH(SO2)NR"R"’,wherein t, R" and Rm are as defined above, including the special case wherein R" and Rm takentogether with the nitrogen atom form an azaheterocyclyl ring;- a group -(CH2).-NHC(=NH)NH2, wherein t is as defined above ;- a group —(CH2).-CH0, wherein t is as defined above;- a group -(CH2).-C(0)R", wherein t and R" are as defined above;- a group —(CH2).-CO2H, wherein t is as defined above, or esters or amides thereof, i.e., -(CH2).-CO2R”, —(CH2).-CONH2, —(CH2).-CONHR”, -(CH2).—CONR“R"', wherein R" and R” are asdefined above, including the special case wherein R" and Rm, taken together with the nitrogenatom fonn an azaheterocyclyl ring;- a group -(CH2).-SO3H, wherein t is as defined above;- a group -(CH2).-S(O)R", wherein t and R“ are as defined above;- a group -(CH2).-SO2R", wherein t and R" are as defined above;— a group -(CH2).-SO2NH2, or -(CH2).-SOZNHR", or -(CH2).-SO2NR"R"', wherein t, R“ and R“are as defined above;- C1-C6 alkyl or C2 -C6 alkenyl;— C3 -C7 cycloalkyl;- phenyl, biphenyl (i.e., -C6H4-C5H5), methylenedioxyphenyl, methylenedioxyphenylrnethyl(hereinafter piperonyl), benzyl, phenethyl, phenpropyl, naphthyl, naphthylmethyl, naphthylethyl,naphthylpropyl, either unsubstituted or substituted by one to three substituents selected from byC1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, chloro and fluoro.When present carboxy, hydroxy, mercapto and amino groups may be either free or in a protectedform. Protected forms of said groups are any of those generally known in the art, as described,for example, by T.W. Greene in “Protective Groups in Organic Chemistry”, Wiley Interscience.Preferably, carboxy groups are protected as esters thereof, in particular methyl, ethyl, tert-butyl,benzyl, and 4-nitrobenzyl esters. Preferably, hydroxy groups are protected as ethers or estersthereof, in particular methoxymethyl ethers, tetrahydropyranyl ethers, benzyl ethers, acetates,1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/042208benzoates, pivalates. Preferably, mercapto groups are protected as thioethers or thioesters, inparticular tert-butyl thioethers, thioacetates, thiobenzoates. Preferably, amino groups areprotected as carbamates, e.g. tert-butoxycarbonyl and benzyloxycarbonyl derivatives, or asamides, e. g. acetamides and benzamides.The present invention provides the salts of those compounds of formula (I) that have salt-fomringgroups, especially the salts of the compounds having an acid group, especially a carboxylic group,a N-hydroxycarbamoyl group, and a sulfo group, or the salts of the compounds having a basicgroup, especially an amino or guanidino group. The salts are especially physiologically tolerablesalts, for example alkali metal and alkaline earth metal salts (e.g. sodium, potassium, lithium,calcium and magnesium salts), ammonium salts and salts with an appropriate organic amine oramino acid (e.g. arginine, procaine salts), and the addition salts formed with suitable inorganicacids (e.g. hydrochlorides, hydrobrornides, sulfates, phosphates) or carboxylic and sulfonicorganic acids (e.g. acetates, trifluoroacetates, citrates, succinates, malonates, lactates,tartrates, fumarates, maleates, methanesulfonates, p-toluenesulfonates). Some compounds offormula (I) which contain a carboxylate and an ammonium group may exist as zwitterions; suchsalts are also part of the present invention.Furthermore, hydrates, solvates of compounds of formula (I), and physiologically hydrolyzablederivatives (i.e., prodrugs) of compounds of formula (I) are included within the scope of thepresent invention. Particularly preferred prodrugs of the compounds of formula (I) are esterderivatives. They include esters of compounds of formula (I) wherein W is -COOI-I, or wherein acaiboxy group is present in any of the substituents R1, R2, R3 and Q, which may be obtained bycondensation of such carboxy group with a pharmaceutically acceptable alcohol, e.g. ethanol; oresters of compounds of formula (I) wherein a hydroxy group is present in any of the substituentsR1, R2, R3 and Q, which may be obtained by condensation of such hydroxy group with apharmaceutically acceptable carboxylic acid, e.g. acetic acid, pivalic acid, benzoic acid and thelike. Other particularly preferred prodrugs within the present invention are the cyclic condensationproducts between compounds of formula (I), wherein W is -CONHOH and R; is hydrogen, andformaldehyde, or an aldehyde of formula T-CHO, or a ketone of formula TT’CO, wherein T andT’ are carbon radicals, such as lower alkyl, phenyl, benzyl, optionally substituted by one to threesubstituents selected from by C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, methylarnino,dirnethylamino, chloro and fluoro. Such condensation products, which are represented herebelow,are obtained by mixing the two components, optionally in the presence of acid catalysts, as thoseemployed for the formation of ketals from alcohols and ketones, and removing water by101520CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042209evaporation, azeotropically or by molecular sieves.HO~N Q (H)NR2The present invention encompasses all the possible stereoisomers (e. g. diastereoisomers, epimers,geometrical isomers) of the compounds of formula (I), as well as their racemic or optically activemixtures.The present invention also includes, within its scope, pharmaceutical compositions comprising oneor more of the compounds (I) as active ingredients, in association with pharmaceuticallyacceptable carriers, excipients or other additives, if desirable.Preferred compounds within the present invention have the structure (I’):Q (1')Zlmmwherein:W is —CONHOH or -COOH;R; and R2 are:— both hydrogen; or- both C1-C4 alkyl, still preferably methyl; orR1 is hydrogen or methyl, and R2 is a group G which is:- C1-Cm alkyl or C2-C1‘) alkenyl, either unsubstituted or substituted by C3-C7 cycloalkyl, or byone to three substituents selected from chloro, fluoro, hydroxy, C,-C4 alkoxy, C1-C4 alkyl,amino, methylarnino, dimethylamino, -CONH2, -CONHCH3 or -CONHC(CH3)3, C;-C410152O2530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/04220alkylthio, C1-C4 alkylsulfonyl, phenoxy, pheriyliilthio and phenylsulfonyl, wherein the phenylgroup may in turn be substituted by chloro, fluoro, methoxy or methyl; or- C3-C7 cycloalkyl; or- an aryl group, more preferably phenyl, methylenedioxyphenyl, naphthyl or indanyl, each ofwhich is optionally substituted by one to three substituents selected from chloro, fluoro,hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl,C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, phenyl, benzyl,phenethyl, phenpropyl, naphthyl and pyridyl, and wherein any phenyl, naphthyl and pyridylring may in turn be substituted by one to three substituents selected from chloro, fluoro,methyl, hydroxy, methoxy, amino, methylamino and dimethylarnino; or- an unsaturated heterocyclyl group selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrazinyl,benzothienyl, benzothiazolyl, benzoxazolyl,pyrimidinyl, isobenzofixranyl,benzofiiranyl, benzimidazolyl, indazolyl, chromenyl, indolyl, oxindolyl, quinolyl, isoquinolyl,pyfidazinyl,isoindolyl, cinnolinyl and purinyl, each of which is optionally substituted by one to threesubstituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino,dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy,phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro,methoxy or methyl; or- a saturated or partially saturated heterocyclyl group selected from pyrrolidinyl,tetrahydrothienyl, tetrahydrofinyl, aziridinyl, oxiranyl, azetidinyl, piperidinyl, piperazinyl,hexahydropyridazinyl, tetrahydropyranyl, 1-oxo-2-isoindolyl, tetrahydroisoquinolyl, hydantoinyl,morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepinyl and thiazolidinyl, wherein any ringnitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a caibonyl, and anyring sulfiir may be oxidized as a sulfoxide or sulfone; and the derivates thereof substituted by oneto three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino,methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may besubstitued by chloro, fluoro, methoxy or methyl; or- C1-C10 alkyl, substituted by any of the unsaturated or saturated heterocyclyl groups asdefined above, wherein any ring nitrogen may be oxidized as an N-oxide, any ring carbon may beoxidized as a carbonyl, and any ring sulfur may be oxidized as a sulfoxide or sulfone; or aderivative thereof substituted by one to three substituents selected from chloro, fluoro,1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/04220hydroxy, C1-C4 alkoxy, amino, methylamino, ilimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, -CONH2, -CONHCH3 and -CONHC(CH3)3, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy,phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro,methoxy or methyl; or— C1-C141 alkyl, substituted by any of the aryl group as defined above, and the derivates thereofsubstituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy,amino, methylarnino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may besubstitued by chloro, fluoro, methoxy or methyl; orR1 is hydrogen or methyl, and R2 is -SO2—G, wherein G is as defined above; orR1 is hydrogen or methyl, and R2 is -CO-G, wherein G is as defined above; orR1 is hydrogen or methyl, and R2 is -CO-O—G, wherein G is as defined above; orR1 is hydrogen or methyl, and R2 is —S02-NH2, —SO2-NHG or -S02-NGG’, wherein G is asdefined above and G’, which is the same or difi"erent, is as defined above for G; orR1 is hydrogen or methyl, and R2 is —SO-NH-G, wherein G is as defined above; orR1 is hydrogen or methyl, and R2 is -CONHG or -CONGG’, wherein G is as defined aboveand G’, which is the same or different, is as defined above for G; orR1 and R2, taken together with the nitrogen atom to which they are attached, form a 3- to 7-membered azaheterocyclyl ring, optionally containing N, O, S or S02 as an additional ringmember, which may be substituted by oxo on one or two carbon ring atoms adjacent to thelinking nitrogen atom, and which is optionally fused with a benzene ring, the azaheterocyclylgroup being either unsubstituted or substituted at one or more carbon and/or nitrogen atomsby chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl,phenyl, 4-fluorophenyl, benzyl, 4-fluorobenzyl, alpha-methylbenzyl, methylenedioxyphenyl, 2-phenethyl, 2-(4-fluorophenyl)ethyl, piperonyl, carbamoyl, -CONHCH3, -CONHC(CH3)3, -CONH-(4-fluorophenyl), -CONH-pyridyl, -CONH-(methylenedioxy)phenyl —CONH-piperonyl;orR1 is hydrogen or methyl and R2 is -SO2—azaheterocyclyl, wherein azaheterocyclyl is asdefined above; orR1 is hydrogen or methyl, and R2 is —C0-azaheterocyclyl, wherein azaheterocyclyl is asdefined above;R3 is -CH2-alkyl, -(CH2),.-cycloalkyl, -(CH2),,-O-alkyl, -(CH2)“-O-(CH2),,,-cycloalkyl, -(CH2),,-O-(CH2),.,-aryl, -(CH2),,-O-(CH2),..-heterocyclyl, -(CH2).,-S-alkyl, -(CH2).,-S-(CH2).,,-1015202530CA 02265671 1999-03-09W0 99/0251 0 PCT/EP98/0422012cycloalkyl, -(CH2),,-S-(CH2),.,-aryl, -(CH2),,-S-(CH2),.,-heterocyclyl, -(CH2),-SO-alkyl, -(CH2)..-SO-(CH2)...-cycloalkyl, -(CH2)..-SO-(CH2),,,-aryl, -(CH2),,—SO-(CH2),..-heterocyclyl, -(CH2).,-S02-alkyl, -(CH2),,-S02-(CH2)...-cycloalkyl, -(CH2),-S02-(CH2),,.-aryl, -(CH2)n‘SO2-(CH2),,,-heterocyclyl, -(CH2)..-C0-alkyl, -(CH2),.-CO-(CH2)...-cycloalkyl, -(CH;1),.-CO-(1 CH2)",-aryl or -(CH2),.-CO-(CH2)...-heterocyclyl, wherein alkyl, cycloalkyl, aryl and heterocyclyl areas defined above, and n and m, being the same or different, are zero or an integer of 1 to 5,and wherein the alkyl, cycloalkyl, aryl and heterocyclyl groups are optionally substituted byone to three substituents selected from chloro, fluoro, cyano, cyanomethyl, hydroxy, C1-C4alkoxy, C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenyl, tolyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-phenoxyphenyl, 4-(4-pyridyl)oxyphenyl, pyridyl; or R3 isselected from isobutyl, n—hexyl, n-heptyl, n-octyl, n—nonyl and cyclopentylmethyl; or R3 isselected from 2-phenylethyl, 3—phenylpropyl, 4-phenylbutyl, 5—phenylpentyl, wherein thephenyl group is either unsubstituted or substituted by chloro, fluoro, cyano, cyanomethyl,methyl, ethyl, propyl, butyl, mesyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, 4-chlorophenoxy, 4—fluorophenoxy, benzyloxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-pyridyl, 4-pyridyloxy; or R3 isselected from phenylsulfonylmethyl or phenylsulphonylethyl, wherein the phenyl group iseither unsubstituted or substituted by chloro, fluoro, cyano, cyanomethyl, methyl, ethyl,propyl, butyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, benzyloxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-pyridyl, 4-pyridyloxy;Q is:- a group -CONHG, -CONGG’, -CONH-CHGG’, CON(CH3)-CHGG’, -CONH-CH2-CHGG’, or -CON(CH3)-CH2-CHGG’, wherein G and G’, being as defined above, arepreferably selected from C1-C5 straight or branched alkyl, C5-C1, cycloalkyl, phenyl, tolyl,methylenedioxyphenyl, piperonyl and pyridyl, either unsubstituted or substituted by one tothree substituents selected from chloro, fluoro, hydroxy, hydroxymethyl, C1-C4 alkoxy,amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, -CONH2, -CONHCH3, -CONHC(CH3)3, -CONH(4-fluorophenyl), -CONH-pyridyl, -CONH-(methylenedioxy)phenyl,-CONH-piperonyl, carbomethoxy, carbethoxy, or a keto group -CO-R", wherein R", being asdefined is selected fiom C1-C4 alkyl,methylenedioxyphenyl, naphthyl, piperonyl, or a sulfone -(CH2),.-S02-R", wherein n and R”are as defined above, or a sulfonamide -(CH2),,-S02-NH2, -(CH2)..-S02-NHR”, -(CH2),,-SO2-above, phenyl, fluorophenyl, chlorophenyl,1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/04220NR" Rm, wherein n, R" and Rm are as define1d3above, including the special case wherein R"and Rm, taken together with the nitrogen atom to which they are attached, constitute anazaheterocyclyl ring, as defined above; or- a group -CO-azaheterocyclyl, wherein azaheterocyclyl, being as defined above, is, eitherunsubstituted or substituted by one to three substituents selected from hydroxy,hydroxymethyl, C1-C4 alkoxy, carbamoyl, carbomethoxy, carbethoxy, mesyl, C.-C6 linear orbranched alkyl, trifluoromethyl, C3-C7 cycloalkyl, aryl, heterocyclyl and aryl-(C.-C3)alkyl orheterocyclyl-(C1-C3)alkyl; or said azaheterocyclyl group is substituted by a group —CONH-R”, wherein R", being as defined above, is selected from methyl, isopropyl, tert~butyl,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-piperidyl, 2-thiazolyl, l-naphthyl, 2-naphthyl, 3-quinolyl, 5-quinolyl, 3-isoquinolinyl, 5-isoquinolyl, 3-quinuclidinyl,methylenedioxyphenyl, piperonyl, 2-benzimidazolyl and 5-tetrazolyl; or said azaheterocyclylgroup is substituted by a keto group —CO-R", or by a carbinol group of formula -CH(OH)-R", wherein R“, being as defined above, is selected from C1-C4 alkyl, phenyl, fluorophenyl,chlorophenyl, methylenedioxyphenyl, naphthyl, piperonyl, or by a sulfone -(CH2),,-S02-R",wherein n and R" are as defined above, or by a sulfonamide -(CH;;_),.-S02-NH2, -(CH2).,-SO2-NI-IR", -(CH2),.-S02-NR“ Rm, wherein n, R“ and Rm are as defined above, including thespecial case wherein R“ and Rm, taken together with the nitrogen atom to which they areattached, constitute an azaheterocyclyl ring, as defined above;and the salts and solvates thereof.When, in the above embodiment R1 and R2 form an azaheterocyclyl ring, the azaheterocyclylring is preferably selected from aziridine, azetidine, morpholine, thiomorpholine, piperidine,pyrrolidine, piperazine, thiazolidine, tetrahydroisoquinoline, hexahydropyridazine,succinimido, phthalimido, saccharinyl, hydantoinyl, and oxoisoindolinyl. When R2 is -CO-azaheterocyclyl or -SO;-azaheterocyclyl, the azaheterocyclyl moiety is preferably morpholinoor piperidino. When Q is a group -CO-azaheterocyclyl, the azaheterocyclyl moiety ispreferably selected from azetidine, morpholine, thiomorpholine, pyrrolidine, piperidine,piperazine, pyridazine, thiazolidine, tetrahydroisoquinoline, hexahydropyridazine andhexamethylenimine. The aryl group or moiety in the definitions of Q is preferably selectedfrom phenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, methylenedioxyphenyl,naphthyl, and heterocyclyl is preferably pyridyl.A further preferred group of compounds are cyclic acetonide prodrugs of formula (II’):10152025CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422014new o «HNR2T T.wherein R2, R3 and Q are as defined above and T is methyl or a hydrogen atom, and T’ ismethyl, C2-C4 lower alkyl, phenyl, benzyl, optionally substituted by one to three substituentsselected from by C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, chloroand fluoro. More preferably, T and T’ are methyl.The present invention also provides a pharmaceutical composition comprising a pharmaceuticallyacceptable diluent or carrier and, as an active ingredient, a compound of the invention as definedabove.Compounds of the general formula (I) may be prepared by any suitable method known in theart, and/or by the following processes, which form another aspect of the invention. In thedescription and formulae below, the groups W, R1 , R2 , R3 and Q are as defined above. It isunderstood that in the processes below any functional group (e.g. carboxyl, hydroxyl oramino), if needed or desired, can be masked by conventional methods and unmasked at theend or when convenient. Suitable protecting groups for such fimctionalities will be apparentto those skilled on the art and are well described in the chemical literature (see, for example:“Protective Groups in Organic Synthesis” by T.W. Greene, Wiley Interscience). It is alsounderstood that any of the groups W, R1 , R2 , R3 and Q can be converted by conventionalmethods into different groups W, R1 , R2 , R3 and Q having any of the meaning previouslydefined, if desired, at the end or at any stage of the processes below. These conversions areknown or will be apparent to those skilled in the art and are well described in the chemicalliterature (see, for example: “Comprehensive Organic Transformation” by R.C. Larock, VCHPublishers).A preferred process for preparing a compound of formula (1) comprises:(a) reacting a beta-lactam compound of formula (III):101520CA 02265671 1999-03-09W0 99/02510 PCT/EP98/04220\_(""'/""\,,wherein R2 and R3 are as defined above, and W’ is COOH, CONHOH or a protectedderivative thereof, with:R3um- a primary or secondary acyclic amine of fonnula G-NH2, GG’NH, GG’CH-NH2, GG’CH-NHCH3, GG’CH-CH2-NH2, or GG’CH-CH2-NHCH3, wherein G and G’ are as definedabove; or- a cyclic saturated or unsaturated secondary amine, represented as azaheterocyclyl-H,wherein azaheterocyclyl is as defined above;to obtain a compound of formula (IV):(IV)NHR2wherein W’, R2 , R3 and Q are as defined above; and then:(b) converting said compound of formula (IV) into a compound of formula (I), wherein W,R1, R2, R3 and Q are as defined above; and then:(c) if desired , removing the protecting groups and/or, if desired, converting any of thegroups W, R1, R2 R3 and Q into different groups W, R1, R2, R3 and Q at the end or at anystage of the process.It is evident that compounds with a desired configuration may be prepared starting fromcompounds (III) and (IV) with the appropriate configurations. Thus, a process for preparingpreferred compounds of formula (I’) comprises:(a’) reacting a beta-lactam compound of general formula (HP):CA 02265671 1999-03-09wo 99/02510 PCT/EP98/04220a3\ iiir-— N0/ \(||l')R2wherein R2 and R3 are as defined above, and W’ is either COOH, CONHOH, or a protectedderivative thereof, with an amine as defined above, to obtain a compound of formula (IV’):R3W‘ av‘)Q Q5 NHR2wherein W’, R2, R3 and Q are as defined above; and(b’) converting this compound of formula (IV’) into a compound of formula (I’):Q (|')Zlmm10 wherein W, R1, R2 , R3 and Q are as defined above.The reaction between the beta-lactam of formula (III) or (III’) and an amine among thosehereabove detailed in step (a) or (a’) above can be carried out in organic solvents, especiallydimethylformamide (hereinafter DMF), tetrahydrofuran (hereinafter THF), acetonitrile,dimethylsulfoxide (hereinafter DMSO) and toluene, or in aqueous organic solvents, especially15 aqueous TI-IF, aqueous DMF, and aqueous acetonitrile, at temperatures ranging from O to120 °C, either in the absence or in the presence of external bases. When the amine is a poornucleophile, in order to accelerate the reaction, and achieving higher yields of the product offormula (IV) or (IV’), the reaction can be run in the presence of nucleophiles (NuH or saltsthereof, wherein Nu is herebelow defined), which cleave the beta-lactam of formula (III) or2 0 (III’) more readily. In this case, an intermediate of formula (Illa) or (III’a) is formed:101520CA 02265671 1999-03-09WO 99/02510 PCT/EP98/0422017R w' R W.H ("'30 (|ll'a)O u \ R2 0 u R2wherein W’, R2 and R3 are as defined above, and Nu is selected from the group consisting ofazido, irnidazole, cyano, lower alkylthio, pyridylthio, phenylthio, and benzylthio. Saidintermediate of fonnula (Illa) or (IIIa’), being an activated carboxylic acid derivative, reactsin the same milieu or in a separate step, and under the same reaction conditions, with theamine selected among those detailed above, giving rise to the product of formula (IV) or(IV’). Particularly preferred external nucleophiles are sodium azide, imidazole, and sodiumand potassium cyanide; particularly preferred solvents are DMF and acetonitrile.When in compounds of formula (III), (III’), (IV), (IV’) above W’ is a protected carboxyderivative, it is preferably benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxy-benzyloxycarbonyl, tert-butoxycarbonyl,benzhydryloxycarbonyl, trityloxycarbonyl,trimethylsilyloxycarbonyl, tert-butyldimethyl-silyloxycarbonyl, phenyl-dimethyl-silyloxy-carbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n-butoxycarbonyl. Whenin compounds of formula (III), (III’), (IV), (IV’) above W’ is a protected derivative ofCONHOH, it is preferably a group of formula CONHORN or CON(Rn)OR10, whereinR10 and R11 are, respectively, hydroxy- and amino-protecting groups, known per se andremovable by hydrogenolysis or by hydrolysis. Preferred R10 and R11 groups, which may bethe same or different, include benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, tert-butyl, tert-butoxycarbonyl, tetrahydropyranyl, and trityl.The conversion of a compound of formula (IV) or (IV’) into a compound of formula (I) or(I’) in step (b) above may include any or all of the following steps in any order:—(b‘):the conversion of the group W’, which is a protected carboxy or hydroxamate1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422018derivative, into a group W, which is the unmasked carboxy or hydroxamic acid. Thisconversion is carried out by methodologies for unmasking of protective groups, which arewell known in the art, as generally referred to above. A preferred conversion of this type ishydrogenolysis, especially in the presence of a palladium catalyst, in an inert organic solventsuch as ethanol or DMF or the like, especially at room temperature and under atmosphericpressure or moderate pressure, which is suitable for the conversion, e.g., of benzyl and p-nitrobenzyl esters into the parent carboxylic acids, or of O-benzyl and O,N-bis-benzylhydroxamates into the parent hydroxamic acids. Another preferred conversion of this type isacid hydrolysis, especially by trifluoroacetic acid, hydrochloric acid, or by aluminiumtrichloride, in the presence or absence of anisole, in inert organic solvents such as THF,acetonitrile and the like, especially between -20 and +30 °C, which is suitable for theconversion, e.g., of tert-butyl esters and p-methoxybenzyl esters into the parent carboxylicacids, or of O-tert-butylhydroxamates, 0-(p-methoxybenzyl)-hydroxamates, and O,N-bis(p-methoxybenzyl) hydroxamates into the parent hydroxamic acids. A fiirther preferredconversion of this type is alkalyne hydrolysis, especially by NaOH, KOH, LiOH,KOSi(CH3)3, in an inert organic solvent or in water or in admixtures thereof, which isparticularly suitable for the conversion of lower alkyl esters, e.g. the methyl, ethyl and n-butyl esters, into the parent carboxylic acids.-(b“): the conversion of the group W’, which is carboxy or an activated derivative thereof,into a group W, which is -CONHOH. This conversion entails the condensation of suchcompounds of formula (IV) with hydroxylarnine or a salt thereof, or with an O-protectedhydroxylamine of formula R1oO—NH2 , or an N,O-diprotected hydroxylamine of formulaR100-NHR11 , wherein R10 and R11 are as defined above, or a salt thereof, and then removalof said protecting groups R10 and R11 , if present, according to (bl) above. Such condensationis carried out according to general methodologies for the conversion of carboxylic acids oractivated derivatives thereof into hydroxamic acids, which are well known in the art. Inparticular, activated derivatives of the carboxy group are the acid chloride, mixed anhydrides,and esters. In particular, the acid chloride is obtained by reacting the acid or a salt thereofwith reagents such as oxalyl chloride or thionyl chloride; mixed anhydrides are obtained byreacting the acid or a salt thereof with chlorocarbonates, such as ethyl chlorocarbonate, orwith acid halides, such as pivaloyl chloride; esters, which are, preferably, the methyl, ethyl, n-butyl, pentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl esters, are obtained byreaction of the acid with the corresponding alcohols in the presence of a dehydrating agent,1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422019for example dicyclohexyl carbodiirnide (hereinafter DCC), N,N-dimethylaminopropyl-N’—ethyl carbodiirnide (EDC), and 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ).Esters, in particular the methyl, ethyl, and n-butyl esters, may be present from the beginningin the azetidinone intermediates of formula (III) and (III’) above. An O-protectedhydroxylamine is, preferably, O-benzylhydroxylamine, O-tert— butylhydroxylamine, O-tert-O-(4-O-(tert-butyldiphenylsilyl hydroxyarnine, O-(4-methoxybenzyl)-hydroxylamine,nitrobenzyl)hydroxylamine, O-trimethylsilylhydroxylamine, andbutoxycarbonyl)hydroxylamine. An N,O-diprotected hydroxylamine is, preferably, N,O-bis(benzyl)hydroxylarnine, N,O—bis(4-methoxybenzyl)hydroxylamine, N,O-bis(tert-butoxy-carbonyl)hydroxylarnine, N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)hydroxylamine,and N—(tert-butoxycarbonyl)-O-(tetrahydropyranyl)hydroxylamine. Preferably, thecondensation reaction with hydroxylamine, O-protected hydroxylamines, N,O-diprotectedhydroxylamines, and the salts thereof, is canied out in an inert organic solvent, such as DMF,TI-IF, acetonitrile, dichloromethane, toluene and the like, at temperatures ranging from -20 to+ 60 °C, optionally in the presence of a tertiary organic base, such as triethylamine and N-methylmorpholine. When protected hydroxylamines are employed, the protecting groups areremoved after the condensation reaction, under the conditions described in (bi) above;-(bill): the conversion of the group NHR2, being R2 different from hydrogen, into a groupNH2. This reaction can be carried out on compounds of formula (I), (I’), or on intermediatesof formula (IV), (IV’), wherein R2 is an amino protecting group, according to methods wellknown per se, for example by the methods of removal of amino protecting groups which arepart of the techniques of peptide chemistry. Particularly preferred R2 groups for suchconversion are electron-withdrawing groups, in particular alkoxy- or benzyloxy—carbonylgroups such as tert-butoxycarbonyl, benzyloxycarbonyl and 4-nitro or 4—methoxy derivativesthereof, since the same particular R1 groups efficiently assist the beta-lactam cleavagereaction detailed in step (a) above. In a preferred embodiment of the present invention, R2 istert-butoxycarbonyl, which can be removed by treatment with trifluoroacetic acid (TFA),optionally in the presence of anisole, in an inert organic solvent; in another preferredembodiment, R2 is benzyloxycarbonyl or 4—nitrobenzyloxycarbonyl, which can be removedby catalytic hydrogenation;_(biv )2hydrogen, into a group NR1R2, to be selected within the specifications stated above.the conversion of the group NHR2 , including the special case wherein R2 isPreferred R1 and R2 groups are the same groups detailed for the preferred compounds of1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422020formula (1). Such conversion encompasses fimctionalizations of amino groups well known inthe art, such as alkylation, acylation, sulfonylation, and the like, and is performed accordingto methods well known per se. In a preferred embodiment of the present invention, suchconversion is performed on compounds of formula (IV) or (IV’) wherein W’ is protectedcarboxy, thereafier removing the protecting group to obtain a compound of formula (I) or(I’) wherein W is carboxy, by the general methodology described under (bl) above and,optionally, by converting the so-obtained compound of formula (I) or (I’) wherein W iscarboxy into the corresponding compound wherein W is -CONHOH, by the generalmethodology described under (b“) above;—(b"): the conversion of any group W, R1, R2, R3 and Q into any different group R1 , R2, R3and Q, to be selected within the specifications stated above, by methodologies known per se.The resultant compounds of formula (I) or (I’) may be converted into the desired salts,prodrugs, hydrates or solvates thereof by means of well known reactions, which include saltpreparation by reaction with a pharmaceutically acceptable acid, or conversion of any hydroxy orcarboxy group into an ester thereof, if desired, by condensation with a pharmaceuticallyacceptable alcohol or with a pharmaceutically acceptable carboxylic acid. In the particular case ofthe cyclic prodrugs described by formula (II) or (II’)_, said compounds are obtained from thecorresponding compounds of formula (I) or (I’) wherein W is -NHOH and R1 is hydrogen, byreaction with an aldehyde of general formula T-CHO or a ketone of general formula TT’CO,wherein T and T’ are as defined above, and removing water by evaporation.The amines used in step (a) above are known compounds or are prepared from knowncompounds by known methods.The beta—lactams of formula (III) or (III’) above are known compounds or can be preparedfrom known compounds by methodologies known per se or by analogy with the specificpreparative examples herein. In particular, a preferred preparation of compounds of formula(H1) or (III’) includes:-(dl): cyclization of an aspartic acid derivative to obtain a compound of formula (III) or (III’)wherein R3 is hydrogen, by reaction with a suitable condensing agent;-(d“): conversion of a compound of formula (III) or (III’) wherein R3 is hydrogen into acompound of formula (III) or (III’) wherein R3 is as described above, by deprotonation witha strong base and alkylation of the resulting beta-lactam enolate with an agent of formula R3-X, wherein X is halo, e.g. chloro, bromo or iodo, or sulfonyloxy, e.g. triflate, mesylate or thelike.1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422021General conditions for step (d’) above are described in the literature, the preferred asparticacid derivative being usually dibenzyl aspartate or di(4-nitro)benzyl aspartate. Some of theresultant azetidinones (III) or (III’) wherein R3 is hydrogen, W’ is carboxy or an esterthereof, and R2 is hydrogen or text-butyldimethylsyl are also commercially available. Apreferred compound in step (d“) is a compound of formula (III) or (HI’) wherein R3 ishydrogen, R2 is tert-butyldimethylsilyl, and W’ is free carboxy, since the carboxylate anionhelps at avoiding racernization at the azetidinone 4-C, and increases regioselectivity ofalkylation by the R3-X reagent at the azetidinone 3—C.The conditions described in steps (a), (b), (C) and ((1) do not usually promote epimerizationor racernization at pre—existing chiral centers. Thus, when the aspartic acid derivative used asa reagent in step (d’) above is an L-aspartic acid derivative, the reaction affords a chiralazetidinone of formula (III’), wherein R3 is hydrogen and R2, W’ are as described above. Insuch chiral azetidinone of formula (III’) wherein R3 is hydrogen, the configuration at the C-4atom addresses stereoselective alkylation, by the R3-X reagent, in a transoid relationship withthe W’ substituent. Therefore, starting from such intennediates of formula (III’), step (d“)above stereoselectively affords the corresponding azetidinones of fonnula (III’) wherein R3,being as described above, is different from hydrogen, with the depicted configurations at thetwo chiral centers. Said configurations of the two chiral centers are the same as found incompounds of fonnula (I’) herein specifically preferred. Accordingly, it can be appreciatedthat steps (di) and (d“) above are essential part of an original, fiilly stereocontrolled route tothe compounds of fonnula (I’).Another process for the preparation of compounds of formula (I) comprises:(e) alkylation of an aspartic acid derivative of formula (V):W (V)Q!NR1R2wherein W’ is either carboxy or a protected derivative thereof, Q’ is either Q as describedabove, or carboxy or protected carboxy, and R1, R2 are as described above, with a reagent offormula R3-X, wherein R3 and X are as described above, to obtain a compound of fonnula(V1):101520CA 02265671 1999-03-09W0 99l02510 PCT/EP98/0422022W‘ (vnQ‘NR1R2wherein W’, R1, R2, R3 and Q’ are as described above; and:(t) conversion of such compound of formula (VI) into the desired compound of formula (I),wherein W, R1, R2, R3 and Q are as described above.We have observed that the configuration at the chiral carbon atom in compounds of formula(V) addresses the configuration at the new chiral center in the product of formula (VI) in ananti-fashion, exclusively or predominantly. Thus, starting from an L-aspartic derivative offormula (V’):(V')Q!N R1 R2wherein W’, R1, R2, R3 and Q’ are as described above, step (e) predominantly or exclusivelyaffords a compound of formula (VI’):R3(VV)3 Q'ENR1R2wherein W’, R1, R2, R3 and Q’ are as described above, from which the preferred compoundsof formula (I’) are obtained by step (i) above.The reaction of step (e) above is carried out according to conventional carbanion chemistry,i.e. with 2-4 equivalents of a strong base, such as LDA and the like, in aprotic organicsolvents, such as TI-H3, DMF, N-methylpyrrolidone, HMPA and the like, at temperatures1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422023ranging fi'om —70°C to room temperature. A preferred W’ group is free carboxy. A preferredR1 group is hydrogen. A preferred R; group is tert—butoxycarbonyl. Preferred Q’ groups areeither the acyclic or cyclic tertiary carboxamides described within Q above, or a carboxyester, which in step (t) can be converted into the group Q above as generally known for thepreparation of carboxamides.The compounds of formula (I) and (I’) provided by the present invention are characterized by highinhibitory activity on matrix metalloproteinases (MMPS), especially collagenases, gelatinases andstromelysins. For example, the following protocol was used to assess the biochemical activity ofcompounds of formula (I’) against MMP-1, MMP-2, and MJVIP-3 (respectively, human interstitialcollagenase, gelatinase A, and stromelysin-1).BIOCHEMICAL ASSAY (Protocol A)Human collagenase (MMP-1) was obtained as tmncated recombinant enzyme encompassingresidues 101-269 and did not require activation. Human gelatinase-A (MMP-2) was obtainedas pro-enzyme (72 kDa) and was activated with 1 mM 4—aminophenylmercuric acetate for 30min at 37 °C immediately prior to use. Human stromelysin-1-255 (MMP-3) was obtained as arecombinant pro-enzyme isolated from E. coli and activated by heat (1 h, 55 °C).The substrate was the commercial quenched-fluorescence peptide Mca-Pro—@;@-Leu-Dpa—Ala-Arg-NH2,dinitrophenyl]-L—2,3-diarnino—propionyl)-Ala-Arg-NH;is (7-methoxycoumarin—4-yl)Acetyl-Pro-mien-(3-[2,4-(C.G. Knight et al., FEBSLett.296:263, 1992). The enzymes cleave at the Gly-Leu bond, removing the internallythatquenching Dpa group. Release of the highly fluorescent peptide Mca-Pro-Leu was followedfluorimetrically at 37°C using a Perkin Elmer LS—5O Fluorescence Spectrophotometer fittedwith a thermostatted four position stirring cell changer. The excitation wavelength was set at326 nm (bandwidth 5 nm) and the emission at 392 nm (bandwidth 20 nm). Km values of thissubstrate for the three MMP's is 70 uM or more G(night et al., reference above). Substrateconcentration was 2 uM in the tests, so that we could approximate to unit the term (1 + [substrate ] / KM) in calculations. The substrate was stable for over 60 minutes in the assayconditions, giving no appreciable increment of fluorescence. Full response was adjustedagainst 200 nM Mca-Pro-Leu-OH (the released fluorescent peptide) and the instrument wascalibrated in the range 0-100 nM Mca-Pro-Leu-OH, corresponding to O-5% extent ofhydrolysis of the 2 uM substrate. The aqueous assay bufifer was 50 mM Tris/HCl pH=7.4containing 0.15 M NaCl, 10 mM CaCl2, 0.01 mM ZnCl2 and 0.05% Brij 35. Theconcentration of the activated enzyme was determined by titration against representative1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422024inhibitors described in the literature and synthesized in house: Roche R031-9790 (N.G.Knebel et al., J. Chromatogr. B 6731213, 1995) for MMP-1, and Celltech CT-1418(compound 1 in S.K. Chander, J. Pharm. Sci. 84:404, 1995) for MMP-2 and MMP-3.Enzyme concentrations in the tests were set at 1.0 nM for MMP—l, 0.04 nM for MMP-2, and3.0 nM for MMP-3. Under our assay conditions, we measured km, / KM values of 26900,669000 and 9740 1/(M><s) for MMP-1, MMP-2 and MMP-3, respectively. All the threeenzymes were found stable for over three hours in the assay conditions.The inhibition constant for compounds of the present invention was measured at steady state(Ki*; see J.F. Morrison and C.T. Walsh, Adv. Enzymol. Relat. Areas Mol. Biol. 61:201,1988), upon preincubation experiment, by measuring V0, the initial rate in the absence ofinhibitor, and V3, the steady-state velocity, at different concentrations of inhibitors in theregion of their enzyme-inhibitor dissociation constants.On a routine basis, 1.94 mL of assay buffer was pre-heated at 37°C in a vial, 0.02 mL ofinhibitor in DMSO (or DMSO only), and 0.02 ml of 100 nM MMP-1 or 4 nM MMP-2 or300 nM MMP-3 were added, mixed, and the vial was held at 37°C for 5-180 minutes. Then0.02 ml of 0.2 mM substrate was added, mixed and transferred into a pre-heated cell. Thesample was allowed to equilibrate in the cuvette for 3-5 min at 37°C against small changes intemperature and changes in the enzyme-inhibitor equilibria related to addition of substrate.Afier that, the linear increase of fluorescence was monitored over 3-5 min, and the slope (Voor Vs) was obtained. Inhibitor concentrations were varied to collect data over Vs/Vo ratioranging from 0.05 to 0.95. The values of Ki* were calculated by nonlinear weightedregression to the tight-binding equation according to Morrison and Walsh above:VsNo=[1/(2 x Et)} x SQR[(Ki* +It -Et)"2 + 4 x Ki* x Et] -(Ki* +It —Et)wherein Et is the total enzyme concentration, and It is the total inhibitor concentration.The following Table I lists Ki* obtained for some representative examples:TABLE 1Ki at steady state (Ki*) for inhibition of MMP-1, MMP-2 and MMP-3 (allmicromolar)Example compound MMP-1 MMP-2 MMP-3Example 2 1.1 2.8 13Example 3 0.088 0.29 2.5Example 5 0.061 0.31 0.94Example 7 0.070 0.25 0.721015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/042202 5Example compound MIVIP-1 lvfl\/IP-2 MMP-3Example 10 0.18 0.34 2.2Example 12 0.041 0.19 0.38Example 15 17 0.63 6.5Example 16 6.4 0.094 2.4Example 17 9.4 0.61 4.3Example 18 0.85 0.079 0.86Example 19 4.5 0.23 1.1Example 20 2.0 0.04 0.39Example 22 0.015 0.067 0.73Example 23 0.003 0.016 0.145Example 24 0.17 0.40 1 1Example 25 0.076 0.19 2.3Example 26 0.071 0.10 0.60Example 27 0.0065 0.02 0.24Example 28 7.5 0.60 10Example 30 0.0036 0.025 0.27Example 32 2.6 0.037 0.50Example 33 >10 0.46 6.6Example 34 2.4 0.021 1.4Example 3 5 0.0029 0.008 0.031Example 37 0.0018 0.0026 0.035Example 39 0.76 0.09 0.806Example 42 1.4 0.016 0.76Example 44 0.0089 0.0023 0.2]Example 47 0.0046 0.028 0.14Example 50 0.026 0.058 0.49Example 61 0.0078 0.066 not determinedSome of the compounds of formula (I) were also shown to possess high activity at inhibitingthe release of TNF of several different cell lines, under different stimulation conditions. Forexample, the following cell-based assay was used to assess such activity:CELLULAR ASSAY (Protocol B]THP-1 cells, cultured in RPMI 1640 supplemented with 10% FCS, were distributed into 24-1015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/0422026well plates, 1 mL of a suspension of 1x106 cells/mL in each well. Compounds to be tested,dissolved in DMSO and diluted with the culture medium ( 1% final DMSO concentration)were added. Plates were incubated for 30 min at 37 °C in 5% CO2 , and lipopolisaccharide(LPS 0l11:B4, 5 ttg/mL) was added as a stimulant. Afier a further 4 h incubation, cells wereharvested, centrifilged (2,000 rpm, 7 min), and the surnatant was collected and freezed (-20°C) until analysis. Analysis was run by classical ELISA methodology (monoclonal anti-TNF-a antibody, rabbit capture policlonal antibody, and peroxidated anti-rabbit antibody).Dichloroisocoumarin was used as a standard. As anticipated above, low aqueous solubility,metabolic instability (high clearance) and poor oral bioavailability is a common problem for the“peptide-based” hydroxamates of the prior art. In these respects, the compounds of the presentinvention are usually characterised by a superior profile. As an example, Table 2 reports thesolubility in water for some representative compounds, detailed in the Examples.TABLE 2Aqueous solubility (mg/mL, 25 °C) of some representative compoundsExample compound Conditions‘ SolubilityExample 2 A >4.5Example 3 A >9.5Example 5 B >6.0Example 7 A 4.0Example 13 A 6.7]Example 14 B >14Example 16 B >9.6Example 18 B >9.6Example 19 A 7.5Example 22 B >8.2Example 27 B 7.1(1) A: pH 7.4 phosphate buffer; from excess solid, after 5 min stining; B: saline, from excesssolid, afler 5 min stiningAs a fUl'thCI' example, Table 3 reports clearance and AUC values measured after intravenousadministration to rats of a 10-15 mg bolus dose of some representative compounds of the presentinvention.1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/042202 7TABLE 3PK parameters in rats (iv route, 10-15 mg/kg) of some representative compoundsExample compound Clearance 1mL/min/kg) AUC (ugmin/mL)lExample 10 24 666Example 12 39 395Example 19 27 563Example 27 23 679(1) Compounds were administered at doses ranging from 10 to 15 mg/kg. Data are referred to a15 mg/kg dose to allow comparison.As an additional example, Table 4 reports the maximum plasma concentration (Cm) and oralbioavailability (%F; calculated from dose-normalised ratio of oral to i.v. mean AUC values) afteroral administration to rats or cynomolgus monkeys of a 10-15 mg single dose of somerepresentative compounds of the present invention .TABLE 4PK parameters (oral route, 10-15 mg/kg) of some representative compoundsExample compound Animal species Cm_;.,_L(r_ig/mL)’ %FExample 10 rat 2120 28Example 12 rat 2440 21Example 22 rat 5487 62Example 27 rat 7908 58Example 27 cynomolgus monkey 3132 34Example 50 rat 3146 50Example 50 cynomolgus monkey 49516 70(1) Compounds were administered at doses ranging from 10 to 15 mg/kg. Data are referred to a15 mg/kg dose to allow comparison.Compounds of formula (I) can be used in human or veterinary medicine in the form ofpharmaceutical preparations which contain them in association with a compatiblepharmaceutical carrier material. Thus, a distinct aspect of the present invention is thepreparation of pharmaceutical compositions carrying a compound of formula (I) as active1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422028ingredient, and a method of management (i.e. treatment or prophylaxis) of diseases orconditions mediated in humans and warm blood animals by MMPs and/or TACE, whichmethod comprises administering an effective amount of a compound of formula (1) above, ora pharmaceutically acceptable salt thereof.In particular, the compounds of formula (I) can be administered:A) Orally, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups or elixirs_ Compositions intendedfor oral use may be prepared according to any method known in the art for the manufacture ofpharmaceutical compositions and such compositions may contain one or more agents selectedfrom the group consisting of sweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic phannaceutically acceptable excipients which aresuitable for the manufacture of tablets. These excipients may be for example, inert diluents, suchas calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents,for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate,stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques todelay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such as glyceryl monostearate orglyceryl distearate may be employed. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the activeingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraflin, or oliveoil. Aqueous suspensions contain the active materials in admixture with excipients suitable for themanufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy propylmethylcellulose, sodium alginate,polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may benaturally-occurring phosphatides, for example lecithin, or condensation products of an alkyleneoxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethyleneoxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, orcondensation products of ethylene oxide with partial esters derived from fatty acids and a hexitolsuch as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide withpartial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene1015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/042202 9sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives,for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or moreflavoring agents, or one or more sweetening agents, such as sucrose or saccharin. Oily suspensionmay be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil,olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensionsmay contain a thickening agent, for example beeswax, hard parafiin or cetyl alcohol. Sweeteningagents, such as those set forth above, and flavouring agents may be added to provide a palatableoral preparation. These compositions may be preserved by the addition of an antioxidant such asascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspensionby the addition of water provide the active ingredient in admixture with a dispersing or wettingagent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agentsand suspending agents are exemplified by those already mentioned above. Additional excipients,for example sweetening, flavoring and coloring agents, may also be present. The pharmaceuticalcompositions of the invention may also be in the fonn of oil-in-water emulsions. The oily phasemay be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may be naturally—occurring gums, forexample gum acacia or gum tragacanth, naturally—occum'ng phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for examplesorbitan mono—oleate, and condensation products of the said partial esters with ethylene oxide, forexample polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening andflavoring agents. Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative andflavoring and coloring agents;B) Parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrastemally, or byinfusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. Thissuspension may be formulated according to the known art using those suitable dispersing ofwetting agents and suspending agents which have been mentioned above. The sterile injectablepreparation may also be a sterile injectable solution or suspension in a non-toxicparenterally—acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil may be employed including syntheticmono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98I0422030injectables;C) By inhalation, in the form of aerosols or solutions for nebulizers;D) Rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperature but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials are cocoa butter and poly-ethyleneglycols;E) Topically, in the fonn of creams ointments, jellies, solutions or suspensions.Daily doses are in the range of about 0.1 to about 50 mg per kg of body weight, according to theactivity of the specific compound, the age, weight and conditions of the subject to be treated, thetype and severity of the disease, and the frequency and route of administration; preferably, dailydosage levels for humans are in the range of 10 mg to 2 g. The amount of active ingredient thatmay be combined with the carrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. For example, a formulationintended for the oral administration to humans, may contain from 5 mg to 2 g of active agentcompounded with an appropriate and convenient amount of carrier material which may vary fromabout 5 to about 95 percent of the total composition. Dosage unit fomis will generally containbetween from about 5 mg to about 1 g of active ingredient.Pharmaceutical compositions containing a compound of formula (I) can be used in medicinefor the treatment of disease states characterised by a systemic or local imbalance of activeMMPS and their natural inhibitors. The rationale for the use of MMP inhibitors in medicinehas been illustrated above, and is well described in the recent literature; see, for example,DE. Levy & A.M. Ezrin, “Matrix Metalloproteinase Inhibitor Drugs”, in: Emerging Drugs:The Prospect for Improved Medicines, Chapter Ten (pp 205-230), Ashley Publications Ltd.,1997. According to this rationale, and proofs of concept already established with other MMPinhibitors, the compounds of the present invention can be used, in particular, for thetreatment of:- inflammatory and autoimmune diseases, especially rheumatoid arthritis, osteoarthritis, boneresorption, periodontal disease, multiple sclerosis, inflammatory bowel diseases;- cancer, including both tumor growth and tumor invasion by secondary metastases, withparticular reference to breast cancer, small cell lung cancer, non-small cell lung cancer,glioblastoma, prostate cancer, ovarian cancer, gastric and esophageal cancers, pancreaticcancer, colorectal tumors, and bony metastases;- angiogenic disorders, especially diabetic retinopathies and macular diseases;1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042203 1- cardiovascular diseases, especially congestive hearth failure and vascular restenosis;- soft and osseous tissue diseases, including ocular inflammation, corneal or tissue ulceration,wound healing;- other disorders in which either MMPS or abnormal release of TNF-alfa is implicated, inparticular shock syndromes, transplant rejection, cachexia, anorexia.The present invention also includes the use of compounds of formula (I), for the treatment ofany of the diseases above, as adjuncts to other conventional treatments; for example, togetherwith anti-inflammatory or immunosuppressive drugs for the treatment of rheumatoid arthritisand multiple sclerosis, and together with cytotoxic or cytostatic drugs for the treatment oftumoral diseases.The following examples are meant to illustrate the present invention, without limiting it.EXAMPLE 1(3S-tert-Butoxycarbonylamino-4-hydroxy-2R-isobutyl)succinyl—piperidinamideAZE T IDINONE ROUTEStep APiperidine (1.6 mL) was added to a solution of 4S—benzyloxycarbonyl-l-tert-butoxycarbonyl-3R—isobutylazetidin-2—one (3.8 g; see Preparation A) in acetonitrile (15 mL). After threehours stirring at room temperature, the solvent was removed in vacuo and the residue,dissolved in EtOAc, was sequentially washed with saturated aqueous NH4Cl and brine.Drying over Na2S04, evaporation and flash chromatography over silica gel (n-hexane/EtOAc) afiorded (4-benzyloxy~3S—tert-butoxycarbonylamino-2R-isobuty1)succinyl-piperidin-amide as a yellow oil (3.6 g). FT-IR (CHCl3) 3433 br (NH), 1753 (ester CO), 1714(carbamate CO), 1626 (amide CO) cm”. H'— NMR (200 MHz, CDCI3) 0.89 and 0.91 (two d,6 H, J= 6.6 Hz); 1.42 (s, 9 H); 1.2-1.8 (m, 9 H); 3.1-3.5 (m, 5 H); 4.48 (dd, 1 H, J= 4.1 and10.0 Hz); 5.06 and 5.19 (two d, 2 H, J= 12.4 Hz); 6.45 (d, l H, J= 10.0 Hz); 7.32 (m, 5 H)ppm.Step BA mixture of (4-benzyloxy-3S-tert-butoxycarbonylamino-2R—isobutyl)succinyl-piperidin-amide (500 mg) and 10% Pd/C (100 mg ) in EtOH (20 mL) was exposed to a hydrogenatmosphere for 3 hours. The catalyst was removed by filtration (Celite filter aid), washedwith additional ethanol, and the solvent was removed in vacuo to leave the title compound(390 mg) as a colourless oil . H‘- NMR (200 MHz, CDCl3) 0.89 and 0.90 (two d , 6 H, J=6.1 Hz) 1.44 (s, 9 H); 1.4-1.8 (m, 9 H); 3.60 (m, 5 H); 4.29 (dd, 1 H, J= 1.9 and 4.9 Hz);1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98l04220325.92 (d, 1 H, J= 4.9 Hz) ppm. FAB—MS 379 (MNa)+, 357 (MH)*, 301, 257, 211, 112, 86,84, 57 m/z.ASPARTIC ROUTEStarting from N-tert-butoxycarbonyl-3R-isobutyl-L-aspartic acid 1-benzyl ester-4-pipen'din-amide, obtained as described in Preparation H, which is (4-benzyloxy-3 S-tert-butoxycarbonylamino-2R-isobutyl)succinyl-piperidin-amide, identical with the compoundobtained as in step A bove, and following the same procedure described in step B above, thetitle product was obtained, identical with the one described above.EXAMPLE 2(3S-tert-Butoxycarbonylamino-4-hydroxyamino-2R-isobuty1)succinyl-piperidinamideStep A(3S-tert-Butoxycarbonylamino-4-hydroxy-2R-isobutyl)succiny1-piperidinamide (390 mg),obtained as indicated in Example 1, was dissolved in CH3CN (20 mL) and treated with O-benzylhydroxylamine hydrochloride (230 mg) and N-methylmorpholine (0.33 ml). After 10min, TBTU (O-1H—benzotriazol-1-yl—N,N,N’,N’-tetramethyluronium tetrafluoroborate; 465mg) was added to the solution, and the mixture was let stir overnight at room temperature.The solvent was removed in vacuo and the residue, dissolved in CH2Cl2, was washed with4% aqueous NaHCO3 , 2% HCl and brine. The organic layer was dried over Na2SO4 andevaporated. The crude product was purified by flash cromatography on silica gel (n-hexane/EtOAc) to afford (4-benzyloxyamino-3 S—tert-butoxycarbonylarnino-2R-isobutyl)-succinyl-piperidinamide as an oil (500 mg). H1- NMR (200 MHz, CDCI3) 0.90 and 092 (twod , 6 H, J= 6.4 Hz); 1.57 (s, 9 H); 1.3-1.7 (m, 9 H); 4.32 (dd, 1 H, J= 3.4 and 8.2 Hz); 4.85(s, 2 H); 6.73 (d, 1 H, J= 8.5 Hz); 7.37 (m, 5 H); 9.13 (s, 1 H) ppm. ESI-MS 500 (MI()“,484 (Mna)+,462 (MH)+, 384, 362, 283, 239, 211, 112 m/z.Step BA mixture of (4-benzyloxyamino-3 S-tert-butoxycarbonylamino-2R-isobutyl)succinyl-piperidinamide (500 mg) and 10% Pd/C (100 mg) in EtOH (50 mL) was exposed to ahydrogen atmosphere for 1 hour. The catalyst was removed by filtration (Celite filter aid) andthe solvent was evaporated to leave the title compound (300 mg) as a white solid. H‘- N1\/IR(200 MHz, CDC13) 0.90 and 0.93 (two (1 , 6 H, J= 6.1 Hz); 1.45 (s, 9 H); 1.2-1.8 (m, 9 H);3.3-3.7 (m, 5 H); 4.43 (dd ,1 H, J= 3.4 and 8.3 Hz); 6.72 (d, 1 H, J= 8.3 Hz); 6.93 (br signal,1 H); 9.31 (br signal, 1 H) ppm. FAB-MS 372 (MH)+, 316, 283, 272, 211, 112, 86, 84, 57m/z.1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/042203 3EXAMPLE 3(3S-Amino-4-hydroxyamino-2R—isobutyl)succinyl-piperidinamide(3 S-tert-Butoxycarbonylamino-4-hydroxyamino-2R-isobutyl)succinyl-piperidinarnide (1 70mg; prepared as described in Example 2) was dissolved in 95% aqueous trifluoroacetic acid(3 mL), and the solution was stirred 2 hours at room temperature. Toluene was added andevaporated in vacuo (several times), thereby obtaining the title compound, trifluoroacetatesalt, as a white solid (115 mg). In DMSO solution, the compound is present as a mixture oftwo rotamers ( M, major; m, minor). H‘- NMR (400 MHz, DMSO-d6) 0.80 and 0.81 (two d, 6 H, J= 6.4 Hz); 1.1-1.6 (m, 9 H); 3.21 (m, 1 H); 3.40 (m, 4 H); 3.64 (d, 1 H, J= 7.3 Hz);8.02 (br signal, 3 H); 9.32 (s, 1 H, M); 9.80 (br signal, 1 H, m); 10.69 (s, 1 H, m); 11.12 (brsignal, 1 H, M) ppm. ESI-MS 294 (MNa)+, 272 (MH)+, 239, 112 m/z.EXAMPLE 4(3S-N,N-Dimethylamino-4-hydroxy-2R-isobuty|)succinyl-piperidinamideStep A(4-Benzyloxy-3S-tert—butoxycarbonylamino-2R-isobutyl)succinyl-piperidinamide (preparedas described Example 1, step A; 1 g) was dissolved in 95% aqueous trifluoroacetic acid (5mL). and the solution was stirred 2 hr at room temperature. Toluene was added andevaporated in vacuo, repeating the process several times, thereby obtaining (3 S—amino-4-benzyloxy-R-isobutyl)succinyl-piperidinamide (triflluoroacetate salt) as a yellow oil (lg).Step BSodium cyanoborohydride (230 mg) was added to a solution of (3 S—amino-4-benzyloxy-2R-isobutyl)succinyl-piperidinamide trifluoroacetate salt (700 mg) in MeOH (10 mL). After 10min, 37% aqueous formaldehyde was added dropwise, and the solution was stirred for 1hour at room temperature. The solvent was removed in vacuo and the residue was dissolvedin EtOAc ; the organic layer was washed with water and dried over Na2S04. Evaporation ofthe solvent lefi crude(4-benzyloxy-3 S-N,N-dimethylamino-2R-isobutyl)succinyl-piperidinamide (552 mg). H]- NMR (200 MHz, CDCI3) 080 and 0.82 (two (1, 6 H, J= 6.6Hz); 0.92 and 1.70 (two In, 2 H); 1.40 (m, 1 H); 1.6 (m, 6 H); 2.25 (s, 6 H); 3.30 (m, 1 H);3.50 (m, 4 H); 3.56 (d, 1 H, J= 10.8 Hz); 5.15 and 5.20 (two d, 2 H, J= 12.2 Hz); 7.36 (m, 5H) ppm.Step C(4-Benzyloxy-3S-N,N-dimethylamino-2R-isobutyl)succinyl-piperidinamide (550 mg), as thecrude product from step B above, was dissolved in EtOH (15 mL). The resulting solution1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/04220was treated with 10% Pd/C (100 mg) and e>3c;osed to a hydrogen atmosphere for 4 hours.The catalyst was removed by filtration (Celite filter aid), washing with additional EtOH. Thesolvent was removed in vacuo to leave the title compound (400 mg) as a yellow oil. FT-IR(KBr ) 3385 br (NH), 1622 br (CO) cm". ESI/CID— MS 307 (MNa)+, 285 (MH)*, 239 (M-COOH)+, 184, 102 m/z.EXAMPLE 5(3S-N,N-Dimethylamino-4—hydroxyamino-2R-isobutyl)succinyl-piperidinlamideStep A(3S-N,N-Dimetylamino-4-hydroxy-2R-isobutyl)succinyl—piperidinlamide (460 mg), preparedas described in Example 4 (step B), was dissolved in CH3CN ( 10 mL) and treated with O-benzylhydroxylamine hydrochloride (310 mg) and N-methylmorpholine (0.44 mL). Afier 10min, TBTU (663 mg) was added to the solution, and the mixture was let stir overnight atroom temperature. The solvent was removed in vacuo and the residue, dissolved in EtOAc,was washed with aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 andevaporated to afford the crude product. Purification by flash cromatography on silica gel (n-hexane/EtOAc) afforded a white solid (230 mg), consisting of (4-benzyloxyan1ino-3S-N,N-dimethylamino-2R—isobutyl)succinyl-piperidinamide. FT-IR (KBr) 3191 br (NH), 1683 br(co) cm". H‘- NMR (400 MHz, DMSO-d6) 0.75 and 0.80 (two d, 6 H, J= 6.4 Hz); 0.9-1.6(m, 9 H); 2.09 (s, 6 H); 2.97 (d, 1 H, J= 10.7 Hz); 3.30 (m, 1 H); 3.3-3.6 (m, 4 H); 4.79 and4.82 (two d, 2 H, J= 12.0 Hz); 7.36 (m, 5 H); 11.13 (s, 1 H) ppm. ESI-MS 412 (MNa)+, 390(MH)’, 305, 239, 207 m/z.Step BThe material from step A above (230 mg) and 10% Pd/C (50 mg) in EtOH (10 mL) wasexposed to a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration (Celitefilter aid ) and the solvent was evaporated to leave the title compound as a white solid (170mg). H1- NMR (400 MHz, DMSO-ds) 0.77 and 0.81 (two d, 6 H, J= 6.7 Hz); 0.9-1.6 (m, 9H); 2.13 (s, 6 H); 3.00 (d, 1 H, J= 10.8 Hz); 3.30 (m, 1 H); 3.3-3.7 (m, 4 H); 8.83 (s, 1 H);10.51 (s, 1 H) ppm. ESI-MS 322 (MNa)+, 300 (MH)+, 239 (M—HONHCO), 117 m/z.EXAMPLE 6(4—Hydroxy—3S-(4-methoxyphenylsu|fonyI)amino-2R-isobutyl)succinyl-piperidinamideStep A(3 S-Amino—4-benzyloxy-2R-isobutyl)succinyl-piperidinamide trifluoroacetate salt (preparedas described in Example 4, step B; 660 mg) was dissolved in CH2Cl2 (100 mL). To thisl01.5202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422035solution, (4-methoxybenzenesulfonyl)chloride (350 mg) and triethylamine (0.5 mL) wereadded. After 24 hours, the solution was washed with saturated aqueous NH4Cl, saturatedaqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated toafford a crude product, which was purified by flash cromatography over silica gel (n-hexane/EtOAc) to give (4-benzyloxy-3S-(4-methoxyphenylsulfony1)amino-2R-isobutyl)—succinyl—piperidinarnide (340 mg) as a white solid. H‘- NMR (200 MHz, CDCl3) 0.86 and0.90 (two d , 6 H, J= 6.1 Hz) 1.2-1.8 (m, 9 H); 3.0-3.5 (m, 5 H); 3.81 (s, 3 H); 4.20 (dd, 1H, J= 3.9 and 9.8 Hz); 4.90 (s, 2 H); 6.72 (d, 1 H, J= 9.8 Hz); 6.82 (d, 2 H, J= 9.0 Hz); 7.30(m, 5 H); 7.75 (d, 2 H, J= 9.0 Hz) ppm. ESI-MS 555 (MH)+, 539 (MNa)+, 454, 112, 91 m/z.Step BThe material fiom step A above (340 mg) and 10% Pd/C (70 mg) were suspended in amixture of Et0H and TI-IF (1:1; 30 mL) and stirred under a hydrogen atmosphere for 2hours. The catalyst was removed by filtration (Celite filter aid ) and the solvent wasevaporated, to leave the title compound as a white solid (245 mg). H'- NMR (400 MHz,CDCI3) 0.91 and 0.94 (two d , 6 H, J= 6.4 Hz) 1.2-1.8 (m, 9 H); 3.5-3.8 (m, 6 H); 3.84 (s, 3H); 6.00 (br signal, 1 H); 6.95 (d, 2 H, J= 9.0 Hz); 7.71 (d, 2 H, J= 9.0 Hz) ppm. ESI-MS465 (MK)+, 449 (MNa)+, 427 (MH)+, 364, 196 m/z.EXAMPLE 7(4-Hydroxyamino-3S-(4-methoxyphenylsulfonyl)amino-2R-isobutyl)succinyl-piperidin-amideStep A(4-Hydroxy-3S-(4-methoxyphenylsu1fonyl)arnino-2R-isobutyl)succinyl-piperidinlamide (245mg; Example 6) was dissolved in CH3CN (20 mL) and treated with O-benzylhydroxylaminehydrochloride (110 mg) and N-methylmorpholine (0.16 mL). After 10 min, TBTU (220 mg)was added, and the mixture was stirred overnight at room temperature. The solvent wasremoved in vacuo and the residue was dissolved in EtOAc and washed with saturatedaqueous NaHC03, 2% aqueous HCl and brine. The organic layer was dried over Na2SO4 andevaporated to afford a crude product which was purified by flash cromatography on silica gel(n-hexane/EtOAc) to obtain a white solid (300 mg), consisting of (4-benzyloxyamino-3 S-(4-methoxyphenylsulfonyl)amino-2R-isobutyl)succinyl-piperidinamide. H‘- NMR (200 MHz,CDCl3) 0.71 and 0.72 (two d , 6 H, J= 6.3 Hz); 0.8-1.7 (m, 9 H); 3.3-3.6 (m, 5 H); 3.81 (dd,1 H, J= 6.6 Hz); 4.80 and 4.83 (two d, 2 H, J= 9.0 Hz); 6.94 (d, 2 H, J= 9.0 Hz); 7.14 (d, 11015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/0422036H, J= 6.4 Hz); 7.39 (m, 5 H); 7.76 (d, 2 H, J= 9.0 Hz); 9.65 (br signal, 1 H) ppm. ESI/C1D-MS 570 (MK)*, 554 (MNa)*, 469 (MH)*, 403, 381, 171, 112, 91 m/z.Step B AThe material from step A above (300 mg) and 10% Pd/C (100 mg) were suspended in BtOH(20 mL) and stirred under a hydrogen atmosphere for 3 hr at room temperature. The catalystwas removed by filtration (Celite filter aid), washing with additional EtOH. The solvent wasremoved in vacuo to give the title compound (210 mg) as white solid. H‘- NMR (400 MHz,CDCI3) 0.70 and 0.71 (two d , 6 H, J= 6.4 Hz); 0.9-1.7 (m, 9 H); 3.3-3.7 (m, 5 H); 3.86 (s, 3H); 3.89 (dd, 1 H, J= 3.0 and 6.6 Hz); 6.98 (d, 2 H, J= 9.0 Hz); 7.23 (d, 1 H, J= 6.6 Hz);7.82 (d, 2 H, J= 9.0 Hz); 9.79 (br signal, 1 H) ppm. ESI-MS 480 (MK)+, 464 (MNa)+, 442(MI-I)‘, 409, 381, 171 m/z.EXAMPLE 8(3S-tert-Butoxycarbonylamino-4-hydroxy-2R-isobutyl)succinyl-morpholinamideStep AIn a manner analogous to that described in Example 1 (step A), (3 S-tert-butoxy-(190mg) was obtained as a yellow oil starting from 1-tert-butoxycarbonyl-3R-isobutyl-4S-p-nitrobenzyloxycarbonylazetidin—2-one (200 mg) and morpholine (0.08 mL). FT-IR (CHCI3)3432 b!’ (NH), 1750-1713 bl‘ (ester and carbamate C0), 1630 (amide co) cm". H‘- NMR(400 lVJHz, CDCI3) 0.92 and 0.98 (two (1, 6 H); 1.2-1.7 (m, 3 H); 1.44 (s, 9 H); 3.4-3.7 (m, 9H); 4.58 (dd, 1 H, J= 4.1 and 10.0 Hz); 5.21 and 5.26 (two d, 2 H, J= 13.7 Hz); 6.36 (d, 1H, J= 10.0 Hz); 7.50 (d, 2 H, J= 9.5 Hz); 8.20 (d, 2 H, J= 9.5 Hz) ppm.Step BIn a manner analogous to that described in Example 1 (step B) , from the material of step Acarbonylamino-2R-isobutyl-4-(4-nitrobenzyloxycarbonyl))succinyl-morpholinylamideabove (500 mg), with 10% Pd/C (50 mg) and under a hydrogen atmosphere, the titlecompound was obtained (290 mg) as a white solid. FT-IR (KBr) 3411 br (NH,OH), 1750-1714 br (acid and carbamate co), 1630 (amide co) cm". H‘- NMR (200 MHz, DMSO—d6)0.82 and 0.83 (two (1, 6 H, J= 6.0 Hz); 1.2-1.6 (m, 3 H); 1.36 (s, 9 H); 3.2-3.6 (m, 9 H); 4.11(dd, 1 H, J= 9.4 Hz); 6.41 (d, 1 H, J= 9.4 Hz); 12.80 (br signal, 1 H) ppm. FD-MS 358(MH)+, 313 (MH-COOH)+, 259 m/z.EXAMPLE 9(3S-tert-Butoxycarbonylamino-4-hydroxyamino-2R-isobuty|)succinyl-morpholinamideStep A1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422037In a manner analogous to that described in Example 2 (step A), reaction of (3S-tert-butoxycarbonylamino-4-hydroxy-2R-isobutyl)succinyl-morpholinamide (290 mg) with O-benzylhydroxylamine hydrochloride (154 mg), N-methylmorpholine (0.22 mL) and TBTU(0.97 mg) afforded (4—benzyloxyamino-3 S-tert-butoxycarbonylamino-2R-isobutyl)succinyl-morpholinamide (300 mg) as a white solid. H'- NMR (400 MHz, CDCI3) 0.91 and 1.11 (two(1, 6 H, J= 6.2 Hz); 1.3-1.6 (m, 3 H); 1.4 (S, 9 H); 3.4-3.8 (m, 9 H); 4.32 (dd, 1 H, J= 3.2 and8.2 Hz); 4.86 (s, 2 H); 6.64 (d, 1 H, J= 8.2 Hz); 7.37 (m, 5 H); 9.12 (s, 1 H) ppm.Step BIn a manner analogous to that described in Example 2 (step B), from the material of step Aabove (300 mg) and 10% Pd/C (60 mg), under a hydrogen atmosphere, the title compoundwas obtained as white solid (240 mg). H'- NMR (400 MHz, CDCI3) 0.90 and 0.92 (two d, 6H, I= 6.7 Hz); 1.2-1.7 (m, 3 H); 1.45 (s, 9 H); 3.3-3.8 (m, 8 H); 3.55 (m, 1 H); 4.43 (m, 1H); 6.63 (d, 1 H, J= 8.2 Hz); 7.20 (br signal, 1 H); 9.34 (br signal, 1 H) ppm. FAB-MS 374(MI-I)+, 318, 285, 274, 213, 114, 88, 57 rn/z.EXAMPLE 10(3S—Amino-4-hydroxyamino-2R—isobuty|)succinyl-morpholinamideIn a manner analogous to that described in Example 3, reaction of (3 S-tert-butoxycarbonylamino-4-hydroxyamin0-2R-isobutyl)succinyl—morpholinarnide (100 mg) with95% aqueous trifluoroacetic acid afforded the title compound, trifluoroacetate salt, as awhite solid (100 mg). In DMSO solution, the compound is present as a mixture of tworotamers (M, major; m, minor). H1- NMR (400 MHz, DMSO-d5) 0.78 and 0.79 (two d, 6 H,J= 6.4 Hz); 1.15-1.5 (two m, 2 H); 1.35 (m, l H); 3.1-3.7 (m, 10 H); 8.10 (br signal, 3 H);9.35 (s, 1 H, M); 9.80 (s, 1 H, m); 10.72 (s, 1 H, m); 11.13 (br signal, 1 H, M) ppm. FAB-MS 274 (MH)+, 213 (M-HONHCO)+, 114, 89, 88 rn/z.EXAMPLE ll(4-Hydroxy-2R-isobutyl-3S-(4-toluenesulfonyl)amino)succiny|-morpholinamideStep A3R-Isobutyl—4S—p-nitrobenzyloxycarbonyl-1-(4-toluenesulfonyl)-azetidin-2-one (300 mg; seePreparation B) was dissolved in dry DMF (15 mL). To this solution, morpholine (0.11 mL)and sodium azide (30 mg) were sequentially added. After overnight stirring at roomtemperature, the solvent was partially removed in vacuo and the residue, taken up in EtOAc,was sequentially washed with saturated aqueous NH4Cl and brine. Drying over Na2SO4,evaporation, and flash cromatography over silica gel (n-hexane/EtOAc) afforded (2R—1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042203 8isobuty1—4-p-nitrobenzyloxycarbonyl-3 S—(4-toluenesulfonyl)arnino)succinyl-morpholinamide(290 mg) as a white solid. FT-IR (CHCI3) 3410 br (NH), 1736 (ester C0), 1674 (amide CO)cm". H’- NMR (400 MHz, CDCI3) 030 and 0.88 (two d, 6 H, J= 6.4 Hz); 1.2-1.6 (m, 3 H);2.36 (s, 3 H); 3.3-3.7 (m, 9 H); 4.27 (dd, 1 H, J= 4.1 and 9.7 Hz); 4.98 and 5.08 (two d, 2 H,J= 13.5 Hz); 6.67 (d, 1 H, J= 9.7 Hz); 7.19 (d, 2 H, J= 8.2 Hz); 7.36 (d, 2 H, J= 8.8 Hz);7.71 (d, 2 H, J= 8.2 Hz); 8.18 (d, 2 H, J= 8.8 Hz) ppm.Step BIn a manner analogous to that described in Example 1 (step B), from the material of step Aabove (290 mg), with 10% Pd/C (50 mg) under a hydrogen atmosphere, the title compoundwas obtained as an amorphous solid (200 mg). H‘- N1\/H1 (400 MHz, CDCI3) 0.90 and 0.93(two d, 6 H); 1.5 (m, 3 H); 2.40 (s, 3 H); 3.5-3.9 (m, 10 H); 6.36 (d, 1 H, J= 3 Hz); 7.29 (d,2 H, J= 8.1 Hz); 7.66 (d, 2 H, J= 8.1 Hz) ppm. FAB-MS 413 (MH)*, 367 (MH-COOH)+,259, 213, 155, 114, 88 m/z.EXAMPLE 12(4-Hydroxyamino-2R-isobutyl-3S-(4-toluenesulfonyl)amino)succinyl-morpholinamideStep AIn a manner analogous to that described in Example 7 (step A), reaction of (4—hydroxy-2R-isobutyl-3 S-(4-toluenesulfonyl)amino)succinyl-morpholinamide (200 mg) with O-benzyl-hydroxylamine hydrochloride (93 mg), N-methylmorpholine (0.13 mL) and TBTU (186 mg)afforded (4-benzyloxyamino-2R—isobutyl-3S-(4-toluenesulfonyl)amino)succinyl-morpholin-amide (176 mg) as a white solid. H‘- NMR (400 MHz, CDCI3) 0.67 and 0.68 (two d, 6 H, J=6.4 Hz); 0.8-1.2 (m, 3 H); 2.42 (s, 3 H); 3.3-3.8 (m, 10 H); 4.80 and 4.86 (two d, 2 H, J=10.8 Hz); 7.04 (d, 1 H, J= 6.4 Hz); 7.30 (d, 2 H, J= 8.6 Hz); 7.39 (m, 5 H); 7.72 (d, 2 H, J=8.6 Hz); 9.53 (s, 1 H) ppm.Step BIn a manner analogous to that described in Example 7 (step B), from the material of step Aabove (170 mg) with 10% Pd/C (50 mg) under hydrogen atmosphere, the title compoundwas obtained as a white solid. H'- NMR (400 MHz, DMSO-d6) 0.67 and 0.70 (two d, 6 H,J= 6.8 Hz); 1.1-1.5 (m, 3 H); 2.30 (s, 3 H); 3.0-3.6 (m, 9 H); 3.72 (m, 1 H); 7.25 (d, 2 H, J=8.1 Hz); 7.53 (d, 2 H, J= 8.1 Hz); 7.89 (d, 1 H, J= 9.4 Hz); 8.82 (s, 1 H); 10.74 (s, 1 H)ppm. FAB-MS 428 (MH)+, 371,367 (M-HONHCO)+, 241, 129, 114, 57 m/z.EXAMPLE 131015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/042203 9(3S-tert-Butoxycarbonylamino-4-hydroxy-2R-(4-methoxy)phenpropyl)succinyl-morpholinamideStep AIn a manner analogous to that described in Example 1 (step A), reaction of 4S-(600mg; see Preparation C) with morpholine (0.23 mL) afforded (4-benzyloxy-3S-tert-benzy1oxycarbonyl- 1 -tert-butoxycarbonyl-3R-(4-methoxy)phenpropyl)azetidin-2—onebutoxycarbonylamino-2R-(4-methoxy)phenpropyl)succinyl-morpholinamide as a yellow oil(700 mg). H1- N1\/IR (400 MHz, DMSO-d5) 1.41 (s, 9 H); 1.4-1.8 (m, 4 H); 2.54 (m, 2 H);3.1-3.5 (m, 8 H); 3.25 (m, 1 H); 3.76 (s, 3 H); 4.53 (dd, 1 H, J= 3.8 and 9.8 Hz); 5.02 and5.19 (two d, 2 H, J= 12.4 Hz); 6.28 (d, 1 H, J= 9.8 Hz); 6.78 (cl, 2 H, J= 8.6 Hz); 7.03 (d, 2H, J= 8.6 Hz); 7.31 (s, 5 H) ppm.Step BIn a manner analogous to that described in Example 1 (step B), from the material of step Aabove (700 mg) with 10% Pd/C (100 mg), under a hydrogen atmosphere, the title compoundwas obtained as a white solid (600 mg). FT-IR (KBr) 3400 br (OH,NH), 1710 (acid CO),nmuwmmmean1fi0@mmcoymfHkNMR@mr&m(Dagrm(g9Hx1.6 (m, 4 H); 2.52 (m, 2 H); 3.3-3.8 (m, 9 H); 3.76 (s, 3 H); 4.32 (dd, 1 H, J= 1.7 and 5.0Hz); 6.04 (d, 1 H, J= 5.0 Hz); 6.80 (d, 2 H, J= 8.5 Hz); 7.02 (d, 2 H, J= 8.5 Hz) ppm. ESI-MS 473 (MNa)+, 451 (MH)+, 395, 351 (M-BOC)* m/z.EXAMPLE 14(3S-Amino-4-hydroxy-2R-(4-methoxy)phenpropyl)succinyl-morpholinamide(3 S-tert-Butoxycarbonylarnino-4-hydroxy-2R-(4-methoxy)phenpropyl)succinyl-morpholin-amide (obtained as described in Example 13; 50 mg) was dissolved in 95% aqueoustrifluoroacetic acid (2 mL), and the solution was stirred 2 hours at room temperature.Toluene was added and evaporated in vacuo to afford the title compound as a white solid (58mg). H'- NMR (400 MHz, DMSO-d5) 1.4-1.6 (m, 4 H); 2.48 (m, 2 H); 3.2-3.6 (m, 9 H);3.70 (s, 3 H); 3.91 (d, 1 H, J= 4.1 Hz); 6.82 (d. 2 H, J= 8.5 Hz); 7.09 (d, 2 H, J= 8.5 Hz);8.1 (hr signal, 2 H) ppm. ESI-MS 373 (MNa)+, 351 (MH)+, 305 (M-COOH)+, 236, 191 m/z.EXAMPLE 15(3S-tert-Butoxycarbonylamino-4-hydroxyamino-2R—(4-methoxy)phenpropyl)succinyl-morpholinamideStep A1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/0422040In a manner analogous to that described in Example 2 (step A), reaction of (3S-tert-butoxycarbonylarnino-4-hydroxy-2R-(4-methoxy)phenpropyl)succinyl—morpholinamide (310mg; obtained as described in Example 13) with O-benzylhydroxylamine hydrochloride (132mg), N-methylmorpholine (0.2 mL) and TBTU (263 mg) afforded (4-benzyloxyamino-3S-tert-butoxycarbonylarnino-2R-(4-methoxy)phenpropyl)succinyl-morpholinarnide as a whitesolid (300 mg). FT-IR (KBr) 3203 br (NH), 1710-1667 br (co), 1632 (amide co) cm". H‘-NMR (400 1\/H-Iz, CDCI3) 1.38 (s, 9 H); 1.5-1.8 (m, 4 H); 2.52 (m, 2 H); 3.3-3.8 (m. 9 H);3.76 (s, 3 H); 4.33 (dd, 1 H, J= 3.0 and 8.0 Hz); 4.83 (s, 2 H); 6.63 (d, 1 H, J= 8.0 Hz); 6.79(d, 2 H, J= 8.5 Hz); 7.03 (d, 2 H, J= 8.5 Hz); 7.35 (m, 5 H); 9.14 (s, 1 H) ppm. ESI-MS 578(MNa )+, 555 (MH)*, 500, 456, 377, 305 m/z.Step BIn a manner analogous to that described in Example 2 (step B), from the material of step Aabove (300 mg), with 10% Pd/C (50 mg) under a hydrogen atmosphere, the title compoundwas obtained as pinkish solid (250 mg). FT—IR (CHCI3) 3254 br (NH,OH), 1712-1614 br(CO) cm". H’- NMR (400 MHz, CDCI3) 1.44 (s, 9 H); 1.4-1.8 (m, 4 H); 2.54 (m, 2 H); 3.3-3.8 (m, 9 H); 3.78 (s, 3 H); 4.46 (dd, 1 H, J= 3.0 and 8.1 Hz); 6.63 (d, 1 H, J= 8.1 Hz); 6.81(d, 2 1-1, J= 8.5 Hz); 7.05 (d, 2 H, J= 8.5 Hz); 7.6 (br signal, 1 H); 8.43 (br signal, 1 H) ppm.ESI-MS 488 (MNa)*, 466 (MH)*, 410, 377, 366, 305 m/z.EXAMPLE 16(3S-Amin0-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-morpholinamideIn a manner analogous to that described in Example 3, reaction of (3 S-tert-butoxy-carbonylarnino-4-hydroxyamino-2R—(4-methoxy)phenpropyl)succinyl-morpholinylamide (200mg; obtained as described in Example 15) with 95% aqueous trifluoroacetic acid (2 mL)afforded the title compound, trifluoroacetate salt, as a white solid (154 mg). The compoundis present in DMSO solution as a mixture of two rotamers (M, major; m, minor). H'- NMR(400 MHz, DMSO-d6) 1.42 (m, 4 H); 2.41 (m, 2 H); 3.14 (m, 1 H); 3.2-3.6 (m, 8 H); 3.66(s, 3 H); 3.72 (m, l H); 6.79 (d, 2 H, J= 8.5 Hz); 7.03 (d, 2 H, ]= 8.5 Hz); 8.0 (br signal, 3H, m); 8.15 (br signal, 3 H, M); 9.39 (br signal, 1 H, M); 9.79 (br signal, 1 H, m); 10.72 (s, 1H, m); 11.15 (s, 1 H, M) ppm. ES/CID-MS 366 (MH)’, 305 (M-HONHCO), 218, 121, 114,88 m/z.EXAMPLE 17(3S—tert-Butoxycarbonylamino-4-hydroxyamino-2R—(4-methoxy)phenpropyl)succinyl-piperidinamide1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422041Step AIn a manner analogous to that described in Example 1 (step A), reaction of 4S-benzyloxycarbonyl-1-tert-butoxycarbonyl-3-(4-methoxy)phenpropyl)azetidin-2-one (350 mg;see Preparation D) with piperidine (0.15 mL) afforded (4-benzyloxycarbonyl-3 S-tert-butoxy-carbonylamino-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide as a yellow oil (400 mg).FT-IR (CHCI3) 3400 br (NH), 1730 (ester CO), and 1641 br (carbamate and amide CO) cm"1. H'- NMR (200 MHz, CDCI3) 1.2-1.8 (m, 10 H); 1.55 (s, 9 H); 2.55 (m, 2 H); 3.1-3.4 (m,5 H); 3.78 (s, 3 H); 4.52 (dd, 1 H, J= 4.1 Hz); 5.06 and 5.18 (two d, 2 H, J= 12.4 Hz); 6.43(d, 1 H, J= 9.8 Hz); 6.81 (d, 2 H, J= 8.5 Hz); 7.06 (d, 2 H, J= 8.5 Hz); 7.32 (s, 5 H) ppm.ESI—MS 561 (MNa)+, 539 (1\/[H)+, 483, 439 m/z.Step BIn a manner analogous to that described in Example 1 (step B), from the material of step Aabove (250 mg), with 10% Pd/C (50 mg) under a hydrogen atmosphere, (3 S-tert-butoxycarbonylarnino-4-hydroxy-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide wasobtained as a colourless oil (200 mg).Step CIn a manner analogous to that described in Example 2 (step A), reaction of (3 S-tert-butoxy-carbonylamino-4—hydroxy-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide (200 mg) withO-benzylhydroxylamine hydrochloride (85 mg), N-methylmorpholine (0.12 mL) and TBTU(172 mg) afforded (4-benzyloxyarnino-3 S-tert-butoxycarbonylamino-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide (240 mg) as a white solid. FT-IR (CHCI3) 3236br (NH), 1705 (benzylhydroxamate CO), 1678 (carbamate CO), 1614 (amide CO) cm". H’-NMR (400 MHz, CDCI3) 1.39 (s, 9 H);1.4-1.8 (m, 10 H); 2.54 (m, 2 H); 3.3-3.6 (m, 5 H);3.78 (s, 3 H); 4.35 (dd, 1 H, J= 3.5 and 8.5 Hz); 4.85 (s, 2 H); 6.73 (d, 1 H, J= 8.5 Hz); 6.81(d, 2 H, J= 8.5 Hz); 7.05 (d, 2 H, J= 8.5 Hz); 7.38 (m, 5 H); 9.18 (s, 1 H) ppm. ESI—MS 576(I\/[Na)+, 554 (MH)', 498, 454, 375, 303 m/z.Step DIn a manner analogous to that described in Example 2 (step B), from the material from step Cabove (240 mg), with 10% Pd/C (50 mg), under a hydrogen atmosphere, the title compoundwas obtained as a pinkish solid (175 mg). FT-IR (CHCI3) 3255 br (OH,NH), 1710(hydroxamic CO), 1665 (carbamate CO), 1612 (amide CO) cm". H1- NMR (400 MHz,DMSO~d6) 1.35 (s, 9 H); 1.3-1.6 (m, 10 H); 2.42 (m, 2 H); 3.2-3.4 (m, 5 H); 3.69 (s, 3 H);4.02 (dd, 1 H, J= 6.2 and 9.1 Hz); 6.58 (d, 1 H, J= 9.1 Hz); 6.80 (d, 2 H, J= 8.5 Hz); 7.041015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/0422042(d, 2 H, J= 8.5 Hz); 8.78 (br signal, 1 H); 10.67 (br signal, 1 H) ppm. ESI-MS 486 (MNa)+,464 (lVIH)+, 408, 375, 364, 303 m/z.EXAMPLE 18(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-piperidinamideIn a manner analogous to that described in Example 3, reaction of (3 S—tert-butoxycarbonyl-amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide (125 mg; fromExample 17) with 95% aqueous trifluoroacetic acid (2 mL) and work-up afibrded the titlecompound, trifluoroacetate salt, as a white solid (90 mg). FT-IR (KBr) 3250 br (OH,NH),1668 (hydroxamic CO), 1603 (amide C0) cm’. In DMSO solution, the compound is presentas a mixture of two rotamers (M, major; m, minor). H1- NMR (400 MHz, DMSO-d6) 1.2-1.6(m, 10 H); 2.44 (m, 2 H); 3.17 (m, 1 H); 3.2-3.8 (m, 5 H); 3.70 (s, 3 H); 6.82 (d, 2 H, J= 8.5Hz); 7.06 (d, 2 H, J= 8.5 Hz); 7.9 (br signal, 3 H); 9.32 (br signal, 1 H, M); 9.7 (br signal, 1H, m); 10.7 (br signal, 1 H, m); 11.1 (br signal, 1 H, M) ppm. ESI/CID-MS 386 (MNa)*, 364(MH)’, 303 (M-HONHCO)+, 112 m/z.EXAMPLE 19(3S-N,N-Dimethylamino-4-hydroxyamino-2R-(4-methoxy)phenpropyI)succinyl-morpholinamideStep AIn a manner analogous to that described in Example 4 (step A), reaction of the compounddescribed in Example 13, step A (600 mg), with 95% aqueous trifluoroacetic acid (5 mL) andwork~up afforded (3 S-arnino-4-benzyloxy-2R-(4-methoxy)phenpropyl)succinyl-morpholin-amide (500 mg), trifluoroacetate salt, as a yellow oil.Step BIn a manner analogous to that described in Example 4 (step B), reaction of the material fromstep A above (350 mg) with 37% aqueous HCHO (10 mL) and NaCNBH3 (100 mg) afibrded(4-benzyloxy-3 S-N,N-dimethylarnino-2R-(4-methoxy)phenpropyl)succinyl—morpholinamideas a colourless oil (250 mg).Step CIn a manner analogous to that described in Example 4 (step C), reaction of the material fromstep B above (250 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded (3 S-N,N-dimethylarnino-4-hydroxy—2R-(4-methoxy)phenpropyl)succinyl-morpholinamide as acolourless oil (190 mg).Step D1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/0422043In a manner analogous to that described in Example 5 (step A), reaction of the material fromstep C above (190 mg) with O-benzylhydroxylamine hydrochloride (95 mg), N-methyl-morpholine (0.15 mL) and TBTU (193 mg) afforded (4-benzyloxyamino-3 S-N,N-dimethylamino-2R-(4-methoxy)phenpropyl)succinyl-morpholinamide (160 mg) as acolourless oil.Step EIn a manner analogous to that described in Example 5 (step B), reaction of the material fromstep D above (160 mg) with 10% Pd/C (30 mg) under a hydrogen atmosphere aflbrded thetitle compound (130 mg) as a white solid. FT-IR (CHCI3) 3229 br (OH, NH); 1659(hydroxamic co); 1614 (amide co) cm". H'- NMR (200 MHz, DMSO-d6) 1.0-1.5 (m, 4H); 2.13 (s, 4 H); 2.40 (m, 2 H); 3.05 (d, 1 H, J= 10.7 Hz); 3.2-3.7 (m, 9 H); 3.69 (s, 3 H);6.80 (d, 2 H, J= 8.8 Hz); 7.04 (d, 2 H, J= 8.8 Hz); 8.85 (br signal, 1 H); 10.50 (br signal, 1H) ppm. ESI-MS 416 (MNa)+, 394 (MH)*, 333 (M-HONHCO)+ m/z.EXAMPLE 20(4-Hydroxyamino-3S-(4-methoxyphenylsulfonyl)amino-2R-(4-methoxy)phenpropyI)-succinyl-morpholinamideStep AIn a manner analogous to that described in Example 6 (step A), reaction of the material fromExample 19, step A (270 mg), with (4-methoxybenzenesulfonyl)chloride (185 mg) andtriethylamine (0.17 mL) afforded (4-benzyloxy-3 S-(4-methoxyphenylsulfonyl)amino-2R-(4-methoxy)phenpropyl)succinyl-morpholinarnide as a white solid (100 mg). H'- NMR (200MHz, CDCI3) 1.5-1.9 (m, 4 H); 2.54 (m, 2 H); 3.12 (m, 1 H); 3.0-3.5 (m, 8 H); 3.78 and3.82 (two s, 6 H); 4.25 (dd, 1 H, J= 3.9 and 9.8 Hz); 4.89 (s, 2 H); 6.52 (d, 1 H, J= 9.8 Hz);6.80 (m, 4 H); 7.06 (d, 2 H, J= 8.8 Hz); 7.1-7.3 (m, 5 H); 7.76 (d, 2 H, J= 8.8 Hz) ppm.ESI/CID-MS 633 (MNa)*, 611 (MI-1)+, 546, 171, 88 m/z.Step BIn a manner analogous to that described in Example 6 (step B), reaction of the material fromstep A above (100 mg) with 10% Pd/C (20 mg) under a hydrogen atmosphere afforded 90mg of (4-hydroxy-3 S-(4-methoxyphenylsulfonyl)amino-2R-(4-methoxy)phenpropyl)succinyl-morpholinamide was obtained as a colourless oil.Step CIn a manner analogous to that described in Example 7 (step A), reaction of the material fromstep B above (90 mg) with O-benzylhydroxylamine (33 mg), N-methylmorpholine (0.05 mL)1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042204 4and TBTU (65 mg) afforded (4-benzyloxyamino-3S-(4-methoxyphenylsulfonyl)amino-2R-(4-methoxy)phenpropyl)succinyl—morpholinamide (88 mg ) as a white solid. H1- NMR (200MHz, CDC13) 1.0-1.5 (m, 4 H); 2.32 (m, 2 H); 3.2-4.0 (m, 10 H); 3.78 and 3.84 (two s, 6H); 4.79 and 4.83 (two d, 2 H, J= 11.0 Hz); 6.81 (d, 2 H, J= 8.7 Hz); 6.92 (m, 4 H); 7.39(m, 5 H); 7.75 (d, 2 H, J= 8.8 Hz); 9.64 (s, 1 H) ppm. ESI-MS 648 (MNa)+, 626 (MH)+,503, 475, 361 m/z.Step DIn a manner analogous to that described in Example 7 (step B), reaction of the material fromstep C above (88 mg) with 10% Pd/C (20 mg) under a hydrogen atmosphere afforded thetitle compound as a white solid (70 mg). FT-IR (CHC13) 3266 br (OH,NH), 1678 br(hydroxarnic co), 1612 (amide co) cm". H‘- NMR (400 MHz, DMSO-d6) 1.0-1.5 (m, 4H); 2.33 (m, 2 H); 2.97 (ddd, 1 H, J= 3.8, 9.8 and 10.7 Hz); 3.1-3.6 (m, 8 H); 3.68 and 3.78(two s, 6 H); 3.78 (d, 1 H, J= 10.7 Hz); 6.79 (d, 2 H, J= 8.5 Hz); 7.00 (m, 4 H); 7.60 (d, 2H, J= 9.0 Hz); 7.80 (br signal, 1 H); 8.84 (s, 1 H); 10.76 (br signal, 1 H) ppm. FAB-MS 536(MH)+, 475 (M-HONHCO)+, 364, 305, 171, 121, 114, 88 m/z.EXAMPLE 21(3S-tert-Butoxycarbonylamino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl-piperidinamideStep AIn a manner analogous to that described in Example 1 (step A), reaction of 4S-(1.25 g,obtained as described in Preparation D) with piperidine (0.65 mL) afforded (4-benzyloxy—3 S-benzyloxycarbony1- 1 -tert-butoxycarbonyl-3R-cyclopentylmethylazetidin-2-onetert-butoxycarbonylamino-2R-cyclopenty1methyl)succinyl-piperidinamide (1.3 g) as a yellowoil. H‘- NMR (400 MHz, DMSO-d5) 0.9-1.7 (m, 17 H); 1.32 (s, 9 H); 3.2-3.4 (m, 5 H); 4.30(dd, 1 H, J= 5.3 and 9.4 Hz); 5.07 and 5.13 (two d, 2 H, J= 12.6 Hz); 6.68 (d, 1 H, J= 9.4Hz); 7.36 (m, 5 H) ppm. ESI-MS 495 (MNa)+, 473 (MH)+, 417, 373 m/z.Step BIn a manner analogous to that described in Example 1 (step B), reaction of the material fromstep A above (500 mg) with 10% Pd/C (100 mg) under a hydrogen atmosphere afforded (3 S-tert-butoxycarbonylamino—2R-cyclopentylmethyl-4-hydroxy)succiny1-piperidinamide as acolourless oil (410 mg).Step C1015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/0422045In a manner analogous to that described in Example 2 (step A), reaction of (3 S-tert-butoxycarbonylarnino—2R-cyclopentylmethyl-4-hydroxy)succinyl—piperidinamide (410 mg)with O-benzylhydroxylamine hydrochloride (205 mg), N-methylmorpholine (0.29 mL) andTBTU (410 mg) afforded (4-benzyloxyamino-3 S-tert-butoxycarbonylamino-2R-cyclopentyl-methyl)succinyl-piperidinamide as a white solid (500 mg). H'- NMR (400 MHz, CDCI3) 1.0and 1.8 (m, 17 H); 1.37 (s, 9 H); 3.4-3.6 (m, 5 H); 4.32 (dd, 1 H, J= 3.4 and 8.5 Hz); 4.83 (s,2 H); 6.73 (d, I I-1, J= 8.5 Hz); 7.37 (m, 5 H); 9.16 (s, l H) ppm. ESI-MS 510 (MNa)*, 488,388, 309, 237 m/z.Step DIn a manner analogous to that described in Example 2 (step B), reaction of the material fromstep C above (500 mg) with 10% Pd/C (100 mg) under a hydrogen atmosphere afforded thetitle compound was obtained as a pink solid (400 mg). H‘- NMR (200 MHz, CDCl3) 1.0 and1.9 (m, 17 H); 1.45 (s, 9 H); 3.3-3.7 (m, 5 H); 4.45 (dd, 1 H, J= 3.2 and 8.3 Hz); 6.77 (cl, 1H, J= 8.3 Hz); 6.80 (br signal, 1 H); 9.32 (br signal, 1 H) ppm. ESI-MS 420 (MNa)+, 398(MH)', 342, 309, 298, 237 m/z.EXAMPLE 22(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl-piperidinamideStep AA solution of 4S-benzyloxycarbonyl-l-tert-butoxycarbonyl-3R-cyclopentylmethylazetidin-2-one (4.6 g; obtained as described in Preparation D) in acetonitrile (100 mL) was treated withpiperidine (2 mL) and stirred at r.t. for 6 h. The mixture was concentrated under vacuumand the residue was poured into EtOAc/water. The organic layer was washed sequentiallywith 4% aqueous hydrochloric acid, brine, 4°/o aqueous hydrogen bicarbonate and brine, thendried over sodium sulfate and rotoevaporated. (4—Benzyloxy-3 S-tert-butoxycarbonylamino-2R-cyclopentylmethyl)succinyl-piperidinamide (5.6 g) was obtained as a yellow oil. H‘-NMR (400 MHz, DMSO-d5) 0.9-1.7 (m, 17 H); 1.32 (s, 9 H); 3.2-3.4 (m, 5 H); 4.30 (dd, 1H, J= 5.3 and 9.4 Hz); 5.07 and 5.13 (two d, 2 H, J= 12.6 Hz); 6.68 (d, l H, J= 9.4 Hz);7.36 (m, 5 H) ppm. ESI-MS 495 (MNa)+, 473 (MH)’, 417, 373 m/z.Step BA mixture of the compound from Step A above (5.6 g) and 5% Pd/C (1.2 g ) in EtOH (200mL) was exposed to a hydrogen atmosphere for 2 hours under stirring. After purging themixture with nitrogen, the catalyst was removed by filtration over Celite, and the filtrate was1015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/0422046concentrated to dryness under reduced pressure, giving (3S-tert-butoxycarbonylamino-2R-cyclopentylmethyl-4-hydroxy)succinyl-piperidinamide (4.5 g) as a colourless oil .Step CThe compound from Step B above (4.5 g) in acetonitrile (150 mL) was treated sequentiallywith O-benzylhydroxylarnine hydrochloride (2.07 g), N-methylmorpholine (2.86 mL) andTBTU (4.17 g). The reaction mixture was stirred at room temperature for 3 hr, thenconcentrated under vacuum to about one third of its initial volume and partitioned betweenEtOAc and water. The upper layer was separated and washed sequentially with 2% aqueoushydrochloric acid, water, 4% aqueous hydrogen bicarbonate and brine. After drying (sodiumsulfate), removal of the solvent aflbrded (4—benzyloxyamino-3 S-tert-butoxycarbonylarnino-2R-cyclopentylmethyl)succinyl—pipefidinamide as a colourless oil (5.65 g). H'- NMR (400MHz, CDCI3) 1.0 and 1.8 (m, 17 H); 1.37 (s, 9 H); 3.4-3.6 (m, 5 H); 4.32 (dd, 1 H, J= 3.4and 8.5 Hz); 4.83 (s, 2 H); 6.73 (d, 1 H, J= 8.5 Hz); 7.37 (m, 5 H); 9.16 (s, 1 H) ppm. ESI-MS 510 (MNa)", 488, 388, 309, 237 m/z.Step DA mixture of the compound from Step C above (5.65 g) and 5% Pd/C (0.56 g) in ethanol(300 mL) was exposed to a hydrogen atmosphere for 1 h under stirring. The reaction mixturewas purged with nitrogen, then filtered over Celite and eventually rotoevaporated to give(3 S-tert-butoxycarbonylamino-2R—cyclopentylmethyl-4-hydroxyamino)succiny1-piperidinamide as a whitish solid (4.6 g). H’- NMR (200 MHz, CDCI3) 1.0 and 1.9 (m, 17H); 1.45 (s, 9 H); 3.3-3.7 (m, 5 H); 4.45 (dd, 1 H, J= 3.2 and 8.3 Hz); 6.77 (d, _l H, J= 8.3Hz); 6.80 (br signal, 1 H); 9.32 (br signal, 1 H) ppm. ESI-MS 420 (MNa)+, 398 (MH)+, 342,309, 298, 237 m/z.Step EThe compound from Step D above (4.6 g) was treated with 95% aqueous trifluoroacetic acid(40 mL) and let stand at r.t. for 45 minutes, afier which time toluene (50 mL) was added,and the resulting mixture was concentrated to dryness under reduced pressure. The residuewas purified by reverse-phase chromatography (LiChroprep RP C-18) eluting withacetonitrile-water mixtures (from 0:100 to 50:50) containing 1% TFA. Product containingfractions were collected and concentrated in vacuo. (3 S—Amino-2R-cyclopentylmethyl-4-hydroxyarnino)-succinyl-piperidinamide was thus obtained as a white powder(trifluoroacetate salt, 3.7 g; ca. 75% overall yield). In DMSO solution, the compound ispresent as a mixture of two rotamers (M, major; m, minor). H]- NMR (400 MHz, DMSO-1015202530CA 02265671 1999-03-09W0 99/02510 PCT /EP98/0422047d5) 0.9-1.8 (m, 17 H); 3.16 (m, 1 H); 3.40 (m, 4 H); 3.67 (m, 1 H); 7.95 (br signal, 3 H, m);8.14 (br signal, 3 H, M); 9.33 (s, 1 H, M); 9.77 (s, 1 H, m); 10.69 (s, 1 H, m); 11.12 (s, 1 H,M) ppm. FAB-MS 298 (MH)+, 237 (M-HONHCO)*, 208, 112, 86, 84 m/z.EXAMPLE 23(2R-Cyclopentylmethyl-4-hydroxyamino-3S-(4-methoxyphenylsulfonyl)amino)succiny|-piperidinamideStep AIn a manner analogous to that described in Example 6 (step A), reaction of (3 S-arnino-4-benzyloxy-2R-cyclopentylmethy1)succinyl-piperidinamide trifluoroacetate salt (630 mg) with(4-methoxyphenylsulfonyl)chloride (400 mg) and triethylamine (0.78 mL) afforded (4-benzyloxy-2R—cyclopentylmethyl-3 S-(4-methoxyphenylsulfonyl)amino)succinyl-pipe1idin-amide as a white solid (200 mg).Step BIn a manner analogous to that described in Example 6 (step B), reaction of the material fromstep A above (200 mg) with 10% Pd/C (60 mg) under a hydrogen atmosphere afforded(2R-cyclopentylmethyl-4-hydroxy-3 S-(4-methoxyphenylsulfonyl)amino)succinyl-piperidinamide as a white solid (250 mg).Step CIn a manner analogous to that described in Example 7 (step A), reaction of the material fromstep B above (250 mg) with O-benzylhydroxylamine hydrochloride (110 mg), N-methyl-morpholine (0.15 mL) and TBTU (215 mg) afforded (4-benzyloxyamino-2R-cyclopentyl—methyl-3 S—(4-methoxyphenylsulfonyl)arnino)succinyl-piperidinarnide (265 mg) as a whitesolid. H’- NMR (400 MHz, CDCI3) 0.7-1.7 (m, 17 H); 3.4-3.6 (m, 5 H); 3.8 (dd, 1 H, J= 2.9and 6.4 Hz); 3.85 (s, 3 H); 4.80 and 4.84 (two d, 2 H, J= 11.1 Hz); 6.95 (d, 2 H, J= 9.1 Hz);7.19 (d, 1 H, J= 6.4 Hz); 7.39 (m, 5 H); 7.76 (d, 2 H, J= 9.1 Hz); 9.69 (s, 1 H) ppm.ESI/CID-MS 580 (MNa)+, 558 (MH)+, 435, 407, 388, 237, 149, 112 m/z.Step DIn a manner analogous to that described in Example 7 (step B), reaction of the material fromstep C above (260 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded thetitle compound (125 mg) as a white solid. Hl- NMR (200 MHz, CDCI3) 0.8-1.8 (m, 17 H);3.2-3.8 (m, 5 H); 3.86 (s, 3 H); 3.90 (m, 1 H); 6.98 (d, 2 H, J= 9.0 Hz); 7.02 (br signal, 1 H);7.29 (s, 1 H); 7.83 (d, 2 H, J= 9.0 Hz); 9.81 (br signal, 1 H) ppm. FAB-MS 468 (MH)+, 435,407, 298, 237, 208, 171, 112, 86, 84 m/z.1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/0422048EXAMPLE 24(3S-Amino-4-hydroxyamino-2R-isobutyl)succinyl-dicyclohexylmethylamideStep ASodium azide (66 mg) and dicyclohexylamine (300 mg; see Preparation G) were added atroom temperature to a solution of 4S—benzyloxycarbonyl-1-tert—butoxycarbonyl—3R-isobutyl-azetidin—2-one (3 60 mg; see Preparation A) in DMF (8 mL). The mixture was stirredovernight, then diluited with EtOAc and washed with H20, saturated aqueous NaHCO3 and2% Hcl. The organic layer was dried over Na2SO4, filtered and evaporated. The crudeproduct was purified by flash cromatography on silica gel (n-hexane/EtOAc) to afford (4-benzyloxy-3 S-tert-butoxycarbonylarnino-2R-isobutyl)succinyl-dicyclohexylmethylamide (230mg) as a white solid. ESI-MS 567 (MNa)+, 545(MH)+, 489, 445, 167 rn/2.Step BIn a manner analogous to that described in Example 1 (step B), reaction of the material fromstep A above (220 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded (3 S-tert-butoxycarbonylarnino-4-hydroxy-2R-isobutyl)succinyl-dicyclohexylmethylamide as an oil(180 mg).Step CIn a manner analogous to that described in Example 2 (step A), reaction of the material fromstep B above (180 mg) with O-benzylhydroxylamine hydrochloride (77 mg), N-methyl-morpholine (0.1 mL) and TBTU (128 mg) afforded (4-benzyloxyarnino-3 S-tert-butoxy-carbonylamino-2R-isobutyl)succinyl—dicyclohexylmethylarnide (200 mg) as a white solid. H‘-NMR (400 MHz, CDC13) 0.80-1.8 (m, 25 H); 0.92 (d, 6 H, J= 6.4 Hz); 1.39 (s, 9 H); 3.02(m, 1 H); 3.56 (m, 1 H); 4.25 (d, 1 H, J= 7.9 Hz); 4.85 (s, 2 H); 5.58 (d, 1 H, J= 9.4 Hz);6.41 (d, I I-1, J= 7.9 Hz); 7.34 (m, 5 H); 9.31 (s, 1 H) ppm. ESI-MS 610 (MK)+, 594(MNa)*, 572 (MH)*, 516, 488, 472, 112 m/z.Step DIn a manner analogous to that described in Example 2 (step B), reaction of the material fromstep C above (180 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded (3 S-tert-butoxycarbonylamino-4-hydroxyarnino-2R-isobutyl)succinyl-dicyclohexylmethylamide(100 mg) as a white solid.Step EIn a manner analogous to that described in Example 3, reaction of the material from step Dabove ( 100 mg) with 95% aqueous trifluoroacetic acid (5 mL) afibrded the title compound,1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042204 9trifluoroacetate salt, as a white solid (85 mg). In DMSO solution, the compound is present asa mixture of two rotamers (M, major; m, minor). H’- NMR (400 MHz, DMSO-d.«,) 0.86 and0.88 (two (1, 6 H, J= 6.8 Hz); 0.9-1.7 (m, 25 H); 2.74 (m, 1 H, M); 3.10 (m, 1 H, m); 3.60(m, 2 H); 7.76 (d, 1 H, J= 9.8 Hz); 8.01 (br signal, 3 H, M); 8.10 (br signal, 3 H, m); 9.25 (brsignal, 1 H, M); 9.57 (s, 1 H, m); 10.67 (s, 1 H, m); 11.00 (s, l H, M) ppm. FAB-MS 382(MH)+, 321 (M-HONHCO)+, 194, 187, 112, 100, 89, 83 m/z.EXAMPLE 25(3S-Amino—4-hydroxyamino-2R-isobutyl)succinyl-diphenylmethylamideStep AIn a manner analogous to that described in Example 28 (step A), reaction of 4S-benzyl-oxycarbonyl-1-tert-butoxycarbonyl-3R-isobutylazetidin-2-one (360 mg; see Preparation A)with diphenylmethylarnine (0.34 ml) and NaN3 (33 mg) afforded (4-benzyloxy-3S—tert-butoxycarbonylamino-2R-isobutyl)succinyl-diphenylmethylamide (150 mg) as a white solid.H‘- NMR (400 MHz, CDCI3) 0.89 and 0.91 (two (1, 6 H, J= 6.7 Hz); 1.2-1.7 (m, 3 H); 1.39(s, 9 H); 2.97 (m, 1 H); 4.46 (dd, 1 H, J= 3.8 and 9.7 Hz); 4.95 and 5.02 (two (1, 2 H, J=12.6 Hz); 6.07 (d, 1 H, J= 9.7 Hz); 6.09 and 6.14 (two d, 2 H, J= 7.6 Hz); 7.1-7.4 (m, 15 H)ppm.Step BIn a manner analogous to that described in Example 1 (step B), reaction of the material fromstep A above (150 mg) with 10% Pd/C (30 mg) under a hydrogen atmosphere afforded (3 S-tert-butoxycarbonylarnino-4-hydroxy-2R-isobutyl)succinyl-diphenylmethylamide as a whitesolid (100 mg).Step CIn a manner analogous to that described in Example 2 (step A), reaction of the material fromstep B above (100 mg) with O-benzylhydroxylamine hydrochloride (42 mg), N-methyl-morpholine (0.06 mL) and TBTU (85 mg) afforded (4—benzyloxyamino-3 S-tert-butoxy-carbonylamino-2R-isobutyl)succinyl-diphenylmethylarnide (100 mg) as a white solid.Step DIn a manner analogous to that described in Example 2 (step B), reaction of the material fromstep C above (100 mg) with 10% Pd/C (20 mg) under a hydrogen atmosphere afforded (3 S-tert-butoxycarbonylamino-4-hydroxyamino-2R-isobutyl)succinyl-diphenylmethylamide as awhite solid (90 mg).Step E1015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/0422050In a manner analogous to that described in Example 3, reaction of the material from step Dabove (90 mg) with 95% aqueous trifluoroacetic acid (5 mL) afforded the title compound asa white solid (85 mg; trifluoroacetate salt). In DMSO solution, the compound is present asmixture of two rotamers (M, major; m, minor). H1- N1\/IR (400 MHz, DMSO-d.r,) 0.74 and0.84 (two d, 6 1-1, J= 6.8 Hz); 1.12 and 1.49 (two in, 2 H); 1.31 (m, 1 H); 2.85 (m, 1 H); 3.58(m, I H); 6.09 (d, 1 H, J= 7.7 Hz); 7.28 (m, 10 H); 8.20 (br signal, 3 H); 9.13 (d, 1 H, J= 8.1Hz, M); 9.25 (d, 1 H, J= 8.1 Hz, in); 9.38 (br signal, 1 H, M); 9.60 (s, 1 H,m); 10.80 (s, 1 H,m); 11.10 (s, 1 H, M) ppm. FAB-MS 370 (MH)+, 309 (M-HONHCO)+, 204, 182, 167, 100m/z.EXAMPLE 26(3S-tert-Butoxycarbonylamino-2R-cyclopentylmethyl-4-hydroxyamino)succiny|-(4-piperonybpiperazinamideStep AIn a manner analogous to that described in Example 1 (step A), reaction of 4S-benzyloxycarbonyl-1-tert-butoxycarbonyl-3R—cyclopentylmethylazetidin—2-one (500 mg; seePreparation D) with l—piperonylpiperazine (545 mg) in acetonitrile afforded (4-benzyl-oxycarbonyl-3 S-tert-butoxycarbonylamino-2R-cyclopentylmethyl)succinyl-(4-piperonyl)-piperazinamide (800 mg) as an oil. H'- NMR (200 MHz, CDCI3) 1.0-1.9 (In, 11 H); 1.41 (s,9 H); 2.30 (m, 4 H); 3.36 (s, 2 H); 3.36 (m, l H); 3.50 (m, 4 H); 4.51 (dd, 1 H, J= 4.1 and9.8 Hz); 5.06 and 5.18 (two d, 2 H, J= 12.4 Hz); 5.94 (s, 2 H); 6.40 (d, 1 H, J= 9.8 Hz); 6.6-6.9 (m, 3 H); 7.33 (m, 5 H) ppm. ESI/CID-MS 630 (MNa)*, 608 (MI-I)+, 508, 372, 221. 135m/z.Step BIn a manner analogous to that described in Example 1 (step B), reaction of the material fromstep A above (800 mg) with 10% Pd/C (100 mg) under a hydrogen atmosphere afforded (3 S-tert-butoxycarbonylamino-ZR-cyclopentylmethyl—4-hydroxy)succinyl-(4-piperonyl)piperazin-amide (600 mg) as a white solid.Step CIn a manner analogous to that described in Example 2 (step A), reaction of the material fromstep B above (600 mg) with O-benzylhydroxylamine hydrochloride (160 mg), N-methyl-morpholine (0.27 mL) and TBTU (385 mg) afforded (4-benzyloxyaminocarbonyl-3 S-tert-butoxycarbonylamino-2R-cyclopentylmethyl)succinyl—(4-piperonyl)piperazinamide (280 mg)as a white solid. H‘- NIVIR (400 MHz, DMSO-d6) 0.9-1.7 (m, 11 H); 1.37 (s, 9 H); 2.1-2.41015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422051(m, 4 H); 3.18 (m, 1 H); 3.30-3.60 (m, 6 H); 4.01 (dd, 1 H, J= 6.4 and 9.0 Hz); 4.74 (s, 2 H);5.97 (s, 2 H); 6.66 (d, 1 H, J= 9.0 Hz); 6.7-6.8 (m, 3 H); 7.34 (m, 5 H); 11.38 (s, 1 H) ppm.ESI-MS 645 (MNa)+, 623 (MH)“‘, 567, 523, 372, 283, 221 m/z.Step DIn a manner analogous to that described in Example 2 (step B), reaction of the material fromstep C above (280 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded thetitle compound (160 mg) as a white solid. H‘- NMR (400 MHz, DMSO—d5) 0.9-1.7 (m, 11H); 1.35 (s, 9 H); 2.1-2.4 (m, 4 H); 4.00 (dd, 1 H, J= 6.8 and 9.0 Hz); 5.97 (s, 2 H); 6.57 (d,1 H, J= 9.0 Hz); 6.6-6.8 (m, 3 H); 8.80 (br signal, 1 H); 10.2 (br signal, 1 H) ppm. ESI-MS555 (MNa)+, 533 (MH)+, 477, 444, 221 m/z.EXAMPLE 27(3S-Amino-ZR-cyclopentylmethyl-4-hydroxyamino)succinyl-(4-piperonyl)piperazin-amideIn a manner analogous to that described in Example 3, reaction of the compound described inExample 26 (140 mg) with 95% aqueous trifluoroacetic acid (3 mL) afforded the titlecompound (bis-trifluoroacetate salt) as a white solid (100 mg). In DMSO solution, thecompound is present as a mixture of two rotamers (M, major; m, minor). H1- NMR (400MHz, DMSO-d6) 1.0-1.8 (m, 11 H); 2.8-4.6 (br m, 10 H); 3.20 (m, 1 H); 3.70 (In, 1 H);6.07 (s, 2 H); 7.00 (m, 3 H); 8.08 (br signal, 3 H, m); 8.22 (br signal, 3 H, M); 9.43 (brsignal, 1 H, M); 10.1 (br signal, 1 H, M); 10.8 (s, 1 H, m); 11.20 (s, 1 H, M) ppm. ESI-MS459 (MNa)+, 433 (MH)+, 299, 238, 221, 135 m/z.By minor variations of the procedures of the examples above, and starting from theappropriate intermediates, the following compounds were obtained:EXAMPLE 28(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropy1)succiny1-azetidinamideTrifluoroacetate salt. H1- N1VIR(400 MI-Iz, DMSO-d6): 1.44 (m, 4 H, CH2CH2-CH2Ph), 2.14(m, 2 H, azetidine 3-methylene), 2.47 (m, 2 H, CH2CH2-C_H2-Ph), 2.58 (m, 1 H, C_H_-phenpropyl), 3.57 (d, J= 6.1 Hz, 1 H, Q1-NH3+), 3.69 (s, 3 H, OMe), 3.86, 4.10 and 4.30(each m; 4 H, azetidine 2-,4—methylene), 6.82 (d, J= 8.2 Hz, 2 H, aromatic protons ortho tomethoxy), 7.07 (cl, J= 8.2 Hz, 2 H, aromatic protons meta to methoxy), 8.00 (br s, 3 H,NH3+), 9.32 (s, 1 H, NH-Q1-_I), and 11.10 ppm (br s, 1 H, @-OH).EXAMPLE 29(3S-Amino-4-hydroxyamino—2R-(4-methoxy)phenpropyl)succinyI-N-cyclohexylamide1015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/04220Trifluoroacetate salt. H'- NMR (400 MHz, l§12vISO~d6; 55 °C): 1.0-1.9 (m, 13 H, Q—I_2§_H2-CH2Ph + cyclohexyl methylene protons), 2.50 (m, 3 H, CH-CH2CH2-Q11;-Ph), 3.45 (d, J=7.3 Hz, 1 H, _ClI_—NH3+), 3.55 (m, 1 H, cyclohexyl methyne proton), 3.70 (s, 3 H, OMe), 6.81(d, J= 8.6 Hz, 2 H, aromatic protons ortho to methoxy), 7.04 (d, J= 8.6 Hz, 2 H, aromaticprotons meta to methoxy), 7.81 (d, J= 7.7 Hz, 1 H, CONE-cyclohexyl), 8.00 (br s, 3 H,NH3+), 9.10 (br s, 1 H, NH-Q_}_I), and 10.0 ppm (br s, 1 H, N_H-OH). At 55 °C, the -NHJprotons were not detectable (7-8 ppm at lower temperatures).EXAMPLE 30(2R-Cyclopentylmethyl-3S-N,N-dimethylamin0-4-hydroxyamino)succinyl-piperidin-amideH'- NMR (400 MHz, DMS0-d5): 0.9-1.9 (m, 17 H, cyclopentylmethyl + piperidine 3—,4-,5-methylene protons), 2.12 (s, 6 H, NMe2), 3.00 (d, J= 10.7 Hz, 1 H, C_H-NMe2), 3.27 (m, 1H, _C_Ii-cyclopentylmethyl), 3.3-3.6 (m, 4 H, piperidine 2-,6-methylene), 8.83 (s, 1 H, NH-O_H), and 10.51 ppm (br s, 1 H, @-OH).EXAMPLE 31(4-Hydroxyamino-2R-(4-methoxy)phenpropyl-3S-phenylmethylsulfonylamino)succinyl-piperidinamideH'- NNIR (400 MHz, DMSO-d5): 1.2-1.6 (m, 10 H, CH- -CH2Ph + piperidine 3-,4-,5-methylene protons), 2.41 (m, 2 H, Qfiz-Ph), 3.16 (m, 1 H, Qfl—phenpropyl), 3.44 (m, 4 H,piperidine 2-,6-methylene), 3.69 (s, 3 H, methoxy), 3.93 (m, 1 H, _C_I_{_-NHSO2), 4.08 and4.19 (each d, J= 13.7 Hz, NHSO2-C_Ii_2-Ph), 6.80 (d, J= 8.6 Hz, 2 H, aromatic protons orthoto methoxy), 7.05 (d, J= 8.6 Hz, 2 H, aromatic protons meta to methoxy), 7.33 (m, 5 H, Ph),7.59 (br s, 1 H, E-802), 9.02 (br s, 1 H, NH-O_H), and 10.90 ppm (br s, 1 H, N__fl-OH).EXAMPLE 32(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-(lR-cyclohexylethyl)-amideTrifluoroacetate salt. H‘- NMR (400 Ml-Iz, DMSO-d6): 0.93 (d, J= 6.8 Hz, 3 H, C_H3-CH),0.8-1.8 (m, 15 H, CH-_(3_H2Q_I12-CH2Ph + cyclohexyl protons), 2.43 (m, 2 H, _(_I_I;I_2-Ph), 2.62(m, 1 H, _(_I_H_-phenpropyl), 3.57 (m, 2 H, _C_I_-I_-CH3 + _(3_H-NH3+), 3.69 (s, 3 H, methoxy), 6.81(d, J= 8.6 Hz, 2 H, aromatic protons ortho to methoxy), 7.05 (d, J= 8.6 Hz, 2 H, aromaticprotons meta to methoxy), 7.93 (d, J= 8.6 Hz, 1 H, CO-flH_-CH), 8.12 (br s, 3 H, N_H_3+),9.33 (s, 1 H, NH-O_H), and 11.05 ppm (s, 1 H, @-OH).EXAMPLE 331015202530CA 02265671 1999-03-09WO 99/02510 PCT/EP98/042205 3(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyI)succinyl-(1S-cyclohexyIethyl)-amideTrifluoroacetate salt. H'- N1\/IR (400 MHz, DMSO-d5): 0.8-1.8 (m, 15 H, CH' 'CH2Ph + cyclohexyl protons), 0.97 (d, J= 6.8 Hz, 3 H, Q13-CH), 2.44 (m, 2 H, _C_I-_I2-Ph),2.61 (m, 1 H, C_H-phenpropyl), 3.62 (m, 2 H, _Cfl-CH3 + Q-I_-NH3+), 3.68 (s, 3 H, methoxy),6.80 (d, J= 8.5 Hz, 2 H, aromatic protons ortho to methoxy), 7.03 (d, J= 8.5 Hz, 2 H,aromatic protons meta to methoxy), 7.92 (d, J= 8.5 Hz, 1 H, CO-E-CH), 8.10 (br s, 3 H,N____I_13+), 9.34 (s, 1 H, NH-Q-1), and 11.08 ppm (s, 1 H, @-OH).EXAMPLE 34(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-(4-tert-butylamino-carbonyl)piperidinamideTrifluoroacetate salt. In DMSO, the compound is present as two conformers, ca. 1:1, whoseH’-NMR signals coalesce upon heating. H‘-NMR (400 MHz, DMSO-d6): 1.21 and 1.22(each s; 9 H, t-Bu of 2 conformers), 1.2-1.8 (m, 8 H, CH-_(_3_Ij2QH2-CH2Ph + piperidine 3-,5-methylene), 2.30 (m, 1 H, piperidine 4-proton), 2.45 (m, 2 H, §_H_2-Ph), 2.55 and 2.92 (eachm; piperidine 2- and 6- axial protons), 3.20 (m, 1 H, Qfl-phenpropyl), 3.69 (s, 3 H,methoxy), 3.69 and 3.70 (each d, J= 7.0 Hz; 1 H, Qfl-NH3* of 2 conformers), 3.87 and 4.35(each m; 2 H, piperidine 2- and 6- equatorial protons), 6.81 (d, J= 8.4 Hz, 2 H, aromaticprotons ortho to methoxy), 7.05 and 7.07 (each d, J= 8.4 Hz; 2 H, aromatic protons meta tomethoxy of 2 conformers), 7.35 (s, 1 H, CO-N_H-tBu), 8.00 (br s, 3 H, N___Ij3+), 9.34 and 9.37(each s; 1 H, NH-O_H of 2 conformers), and 11.10 ppm (br s, 1 H, N_fi_-OH).EXAMPLE 35(2R-Cyclopentylmethyl-3S-N,N-dimethylamino-4~hydroxyamino)succinyl-(4-piperonyl)-piperazinamideH‘- NMR (400 MHz, CDCI3): 1.0-1.8 (m, 11 H, cyclopentylmethyl), 2.28 (s, 6 H, NMe2),2.38 and 2.46 (each m; 4 H, piperazinamide 3-,5-methylene), 3.35 (m, 2 H, Q31;dimethylamino + _C_I_I-cyclopentylmethyl), 3.42 (s, 2 H, N-Q11;-Ar), 3.6-3.8 (m, 4 H,piperazinamide 2-,6-methylene), 5.95 (s, 2 H, O-QH2-O), 6.75 and 6.85 (each m; 3 H, Ar),8.00 (br s, 1 H, NH-_fl), and 10.00 ppm (br s, 1 H, E-OH).EXAMPLE 36(3S-(N-Cyclohexylmethyl-N-methyl)amino-4-hydroxyamino-2R-(4-methoxy)-phenpropyl)-succinyl-piperidinamide1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422054H‘- NMR (400 MHz, DMSO-d6): 0.6-1.8 (m, 21 H, CH-QI;I_2Q_I_~_I2-CH2Ph + piperidine 3-,4-,-5-methylene + cyclohexyl protons), 2.10 (m, 2 H, C_H2-Ph), 2.12 (s, 3 H, NMe), 2.40 (m, 2H, N-C_H2-cyclohexyl), 3.06 (d, J= 10.7 Hz, 1 H, CO-_C_Ij-N), 3.2-3.5 (m, 5 H, Qfl-phenpropyl + piperidine 2-,6-methylene), 3.69 (s, 3 H, methoxy), 6.80 (d, J= 8.5 Hz, 2 H,aromatic protons ortho to methoxy), 7.02 (d, J= 8.5 Hz, 2 H. aromatic protons meta tomethoxy), and 9.00 ppm (br s, 1 H, NH-O_H); N__}_1-OH not detected.EXAMPLE 37(2R-Cyclopentylmethyl-4-hydroxyamino-3S-(4-methoxyphenyl)sulfonylamino)succinyl-(4-piperonyl)-piperazinamideTrifluoroacetate salt. In DMSO, the compound is present as a mixture of two confonners(coalescence of N1\/[R signals upon heating). H’- NMR (400 MHz, DMSO-d5): 0.8-1.6 (m,11 H, cyclopentylmethyl), 2.5-3.5 (m, 7 H, C_H-cyclopentylmethyl + piperazinamide 3-,5-methylene + C_H2-Ar), 3.5-4.5 (m, 5 H, C_H-NHSO2 + piperazinamide 2-,6-methylene), 6.07(s, 2 H, O-_C_I-12-O), 6.9-7.1 (m, 5 H, piperonyl Ar protons + aromatic protons ortho tomethoxy), 7.63 (d, J= 8.6 Hz, 2 H, aromatic protons meta to methoxy), 7.73 and 7.86 (d, J=9.0 Hz, flH_-S02), 8.89 (br s, 1 H, NIT), 9.70 and 9.80 (br s, 1 H, NH-E), and 10.77,10.82 ppm (br s, 1 H, @-OH).EXAMPLE 382R-(4S-(2-Dimethyl-1-hydroxy-2-oxo-3H-imidazolidinyl)-3-cyclopentylpropionic acid(4-piperonyl)-piperazinamideObtained as a white solid by stirring (3 S-amino-2R-cyclopentylmethyl-4-hydroxyarnino)-succinyl-(4-piperonyl)piperazinarnide (Example 27) in neat acetone, followed by removal ofwater and solvent by rotoevaporation with anhydrous ethanol. Trifluoroacetate salt. H‘-NMR (400 MHz, DMSO-d5): 1.0-1.8 (m, 11 H, cyclopentylmethyl), 1.16 and 1.17 (each s, 3H, Me), 2.9-4.4 (m, 10 H, Q1-cyclopentylmethyl + piperazine methylene protons + C_H2-Ar+ CI;I-NH;;_+-), 6.05 (s, 2 H, O-C_I‘_I,2-O), 6.9-7.1 (m, 3 H, piperonyl Ar protons), 9.64 (s, 1 H,N-£1), and 9.9 ppm (br s, 2 H, -Nljf-).EXAMPLE 39(4-Hydroxyamino-2R-(4-methoxy)phenpropyl-3S-(3-pyridyl)methylamino)succinyl-piperidinamideH'- NMR (400 MHz, DMS0-d5): 1.1-1.6 (m, 10 H, CH-Qflzgljz-CH2Ph + piperidine 3—,4—,5-methylene protons), 2.40 (m, 2 H, _Cfl2-Ph), 3.06 (m, 2 H, E-NH + _C__1-1-phenpropyl),3.2-3.6 (m, 4 H, piperidine 2-,6—methylene), 3.37 and 3.70 (each d, J= 16.2 Hz; 2 H, NH-1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422055QL2-pyridine), 3.68 (s, 3 H, methoxy), 6.79 (d, J= 7.6 Hz, 2 H, aromatic protons ortho tomethoxy), 7.10 (d, J= 7.6 Hz, 2 H, aromatic protons meta to methoxy), 7.26 (dd, J= 4.7 and7.7 Hz, 1 H, 5-pyridine proton), 7.60 (ddd, J= 1.7, 2.1 and 7.7 Hz, 1 H, 4-pyridine proton),8.38 (dd, J= 1.7 and 4.7 Hz, 1 H, 6-pyridine proton), and 8.39 ppm ((1, J= 2.1 Hz, 1 H, 2-pyridine proton); NH-Q11 and _N_I_vI_-OH not detected.EXAMPLE 40N-((3S-Amino-4-hydroxyamino-2R—(4-methoxy)phenpropyl)succiny|)—L-proline-piperonylamideTrifluoroacetate salt. H‘— N1\/[R (400 MHZ, DMSO-d.»,): 1.4-2.1 (m, 8 H, cH—_c_r_12g2—CH2Ph + proline 3-,4-methylene), 2.45 (m, 2 H, CH -Ph), 2.95 (m, 1 H, E-phenpropyl),3.5-3.7 (m, 3 H, Q1-I_-NH3* + proline 5-methylene), 3.67 (s, 3 H, methoxy), 4.16 and 4.21(each dd, J= 5.6 and 13.7 Hz, 1 H, CONH—_C_I1(H)-Ar), 4.34 (dd, .l= 4.3 and 8.1 Hz, prolineN-_C_H_-CO), 6.07 (s, 2 H, O-C_PI_;-O), 6.6-6.9 (m, 5 H, piperonyl Ar protons + aromaticprotons ortho to methoxy), 7.06 (d, J= 8.6 Hz, 2 H, aromatic protons meta to methoxy),8.15 (br s, 3 H, NH3+), 8.31 (dd, J= 5.6 Hz, 1 H, CO-E-CH2-Ar), 9.39 (s, 1 H, NH-O_H),and 11.16 ppm (5, 1 H, N_fi-OH).EXAMPLE 41(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-N-isopropyl-N-methylamide, and(3R-Amino-4-hydroxyamin0-2R-(4-methoxy)phenpropyl)succinyl-N-isopropyl—N-methylamideA solution of 4S-benzyloxycarbonyl-1-tert-butoxycarbonyl—3R-(4-methoxy)phenpropyl-azetidin-2-one (350 mg; see Preparation C) in DMF (6 mL) was allowed to react withsodium azide (10 mg) and N-isopropyl-N-methylamine (0.16 mL) for 30 hr at roomtemperature. Workup and flash chromatography over silica (n-hexane/EtOAc) afforded, inthis order, (4-benzyloxycarbonyl-3 S-tert-butoxycarbonylarnino-2R-(4-methoxy) phenpropyl)succinyl-N-isopropyl-N-methylamide (160 mg) and the product from base-assistedepimerization, (4-benzyloxycarbonyl-3R-tert-butoxycarbonylamino-2R-(4-methoxy)phenpropyl) succinyl-N-isopropyl-N-methylamide (80 mg). . ESI—MS (both isomers) 527(MH)+-Separate elaboration of the two diastereoisomers above, in a manner analogous to thatdescribed in Examples 1-3, afibrded the title compounds (both trifluoroacetate salts). In1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422056DMSO, bot compounds exist as a 2:1 mixture (M, major; m, minor; H’- NMR) of rotamersat the tertiary amide.3S-Isomer: H1- NMR (600 MHz, DMSO-d5): 0.97 and 1.02 (each d, J= 7.0 Hz; 6 H, CH_M_e2of M), 1.01 and 1.11 (each d, J= 7.0 Hz; 6 H, CH_1\@2 of m), 1.47 (m, 4 H, CH-C_H2_C_I_{_2-CH2Ph), 2.44 (m, 2 H, §_I:I_2-Ph), 2.65 (s, 3 H, N1;/I_e of m), 2.77 (s, 3 H, Nfi of M), 3.11(m, 1 H, Qfl-phenpropyl of M), 3.18 (m, 1 H, Q-I_-phenpropyl of m), 3.69 (s, 3 H, methoxy),3.71 (m, 1 H, E-NH3+ of M), 3.76 (m, 1 H, Q11-NH3+ of m), 4.03 (m, 1 H, C_I-1-Meg of m),4.69 (m, 1 H, Q11-Me; of M), 6.82 (d, J= 8.6 Hz, 2 H, aromatic protons ortho to methoxy),7.05 (d, J= 8.6 Hz, 2 H, aromatic protons meta to methoxy), 7.98 (br s, 3 H, NH3* of m),8.13 (br s, 3 H, NH3+ ofM), 9.36 (s, 1 H, NH-fl ofM), 9.37 (s, 1 H, NH-QH ofm), 11.12(s, 1 H, N_l—I_-OH of M), and 11.15 ppm (s, 1 H, L\I_H_-OH of m).3R-Isomer: H'- NMR (600 MHz, DMSO-d6): 0.98 and 1.00 (each d, J= 6.5 Hz; 6 H, CHMe3ofM), 1.04 and 1.11 (each d, J= 6.5 Hz; 6 H, Cfllfiz ofm), 1.3-1.8 (m, 4 H, CH-Q_H2_C_H2-CH2Ph), 2.46 (m, 2 H, Q;-I_2-Ph), 2.64 (s, 3 H, NM; of m), 2.80 (s, 3 H. N_M_e of M), 3.17(m, 1 H, _C_Ij-phenpropyl, 3.59 (m, 1 H, _C_I-I_-NH3+), 3.69 (s, 3 H, methoxy of M), 3.70 (s, 3H, methoxy of m), 4.12 (m, 1 H, C_H-Meg of m), 4.67 (m, 1 H, _QH_-Me; of M), 6.81 (d, J=8.5 Hz, 2 H, aromatic protons ortho to methoxy of M), 6.83 (d, J= 8.5 Hz, 2 H, aromaticprotons ortho to methoxy of m), 7.05 (d, J= 8.5 Hz, 2 H, aromatic protons meta to methoxyof M), 7.09 (d, J= 8.5 Hz, 2 H, aromatic protons meta to methoxy of m), 8.21 (br s, 3 H,NH3+), 9.20 (br s, 1 H, NH-O_H of m), 9.22 (br s, 1 H, NH-Q1-I_ of M), and 10.99 ppm (br s,1 H, @-OH).EXAMPLE 42(3S-Amino-4-hydroxyamin0-2R-(4-methoxy)phenpropyl)succiny1-4-(2-pyridyl)-piperazinamideTrifluoroacetate salt. H'- NMR (400 MHz, DMSO-d6): 1.48 (m, 4 H, CH-_C_I_-LQH2-CH2Ph),2.44 (m, 2 H, C_I-I2-Ph), 3.22 (m, 1 H, Q-I_-phenpropyl), 3.3-3.8 (m, 9 H, CH-NH3+ andpiperidine methylene protons), 3.68 (s, 3 H, methoxy), 6.70 (dd, J= 5.1 and 6.8 Hz, 5-pyridine proton), 6.78 (d, J= 8.6 Hz, 2 H, aromatic protons ortho to methoxy), 6.88 (d, J=8.6 Hz, 1 H, 3-pyridine proton), 7.05 (d, J= 8.6 Hz, 2 H, aromatic protons meta to methoxy),7.60 (ddd, J= 1.7, 6.8 and 8.6 Hz, 1 H, 4-pyridine proton), 8.10 (dd, J= 1.7 and 5.1 Hz, 1 H,6-pyridine proton), 8.20 (br s, 3 H, NHJ), 9.40 (br s, 1 H, NH—Q_I_-I_), and 11.19 ppm (s, 1H, @-OH).EXAMPLE 431015202530CA 02265671 1999-03-09wo 99/02510 PCT/EP98/0422057(3S-Amino-4—hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-(4-(2,3-methylene-dioxy)phenylaminocarbonyl)piperidinamide ,Trifluoroacetate salt. H1- NMR (400 MHZ, DMSO-d5): In DMSO, the compound is presentas two confonners, ca. 1:1, whose H1-NMR signals coalesce upon heating. H'—Nl\/[R (400MHz, DMSO-d6): 1.2-1.9 (m, 8 H, CH-CH2CH2-CH2Ph + piperidine 3-,5-methylene), 2.45(m, 2 H, QH2-Ph), 2.50 (m, 1 H, piperidine 4-proton), 2.70 and 3.00 (each m; piperidine 2-and 6- axial protons), 3.20 (m, 1 H, Qfl-phenpropyl), 3.66 and 3.70 (each s; 3 H, methoxy of2 confonners), 3.70 (m, 1 H, Q11-NH3*), 3.90 and 4.40 (each m; 2 H, piperidine 2- and 6-equatorial protons), 5.95 (s, 2 H, O-QQ-O), 6.8-7.3 (m, 7 H, aromatic protons), 8.00 (br s,3 H, N_H3+), 9.38 and 9.39 (each s; 1 H, NH-QH of2 conformers), 9.82 and 9.83 (each s; 1H, CO-N__H_-Ar), and 11.15 ppm (br s, 1 H, @—OH).In a manner analogous to that described in the previous Examples, there were prepared thefollowing compounds:EXAMPLE 44(3S-Amino-4-hydroxyamino-2R-isobutyl)succinyl-N-methyI-N- (IS-methylaminocarbonyl-2-phenyl)ethylamide, trifluoroacetate salt.H‘- NMR (600 MHz, DMSO-d.«,): 0.73, 0.80 (two d, J=6.3 Hz, 6H), 1.1-1.5 (m, 3H), 2.55(d, J= 4.4 Hz, 3H), 2.83 (s, 3H), 3.05, 3.30 (two m, 2H), 3.10 (m, 1H), 3.60 (m, 1H), 4.70(m, 1H), 7.0-7.3 (m, 5H), 7.81 (q, J= 4.4 Hz, 1H), 8.28 (broad signal, 3H), 9.40 (broadsignal, 1H), 11.13 (s, 1H).EXAMPLE 45(3S-Amin0-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-(4-piperonyl)piperazinamideEXAMPLE 46(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-4-(4-fluorophenylsulfonyl) piperazinamideEXAMPLE 47(ZR-Cyclopentylmethyl-4-hydroxyamino-3S-(methylsulfonyl)amino)succinyl-(4-piperonyl)piperazinamideEXAMPLE 48(3S-Amino-4-hydroxyamin0-2R-(4-methoxy)phenpropyl)succinyl-4-(4-acetylphenyl)piperazinamideEXAMPLE 49101520253035CA 02265671 1999-03-09wo 99/02510 PCT/EP98/042205 8(3S-Amino-4-hydroxyamino-ZR-(4-methoxy)phenpropyl)succinyl-4-(1-piperidyl)piperidinamideEXAMPLE 50(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl-(1R-cyc|ohexylethyl)amide, trifluoroacetate salt.H'- NMR (400 MHz, DMSO—d5): 0.9-1.9 (m, 22H); 0.95 (d, J= 6.8 Hz, 3H), 2.60 (m, 1H),3.55 (m, 2H), 7.87 (d, J=7.1Hz, 1H), 8.0 (broad signal, 31-D 9.27 (s, 1H), 11.0] (broadsignal, 1H).EXAMPLE 51(4-Hydroxyamino-3S—(4—methoxyphenylsulfony|)amino-2R-(4-methoxy)phenpropyl)succinyl-piperidinamideEXAMPLE 52(3S-(4-Fluorophenylsulfonyl)amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-piperidinamideEXAMPLE 53(3S—Amin0-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-cyclohexylamideEXAMPLE 54(3S-Amino-2R-cyclopentylmethyl-4—hydroxyamino)succinyl-piperazinamideEXAMPLE 55(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropy|)succinyl-cyclopentylamideEXAMPLE 56(3S—Amino-4-hydroxyamin0-2R-(4-methoxy)phenpropyl)succinyl-(2R,S-methyl)piperidinamideEXAMPLE 57(3S-Amin0-4-hydroxyamino-2R-(4—methoxy)phenpropyl)succinyl-2-(1-morpholino)ethylamideEXAMPLE 58(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl-2-(N-methyl-N-piperonyl)aminoethylamideEXAMPLE 59(3S-Amino-4-hydroxyamino-2R-(4—methoxy)phenpropyl)succinyl-4-(1,1-di(4-fluoro)phenylmethyl)piperazinamideEXAMPLE 60(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl-N-methyl-N-(2-(N-methyhN-piperonyl)-aminoethylamide1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/042205 9EXAMPLE 61(2R-Cyclopentylmethyl-3S-(4-fluorophenylsulfonyl)amino-4-hydroxyamino)succinyI-piperidinamide 0EXAMPLE 62(3S-Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyI)succinyl-4-(4-piperidinecarbonyl)piperazinamideEXAMPLE 63(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl-(3,5-dimethyI)piperazinamideEXAMPLE 64(3S-Amino-2R-biphenpropyl-4-hydroxyamino)succinyl-(4—piperonyl)piperazinamide,trifluoroacetate salt.H]- N1VlR(500 MI-Iz, DMSO-d5): 1.60 (m, 4H), 2.60, 2.70 (two m, 2H), 3.0-4.0 (broadsignal, 10H), 3.30 (m, 1H), 4.02 (d, J=7.2 Hz, 1H), 5.93 (s, 2H), 6.6-6.8 (m, 3H), 7.30-7.70(m, 9H).EXAMPLE 65(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyI-(1R-cyclohexyl-2-hydroxy)ethylamideEXAMPLE 66(3S—Amino-4-hydroxyamino-2R-(4-methoxy)phenpropyl)succinyl-4-(2-hydroxyethyl)piperazinamideEXAMPLE 67N-((3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl)-L-pro|ine--N-(2,3-methylenedioxyphenyl)-carboxamideEXAMPLE 68N-((3S-Amino-2R—cyclopentylmethyl-4-hydroxyamino)succinyl)-D-proline--N-(2,3-methylenedioxyphenyl)-carboxamideEXAMPLE 69(2R-Cyclopentylmethyl-4-hydroxyamino-3S-(toluenesulfonyl)amino)succinyl-(1R-cyclohexylethy|)amideEXAMPLE 70(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl-(2S-methyl-4-piperonyl)piperazinamideEXAMPLE 711015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422060(2R-Cyclopentylmethyl-4-hydroxyamino-3S-(8-(1,2,3,4-tetrahydroquinoline)sulfonyl)amino)succinyl-(1R-cyclohexylethyl)amideH‘- NMR (400 MHz, DMSO-d5): 0.89 (d, J= 6.8 Hz, 3H), 0.9-1.9 (m, 22H), 2.43 (m, 1H),2.67 (m, 2H), 3.30 (m, 2H), 3.50 (m, 2H), 5.94 (s, 1H), 6.45 (dd J= 7.3, 7.8 Hz, 1H), 7.03(d, J= 7.3 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.3, 7.6 (two broad signals, 2H), 8.72 (broadsignal, 1H) 10.50 (broad signal, IH).EXAMPLE 72(3S-Amino-2R-cyclopentylmethyl-4-hydroxyamino)succinyl- (1S-cyclohexy|-1-dimethylaminocarbonyl)-methylamideH‘- NMR (400 MHz, DMSO-d6): 0.9-1.9 (m,22H), 2.68 (m,lH), 2.79,3.06 (two singlets,6H), 3.47 (m,1H), 4.50 (dd, J= 7.3, 8.8 Hz, 1H), 7.80 (broad signal, 3H), 8.16 (d, .1’-=7.3 Hz,1H), 9.21 (broad signal, 1H), 11.00 (broad signal, 1H).EXAMPLE 73(3S-Amino-2R-biphenpropyl-4-hydroxyamino)succinyI-(1R-cyclohexylethyl)amide,trifluoroacetate salt.H‘- NNIR (400 MHz, DMSO-d5): 0.90-1.9 (m, 15H), 0.94 (d, J= 6.8 Hz, 3H), 2.57 (m, 2H),2.62 (m, 1H), 3.57 (m, 1H), 3.67 (m, 1H), 7.25, 7.55 (two doublets, J=8.3 Hz, 4H), 7.30(m,1H), 7.42 (m, 2H), 7.60 (m,2H), 8.02 (d, J=8.8 Hz, 1H), 8.18 (broad signal, 3H), 9.32 (s,1H), 11.20 (s,1H).PREPARATION A4S-Benzyloxycarbonyl-1—tert-butoxycarbonyl-3R-isobutylazetin-2-oneStep AA solution of 1-tert-butyldimethylsilyl-4S-carboxyazetidin-2-one (6.2 g) in dry THF (100mL) was teated dropwise at 0-5°C with a 2M solution of LDA (28.4 ml) in the same solvent,to ontain an orange solution of the di-anion. Afier 15 min, isobutyl iodide (6.8 mL) wasadded at 0°C under stirring, and the resulting yellow-green solution was left at the sametemperature overnight. Quenching with 1M aqueous KHSO4 (300 mL), followed bywith EtOAc, affordedisobutylazetidin-2-one as an orange syrup (7 g).extraction crude 1-tert butyldimethylsilyl-4S-carboxy-3R-The above material was dissolved in dry DMF (20 mL) and treated dropwise, in this order,with triethylamine (5.85 mL) and benzyl bromide (4.8 mL). After 4 hours at roomtemperature, the mixture was partitioned between water and EtOAc. The organic layer waswashed with brine, dried and evaporated to give crude 4S-benzyloxycarbonyl-1-ternbutyldimethylsilyl-3R-isobutylazetidin-2-one as an orange oil. This material was dissolved in1015202530CA 02265671 1999-03-09WO 99/02510 PCT /EP98I0422061THF (10 mL) and left overnight in the presence of tetrabutylammonium fluoride (2.6 g) andacetic acid (1.7 mL). The mixture was partioned between saturated aqueous NaHCO3 andEtOAc, and the organic phase was dried and evaporated. Flash cromatography over silica gel(n-hexane/EtOAc) afforded 4S-benzyloxycarbonyl-3R-isobutylazetidin-2-one (4.7 g) as whiteneedles. FT-IR (KBr) 3229 (N), 1744-1750 br (CO) cm". H-NMR (200 MHz, CDCI3) 0.87(d, 3 H, J= 6.5 Hz); 0.94 (d, 3 H, J= 6.5 Hz); 1.57-1.82 (m, 3 H); 3.32 (m, 1 H); 3.90 (d, 1H, J= 2.4 Hz); 5.22 (ABq, 2 H); 5.96 (br s, 1 H); 7.36 (m, 5 H) ppm.Step BA solution of the material from step A above (1 g) in CH3CN (15 mL) was treated withDMAP (4-dimethylaminopyridine; 46 mg) and Boc2O (di-tert-butyldicarbonate; 1.67 g) at 40°C for 30 min and then at room temperature overnight. After removal of the solvent invacuo, the residue was dissolved in EtOAc and sequentially washed with aqueous 1MKHS04, aqueous saturated NaHCO3 and brine. Drying over Na2S04 and evaporation lefi thetitle compound as a yellow oil. FT-IR (CHCI3) 1820 (azetidinone CO), 1750 (ester CO);1728 (carbamate CO) cm".PREPARATION B3R-lsobutyl-4S-(4-nitro)benzyloxycarbonyl-1-(4-toluenesulfonyl)azetidin-2—oneStep AIn a manner analogous to that described in Preparation A, reaction of l-tert—butyl-dimethylsilyl-4S-carboxyazetidin-2-one (4.1 g) with a 2M solution of LDA in THF (18.8 mL)and isobutyl iodide (4.53 mL), followed by reaction with p-nitrobenzyl bromide (4.25 g) andtriethylamine (3.7 mL), mL) andtetrabutylammonium fluoride ( 1.1 g), afforded 3R-isobutyl-4S-(4-nitro)benzyloxycarbonyl-and finally by reaction with acetic acid (1azetidin-2-one (3.6 g) as a yellow solid.Step BA solution of the material from Step A above (630 mg) in CHZCI2 (10 mL) was treated withtriethylamine (0.65 ml) and p-toluenesulfonyl chloride (783 mg) at room temperatureovernight under a’ nitrogen atmosphere. After quenching with saturated aqueous NaHCO3,the organic layer was collected, washed with aqueous saturated NI-I4Cl, brine and dried overNa2SO4. Evaporation and purification by flash cromatography on silica gel (n—hexane/EtOAc)afforded the title compound (3 20 mg) as an oil. FT-IR (CHCI3) 1802 (azetidinone CO), 1752(ester co) cm". H‘—NMR (400 MHz, CDCI3) 0.79 (d, 3 H, J= 6.4 Hz); 0.88 (d, 3 H, J= 6.41015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422062Hz); 1.54-1.72 (m, 3 H); 2.44 (s, 3 H); 3.20 (m, 1 H); 4.32 (d, l H, J= 3.2 Hz); 5.19 (s, 2 H);7.31 (d, 2 H, J= 8.5 Hz); 7.33 (m, 5 H), 7.87 (d, 2 H, J= 8.5) ppm.PREPARATION C4S—Benzyloxycarbonyl—l—tert-butoxycarbonyl-3R-(4-methoxy)phenpropylazetidin-2-oneStep AIn a manner analogous to that described in Preparation A, reaction of l-tert-butyl-dimethylsilyl-4S-carboxyazetidin-2-one (21 g) with a 2M solution of LDA in THF (93.8 mL)and (4-methoxy)phenpropyl iodide (45.9 g; see Preparation F). followed by reaction withbenzyl bromide (32.6 mL) and triethylamine (15.3 mL), afforded crude 4S-benzyloxy-carbonyl-1-tert-butyldimethylsilyl-3R-(4-methoxy)phenpropylazetidin-2-one (90.4 g).This material, dissolved in CH3CN and aqueous 2N HCl, was let stirring at room temperatureovernight. The solvent was evaporated and the aqueous phase was extracted with EtOAcseveral times. The organic layer was dried over Na2SO4 and evaporated. The residue waspurified by flash cromatography on silica gel (n-hexane/EtOAc) to afford 4S-benzyloxycarbonyl-3R-(4-methoxy)phenpropylazetidin-2-one (8.6 g) as a white solid.Step BIn a manner analogous to that described in Preparation A (step B), reaction of the materialfrom step A above (8.6 g) with DMAP (300 mg) and Boc2O (7.93 g) afforded the titlecompound as a yellow oil (9.1 g). H1-NMR (200 MHz, CDCI3) 1.44 (s, 9 H); l.6—l.9 (m, 4H); 2.55 (In, 2 H); 3.15 (m, l H); 3.79 (s, 3 H); 4.09 (d, 1 H, J=3.2 Hz); 5.19 and 5.25 (twod, 2 H, J= 12.2 Hz); 6.81 (d, 2 H, J= 8.7 Hz); 7.02 (d, 2 H, J= 8.7 Hz); 7.34 (m, 5 H) ppm.PREPARATION D4S-Benzyloxycarbonyl-1—tert-butoxycarbonyl-3R-cyclopentylmethylazetidin-2-oneStep AIn a manner analogous to that described in Preparation A, reaction of l-tert-butyl-dimethylsilyl-4S-carboxyazetidin-2-one (l g) with a 2M solution of LDA in THF (4.6 mL)and cyclopentymethyl iodide (2 g; see Preparation E), followed by treatment with benzylbromide (0.93 mL) and triethylamine (1 mL), afforded crude 4S—benzyloxycarbonyl—l-tert-butyldimethylsilyl-3R-cyclopentylmethylazetidin—2—one (6 g).Step BThis material, dissolved in CH3CN and aqueous 2N HCl, was let stirring at room temperatureovernight. The solvent was evaporated and the aqueous phase was extracted with EtOAc1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422063several times. The organic layer was dried over Na2SO4 and evaporated. The residue waspurified by flash cromatography on silica gel (n-hexane/EtC)Ac) to afford 4S-benzyloxy-carbonyl-3R-cyclopenty1methylazetidin-2-one (1.3 g) as a yellow solid.Step CIn a manner analogous to that described in Preparation A (step B), reaction of the materialfrom step B above (1.3 g) with DMAP (21 mg) and Boc2O (566 mg) afforded the titlecompound as a colourless oil (530 mg). H’-NMR (200 MHz, CDCI3) 0.9-2.0 (m, 11 H); 1.45(s, 9 H); 3.15 (m, 1 H); 4.12 (d, 1 H, J= 3.0 Hz); 5.17 and 5.30 (two d, 2 H, J= 12.0 Hz);7.35 (m, 5 H) ppm. FAB- MS 388 (MH)+, 332, 288, 252, 135, 91, 57 rn/z.PREPARATION ECyclopentylmethyl iodideMethanesulfonyl chloride (25.5 mL) was added dropwise to a solution of cyclopentane—methanol (32.4 mL) and triethylamine (46 mL) in dichloromethane (500 ml) at 0 °C. Afterstirring overnight at room temperature, the mixture was sequentially washed with water, 2%hydrochloric acid, 4% aqueous sodium bicarbonate and water again. Following drying oversodium sulfate, the solvent was removed under vacuum, affording crude cyclopentylmethylmethanesulfonate (ca. 50 g) as a colourless oil. A mixture of this product and sodium iodidein acetone (600 ml) was heated at reflux in the dark for 16 hours. After cooling to roomtemperature, the reaction mixture was poured into petrol ether/water 2:] (1.5 L) understirring. The organic layer was washed twice with water, dried (NazSO4) and carefullyconcentrated under reduced pressure (50 mm; temperature of the bath <30 °C). The residuewas distilled in vacuo. The title product was obtained as a light yellow oil (39 g), bycollecting the fraction boiling at 101-102°/70mm.PREPARATION F3-(4-Methoxyphenyl)-1-propyl iodideMethanesulfonyl chloride (31 mL) was added dropwise to a solution of 3-(4-methoxyphenyl)-1-propanol (50 g) and triethylarnine (56 mL) in dichloromethane (800 mL)at 0 °C. The resulting mixture was stirred overnight at room temperature. After washing withwater, 2 % hydrochloric acid and 4 % aqueous sodium bicarbonate, the organic solution wasdried over sodium sulfate and rotoevaporated to yield crude 3-(4-methoxyphenyl)-1-propylmethanesulfonate as a colourless solid (ca. 83 g). This product and sodium iodide (75 g) inacetone (800 mL) were heated at reflux in the dark for 20 hours. Afier cooling to roomtemperature, the reaction mixture was poured into n-hexane/EtOAc/water 1:121 (1.5 L)1015202530CA 02265671 1999-03-09W0 99/02510 PCT/EP98/0422064under stirring. The organic layer was washed with water, diluted aqueous sodiummetabisulfite and 4 % aqueous sodium bicarbonate, then dried (Na2S04) and concentratedunder reduced pressure. The residue was purified by passing it through a short pad of silicagel (eluting with n-hexane/EtOAc 95:5). The title compound was obtained as a pale yellowsolid (75 g).PREPARATION GDicyclohexylmethyl amineA solution of dicyclohexylacetic acid (4.5 g) in dichloromethane (50 mL) was treated withoxalyl chloride (2.5 mL). Addition of a catalytic amount of N,N—dimethylformamide (1 drop)caused immediate gas evolution to take place. The reaction mixture was stirred for 2 hr,then concentrated to dryness. The residue, consisting of crude dicyclohexylacetyl chloride,was dissolved in acetone (45 mL) and treated at 0 °C with a solution of sodium azide (2.6 g)in water (45 mL). After stirring for 1 hr at 0 °C, toluene (100 mL) was added. The organiclayer (mainly containing dicyclohexylacetyl azide as shown by IR absorption band at 2128cm") was separated, washed twice with brine, dried (Na2SO4), then heated at reflux for 2 hr.Following evaporation of the solvent, a waxy solid was obtained which mainly consisted ofdicyclohexylmethyl isocyanate (IR absorption band at 2275 cm"). This crude isocyanate wassuspended in 20% hydrochloric acid (100 mL) and heated at reflux for 8 h. The insolublematerial was filtered off and the filtrate was concentrated in vacuo. The solid residue wastaken up in diethyl ether /1N aqueous NaOH and the aqeous layer was re-extracted withethyl ether. The organic phases were joined and washed with brine, then dried (Na2SO4) androtoevaporated. The title product was thus obtained as a colourless oil (1.8 g). H’-NMR(200 MHZ, DMSO—d5) 0.8-1.8 (m, 22 H); 2.01 (t, 1 H, J= 5.4 Hz) ppm.PREPARATION HN-(tert-Butoxycarbonyl)-3R-isobutyl-L-aspartic acid 4-piperidinamide(“ASPARTIC ROUTE ”2Step AA solution of N-(tert-butoxycarbonyl)—L—aspartic acid 1-benzyl ester (1 g) and piperidine(0.32 mL) in acetonitrile (15 mL) was allowed to react with N—methylmorpholine (0.42 mL)and TBTU (1.2 g) for 6 hr at room temperature. The solvent was removed and the residue,dissolved in EtOAc, was sequentially washed with 2% aqueous hydrochloric acid, saturatedaq. NaHCO3 and brine. After drying (Na2SO4) and rotoevaporation, the resulting yellowish1015202530CA 02265671 1999-03-09wo 99/02510 PCTIEP98/0422065oil was purified by flash chromatography over silica to obtain N-(tert-butoxycarbonyl)-L-aspartic acid 1-benzyl ester-4-piperidinamide (900 mg) as a colorless oil.Step BA solution of the compound from step A above (700 mg) in ethanol (30 mL) was exposed toa hydrogen atmosphere in the presence of 10% Pd-C (70 mg) for 4 hr at room temperature.After filtration (Celite filter aid) and rotoevaporation, N-(tert-butoxycarbonyl)—L-asparticacid 4-piperidinamide (500 mg) was obtained as a yellowish foam.Step CThe material from step B above (200 mg) in dry THF (5 mL) was treated at -40 °C under anitrogen atmosphere with a 2 M solution of LDA in heptane/TI-IF/benzene (Aldrich; 1.07mL). Isobutyl iodide (0.09 mL) was then added, and the mixture lefi rise to roomtemperature. After 4 hr, the reaction mixture was quenched with saturated aqueous NH4Cland extracted with EtOAc. Washing with saturated aqueous NaHCO3, drying over sodiumsulfate and rotoevaporation afforded a mixture of the unreacted starting material and N-(tert-butoxycarbonyl)-3R-isobutyl-L-aspartic acid 4-piperidinamide.Step DThe crude material from step C above in DMF (10 mL) was allowed to react with benzylbromide (0.16 mL) and triethyl amine (0.24 mL) for 1 day at room temperature. Afierworkup, the title compound was isolated by flash chromatography (gradient n-hexana/EtOAcmixtures) to obtain the title compound as a yellowish oil, which is the same as (4-benzyloxy-obtained from the“azetidinone route” and described in Example 1 above. FT-IR (CHCI3) 3433 br (NH), 1753(ester co), 1714 (carbamate co), 1626 (amide CO) cm". H‘- NMR (200 MHz, CDCI3) 0.89and 0.91 (two d, 6 H, J= 6.6 Hz); 1.42 (s, 9 H); 1.2-1.8 (m, 9 H); 3.1-3.5 (m, 5 H); 4.48 (dd,1 H, J= 4.1 and 10.0 Hz); 5.06 and 5.19 (two (1, 2 H, J= 12.4 Hz); 6.45 (d, 1 H, J= 10.0 Hz);7.32 (m, 5 H) ppm.3S-tert-butoxycarbonylamino-2R-isobutyl)succinyl-piperidinarnideEXAMPLE 74Tablets containing the following ingredients may be produced in a conventional manner:Ingredient Per TabletAmine derivative 25.0 mgLactose 125 .0 mgMaize starch 75.0 mgCA 02265671 1999-03-09WO 99/025106 6TalcMagnesium stearateTotal weightEXAMPLE 75PCT/EP98/042204.0 mg1.0 mg230.0 mg5 Capsules containing the following ingredients may be produced in a conventional manner:IngredientAmine derivativeLactose1 0 Maize starchTalcCapsule fill weightPer capsule50.0 mg165.0 mg20.0 mg5.0 mg2400 mg

Claims (12)

67
1. A compound which is an amine derivative of formula (I) wherein W is -CONHOH or -COOH;
R1 and R2, which are the same or different, are each hydrogen or - a group G, which is methyl, C2-C10 alkyl, C2-C10 alkenyl, C3-C7 cycloalkyl, cycloalkyl-C1-C10- alkyl, aryl, aryl-C1-C10-alkyl, aryl-C2-C10-alkenyl, heterocyclyl, heterocyclyl-C1-C10-alkyl or heterocyclyl-C2-C10-alkenyl, the said methyl, alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl groups being unsubstituted or substituted by one to three substituents; or -SO2-G, wherein G is as defined above; or -SO-G, wherein G is as defined above; or -CO-G, wherein G is as defined above; or -COO-G, wherein G is as defined above; or -SO2-NH2, -SO2-NHG or -SO2-NGG', wherein G is as defined above and G', which is the same or different, is as defined above for G, or G and G', together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or - a group -CONH2, -CONHG or -CO-NGG' wherein G and G' are as defined above, or Gand G', together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated 4- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom;
R3 is C1 -C15 alkyl, either unsubstituted or substituted by a C3 -C7 cycloalkyl group, the alkyl and/or the cycloalkyl group being either unsubstituted/ or substituted by one to three substituents selected from methyl, ethyl, C3-C4 linear or branched alkyl, fluoro. chloro, C1-C4 alkoxy, nitro, amino, dimethylamino, carboxy and carboxymethyl; or R3 is a group -R-X-R 1 wherein R is a chemical bond, -CH2-, -(CH2)m- wherein m is an integer from 2 to 5, -CH=CH-, -CH2CH=CH-, phenylene (i.e., -C6H4-), -CH2CH=CH-C6H4-, -CH2CH2CH=CH-, -CH2-CC-, -CH2CH2-CC-, -CH2CH2CH=CH-C6H4- , -CH2-CC-C6H4-, or -CH2CH2-CC-C6H4-; X is a direct bond, an oxygen atom, a sulfur atom, or a sulfinyl -S(O)-, sulfonyl -S(0)2 or carbamoyl group -CONH- or -NHCO-; and R1 is C1-C6 alkyl, C2-C6 alkenyl, phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C2 -C6)-alkenyl, heterocyclyl, orheterocyclyl-(C1-C6)-alkyl, either unsubstituted or substituted by a group selected from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, alkylthio, arylthio, alkylsulfonyl, and arylsulfonyl;
Q, being a secondary or tertiary carboxyamide, is:
- a group -CONHG or -CONGG', wherein G and G' are as defined above; or - a group -CONH-CHGG', wherein G and G' are as defined above; or a group -CONG"-CHGG', wherein G", being the same or different, is defined as G above; or - a group -CONH-CH2-CHGG' or a group -CONG"-CH2-CHGG', wherein G, G' and G"
are as defined above; or - a group -CO-azaheterocyclyl, which is either unsubstituted or substituted at any carbon or additional nitrogen atom, with the proviso that when Q is -CONHG, and G is methyl, alkyl-methyl, cycloalkyl-methyl, aryl-methyl or hetherocyclyl-methyl, then such methyl or substituted methyl cannot be further substituted by a group -(CH2), -CO2H, wherein t is 0, or esters and amides thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
2. A compound as claimed in claim 1 wherein the amine derivative has the formula (I'):

wherein:
W is -CONHOH or -COOH;
R1 and R2 are:
- both hydrogen; or - both C1-C4 alkyl, or R1 is hydrogen or methyl, and R2 is a group G which is:
- C1-C10 alkyl or C2-C10 alkenyl, either unsubstituted or substituted by C3-C7 cycloalkyl, or by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, amino, methylamino, dimethylamino, -CONH2, -CONHCH3 or -CONHC(CH3)3, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl group may in turn be substituted by chloro, fluoro, methoxy or methyl; or - C3-C7 cycloalkyl; or - an aryl group which is optionally substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, Cl-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, phenyl, benzyl, phenethyl, phenpl opyl, naphthyl and pyridyl, and wherein any phenyl, naphthyl and pyridyl ring may in turn be substituted by one to three substituents selected from chloro, fluoro, methyl, hydroxy, methoxy, amino, methylamino and dimethylamino; or - an unsaturated heterocyclyl group selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, benzimidazolyl, indazolyl, chromenyl, indolyl, oxindolyl, quinolyl, isoquinolyl, isoindolyl, cinnolinyl and purinyl, each of which is optionally substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or - a saturated or partially saturated heterocyclyl group selected from pyrrolidinyl, tetrahydrothienyl, tetrahydrofuryl, aziridinyl, oxiranyl, azetidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, tetrahydropyranyl, 1-oxo-2-isoindolyl, tetrahydroisoquinolyl, hydantoinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepinyl and thiazolidinyl, wherein any ring nitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a carbonyl, and any ring sulfur may be oxidized as a sulfoxide or sulfone; and the derivates thereof substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or - C1-C10 alkyl, substituted by any of the unsaturated or saturated heterocyclyl groups as defined above, wherein any ring nitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a carbonyl, and any ring sulfur may be oxidized as a sulfoxide or sulfone; or a derivative thereof substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, -CONH2, -CONHCH3 and -CONHC(CH3)3, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or - C1-C10 alkyl, substituted by any of the aryl group as defined above, and the derivates thereof substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or R1 is hydrogen or methyl, and R2 is -SO2-G, wherein G is as defined above; or R1 is hydrogen or methyl, and R2 is -CO-G, wherein G is as defined above; or R1 is hydrogen or methyl, and R2 is -CO-O-G, wherein G is as defined above; or R1 is hydrogen or methyl, and R2 is -SO2-NH2, -SO2-NHG or -SO2-NGG', wherein G is as defined above and G', which is the same or different, is as defined above for G; or R1 is hydrogen or methyl, and R2 is -SO-NH-G, wherein G is as defined above; or R1 is hydrogen or methyl, and R2 is -CONHG or -CONGG', wherein G is as defined above and G', which is the same or different, is as defined above for G; or R1 and R2, taken together with the nitrogen atom to which they are attached, form a 3- to 7-membered azahetprocyclyl ring, optionally containig N, O, S or SO2 as an additional ring member, which may be substituted by oxo on one or two carbon ring atoms adjacent to the linking nitrogen atom, and which is optionally fused with a benzene ring, the azaheterocyclyl group being either unsubstituted or substituted at one or more carbon and/or nitrogen atoms by chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, phenyl, 4-fluorophenyl, benzyl, 4-fluorobenzyl, alpha-methylbenzyl, methylenedioxyphenyl, 2-phenethyl, 2-(4-fluolopllenyl)ethyl, pipero.lyl, carbamoyl, -CONHCH3, -CONHC(CH3)3, -CONH-(4-fluorophenyl), -COMH-pyridyl, -CONH-(methylenedioxy)phenyl -CONH-piperonyl;
or R1 is hydrogen or methyl and R2 is -SO2-azaheterocyclyl, wherein azaheterocyclyl is as defined above; or R1 is hydrogen or methyl, and R2 is -CO-azaheterocyclyl, wherein azaheterocyclyl is as defined above, R3 is -CH2-alkyl, -(CH2)n-cycloalkyl, -(CH2)n-O-alkyl, -(CH2)n-O-(CH2)m-cycloalkyl.
-(CH2)n-O-(CH2)m-aryl, -(CH2)n-O-(CH2)m-heterocyclyl, -(CH2)D-S-alkyl, -(CH2)n-s-(CH2)m-cycloalkyl, -(CH2)n-S-(CH2)m-aryl, -(CH2)n-S-(CH2)m-heterocyclyl, -(CH2)n-SO-alkyl, -(CH2)n-SO-(CH2)m-cycloalkyl, -(CH2)n-SO-(CH2)m-aryl, -(CH2)n-SO-(CH2)m-heterocyclyl, (CH2)n-SO2-alkyl, -(CH2)n-SO2-(CH2)m-cycloalkyl, -(CH2)n-SO2-(CH2)m-aryl, -(CH2)n-SO2-(CH2)m-heterocyclyl, -(CH2)n-co-alkyl, -(CH2)n-CO-(CH2)m-cycloalkyl -(CH2)n-co-(CH2)m-aryl or -(CH2)n-CO-(CH2)m-heterocyclyl, wherein alkyl, cycloalkyl, aryl and heterocyclyl are as defined above, and n and m, being the same or different, are zero or an integer of 1 to 5, and wherein the alkyl, cycloalkyl, aryl and heterocyclyl groups are optionally substituted by one to three substituents selected from chloro, fluoro, cyano, cyanomethyl, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenyl, tolyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-phenoxyphenyl, 4-(4-pyridyl)oxyphenyl, pyridyl; or R3 is selected from isobutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and cyclopentylmethyl; or R3 is selected from 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, wherein the phenyl group is either unsubstituted or substituted by chloro, fluoro, cyano, cyanomethyl, methyl, ethyl, propyl, butyl, mesyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, benzyloxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-pyridyl, 4-pyridyloxy; or R3 is selected from phenylsulfonylmethyl or phenylsulphonylethyl, wherein the phenyl group is either unsubstituted or substituted by chloro, fluoro, cyano, cyanomethyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, benzyloxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-pyridyl, 4-pyridyloxy;
Q is:
- a group -CONHG, -CONGG', -CONH-CHGG', CON(CH3)-CHGG', -CONH-CH2-CHGG', or -CON(CH3)-CH2-CHGG', wherein G and G', being as defined above, are selected from C1-C6 straight or branched alkyl, C5-C6 cycloalkyl, phenyl, tolyl, methylenedioxyphenyl, piperonyl and pyridyl, either unsubstituted or substituted by one to three substituents selected from chloro, fluoro, hydroxy, hydroxymethyl, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, -CONH2, -CONHCH3, -CONHC(CH3)3, -CONH(4-fluorophenyl), -CONH-pyridyl, -CONH-(methylenedioxy)phenyl, -CONH-pipelonyl, carbomethoxy, carbethoxy, or a keto group -CO-R II, wherein RD, being as defined above, is selected from C1-C4 alkyl, phenyl, fluorophenyl, chlorophenyl,methylenedioxyphenyl, naphthyl, piperonyl, or a sulfone -(CH2)n-S02-R II, wherein n and R II
are as defined above, or a sulfonamide -(CH2)n-SO2-NH2, -(CH2)n-SO2-NHRn, -(CH2)n-SO2-NR II R II, wherein n, R II and R II are as defined above, including the special case wherein R II
and R II, taken together with the nitrogen atom to which they are attached, constitute an azaheterocyclyl ring, as defined above; or - a group -CO-azaheterocyclyl, wherein azaheterocyclyl, being as defined above, is either unsubstituted or substituted by one to three substituents selected from hydroxy,hydroxymethyl, C1-C4 alkoxy, carbamoyl, carbomethoxy, carbethoxy, mesyl, C1-C6 linear or branched alkyl, trifluoromethyl, C3-C7 cycloalkyl, aryl, heterocyclyl and aryl-(C1-C3)alkyl or heterocyclyl-(C1-C3)alkyl; or said azahrterocyclyl group is substituted by a group -CONH-R II, wherein R II, being as defined above, is selected from methyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-piperidyl, 2-thiazolyl, 1-naphthyl, 2-naphthyl, 3-quinolyl, 5-quinolyl, 3-isoquinolinyl, 5-isoquinolyl, 3-quinuclidinyl, methylenedioxyphenyl, piperonyl, 2-benzimidazolyl and 5-tetrazolyl; or said azaheterocyclyl group is substituted by a keto group -CO-R II, or by a carbinol group of formula -CH(OH)-R II, wherein R II, being as defined above, is selected from C1-C4 alkyl, phenyl, fluorophenyl, chlorophenyl, methylenedioxyphenyl, naphthyl, piperonyl, or by a sulfone -(CH2)n-SO2-R II, wherein n and R II are as defined above, or by a sulfonamide -(CH2)n-SO2-NH2, -(CH2)n-S02-NHR II, -(CH2)n-SO2-NR II R III, wherein n, R II and R III are as defined above, including the special case wherein R II and R III, taken together with the nitrogen atom to which they are attached, constitute an azaheterocyclyl ring, as defined above;
and the salts and solvates thereof.
3. A compound of formula (II'), which is a cyclic prodrug of a compound of formula (I') as claimed in claim 2:

wherein R2, R3 and Q are as defined in claim 2, T is methyl or a hydrogen atom, and T' is methyl, C2-C4 lower alkyl, phenyl, benzyl, optionally substituted by one to three substituents selected from by C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, methylarnino, dimethylamino, chloro and fluoro.
4. A compound as claimed in claim 2 wherein R3 is selected from isobutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopentylmethyl; or is selected from 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 3-(p-diphenyl)propyl, 3-(4-pyridyl-4-phenyl)propyl, phenoxymethyl, 2-phenoxyethyl, 2-(phenylmethoxy)ethyl, 3-phenoxypropyl, 4-(phenylmethoxy)butyl,phenylsulfonylmethyl, 2-(phenylsulfonyl)ethyl, 3-(4-benzoylphenyl)propyl, including derivatives thereof substituted at any phenyl carbon atom by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkyl and C1-C4 alkoxy.
5. A process for producing a compound as defined in claim 1, comprising:
(a) reacting a beta-lactam compound of formula (III):

wherein R2 and R3 are as defined in claim 1 and W' is COOH, CONHOH, or a protected derivative thereof, with a primary or secondary acyclic amine of formula G-NH2, GG'NH, GG'CH-NH2, GG'CH-NHCH3, GG'CH-CH2-NH2, or GG'CH-CH2-NHCH3, wherein G and G' are as defined in claim 1, or with an amine of formula G-NH2, GG'NH, GG'CH-NH2 or GG'CH-CH2-NH2, wherein G and G' are as defined above; including the special case wherein G and G', taken together with the nitrogen atom to which they are attached, constitute an azaheterocyclyl ring, wherein azaheterocyclyl is as defined in claim 1, to obtain a compound of formula (IV):

wherein W', R2 and R3 are as defined above and Q is defined as in claim 1; and (b) converting said compound of formula (IV) into a compound of formula (I):

wherein W, R1, R2, R3 and Q are as defined in claim l; and (c) if desired, removing the protecting groups and/or if desired, converting any of the groups W, R, R1 R2, R3 and Q into different groups W, R, R1, R2, R3 and Q at the end or at any stage of the process.
6. A process for producing a compound as defined in claim 2, which process comprises (a) reacting a beta-lactam compound of general formula (III'):

wherein R2 and R3 are as defined in claim 2, and W' is COOH or CONHOH, or a protected derivative thereof, with an amine as defined in claim 5, to obtain a compound of formula (IV'):

wherein W', R2, R3 and Q are as defined in claim 2; and (b) converting this compound of formula (IV') into a compound of formula (I'):

wherein W, R1, R2, R3 and Q are as defined in claim 2; and (c) if needed, removing the protecting groups and/or, if desired, converting any of the groups W, R, R1, R2, R3 and Q into different groups W, R, R1, R2, R3 and Q at the end or at any stage of the process.
7. A process for producing a compound of formula (I) as defined in claim 1, which process comprises:
(a) reacting an aspartic acid derivative of formula (V):

wherein W' is either carboxy or a protected derivative thereof, Q' is either Q as described above, or carboxy or protected carboxy, and R1, R2 are as defined in claim 1, with a reagent of formula R3-X, wherein R3 is as defined in claim 1, and X is chloro, bromo or iodo, or sulfonyloxy, e.g. triflate or mesylate, to obtain a compound of formula (VI):

wherein W', R1, R2, R3 and Q' are as described above; and (b) converting of such compound of formula (VI) into a compound of formula (I):

wherein W, R1, R2, R3 and Q are as described above; and (c) if needed, removing the protecting groups and/or, if desired, converting any of the groups W, R, R1, R2, R3 and Q into different groups W, R, R1, R2, R3 and Q at the end or at any stage of the process.
8. A pharmaceutical composition which comprises a pharmaceutically acceptable diluent or carrier and, as an active ingredient, a compound as defined in any of claims 1 to 4.
9. A compound as defined in any one of claims 1 to 4 for use in a method of treatment of the human or animal body by therapy or prophylaxis..
10. A compound as claimed in claim 9 for use as an inhibitor of a matrix metalloproteinase.
11. A compound as claimed in claim 9 for use as an inhibitor of the release of TNF-.alpha. from cells.
12. A compound as claimed in any one of claims 9, 10 and 11 for use in the therapeutic or prophylactic treatment of a tumoural or inflammatory disease.
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