MXPA00012854A - Hydroxamic acid derivatives as inhibitors of the production of human cd23 and ofthe tnf release - Google Patents

Abstract

Compounds of formula (I) wherein:R is methyl substituted by one to three groups selected from alkyl, aryl, alkenyl, and alkynyl;n is 0 or 1;R1 is arylmethyl or heterocyclylmethyl;R2 is alkyl, alkenyl, cycloalkyl or cycloalkenyl;and R3 is hydrogen, alkyl, alkenyl, alkynyl or aryl;are useful in the treatment of disorders mediated by s-CD23.

Description

HYDROXAMIC ACID DERIVATIVES AS INHIBITORS OF THE PRODUCTION OF HUMAN CD23 PROTEIN AND RELEASE OF THE TUMOR NECROSIS FACTOR DESCRIPTIVE MEMORY This invention relates to novel inhibitors of the formation of soluble human CD23, and to its use in the treatment of conditions associated with excessive production of soluble CD23 (s-CD23), such as autoimmune diseases and allergies. The compounds of the invention are also inhibitors of the release of tumor necrosis factor (TNF). CD23 (the low affinity IgE receptor FceRII, Blasto 2), is a 45 kDa type II integral protein expressed on the surface of a variety of mature cells, including B and T lymphocytes, macrophages, natural killer cells, cells of Langerh? ns, monocytes and platelets (Delespesse et al., Adv. Immunol., 49 [1991] 149-191). There is also a CD23 type molecule in eosinophils (Grangette et al., J. Immunol 143 [1989] 3580-3588). CD23 has been implicated in the regulation of the immune response (Delespesse et al., Immunol. Rev., 125 [1992] 77-97). Human CD23 exists as two differentially regulated isoforms, a and b, which are different only at the intracellular N-terminal amino acids (Yokota et al., Cell, 55 [1988] 611-618). In man, the constitutive isoform is found only in B lymphocytes, while type b, produced by IL4, is found on all cells capable of expressing CD23. It is known that intact CD23 bound to cell (¡-CD23), undergoes segmentation from the surface of the cell, leading to the formation of a number of well-defined soluble fragments (S-CD23), which are produced as a result of a complex sequence of proteolytic events, the mechanism of which is still poorly understood (Bourget et al., J. Biol. Chem. 269 [1994] 6927-6930). Although it has not been tested so far, it is believed that the main soluble fragments (Mr 37, 33, 29 and 25 kDa) of these proteolytic events, all of which retain the C-terminal lectin domain common to ¡-CD23, occur sequentially by means of the initial formation of the 37 kDa fragment (Letellier et al., J. Exp. Med., 172 [1990] 693-700). An alternative intracellular cleavage pathway leads to a stable 16 kDa fragment in the C terminal domain of -CD23 (Grenier-Brosette et al., Eur. J. Immunol., 22 [1992] 1573-1577). Several activities have been attributed to human-membrane bound CD23 -CD23, all of which have been shown to play a role in the regulation of IgE. Particular activities include: a) presentation of antigens, b) IgE-mediated eosinophil cytotoxicity, c) return of B cells to germinal centers of lymph nodes and spleen, and d) down-regulation of IgE synthesis (Delespesse et al. Adv. Immunol. 49, [1991] 149-191). The three highest molecular weight soluble CD23 fragments (Mr 37, 33 and 29 kDa) have multifunctional cytokine properties that appear to play a major role in the production of IgE. In this way, excessive S-CD23 formation has been implicated in the overproduction of IgE, the hallmark of allergic diseases such as extrinsic asthma, rhinitis, allergic conjunctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould, Nature, 366, [1993] 421-428). Other biological activities attributed to S-CD23 include the stimulation of B cell growth and the induction of mediator release from monocytes. In this way, elevated levels of S-CD23 have been observed in the serum of patients who have B-chronic lymphocytic leukemia (Sarfati et al., Blood, 71 [1988] 94-98) and in synovial fluids of patients with rheumatoid arthritis. (Chomarat et al., Arthritis and Rheumatism, 36 [1993] 234-242). A number of sources suggest that there is a role for CD23 in inflammation. First, it has been reported that sCD23 binds to extracellular receptors that when activated are involved in cell-mediated inflammation events. Thus, it is reported that rCD23 directly activates the release of monocytic TNF, IL-1 and IL-6 (Armant et al., Vol 180, J. Exp. Med., 1005-1011 (1994)). It has been reported that CD23 interacts with the adhesion molecules of B2-integrin, CD11b and CD11c, in monocytes / macrophages (S. Lecoanet-Henchoz et al., Immunity, vol.; 119-125 (1995)) which activate the release of NO2", hydrogen peroxide and cytokine (IL-1, IL-6 and TNF) Finally, IL-4 or IFN induce the expression of CD23 and its release as sCD23 by human monocytes The ligation of the membrane-bound CD23 receptor with immune complexes IgE / anti-IgE or anti-CD23 mAb activates the production of cAMP and IL-6 and the formation of thromboxane B2, demonstrating a role mediated by CD23 receptors in Inflammation Due to these various properties of CD23, compounds that inhibit the formation of S-CD23 must have double actions of a) increasing inhibition by negative feedback of IgE synthesis by maintaining ¡-CD23 levels on the surface of B cells and b) inhibiting the immunostimulatory cytokine activities of soluble S-CD23 fragments of higher molecular weight (Mr 37, 33 and 29 kDa) In addition, the inhibition of CD23 cleavage must mitigate the activation of monocytes induced by S-CD23 and the formation of mediators, thereby reducing the inflammatory response. TNFa is a pro-inflammatory cytokine that is released from stimulated cells by specifically cutting a signal sequence of 76 amino acids in the inactive precursor to generate the mature form. It has been reported that the TNFa cut is carried out by a metalloprotease (Gearing, AJH et al., (1994) Nature 370, 555-557; McGeehan, GM et al., (1994) Nature 370, 558-561; Mohler, KM and others, (1994) Nature 370, 218-220). The compounds reported to inhibit TNFα cleavage by the TNF-processing enzyme can be broadly described as matrix metalloprotease inhibitors, particularly of the hydroxamic acid class.

TNFa is induced in a variety of cell types in response to bacteria, endotoxins, various viruses and parasites, so a physiological function assigned to TNFa is a contribution to the inflammatory response to acute infection by bacteria, parasites, etc. (Dinarello, C.A. (1992) Immunol., 4, 133-145). Overproduction of TNFα has been implicated in disease states such as rheumatoid arthritis, septic shock, Crohn's disease and cachexia (Dinarello, 1992). The inhibition of the processing of TNFa to the mature and active form would therefore be beneficial in the treatment of these inflammatory disorders. TNFa can also contribute to tissue destruction in autoimmune diseases, although it is not a starting factor in these diseases. Confirming the importance of TNFa in rheumatoid arthritis, TNFα antibodies have been shown to reduce the severity of the disease in short-term studies in rheumatoid arthritis models (Elliott, MJ, et al., (1993) Arthrit. Rheum. 12, 1681- 1690; Elliott et al., (1994) Lancet 344, 1125-1127). International patent application No. WO 96/02240 (Smithlkline Beecham foot) discloses that compounds that inhibit the action of matrix metalloproteases (eg, collagenase, stromelysin and gelatinase) are effective inhibitors of the release of soluble human CD23 transfected in Human cell culture systems. British patent application No. 9601041.8 (Smithkline Beecham foot) discloses that certain compounds of the formula (I) are effective inhibitors of the release of transfected human soluble CD23 in human cell culture systems: (i) According to the present invention, there is provided a compound of the formula (I) above, wherein: n is O or l; R is methyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkynyl; R1 is arylmethyl or heterocyclylmethyl; R 2 is alkyl, alkenyl, aryl, cycloalkyl or cycloalkenyl; and R3 is hydrogen, alkyl, alkenyl, alkynyl or aryl. The alkyl, alkenyl and alkynyl groups referred to herein include straight and branched groups containing up to six carbon atoms, and are optionally substituted with one or more groups selected from the group consisting of aryl, heterocyclyl, Cth-6 alkylthio, alkoxy of d-β, arylalkoxy of C 1-6, arylalkylthio of C-α-6, amino, mono- or dialkylamino of d-β, cycloalkyl, cycloalkenyl, carboxy and esters thereof, hydroxy and halogen.

The cycloalkyl and cycloalkenyl groups referred to herein include groups having from three to eight carbon atoms and are optionally substituted as described hereinabove with alkyl, alkenyl and alkynyl groups. When used herein, the term "aryl" means individual and fused rings suitably containing from 4 to 7, preferably 5 or 6, ring atoms in each ring, rings which may each be unsubstituted or substituted with, for example, up to three substituents. A system of fused rings can include aliphatic rings and only needs to include an aromatic ring. Suitable aryl groups include phenyl and naphthyl, such as 1-naphthyl or 2-naphthyl. Suitably, any aryl group, including phenyl and naphthyl, may be optionally substituted with up to five, preferably up to three, substituents. Suitable substituents include halogen, d-β alkyl, aryl, C 1 -6 arylalkyl, d-β alkoxy. C -? - 6 alkoxy of C -? - 6, haloalkyl of Ci-β, arylalkoxy of d-β, hydroxy, nitro, cyano, azido, amino, mono- and di-? / - alkylamino of C? -6, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-? / - alkylcarbamoyl of d-6, alkoxycarbonyl of d-β, aryloxycarbonyl, ureido, guanidino, sulfonylamino, aminosulfonyl, alkylthio of d-β, Ci-β alkylsulfinyl. alkylsulfonyl of d-6, heterocyclyl and heterocyclylalkyl of d-β. further, two adjacent ring carbon atoms can be linked by an alkylene chain of C3-5 to form a carbocyclic ring. When used herein the terms "heterocyclyl" and "heterocyclic" suitably include, unless otherwise defined, individual and fused aromatic and non-aromatic rings, suitably containing up to four heteroatoms in each ring, each of which which is selected from oxygen, nitrogen and sulfur, rings which may be unsubstituted or substituted with, for example, up to three substituents. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A system of fused heterocyclic rings can include carbocyclic rings and only needs to include a heterocyclic ring. Preferably, a substituent for a heterocyclic group is selected from halogen, d-6 alkyl, d-β arylalkyl, β-alkoxy, d-β-alkyl alkoxy, C?-6 haloalkyl, hydroxy, amino, mono- and di-? / - alkylamino of d-β, acylamino, carboxy salts, carboxy esters, carbamoyl, mono- and di- / V-alkylcarbonyl of C? -6, aryloxycarbonyl, alkoxycarbonyl of d-6-alkyl of d-ß, aryl, oxy, ureido, guanidino, sulfonylamino, aminosulfonyl, dithio alkylthio, d-β alkylsulfinyl, C1.6 alkylsulfonyl, heterocyclyl and heterocyclylalkyl groups of C-α-6- In a particular aspect of the invention, R is allyl, propyl, ethyl or isopropyl, and / or R1 is 1- or 2-naphthylmethyl; and / or R2 is t-butyl; and / or R3 is hydrogen or methyl. In a further aspect of the invention, each of R a R 3 is selected from the group consisting of the values assigned to it in the examples below herein. Preferably, the compound of the formula (I) of the invention is selected from the group consisting of the compounds described in the examples below herein. According to a further aspect, the present invention provides the use of a compound of the formula (I) in the production of a medicament for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders and autoimmune diseases, in which it is involved the overproduction of S-CD23. In another aspect, the invention provides a method for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders and autoimmune diseases, in which the overproduction of S-CD23 is involved, which method comprises the administration of a compound of the formula ( I) to a human or non-human mammal that requires it. The invention also provides a pharmaceutical composition for the binding or prophylaxis of disorders such as allergy, inflammatory disorders and autoimmune diseases, in which the overproduction of S-CD23 is involved, which comprises a compound of the formula (I) and optionally a pharmaceutically acceptable vehicle for the same. According to a further aspect, the present invention provides the use of a compound of the formula (I) in the production of a medicament for the treatment or prophylaxis of conditions mediated by TNF, including, but not limited to, inflammation, fever, cardiovascular effects, lHM IH £ YI * dí -i-i hemorrhages, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, graft-versus-host reactions and autoimmune diseases. In a further aspect, the invention provides a method for the treatment or prophylaxis of conditions mediated by TNF, which method comprises the administration of a compound of the formula (I) to a human or non-human mammal that requires it. The invention also provides a pharmaceutical composition for the treatment or prophylaxis of conditions mediated by TNF, which comprises a compound of the formula (I) and optionally a pharmaceutically acceptable carrier therefor. Particular inflammatory disorders include CNS disorders such as Alzheimer's disease, multiple sclerosis and multi-infarct dementia, as well as the sequelae mediated by embolism inflammation and cranial trauma. It is understood that pharmaceutically acceptable salts, solvates and other pharmaceutically acceptable derivatives of the compound of the formula (I) are also included in the present invention. The salts of the compounds of the formula (I) include, for example, acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, iodides, p-toluenesulfonates, phosphates, sulphates, acetates, trifluoroacetates, propionates, citrates, maleates. , fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.

The salts can also be formed with bases. Said salts include salts derived from inorganic or organic bases, for example, alkali metal salts such as sodium or potassium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts. It has surprisingly been found that the compounds of the present invention are potent and selective inhibitors of the processing of CD23 and the release of TNF, while exhibiting reduced collagenase inhibitory activity compared to the prior art compounds mentioned above. The compounds of the invention also exhibit suitable in vivo absorption properties by means of the oral route. The compounds of the invention can be prepared by using any suitable conventional method, for example by analogy with the methods described in patent publication WO 97/02239 (BBL). Accordingly, a further aspect of the invention provides a method for preparing a compound of formula (I) as defined hereinbefore, which comprises: a) deprotecting a compound of formula (II): (N) wherein n and R to R3 are as defined hereinabove, and X is a protecting group such as benzyl or trimethylsilyl, or b) reacting a compound of the formula (III): (III) wherein n and R to R3 are as defined hereinabove, and any hydroxy group is optionally protected, with hydroxylamine or a salt thereof, or c) converting a compound of the formula (I) to a different compound of formula (I) as defined hereinabove. The compounds of the formulas (II) and (III) are novel and form a further aspect of the invention. The compounds of the formula (II) can be prepared from compounds of the formula (III) by reaction with a protected hydroxylamine. The compounds of the formula (III) having one or more protected hydroxy groups can be converted by hydrolysis to a corresponding compound of the unprotected formula (III). Suitable protecting groups for a hydroxamic acid are well known in the art, and include benzyl, trimethylsilyl, t-butyl and t-butyldimethylsilyl.

Suitable protecting groups for a carboxylic acid are well known in the art and include t-butyl, benzyl and methyl. The compounds of the formula (III) can be prepared by reacting a compound of the formula (IV) or (IVa): (IV) (IVa) wherein R and R1 are as defined above in the present and Y is a protective group for carboxyl, with a compound of the formula (V): (V) wherein n, R2 and R3 are as defined hereinbefore, or an activated derivative thereof. If (IVa) is used then the alkylation or subsequent acylation of the hydroxyl group may be required. The compounds of the formula (IV) can be prepared by protecting a corresponding compound in which Y is hydrogen, which in turn can be prepared: a) by reacting a compound of the formula (VI): (SAW) wherein R1 is as defined hereinabove and Z is a protective group for carboxyl, with an alkylating agent; and b) removing the protective groups. Compounds of the formula (VI) in which Zond is hydrogen can be prepared by reacting a diester (such as the dimethyl or diethyl ester) of 2-hydroxysuccinic acid with a compound of the formula R1X 'in the presence of a strong base such as diisopropylamide of lithium, wherein X 'is a leaving group such as bromine or iodine, and then hydrolyzing the resulting compound to remove the ester groups. The isomers, including stereoisomers, of the compounds of the present invention can be prepared as mixtures of such isomers iMi-fii? láiMiiMtiiWta or as individual isomers. The individual isomers can be prepared by any suitable method, for example, individual stereoisomers can be prepared by stereospecific chemical synthesis starting from chiral substrates or separating mixtures of diastereomers using known methods. In a preferred aspect, the invention provides compounds of the formula (IA): (1A) It is preferred that the compounds be isolated in substantially pure form. As indicated herein, an inhibitor of the formation of soluble human CD23 has useful medical properties. Preferably, the active compounds are administered as acceptable pharmaceutical compositions. The compositions are preferably adapted for oral administration. However, they can be adapted for other modes of administration, for example in the form of a spray, aerosol or other method for conventional inhalation, to treat disorders of the respiratory tract; or parenteral administration for patients suffering from heart failure.

Other alternative modes of administration include sublingual or transdermal administration. The compositions may be in the form of tablets, capsules, powders, granules, troches, suppositories, reconstitutable powders or liquid preparations, such as oral or sterile parenteral solutions or suspensions. To obtain administration consistency it is preferred that a composition of the invention be in the form of a unit dose. The unit dosage forms for oral administration may be tablets and capsules, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; rattle lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. The solid oral compositions can be prepared by conventional mixing, filling or tapping methods. Repeated mixing operations can be used to distribute the active agent uniformly in compositions employing large amounts of fillers. Said operations are of course conventional in the art.

The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Said liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats.; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavoring or coloring agents. For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, and, depending on the concentration used, they can be suspended or dissolved in the vehicle. To prepare solutions the compound can be dissolved in water for injection and sterilized in a filter before filling it in a suitable vial or vial and sealing. Suitably, auxiliaries such as a local anesthetic, a preservative and buffer can be dissolved in the vehicle. To increase stability, the composition can be frozen after placing it in the bottle, and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization can not be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in the sterile vehicle. Suitably, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions of this invention may also be suitably presented for administration to the respiratory tract as an inhalation or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the active compound suitably have diameters of less than 50 microns, preferably less than 10 microns, for example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns. Where appropriate, small amounts of other anti-asthmatics or bronchodilators may be included, for example, sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline, and corticosteroids such as prednisolone and adrenal stimulants such as ACTH. The compositions may contain from 0.1% to 99% by weight, preferably 10-60% by weight, of active material, depending on the method of administration. A scale that is preferred for inhaled administration is 10-99%, especially 60-99%, for example 90, 95 or 99%. The microfine powder formulations can be suitably administered in an aerosol as a metered dose or by means of an appropriate breath activated device. Suitable metered dose aerosol formulations comprise conventional propellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulfate, and density modifiers such as sodium chloride. Suitable solutions for a nebulizer are isotonic sterilized solutions, optionally buffered, for example at a pH of between 4 and 7, containing up to 20 mg / ml of compound, but more generally 0.1 to 10 mg / ml, for use with equipment of standard nebulization. An effective amount will depend on the relative efficacy of the compounds of the present invention, the severity of the disorder being treated and the weight of the patient. Suitably, a unit dose form of a composition of the invention may contain from 0.1 to 1000 mg of a compound of the invention (0.001 to 10 mg by inhalation) and more usually from 1 to 500 mg, for example 1 to 25 or 5 to 500 mg. Such compositions may be administered one to six times a day, more commonly 2 to 4 times a day, in a manner such that the daily dose is from 1 mg to 1 g for a 70 kg human adult, and more particularly 5 to 500 mg. This is on the scale of approximately 1.4 x 10"2 mg / kg / day to 14 mg / kg / day, and very particularly on the scale of approximately 7 x 10" 2 mg / kg / day to 7 mg / kg / day. The following examples illustrate the invention but do not limit it in any way.

Biological test methods Procedure 1: The ability of test compounds to inhibit the release of soluble CD23 was investigated by the use of the following procedure.

CD23 Cutting Activity Test on RPMI 8866 Cell Membrane Membranes of RPMI 8866 cells, a line of B cells transformed with Epstein-Barr virus (Sarfati et al., Immunology 60 [1987] 539-547) expressing high levels of CD23, are purified using an aqueous extraction method. Cells resuspended in homogenization buffer (20 mM HEPES pH7.4, 150 mM NaCl, 1.5 mM MgCl2, 1 mM DTT) are disrupted by cavitation with N2 in a Parr pump, and the membrane fraction of plasma mixed with other membranes it is recovered by centrifugation at 10,000 Xg. The light pellet is resuspended in 0.2 M potassium phosphate, pH 7.2 using 2 ml per 1-3 g of wet cells and the nuclear pellet is discarded. The membranes are further divided by dividing them between Dextran 500 (6.4% w / w) and polyethylene glycol (PEG) 5000 (6.4% w / w) (ref), in sucrose 0.25 M in a total of 16 g per 10-15 mg of protein membrane [Morre and Morre, BoiTechniques, 946-957 (1989)]. The phases are separated by brief centrifugation at 1000 Xg and the PEG phase (upper) is collected, diluted 3-5 times with 20 mM potassium phosphate buffer, pH7.4, and centrifuged at 100,000 Xg to recover the membranes in that phase. The pellet is resuspended in phosphate-buffered saline, and consists of plasma membranes enriched 3-4 times, as well as some other cell membranes (eg, lysosomes, Golgi). Aliquots of the membranes are formed and stored at -80 ° C. Fractionation at 6.6% in Dextran / PEG produces plasma membranes enriched 10 times. The fractionated membranes are incubated at 37 ° C for up to 4 hours to produce CD23 fragments which are separated from the membrane by filtration in 0.2 micron Durapore filter plates (Millipore), after quenching the test with a preparation 1 of 5 μM of P 30994. The sCD23 released from the membrane is determined using the EIA equipment from The Binding Site (Birmingham, UK) or a similar one using MHM6 anti-CD23 mAb [Rowe et al., Int. J. Cancer, 29, 373 -382 (1982)] or another anti-CD23 mAb as the capture antibody in a sandwich ElA. The amount of soluble CD23 made per 0.5 μg membrane protein in a total volume of 50 μl of phosphate buffered saline is measured by ElA and compared to the amount made in the presence of various concentrations of inhibitors. The inhibitors are prepared in solutions of water or dimethyl sulfoxide (DMSO) and the final DMSO concentration is not more than 2%. The IC50 are determined by curve fitting as the concentration where 50% inhibition of sCD23 is observed in relation to the difference in sCD23 among the incubated controls without inhibitor.

Method 2: The ability of test compounds to inhibit collagenase was investigated using the following procedure.

Collaqase inhibition test The potency of the compounds to act as collagenase inhibitors was determined by the method of Cawston and Barrett (Anal. Biochem 99, 340-345, 1979), incorporated herein by reference, with a 1 mM solution of the inhibitor being tested or dilutions thereof, was incubated at 37 ° C for 18 hours with collagenase and human recombinant collagenase, from cloned synovial fibroblasts, expressed and purified from E. coli , (buffered with 150 mM Tris, pH 7.6, containing 15 mM calcium chloride, 0.05% Brij 35, 200 mM sodium chloride and 0.02% sodium azide). Collagen was acetylated 3H type 1 bovine collagen prepared by the method of Cawston and Murphy (Methods in Enzymology 80, 711, 1981). The samples were centrifuged to pellet undigested collagen and an aliquot of the radioactive supernatant was removed for testing in a scintillation counter as a measure of hydrolysis. Collagenase activity was compared in the presence of 1 mM inhibitor, or dilution thereof, with activity in a control without inhibitor, and the results are reported as the concentration that effects 50% of the collinegue (IC50).

Method 3: The ability of the test compounds to inhibit the release of TNF using the following procedure was investigated.

Test for the inhibition of TNFa release from human monocytes stimulated by lipopolysaccharide endotoxin ÍLPSJ Human monocytes, cultured in RPM I 1640 medium supplemented with 10% fetal calf serum, centrifuged at 1000 Xg for 5 minutes and then resuspend in medium at 2 X 106 cells / ml. Aliquots of the cell suspension are formed in 24-well plates, 1 ml per well. The compounds to be tested are dissolved in concentrated dimethyl sulfoxide (DMSO) and added to the culture with the final concentration of 0.1% DMSO. The compounds are added to the cells in triplicate cavities. The release of TNFa is stimulated by the addition of LPS to the cells at a final concentration of 200 ng / ml. Suitable control cultures are also established in triplicate. The plates are incubated for 18-20 hours at 37 ° C, 5% CO2 and then centrifuged at 1000 Xg for 5 minutes. A specific ELISA test for human TNFα (Smithkline Beecham) is used to measure TNF levels in cell-free culture supernatants.

Preparation of N-f4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) -succiniH-S-ter-leucinamide a) 3S-t-Butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone (t-Butyl- (3R) -carboxy-4- (2-naphthyl) butyrate (10 g, 31.9 mmol) in THF (160 mL) was stirred at -70 ° C under argon and bis (trimethylsilyl) was added dropwise. lithium amide (63.7 ml c'a 1 M solution in THF, 63.7 mmol) The mixture was stirred at -60 ° C to -70 ° C for one hour and then cooled to -80 ° C and added with a Cannula N-iodosuccinimide (7.17 g, 31.9 mmol) in THF (20 ml) The mixture was allowed to warm to about -30 ° C for one hour and then quenched with saturated ammonium chloride solution. the two phase mixture was stirred rapidly at room temperature for 1.5 hours.The layers were separated and the aqueous layer was extracted with ethyl acetate (2x) and the layers .di.ñi.aÉi.ía.i.MMM.

The combined organics were washed with 5% sodium thiosulfate solution and brine and then dried (Na2SO) and evaporated. Chromatography on silica gel (elution with 10% ethyl acetate in hexane) and trituration of the product recovered with hexane gave 5.70 g of a white solid (63%). MS (AP + ve) M + Na = 335 1 H NMR (CDCl 3): 1.31 (9H, s), 3.29 (1 H, dd, J = 8.5, 14.6 Hz), 3.38 (1 H, dd, J = 6.1, 14.6 Hz), 4.06 (1 H, m), 4.45 (1 H, d, J = 4.4 Hz), 7.34 (1 H, dd, J = 1.7, 8.5 Hz), 7.48 (2 H, m), 7.68 (1 H, s), 7.82 (3H, m). b) N-f4-t-Butoxy-3S- (hydroxy) -2R- (2-naphthalethyl) succinin-S-ter-leucinamide 3S-t-Butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone (5.0 g, 16.0 mmol) and (S) -t-leucinamide (2.47 g, 19.2 mmol) were stirred together in THF (30 mL) at room temperature for 48 hours. hours. The THF was evaporated, ethyl acetate was added and the solution was washed with 2N HCl, water and brine, and then dried (MgSO 4) and evaporated. The resulting solid was triturated with hexane and dried to give 6,373 g of product (90%). MS (ES + ve) M + Na = 465, M + H = 443 1 H NMR (DMSO-d 6): 0.91 (9H, s), 1.39 (9H, s), 2.85-3.20 (3H, m), 3.85 ( 1 H, dd, J = 5.0, 7.4 Hz), 4.17 (1 H, d, J = 9.3 Hz), 5.65 (1 H, d, J = 7.4 Hz), 6.91 (1 H, s), 7.29 (1 H , s), 7.38-7.48 (3H, m), 7.69 (1 H, s), 7.80-7.87 (4H, m).

Preparation of N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl-1-S-ter-leucine methylamide It was carried out by opening 3S-t-butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone with ter-leucine methylamide as in b) above to give the product as a white solid. MS (AP + ve) M + H = 457, M + Na = 479 1 H NMR (DMSO-ds): 0.85 (9H, s), 1.41 (9H, s), 2.32 (3H, d, J = 4.6 Hz) , 2.90 (1 H, dd, J = 6.5, 13.5 Hz), 3.03 (1 H, dd, J = 8.6, 13.5 Hz), 3.14 (1 H, m), 3.88 (1 H, dd, J = 5.7, 7.3 Hz), 4.12 (1 H, d, J = 9.3 Hz), 5.62 (1 H, d, J = 7.5 Hz), 7.36 (1 H, m), 7.45 (2 H, m), 7.60 (1 H, m), 7.65 (1 H, s), 7.77-7.90 (4H, m).

Preparation of N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethi-succinyl-S-ter-leucine ethylamide It was carried out by opening 3S-t-butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone with ter-leucine ethylamide as in b) above, to give the product as a white solid (86%). MS (ES + ve) M + H = 471, M + Na = 493 H NMR (DMSO-de): 0.84 (3H, t, J = 7.3 Hz), 0.86 (9H, s), 1.41. (9H, s), 2.80-2.92 (3H, m), 3.03 (1 H, dd, J = 8.5, 13.6 Hz), 3.16 (1 H, m), 3.88 (1 H, dd, J = 5.8, 7.3 Hz), 4.12 (1 H, d, J = 9.4 Hz), 5.63 (1 H, d, J = 7.4 Hz), 7.37 (1 H, dd, J = 1.5 , 8 Hz), 7.44-7.47 (2H, m), 7.65 (1 H, m), 7.70 (1 H, m), 7. 77-7.81 (4H, m).

Preparation of 3S-hydroxy-2R- (2- (7-fluoro) naphthylmethyl) succinic acid diethyl ester a) 2-Bromomethyl-6-fluoronaphthalene 6-Fluoro-2-methylnaphthalene (20.5 g, 128 mmol, prepared by adaptation of the Wolinska-Mocydlarz ef al2 method) and NBS (22.8 g, 128 mmol) were heated at reflux for 16 hours in CCI4 (210 mL), time during which benzoyl peroxide was added in portions. The cooled solution was filtered and evaporated and the residue carefully extracted with hexane (4 x 250 mL). The extracts were decanted from the brownish material, combined and evaporated to give the product as a yellow solid, 29.8 g (97%). 1 H NMR (CDCl 3): 4.65 (2H, s), 7.27 (1 H, dt, J = 9, 3 Hz), 7.43 (1 H, dd, J = 10, 2 Hz), 7.53 (1 H, dd, J = 9, 1 Hz), 7.74-7.85 (3H, m). b) 3S-hydroxy-2R- (2- (7-fluoro) -naphthylmethylpuccinic acid diethyl ester A mixture of LHMDS solution (1.0 M in THF, 262 L) and THF (80 mL) was cooled to -72 ° C, and a solution of S-diethyl malate (23.7 g, 124.6 mmol) in THF (100 mL) was added by drip keeping the reaction at < -68 ° C. The mixture was allowed to warm to -40 ° C for 15 minutes and then re-cooled to -72 ° C. Bromomethyl-6-fluoronaphthalene (29.8 g, 124.7 mmol) in THF (180 mL) was added dropwise and the mixture was stirred overnight while warming slowly to room temperature. The mixture was poured into 0.5 M HCl and extracted with Et2O (2x), the organic extracts were washed with 0.5 M HCl, NaHCO3 solution, water and silare; dried (MgSO) and evaporated to an oil which was chromatographed on silica (hexane / Et2O, 0 to 35%) to give the product as a gum which was then solidified, 17.3 g (40%). 1 H NMR (CDCl 3): 1.20 (3H, t, J = 7 Hz), 1.27 (3H, t, J = 7 Hz), 3.14 (1 H, dd, J = 12, 9 Hz), 3.20-3.42 (3H , m), 4.09-4.29 (5H, m), 7.25 (1 H, dt, J = 9, 2.5 Hz), 7.43 (2H, m), 7.73 (1 H, s), 7.75-7.89 (2H, m ).

- ** - -Y * -Íti ~ 'r (Wf References 1. G M Carrera and D Garvey, J. Heterocyclic Chem, 1992, 29, 847. 2. J Wolinska-Mocydlarz, P Canonne and LC Leitch, Synthesis, 1974, 566.

EXAMPLE 1 N'-r3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucinamide a) N-r4-t-Butoxy-3S- (allyloxy) -2R- (2-naphthylmethsuccinin-S-ter-leucinamide) To a solution of N- [4-t-Butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (221 mg, 0.5 mmol) in tBuOH (10 ml) was added allyl bromide (0.4 ml, 5 mmol) followed by NaH (60% dispersion in mineral oil, 22 mg). It was stirred for one hour and then poured into dilute HCl and extracted with diethyl ether. The extracts were washed with water, dried (MgSO) and evaporated. The residue was subjected to chromatography (50% ethyl acetate / hexane) to give the product as a white foam. MS (ES + ve), M + Na = 505, M + H = 483 1 H NMR (DMSO-de): 0.75 (9H, s), 1.30 (9H, s), 2.64 (1 H, dd, J = 14 , 4.5 Hz), 2.90 (1 H, dd, J = 14, 10 Hz), 3.06-3.2 (1 H, m), 3.69-3.75 (1 H, obs), 3.74 (1 H, d, J = 8 Hz), 3.89 (1 H, d, J = 8 Hz), 4.03 (1 H, d, J = 9 Hz), 5.02 (1 H, dd, J = 10, 2 Hz), 5.14 (1 H, dd , J = 17, 2 Hz), 5.64-5.75 (1 H, m), 6.71 (1 H, br), 7.03 (1 H, br), 7.16 (1 H, dd, J = 8.5, 1.5 Hz), 7.28-7.33 (2H, m), 7.48 (1 H, s), 7.62-7.71 (4H, m). b) N-f3S- (Allyloxy) -4-hydroxy-2R- (2-naphthylmethylsuccinyl] -S-tert-leucinamide A solution of N- [4-t-Butoxy-3S- (allyloxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (0.18 g, 0.4 mmol) in dichloromethane / trifluoroacetic acid (5/2 ml) was stirred for 18 hours. Concentrate to give the product as a white solid. MS (ES + ve), M + Na = 449, M + H = 427 1 H NMR (DMSO-de): 0.9 (9H, s), 2.85 (1 H, dd, J = 14, 4.5 Hz), 3.05 ( 1 H, dd, J = 14, 10 Hz), 3.22-3.31 (1 H, m), 3.85 (1 H, dd, J = 12.5, 5.5), 3.94 (1 H, d, J = 8 Hz), 4.08 (1 H, dd, J = 12.5, 5 Hz), 4.17 (1 H, d, J = 9 Hz), 5.15 (1 H, d, J = 10 Hz), 5.41 (1 H, d, J = 17), 5.87-5.90 (1 H, m), 6.87 (1 H, br), 7.17 (1 H, br), 7.33 (1 H, d, J = 8.5 Hz), 7.43-7.47 (2H, m) , 7.65 (1 H, s), 7.62-7.71 (4H, m). c) N'-r3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl-S-ter-leucinamide A solution of N- [3S- (allyloxy) -4-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (0.96 g, 2.25 mmole) in anhydrous DMF (10 ml) was treated sequentially with HOAT (0.613 g, 4.50 mmol) and EDC (0.846 g, 4.50 mmol), and the reaction solution was stirred at room temperature for 0.25 hours. Then, hydroxylamine hydrochloride (0.47 g, 6.75 mmol) and N-methylmorpholine (0.682 g, 6.75 mmol) were added and the reaction solution was stirred for 16 hours at room temperature. The reaction solution was evaporated to dryness and the residue was partitioned between ethyl acetate and 10% citric acid. The phases were separated and the organic phase was washed with more 10% citric acid (x2) and saturated sodium bicarbonate solution (x3). The precipitated product was filtered, washed with water and ethyl acetate and then dried under vacuum to give the title compound as a white solid (0.22 g, 22%). The organic phase of the filtrate was washed with brine, dried (MgSO) and evaporated, and the residue was recrystallized from methanol / diethyl ether to give the title compound (0.26 g, 26%). MS (ES + ve), MH = 440 1 H NMR (DMSO-d 6): 0.97 (9H, s), 2.64 (1 H, m), 2.93 (1 H, m), 3.23 (1 H, m), 3.81 (2H, m), 3.95 (1 H, m), 4.12 (1 H, d, J = 9.4 Hz), 5.11 (1 H, d, J = 10.6 Hz), 5.23 (1 H, d, J = 17.3 Hz), 5.78 (1 H, m), 6.75 (1 H, s), 6.96 (1 H, s), 7. 25 (1 H, d, J = 8.7 Hz), 7.43 (2H, m), 7.59 (1 H, s), 7.65-7.83 (4H, m), 9.12 (1 H, s), 10.95 (1 H, s). N- [3S- (Allyloxy) -4-N-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide can also be prepared from (3R-naphthyl) -3-cyclohexyl-diethyl ester. 2S-hydroxysuccinic as follows: d) 3S-Allyloxy-2R-naphthylmethylsuccinic acid diethyl ester To a stirred solution of (3R-naphthylmethyl) -2S-hydroxysuccinic acid diethyl ester (4.0 g, 12 mmol) in benzene (80 ml) was added thallium (I) ethoxide (2.99 g, 12 mmol) and the mixture room temperature was stirred. A gelatinous precipitate formed and after one hour the solvent was removed in vacuo. The precipitate was then suspended in DMF (120 ml) and allyl bromide (1.45 g, 1.04 ml, 12 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered to remove thallium salts, water and ethyl acetate were added and the product was extracted into ethyl acetate. The extracts were washed successively with water and brine and dried (MgSO4) and concentrated. Purification by chromatography on silica gel (elution with 5% ethyl acetate in 40-60 petroleum ether) gave the product as an oil (1.40 g, 32%). MS (ES + ve) M + Na = 393 1 H NMR (CDCl 3): 1.10 (3H, t, J = 7.2 Hz), 1.29 (3H, t, J = 7.2 Hz), 3. 03 (1 H, dd, J = 6.9, 13.5 Hz), 3.16-3.33 (2H, m), 3.91 (1 H, dd, J = 6.1, 12.6 Hz), 4.02-4.30 (6H, m), 5.20 ( 1 H, dd, J = 1.3, 10.3 Hz), 5.28 (1 H, dd, J = 1.6, • M- ^ MMÍ tliUMIa 17.2 Hz), 5.91 (1 H, m), 7.33 (1 H, dd, J = 1.7, 8.4 Hz), 7.45 (2H, 'm), 7.64 (1 H, s), 7.78 (3H, m). e) using known methodology, for example, WO9702239, 3S-allyloxy-2R-naphthylmethyl-succinic acid diethyl ester can be hydrolysed, treated with trifluoroacetic anhydride and then methanol, coupled to (S) -ter leucinamide and hydrolyzed to give N- [3S- (allyloxy) -4- (N-hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide. The spectral data are the same as those in example 1 b) above.

EXAMPLE 2 N, -r3S- (Allyloxy) -4- (N-hydroxyamino) -2R-f2-naphthylmethyl) succinyl-S-tert-leucine methyl-amide It was prepared in the same manner as in example 1 d) + e) from 3S-allyloxy-2R-naphthylmethyl-succinic acid diethyl ester, but by coupling with N-methyl- (S) -tele-leucinamide, instead of (S) ) -ter-leucinamide. MS (ES + ve), M + H = 456, M + Na = 478 1 H NMR (DMSO-d 6): 0.81 (9H, s), 2.05 (3H, d, J = 4.4 Hz), 2.65 and 2.80 (2H , m), 3.25 (1 H, m), 3.78 and 3.93 (2 H, dd, J = 12.7, 5.4 Hz), 3.85 (1 H, d, J = 9.7 Hz), 4.05 (1 H, d, J = 9.5 Hz), 5.09 (1 H, dd, J = 10.4, 1.6 Hz), 5.22 (1 H, dd, J = 17.3, 1.6 Hz), 5.75 (1H, m), 7.12 (1 H, d, J = 4.4 Hz), 7.24 (1H, m), 7.46 (2H, m), 7.57 (1 H, s), 7.75 (4H, m), 9.14 (1 H, s), 10.99 (1 H, s).

EXAMPLE 3 N'-f4- (N-Hydroxyamino) -2R- (2-naphthylmethyl-3S- (propyloxy) succinin-S-ter-leucine methyl-amide It was prepared in the same manner as in Example 2 from 3S-allyloxy-2R-naphthylmethyl-succinic acid diethyl ester, but the compound was hydrogenated using Pd / BaSO4 before the formation of hydroxamic acid. MS (ES + ve), M + H = 458, M + Na = 480 1 H NMR (DMSO-de): 0.82 (12H, m), 1.43 (2H, m), 2.04 (3H, d, J = 4.4 Hz ), 2.64 and 2.81 (2H, m), 3.25 (3H, m), 3.78 (1 H, d, J = 9.6 Hz), 4.03 (1 H, d, J = 9.4 Hz), 7.06 (1 H, d , J = 4.4 Hz), 7.25 (1 H, d, J = 8.5 Hz), 7.44 (2 H, m), 7.57 (1 H, s), 7.62 (1 H, d, J = 9.4 Hz), 7.80 ( 3H, m), 9.14 (1 H, s), 10.95 (1 H, s).

EXAMPLE 4 N '^ - ÍN-Hydroxyamino ^ -SR ^ -naftilmetiD-SS-IpropiloxDsuccinin-S-ter-leucinamide It was prepared in the same manner as in example 1 d) + e) from 3S-allyloxy-2R-naphthylmethyl-succinic acid diethyl ester, but the compound was hydrogenated using Pd / BaSO4 before the formation of hydroxamic acid. MS (ES + ve), M + H = 444, M + Na = 466 1 H NMR (DMSO-de): 0.82 (3H, t, J = 7.5 Hz), 0.89 (9H, s), 1.45. (2H, m), 2.64 and 2.91 (2H, m), 3.12-3.40 (3H, m), 3.75 (1 H, d, J = 9.5 Hz), 4.11 (1 H, d, J = 9.5 Hz), 6.79 (1 H, s), 7.25 (1 H, m), 7.44 (2H, m), 7.59 (1 H, s), 7.73 (4H, m), 9.10 (1 H, br s) and 10.95 (1 H, s).

EXAMPLE 5 N'-f3S- (Alloxy) -4- (N-hydroxyamino) -2R- (2- (7-fluoronaphthylmethyl) succinyl-S-ter-leucinamide It was prepared in the same manner as in example 1 d) + e) from 3S-hydroxy-2R- (2- (7-fluoro) naphthylmethyl) succinic acid diethyl ester. MS (ES + ve), MH = 458 1 H NMR (DMSO-de): 0.89 (9H, s), 2.69 (1H, dd, J = 14, 4 Hz), 2.95 (1H, dd, J = 14, 10 Hz), 3.11-3.19 (1H, m), 3.74-3.81 (2H, m), 3.74-3.81 (2H, m), 3.96 (1H, dd, J = 12.5, 5 Hz), 4.07 (1H, d, J = 9.5 Hz), 5.10 (1H, dd, J = 10, 1 Hz), 5.22 (1H, dd, J = 16, 1 Hz), 5.75-5.86 (1H, m) 6.69 (1H, s), 7.11 (1H, s), 7.24 (1H, d, J = 9.5 Hz), 7.33 (1H, dd, J = 9, 2.5 Hz), 7.54 (1H, dd, J = 10.5, 2.5 Hz), 7.59 (1H, s), 7.77 (1H, d, J = 8.5 Hz), 7.77-7.82 (1H, obs), 7.89 (1H, dd, J = 8.5, 6 Hz), 9.12 (1H, s), 10.91 (1H, s ).

EXAMPLE 6 N'-r3S- (Ethoxy) -4- (N-hydroxyamino-2R-f2- (7-fluoronaphthylmethylsuccinin-S-ter-leucinamide It was prepared in the same manner as in Example 1 d) + e) from 3S-hydroxy-2R- (2- (7-fluoro) naphthylmethyl) succinic acid diethyl ester, alkylating with iodoethane instead of allyl bromide. EM (ES + ve), M-H = 446? NMR (DMSO-d6): 0.89 (9H, s), 1.05 (3H, t, J = 7 Hz), 2.63 (1H, dd, J = 14, 3 Hz), 2.90 (1H, dd, J = 14, 10.5 Hz), 3.17 (1H, dd, J = 9, 3 Hz), 3.23-3.27 (1H, m), 3.31-3.47 (1H, m), 3.75 (1H, d, J = 9 Hz), 4.11 ( 1H, d, J = 9.5 Hz), 6.76 (1H, s), 6.93 (1H, s), 7.22 (1H, dd, J = 8.5, 1 Hz), 7.32 (1H, dt, J = 8.5, 2.5 Hz ), 7.53-7.58 (1H, obs), 7.58 (1H, s), 7.65 (1H, d, J = 9 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.90 (1H, dd, J = 9.6 Hz), 9.11 (1H, s), 10.94 (1H, s).

EXAMPLE 7 N, -r4-fN-Hydroxyamino-2R- (2-f7-fluoro) naphthylmethyl) -3S- (propyloxy) succinin-S-ter-leucinamide It was prepared in the same manner as in Example 5 from 3S-hydroxy-2R- (2- (7-fluoro) naphthylmethyl) succinic acid diethyl ester, but hydrogenated using Pd / C prior to the preparation of hydroxamic acid. EM (ES + ve), M-H = 460? NMR (DMSO-de): 0.82 (3H, t, J = 7.5 Hz), 0.89 (9H, s), 1.40-1.52 (2H, m), 2.63 (1 H, dd, J = 14, 3.5 Hz), 2.89 (1 H, dd, J = 14, 10 Hz), 3.15 -3.37 (3H, m), 3.75 (1 H, d, J = 9.5 Hz), 4.09 (1 H, d, J = 9.5 Hz), 6.75 (1 H, s), 6.91 (1 H, s), 7.23 (1 H, dd, J = 8, 1 Hz), 7.32 (1 H, dt, J = 8.5, 2), 7.58 (1 H, s), 7.49-7.60 (2H, m), 7.78 (1 H, d, J = 8.5), 7.90 (1 H, dd, J = 9, 8 Hz), 9.10 (1 H, br) and 10.91 (1 H, br).

EXAMPLE 8 NW3S- (Ethoxy- (N-hydroxyamino) -2R- (2-naphthmethyl) succinyl-S-ter-leucinamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide , by alkylation with iodoethane instead of allyl bromide. EM (ES -ve), M-H = 460? NMR (DMSO-de): 0.94 (9H, s), 1.06 (3H, t, J = 7 Hz), 2.68 (1H, dd, J = 14, 4 Hz), 2.94 (1H, dd, J = 24, 11 Hz), 3.05 - 3.19 (1H, m), 3.05-3.19 (1H, m), 3.22-3.29 (1H, m), 3.36-3.47 (1H, m), 3.70 (1H, d, J = 8.5 Hz ), 4.09 (1H, d, J = 9.5 Hz), 6.78 (1H, s), 7.22 (1H, s), 7.28 (1H, d, J = 8.5 Hz), 7.42-7.48 (2H, m), 7.61 (1H, s), 7.76 (1H, d, J = 8.5 Hz), 7.80-7.87 (3H, m), 8.97 (1H, s), 10.92 (1H, s).

- ~ * ® ** ^ EXAMPLE 9 N'-f4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (propyloxy) succinyl-S- (.beta.-dimethyl-Ne- methylisinamide). salt TFA It was prepared in the same manner as in example 1 d) + e) from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester, but the compound was coupled with β, β-dimethyl-Ne-methyl-lysinamide (instead of (S) -ter-leucinamide) and was hydrogenated using Pd / BaSO4 before the formation of hydroxamic acid. EM (ES -ve), M-H = 499, MS (ES + ve), M + H = 501? NMR (DMSO-de): 0.84 (3H, t, J = 7.4 Hz), 0.86 (6H, s), 1.22 (2H, m), 1.48 (2H, m), 1.55 (2H, m), 2.55 (3H , s), 2.70 (3H, s), 2.70 (3H, m), 2.93 (1 H, m), 3.21 (2H, m), 3.35 (1 H, m, partially obscured by water), 3.76 (1 H , d, J = 8.9 Hz), 4.17 (1 H, d, J = 8.9 Hz), 4.17 (1 H, d, J = 9.5 Hz), 6.82 (1 H, s), 6.95 (1 H, s) , 7.27 (1 H, m), 7.27 (1 H, m), 7.43 (2 H, m), 7.59 (1 H, s), 7.76 (4 H, m), 8.25 (2 H, br s), 9.12 (1 H, s), 10.91 (1 H, s).

EXAMPLE 10 N'-r4- (N-Hydroxyamino) -2R- (2-f6-fluoro) naphthylmethyl) -3S- (propyloxy) succinin-S-ter-leucinamide Prepared in the same manner as in example 1 d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxysuccinic acid diethyl ester, but the compound was hydrogenated using Pd / C before the formation of hydroxamic acid. MS (ES -ve), M-H = 460, MS (ES + ve), M + H = 462? NMR (DMSO-de): 0.82 (3H, t, J = 7 Hz), 0.88 (9H, s), 1.45. (2H, m), 2.63 (1 H, br d, J - 12Hz), 2.89 (1 H, br t), 3.20 (2H, m), ax. 3.3 (1 H, m, partially obscured by water signal), 3.76 (1 H, d, J = 9 Hz), 4.08 (1 H, d, J = 9 Hz), 6.71 (1 H, br s), 6.89 (1 H, br s), 7.28-7.36 (2H, m), 7.58-7.63 (3H, m), 7.74 (1 H, d, J = 8 Hz), 7.86-7.89 (1 H, m), 9.09 (1 H, br s), 10.90 (1 H, br s).

EXAMPLE 11 N'-f3S- (AIlloxy) -4- (N-hydroxyamino> -2R- (2- (6-fluoro) naphthylmethyl) succinyl-S-ter-leucinamide It was prepared in the same manner as in example 1 d) + e) from diethyl ester of 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxysuccinic acid. MS (ES -ve), M-H = 458, MS (ES + ve), M + H = 460? NMR (DMSO-de): 0.87 (9H, s), 2.64 (1H, dd, J = 14, 3 Hz), 2.90 (1H, dd, J = 14, 14 Hz), 3.22 (1H, m), 3.78 (1H, dd, J = 13, 6 Hz), 3.82 (1H, d, J = 10 Hz), 3.95 (1H, dd, J = 13, 5 Hz), 4.10 (1H, d, J = 9 Hz) , 5.10 (1H, d, J = 10 Hz), 5.22 (1H, dd, J = 17, 1 Hz), 5.73-5.83 (1H, m), 6.71 (1H, br s), 6.92 (1H, br. s), 7.29 (1H, d, J = 8 Hz), 7.34 (1H, m), 7.58-7.67 (3H, m), 7.74 (1H, d, J = 8 Hz), 7.88 (1H, m), 9.10 (1H, brs), 10.95 (1H, brs).

M-¡-kB --- Í > -l-a-l -? - á | - > EXAMPLE 12 N'-r3S- (Hexyloxy) -4- (N-hydroxyamino) -2R- (2- (6-fluoronaphthylmethylisuccinin-S-ter-leucinamide It was prepared in the same manner as in example 1 d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxysuccinic acid diethyl ester, alkylating with hexyl iodide instead of bromide. alilo. MS (ES -ve), M-H = 502, MS (ES + ve), M + H = 504, M + Na = 526 15? NMR (DMSO-de): 0.85 (3H, t, J = 7 Hz), 0.88 (9H, s), 1.22 (6H br m), 1.43 (2H, m), 2.64 (1H, m) "2.90 (1H, m), 3.20 (2H, m), 3.35 (1H, m), 3.75 (1H, d) , J = 9 Hz), 4.08 (1 H, d, J = 9 Hz), 6.72 (1 H, b. S), 6.90 (1 H, br s), 7.27-7.39 (2H, m), 7.57- 7.65 (3H, m), 7.74 (1 H, d, J = 9 Hz), 7.87 (1 H, m), 9.10 (1 H, br s), 10.90 (1 H, br s). ^ > ^ EXAMPLE 13 N'-r3S - ((4-Fluoro) benzyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl-succinyl-S-ter-leucinamide) Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by alkylation with 4-fluorobenzyl bromide in place of allyl bromide. Er 1 (ES -ve), M-H = 508, EM (ES + ve) M + H = 510, M + Na = 532? NMR (DMSO-de): 0.76 (9H, s), 2.69 (1 H, m), 2.95 (1 H, m), 3.25 (1 H, m), 3.94 (1 H, d, J = 9 Hz) , 4.30 (1 H, A of Abq, J = 11 Hz), 4.46 (1 H, B of Abq, J = 11 Hz), 6.75 (1 H, br s), 6.98 (1 H, br s), 7.13 (2H, m), 7.24-7.35 (3H, m), 7.42-7.46 (2H, m), 7.60 (1 H, br s), 7.66 (1 H, d, J = 10 Hz), 7.74 (1 H , d, J = 8 Hz), 7.81 (2H, m), 9.17 (1 H, br s), 11.00 (1 H, br s).

EXAMPLE 14 N'-r3S - ((4-Fluoro) benzyloxy) -4-N-hydroxyamino) -2R- (2-6-fluoro) natylmethyl) succinin-S-ter-leucinamide Prepared in the same manner as in Example 1 d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3-S-hydroxy-succinic acid diethyl ester by alkylation using 4-fluorobenzyl bromide instead of allyl bromide. MS (ES -ve) M-H = 526, MS (ES + ve) M + H = 528.? NMR (DMSO-de): 0.76 (9H, s), 2.68 (1H, m), 2.93 (1H, m), 3.27 (1H, m), 3.95 (1H, d, J = 10Hz), 4.08 (1H, d, J = 8Hz), 4.28 (1H, A of Abq, J = 11Hz), 4.46 (1H, B of Abq, J = 11Hz), 6.73 (1H, br s), 6.93 (1H, br s), 7.12 (2H, m), 7.29-7.39 (4H, m), 7.57-7.68 (3H, m), 7.74 (1H, d, J = 9Hz), 7.89 (1H, m), 9.17 (1H, brs), 11.00 (1H brs).

EXAMPLE 15 N'-r3S-Benzoyloxy-4- (N-hydroxyamino? -2R- (2-naphthylmethyl) succinop-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by acylation with benzoyl chloride instead of alkylation with allyl bromide. MS (ES -ve) M-H = 504, MS (ES + ve) M + H = 506, M + Na = 528? NMR (DMSO-d6): 0.73 (9H, s), 2.73-2.89 (1 H, m), 3.00-3.10 (1 H, m), 3.58-3.67 (1 H, m), 4.10 (1, d, J = 9 Hz), 5.21 (1 H, d, J = 10 Hz), 6.73 (1 H, br s) , 7.10 (1 H, br s), 7.31 (1 H, d, J = 9 Hz), 7.43-7.52 (4H, m), 7.65 (2H, m), 7.74-7.85 (3H, m), 8.04 ( 3H, m), 9.15 (1 H, s), 11.22 (1 H, s).

EXAMPLE 16 N'-r3S- (2- (N.N-D.methylacetamidoxy)) - 4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by alkylation with 2-bromo-N, N-dimethylacetamide instead of allyl bromide. MS (ES -ve) M-H = 485, MS (ES + ve) M + H = 487, M + Na = 509? NMR (DMSO-d6): 0.85 (9H, s), ax. 2.75-2.83 (1 H, m), 2.79 (3H, s), 2.91 (3H, s), 3.01 (1 H, dd, J = 14 Hz), a;. 3.3 (1 H, m), 3.94 (1 H, d, J = 8 Hz), 4.06-4.15 (3 H, m), 6.78 (1 H, s), 7.03 (1 H, s), 7.29 (1 H , d, J = 8 Hz), 7.39-7.46 (2H, m), 7.63 (1 H, s), ax. 7.64 (1 H, d, J = 8 Hz), 7.75 (1 H, d, J = 8 Hz), 7.79-7.83 (2 H, m), 9.09 (1 H, s), 11.18 (1 H, br m ). d-a-M-MU-a-al | t | -i-fÍ- > UUaj-.

EXAMPLE 17 N'-f3S- (2- (N-t-Butylacetamidoxy)) - 4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by alkylation with bromoacetonitrile in place of allyl bromide and the subsequent treatment with TFA before the preparation of hydroxamic acid. MS (ES -ve) M-H = 508, MS (ES + ve) M + H = 510, M + Na = 532? NMR (DMSO-de): 0.89 (9H, s), 1.29 (9H s), 2.67-2.75 (1H, m), 2.90-2.96 (1H, m), ax. 3.33 (1H, m), 3.62 and 3.78 (2x1 H, Abq, J = 15 Hz), 3. 93 (1 H, d, J = 9 Hz), 4.22 (1 H, d, J = 10 Hz), 6.82 (1 H, s), 7.04 (1 H, s), 7.11 (1 H, s), 7.27 (1 H, d, J = 8 Hz), 7.41-7.47 (2 H, m), 7.60 (1 H, s), 7.60 (1 H, s), 7.75 (1 H, d, J = 9 Hz), 7.81-7.84 (2H, m), 7.90 (1 H, d, J = 8 Hz), 9.19 (1 H, s), 11.13 (1 H, br s).

EXAMPLE 18 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl-3S- (N-phenylcarbamoyloxy) -succinyl-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by acylation with phenyl isocyanate / DMAP instead of alkylation with allyl bromide. MS (ES -ve) M-H = 519, MS (ES + ve) M + H = 521? NMR (DMSO-de): 0.83 (9H, s), 2.76 (1 H, dd, J = 12, 4 Hz), 2. 95-3.08 (1 H, m), 3.36-3.41 (1 H, m), 4.17 (1 H, d, J = 9.5 Hz), 5.17 (* '?, D, J = 9.5 Hz), 6.78 (1 H, br), 6.91-7.00 (1H, m), 7.19 (1H, br), 7.22-7.Zl (3H, m), 7.41-7.45 (4H, m), 7.6-7.7 (1H, obs ), 7.61 (1 H, s), 7.75 (1 H, d, J = 9.5 Hz), 7.76-7.82 (2 H, m), 9.08 (1 H, s), 9.62 (1 H, br), 11.09 (1 H, br).

EXAMPLE 19 N'-r4- (N-Hydroxyamino) -3S- (N-methyl-N-phenylcarbamoyloxy) -2R- (2-naphthylmethyl) succinin-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by acylation with N-methyl-N-phenylcarbamoyl chloride / NaH instead of alkylation with allyl bromide (see example 27). MS (ES -ve) M-H = 533, MS (ES + ve) M + H = 535? NMR (DMSO-de): 0.78 (9H, s), 2.76 (1 H, dd, J = 14, 4 Hz), 2.98 (1 H, dd, J = 14, 10.5 Hz), 3.26 (3H, s) , 3.35-3.41 (1 H, m), 4.10 (1 H, d, J = 9 Hz), 5.03 (1 H, d, J = 9 Hz), 6.72 (1 H, s), 7.06 (1 H, s), 7.18 (1 H, t, J = 6 Hz), 7.25-7.38 (5H, m), 7.38-7.46 (3H, m), 7.60 (1 H, s), 7.74 (1 H, d, J = 9 Hz), 7.79-7.90 (1 H, s), 11.02 (1 H, br.).

EXAMPLE 20 N'-f3S- (Cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucinamide a) N-r4-t-Butoxy-3S- (cyclohexyloxy) -2R- (2-naphthylmethylisuccinyl-1-S-ter-leucinamide) A solution of N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (1.0 g, 2.26 mmole) and 3-bromocyclohexene (2.60 ml, 22.6 mmole) ) in N-methylpyrrolidinone (18 ml) was stirred at 0 ° C under argon and lithium bis (trimethylsilyl) amide (2.50 ml of 1 M solution in THF, 2.50 mmol) was added dropwise. The mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate / 1 N HCl and the product was extracted into ethyl acetate. The organic extracts were washed with saturated NaHCO3 solution, water (3x) and brine and then dried (Na2SO4) and concentrated. Trituration with hexane to remove excess alkylating agent, followed by chromatography on silica gel (elution with 1: 1 ethyl acetate / hexane) gave the product as a foam (378 mg) MS (ES + ve) M + H = 523. This product (340 mg), cyclohexene (1.5 ml) and 10% Pd-C (30 mg) in methanol (15 ml) were refluxed together under argon overnight. After cooling, the mixture was filtered through Celite and concentrated to give a white solid (310 mg). MS (ES + ve) M + H = 525? NMR (CDCl 3): 1.09 (9H, s), 1.15-2.0 (10H, m), 1.42 (9H, s), 3.0-3.10 (2H, m), 3.20-3.30 (2H, m), 3.86 (1H , d, J = 3.0 Hz), 4.10 (1 H, d, J = 8.5 Hz), 5.06 (1 H, s), 6.55 (1 H, s), 7.36-7.50 (4H, m), 7.67 (1 H, s), 7.70-7.85 (3H, m). b) N'-r3S- (Cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) -succinyl-S-ter-leucineamide A solution of N- [4-t-butoxy-3S- (cyclohexyloxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (310 mg) in dichloromethane (5 ml) / trifluoroacetic acid (2) ml) was stirred at room temperature for 4 hours. Solvents evaporated and the product was re-evaporated from toluene (3x) to give the carboxylic acid as a colorless glassy solid. This product in DMF (10 ml) was treated with EDC (0.23 g, 1.18 mmol) and HOAT (0.16 g, 1.18 mmol) followed by a solution of hydroxylamine hydrochloride (0.12 g, 1.77 mmol) and N-methylmorpholine (0.20 ml). , 1.77 mmole) in DMF (5 ml). The mixture was stirred at room temperature overnight and then concentrated on the rotary evaporator. The residue was partitioned between ethyl acetate / 1 N HCl and the product was extracted into ethyl acetate. The extracts were washed with 1 N HCl, water and brine, and then dried (MgSO 4) and evaporated. Trituration with ether gave a white solid (94 mg). MS (ES -ve) M-H = 482? NMR (DMSO-de): 0.90 (9H, s), 1.0-1.95 (10H, m), 2.68 (1 H, dd, J = 3.9, 13.8 Hz), 2.92 (1 H, dd, J = 10.6, 13.8 Hz), 3.10-3.20 (2H, m), 3.95 (1 H, d, J = 9.0 Hz), 4.04 (1 H, d, J = 9.3 Hz), 6.72 (1 H, s), 6.88 (1 H , s), 7.27 (1 H, d, J = 9 Hz), 7.43 (2H, m), 7.60 (2H, m), 7.74 (1 H, d, J = 8.5 Hz), 7.81 (2H, m) , 9.04 (1 H, s), 10.86 (1 H, s).

EXAMPLE 21 N'-r3S- (Cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucine ethylamide It was prepared from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide by alkylation, hydrogenation, cleavage with t-butyl ester and the formation of hydroxamic acid in the same manner as in Example 20 to give N '- [3S- (cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide. EM (ES -ve) M-H = 510? NMR (DMSO-de): 0.65 (3H, t, J = 7.2 Hz), 0.85 (9H, s), 1.0-1.25 (5H, m), 1.47 (1 H, m), 1.45 (1 H, m), 1.85 (1 H, m), 2.45 -2.69 (3H, m), 2.83 (1H, m), 3.20 (2H, m), 3.96 (1H, d, J = 9.2 Hz), 3.98 (1H, d, J = 9.1 Hz), 7.12 (1H, m), 7.26 (1H, dd, J = 1.1, 8.3 Hz), 7.43 (2H, m), 7.53 (1H, d, J = 10 Hz), 7.58 (1H, s), 7.72-7.85 (3H, m ), 9.07 (1H, s), 10.85 (1H, s).

EXAMPLE 22 N'-r3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-naphthalenesuccinin-S-ter-leucine methylamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucine me * lamida by alkylation with iodoethane instead of allyl bromide. MS (ES -ve) M-H = 442? NMR (DMSO-de): 0.84 (9H, s), 1.04 (3H, t, J = 7.0 Hz), 2.07 (3H, d, J = 4.5 Hz), 2.64 (1H, dd, J = 3.8, 13.6 Hz) ), 2.83 (1H, m), 3.20-3.27 (2H, m), 3.44 (1H, m), 3.77 (1H, d, J = 9.6 Hz), 4.05 (1H, d, J = 9.8 Hz), 7.06 (1H, m), 7.24 (1H, dd, J = 1.5, 8.4 Hz), 7.44 (2H, m), 7.56 (1H, s), 7.59 (1H, d, J = 10 Hz), 7.72-7.85 ( 3H, m), 9.08 (1H, s), 10.92 (1H, s).

EXAMPLE 23 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (f3-phenyl) propyloxy) succinyl-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by alkylation with cinnamyl bromide, followed by reduction, deprotection and formation of hydroxamic acid. MS (ES + ve) M + H = 520, MS (ES -ve) MH = 518 1 NMR (DMSO-de): 0.9 (9H, s), 1.70-1.80 (2H, m), 2.50-2.70 (3H , m), 2.85-2.95 (1 H, m), 3.18-3.3 (2H, m), 3.35-3.45 (1 H, m), 3.75 (1 H, d, J = 9.4 Hz), 4.10 (1 H , d, J = 9.5 Hz), 6.75 (1 H, s), 6.95 (1 H, s), 7.10-7.20 (3H, m), 7.25-7.30 (3H, m) 7.35-7.45 (2H, m) , 7.60 (1 H, s), 7.68-7.85 (4H, m), 9.10 (1 H, s), 10.9 (1 H, s).

EXAMPLE 24 N'-r4- (N-Hydroxyamino) -2R-f2-naphthylmethyl-3S- (thiazol-2-ylmethoxy) succinyl-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by alkylation with 2-bromomethylthiazole instead of allyl bromide. MS (ES + ve) M + H = 499, MS (ES -ve) M-H = 497? NMR (DMSO-de): 0.80 (9H, s), 2.65-2.70 (1 H, m), 2.88-2.97 (1 H, m), 3.30-3.50 (1 H, rr.), 4.05 (1 H, d, J = 9.6 Hz), 4.10 (1 H, d, J = 9.3 Hz), 4.65 (1 H, d, J = 12.9 Hz), 4.75 (1 H, d, J = 12.94 Hz), 6.70 (1 H, s), 6.95 (1 H, s), 7.25 (1 H, d, J = 8.6 Hz), 7.40-7.50 (2H, m), 7.60 (1 H, s), 7.70-7.80 (4H, m ), 7.80-7.88 (2H, m), 9.20 (1 H, s), 11.05 (1 H, s).

EXAMPLE 25 N'-f3S- (Cyclohexylcarbonylloxyl-4- (N-hydroxyamino) -2R- (2-naphthylmethyl-Succinyl-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by acylation with cyclohexyl chloride in place of alkylation with allyl bromide (see example 27). MS (ES + ve) M + H = 512? NMR (DMSO-de): 0 88 (9H, s), 1.10-1.38 (5H, m), 1.50-1.88 (5H, m), 2.22 (1 H, m), 2.80 (1 H, dd, J = 4, 14 Hz), 2.97 (1 H, dd, J = 10, 14 Hz), 3.41 (1 H, m), 4.09 (1 H, d, J = 9 Hz), 4.90 (1 H, d, J = 10 Hz), 6.76 (1 H, s), 7.01 (1 H, s), 7.28 (1 H, d), 7.47 (2 H, m), 7.61 (1 H, s), 7.74 (1 H, d , J = 9 Hz), 7.82 (3H, m), 9.07 (1 H, s), 11.01 (1 H, s).

EXAMPLE 26 N'-r3S-ft-Butylcarbonyloxy) -4- N-hydroxyamino) -2R-f2-naphthylmethyl) succinin-S-ter-leucinamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucinamide by acylation with pivaloyl chloride in place of alkylation with allyl bromide (see example 27). MS (ES + ve) M + H = 486? NMR (DMSO-de): 0.87 (9H, s). 1.11 (9H, s), 2.84 (1 H, dd, J = 5, 14 Hz), 2.93 (1 H, dd, J = 9, 14 Hz), 4.03 (1 H, d, J = 9 Hz), 4.95 (1 H, d, J = 9 Hz), 6.73 (1 H, s), 6.99 (1 H, s), 7.31 (1 H, d, J = 8 Hz), 7.44 (2 H, m), 7.64 (1 H, s), 7.75 (1 H, d, J = 9 Hz), 7.81 (3 H, m), 9.05 (1 H, s), 11.00 (1 H, s).

EXAMPLE 27 N'-r3S-benzoyloxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucinamide a) N-r3S-Benzoyloxy) -4-t-butoxy-2R- (2-naphthylmethyl) succ-nin-S-ter-leucinamide To a solution of N- [4-t-butoxy-3S-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (0.3 g, 0.678 mmol) in DME (5 mL), NaH was added (60% suspension in mineral oil, 0.03 g, 0.75 mmol) followed after 30 seconds by benzo! or (0.087 mL, 0.075 mmol). The mixture was stirred for one hour at room temperature and then poured into 0.5 M HCl and extracted (2x) with EtOAc. The extracts were washed with NaHCO3 solution, water and brine; dried (MgSO4) and evaporated to a foam which was recrystallized after addition of ether. The product was obtained as a white crystalline solid, 0.33 g (89%). MS (ES + ve) M + H = 547, (M + Na) = 569? NMR (DMSO-de): 0.85 (9H, s), 1.40 (9H, s), 3.00 (1H, m), 3.18 (1H, m), 3.65 (1H, m), 4.20 (1H, d) , J = 8 Hz), 5.04 (1 H, d, J = 7 Hz), 6.89 (1 H, br s), 7.34 (1 H, br s), 7.38-753 (5H, m), 7.67 -7.72 (2H, m), 7.78-7.88 (3H, m), 7.98 (2H, d, J = 8 Hz), 8.06 (1 H, d, J = 8 Hz). b) N '- [3S-Benzoyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethin-succinin-S-ter-leucinamide) It was prepared from N- [3S-benzoyloxy-4-t-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide in a manner similar to that of Example 1b) + c). MS (ES -ve) MH = 504, MS (ES + ve) M + H = 506, M + Na = 528 1 H NMR (DMSO-de): 0.73 (9H, s), 2.73-2.89 (1 H, m ), 3.00-3.10 (1 H, m), 3.58-3.67 (1 H, m), 4.10 (1 H, d, J = 9 Hz), 5.21 (1 H, d, J = 10 Hz), 6.73 ( 1 H, br. S), 7.10 (1 H, br. S), 7.31 (1 H, d, J = 9 Hz), 7.43-7.52 (4H, m), 7.65 (2H, m), 7.74-7.85 (3H, m), 8.04 (3H, m), 9.15 (1 H, s), 11.22 (1 H, s).

EXAMPLE 28 N'-r3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-quinolinylmethyl) succinyl-S-ter-leucine methylamide A solution of N '- [3S- (Ethoxy) -4- (N-hydroxy) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucine methylamide hydrochloride solution (prepared in a manner similar to that of the example 1 b from 3- (3-quinoline) propionic acid, 0.19 g, 0.42 mmole) in anhydrous DMF (5 ml) was treated sequentially with HOAT (0.11 g, 0.84 mmol) and EDC (0.16 g, 0.84 mmol) and the The solution was stirred at room temperature for 0.25 hours. Then, hydroxylamine hydrochloride (0.09 g, 1.26 mmol) and N-methylmorpholine (0.18 ml, 1.35 mmol) were added and the solution was stirred for 3 hours at room temperature. The solution was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with more water and saturated sodium bicarbonate solution and dried with brine and magnesium sulfate. The organic phase was then evaporated and dried with the drying gun at 50 ° C for 3 hours to give the title compound as a solid (0.01 g, 5%).

. ^. ^ Htta ^ EM (ES + ve) M + H = 445? NMR (DMSO-d6): 0.82 (9H, s), 1.04 (3H, t, J = 6.9 Hz), 2.06 (3H, d, J = 4.5 Hz), 2.72 (1H, m), 2.75 (1H, m ), 3.26 (1H, m), 3.31 (1H, m), 3.44 (1H, m), 3.80 (1H, d, J = 9.7 Hz), 4.05 (1H, d, J = 9.6 Hz), 7.22 (1H , q, J = 5.6 Hz), 7.53 (1H, t, J = 6.0 Hz), 7.66 (1H, d, J = 6.6 Hz), 7.70 (1H, t, J = 7.3 Hz), 7.84 (1H, d , J = 6.7 Hz), 7.94 (1H, d, 7.9 Hz), 7.97 (1H, s), 8.60 (1H, d, H = 2Hz), 9.11 (1H, s), 10.96 (1H, s).

EXAMPLE 29 N'-r4- (N-Hydroxyamino) -3S-methoxy-2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucine methylamide by acylation with iodomethane in place of alkylation with allyl bromide. MS (ES + ve) M + H = 430 M ^ MalHta ^ H? NMR (DMSO-de): 0.83 (9H, s), 2.10 (3H, d, J = 4.5 Hz), 2.63 (1 H, dd, J = 4, 14 Hz), 2.84 (1 H, dd, J = 11, 14 Hz), 3.17 (3H, s), 3.20 (1 H, m), 3.67 (1 H, d, J = 10 Hz), 4.08 (1 H, d, J = 10 Hz), 7.14 (1 H, q, J = 4.5 Hz), 7.25 (1 H, m), 7.43 (2 H, m), 7.56 (1 H, s), 7.61 (1 H, d, J = 10 Hz), 9.09 (1 H , s), 10.94 (1 H, s).

EXAMPLE 30 N, -r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) succinop-3S-propanoyloxy-1-S-ter-leucine methylamide It was prepared in the same manner as in Example 1 a) + b) + c) from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucine methylamide by acylation with iodomethane in place of alkylation with allyl bromide. EM (APCl + ve) M + Na = 494? NMR (DMSO-de): 0.82 (9H, s), 0.99 (3H, t, J = 7.5 Hz), 2.07 (3H, d, J = 4.5 Hz), 2.22 (2H, m), 2.78 (1H, dd , J = 4, 13.5 Hz), 2.88 (1 H, dd, J = 11, 14 Hz), 3.42 (1 H, m), 4.03 (1 H, d, J = 9 Hz), 4.96 (1 H, d, J = 10 Hz), 7.16 (1 H, q, J = 4.5 Hz), 7.25 (1 H, m), 7.44 (2H, m), 7.57 (1 H, s), 7.80 (4H, m) , 9.09 (1 H, s), 11.07 (1 H, s).

EXAMPLE 31 N'-r3S- (Ethoxy) -4-fN-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide It was prepared in the same manner as in Example 1 from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide by acylation with iodoethane instead of allyl bromide, then the cutting of the tert-butyl ester and the formation of hydroxamic acid. MS (ES -ve) M-H = 456? NMR (DMSO-de): 0.67 (3H, t, J = 7.0 Hz), 0.84 (9H, s), 1.05 (3H, t, J = 7.0 Hz), 2.55 (1 H, m), 2.65 (2H, m), 2.82 (1 H, t, J = 11.0 Hz), 3.17- 3.30 (2H, m, partially obscured), 3.44 (1 H, m), 3.77 (1 H, d, J = 9.5 Hz), 4. 05 (1 H, d, J = 9.5 Hz), 7.23-7.25 (2H, m), 7.38-7.48 (2H, m), 7.56-7.59 (2H, m), 7.72 (1 H, d, J = 8.5 Hz), 7.76-7.83 (2H, m), 9.08 (1 H, s), 10.93 (1 H, s).

EXAMPLE 32 N'-f4- (N-Hydroxyamino) -2R- (2-naphthylmethyl-3S- (2-methylpropoxy) succinin-S-ter-leucine methylamide It was prepared in the same manner as in Example 1 from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by alkylation with methallyl bromide , hydrogenation, cutting of the tert-butyl ester and the formation of hydroxamic acid. MS (ES -ve) M-H = 470? NMR (DMSO-de): 0.79-0.83 (6H, m), 0.83 (9H, s), 1.72 (1 H, m), 2.04 (3H, d, J = 4.5 Hz), 2.65 (1 H, dd, J = 4.0, 13.5 Hz), 2.82 (1 H, dd, J = 11.0, 13.5 Hz), 3.04 (1 H, dd, J = 6.5, 9.0 Hz), 3.12 (1 H, dd, J = 7.5, 9.0 Hz), 3. 26 (1 H, m), 3.78 (1 H, d, J = 9.5 Hz), 4.00 (1 H, d, J = 9.3 Hz), 6.99 (1 H, m), 7. 27 (1 H, dd, J = 1.5, 8.5 Hz), 7.44 (2H, m), 7.55 (1 H, d, J = 10.5 Hz), 7.57 (1 H, s), 7.74 (1 H, d, J = 8.5 Hz), 7.77-7.85 (2H, m), 9.09 (1 H, s), 10.88 (1 H, s).

EXAMPLE 33 N'-f4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (2-propoxysuccinin-S-ter-leucine ethylamide N '- [4-Hydroxy-2R- (2-naphthylmethyl) -3S-propoxysuccinyl] -S-tert-leucine ethylamide (0.17 g, 0.372 mmol) (prepared analogously to Example 1) was treated from N- [4-t-Butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide by alkylation with allyl bromide, hydrogenation, then decomposition of tert-butyl ester), treated with HOAT (0.1 g, 0.735 mmol), DEC (0.142 g, 0.74 mmol), hydroxylamine hydrochloride (0.78 g, 1.12 mmol) and N-methylmorpholine (0.123 mL, 1.12 mmol), in DMF (4.3 mL) in the standard way. The normal treatment procedure gave the product as a white solid, 0.1 g, (57%). MS (ES + ve) M + H = 472, M + Na = 494.? NMR (DMSO-de): 0.66 (3H, t, J = 7 Hz), 0.82 (3H, t, J = 7.5 Hz), 0.84 (9H, s), 1.45 (2H, sextet, J = 7 Hz), 2.53 (1 H, m), 2.65 (2H, m), 2.84 (1 H, m), 3.20 (2H, m ), ax. 3.30 (1 H, m, partially obs.), 3.77 (1 H, d, J = 9.5 Hz), 4.03 (1 H, d, J = 9.5 Hz), 7.21 (1 H, br.t, J = 4 Hz), 7.25 (1 H, dd, J = 8.5, - "*" ** - "- 1.5 Hz), 7.43 (2H, m), 7.56 (1 H, d, J = 8.5 Hz), 7.57 (1 H, s), 7.72 (1 H, d, J = 8.5 Hz), 7.75-7.83 (2H, m), 9.10 (1 H, s), 10.89 (1 H, br. S).

EXAMPLE 34 N'-r3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethsuccinin-S-ter-leucine methylamide) a) N'-f4- (N-Benzyloxyamino) -3S-hydroxy-2R- (2-naphthylmethyl) succinyl-1-S-ter-leucine methylamide N '- [3S, 4-D-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-methylamide (1.5 g, 3.75 mmol) in DMF (25 mL), was treated with HOBT (1.15 g, 7.51 mmoles) and DEC (1.44 g, 7.51 mmoles). After stirring the mixture for 20 minutes, O-benzylhydroxylamine (0.92 mL) was added. The reaction was stirred at room temperature for six hours and the DMF was then removed in vacuo. To the residue was added NaHCO3 solution and the mixture was extracted (2X) with EtOAc. The combined extracts were washed with NaHCO3 solution, water and brine; dried (MgSO 4) and evaporated to a gum which was purified by column chromatography on silica (hexane / EtOAc, 0-100%), giving the product as a white foam, 0.73 g (39%). MS (ES + ve) M + H = 506, M + Na = 528.? NMR (DMSO-de): 0.85 (9H, s), 2.29 (3H, d, J = 4.5 Hz), 2.74 (1H, dd, J = 13.5, 6 Hz), 2.93 (1H, dd, J = 13.5, 9.5 Hz), 3.13 (1H, m), 3.86 (1 H, t, J = 7.5 Hz), 4.11 (1 H, d, J = 9.5 Hz), 4.80 (2H, s), 5.71 (1 H, d , J = 7.5 Hz), 7.29-7.48 (8H, m), 7.53-7.58 (2H, m), 7.61 (1 H, s), 7.76-7.80 (2H, m), 7.85 (1 H, d, J = 7 Hz), 11.27 (1 H, s). b) N'-í4- (N-Benzyloxyamino) -3S-tert-butoxy-2R- (2-naphthylmethyl) succinin-S-tert-leucine methylamide N '- [4- (N-Benzyloxyamino) -3S-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (0.69 g, 1.36 mmol) was dissolved in DCM (30 mL) and the solution It was cooled in an ice-salt bath. In the cooled solution, isobutylene (at 30 mL) was condensed by means of a cardiac-acetone condenser. Concentrated H2SO4 (12 drops) was added and the mixture allowed to stir while warming to room temperature overnight. The mixture was diluted with 3-4 times its volume of EtOAc and washed with NaHCO3, water and brine.; dried (MgSO4) and evaporated to a gum which was purified by column chromatography on silica (hexane / EtOAc, 0-100%). The product was obtained as a white foam 0.31 g (41%). MS (ES + ve) M + H = 562, M + Na = 584. 1 H NMR (DMSO-de): 0.84 (9H, s), 1.10 (9H, s), 1.98 (3H, d, J = 4.5 Hz ), 2.65 (1 H, dd, J = 11, 4 Hz), 2.76 (1 H, dd, J = 11, 11 Hz), 3.08 (1 H, m), 3.94 (1 H, d, J = 9 Hz), 4.02 (1 H, d, J = 9 Hz), 4.81 (d, J = 13.5 Hz) and 4.86 (d, J = 13.5 Hz) (Abq), 6.93 (1 H, br. Q, J = 4.5 Hz) 7.22 (1 H, d, J = 8.5 Hz), 7.30-7.47 (8H, m), 7.53 (1 H, s), 7.73 (1 H, d, J = 8.5 Hz), 7.78 (1 H , d, J = 8 Hz), 7.84 (1 H, d, J = 8 Hz), 11.35 (1 H, s). c) N'-r3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide N '- [4- (N-Benzyloxyamino) -3S-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (0.305 g, 0.54 mmole) was hydrogenated for four hours at room temperature and atmospheric pressure in the presence of Pb-BaSO4 (0.31 g). The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated with ether to give the product as an off-white solid, 0.152 g (59%). MS (ES + ve) M + H = 472, M + Na = 494. 1 H NMR (DMSO-de): 0.84 (9H, s), 1.11 (9H, s), 1.93 (3H, d, J = 4.5 Hz ), 2.70 (1 H, dd, J = 11, 4 Hz), 2.80 (1 H, dd, J = 11, 11 Hz), 3.11 (1 H, m), 3.93 (1 H, d, J = 9 Hz), 4.02 (1 H, d, J = 9 Hz), 6.84 (1 H, br.q, J = 4.5 Hz), 7.25 (1 H, d, J = 8.5 Hz), 7.40-7.46 (3H, m), 7.56 (1 H, s), 7.74 (1 H, d, J = 8.5 Hz), 7.78 (1 H, d, J = 8 Hz), 7.84 (1 H, d, J = 8 Hz), 8.96 (1 H, s), 10.74 (1 H, br. S).

EXAMPLE 35 N'-3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-ter-leucine ethylamide N '- [4- (N-Benzyloxyamino) -3S-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide was prepared and hydrogenated as described in Example 34 to give the product as a slightly grayish solid, 0.224 g (88%).

MS (ES + ve) M + H = 486, M + Na = 508. 1 H NMR (DMSO-de): 0.63 (3H, t, J = 7 Hz), 0.85 (9H, s), 1.12 (9H, s ), 2.39 (1H, m), 2.55 (1H, m), 2.70 (1H, dd, J = 11, 4 Hz), 2.81 (1H, dd, J = 11, 11 Hz), 3.11 (1H, m) , 3.92 (1H, d, J = 9 Hz), 4.02 (1H, d, J = 9 Hz), 7.05 (1H, br.t, J = 4.5 Hz), 7.26 (1H, dd, J = 8.5, 1.5 Hz), 7.40-7.46 (3H, m), 7.57 (1H, s), 7.73 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8 Hz), 7.82 (1H, d, J = 8 Hz), 8.95 (1H, s), 10.73 (1H, br. S).

EXAMPLE 36 N "-4- (N-Hydroxyamino) -3S- (2-oxy-N- (N,. N, -2-dimethylaminoethyl) acetamido) -2R- (2-naphthylmethyl) succinyl-S-ter-leucine methylamide a) N'-r4-t-Butoxy-3S- (2-oxybenzyl acetate) -2R- (2-naphthylmethiPsuccinyl-S-ter-leucine methylamide) The title compound was prepared by alkylating N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide with 2-bromobenzyl acetate in acetonitrile (see example 1a) . MS (ES + ve) M + H = 605, M + Na = 629. 1 H NMR (CDCl 3): 1.02 (9H, s), 1.42 (9H, s), 2.59 (3H, d, J = 5 Hz), 3.07-3.30 (3H, m), 3.77 (1 H, d, J = 3.5 Hz), 3.98 (1 H, d, J = 16 Hz), 4.12 (1 H, d, J = 9 Hz), 4.35 ( 1H, d, J = 16 Hz), 5.26 (2H, s), 6.23 (1H, q, J = 4 Hz), 7.04 (1 H, d, J = 9 Hz), 7.29-7.48 (8H, m) , 7.64 (1 H, s), 7.68-7.83 (3H, m).

IHihMbaáí MiNMIMIM b) N'-r4-t-Butoxy-3S- (2-oxyacetic acid) -2R- (2-naphthylmethyl) succinop-S-ter-leucine methylamide N '- [4-t-Butoxy-3S- (2-oxybenzyl acetate) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (2.71 g, 4.49 mmol) in methanol (70 ml) was hydrogenolized with Pd / BaSO4 (0.51 g) at room temperature and atmospheric pressure for four hours. The solution was filtered through Celite and concentrated to give 2.30 g of a white solid (100%). MS (ES + ve) M + H = 515 MS (ES -ve) MH = 513 1 H NMR (DMSO-de): 0.84 (9H, s), 1.44 (9H, s), 2.25 (3H, d, J = 7.2 Hz), 2.75-3.03 (2H, m), 3.27 (1 H, m), 3.96-4.13 (4H, m), 7.30 (1 H, dd, J = 1.4, 8.4 Hz), 7.44 (3H, m ), 7.74 (1 H, s), 7.74-7.88 (4H, m), 12.65 (1 H, s). c) N "-r4-Butoxy-3S- (2-oxy-N- (N'.N'-2-dimethylaminoetipatamido) -2R- (2-naphthylmethyl) succinyl-1-S-ter-leucine methylamide N '- [4-t-Butoxy-3S- (2-oxyacetic acid) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (0.6 g, 1.16 mmole), EDC (0.25 g, 1.28 mmole) ) and HOAT (0.17 g, 1.28 mmol) were stirred in DMF (11 ml) under argon at room temperature for 10 minutes and then 2- (dimethylamino) ethylamine (0.15 ml, 1.40 mmol) was added. The reaction was stirred overnight under argon at room temperature. The DMF was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water (x2), sodium bicarbonate solution (x2) and brine, then dried (Na2SO4) and evaporated. Chromatography on silica gel (dichloromethane-methanol) gave the title compound (62%). MS (ES + ve) M + H = 585 1 H NMR (DMSO-d 6): 0.83 (9H, s), 1.45 (9H, s), 2.18 (6H, s), 2.30 (3H, d, J = 4.5 Hz ), 2.36 (2H, t, J = 6.8 Hz), 2.82-3.05 (2H, m), 3.19-3.40 (4H, m), 3.77 (1 H, d, J = 15.5 Hz), 3.94 (1 H, d, J = 17.0 Hz), 4.15 (1 H, d, J = 9.5 Hz), 7.29 (1 H, dd, J = 1.5, 8.5 Hz), 7.46 (2 H, m), 7.59 (1 H, s) , 7.67 (1 H, m), 7.75-7.86 (5H, m). d) N "- [4- (N-Hydroxyamino) -3S- (2-oxy-N- (N'N'-2-d-methylamino-phenyl) acetamido) -2R- (2-naphthylmethyl) succinyl] - S-ter-leucine methylamide Decomposition of the tert-butyl ester and formation of the hydroxamic acid by coupling the carboxylic acid with O-benzylhydroxylamine followed by hydrogenolysis with Pd-BaSO 4 gave the title compound. MS (ES + ve) M + Na = 556, M + H = 544 MS (ES -ve) MH = 542 1 H NMR (DMSO-d 6): 0.81 (9H, s), 2.20 (3H, d, J = 4.5 Hz), 2.74 (1 H, dd, J = 3.7, 13.6 Hz), 2.82 (3H, s), 2.83 (3H, s), 2.89 (1H, d, J = 13.7 Hz), 3.14 (2H, d, J = 5.2 Hz), 3.33 (1 H, td, J = 4.0, 10.2 Hz), 3.43 (2H, m), 3.43 (2H, m), 3.82 (1 H, d, J = 15.5 Hz), 3.93 ( 1 H, d, J = 15.5 Hz), 3.97 (1 H, d, J = 9.6 Hz), 4.11 (1 H, d, J = 9.5 Hz), 7.22 (1 H, dd, J = 1.2, 8.4 Hz) , 7.45 (3H, m), 7.54 (1 H, s), 7.74 (1 H, d, J = 8.5 Hz), 7.77 (1H, d, J = 7.5 Hz), 7.84 (2H, d, J = 8.7 Hz), 8.00 (1 H, t, J = 5.7 Hz), 9.29 (1 H, s), 11.09 (1 H, s).

EXAMPLE 37 N'-r4- (N-Hydroxyamino) -3S- (2-oxy-N- (2'-acetoxy-ethinacetamido) -2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide a) N'-r4-t-Butoxy-3S- (2-oxy-N- (2-hydroxyethyl) acetamido-2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide The reaction of 2-aminoethanol with N '- [4-t-butoxy-3S- (2-oxyacetic acid) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide as in example 36c gave the title compound.

MS (ES + ve) M + Na = 580, M + H = 558 1 H NMR (DMSO-de): 0.83 (9H, s), 1.45 (9H, s), 2.29 (3H, d, J = 4.5 Hz) , 2.85 (1 H, m), 2.95 (1 H, m), 3.20 (2 H, m), 3.32 (1 H, m), 3.42 (2 H, m), 3.78 (1 H, d, J = 15.3 Hz ), 3.94 (1 H, d, J = 15.3 Hz), 3.98 (1 H, d, J = 8.1 Hz), 4.15 (1 H, d, J = 9.60 Hz), 4.68 (1 H, t, J = 5.6 Hz), 7.28 (1 H, dd, J = 1.6, 8.4 Hz), 7.45 (2H, m), 7.59 (1 H, s), 7.68 (2H, m), 7.77 (2H, m). b) N'-r4-t-Butoxy-3S- (2-oxy-N- (2-acetoxy-acetanamido-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide To a solution of N '- [4-butoxy-3S- (2-oxy-N- (2-hydroxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (0.8 g , 1.05 mmole), pyridine (0.25 ml, 3.15 mmole) and DMAP (few crystals) in dichloromethane (8.5 ml) at 0 ° C was added acetic anhydride. The mixture was stirred at 0 ° C for one hour and then diluted with ethyl acetate and washed with dilute HCl (x2), NaHCO3 solution and brine; dried (Na2SO4) and concentrated. Chromatography on silica gel (hexane / ethyl acetate -1: 4) gave 0.56% of product (88%). MS (ES + ve) M + H = 600 1 H NMR (DMSO-de): 0.82 (9H, s), 1.45 (9H, s), 1.99 (3H, s), 2.31 (3H, d, J = 4.5 Hz), 2.82-3.05 (2H, m), 3.31-3.40 (3H, m), 3.79 (1 H, d, J = 15.5 Hz), 3.95 (1 H, d, J = 6.3 Hz), 4.02 (1 H, d, J = 16.4 Hz), 4.16 (1 H, d, J = 9.6 Hz), 7.28 (1 H, dd, J = 1.3, 8.3 Hz), 7.46 (2H, m), 7.59 (1 H, s), 7.70-7.93 (6H, m). c) N '- [4- (N-Hydroxyamino) -3S- (2-oxy-N- (2'-acetoxyethyl) acetamido-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide Removal of N '- [4-Butoxy-3S- (2-oxy-N- (2-acetoxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide with tert-butyl ester TFA, followed by coupling with hydroxylamine as previously described, gave the title compound. MS (ES + v &) M + Na = 581, M + H = 559 1 H NMR (DMSO-de): 0.80 (9H, s), 2.01 (3H, s), 2.17 (3H, d, J = 4.5 Hz ), 2.75 (1 H, m), 2.88 (1 H, m) "3.32 (3H, m), 3.70 (1 H, d, J = 15.6 Hz), 3.90 (1 H, d, J = 16.0 Hz) , 3.94 (1 H, d, J = 9.9 Hz), 4.03 (2 H, d, J = 5.7 Hz), 4.13 (1 H, d, J = 9.6 Hz), 7.22 (1 H, dd, J = 1.3, 8.3 Hz), 7.43 (3H, m), 7.54 (1 H, s), 7.72 (1 H, d, J = 8.5 Hz), 7.76 (1 H, d, J = 9.0 Hz), 7.83 (2H, m ), 7.86 (1 H, d, J = 9.7 Hz), 9.19 (1 H, s), 11.07 (1 H, s).

EXAMPLE 38 N'-r4- (N-Hydroxyamino) -3S-N- (2-hydroxyethyl) carbamoylmethoxy-2R- (2-naphthylmethyl) succinyl-S-ter-leucine methylamide N '- [4- (N-Hydroxyamino) -3S- (2-oxy-N- (2'-acetoxyethyl) acetamido-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (0.27 g, 0.49 mmoles) in dioxane (4.4 ml) / agar (3 ml) was stirred with LiOH.H2O (0.062 g, 1.47 mmole) at room temperature for two hours, Amberlite resin IR-120 (plus) was added until pH = 4 and then the mixture leaked, concentrated, azeotropically distilled with toluene and dried in vacuo to give a white solid. Purification by preparative HPLC gave the title compound. MS (ES + ve) M + Na = 539, M + H = 517 MS (ES -ve) MH = 515 1 H NMR (DMSO-de): 0.81 (9H, s), 2.15 (3H, d, J = 4.5 Hz), 2.72 (1H, dd, J = 3.9, 13.5 Hz), 2.85 (1 H, dd, J = 10.7, 13.5 Hz), 3.12 (1 H, m), 3.21 ü ^ U ^ t ^ Mm? ^ (1 H, m), 3.34 (1 H, m), 3.42 (2 H, t, J = 6.5 Hz), 3.69 (1 H, d, J = 15.4 Hz), 3.87 (1 H, d, J = 15.4 Hz), 3.93 (1 H, d, J = 9.7 Hz), 4.12 (1 H, d, J = 9.7 Hz), 7.23 (1 H, dd, J = 1.5, 8.4 Hz), 7.45 (3H, m), 7.54 (1 H, s), 7.61 (1 H, t, J = 5.8 Hz), 7.72 (1 H, d, J = 8.5 Hz), 7.77 (1 H, d , J = 7.5 Hz), 7.82 (1 H, d, J = 8.1 Hz), 7.89 (1 H, d, J = 9.6 Hz), 9.30 (1 H, s), 11.09 (1 H, s).

EXAMPLE 39 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethylisuccinyl1-3S- (2-oxyphenazim-S-ter-leucine methylamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by alkylation with phenacyl bromide instead of allyl bromide. MS (ES -ve), MH = 532 1 H NMR (DMSO-de): 0.89 (9H, s), 2.5-2.53 (3H, obs), 3.20 (2H, d, J = 8 Hz), 3.50-3.60 ( 1 H, m), 3.83 (1 H, d, J = 15 Hz), 3.91 (1 H, d, J = 15), 4.19 (1 H, d, J = 9 Hz), 4.21 (1 H, d, J = 5 Hz), 6.89 (1 H, s), 7.3-7.49 (8H, m), 7.76 (1 H, s), 7.8-7.9 (4H, m), 7.97 (1 H, br d, J = 9), 9.39 (1 H, s). a) N'-f4-t-Butoxy-3S- (2RS-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide vb) N'-f4-t-butoxy- 3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl-1-S-ter-leucine methylamide N '- [3S-Allyloxy-4-t-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (4.0 g, 8.05 mmol) and Wilkin's catalyst (225 mg) in THF ( 70 ml) were cooled to 0 ° C and catechin borane syringe (2.58 ml, 24.2 mmol) was added with a syringe. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for one hour and then 1: 1 THF / ethanol (25 ml), pH 7, phosphate buffer (25 ml) and hydrogen peroxide solution were added. to 27.5% (25 ml), and the mixture was stirred at room temperature for 24 hours. The THF was removed and brine and ethyl acetate were added. The product was extracted into ethyl acetate and the extracts were washed with sodium carbonate solution and brine and then dried (Na2SO) and concentrated. Purification by column chromatography on silica gel (ethyl acetate / hexane) gave A) 0.627 g (15%) and B) 1958 g (47%). A) MS (ES + ve), M + H = 515 1 H NMR (DMSO-de): 0.84 (9H, s), 1.04 and 1.05 (3H, 2 x d, J = 6.0 Hz), 1.44 (9H, s), 2.24 and 2.26 (3H, 2 x d, J = 4.5 Hz), 2.84 (1 H, dd, J = 5.0, 14. 0 Hz), 2.96 (1 H, m), 3.10-3.38 (3H, m), 3.69 (1 H, m), 3.85 and 3.87 (1 H, 2 x d, J = 8.0 Hz), 4.09 (1 H, d, J = 9.5 Hz), 4.48 and 4.53 (1 H, 2 xd, J = 4.5 Hz), 7.30 (1 H, dd, J = 1.5, 8.5 Hz), 7.44 (3H, m), 7.61 (1 H, s), 7.69-7.86 (4H, m). B) MS (ES + ve), M + H = 515, M + Na = 537 1 H NMR (DMSO-de): 0.84 (9H, s), 1.45 (9H, s) 1.63 (2H, m), 2.20 (3H, d, J = 4.5 Hz), 2.76 (1 H, dd, J = 5.0, 13.5 Hz), 2.95 (1 H, dd, J = 10.0, 13.5 Hz), 3.20 (1 H, m), 3.32-3.55 (4H, m), 3.79 (1 H, d, J = 8.5 Hz), 4.08 (1 H, d, J = 9.5 Hz), 4.35 (1 H , t, J = 5.0 Hz), 7.29 (1 H, dd, J = 1.5, 8.5 Hz), 7.32 (1 H, m), 7. 44 (2H, m), 7.60 (1 H, s), 7.70 (1 H, d, J = 9.5 Hz), 7.74-7.84 (3H, rr).

EXAMPLE 40 N'-f3S- (3-Acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl-S-ter-leucine methylamide a) N'-f3S- (3-Acetoxypropoxy) -4-t-butoxy-2R- (2-naphthylmethyl) succinyl-1-S-ter-eucine methylamide To a solution of N '- [4-t-butoxy-3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (193 mg, 0.38 mmol), pyridine (0.092) ml, 1.14 mmol) and DMAP (few crystals) in dichloromethane (3 ml) at 0 ° C was added acetic anhydride (0.053 ml, 0.56 mmol). The mixture was stirred at room temperature for one hour and then diluted with ethyl acetate and washed with 1N HCl (2x), NaHCO3 solution and brine, and then dried and concentrated to give 207 mg of product. 1 H NMR (DMSO-de): 0.83 (9H, s), 1.45 (9H, s) 1.78 (2H, m), 1.99 (3H, s), 2.20 (3H, d, J = 4.5 Hz), 2.76 (1 H, dd, J = 5.0, 14.0 Hz), 2.95 (1 H, dd, J = 10.0, 14.0 Hz), 3.21 (1 H, m), 3.39 (1 H, m), 3.50 (1 H, m) , 3.82 (1 H, d, J = 8.5 Hz), 4.05 (2H, m), 4.08 (1 H, d, J = 9.5 Hz), 7.28 (1 H, dd, J = 1.5, 8.5 Hz), 7.33 (1 H, m), 7.44 (2H, m), 7.59 (1 H, s), 7.71 (1 H, d, J = 9.5 Hz), 7.75-7.85 (3H, m). b) N'-r3S- (3-Acehoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl! 1-S-ter-! eucine methylamide Prepared from N '- [3S- (3-acetoxypropoxy) -4-t-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by deprotection with TFA ,,: »of the ester and coupling of the resulting acid with hydroxylamine to give the title compound. MS (ES -ve) M-H = 514 MS (ES + ve) M + H = 516 H NMR (DMSO-de): 0.82 (9H, s), 1.74 (2H, m), 1.99 (3H, s), 2.05 (3H, d, J = 4.5 Hz), 2.65 (1 H, dd, J = 3.0, 13.5 Hz), 2.82 (1 H, dd, J = 11.0, 13.5 Hz), 3.23 (1 H, m), 3.29 (1 H, m, partially obscured), 3.45 (1 H, m), 3.79 (1 H, d, J = 9.5 Hz), 3.96-4.04 (3H, m), 7.01 (1 H, m), 7.25 ( 1 H, dd, J = 1.5, 8.5 Hz), 7.44 (2H, m), 7.57 (1 H, s), 7.61 (1 H, d, J = 8.5 Hz), 7.74 (1 H, d, J = 8.5 Hz), 7.78 (1 H, d, J = 7.5 Hz), 7.84 (1 H, d, J = 7.5 Hz), 9.12 (1 H, s), 10.91 (1 H, s).

EXAMPLE 41 N'-r4- (N-Hydroxyamino) -3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide N '- [3S- (3-Acetoxipropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (115 mg, 0.223 mmol) and LiOH.H2O (28 mg , 0.67 mmole) were stirred in 1,4-dioxane (2 ml) / water (1.5 ml) at room temperature for one hour. Amberlite IR-120 (plus) resin was added to lower the pH to 3-4 and the mixture was filtered and evaporated. The product was then azeotropically distilled with toluene, triturated with ether and dried under high vacuum to give the product as a white solid (89 mg). ES ES -ve MH = 472 ES ES + ve M + H = 474 1 H NMR (DMSO-de): 0.83 (9H, s), 1.59 (2H, m), 2.06 (3H, d, J = 4.5 Hz), 2.66 (1 H, dd, J = 4.0, 13.5 Hz), 2.83 (1 H, dd, J = 11.0, 13.5 Hz), 3.20 (1 H, m), 3.24 (1 H, m, partially obscured), 3.36 -3.48 (3H, m), 3.76 (1 H, d, J = 9.5 Hz), 4.02 (1 H, d, J = 9.5 Hz), 4.35 (1 H, br s, interchangeable with D2O), 7.04 (1 H, m), 7.25 (1 H, d, J = 8.5 Hz), 7.44 (2 H, m), 7.57 (1 H, s), 7.58 (1 H, d, J = 8.5 Hz), 7.74 (1 H , d, J = 8.5 Hz), 7.78 (1 H, d, J = 7.5 Hz), 7.83 (1 H, d, J = 7.5 Hz), 9.08 (1 H, s), 10.91 (1 H, s) .

EXAMPLE 42 N'-r3S- (3-Dimethylaminopropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethylpuccinyl-S-ter-leucine methylamide a) N'-r4-t-Butoxy-3S- (3-dimethylaminopropoxy) -2R- (2-naphthylmetissuccinyl-S-ter-leucine methylamide) To a solution of N '- [4-t-butoxy-3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (800 mg, 1.56 mmole) and triethylamine (0.326) ml, 2.34 mmol) in dichloromethane (8 ml) at 0 ° C methanesulfonyl chloride (0.145 ml, 1.87 mmol) was added. The mixture was stirred for 40 minutes and then diluted with dichloromethane and washed with 2N HCl and brine, and dried (Na 2 SO 4) and concentrated to give the mesylate as a white foam (895 mg, 97%). The mesylate (660 mg) was stirred in ethanol (6 ml) with dimethylamine (3 ml) in a sealed container for 20 hours. The solvents were evaporated and ethyl acetate and saturated sodium carbonate solution were added and the product was extracted into ethyl acetate. The extracts were washed with brine, dried (Na 2 SO 4) and evaporated. Filtration through a short column of silica gel (elution with dichloromethane / methanol) gave a white foam (520 mg, 86%). ES ES + ve M + H = 542 1 H NMR (DMSO-de): 0.84 (9H, s), 1.44 (9H, s), 1.61 (2H, m), 2.11 (6H, s), 2.20 (3H, d) , J = 4.5 Hz), 2.27 (2H, m), 2.76 (1 H, dd, J = 4.5, 13.5 Hz), 2 95 (1 H, dd, J = 10.0, 13.5 Hz), 3.19 (1 H, m), 3.32 (1 H, m, partially obscured), 3.46 (1 H, m), 3.80 (1 H, d, J = 8.5 Hz), 4.09 (1 H, d, J = 9.5 Hz), 7.28 ( 1 H, dd, J = 1.5, 8.5 Hz), 4.09 (1 H, d, J = 9.5 Hz), 7.28 (1 H, dd, J = 1.5, 8.5 Hz), 7.33 (1 H, m), 7.44 (2H, m), 7.60 (1 H, s), 7.69 (1 H, d, J = 9.5 Hz), 7.75 (1 H, d, J = 8.5 Hz), 7.78 (1 H, d, J = 7.5 Hz), 7.84 (1 H, d, J = 7.5 Hz). b) N'-r3S- (3-Dimethylaminopropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide The removal of the t-butyl ester of N '- [4-t-butoxy-3S- (3-dimethylaminopropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide with TFA, conversion of the TFA salt to the HCl salt and coupling with O-benzylhydroxylamine and removal of the O-benzyl group by hydrogenolysis gave the title compound. ? M ES -ve MH = 499 ES ES + ve M + H = 501 1 H NMR (DMSO-de): 0.83 (9H, s), 1.59 (2H, m), 2.09 (3H, d, J = 4.5 Hz) , 2.14 (6H, s), 2.27 (2H, m), 2.74 (1 H, dd, J = 4.0, 13.5 Hz), 2.85 (1 H, dd, J = 11.0, 13.5 Hz), 3.19 (1 H, m), 3.37 (2H, m, partially obscured), 3.76 (1 H, d, J = 9.0 Hz), 4.05 (1 H, d, J = 9.5 Hz), 7.12 (1 H, m), 7.26 (1 H, dd, J = 1.0, 8.5 Hz), 7.43 (2H, m), 7.56 (1H, d, J = 9.5 Hz), 7.57 (1H, s), 7.74 (1 H, d, J = 8.5 Hz) , 7.78 (1 H, d, J = 7.5 Hz), 7.83 (1 H, d, J = 7.5 Hz), 9.03 (1 H, s), 11.25 (1 H, s broad).

EXAMPLE 43 N, -r3S- (2-RS-Acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) -succinyl-S-ter-leucine methylamide Prepared from N '- [4-t-butoxy-3S- (2RS-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide as in Example 40. MS ES -vr MH = 514 MS ES + ve M + H = 516 1 H NMR (ÜMSO-dβ): mixture approx. 2: 1 diastereoisomers, 0.82 (9H, s), 1.11 and 1.12, (3H, 2 xd, J = 6.5 Hz), 1.96 and 1.97 (3H, 2 xs), 2.02 and 2.05 (3H, 2 xd, J = 4.5 Hz), 2.68 (1 H, m), 2.80 (1 H, m), 3.23-3.50 (3 H, m), 3.86 (1 H, m), 4.00 and 4.01 (1 H, 2 xd, J = 9.5 Hz), 4.80 (1 H, m), 7.0 (1 H, m), 7.25 (1 H, d, J = 8.5 Hz), 7.44 (2 H, m), 7.57 (1 H, s), 7.61 (1 H, m), 7.74 (1 H, d, J = 8.5 Hz), 7.77-7.84 (2H, m), 9.12 and 9.14 (1 H, 2 xs), 10.90 (1 H, s).

EXAMPLE 44 N, -r4- (N-Hydroxyamino) -3S-f2-RS-hydroxypropoxy) -2R- (2-naphthylmethylsuccinyl-S-ter-leucine methylamide) It was prepared by decomposing the acetate into N '- [3S- (2-RS-acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide with lithium hydroxide as in example 41. MS ES -ve MH = 472 MS ES + ve M + H = 474 1 H NMR (DMSO-dβ): mixture approx. 2: 1 of diastereoisomers, 0. 83 (9H, s), 0.98 and 1.00, (3H, 2 xd, J = 6.5 Hz), 2.09 and 2.11 (3H, 2 xd, J = 4.5 Hz), 2.67-2.89 (2H, m), 3.08-3.29 (3H, m), 3.65 (1 H, m), 3.83 and 3.84 (1 H, 2 xd, J = 9.5 Hz), 4.03 (1 H, d, J = 9.5 Hz), 4.50 and 4.51 (1 H, 2 xd, J = 4.5 Hz), 7.12 and 7.19 (1 H, 2 xm), 7.25 (1 H, m), 7.44 (2 H, m), 7.57 (1 H, s), 7.62 (1 H, m) , 7.74 (1 H, d, J = 8.5 Hz), 7.77-7.84 (2H, m), 9.09 and 9.11 (1 H, 2 xs), 10.86 and 10.90 (1 H, s). a) N'-r4-t-Butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl-S-ter-leucine methylamide A mixture of N '- [3S-allyloxy-4-t-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (2.0 g, 4.03 mmole), N-methylmorpholine N-oxide ( 520 mg, 4.43 mmol) and osmium tetroxide (0.8 ml of 2.5% solution in t-butanol) in acetone (24 ml), t-butanol (6 ml) and water (6 ml), was stirred at room temperature for 24 hours. Few crystals of solid osmium tetroxide were added and the mixture was stirred for a further 24 hours. The solvents were removed and the mixture was filtered through a short column of silica gel (ethyl acetate) to give the intermediate diol as a white foam (2.098 g, 98%). The diol and sodium periodate (973 mg, 4.55 mmol) in 1,4-dioxane (36 ml) / water (12 ml) were stirred at room temperature for five hours. An additional batch of sodium periodate (90 mg) was added and stirring was continued for an additional hour. Sodium borohydride (757 mg, 20 mmol) was added and after stirring for 30 minutes the reaction was quenched with saturated ammonium chloride solution and the solvents were removed. Ethyl acetate and 1 N HCl were added and the product was extracted into ethyl acetate. The extracts were washed with sodium bicarbonate solution and brine and then dried (Na 2 SO 4) and concentrated. Chromatography on silica gel (80% ethyl acetate in hexane) gave the product as a white foam (1.63 g, 82%). EM ES + ve M + H = 501? NMR (DMSO-d6): 0.84 (9H, s), 1.44 (9H, s), 2.25 (3H, d, J = 4. 5 Hz), 2.82 (1 H, dd, J = 5.0, 13.5 Hz), 2.96 (1 H, dd, J = 10.0, 13.5 Hz), 3.20 (1H, m), 3.36 (1H, m), 3.46-3.54 (3H, m), 3.88 (1H, d, J = 8.0 Hz), 4.10 (1H, d, J = 9.5 Hz), 4.51 ( 1 H, t, J = 5.5 Hz), 7.30 (1 H, dd, J = 1.5, 8.5 Hz), 7.44 (3H, m), 7.61 (1 H, s), 7.72-7.86 (4H, m).

EXAMPLE 45 N'-r3S- (2-Acetoxyethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-terleucine methylamide It was prepared from N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide in a manner similar to that described above for Example 40 EM ES -ve MH = 500 EM ES + ve M + H = 502? NMR (DMSO-de): 0.82 (9H, s), 1.99 (3H, s), 2.05 < 3H, d, J = 4.5 Hz), 2.67 (1 H, m), 2.82 (1 H, dd, J = 11.0, 13.0 Hz), 3.26 (1 H, m, partially obscured), 3.46 (1 H, m ), 3.59 (1 H, m), 3.85 (1 H, d, J = 9.5 Hz), 4.00-4.04 (3 H, m), 7.02 (1 H, m), 7.24 (1 H, dd, J = 1.5 , 8.5 Hz), 7.44 (2H, m), 7.57 (1 H, s), 7.63 (1 H, d, J = 9.5 Hz), 7.74 (1 H, d, J = 8.5 Hz), 7.77 (1 H , d, J = 7.5 Hz), 7.83 (1 H, d, J = 7.5 Hz), 9.14 (1 H, s), 10.92 (1 H, s). - - -i ^^ attJifaB ^^. ^.

EXAMPLE 46 N '- [4- (N-Hydroxyamino) -3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl-S-terleucine methylamide It was prepared from N '- [3S- (2-acetoxyethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by decomposition of the acetate with lithium hydroxide . ES ES -ve MH = 458 ES ES + ve M + H = 460 1 H NMR (DMSO-de): 0.83 (9H, s), 2.12 (3H, d, J = 4.5 Hz), 2.74 (1H, dd, J = 4.0, 13.5 Hz), 2.85 (1 H, dd, J = 10.5, 13.5 Hz), 3.19 (1 H, m), 3.29-3.43 (4H, m), 3.83 (1 H, d, J = 9.0 Hz) , 4.05 (1 H, d, J = 9.5 Hz), 4.51 (1 H, broad s, exchanges with D2O), 7.19 (1 H, m), 7.25 (1 H, dd, J = 1.5, 8.5 Hz), 7.43 ( 2H, m), 7.57 (1 H, s), 7.62 (1 H, d, J = 9.5 Hz), 7.74 (1 H, d, J = 8.5 Hz), 7.78 (1 H, d, J = 7.5 Hz ), 7.83 (1 H, d, J = 7.5 Hz), 9.07 (1 H, s), 10.96 (1 H, s broad). liÉHMááÉ Ét-ii? EXAMPLE 47 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) succinin-3S- (2-N-succinimidylethoxy) -S-tert-leucine methylamide a) N'-r4-t-Butoxy-2R- (2-naphthylmethyl) -3S- (2-N-succinimidylethoxy) succinin-S-ter-leucine methylamide A mixture of N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide (320 mg, 0.64 mmol), triphenylphosphine (336 mg, 1.28 mmoles), DEAD (0.202 ml, 1.28 mmoles) and succinimide (127 mg, 1.28 mmoles) in THF (4 ml) was treated at room temperature overnight. The solvents were evaporated and the residue was chromatographed on silica gel (elution with ethyl acetate / hexane) to give the title compound contaminated with a small amount of triphenylphosphine oxide which was removed in the next step. ES ES + ve M + H = 582, M + Na = 604. b) N'-f4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (2-N-succinimidylethoxy) succinyl-1-S-ter-leucine methylamide The decomposition of the t-butyl ester of N '- [4-t-butoxy-2R- (2-naphthylmethyl) -3S- (2-N-succinimidylethoxy) succinyl] -S-tert-leucine methylamide with TFA, followed by chromatography (to remove the triphenylphosphine oxide) and conversion of the carboxylic acid to the hydroxamic acid using standard conditions, gave the title compound.

MS ES -ve M-H = 539 MS ES + ve M + H = 541, M + Na = 563? NMR (DMSO-d6): 0.85 (9H, s), 2.06 (3H, d, J = 4.5 Hz), 2.60 (4H, s), 2.64 (1 H, dd, J = 3.5, 13.5 Hz), 2.82 ( 1 H, dd, J = 11.0, 13.5 Hz), 3.22 (1H, m), 3.27-3.50 (4H, m, partially obscured), 3.81 (1 H, d, J = 9.5 Hz), 4.04 (1 H, d, J = 9.5 Hz), 7.04 (1 H, m), 7.23 (1 H, dd, J = 1.5, 8.5 Hz), 7.44 (2H, m), 7.57 (1 H, s), 7.61 (1 H , d, J = 9.5 Hz), 7.73 (1 H, d, J = 8.5 Hz), 7.78 (1 H, d, J = 7.5 Hz), 7.84 (1 H, d, J = 7.5 Hz), 9.13 ( 1 H, s), 10.92 (1 H, s).

EXAMPLE 48 N'-r3S- (2-Dimethylaminoethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethio-Succinyl-S-terleucine methylamide It was prepared from N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide in a manner similar to that of example 42.

EM ES -ve M-H = 485 EM ES + ve M + H = 487? NMR (DMSO-de): 0.84 (9H, s), 2.10 (3H, d, J = 4.5 Hz), 2.14 (6H, s), 2.35 (2H, m), 2.74 (1 H, dd, J = 4.0 , 13.5 Hz), 2.86 (1 H, dd, J = 10.5, 13.5 Hz), 3.22 (1 H, m), 3.30-3.50 (2H, m, partially obscured), 3.80 (1 H, d, J = 9.0 Hz), 4.04 (1 H, d, J = 9.5 Hz), 7.12 (1 H, m), 7.25 (1 H, dd, J = 1.0, 8.5 Hz), 7.44 (2H, m), 7.56 (1 H , d, J = 9.5 Hz), 7.58 (1 H, s), 7.74 (1 H, d, J = 8.5 Hz), 7.78 (1 H, d, J = 7.5 Hz), 7.84 (1 H, d, J = 7.5 Hz), 9.06 (1 H, s), 11.08 (1 H, s wide).

EXAMPLE 49 N'-r3S- (2-Acetoxyethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinin-S-terleucine ethylamide It was prepared from N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide in a manner similar to that of Example 40.

EM ES -ve M-H = 514 EM ES + ve M + H = 516, M + Na = 538? NMR (DMSO-d6): 0.66 (3H, t, J = 7.0 Hz), 0.83 (9H, s), 1.99 (3H, s), 2.50-2.70 (3H, m, partially obscured), 2.84 (1H, m), 3.28 (1 H, m, partially obscured), 3.47 (1 H, m), 3.60 (1 H, m), 3.85 (1 H, d, J = 9.5 Hz), 4.01-4.04 (3H, m ), 7.21 (1 H, m), 7.25 (1 H, dd, J = 1.5, 8.5 Hz), 7.43 (2 H, m), 7.57 (1 H, s) 7.63 (1 H, d, J = 8.5 Hz ), 7.72 (1 H, d, J = 8.5 Hz), 7.75-7.85 (2H, m), 9.14 (1 H, s), 10.93 (1 H, s).

EXAMPLE 50 N'-r4- (N-Hydroxyamino) -3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl-S-terleucine ethylamide It was prepared by decomposing the acetate from N '- [3S- (2-acetoxy-ethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide with lithium hydroxide. EM ES -ve M-H = 472 EM ES + ve M + H = 474? NMR (DMSO-de): 0.71 (3H, t, J = 7.0 Hz), 0.84 (9H, s), 2.58- 2.76 (3H, m), 2.86 (1H, m), 3.20 (1H, m), 3.29. -3.44 (4H, m), 3.82 (1H, d, J = 9.5 Hz), 4.05 (1H, d, 9.5 Hz), 4.53 (1H, t, J = 5.5 Hz), 7.25 (1H, dd, J = 1.5, 8.5 Hz), 7.35 (1H, m), 7.43 (2H, t), 7.57 (1H, s), 7.61 (1H, d, J = 9.5 Hz), 7.73 (1H, d, J = 8.5 Hz) , 7.77 (1H, d, J = 7.5 Hz), 7.83 (1H, d, J = 7.5 Hz), 9.09 (1H, s), 10.88 (1H, s).

EXAMPLE 51 N'-r3S- (2-D-methylaminoethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethylOsuccinyl-S-terleucine ethylamide It was prepared from N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide in a manner similar to that of Example 42. MS ES -ve MH = 499 EM ES + ve M + H = 501? NMR (DMSO-de): 0.70 (3H, t, J = 7.0 Hz), 0.85 (9H, s), 2.22 (6H, s), 2.45 (2H, m, partially obscured), 2.60-2.76 (3H, m ), 2.87 (1H, dd, J = 10.5, 13.0 Hz), 2.24 (1H, m), 3.41 (1H, m), 3.49 (1H, m), 3.81 (1H, d, J = 9.0 Hz), 4.04 (1H, d, J = 9.5 Hz), 7.26 (1H, dd, J = 1.0, 8.5 Hz), 7.30 (1H, s), 7.44 (2H, m), 7.56 (2H, m), 7.72 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 7.5 Hz), 7.80 (1 H, m), 9.08 (1H, s), 11.10 (1 H, br s).

EXAMPLE 52 N'-r4- (N-Hydroxyaminol-3S- (2- (1-imidazolenetoxy) -2R- (2-naphthylmethio-Succinyl-S-ter-leucine ethylamide a) N'-r4-t-Butoxy-3S- (2- (1-imidazolyl) ethoxy) -2R- (2-naphthylmetissuccinyl-S-tert-leucine ethylamide) A solution of mesylate (456 mg, 0.770 mmol) prepared from N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leyline ethylamide ( in the same manner as in example 42) and imidazole (115 mg, 1.69 mmol) in DMF (10 ml) was heated at 100 ° C for 7 hours. The DMF was evaporated and ethyl acetate and sodium carbonate solution were added. The product was extracted into ethyl acetate and the extracts were washed with brine and then dried (Na 2 SO 4) and evaporated. Chromatography on silica gel (elution with dichloromethane / methanol) gave the title compound as a white foam (44%). EM ES + ve M + H = 565? NMR (DMSO-de): 0.80 (3H, t, J = 7.0 Hz), 0.86 (9H, s), 1.37 (9H, s), 2.70-2.85 (3H, m), 2.96 (1H, dd, J = 9.5, 13.0 Hz), 3.25 (1 H, m), 3.57 (1 H, m), 3.70 (1 H, m), 3.80 (1 H, d, J = 7.5 Hz), 4.04-4.20 (3H, m, including da 4.12, J = 9.5 Hz), 6.90 (1 H , s), 7.23 (1 H, m), 7.26 (1 H, s), 7.40-7.48 (3H, m), 7. 62 (1 H, m), 7.70 (1 H, s), 7.74-7.85 (4H, m). b) N'-r4- (N-Hydroxyamino) -3S- (2- (1-imidazolyl) ethoxy) -2R- (2-naphthylmethio-succinyl-S-ter-leucine ethylamide) The removal of the t-butyl ester of N '- [4-t-butoxy-3S- (2- (1-imidazolyl) ethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide with TFA, conversion of the TFA salt to the HCl salt and coupling with O-benzylhydroxylamine and removal of the O-benzyl group by hydrogenolysis gave the title compound. EM ES -ve M-H = 522 EM ES + ve M + H = 524? NMR (DMSO-de): 0.67 (3H, t, J = 7.0 Hz), 0.82 (9H, s), 2.50-2.68 (3H, m), 2.84 (1 H, dd, J = 11.0, 13.5 Hz), 3.32 (1 H, m, partially obscured), 3.55 (1 H, m), 3.65 (1 H, m), 3.88 (1 H, d, J = 9.5 Hz), 4.01.4.11 (3H, m), 6.87 (1 H, s), 7.18 (1 H, s), 7.19-7.26 (2 H, m), 7.43 (2 H, m), 7.55 (1 H, s), 7.62 (1 H, s), 7.71 (1 H, d, J = 9.5 Hz), 7.73 (1 H, d, J = 8.5 Hz), 7.77 (1 H, d, J = 7.5 Hz), 7.80 (1 H, d, J = 7.5 Hz), 9.15 (1 H, s), 10.93 (1 H, s).

^^ "^ ^ ^ EXAMPLE 53 N'-r4- (N-Hydroxyamino) -3S- (2-methoxyethoxy) -2R- (2-naphthylmethyl) -succinin-S-ter-leucine ethylamide a) N'-r4-t-Butoxy-3S- (2-methoxyetho-2R- (2-naphthylmethyl) succinop-S-ter-eucine ethylamide To a solution of N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide (617 mg, 1.2 mmol) and proton sponge ( 514 mg, 2.4 mmol) in dichloromethane (10 ml) was added trimethyloxonium tetrafluoroborate (355 mg, 2.4 mmol). After stirring at room temperature for three hours, additional amounts of proton sponge (130 mg) and trimethyloxonium tetrafluoroborate (90 mg) were added and the mixture was stirred for two more hours. Ethyl acetate and 2N HCl were added and the product was extracted into ethyl acetate. The extracts were washed with concentrated sodium bicarbonate solution and brine, and then dried (MgSO 4) and concentrated. The product was chromatographed on silica gel (elution with ethyl acetate / hexane) to give the product as a white foam (88% yield). EM ES + ve M + H = 529, M + Na = 551? NMR (DMSO-de): 0.77 (3H, t, J = 7.2 Hz), 0.86 (9H, s), 1.44 (9H, s), 2.72-2.81 (3H, m), 2.97 (1 H, dd, J = 10.0, 14.0 Hz), 3.22 (1 H, m), 3.24 (3H, s), 3.41-3.47 (3H , m), 3.60 (1 H, d, J = 8.0 Hz), 4.09 (1 H, d, J = 9.5 Hz), 7.29 (1 H, dd, J = 8.5, 10.0 Hz), 7.40-7.55 (3H , m), 7.60 (1 H, s), 7.70 (1 H, d, J = 9.5 Hz), 7.75 (1H, d, J = 8.5 Hz), 7.77-7.85 (2H, m). b) N'-r4- (N-Hydroxyamino) -3S- (2-methoxyethoxy) -2R- (2-naphthylmethyl) succinin-S-tert-leucine ethylamide The N'- [4-t-butoxy-3S- (2-methoxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine ethylamide t-butyl ester was removed with TFA and the resulting carboxylic acid converted to hydroxamic acid as above to give the title compound. EM ES -ve M-H = 486 EM ES + ve M + H = 488, M + Na = 510? NMR (DMSO-de): 0.67 (3H, t, J = 7.5 Hz), 0.85 (9H, s), 2.50-2.69 (3H, m, partially obscured), 2.84 (1H, m), 3.20 (3H, s) ), 3.24 (1H, m), 3.39 (3H, m), 3.52 (1 H, m), 3.80 (1 H, d, J = 9.5 Hz), 4.03 (1 H, d, J = 9.5 Hz), 7.24 (2H, m), 7.43 (2H, m), 7.58 (2H, m), 7.72 (1 H, d, J = 8.5 Hz), 7.75-7.85 (2H, m), 9.10 (1 H, s) , 10.90 (1 H, s).

EXAMPLE 54 N'-r3S- (Ethoxy) -4- (N-hydroxyaminol-2R-2-benzothiophenylmethyl) succinip-S-ter-leucine methylamide It was prepared in the same manner as in Example 1 a) + b) + c) from N-3S-hydroxy-2R-4-methoxy- (2-benzothiophenylmethyl) succinyl] -S-tert-leucine methylamide by alkylation with iodoethane instead of allyl bromide. MS (ES + ve), M + H = 450? NMR (DMSO-de): 0.87 (9H, s), 1.04 (3H, t, J = 6.9 Hz), 2.23 (3H, d, J = 4.5 Hz), 2.71 (1 H, td, J = 1.8 Hz, 15.6 Hz), 2.99 (1 H, t, J = 15.6 Hz), 3. 21 (2H, m), 3.43 (1 H, m), 3.74 (1 M, d, J = 9.5 Hz), 4.14 (1 H, d, J = 9.5 Hz), 7. 07 (1 H, s), 7.28 (2H, m), 7.40 (1 H, q, J = 4.6 Hz), 7.65 (1 H, d, J = 7.3 Hz), 7. 82 (2H, m), 9.10 (1 H, s), 10.90 (1 H, s).

EXAMPLE 55 N'-r4- (N-Hydroxyamino) -3S-cyclohexytoxy-2R- (2-naphthylmethyl) succinyl-S-ter-leucine methylamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by alkylation with cyclohexenyl bromide (instead of allyl bromide), followed by hydrogenation. EM (ES + ve), M + H = 498? NMR (DMSO-de): 0.84 (9H, s), 1.10 (5H, m), 1.45 (1H, m), 1. 64 (2H, m), 1.75 (1 H, m), 1.84 (1 H, m), 2.01 (3H, d, J = 4.5 Hz), 2.67 (1 H, J = 4, 13.5 Hz), 2.82 ( 1 H, dd, J = 13.5, 11 Hz), 3.19 (2H, m), 3.97 (2H, m), 6.91 (1 H, q, J = 4.5 Hz), 7.28 (1 H, m), 7.43 ( 2H, m), 7.52 (1 H, d, J = 9 Hz), 7.59 (1 H, s), 9.07 (1 H, s), 10.87 (1 H, s). düttábM EXAMPLE 56 N'-r4- (N-Hydroxyaminol-3S- (2-hydroxy-2-phenylethoxy-2R- (2-naphthylmethyl-Succinyl-S-ter-leucine-methylamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by alkylation with phenacyl bromide in place of allyl bromide, and reduction with triethylsilane TFA. MS (ES + ve), M + H = 536? NMR (DMSO-de): 0.88 (9H, s), 2.19 (3H, d, J = 4.5 Hz), 2.82 (2H, m), 3.23 (1 H, m), 3.40 (2H, d), 3.89 ( 1 H, d, J = 9 Hz), 4.09 (1 H, d, J = 9 Hz), 4.70 (1 H, m), 5.32 (1 H, br s), 7.28 (7 H, m), 7.43 (2H, m), 7.54 (1 H, s), 7.66 (1 H, d), 7.78 (3H, m), 9.11 (1 H, s), 10.86 (1 H, s). d ^ arid = t ^ B. * EXAMPLE 57 N, -r4- N-Hydroxyamino) -3S-rmorfoli-4-n-2-oxoethoxy1-2R- (2-naphthylmethiPsuccinyl-S-ter-leucine methylamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by alkylation with N- (2-bromoacetyl) morpholinemide instead of allyl bromide. MS (ES + ve), M + H = 543? NMR (DMSO-d6): 0.80 (9H, s), 2.11 (3H, d, J = 4.5 Hz), 2.71. (1 H, dd, J = 4, 14 Hz), 2.87 (1 H, dd, J = 11, 14 Hz), 3.27-3.64 (9H, m), 3.91 (1 H, d, J = 9 Hz), 3.96 (1 H, d, J = 12.5 Hz), 4.03 (1 H, d, J = 9.5 Hz), 4.13 (1 H, d, J = 12.5 Hz), 7.19 (1 H, q, J = 4.5 Hz), 7.26 (1 H, m), 7.45 (2 H, m), 7.58 (1 H, s), 7.75 (4 H, m), 9.14 (1 H, s) , 11.08 (1 H, s).

EXAMPLE 58 N'-r4- (N-Hydroxyamino) -3S-ethoxy-2R- (2-naphthylmethyl) succinyl-S- (N-dimethylisine) methylamide EM (ES + ve), M + H = 487? NMR (DMSO-d6): 1.06 (3H, t, J = 7 Hz), 1.13 (1H, m), 1.30 (4H, m), 1.59 (1H, m), 1.84 (3H, d, J = 4.5 Hz ), 2.08 (8H, m), 2.65 (1H, dd), 2.81 (1H, dd), 3.16 (1H, m), 3.30 (1H, m, partially obscured by water), 3.45 (1H, m), 3.78 (1H, d, J = 9.5 Hz), 4.00 (1H, m), 5.86 (1H, m), 7.29 (1H, m), 7.45 (2H, m), 7.64 (1H, s), 7.85 (3H, m), 7.98 (1H, d), 9.02 (1H, br. s), 11.00 (1H, br. s).

EXAMPLE 59 N'-f4- (N-H -droxyamino) -3S-propoxy-2R- (2-naphthylmethysuccinyl-S- (N-dimethyl-β-β-dimethyl-lysine) ethylamide MS (ES + ve), M + H = 543? NMR (DMSO-de): 0.66 (3H, t, J = 7 Hz), 0.84 (9H, m), 1.15 (2H, m), 1.35 (2H, m), 1.47 (2H, m), 2.07 (8H , m), 2.63 (2H, m), 2.84 (1 H, dd, J = 11, 14 Hz), 3.16-3.40 (m, obscured by water), 3.76 (1 H, d, J = 9.5 Hz), 4.08 (1 H, d, J = 9.5 Hz), 7.26 (2 H, m), 7.43 (2 H, m), 7.52 (1 H, d, J = 9.5 Hz), 7.57 (1 H, s), 7.75 ( 3H, m), 9.14 (1 H, v.br.s), 10.87 (1 H, v.br.s).

EXAMPLE 60 N'-r4- (N-Hydroxyamino) -3S-f2- (4-methylpiperazin-1-yl) -2-oxoethoxy-1-2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methylamide by alkylation with N- (2-bromoacetyl) -N'-methylpiperazinamide instead of allyl bromide. MS (ES + ve), M + H = 556? NMR (DMSO-de): 0.81 (9H, s), 2.11 (3H, d, J = 4.5 Hz), 2.17 (3H, s), 2.18-2.35 (4H, m), 2.72 (1H, dd, J = 4, 14 Hz), 2.88 (1 H, dd, J = 11, 14 Hz), 3.27-3.52 (m, partially obscured by water), 3.91 (1 H, d, J = 9.0 Hz), 3.96 (1 H , d, J = 12.5 Hz), 4.03 (1H, d, J = 9.5 Hz), 4.13 (1 H, d, J = 12.5 Hz), 7.16 (1 H, q, J = 4.5 Hz), 7.26 (1 H, m), 7.44 (2H, m), 7.58 (1 H, s), 7.65 (1 H, d, J = 9.5 Hz), 7.70-7.86 (3H, m), 9.12 (1 H, s), 11.09 (1 H, s).

EXAMPLE 61 N'-r4- (N-Hydroxyamino) -3S-ethoxy-2R- (2-naphthylmethyl) succinin-S-ter-leucine t-butylamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine t-butylamide by alkylation with iodoethane instead of allyl bromide. MS (ES + ve), M + H = 486? NMR (DMSO-de): 0.84 (9H, s), 0.92 (9H, s), 1.05 (3H, t, J = 7 Hz), 2.62 (1 H, dd, J = 3, 13.5 Hz), 2.85 ( 1 H, dd, J = 13, 11.5 Hz), 3.19 (1 H, m), 3.29 (1 H, m obscured by water), 3.44 (1 H, m), 3.75 (1 H, d, J = 10 Hz), 4.08 (1 H, d, J = 9.5 Hz), 7.07 (1 H, s), 7.25 (1 H, d, J = 8.5 Hz), 7.41 (2 H, m), 7.48 (1 H, d , J = 9.5 Hz), 7.56 (1 H, s), 7.71 (1 H, d, J = 8.5 Hz), 7.77 (2 H, d, J = 8.5 Hz), 9.10 (1 H, s), 10.92 ( 1 H, s).

«Z -j -.» EXAMPLE 62 N'-r4- (N-H -droxyamino) -3S-alyloxy-2R- (2-naphthylmethyl) succinyl-S-tert-leucine t-butylamide It was prepared in the same manner as in example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S- ter- leucine t-butylamide by alkylation with allyl bromide. EM (ES + ve), M + H = 498? NMR (DMSO-de): 0.82 (9H, s), 0.92 (9H, s), 2.63 (1H, dd), 2.83 (1H, dd), 3.24 (1H, m), 3.79 (1H, dd), 3.82 (1H, d, J = 10 Hz), 3.94 (1H, dd), 4.07 (1H, d, darkened), 5.10 (1H, dd), 5.22 (1H, dd, J = 1.5, 17.5 Hz), 5.77 ( 1H, m), 7.07 (1H, s), 7.25 (1H, dd), 7.41 (2H, m), 7.54 (2H, m), 7.71 (1H, d, J = 8.5 Hz), 7.78 (2H, dd , J = 8.5 Hz), 9.10 (1H, s), 10.93 (1H, s).

EXAMPLE 63 N'-r4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinin-S-ter-leucine t-butylamide Prepared in the same manner as in Example 1 a) + b) + c) from N-4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine t-butylamide by alkylation with iodopropane instead of allyl bromide. EM (ES + ve), M + H = 500? NMR (DMSO-de): 0.82 (3H, t, J = 7.5 Hz), 0.84 (9H, s) 1.45 (2H, m), 2.63 (1 H, dd, J = 3.5, 13.5 Hz), 2.85 (1 H, dd, J = 11.5 Hz), 3.18 (2H, m), 3.11 (1 H, m obscured by water), 3.75 (1 H, d, J = 9.5 Hz), 4.07 (1 H, m), 7.06 (1 H, s), 7.25 (1 H, d, J = 8.5 Hz), 7.44 (3 H, m), 7.56 (1 H, s), 7.72 (1 H, d, J = 8.5 Hz), 7.78 ( 2H, d, J = 8.5 Hz), 9.09 (1 H, s), 10.88 (1 H, s).

EXAMPLE 64 Benzyl ester of N'-r4- (N-hydroxyamino) -3S-allyloxy-2R- (2-naphthylmethyl-succinyl-S-ter-leucine) MS (ES + ve), M + H = 533? NMR (DMSO-de): 0.81 (9H, s), 2.63 (1H, dd, J = 3.5, 13.5 Hz), 2.82 (1H, dd, J = 13.5, 8 Hz), 3.35 (1H, m), 3.76 (1H, dd, J = 5.5, 13 Hz), 3.84 (1H, d, J = 10 Hz), 3.93 (1H, dd, J = 5, 13 Hz), 4.18 (1H, d, J = 9 Hz) , 4.42 (1H, d, J = 12 Hz), 4.59 (1H, d, J = 12.5 Hz), 5.08 (1H, d, J = 10.5 Hz), 5.20 (1H, d, J = 17 Hz), 5.74 (1H, m) 7.13 (2H, m), 7.23 (1H, d, J = 8.5 Hz), 7.29 (2H, m), 7.42 (2H, m), 7.57 (1H, s), 7.68 (1H, d) , J = 8.5 Hz), 7.80 (2H, m), 8.05 (1H, d), 9.11 (1H, s), 10.98 (1H, s).

EXAMPLE 65 N'-r4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinin-S-tert-leucine methoxyamide EM (ES + ve), M + H = 474? NMR (DMSO-de): 0.81 (3H, t, J = 7.5 Hz), 0.85 (9H, s), 1.44 (2H, m), 2.64 (1H, dd, J = 3.5, 13.5 Hz), 2.85 (1H , dd, J = 13.5, 11 Hz), 3.12 (1H, s), 3.20 (3H, m), 3.77 (1H, d, J = 9.5 Hz), 3.96 (1H, d, J = 9.5 Hz), 7.26 (1H, d, J = 8.5 Hz), 7.41 (2H, m), 7.56 (1H, s), 7.72 (1H, d, J = 8.5 Hz), 7.78 (3H, m), 9.09 (1H, s) , 10.88 (1H, s) .10.94 (1H, s).

EXAMPLE 66 N, -r4-fN-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl-S-tert-leucine (N-dimethylamino-2-yl) amide MS (ES + ve), M + H = 514 1 H NMR (DMSO-de): 0.82 (3H, t, J = 7.5 Hz), 0.84 (9H, s), 1.45 (2H, m), 2.01 (6H, s), 2.59 (1 H, m), 2.64 (1 H, dd), 2.74 (1 H, m), 2.84 (1 H, dd), 3.20 (2H, m), 3.77 (1H, d, J = 9.5 Hz), 7.23 (2H, m), 7.43 (2H, m), 7.58 (2H, m), 7.77 (3H, m), 9.10 (1 H, s), 10.90 (1 H, s).

EXAMPLE 67 N'-r4-fN-Hydroxyamino) -3S-propoxy-2R-f2-naphthylmethyl) succinin-R-ter-leucine (N.N-dimethylaminoet-2-yOamide EM (ES + ve), M + H = 514? NMR (DMSO-de): 0.33 (9H, s), 0.76 (3H, t, J = 7.5 Hz), 1.37 (2H, m), 2.12 (6H, s), 2.70 (1H, dd), 2.77 (1H , dd, J = 13.5, 12 Hz), 3.10 (4H, m), 3.51 (1H, m), 3.72 (1H, d, J = 10 Hz), 4.00 (1H, d, J = 9.5 Hz), 7.35 (1H, d, J = 8.5 Hz), 7.41 (2H, m), 7.64 (1H, d, J = 9.5 Hz), 7.70 (1H, s), 7.77 (4H, m), 9.09 (1H, s) , 10.92 (1H, s).

EXAMPLE 68 N'-r4- (N-Hydroxyamino) -3S-ethoxy-2R- (2-naphthylmethyl-succinyl-S- (O-benzyl) ter-leucinol EM (ES + ve), M + H = 521? NMR (DMSO-de): 0.79 (9H, s), 0.82 (3H, t), 1.42 (2H, m), 2.63 (2H, m), 2.82 (2H, m), 3.19 (2H, m), 3.29 (1H, t), 3.64 (1H, m), 3.70 (2H, d, J = 7 Hz), 3.79 (1H, d, J = 10 Hz), 6.99 (1H, d, J = 6.5 Hz), 7.25 (4H, m), 7.42 (3H, m), 7.60 (1H, s), 7.68 (1H, d, J = 8.5 Hz), 7.79 (2H, m), 9.10 (1H, s), 10.97 (1H, s).

EXAMPLE 69 N'-r4-fN-Hydroxyamino) -3S-propoxy-2R-rS-1 (1.2.3.4-tetrahydronaphthalen-2-yl) methyl) succinop-S-ter-leucine methylamide i) Alcohol 2R-1.2.3.4-tetrahydronaphthaten-2-methyl 2R-1, 2,3,4-tetrahydronaphthoic acid (2.26 g, 12.84 mmol) (prepared as described by Charlton et al., Synlett. (1990), 333) in dry THD (35 ml) at 0-5 ° C it was treated with a 1M solution of LYH4 in THF (12.85 ml) and the resulting mixture was stirred at 0-5 ° C for 0.25 hours followed by one hour at room temperature. The reaction mixture was then treated with water (1 ml), 2M NaOH solution (1 ml) and water (1 ml) and then filtered through Celite. The filtrate was evaporated to dryness and the residue was partitioned between diethyl ether and dilute NaHCO3 solution. The ether layer was separated, washed with dilute NaHC 3 solution (x3) and brine (x1), and then dried over MgSO. It was filtered and evaporated to dryness. The crude product was purified by chromatography on silica gel to give the title compound, 1.51 g. ? NMR (CDCl 3) 1.45 (2H, m), 1.97 (2H, m), 2.50 (1 H, dd, J = 10.5, 16.5 Hz), 2.87 (3H, m), 3.64 (2H, br.s), 7.09 (4H, m). [a] +88.2 (c = 0.53, CHCI3) ii) Ester f (R) -1- (1, 2,3,4-tetrahydronaphthalen-2-yl) methyl 1 of trifluoromethanesulfonic acid The alcohol (1.47 g, 9.07 mmol) and pyridine (0.72 g, 9.07 mmol) in dry dichloromethane (20 ml) were added dropwise to a solution of triflic anhydride (2.56 g, 9.07 mmol) in dichloromethane at 0.5 ° C. The resulting mixture was stirred at that temperature for two hours before being washed with dilute and cold H2SO4 (x3), cold and diluted NaHC? 3 solution (x3) and brine (x1). The organic solution was dried over MgSO4, filtered and evaporated to yield the title compound as a golden oil (2.56 g). ? NMR (CDCl 3) 1.55 (1 H, m), 2.05 (1 H, m), 2.35 (1 H, m), 2.60 (1 H, dd, J = 10.5, 16.5 Hz), 2.88 (3H, m), 4.48 (1 H, d, J = 9.5 Hz), 4.53 (1 H, d, J = 9.5 Hz), 7.14 (4H, m).

-BÉÉ ^ ÉÉ? ÉÉilÉi? -ÉÉ? -ÉßÉ- ^ iii) (2R, 3S) -3-Hydroxy-2-r (S) -1-d .2.3.4-tetrahydronaphthalen-2-diethylmethemeuccinate S-diethyl malate (2.94 g, 15.3 mmol) in dry THF (25 mL) was added dropwise to a 1 M solution of LHMDS in THF (33.7 mL) at -70 ° C under argon, keeping the temperature below - 50 ° C during the addition. The solution was stirred at -70 ° C for two hours and then a solution of the above triflate (15.3 mmoles) in dry THF (20 ml) was slowly added dropwise keeping the temperature below -60 ° C. The reaction solution was then stirred at -70 ° C at room temperature for 18 hours and then poured into dilute and cold HCl and the product was extracted with diethyl ether (x3). The combined extracts were washed with dilute HCl (x1), saturated NaHCO3 solution (x3) and brine (x1) before being dried with MgSO4, filtered and evaporated to leave the crude product. Chromatography on silica gave the pure title compound (2.11 g). MS (ES + ve), M + H = 357? NMR (CDCl 3) 1.24 (3 H, t, J = 7.0 Hz), 1.32 (3 H, t, J = 7.0 Hz), 1.45 (1 H, m), 1.67 (1 H, m), 1.83 (1 H, m ), 1.97 (1 H, m), 2.45 (1 H, dd, J = 10, 16 Hz), 2.82 (2 H, m), 2.93 (1 H, dd, J = 4, 16 Hz), 3.18 (1 H, d, J = 7.5 Hz), 4.13 (2H, m), 4.27 (3H, m), 7.08 (4H, m). iv) (2R.3S) -3-Allyloxy-2-r (S) -1 - (1, 2,3,4-tetrahydronaphthalen-2-methyl-diethylamine) The alcohol from iii) above (1.62 g, 4.85 mmol) and allyl bromide (5.87 g, 48.5 mmol) in dry DMF (15 ml) were treated with 60% NaH in oil (0.233 g, 5.82 mmol) and the mixture it was stirred at room temperature for 1.25 hours. Then, saturated NH 4 Cl solution was added and the mixture evaporated almost to dryness. The residue was partitioned between diethyl ether and water and the organic layer was separated and washed with dilute HCl (x4) and brine (x1). The solution was dried (MgSO), filtered and evaporated to leave an orange oil. This was purified on silica to give the title compound (1.61 g). EM (ES + ve), M + H = 375? NMR (CDCl 3) 1.26 (6H, m), 1.38 (2H, m), 1.71 (1H, m), 1.86 (2H, m), 2.37 (1H, dd), 2.79 (2H, m), 2.96 ( 1 H, dd), 3.07 (1 H, m), 3.93 (1 H, dd, J = 6, 12.5 Hz), 4.07 (1 H, d, J = 8 Hz), 4.17 (5H, m), 5.18 (1 H, dd, J = 1, 10.5 Hz), 5.25 (1 H, dd, J = 1, 15.5 Hz), 5.85 (1 H, m), 7.07 (4H, m). v) (2R.3S) -3-Propoxy-2-r (S) -1-d .2.3,4-tetrahydronaphthalen-2-diethyl methyl-succinate The O-allyl derivative of iv) above (1.61 g, 4.30 mmol) in methanol (30 ml) was hydrogenated at atmospheric pressure over 10% Pd / C (500 mg) for two hours. The catalyst was filtered and the filtrate was evaporated to dryness to give the title compound as a colorless oil. (1.56 g). EM (ES + ve), M + H = 377? NMR (CDCl 3) 0.89 (3H, t, J = 7.5 Hz), 1.26 (6H, m), 1.38 (2H, m), 1.58 (2H, m), 1.70 (1 H, m), 1.83 (2H, m ), 2.35 (1 H, dd), 2.78 (2 H, m), 2.95 (1 H, dd), 3.03 (1 H, m), 3.30 (1 H, m), 3.53 (1 H, m), 3.99 (1 H, d, J = 8.5 Hz), 4.17 (4H, m), 7.06 (4H, m). vi) Acid (2R.3S) -3-propoxy-2 - [(S) -1 -M, 2,3,4-tetrahydronaphthalen-2-methylsuccinic acid The diethyl ester from v) above (1.54 g, 4.1 mmol) in dioxane (12 ml) was treated with 2M KOH solution (6.15 ml) and the mixture was stirred at room temperature for 22.5 hours followed by three hours at 80 ° C. . The solution was evaporated to dryness and the resulting residue was dissolved in water and washed with ethyl acetate. The aqueous solution was then saturated with NaCl and the pH was adjusted to 1 with dilute HCl. The product was extracted into ethyl acetate (x3) and the combined extracts were washed with brine (x1), dried (MgSO4), filtered and evaporated to give the title compound as a white solid (1.35 g) . MS (ES -ve), MH = 319 1 H NMR (DMSO-de) 0.84 (3H, d, J = 7.5 Hz), 1.33 (2H, m), 1.47 (2H, m), 1.67 (2H, m), 1.82 (1 H, m), 2.30 (1 H, dd), 2.67-2.91 (4H, m), 3.25 (1 H, m), 3.48 (1 H, m), 3.85 (1 H, d, J = 8 Hz), 7.05 (4H, m), 12.20-13.00 (2H, v.br.s). vii) 4-methytic (2R, 3S) -3-propoxy-2 - [(S) -1 - (1.2.3.4-tetrahydronaphthalen-2-y!) methylsuccinic acid ester The diacid from vi) above (1.3 g, 4.1 mmol) in dry dichloromethane (15 ml) was cooled in an ice bath and treated with trifluoroacetic anhydride (8 ml). The resulting solution was stirred at 0.5 ° C for 10 minutes followed by two hours at room temperature. The solution was then evaporated to dryness to leave the corresponding anhydride as a colorless oil (vmax 1788 cm'1). This was dissolved in methanol (20 ml) and stirred at room temperature for 16 hours. Evaporation of the solvent gave e, the title compound as a pale yellow oil (1.43 g). EM (ES -ve), M-H = 333? NMR (CDCl 3) 0.90 (3H, t, J = 7.5 Hz), 1.44 (2H, m), 1.62 (2H, m), 1.77-1.96 (3H, m), 2.40 (1H, dd), 2.80 (2H , m), 2.97 (1 H, dd), 3.10 (1 H, m), 3.34 (1 H, m), 3.71 (1 H, m), 3.76 (3 H, s), 4.03 (1 H, d, J = 7.5 Hz), 7.07 (4H, m). viii) N'-r4-Methoxy-3S-propoxy-2R-rS-1 - (1, 2,3,4-tetrahydronaphthalen-2-yl) methylsuccinyl!) - S-ter-leucine methylamide A solution of the acid from vii) above (1.43 g, 4.28 mmol) in dry DMF (15 ml) was treated with HOBt (1.16 g, 8.56 mmol) and EDC (1.64 g, 8. 56 mmoles) and the resulting solution was stirred at room temperature during minutes. Then S-ter-leucine methylamide hydrochloride (0.85 g, 4.71 mmol) was added followed by DIPEA (0.66 g, 5.14 mmol) and the reaction solution was stirred at room temperature for 1.25 hours. It was then evaporated to dryness and the residue was partitioned between EtOAc and dilute HCl.

The organic layer was rinsed and washed with dilute HCl (x3), dilute NaHCO3. (x3) and brine (x1). It was dried (MgSO 4) and evaporated to leave the crude product which was purified on silica to give the title compound (1.44 g). MS (ES + ve), M + H = 461 1 H NMR (CDCl 3) 0.96 (3H, t, J = 7.5 Hz), 1.03 (9H, s), 1.32-1.74 (5H, m), 1.88 (2H, m), 2.42 (1H, dd), 2.73 (3H, d, J = 5 Hz), 2.76-3.00 (5H, m), 3. 33 (1 H, m), 3.62 (1 H, m), 3.77 (3 H, s), 3.99 (1 H, d, J = 5 Hz), 4.09 (1 H, d, J = 9 Hz), 6.29 (1 H, m), 7.03 (5H, m). ix) N'-f4-Hydroxy-3S-propoxy-2R-fS-1- (1,2,3,4-tetrahydronaphthalen-2-yl) methy!) succinyl-S-ter-eucine methylamide A solution of the ester from viii) above (0.68 g) in dioxane (12 ml) was treated dropwise with a solution of LiOH.H20 (0.142 g) in water (5 ml).

The resulting solution was stirred at room temperature for 1.75 hours and then evaporated almost to dryness. The residue was partitioned between water and EtOAc and the aqueous phase was separated and washed with EtOAc (x1) before being saturated with NaCl, acidified to pH1 and extracted with EtOAc (x3). The combined extracts were washed with brine (x1), dried (MgSO4) and evaporated to give the product as a white solid (0.63 g). EM (ES + ve), M + H = 447? NMR (DMSO-de) 0.82 (3H, t, J = 7.5 Hz), 0.90 (9H, s), 1.22 (2H, m), 1.40-1.61 (4H, m), 1.73 (1 H, m), 2.24 (1 H, dd, J = 10, 16 Hz), 2.40 (3H, d, J = 4.5 Hz), 2.67 (2H, m), 2.95 (2H, m), 3.21 (1 H, m), 3.38 (1 H, m, darkened with water), 3.78 (1 H, d, J = 9 Hz), 4.18 (1 H, d, J = 9.5 Hz), 7.01 (4H, m), 7.71 (1 H, q, J = 4.5 Hz), 7.90 (1 H, d, J = 9.5 Hz), 12.84 (1 H, br.s), x) N '- [4- (N-Hydroxyamino) -3S-propoxy-2R-fS-1-p .2.3.4-tetrahydronaphthalen-2-iPmetiPsuccinill-S-ter-leucine methylamide A solution of the acid from ix) above (0.61 g) in dry DMF (10 ml) was treated with HOAt (0.372 g) and EDC (0.524 g) and stirred at room temperature for 10 minutes. Then, hydroxylamine hydrochloride (0.285 g) and NMM (0.414 g) were added and the reaction mixture was stirred at room temperature for two hours. It was then evaporated to dryness and the residue was partitioned between EtOAc and dilute HCl. The organic phase was separated and washed with dilute HCl, dilute NaHCO3 and water, and then evaporated to dryness to leave a white solid. This was triturated with diethyl ether and then filtered and dried under vacuum to give the title compound (0.434 g). MS (ES + ve), M + H = 462 1 H NMR (DMSO-d 6) 0.80 (3H, t, J = 7.5 Hz), 0.90 (9H, s), 1.08. (1 H, m), 1.23 (1 H, m), 1.45 (4 H, m), 1.70 (1 H, m), 2.19 (1 H, dd), 2.35 (3 H, d, J = 4.5 Hz), 2.65 (2H, m), 2.97 (2H, m), 3.14 (1 H, m), 3.27 (1 H, m), 3.63 (1 H, d, J = 9.5 Hz), 4.18 (1 H, d, J = 9.5 Hz), 7.02 (4H, m), 7.59 (1 H, q, J = 4.5 Hz), 7.83 (1 H, d, J = 9.5 Hz), 9.02 (1 H, s), 10.78 (1 H, s).

EXAMPLE 70 N'-f3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-auinolinylmethyl) succinin-S-ter-leucine ethylamide % Pd-BaSO4 (50 mg) was added to a solution of N '- [4- (N-benzyloxyamino) -3S- (ethoxy) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucine ethylamide ( 0.17 g, 0.3 mmol) in methanol (15 ml) and cyclohexene (5 ml) under argon. The mixture was refluxed for six hours and then cooled and filtered through a plug of celite. The filtrate was evaporated to give a solid which was triturated with ether (3 x 2 mL) to give the title compound as a white solid (0.13 g, 0.28 mmol, 92%). MS (ES + ve), [M + H] + = 459 1 H NMR (DMSO-de) 0.66 (3H, t, J = 7.2 Hz), 0.83 (9H, s), 1.04 (3H, t, J = 7.0 Hz), 2.58 (2H, m), 2.70 (1 H, m), 2.84 (2H, m), 3.39 (2H, m), 3.81 (1 H, d, J = 9.7 Hz), 4.05 (1 H, d, J = 9.6 Hz), 7.35 (3H, t, J = 5.3 Hz), 7.55 (3H, t, J = 7.4 Hz), 7.68 (1 H, d, J = 8.5 Hz), 7.70 (1 H, d, J = 10.4 Hz), 7.83 (1 H, d, J = 7.6 Hz), 7.94 (1 H, d, J = 7.9 Hz), 7.97 (1 H, s), 8.60 (1 H, d, J = 2 Hz), 9.11 (1 H, s), 10.96 (1 H, s).

EXAMPLE 71 N'-r4- (N-Hydroxyamino) -3S- (propoxy) -2R- (2-quinolinylmethiPsuccinin-S-ter-leucine ethylamide % Pd-BaSO4 (50 mg) was added to a solution of N '- [4- (N-benzyloxyamino) -3S- (propoxy) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucine ethylamide ( 0.12 g, 0.21 mmol) in methanol (15 ml). The mixture was stirred under a hydrogen atmosphere for 48 hours and then filtered through a plug of celite. The filtrate was evaporated to give a solid which was triturated with ether (3 x 2 mL) to give the title compound as a white solid (0.05 g, 0.11 mmol, 54%). MS (ES + ve), [M + H] + = 473 1 H NMR (DMSO-de): 0.66 (3H, t, J = 7.2 Hz), 0.81 (3H, t, J = 7.0 Hz), 0.83 (9H , s), 1.43 (2H, m), 2.58 (2H, m), 2.70 (1H, m), 2.84 (2H, m), 3.39 (2H, m), 3.81 (1H, d, J = 9.7 Hz), 4.05 (1 H, d, J = 9.6 Hz), 7.35 (1 H, t, J = 5.3 Hz), 7.55 (1 H, t, J = 7.4 Hz), 7.68 (1 H, d, J = 8.5 Hz), 7.70 (1 H, d, J = 10.4 Hz), 7.83 (1 H, d, J = 7.6 Hz), 7.94 (1 H, d, J = 7.9 Hz), 7.97 (1 H, s ), 8.60 (1 H, d, J = 2 Hz), 9.11 (1 H, s), 10.96 (1 H, s).

EXAMPLE 72 N'-r3S- (EtoxP-2R-f2- (6-fluoro) -naphthylmethyl-4-fN-hydroxyamino) succinin-S-ter-leucine ethylamide % Pd-BaSO4 (50 mg) was added to a solution of N '- [4- (N-benzyloxyamino) -3S- (ethoxy) -2R- (2- (6-fluoro) naphthylmethyl) succinyl] -S- ter-leucine ethylamide (0.17 g, 0.3 mmol) in methanol (15 ml) and cyclohexene (5 ml) under argon. The mixture was refluxed for four hours and then cooled and filtered through a plug of celite. The filtrate was evaporated to give a solid which was triturated with ether (3 x 2 mL) to give the title compound as a white solid (0.12 g, 0.26 mmol, 62%). MS (ES + ve), [M + H] + = 476 - - * - «» '- • > - 1 H NMR (DMSO-de): 1.04 (9H, s), 1.21 (3H, t, J = 7.0 Hz), 1.43 (3H, t, J = 6.6 Hz), 3.08 (2H, m), 3.41 (2H , m), 3.48 (2H, q, J = 7.0 Hz), 3.64 (1 H, d, J = 2.8 Hz), 3.82 (3H, t, J = 7.2 Hz), 4.00 (1 H, d, J = 9.1 Hz), 7.14 (1 H, m), 7.22 (1 H, m), 7.43 (2 H, m), 7.71 (4 H, m), 7.96 (1 H, d, J = 10.5 Hz), 9.51 (1 H , br s).

EXAMPLE 73 N'-r4- (N-hydroxyamino) -3S-allyloxy-2R- (2-naphthylmethyl-succinyl-S-ter-leucine methyl ester) It was prepared in a manner similar to that of Example 64. MS (ES + ve), [M + H] + = 445 1 H NMR (DMSO-de): 0.84 (9H, s), 1.01 (3H, t, J = 7 Hz), 2.68 (1 H, dd, J = 13.5, 4 Hz), 2.73-2.83 (1 H, m), 3.20-3.79 (3 H, m), 3.27 (3 H, m), 3.77 (1 H, d , J = 10 Hz), 4.15 (1 H, d, J = 9 Hz), 7.21 (1 H, dd, J = 8, 1.5 Hz), 7.40-7.46 (2H, m), 7.55 (1 H, s ), 7.74 (1 H, d, J = 9 Hz), 7.75-7.81 (2H, m), 7.90 (1 H, d, J = 9 Hz), 9.09 (1H, d, J = 0.5 Hz), 10.96 (1H, d, J = 0.5 Hz).

EXAMPLE 74 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl-3S-propoxPsuccinip-S-ter-leucine isopropylamide It was prepared in a manner similar to that of Example 1 from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine isopropylamide by alkylation with allyl bromide , hydrogenation, cutting with t-butyl ester and formation of hydroxamic acid. MS (ES -ve) [M-H] + = 484 1 H NMR (DMSO-d 6): 0.72 (3H, d, J = 6.5 Hz), 0.75 (3H, d, J = 6.5 Hz), 0.82 (3H, t, J = 7.5 Hz), 0.84 (9H, s), 1.40-1.51 (2H, m), 2.64 (1 H, dd, J = 13, 3 Hz), 2.77-2.91 ( 1 H, m), 3.18-3.37 (3 H, m), 3.44-3.50 (1 H, m), 3.77 (1 H, d, J = 10 Hz), 4.06 (1 H, d, J = 10 Hz) , 7.24 (1 H, dd, J = 8, 1.5 Hz), 7.36-7.44 (3H, m), 7.53 (1 H, d, J = 10 Hz), 7.55 (1 H, s), 7.70 (1 H , d, J = 8.5 Hz), 7.72-7.79 (2H, m), 9.09 (1 H, s), 10.89 (1 H, s).

EXAMPLE 75 N'-f3S-Ethoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) Ssuccinin-S-ter-leucine isopropylamide It was prepared in a manner similar to that of Example 1 from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine isopropylamide by alkylation with iodoethane, cut with t-butyl ester and hydroxamic acid formation. MS (ES -ve) [M-H] + = 470 1 H NMR (DMSO-de): 0.72 (3H, d, J = 6.5 Hz), 0.76 (3H, d, J = 6.5 Hz), 0.84 (9H, s), 1.05 (3H, t, J = 7 Hz), 2.63 (1 H, dd, J = 13, 3 Hz), 2.80-2.91 (1 H, m), 3.17-3.27 (2H, m), 3.41-3.51 (2H, m), 3.76 (1 H, d, J = 10 Hz), 4.08 (1 H, d, J = 10 Hz), 7.24 (1 H, dd, J = 8, 1.5 Hz), 7.39-7.44 (3H, m), 7.53 (1 H, d, J = 10 Hz), 7.55 (1 H, s), 7.69 (1 H, d, J = 8 Hz), 7.71 -7.78 (2H, m), 9.08 (1 H, s), 10.89 (1 H, s).

EXAMPLE 76 N'-r3S-Ethoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl-S-ter-leucine (2.2.2-trifluoroetiPamide It was prepared in a manner similar to that of Example 1 from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine- (2.2.2 -trifluoroethyl) -amide by alkylation with allyl bromide, hydrogenation, cutting with t-butyl ester and formation of hydroxamic acid. MS (ES-ve) [MH] + = 524 1 H NMR (DMSO-de): 0.81 (3H, t, J = 7.5 Hz), 0.83 (9H, s), 1.41- 1.47 (2H, m), 2.62- 2.67 (1 H, m), 2.81 (1 H, app t, J = 13.5 Hz), 3.17-3.80 (5H, m), 3.79 (1 H, d, J = 9.5 Hz), 4.17 (1 H, d , J = 9.5 Hz), 7.22 (1 H, dd, J = 10, 1.5 Hz), 7.42-7.46 (2 H, m), 7.53 (1 H, s), 7.55 (1 H, s), 7.63 (1 H, d, J = 9.5 Hz), 7.72 (1 H, d, J = 8.5 Hz), 7.76 (1 H, d, J = 8.5 Hz), 7.83 (1 H, d, J = 8.5 Hz), 8.06 (1 H, app t, J = 6 Hz), 9.09 (1 H, s), 10.92 (1 H, s).

EXAMPLE 77 N'-r3S-Ethoxy-4- (N-hydroxyamino-2R- (2-naphthylmethyl) succinin-S-ter-leucine (2.2.2-trifluoroetiPamide It was prepared in a manner similar to that of Example 1 from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine (2,2,2- trifluoroethyl) amide by alkylation with allyl bromide, cutting with t-butyl ester and formation of hydroxamic acid. MS (ES -ve) [M-H] + = 522 1 H NMR (DMSO-de): 0.81 (9H, s), 2.64-2.74 (2H, m), 3.24-3.31. (3H, m), 3.78 (1H, dd, J = 8, 3.5 Hz), 3.86 (1 H, d, J = 6 Hz), 3.95 (1H, dd, J = 8, 3.5 Hz), 4.19 (1 H, d, J = 6 Hz), 5.07-5.24 (2H, m), 5.74-5.81 (1 H, m), 7.22 (1 H, d, J = 5 Hz), 7.41-7.46 (2H, m) , 7.53 (1 H, s), 7.66-7-84 (4H, m), 8.12 (3H, t, J = 4 Hz), 9.11 (1 H, s), 10.92 (1 H, s).

EXAMPLE 78 N'-r4- (N-Hydroxyamino-3S-propoxy-2R-rS or R-1 - (1, 2,3,4-tetrahydronaphthalen-2-iPmetiPsuccinin-S-ter) -leucinamide MS (ES -ve) [M-H] + = 446 EXAMPLE 79 N'-r2R- (2-fFluoronaphthiPmetiP-4- (N-hydroxyamino) -3S-propoxPsuccinin-S-ter-leucine ethylamide Prepared in the same manner as in Example 1 d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxysuccinic acid diethyl ester, alkylating using allyl bromide.

MS (ES + ve) M + H = 490, M + Na = 512 1 H NMR (DMSO-de): 0.67 (3H, t, J = 7 Hz), 0.81 (3H, t, J = 7.5 Hz), 0.84. (9H, s), 1.45 (2H, sextet, J = 7 Hz), 2.53-2.68 (3H, m), 2.82 (1 H, m), 3.16-3.25 (3H, m), 3.77 (1 H, d , J = 9.5 Hz), 4.02 (1 H, d, J = 9.5 Hz), 7.26-7.30 (2H, m), 7.35 (1 H, m), 7.55-7.62 (2H, m), 7.61 (1 H , s), 7.72 (1 H, d, J = 8.5 Hz), 7.85 (1 H, m), 9.09 (1 H, br s), 10.86 (1 H, br s).

EXAMPLE 80 N'-r3S-Ethoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl-Succinin-S-ter-leucine cyclopropylamide It was prepared in the same manner as in Example 1 from N- [4-t-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine cyclopropylamide by alkylation with allyl bromide , hydrogenation, cutting with tert-butyl ester and formation of hydroxamic acid. EM (ES + ve), M + H = 470, M + Na = 492. 1 H NMR (DMSO-de): 0.06 (2H, m), 0.42 (2H, m), 0.83 (9H, s), 1.05 (3H, t, J = 7 Hz), 2.20 (1 H, m), 2.63 (1 H, dd, J = 14, 3.5 Hz), 2.87 (1 H, dd, J = 14, 11 Hz), 3.19 (1 H, m), ax . 3.28 and 3.44 (2H, 2 xm, partially obscured by H20 signal), 3.76 (1H, d, J = 9.5 Hz), 4.05 (1H, d, J = 9.5 Hz), 7.23 (1H, dd, J = 8.5 , 1.5 Hz), 7.42 (2H, m), 7.55 (1H, s), 7.59 (1H, d, J = 9.5 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.80 (2H, m), 9.09 (1H, br. S), 10.88 (1H, br. S).

EXAMPLE 81 N'-r3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl-succinyl-S-ter-leucinamide) It was prepared in a manner similar to that of Example 34. MS (ES + ve), M + H = 458, M + Na = 480. 1 H NMR (DMSO-de): 0.90 (9H, s), 1.12 (9H, s) ), 2.73 (1H, dd, J = 14, 3.5 Hz), 2.90 (1H, dd, J = 14, 11 Hz), 3.04 (1H, m), 3.99 (1H, d, J = 9.5 Hz), 4.01 (1H, d, J = 9 Hz), 6.63 (1H, br. S), 6.83 (1H, br.s), 7.26 (1H, dd, J = 8.5, 1.5 Hz), 7.43 (2H, m), 7.55 (1H, d, J = 9 Hz), 7.59 (1H, s), 7.74 (1H, d, J = 8.5 Hz), 7.81 (2H, m), 8.95 (1H, br. S), 10.71 (1H , br. s).

EXAMPLE 82 N'-r4- (N-Hydroxyamino?) - 3S- (1.2.4-oxadiazol-3-iDmethoxy) -2R- (2-naphthylmethiDsuccinyl-S-ter-leucine methylamide) MS (ES + ve), M + Na = 520, M + N = 498 MS (ES -ve), M-Na = 496 1 H NMR (DMSO-de): 0.70 (9H, s), 2.04 (3H, d , J = 4.5 Hz), 2.67 (1H, m), 2.84 (1H, dd, J = 11.2, 13.6 Hz), 3.36 (1H, m), 3.98 (1H, d, J = 9.5 Hz), 4.04 (1H , d, J = 10.9 Hz), 4.48 (1H, d, J --- 12.3 Hz), 4.63 (1H, d, J = 12.3 Hz), 6.99 (1H, q, J = 4.4 Hz), 7.24 (1H , d, J = 8.4 Hz), 7.44 (2H, m), 7.57 (1H, s), 7.63 (1H, d, J = 8.5 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.78 (1H , d, J = 8.3 Hz), 7.84 (1H, d, J = 8.3 Hz), 9.20 (1H, s), 9.58 (1H, s), 11.05 (1H, s).

EXAMPLE 83 N'-r4- (N-Hydroxyaminol-3S- (2-thiazolylmethoxy) -2R- (2-naphthylmethyl) succinin-S-ter-leucine methylamide MS (ES + ve), M + Na = 535, M + N = 512 MS (ES -ve), M-Na = 511 1 H NMR (DMSO-d 6): 0.74 (9H, s), 2.04 (3H, d , J = 4.5 Hz), 2.70 (1H, m), 2.84 (1H, t, J = 13.5 Hz), 3.36 (1H, m), 4.01 (1H, d, J = 9.4 Hz), 4.07 (1H, d , J = 9.8 Hz), 4.65 (1H, d, J = 12.9 Hz), 4.77 (1H, d, J = 12.8 Hz), 7.04 (1H, d, J = 4.7 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.44 (2H, m), 7.58 (1H, s), 7.74 (4H, m), 7.78 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 8.3 Hz), 9.20 (1H, s), 11.05 (1H, s).

• Aaniaittiui EXAMPLE 84 N'-f2R- (4-benzocycloheptypromethyl-4- (N-hydroxyamino) -3S- (propoxy) succinin-S-ter-leucine methylamide MS (ES + ve), M + Na = 476, M + Na = 498 MS (ES -ve), MH = 474 1 H NMR (DMSO-de): 0.79 (3H, t, J = 7.3 Hz), 0.93 ( 9H, s), 1.32-1.45 (3H, m), 1.70 (1H, m), 2.05 (1H, m), 2.45-2.56 (4H, m), 2.58-2.67 (7H, m), 2.91 (1H, m), 3.11 (1H, m), 3.26 (1H, m), 3.59 (1 H, d, J = 9.6 Hz), 4.24 (1 H, d, J = 9.5 Hz), 7.04 (4H, m), 7.76 (1 H, d, J = 9.5 Hz), 7.82 (1 H, d, J = 4.5 Hz), 8.97 (1 H, s), 10.72 (1 H, s).

EXAMPLE 85 N'-r2R- (3-Benzocyclopentymethyl-4- (N-hydroxyamino) -3S- (propoxps? Ccinin-S-ter-leucine methylamide MS (ES + ve), M + H = 448, M + Na = 470 MS (ES -ve), MH = 446 1 H NMR (DMSO-de): 0.79 (3H, t, J = 7.4 Hz), 0.92 ( 9H, s), 1.25 (1H, m), 1.42 (2H, m), 1.56 (1H, m), 2.20 (1H, m), 2.50 (4H, m), 2.88 (2H, m), 3.00 (1H , m), 3.13 (1H, m), 3.26 (1H, m), 3.63 (1H, d, J = 9.8 Hz), 4.23 (1H, d, J = 9.5 Hz), 7.06 (3H, m), 7.14 (1H, d, J = 3.6 Hz), 7.83 (2H, m), 9.00 (1H, s), 10.78 (1H, s).

EXAMPLE 86 N'-f2R- (3-BenzocyclopentiPmethyl-4- (N-hydroxyamino) -3S- (propoxPsuccinin-S-ter-leucine methoxyamide MS (ES + ve), M + H = 464, M + Na = 486 MS (ES -ve), MH = 462 1 H NMR (DMSO-de): 0.78 (3H, t, J = 7.4 Hz), 0.94 ( 9H, s), 1.23 (1H, m), 1.41 (2H, m), 1.55 (1H, m), 2.20 (1H, m), 2.36 (1H, m), 2.47 (1H, m), 2.88 (1H , m), 2.93-3.08 (2H, m), 3.12 (1H, m), 3.26 (1H, m), 3.45 (3H, s), 3.63 (1H, d, J = 9.9 Hz), 4.09 (1H, d, J = 9.4 Hz), 7.05 (3H, m), 7.14 (1H, m), 8.01 (1H, d, J = 9.4 Hz), 9.00 (1H, s), 10.79 (1H, s), 11.23 ( 1H, s).

EXAMPLE 87 N'-r3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethylPsuccinyl-S- (S- (4-methoxybenzylpenicillamide MS (ES + ve), M + H = 580, M + Na = 602 MS (ES -ve), MH = 578 1 H NMR (DMSO-de): 1.28 (3H, s), 1.29 (3H, s), 2.67 (2H, m), 2.95 (1H, m), 3.24 (1H, m), 3.68-3.86 (6H, m), 3.95 (1H, m), 4.49 (1H, d, J = 9.4 Hz), 5.07 (1H, dd, J = 1.6 , 10.5 Hz), 5.20 (1H, dd, J = 1.7 Hz, 17.4 Hz), 5.78 (1H, m), 6.82 (2H, d, J = 8.7 Hz), 6.93 (1H, s), 7.21 (2H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.7 Hz), 7.34 (1H, s), 7.45 (2H, m), 7.60 (1H, s), 7.74 (1H, d, J = 8.5 Hz), 7.81 (2H, t, J = 8.4 Hz), 7.90 (1H, d, J = 8.7 Hz), 9.10 (1H, s), 10.95 (1H, s).

EXAMPLE 88 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl-3S- (2 - / - propoxyethoxp-succinyl-S-ter-leucine ethylamide a) N'-f4-t-Butoxy-2R- (2-naphthylmethyl-3S- (2 - / - propoxyethoxy) succinyl-11-S-ter-leucine ethylamide To a solution of N '- [4-t-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-N-ethylamide (220 mg, 0.428 mmol) and sponge of proton (128 mg, 0.600 mmol) in dichloromethane (2 ml) was added methyltriisopropoxyphosphonium tetrafluoroborate (155 mg, 0.566 mmol). After stirring at room temperature for three hours, additional amounts of proton sponge (128 mg) and methyltriisopropoxyphosphonium tetrafluoroborate (155 mg) were added and the mixture was stirred for a further 24 hours before the addition of proton sponge batches ( 128 mg) and methyltriisopropoxyphosphonium tetrafluoroborate (155 mg). After stirring for a further 48 hours, ethyl acetate and 2N HCl were added and the product was extracted into ethyl acetate. The extracts were washed with concentrated sodium bicarbonate solution and brine, and then dried (MgSO) and concentrated. The product was chromatographed on silica gel (elution with ethyl acetate / hexane) to give the product as a gum (141 mg, 59% yield). ES ES + ve M + H = 557, M + Na = 579 1 H NMR (DMSO-de): 0.77 (3H, t, J = 7.5 Hz), 0.86 (9H, s), 1.07 (3H, d, J = 6.0 Hz), 1.08 (3H, d, J = 6.0 Hz), 1.44 (9H, s), 2.71-2.83 (3H, m), 2.97 (1 H, dd, J = 10.0, 14.0 Hz), 3.22 (1 H, m), 3.26-3.48 (3H, m), 3.53-3.62 (2H, m), 3.85 (1H, d, J = 8.0 Hz), 4.09 (1 H, d, J = 9.5 Hz), 7.31 (1H, dd, J = 1.5, 8.5 Hz), 7-40.7.51 (3H, m), 7.63 (1 H, s), 7.70 (1 H, d, J = 9.5 Hz) , 7.75 (1 H, d, J = 8.5 Hz), 7.76-7.85 (2H, m). b) N'-r4- (N-Hydroxyamino) -2R- (2-naphthyl-P-3S- (2 - / 'propoxyethoxy) -succinyl-S-ter-leucine ethylamide The t-butyl ester was removed with TFA and the resulting carboxylic acid was converted to the hydroxamic acid as above to give the title compound. MS ES -ve M-H = 514 MS ES + ve M + H = 516 1 H NMR (DMSO-de): 0.68 (3H, t, J = 7.0 Hz), 0.85 (9H, s), 1.06 (6H, d, J = 6.0 Hz), 2.50-2.75 (3H, m, partially obscured), 2.85 (1 H, m), 3. 24 (1 H, m), 3.39 (3 H, m), 3.45-3.55 (2 H, m), 3.80 (1 H, d, J = 9.5 Hz), 4.03 (1 H, d, J = 9.5 Hz), 7.26 (2H, m), 7.43 (2H, m), 7.58 (2H, m), 7.72 (1H, d, J = 8. 5 Hz), 7.75-7.85 (2H, m), 9.09 (1 H, s), 10.84 (1 H, s).

EXAMPLE 89 N'-r4- (N-Hydroxyamino) -3S-propoxy-2R-f (3R, S-chroma-3-ipmetillsuccinyl-S-ter-leucine methylamide ES ES + ve M + H = 464 1 H NMR (DMSO-de): 0.79 (3H, m), 0.91 (9H, s), 1.08 (1 H, m), 1.40 (3H, m), 1.77 (1 H , m), 2.30 (1 H, m), 2.39 (1.5 H, d), 2.49 (1.5 H, d, obscured by DMSO), 2.68 (0.5 H, m), 2.98 (1.5 H, m), 3.13 ( 1 H, m), 3.28 (1 H, m), 3.61 (1.5 H, m), 4.01 (0.5 H, br.d), 4.19 (2H, m), 6.66 (1 H, m), 6.78 (1 H, m), 7.0C (2H, m), 7.65 (0.5 H, m), 7.76 (0.5 H, m), 7.91 (0.5 H, d), 7.99 (0.5 H, d), 9.02 (1 H, s), 10.80 (1 H, s).

EXAMPLE 90 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl-3S- (propoxy) -succinyl-S-ter-leucine phenoxyamide MS (ES -ve) MH = 534 1 H NMR (DMSO-de): 0.84 (3H, t, J = 7.4 Hz), 0.95 (9H, s), 1.46 (2H, m), 2.66 (1H, m), 2.96 (1H, m), 3.20 (1H, m), 3.34 (2H, m), 3.78 (1H, d, J = 9.6 Hz), 4.22 (1H, d, J = 8.8 Hz), 6.88 (2H, d , J = 8.0 Hz), 6.95 (1H, m), 7.16 (2H, t, J = 7.8 Hz), 7.26 (1H, d, J = 8.4 Hz), 7.40 (2H, m), 7.58 (1H, s ), 7.68 (2H, m), 7.80 (1H, m), 8.01 (1H, d, J = 9.5 Hz), 9.10 (1H, s), 10.92 (1H, s), 11.92 (1H, s).

EXAMPLE 91 N'-r4- (N-Hydroxyamino-3S-propoxy-2R- (2-naphthylmethylpuccinin-S-ter-leucine N-ethoxyamide ES ES + ve M + H = 488 1 H NMR (DMSO-de): 0.83 (15 H, m), 1.44 (2 H, m), 2.63 (1 H, dd, J = 3.5, 13.5 Hz), 2.84 (1 H, dd, J = 11, 13.5 Hz), 3.25 (5H, m), 3.77 (1H, d, J = 6.5 Hz), 3.98 (1H, d, J = 9.5 Hz), 7.26 (1H, dd, J = 1.0 , 8.5 Hz), 7.42 (2H, m), 7.70 (1H, s), 7.75 (4H, m), 9.09 (1H, s), 10.78 (1H, s), 10.88 (1H, s).

EXAMPLE 92 N'-f4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinin-S-tert-leucine N-isopropyloxyamide ES ES + ve M + H = 502 1 H NMR (DMSO-de): 0.85 (18 H, m), 1.45 (2 H, m), 2.64 (1 H, dd, J = 3, 13.5 Hz), 2.87 (1 H, dd, J = 11, 13.5 Hz), 3.19 (1H, m), 3.30 (2H, m), 3.48 (1H, m), 3.76 (1H, d, J = 9.5 Hz), 4.03 (1H, d, J = 9.5 Hz), 7.26 (1H, dd, J = 1.0, 8.4 Hz), 7.42 (2H, m), 7.57 (1H, s), 7.76 (4H, m), 9.09 (1H, s), 10.63 (1H , s), 10.90 (1H, s).

EXAMPLE 93 N'-r4- (N-Hydroxyamino) -2R- (2-naphthylmethyl-3S- (propoxysuccinin-S-ter-leucine N.N-dimethylhydrazide MS (ES + ve) M + H = 599 MS (ES -ve) MH = 485, M + TFA = 599 1 H NMR (DMSO-d 6): 0.81 (3H, t, J = 7.4 Hz), 0.85 (9H, s), 1.45 (2H, m), 2.21 (6H, s), 2.66 (1H, m), 3.19 (1H, m), 3.32 (2H, m), 3.76 (1H, d, J = 9.6 Hz), 3.99 (1H, d, J = 9.3 Hz), 7.26 (1H, d, J = 8.4 Hz), 7.43 (3H, m), 7.56 (1 H, s), 7.70 (2H, m), 7.78 (2H, m), 9.22 (1 H, s), 10.88 ("H, s).

EXAMPLE 94 N'-r3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethiPsuccinin-S-ter-leucine cyclopropylamide The title product was prepared as described above (Example 80) and crystallized from Et2O / EtOAc (MeOH, to give a cream colored solid, 0.276 g (76%). MS (ES + ve) M + H = 498, M + Na = 520 1 H NMR ( DMSO-de): 0.05 (2H, m), 0.38 (2H, m), 0.83 (9H, s), 1.12 (9H, s), 2.10 (1H, m), 2.70 (1H, dd, J = 14, 3.5 Hz), 2.84 (1 H, dd, J = 14, 11 Hz), 3.05 (1 H, m), 3.94 (1 H, d, J = 9.0 Hz), 4.01 (1 H, d, J = 9.0 Hz), 7.24 (1 H, dd, J = 8.5, 1.5 Hz), 7.38-7.47 (4H, m), 7.55 (1 H, s), 7.73 (1 H, d, J = 8.5 Hz), 7.80 (2H, m), 8.94 (1 H, br s), 10.69 (1 H, br s).

EXAMPLE 95 N'-r4- (N-Hydroxyamino) -3S-propoxy-2R- (2R.S- 1.2.3.4- tetrahydronaphthiPrnetiPsuccinyl-S-tert-leucine methoxyamide) The title product was prepared in the same manner as in Examples 10 and 65, from (2R, 3S) -3-hydroxy-2 - [(R / S) -1 - (1, 2,3,4- diethyl tetrahydronaphthalen-2-yl) methyl] succinate and the final compound was triturated with Et2O to give a pale buff solid, 0.396 g (83%). MS (ES + ve) M + H = 478, M + Na = 500 EXAMPLE 96 N'-f4- (N-Hydroxyamino) -3S-isopropoxy-2R- (2-naphthylmethyl) -succinyl-S-ter-leucine methoxyamide The title product was prepared in the same manner as in Example 65 (alkylating N- [4-t-butoxy-3S-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine benzyl ester with 'PrOTf ) and triturating the final compound with Et2O / EtOAc, to give a cream colored solid, 0.321 g (69%). MS (ES + ve) M + H = 474, M + Na = 496 1 H NMR (DMSO-de): 0.86 (9H, s), 1.00 (3H, d, J = 6 Hz), 1.04 (3H, d, J = 6 Hz), 2.64 (1 H, dd, J = 14, 3.5 Hz), 2.86 (1 H, dd, J = 14, 11 Hz), 3.12 (3 H, s), 3.22 ( 1 H, m), 3.51 (1 H, m), 3.89 (1 H, d, J = 9.5 Hz), 3.96 (1 H, d, J = 9.5 Hz), 7.27 (1 H, dd, J = 8.5 , 1.5 Hz), 7.41 (3H, m), 7.56 (1 H, s), 7.71 (2H, apparent d, J = 9 Hz), 9.08 (1 H, s), 10.89 (1 H, s), 10.92 (1 H, s).

EXAMPLE 97 N'-r4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl-S-ter-leucine N-tert-butoxyamide MS (ES + ve) M + H = 516 1 H NMR (DMSO-de): 0.82 (3H, t, J = 7.5 Hz), 0.86 (9H, s), 0.87 (9H, s), 1.45 (2H, m ), 2.62 (1H, dd, J = 3.5, 13.5 Hz), 2.90 (1H, dd, J = 11, 13.5 Hz), 3.26 (3H, m), 3.75 (1H, d, J = 9.5 Hz), 4.12 (1H, d, J = 9.5 Hz), 7.24 (1H, m), 7.41 (2H, m), 7.55 (1H, s), 7.71 (2H, m), 7.78 (2H, m), 9.08 (1H, s), 10.14 (1H, s), 10.89 (1H, s).

EXAMPLE 98 N'-r3S-tert-Butoxy-4-N-hydroxyamino) -2R- (2R.S- (1.2.3.4- tetrahydronaphthiDmetiDsuccinyl-S-ter-leucinamide The title product was prepared in the same manner as in Examples 10 and 81 from (2R, 3S) -3-hydroxy-2 - [(R, S) -1 - (1, 2,3,4-tetrahydronaphthalene -2-? L) methyl] diethyl succinate. MS (ES + ve) M + H = 462, M + Na = 484 EXAMPLE 99 N'-f4- (N-Hydroxyamino) -2R- (5-methylenebenzof 61-thiophene) -3S-propoxy-succinyl-N-methyl-S-ter-leucinamide A solution of N '- [4-hydroxy-2R- (5-methylbenzo [6] thiophene) -3S-propoxy-succinyl] -N-methyl-S-ter-leucinamide (60 mg, 0.13 mmol) in anhydrous DMF ( 5 ml) was treated sequentially with HOAT (36 mg, 0.27 mmol) and EDC (51 mg, 0.27 mmol), and the reaction solution was stirred at room temperature for 0.25 hours. Then, hiroxylamine hydrochloride (28 mg, 0.40 mmol) and N-methylmorpholine (0.04 ml, 0.40 mmol) were added and the reaction solution was stirred for three hours at room temperature. The reaction solution was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with additional water and saturated sodium bicarbonate solution, and dried with brine and magnesium sulfate. The organic phase was then evaporated and triturated with diethyl ether to give the hydroxamic acid as a white solid (15 mg, 24%).

MS (ES + ve) [MH] + = 463 1 H NMR (DMSO-de): 0.89 (9H, s), 0.91 (3H, t, J = 7.0 Hz), 1.57 (2H, m), 2.24 (3H, d, J = 4.9 Hz), 2.82 (2H, m), 3.07 (1H, m), 3.31 (2H, m), 3.84 (1H, d, J = 9.7 Hz), 4.05 (1H, s), 7.14 ( 1H, d, J = 5.3 Hz), 7.22 (1H, q, J = 5.6 Hz), 7.27 (1H, d, J = 3.4 Hz), 7.50 (1H, d, J = 3.4 Hz), 7.53 (3H, t, J = 6.0 Hz), 7.59 (1H, s), 7.75 (1H, d, J = 5.3 Hz), 9.11 (1H, s), 10.96 (1H, s).

EXAMPLE 100 N'-r4- (N-Hydroxyamino) -3S-cyclohexyloxy-2R- (2-naphthylmethylPsuccinin-S-ter-leucine N-methoxyamide) MS (ES + ve) M + H = 514 1 H NMR (DMSO-de): 0.86 (9H, s), 1.00-1.22 (5H, m), 1.45 (1H, m), 1.63 (2H, m), 1.76. (1H, m), 1.87 (1H, m), 2.67 (1H, d, J = 3.5, 13.5 Hz), 2. 85 (1H, dd, J = 13.5, 11 Hz), 3.13 (3H, s), 3.21 (2H, m), 3.95 (2H, m), 7.28 (1H, m), 7.41 (2H, m), 7.56 (1H, s), 7.72 (2H, m), 7.78 (2H, m), 9.07 (1H, s), . 84 (1H, s), 10.90 (1H, s).

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (I):

(IA) wherein: R is methyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkynyl; n is 0 or 1; R1 is arylmethyl or heterocyclylmethyl; R 2 is alkyl, alkenyl, aryl, cycloalkyl or cycloalkenyl, and R 3 is hydrogen, alkyl, alkenyl, alkynyl or aryl. 2. A compound according to claim 1, further characterized in that R is allyl, propyl, ethyl or isopropyl, and / or R1 is 1-or 2-naphthylmethyl; and / or R2 is t-butyl; and / or R3 is hydrogen or methyl.

3. A compound according to claim 2, further characterized in that each of n and R to R3, is selected from the group consisting of the values assigned thereto in the examples herein.

4. - A compound according to claim 2, selected from the group consisting of the compounds described above in the examples. 5. A compound according to claim 1 or 2, which is a compound of the formula (IA):

("A)

6. The use of a compound according to any of the preceding claims, in the production of a medicament for the treatment or prophylaxis of disorders such as allergies, inflammatory disorders and autoimmune diseases in which overproduction is implicated. of S-CD23.

7. A pharmaceutical composition for the treatment or prophylaxis of disorders such as allergies, inflammatory disorders and autoimmune diseases in which the overproduction of S-CD23, which comprises a compound according to any of claims 1 to 5, is involved. and optionally a pharmaceutically acceptable carrier therefor.

8. - A process for preparing a compound according to any of claims 1 to 5, which comprises: (a) deprotecting a compound of the formula (II): (II) wherein n and R to R3 are as defined hereinabove, and X is a protecting group such as benzyl or trimethylsilyl, or (b) reacting a compound of the formula (III): (lll) wherein n and R to R3, are as defined hereinabove, and any hydroxy group is optionally protected, with hydroxylamine or a salt thereof, or (c) converting a compound of the formula (I) to a different compound of formula (I) as defined hereinabove.

9. A compound of the formula (II) or (III) as defined in claim 8.