MXPA98010329A - Metaloproteinase inhibitors of mat - Google Patents

Abstract

The succinic amide derivatives of the formula (I) wherein: W is a group -CO2H or -CONHOH; R, R1 and R2 are, each of them, hydrogen or an organic residue, R3 is the residue of an alpha-amino acid and R4 is an organic group, constituting the inhibitors of matrix metalloproteinases (MMPS) and the release of tumor necrosis factor-alpha (TNF) from the cells and which, consequently, are useful for the prevention, control, and the treatment for the diseases in which MMPS or TNF are involved. Also described is a process for carrying out its preparation and the pharmaceutical compositions containing them

Description

NEW MATRIX METALOPROTEINASE INHIBITORS FIELD OF THE INVENTION The present invention relates to new inhibitors of matrix metalloproteinases (hereinafter MMPS), to a process for their preparation, to compositions containing them, and to the use of said compounds for the prevention, control and treatment of diseases in which the proteolytic action of MMPS is involved. Additionally, since the compounds described herein, inhibit the release of tumor necrosis factor-alpha (hereafter, TNF) from the cells, it is another object of the present invention to use pharmaceutical compositions which they contain said compounds to effect the treatment or prophylaxis of inflammatory, immunological or infectious diseases promoted by said cytokine.

BACKGROUND OF THE INVENTION At present, compounds with a low molecular weight are considered as compounds capable of inhibiting Ref. 029007 one or more of the matrix metalloproteinases, in particular, stromelysin-1 (MMP-3; EC 3.4.24.17), gelatinous A (MMP-2; EC 3.4.24.24), interstitial collagenase (MMP-1; EC 3.4.27.7), collagenase-2 (neutrophil collagenase; MMP-8), collagenase-3 (MMP-13), and metalloproteinases of the membrane type (in particular, MT-MMP-1; MMP-14) as promising therapeutic agents in degenerative, tumor and autoimmune pathologies (for example, PD Brown: "Matrix metalloproteinase inhibitors: A new class of anticancer agent "[matrix metalloproteinase inhibitors: a new class of anticancer agent], Curr Opin, Invest. Drugs, 2: 617-626, 1993; A. Krantz:" Proteinases in Inflammation ", Annu Rep. Med. Chem. 28: 187-195, 1993). Many of these compounds that have been described so far constitute derivatives of a peptide or pseudopeptides, which have analogies with the peptide substrates recognized for these enzymes and which, furthermore, are characterized by a functional group capable of binding the Zn atom. (II) that is present in the catalytic site of said enzymes. The known classes of MMP inhibitors include those in which the linking group Zn is a carboxylic or hydroxamic acid, which is part of a succinic (substituted) half, in particular, a succinic amide with an amino acid, which at its once it is derived as a primary or secondary amide, such as those represented by the general formula (A) where W is -C02H or -CONHOH, and Ra, Rb, Rc, and Rd are hydrogen atoms or substituents that are appropriate (eg, N.R.A. Beeley et al., "Inhibitors of matrix metalloproteinases (MMP'S) "[Inhibitors of matrix metalloproteinases (MMPs)], Curr. Opin *. Trier., Patents 4: 7-16, 1994; J.R.

Porter and his collaborators, "Recent developments in matrix metalloproteinase inhibitors", Exp. Opin. Trier., Patents 5: 1287-1296, 1995; J.R. Morphy and colleagues, "Matrix metalloproteinase inhibitors: current status" [Matrix metalloproteinase inhibitors: current status], Curr. Med. Chem. 2: 743-762, 1995; R.P. Beckett and his collaborators, "Recent advances in matrix metalloproteinase research", DDT 1: 16-26, 1996). Additionally, it is now recognized that compounds of the same general formula (A), in which W is, in particular, -CONHOH, may be able to inhibit the TNF release of the precursor anchored in the cell membrane, pro-TNF (for example, GM McGeehan and his collaborators, "Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor", [Regulation of the processing of tumor necrosis factor-alpha by means of a metalloproteinase inhibitor] Nature 370: 558-561, 1994). While MMPs have been recognized as drug targets for at least 20 years, and the MMP inhibitors comprised by the general formula (A) have been presented since 1986 or before (for example, see JP Dickens et al., U.S. Patent 4,599,361), none of these drugs has yet reached the market. This is not due to questions about the therapeutic potential of MMP inhibitors, but is due to the problems of the "first generation" compounds, such as, for example, the potency, the selectivity, the aqueous solubility, the duration of the in vivo action, the oral bioavailability, and the potential toxicity of the inhibitor (eg, JR Porter, previous reference; J. Hodgson, "Remodeling MMPIs" [Remodeling of MMPIs], Biotechnology 13: 554-557, 1995). In addition, the precise role that each MMP performs individually in many disease states has not yet been elucidated. In this way, there is a great need to have better and diversified molecules, especially in regard to the properties mentioned above. According to what was mentioned above, an impressive amount of MMP inhibitors of the general formula (A) in which W is -COOH or -CONHOH has been debed in the literature, as has also been done in patents and published patent applications. Although they refer to the common general structure (A), each presentation is characterized by subtle variations in the nature of the Ra-Rd substituents. In fact, the balance between the intrinsic level of activity, the degree of specificity of the individual MMPs, and the physicochemical and pharmacokinetic properties can vary in a predictable manner as the Ra-Rd substituents vary. Although a large number of different possible values for Ra-Rd have been debed, research on the compounds of the formula (A), where Ra is other than hydrogen, has so far been very limited. In particular, the class of compounds of the formula (A), in which Ra is a heteroatom or a derivative thereof, is virtually unprecedented, in addition to the particular case where Ra is hydroxy, which includes a compound which, At present, it is under clinical development, British Biotechnology BB-2516 (which is also known as "marimastat"). Currently, we have discovered a group of particular compounds of the general formula (I), which are characterized by having a very potent biochemical activity against MMPS, in particular, stromelysin / s, gelatinase / s and / s collagenase / s, combined with physicochemical and far acocinetic properties that make these compounds suitable for their potential use as drugs in the treatment of a large number of diseases, in which an uncontrolled activity of said MMPS was involved; in addition, we have discovered that many such compounds effectively inhibit the release of TNF from the cell membrane precursor, pro-TNF; also, we have discovered a convenient and stereoselective method to carry out its preparation from commercial intermediates.

DEPTION OF THE INVENTION The present invention provides compounds of the formula (I), where W is a group COOH or -CONHOH; R is hydrogen, Ci-Cß alkyl, phenyl, or benzyl; Ri is hydrogen or: lower alkyl, especially methyl, ethyl, propyl, isopropyl, isobutyl, tere-butyl; aryl, especially phenyl and naphthyl; and aryl- (lower alkyl), especially benzyl; these groups may be unsubstituted or substituted by one or more substituents, which may be the same or different, which are selected from methyl, ethyl, isopropyl, tere-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy , methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or a group - (CH2) m -heterocyclyl or - (CH2) m cyclopropyl, where m is zero or an integer ranging from one to three, and a heterocyclyl represents a closed chain of heterocyclyl possessing between 3 and 6 members, simple or condensed with a closed chain of benzene or naphthalene, which contains at least one nitrogen atom; more preferably succinimido, phthalimide, saccharin, hydantoin, indolyl, oxyindolyl, 2-oxo-isoindolinyl, imidazolyl, pyridyl, morpholino, pyrrolidino, 2-oxopyrrolidino, piperazino; and wherein said heterocyclyl group is unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or - a group - (CH2) nCOOH or a group - (CH2,) m COOR1, in which n can be 1, 2 or 3, m can be 0, 1, 2 or 3, and R is methyl, ethyl, propyl, isopropyl, isobutyl, tere-butyl, phenyl, benzyl, allyl, styryl, 1-naphthyl, 2-naphthyl, whether unsubstituted or substituted by one to three substituents selected from methyl, ethyl, isopropyl , tere-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or - a group that is selected from - (CH2) m SO2R1, - (CH2) mS02NH2, - (CJH2) mS02 (Me) 2, - (CH2) mS02NHRI, where, R and the possible substituents of said group R1 are as defined above, or a group (CH2) mS02- (4-morpholino), - (CH2) mS02- (1-piperazino), (CH2) mS02- (4-methyl-l-piperazino); or - a group - (CH2) nS? 3H, where n is as defined above; acyl, especially acetyl, or benzoyl, or phenacetyl, either unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo , carboxy, and nitro; or a -C (o) -Rp-C (o) R group, wherein -R11- is selected from a chemical bond, -CH2-, CH2 (CH2) m CH2- where it is as defined above, -CJH = CH-, -CH2CH = CH-, phenylene (ie, -C6H4-), CH2CH = CH-C6H4-, -CH2CH2CH = CH-, -CH2-CC-, -CH2CH2-CC-, -CH2CH2CH = CH-C6H4-, -CH2-CC-C6H4-, -CH2CH2-CC-C6H4-, and R111 is selected from methyl, ethyl, phenyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, and morpholino; or a -c (o) -heterocyclyl group, in which heterocyclic is as defined above, and in which said heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or - a -C (o) -Rp-heterocyclyl or -C (o) -R-aryl group, wherein R, heterocyclyl, aryl and the possible substituents of said heterocyclyl or aryl are as described above; or R and Ri, taken together with the nitrogen atom to which they are attached, represent morpholino, pyrrolidino, piperazino, N-methylpiperazino, succinimido, or phthalimido; R2 is straight or branched alkyl Q5-C15, either unsubstituted or substituted by a C3-C7 cycloalkyl group; or R2 is a group -Rp-H, "where Rp is as defined above, either unsubstituted or substituted by one to three substituents selected from methyl, ethyl, straight or branched C3-C alkyl, fluoro, chloro, C1-C4 alkoxy, nitro, amino, dimethylamino, carboxy, carboxymethyl, or R2 is a group -R -H, where R is as defined above, either unsubstituted or substituted by between one and three substituents which are selected from methyl, ethyl, linear or branched C3-C4 alkyl, fluoro, chloro, C1-C4 alkoxy, nitro, amino, dimethylamino, carboxy, carboxymethyl, or R2 is a group -Rp-X-RIV, where Rp is as defined above, RIV is C2-C6 Ci-C2 alkenyl alkyl, phenyl, phenyl alkyl (Ci-Cd), or phenyl (C2-C6) alkenyl, either unsubstituted or substituted by a group selected from F, Cl, Br, Ci-C4 alkyl, C2-C4 alkoxy, and X is a direct bond, or an oxygen atom, a sulfur atom, or a sulfinyl -S (o) -, sulfonyl -S (or ) 2 or a carbamoyl group -CONH- or -NHCO-; R3 is the group that characterizes a natural or non-natural alpha-amino acid in which any functional group, if present, may be protected; including linear or branched C1-C9 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, indolyl, naphthyl, adamantyl; or (C3-O7) cycloalkyl (Ci-Cß) alkyl, phenyl (C1-C6) alkyl, naphthyl (C? -Cts), indolyl (Ci-C?) alkyl where the alkyl, alkenyl, cycloalkyl, phenyl, indolyl groups and naphthyl may be substituted by ethyl, methyl, hydroxy, mercapto, carboxy, C6-C6 alkoxy, phenoxy, benzyloxy, Ci-Cß alkylthio, phenylthio, benzylthio, C'-C6 alkylsulfinyl, C'-C alqu alkylsulfonyl, phenylsulfonyl, benzylsulfonyl , amino, monoalkylamino (C? -C6) di-alkylamino (Ci-C?), guanidino; R4 is o-alkyl, where alkyl is a linear or branched C1-C4 alkyl group, especially methyl, ethyl and t-butyl, or is o-phenyl, and derivatives thereof substituted by between one and three substituents they are selected from linear or branched C1-C4 alkyl, chloro and methoxy; or R 4 is -NH 2, -NH (C 1 -C 6 alkyl) -NH-aryl, -NH-heterocyclyl; or R 4 is -NH (C 1 -C 6 alkyl) substituted by phenyl or heterocyclyl; or R4 is -NH (C2-C6 alkyl) substituted by a group selected from -CONH2, -NHCONH2, -S02NH2, -NHS02NH2, or derivatives thereof, in which the terminal nitrogen atom is substituted by one or two methyl groups, or derivatives thereof in which the terminal nitrogen atom is part of a closed chain of morpholino, pyrrolidino, piperazino, or N-methylpiperazino; or R 4 is -NH (C 2 -C 6 alkyl) substituted by amino, protected amino, mono alkylamino (Ci-Cβ) di alkylamino (Ci-Cd), guanidino, morpholino, piperazino or N-methylpiperazino; or R3 and R4, taken together, are a group of the formula - (CH2) m-NH-, where m ranges from 5 to 12, optionally interrupted by a group -NR5-, where R5 is selected from from hydrogen, alkyl (Cj-Cß) alkoxycarbonyl (Ci-Cß), aryl, aryl (Ci-Cß) alkyl, or aryl alkoxycarbonyl (Ci-Cß), or interrupted by a -C6H4-o- group, or interrupted by a closed chain of indole bound by its C-3 and its nitrogen atoms; and wherein alkyl, alkenyl, phenyl, benzyl, cycloalkyl, heterocyclyl, phenyl (d-Cß) alkyl, phenyl (C2-C6) alkenyl, heterocyclyl (C? -C6) alkyl, cycloalkyl (d-C6) alkyl in any of the The aforementioned definitions of R, Rj., R2, R3, R4 and A are unsubstituted or substituted by one or more substituents, according to what will be specified below; and the salts, solvates and hydrates thereof, provided that, when -NRRj. is -NH2, amino or protected acylamino, R3 is tert-butyl and R4 is amino or alkylamino, then R2 is other than isobutyl. As used in the present, the term "alkyl" refers to a straight or branched chain alkyl moiety having between 1 and 9 carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, sec-butyl, tert-butyl, butyl, n-pentyl, isopentyl, n-hexyl, among others. The term "Xalquep_lo" refers to a straight or branched chain alkenyl moiety possessing between 2 and 6 carbon atoms, and which also possesses a double bond of E or Z stereochemistry in those cases in which it is applicable. Alkenyl groups are: vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, methallyl, crotyl, etc. The term "aryl" refers to a group of monocyclic or bicyclic aromatic hydrocarbons having between 6 and 10 carbon atoms, such as, for example, phenyl, naphthyl, indanyl The term "cycloalkyl" refers to a saturated carbocyclic group having between 3 and 7 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl The term "heterocyclyl" refers to a closed chain of saturated or unsaturated heterocyclyl having between 3 and 7 members that contains at least one heteroatom which is choose between O, S and N, where any closed chain nitrogen can be oxidized as an N-oxide, any closed chain carbon can be oxidized as a carbonyl, and any closed chain sulfur can be oxidized as a sulphoxide or a sulfone; and wherein said closed heterocyclyl chain may optionally be fused with a second closed chain of 5 or 6 membered saturated or unsaturated heterocyclyl, or with a closed cycloalkyl C3 ~ C chain or with a closed chain of benzene or naphthalene. Examples of the heterocyclyl groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furyl, aziridinyl, oxiranyl, azetidinyl, succinimido, pyridyl, pyrazinyl, pyrimidinyl, pyranyl, pyridazinyl, hydantoinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl and azepinyl, among others. When, in the definition of "aryl" and "heterocyclyl" mentioned above, said aryl or heterocyclyl groups are fused with a second closed chain, the latter can be phenyl, C4-C7 cycloalkyl, or a closed chain of saturated heterocyclyl. or unsaturated having between 3 and 7 members, containing between one and three heteroatoms that are selected from 0, S and N, where any closed chain nitrogen can be oxidized as an N-oxide, any closed chain carbon can be oxidized as a carbonyl, and any closed chain sulfur may be oxidized as a sulfoxide or a sulfone. Examples of such fused aryl or heterocyclyl groups are benzoxylenyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, chromonyl, indolyl, oxindolyl, phthalimido, quinolyl, isoquinolyl, indolizinyl, isoindolyl. , 2-oxoisoindolyl, saccharinyl, cinolinyl, indazolyl, purinyl, cyclopentylphenyl, cyclohexylphenyl, cyclopentylpyridyl and 1,3-benzodioxole, among others. Such bicyclic closed chains can be attached to the rest of the molecule, either in one or other of the constituents of the closed chain atom; for example, a cyclohexylpyridyl substituent includes both a cyclohexyl group fused to an "erroneous" pyridyl chain and a fused pyridyl group with a closed cyclohexyl chain.The term "side chain of a naturally occurring a-amino acid" comprises the side chains of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and penicillamine. The term "side chain of an unnatural α-amino acid" encompasses the side chain of the known α-amino acids that do not correspond to the category of "naturally occurring a-amino acids", such as for example a-amino acid -n-butyric acid, a-amino-n-pentanoic acid, a-amino-n-hexanoic acid, a-amino-neohexanoic acid, a-amino-neoheptanoic acid, S-methyl penicillamine and its sulfoxides and sulfones, tert-butylglycine, phenylglycine, (diphenylmethyl) glycine, cyclohexylalanine, homophenylalanine, homocysteine, homoserine, alloisoleucine, allotreonin, 3,4-dihydroxyphenylalanine, 5-hydroxylysine, 4-hydroxyproline , la or itina and other similar. Substituents which may be present in the alkyl, alkenyl, phenyl, benzyl, cycloalkyl, heterocyclyl, phenyl alkyl (d-Cd), phenyl alkenyl (C2-C6), heterocyclyl alkyl (d-Cß), cycloalkyl (C2-C6) alkyl ) that were previously mentioned in any of the aforementioned definitions of R, RI R2, R3, R4 and A are selected from the following: halo (ie fluoro, bromo, chloro or iodo); hydroxy; nitro; azido; mercapto (ie, -SH), and the acetyl or phenylacetyl esters thereof (ie, -SCOCH3 and -SCOCH2C6H5); amino (i.e., -NH2 or -NHRV or -NRVI, where Rv and RVI, which are the same or different, are a straight or branched d6-C6 alkyl group, phenyl groups optionally substituted with d-C6 alkyl or phenyl (d) alkyl -Có), or Rv and R, taken together with the nitrogen atom, form a closed chain such as piperidino, morpholino or a pyrrolidino or piperazino group and, optionally, can be substituted by any of the substituents listed at the moment); - guanidino, that is, -NHC (= NH) NH2; - formyl (i.e., -CHO); - cyano; carboxy (ie, -COOH), or esters thereof (ie, -C00Rv), or amides thereof (ie, -CONRvRVI), where Rv and R ^ are as defined above, and include morpholino-amides, pyrrolidino-amides, and carboxymethyl idas -CONHCH2COOH; sulfo (i.e., -SO3H); acyl, that is, -C (0) Rv, where Rv is as defined above, and includes monofluoacetyl, difluoacetyl, trifluoacetyl; carbamoyloxy (i.e., -OCONH2) and N-methylcarbamoyloxy; acyloxy, that is, -0C (o) Rv, where Rv is as defined above, or formyloxy; acylamino, that is, -NHC (0) Rv, or -NHC (0) ORv, where Rv is as defined above, or is a group - (CH2) tCOOH, where t is 1, 2 or 3; ureido, that is, -NH (CO) NH2, -NH (CO) NRv, -NH (CO) NRvRVI, where Rv and R ^ are as defined above, and include -NH (CO) - (4-morpholino), -NH (CO) - (1-pyrrolidino), -NH (CO ) - (1-piperazino), -NH (CO) - (4-methyl-1-piperazino); - sulfonamido, that is, -NHS02R, where R is as defined above; - a group - (CH2) tCOOH, and the esters and amides thereof, that is, - (CH2) tCOORv and - (CH2) tCONH2, (CH2,) tCONRv, - (CH2) tCONHRvRVI, where t, Rv and RVI are as defined above; - a group -NH (S02) NH2, -NH (S02) NHRV, -NH (S02) NRVRVI, where R and R are as defined above, and include -NH (S02) - (4-morpholino), -NH (S02) - (1-pyrrolidino), -NH (S02) - (1-piperazino), -NH (S02) - (4-methyl-1-piperazino); - a group -OC (0) ORv, where Rv is as defined above; - a group -0RV, where R is as defined above, and includes -OCH2COOH; a group -SR, where R is as defined above, and includes -SCH2COOH; - a group -S (0) Rv, where Rv is as defined above; - a group -S (02) RV, where Rv is as defined above; - a group -S02NH2, -S02NHRv, or -S02NRvRVI, where Rv and R ^ are as defined above; - C 1 -C 6 alkyl or C 2 -C 6 alkenyl, - C 4 -C 7 cycloalkyl - substituted methyl, which is selected from chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, N, N-dimethylaminomethyl, azidomethyl, cyanomethyl, carboxymethyl , sulfomethyl, carbamoylmethyl, carbamoyloxymethyl, hydroxymethyl, alkoxycarbonylmethyl and guanidinomethyl When they are present, the carboxy, hydroxy, thiol and amino groups may be in free form or in protected form.The protected forms of said groups are any of those which generally result known in the art and, according to what is described, for example, TW Greene in "Protective Groups in Organic Chemistry", Wiley Interscience Preferably, carboxy groups are protected as esters thereof , in particular, esters of methyl, ethyl, tert-butyl, benzyl, and 4-nitrobenzyl.The hydroxy, thiol and amino groups, when protected, are they are preferably in the form of esters, thioesters, and amide derivatives respectively, for example, acetates, thioacetates, acetamides. The present invention provides the salts of those compounds of the formula (I) which possess salt-forming groups, especially the salts of the compounds which possess a carboxyl group, an N-hydroxycarbamoyl group, and a sulfo group, or the salts of the compounds that possess a basic group, in particular, an amino or guanidino group. The salts are, in particular, physiologically tolerable salts, for example the alkali metal or alkaline earth metal salts (for example, sodium, potassium, lithium, calcium and magnesium salts), the ammonium salts and the salts with a amine or an appropriate organic amino acid (eg, salts of arginine, procaine), and the addition of salts formed with suitable organic or inorganic acids (eg, hydrochlorides, hydrobromides, sulphates, phosphates) or organic carboxylic and sulphonic acids (eg. , acetates, citrates, succinates, malonates, lactates, tartrates, fumarates, maleates, methancsulfonates, p-toluenesulfonates). There may be some compounds of the formula (I) which contain a carboxylate and an ammonium group such as zwitterions; said salts also form part of the present invention. Additionally, the hydrates and solvates of the compounds of the formula (I), and the physiologically hydrolysable derivatives (ie, prodrugs) of the compounds of the formula (I) are included within the scope of the present invention. The prodrugs that are particularly preferred are the compounds of the formula (I) are ester derivatives. They include the esters of the compounds of the formula (I), where W is -COOH, or where a carboxy group is present in any of the substituents R, R1-R4, which are obtained by means of the condensation of said carboxy group with a pharmaceutically acceptable alcohol, for example ethanol; or the esters of the compounds of the formula (I) wherein a hydroxy group is present in any of the substituents R, R1-R4, which are obtained by means of the condensation of said hydroxy group with a pharmaceutically acceptable carboxylic acid, for example, acetic acid, pivalic acid, benzoic acid and the like. Other prodrugs that are particularly preferred within the scope of the present invention are the cyclic condensation products between the compounds of the formula (I), wherein W is -CONHOH and R is hydrogen and a pharmaceutically acceptable aldehyde of the general formula T-CHO or a ketone of the general formula TT'CO, where T and T 'are carbon radicals, such as for example lower alkyl, phenyl and benzyl. Said condensation products, which are represented below, are obtained by mixing two components, and extracting the water by evaporation.

The present invention further includes, within its scope, pharmaceutical compositions comprising one or more of the compounds (I) as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if desired. Preferred compounds, within the scope of the present invention, possess structure (I '): where: W is a group -COOH or -CONHOH; R is hydrogen, methyl, ethyl, or benzyl; Ri is hydrogen, or: lower alkyl, especially methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl; aryl, especially phenyl and naphthyl; and aryl- (lower alkyl), especially benzyl; these groups may be unsubstituted or substituted by one or more substituents, which may be the same or different, which are selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy , methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or - a group - (CH2) m-heterocyclyl or - (CH2) m cyclopropyl, where m is zero, or an integer ranging from one to three, and a heterocyclyl represents a closed chain of heterocyclyl possessing between 3 and 6 members , simple or condensed with a closed chain of benzene or naphthalene, containing at least one nitrogen atom; more preferably, succinimido, phthalimido, saccharin, hydantoin, indolyl, oxyindolyl, 2-oxo-isoindolinyl, imidazolyl, pyridyl, morpholino, pyrrolidino, 2-oxopyrrolidino, piperazino; and wherein said heterocyclyl group is unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or - a group - (CH2) nC00H or a group - (CH2) ra COOR1, in which n can be 1, 2 or 3, can be 0, 1, 2 or 3, and R1 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, phenyl, benzyl, allyl, styryl, 1-naphthyl, 2-naphthyl, whether unsubstituted or substituted by one to three substituents selected from methyl, ethyl, isopropyl, tert-butyl, butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or - a group - (CH2) m CON2 or- (CH2) mCON (CH3) 2, or - (CH2) mCONHR1, where m, R1 and the possible substituents of said group R1 are as defined above, or a group - (CH2) mCO- (4-morpholino), (CH2) mCO- (1-piperazino), and - (CH2) mC0 (4-methyl-l-piperazino); or - a group that is selected from - (CH2) m SO2R1, (CH2) mS02NH2, - (CH2) mS02N (Me) 2, - (CH2) mS02NHRI, where m, R1 and the possible substituents of said group R1 are as defined above, or a group (CH2) mS02- (4-morpholino), - (CH2) mS02- (1-piperazino), (CH2) mS02- (4-methyl-l-piperazino); or - a group - (CH2) nS03H, where n is as defined above; acyl, especially acetyl, or benzoyl, or phenacetyl, either unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or a group -C (O) -Rp-C (0) Rp ?, where -Rp- is selected from a chemical bond, -CH2-, -CH2 (CH2) m CH2- where m is such as is define before, -CH = CH-, -CH2CH = CH-, phenylene (ie, -C6H4-), -CH2CH = CH-C6H4-, -CH2CH2CH = CH-, -CH2-CC-, -CH2CH2-CC- , -CH2CH2CH = CH-C6H4-, -CH2-CC-C6H4-, -CH2CH2-CC-C6H4-, and R is selected from methyl, ethyl, phenyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, and morpholino; or a -C (0) -heterocyclyl group, in which heterocyclic is as defined above, and in which said heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or - a -C (O) -Rp-heterocyclyl or -C (O) -Rp-aryl group, wherein Rp, heterocyclyl, aryl and the possible substituents of said heterocyclyl or aryl are as described above; or R and Ri, taken together with the nitrogen atom to which they are attached, represent morpholino, pyrrolidino, piperazino, N-methylpiperazino, succinimido, or phthalimido; R2 is C3-CJ.5 linear or branched alkyl, either unsubstituted or substituted by a C3-C7 cycloalkyl group; or R2 is a group Rp-H, where Rp is as defined above, either unsubstituted or substituted by between one and three substituents selected from methyl, ethyl, linear or branched C3-C4 alkyl fluoro, chloro, alkoxy C1-C4, nitro, amino, dimethylamino, carboxy, carboxymethyl; or R2 is a group -R -X-RIV, where -R11- is as defined above, -X- is a direct bond, -0-, -S-, -SO-, -S0-, -CONH- or -NHCO-, and RV is Ci-Ce alkyl, C2-C6 alkenyl, methyl, ethyl, propyl, butyl, phenyl, or benzyl, the closed benzene chain of the groups phenyl and benzyl is substituted or unsubstituted by one or more substituents which are selected from methyl, ethyl, propyl, butyl, hydroxy, methoxy, ethoxy, chloro, fluoro, trifluoromethyl or nitro; - R3 is phenylmethyl, cyclohexylmethyl, isobutyl, tertbutyl, -C (CH3) 2C6H5, -C (CH3) 2SCH3, C (CH3) 2SCH3, C (CH3) 2SOCH3 C (CH3) 2S02CH3 -CH (C6H5) 2, CH ( CH3) 0H, -CH (CH4) OMe, -CH (CH4) 0-isopropyl, -CH (CH2) or-tert-butyl, -CH (CH3) 0Ph, -CH (CH3) 0CH2Ph, (4-methoxy) phenylmethyl, (4-hydroxy) -phenylmethyl, indolylmethyl, (N-ethyl) indonylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, (4-carboxy-methoxy) -phenylmethyl, cyclohexyl, phenyl, pyridyl, thiazolyl, thienyl, pyridylmethyl, thiazolylmethyl , thienylmethyl, and derivatives thereof, wherein the phenyl, pyridyl, thiazolyl, and thienyl groups are substituted by chloro, fluoro, methoxy, or C 1 -C 3 alkyl; R4 is O-alkyl, where alkyl is a linear or branched C1-C4 alkyl group, especially methyl, ethyl and t-butyl, or is 0-phenyl, and derivatives thereof substituted by between one and three substituents they are selected from linear or branched C1-C4 alkyl, chloro and methoxy; or R 4 is -NH 2, -NH-alkyl, wherein alkyl is selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, such as, for example, linear or branched alkyl groups which are unsubstituted or substituted by a group selected from phenyl, benzyl, 2-pyridyl, 3-pyridyl, 1, 3, 4-thiadiazolyl-2-yl, 2-thiazolyl, these groups in turn are unsubstituted or substituted by a substituent selected from methyl, ethyl, methoxy, amino, methylamino, dimethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, -SO2NH2, SO2NHC6H5, -S02-morpholino, -S02CH3, -CO-morpholino; or R4 is a group -NHCH2CH2Y, -NHCH2CH2CH2Y, NHCH2CH2CH2CH2Y, -NHCH2CH (CH3) Y or -NHCH2C (CH3)? i, where Y is amino, methylamino, dimethylamino, morpholino, pyrrolidino, piperazino, N-methylpiperazino, hydroxy, methoxy , ethoxy, methylthio, 2 (dimethylamino) ethylthio, 2- (morpholino) ethylthio, Cl, F, Br, phenoxy or phenylthio, wherein the closed phenyl chain may be substituted by hydroxy or methoxy; or R 4 is -NH-aryl, -NH-heterocyclyl; NH-CH-aryl, -NH- (CH2) 2-aryl, -NH-CH2-heteroaryl, or -NH- (CH2) 2-heterocyclyl, wherein the aryl group is selected from phenyl, 4-fluorophenyl, -methoxyphenyl, 1,3-benzodioxolyl, 4-tolyl, 1-indanyl, 5-indanyl, and the heterocyclyl group is selected from 2-benzimidazolyl, 2-benzothiazolyl, 1-benzotriazolyl, 2, 5-dimethyl-l-pyrrolidinyl, 2,6-dimethylpiperidinyl, 2-imidazolyl, 1-indolyl, 5-indolyl, 5-indazolyl, 1-isoquinolyl, 5-isoquinolyl, 2-methoxy-5-pyridyl, 1- methyl-2-benzimidazolyl, 4-methyl-7-coumarinyl, 3-methyl-5-isothiazolyl, 5-methyl-3-isoxazolyl, pyrazinyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 3-quinolyl, 5-tetrazolyl, 1-methyl-5-tetrazolyl, 1, 3, 4-thiadiazol-2-yl, 2-thiazolyl, 1,2,4-triazin-3-yl, and 1 2, 4-triazol-3-yl; or R4 is -NH (C2-C6 alkyl), wherein the alkyl group is substituted by a substituent selected from -C0NH2, -CONHMe, -NHC0NH2, NHCONMe2, -NHCO- (4-morpholino), -NHCO - (4-methyl-l-piperazino), -NHS02NH2, -NHS02NMe2, -NHS02- (4-morpholino) and -NHSO2- (4-methyl-l-piperazino); or R3 and R4, taken together, are a group of the formula - (CH2) 10-NH-, or a group of the formula - (CH2) 4 ~ NH- (CH2) 5-NH-; or R3 and R4, taken together, are a group of the formula (B) which is presented below: or a group of the formula (C) that is detailed below: (C) where n is an integer that ranges from 3 to 6; and pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof, in accordance with what was previously described, provided that when -NRRi is -NH2, amino or protected acylamino, R3 is tert-butyl and R4 is amino or alkylamino, then R2 is other than isobutyl.

A group of compounds that is preferred within the scope of the present invention comprises the compounds of the formula (I '), wherein: R 2 is isobutyl; R3 is phenylmethyl; and W, R, Ri and R4 are as defined above.

Some representative examples within this group of compounds that are particularly preferred are those listed in Table I below: Table I 1-1 COOH H NHMe 1-2 CONHOH H NHMe 1-3 CONHOH H NH-iBu 1-4 CONHOH CH2-CdH4-F NHMe 1-5 CONHOH H NHCH2CH2Ph 1-6 CONHOH H NHCH2CH2-morfoli.no 1-7 CONHOH H NHCH2CH2COOMe 1-8 CONHOH H HCH2CH2CJH4- -S02NH2 1-9 CONHOH H NHCH2COOEt 1-10 CONHOH H NHCH (CHMe2) COOH 1-11 CONHOH H NHCH2CH2COOH 1-12 CONHOH H NHCH2Ph 1-13 CONHOH H NHCH2- (3-pyridyl) 1-14 CONHOH H NH (CH2) 2NMe2 1-15 CONHOH H NHCHzC ^ OC ^ - ^ - OMe 1-16 CONHOH Me NH-tBu 1-17 CONHOH C ^ -p-OMe NHMe 1-18 CONHOH NH-CH2- (3-pyridyl) 1-19 CONHOH H NH-CH2- (2-thiazolyl) 1-20 CONHOH H NH-CH2- (5-methyl-l, 3,4-thiadiazol-2-yl) 1-21 CONHOH H NH-tBu 1-22 CONHOH H NHCH2CMe2OH 1-23 CONHOH H NHCH2CH2NH2 1-24 COOH COOCMe3 NHMe 1-25 CONHOH COOCMe3 NHMe 1-26 CONHOH COOCMe3 NHCH2CH2-morpholino 1-27 CONHOH COOCMe3 NHCH2CH2CO-morpholino 1-28 CONHOH COOCMe3 NHCH2CH2S02-morpholino 1-29 COOH COOCMe3 NHCHzC ^ C ^ - ^ - SOzlqHz 1-30 CONHOH COOCMe3 NHCH2CH2C6H4-P-SO2NH, 1-31 COOH COOCMe3 NH2 1-32 CONHOH COOCMe3 NH2 1-33 CONHOH COOCMe3 NH (CH2) 3CONH2 1-34 CONHOH COOCMe3 NHCH2CH2COOH 1-35 CONHOH COOCMe3 NH (CH2) 4NMe2 1-36 CONHOH COOCMe3 NHCH2CH2SCH2CH2- morpholino 1-37 CONHOH COOCMe3 NHCH2CH2SCH2CH2NMe 1-38 CONHOH COOCMe3 NHCH2CH2SMe 1-39 CONHOH COOCMe3 NHCH2CH2NMe2 1-40 CONHOH COOCMe3 NHCH2CH2OMe 1-41 CONHOH COOCMe3 NH (CH2) 4-morpholino 1-42 CONHOH COOCMe3 NHC2CH2NHS02-morpholino 1-43 COOH S02C6H4-jp-Me NHME 1-44 CONHOH S02C6H4 - /? - Me NHMe 1-45 CONHOH SOzCsRr / J-Me NH2 1-46 CONHOH S02C6H4 - /? - Me NHCH2CH2-morfohno 1-47 CONHOH NH (CH2) 4-morpholino 1-48 CONHOH S02C6H4- £ '-Me NHCH2CH2COOH 1-49 CONHOH S02C6H4 - /? - Me NHCH (CMe3) COOH 1-50 CONHOH S02C6H4- / 7-Me NHCH2- (3-pyridyl) 1-51 CONHOH S02C6H4 - ^ - OMe NHCH2CH2-Morpholino 1-52 CONHOH S02 Cßt -p-Me NHCH2CH2CO-morpholino 1-53 CONHOH S02 1-54 CONHOH SOzCeH ^ -p-Me NHCH2CH2NMe2 1-55 CONHOH CONHCH2Ph NHMe 1-56 CONHOH CONHCH2Ph NHCH2CH2-morpholino 1-57 CONHOH CONHMe NHMe 1-58 CONHOH CONMe2 NHMe 1-59 CONHOH CONH2 NHMe 1-60 COOH CO-morpholino NHMe 1-61 CONHOH CO-morpholino NHMe 1-62 CONHOH CO-morpholino NHCH2CH2C6H4 - /, - S02NH2 1-63 CONHOH CO-morpholino NH-tBu 1-64 COOH COOCH2Ph NHMe 1-65 CONHOH COOCH2Ph NHMe 1-66 CONHOH COCH3 NHMe 1-67 CONHOH COCH2CH2COOMe NHMe 1-68 CONHOH COCH2CH2COOH NHMe 1-69 CONHOH COCH2CH2COOH? CH2CH2C6H4- / > -S02NH2 1-70 CONHOH COCH2CH2CONH2 NHMe 1-71 COOH COPH NHMe 1-72 CONHOH COPH NHMe 1-73 CONHOH COCH2Ph NHMe 1-74 CONHOH NHMe 1-75 CONHOH COC6H4- / NHAC NHMe 1-76 CONHOH COCβHí-o-OAc NHMe 1- 77 CONHOH COCsH O-COOH NHMe 1-78 CONHOH COCeHrP-COOH NHMe 1-79 CONHOH COCH2- (I-phthalimido) NHMe 1-80 CONHOH COCH2- (N-saccharinyl) NHMe 1-81 CONHOH COCH2- (S-Indantoinyl) NHMe 1-82 CONHOH COCH-2- (3-methi 1 - 1-hydantoinyl) NHMe 1-83 CONHOH COCH2- (3-benzyl-1-1-hydantoinyl) NHMe 1-84 CONHOH COCH2- (I-hydantoinyl) NHMe 1 -85 CONHOH COCH2- (3-hydantoinyl) NHMe 1-86 CONHOH COCH2- (1, 5,5-diethi 1-3-hydantoinyl) NHMe 1-87 CONHOH COCH2CH20H NHMe 1-88 CONHOH COCH 2NH2 NHMe 1-89 CONHOH COCH2NHAc NHMe 1-90 CONHOH COCH2CH (NHCOOCMe3) COOH NHMe 1-91 CONHOI-I COCH (CH3) NHAc NHMe 1-92 CONHOH prolilo NHMe 1-93 CONHOH 3-Hydroxyprolyl NHMe 1-94 COOH CO- (2-pyridyl) NHMe 1-95 CONHOH CO- (2-pyridyl) NHMe 1-96 CONHOH CO- (3-pyridyl) NHMe 1-97 CONHOH CO- (2-thienyl) NHMe 1-98 CONHOH benzoyl NHMe 1-99 CONHOH CO- (2-acetoxyphenyl) NHMe I- 100 CONHOH duoacetyl NHMe 1-101 CONHOH S02CF3 NHMe 1-102 CONHOH S02Me NHMe 1-103 CONHOH S02Me NHCH2CH2-morpholino 1-104 CONHOH S02-CH = CH-C6H4- -Me NHCH2CH2-morpholino 1-105 CONHOH S02-morpholino NHMe 1-106 CONHOH Me NHMe 1-107 CONHOH CH2Ph NHMe 1-108 CONHOH H NH-isopropyl 1-109 CONHOH H NHCH2- • (2-pyridyl) 1-110 CONHOH COOCMe3 NHCH2- - (2-pyridyl) 1-111 CONHOH H NHCH2- - (3-pyridyl) - 1-112 CONHOH COOCMe3 NHCH2- (3-pyridyl) 1-113 CONHOH H NHCH2CH2NHCO- (morpholino) 1-114 CONHOH COOCMe3 NHCH2CH2NHCO- (morpholino) 1-115 CONI-IOH H NHCH2CH2NHS02- (morpholino) 1-116 CONHOH COOCMe3 NHCH2CH2NHS02- (modolino) 1-117 CONHOH CO-morpholino NHCH2CH2NHS02- (morpholino) 1-118 CONHOH H NHCH2CHNHS02- (4-methylpiperazino) 1-119 CONHOH COOCMe3 NHCH2CH2NHS02- (4-methylpiperazino) 1-120 CONHOH S02Ctfí4-p-Mß NHCH2CH2NHS02- (4-methylpiperazino) Another preferred group of the compounds within the context of the present invention encompasses the compounds of the formula (I 1), wherein: R 2 is isobutyl; R3 is 4-fluorophenylmethyl, 4-hydroxyphenylmethyl, 4-methoxyphenylmethyl; or R3 is selected from phenyl, pyridyl, thiazolyl, thienyl, pyridylmethyl, thiazolylmethyl, thienylmethyl, quinolylmethyl, isoquinolylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, indolylmethyl, N-methylindolylmethyl, imidazolylmethyl, and includes the derivatives thereof substituted in the Closed chain of phenyl, pyridyl, thiazolyl, thienyl, quinolyl or isoquinolyl by one or two substituents which are selected from chloro, fluoro, hydroxy, methoxy, methyl, ethyl, t-butyl, OCH2COOH; or R3 is cyclohexyl or cyclohexylmethyl; or R3 is selected from -C (CH3) 2OCH3, C (CH3) 2SCH3, -C (CH3) 2SOCH3, -C (CH3) 2S02CH3, -CH (CH3) OH, CH (CH3) OMe, -CH ( CH 3) o-isopropyl-CH (CH 3) O-tert-butyl -C (CH 3) 2 CH 2 OH, - (CH 2) OH; or R3 is a group that is selected from -CH (C6H5) 2, -C (CH3) 2C6H5, -CH (CH3) OPh, -CH (CH3) OCH2Ph, including the derivatives thereof substituted in the / the closed chain (s) of phenyl by one or two substituents which are selected from chloro, fluoro, hydroxy, methoxy, methyl, ethyl, propyl or t-butyl; or R3 and R4, taken together, constitute a group of the formula - (CH2) 10-NH-, or a group of the formula (B) or (C) mentioned above, wherein n is 6; and W, R, Ri and R4 are as defined above.

Some representative examples within this group of compounds that are particularly preferred are those listed in Table II which is presented below: Table II # NRR! R3 R4 II- 1 NH2 CH2C6H4-p-OMe NHMe p-2 NH2 ClPh2 NH2 11-3 NH2 C (Me) 2SMe NHMe p-4 NHCOOCMe3 C (Me) 2SMe NHMe 11-5 NH2 C (Me) 2SOMe NHMe p- 6 NH2 C (Me) 2S02Me NHMe 11-7 NHCOOCMe3 C (Me) 2S02Me NHMe p-8 NH2 CH2C6Hj 1 NHCH2CH2C6H4-p- S02NH2 p-9 NH2 C (Me) 2SMe NH-tBu p- 10 NH2 C (Me) 2SMe NH- (CH2) 2-C6H4-p- S02NH2 11-11 NHMe C (Me) 2SMe NH-tBu p- 12 NH2 C (Me) 2SMe NH (2-pyridylmethyl) p-13 NHCOOCMe3 C (Me) 2SMC NH ( 2-pyridylmethyl) 11-14 NH2 C (MC) 2SMe NH (3-pyridylmethyl) II- 15 NHCOOCMe3 C (Me) 2SMe NH (3-pyridimethyl) II- 16 NHCOOCMe3 C (Me) 2SMe NHCH2CH2-morpholino 11-17 NHS02Me C (Me) 2SMe NHCH2CH2-morpholino p-i8 NHS02Me C (MC) 2SMe NH (3-pyridylmethyl) p-i9 NHSOzCelL-p-Me C (Me) 2SMe NH2 p-20 NHSOzCsIL-p-Me C (Me) 2SMe NHCH2CH2-morpholino p-2i NHSOaCßHrjo-Me C (Me) 2SMe NH (3-pyridylmethyl) p-22 NHCOMe C (Me) 2SMe NHMe p-23 NHCOMe C (Me) 2SMe NH (3-pyridylmethyl) 11-24 NHCO-morpholino C (Me) 2SMe NHMe p-25 NHCO-morpholino C (Me) 2SMe NHCH 2 CH 2 -morpholino p-26 NHCO-morpholino C (Me) 2SMe NH (3-pyridylmethyl) p-27 NHMe J (Me ) 2SMe NHMe 11-28 NMe2 C (Me) 2SMe NHMe 11-29 NHC0CH2CH2C0NH2 C (Me) 2SMe NHMe p-30 NHC0CH2CH2C0NH2 C (Me) 2SMe NHCHzCHa-morpholino 11-31 NHC0CH2CH2C0NH2 C (Me) 2SMe NH (3-pyridylmethyl) 11-32 4-morpholinyl C (Me) 2SMe NHMe 11-33 NHCOCH2- (1-phthalimido) C (Me) 2SMe NHMe 11-34 NHCOCH2- (1-phthalimido) C (Me) 2SMe NH (3-pyridylmethyl) p -35 1-phthalimido C (Me) 2SMe NHCH 2 CH 2 -morpholino p-36 1 -phthalimido C (Me) 2SMe NH (3-pyridylmethyl) 11-37 1-phthalimido C (Me) 2SMe NHMe 11-38 1-succinimido C (Me) 2SMe NHMe p-39 1-succinimido C (Me) 2SMe NHCH 2 CH 2 -morpholino p-40 NHC0CH2- (1 -oxo-2- isoindolindo) C (Me) 2SMe NHMe p-41 NHC? CH2- (l-oxo-2-isoindolyl) C (Me) 2SMe NHCH2CH2-morpholino p-42 NH2 C (Me) 2SMe NHCMe3 p-43 NH2 C (Me) 2SMe NH-isobutyl p-44 NH2 CH (CH3) OH NHMe p-45 NH2 CH (CH3) OH NHC (Me) 3 p-46 NHCOOCMe3 CH (CH3) OH NHMe p-47 NHCO-morpholino CH (CH3) OH NHC (Me) 3 p-48 NH2 CH (CH3) OCMe3 NHMe p-49 NHCOOCMe3 CH (CH3) 0Me3 NHMe p-50 NH2 CH (CH3) OCMC3 NH (2-thiazolyl) p-5i NH2 CH (CH3) OCMe3 NH (2-pyridyl) p-52 NHCOOCMe3 CH3 (CH3) 3OCMe NH (2-pyridyl) p-53 NH2 CH (CH3) OCMe3 NH (5-indanyl) p-54 NH2 CH (CH3) OCMe3 NH-phenyl p-55 NH2 CH (CH3) OCMe3 NH (3-pyridylethyl) p-56 NHCOOCMe3 CH (CH3) OCMe3 NH (3-pyridylmethyl) p-57 NHCOOCMe3 CH (CH3) OCMe3 NHCH2CH2-morpholino p- 8 NHS02Me CH (CH3) OCMe3 NHCH2CH2-morpholino p-59 NHS02Me CH (CH3) OCMe3 NH (3-pyridylmethyl) ) p-60 NHSOzCßHt-p-Me CH (CH3) OCMe3 NHCH2CH2-morpholino p-6i NHS02C6H4 - ^ - Me CH (CH3) OCMe3 NH (3-pyridylmethyl) p-62 NHCOMe CH (CH3) OCMe3 NHMe p-63 NHCOMe CH (CH3) OCMe3 NHCH2CH2N? S02- morpholino p-64 NHCO-morpholino CH (CH3) OCMe3 NHMe p-65 NHCO-morpholino CH (CH3) OCMe3 NHCH2CH2-morpholino p-66 NHCO-morpholino CH (CH3) OCMe3 NH (3 -pyridylmethyl) p-67 NHMe CH (CH3) OCMe3 NHMe p-68 NMe2 CH (CH3) OCMe3 NHMe p-69 4-morpholimide CH (CH2) OCMe3 NHMe p-70 N HCOCH2- (l-phthalimido) CH (CH3) OCMe3 NH (3-pyridylmethyl) p-71 1 -phthalimido CH (CH3) OCMe3 NHCH2CH2-morpholino 11-72 1 -phthalimido CH (CH3) OCMe3 NHMe 11-73 NHC? CH2- (l-oxo-2-isoindoliniIo) CH (CH3) OCMe3 NHMe 11-74 NHC? CH2- (l-oxo-2-isoindolinyl) CH (CH3) OCMe3 NHCH2CH2-morpholino 11-75 NH2 CH (CH3) OCMe3 NH-tBu 11-76 NH2 CH (CH3) OCMe3 NH-isobutyl 11-77 NHCH2C0NH2 CH (CH3) OCMC3 NHMe 11-78 NHCH2CONMe2 CH (CH3) OCMe3 NHMe 11-79 NHCH2CO-morpholino CH (CH3) OCMe3 NHMe 11-80 NHCOCH2- (1-hydantoinyl) CH (CH3) OCMC3 NHMe 11- 81 NHCOCH2- (3-hydantoinyl) CH (CH3) OCMe3 NHMe 11-82 NHCOCH2- (1, 5,5-trimethyl-CH (CH3) OCMe3 NHMe 3 -hydantoinyl) 11-83 NHCO-morpholino CH2-indolyl NHMe p- 84 NH2 CH2-indolyl NH-tBu p-85 NH2 CH2-indolyl NHMe 11-86 NHCOOCMe3 CH2-indolyl NHMe 11-87 NH2 CMe2Ph NHMe 11-88 NHCOOCMe3 CH.C ^ - ^ - OCHzCOOH NHMe p-89 NHCOOCMe3 CH2C6H4-7 -0CH2C00H NH-tBu p-90 NHCOOCMe3 CHzdlL - ^ - OCHzCOOH NH-tBu p-9i NH2 - (CH2) I0-NH-p-92 NHCOOCMe3 - (CH2) 10-NH- 11-93 NHC? CH2- (1 -oxo-2-isoindo! inyl) - (CH2) 10-NH-p-94 NHCO-morpholino - (CH2) 10-NH-p-95 NHS02-morpholino - (CH2) 10-NH-p-96 NHCOCH2- (1-hydantoinyl) - (CH2) 10-NH- 11-97 NH2 - (CH2) 4-NH- (CH2) 5-NH- 11-98 NHCOOCMe3 - (CH2) 4-NH- (CH2) 5-NH -p-99 NHCOCH2- (l-oxo-2- (CH2) 4-NH- (CH2) 5-NH-isoindolinyl) p-ioo NHCH2-C6H4- / > -F- (CH2) 4-NH- (CH2) 5-NH- 11-101 NHCH2CH6H4- / 7-F - (CH2) 4-NH- (CH2) 5-NH-p-i02 NH2 -CH2- (3 , l-indolylene) - (CH2) 6- -NH 11-103 NH2 -CH2-C6H4-po- (CH2) 3-NH-p-i04 NH2 CH2-C6H4- / 7-OH NHMe II-105 NHCOOCMe3 CHz-CgK -p-OH NHMe p-i06 NH2 CH2- (1 -naphthyl) NHMe 11-107 NH2 CH2- (2-naphthyl) NHMe 11-108 NH2 CH2- (N-methylindolyl) NHMe p-i09 NH2 CH (CH3) OMe NHMe II-110 NH2 CH (CH3) 0-iPr NHMe 11-111 NH2 CH (CH3) OPh NHMe II- 112 NH2 4-fluophenylmethyl NHMe p-? i3 NH2 4-fluophenylmethyl NH-tBu II- 114 NH2 3-pyridylmethyl NH-tBu 11-115 NH2 2-tiazohJ? NetiIo NH-tBu p-? i6 NH2 cyclohexyl NHMe p-? i7 NH2 cyclohexyl NH-tBu p-118 NH2 cyclohexyl NH-CHPh2 p-? i9 NH2 7-isoquinolylmethyl NHMe II- 120 NH2 7-isoquinolimetouo NH-tBu 11-121 NH2 - (CH2) 3OH NH-tBu 11-122 NMe2 tBu NHMe II- 123 NH-CH2-C6H4 - ^ - F tBu NH-tBu Another group of compounds which is particularly preferred of the present invention comprises the compounds of the formula (II) mentioned above, in which: R2 is a linear alkyl C7-Ci5; or R2 is cyclopentylmethyl; or R2 is cinnamyl, benzyl, (phenyl) ethyl, (phenyl) propyl, (phenyl) butyl, 4-phenyl-3-butenyl, 4-phenyl-3-butynyl, (phenyl) pentyl, (phenoxy) methyl, (phenoxy) ethyl, (phenoxy) propyl, (phenoxy) butyl, (phenoxy) -butyl, (benzylaminocarbonyl) propyl, phenylthio, (phenylthio) methyl, (phenylthio) ethyl, (phenylthio) propyl, phenylsulfonyl, (phenylsulfonyl) methyl, (phenylsulfonyl) -ethyl, (phenylsulfonyl) propyl, including derivatives in which the closed benzene chain of said groups is substituted , preferably, in the para position by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hydroxy, methoxy, chloro, fluoro, trifluoromethyl phenyl, fluorophenyl, methoxyphenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl; and W, R, Ri, R3 and R4 are as defined above. Some representative examples within this group of compounds that are particularly preferred are those listed in Table III, which is presented below: Table III NRJRj R2 R3 R, III- 1 NH2 CH2CH = CHPh (E) tBu NHMe? P-2 NHCOOCMe3 CH2CH2CH2Ph tBu NHMe 111-3 NH2 CH2CH2CH2Ph tBu NHMe 111-4 NHCOOCMe3 CH2CH2CH2Ph tBu NH-tBu 111-5 NH2 CH2CH2CH2Ph tBu NH-tBu IH-6 NHCO- morpholino CH2CH2CH2Ph tBu NHMe 111-7 NH2 (CH2) 3-C6H4-Jp-OMe tBu NHMe? p-8 NH2 (CH2) 3-C6H4 - ^ - OMe tBu NH-tBu 111-9 NH2 (CH2) 3-C6H4- ^ -OMe tBu NH- (CH2) 2-C6H4- -S02N H2 III- 10 NMe2 (CH2) 3-C6H4- / > -OMe tBu NH-tBu? P-11 4-morpholino (CH ^ -CeHrp-OMe tBu NH-tBu? P-12 1-phthalimido (CH2) 3-C6H4- -OMe tBu NHMe? P-13 1-succinitnido ( CH2) 3-C6H, - /? - OMe tBu NHMe? P-14 NH2 (CR2 -C? Rp-Cl tBu NHMe p? -15 NH2 (CH2) 3-C6H4-7-OMe tBu NHMe m-i6 NHCO -morpholino (CH2) 3-C6H4 p-OMe tBu NHMe m-i7 NH2 (CH2) 3-C6H4 - /? - CF3 tBu NHMe? p-i8 NH2 (CH2) 5-Ph tBu NHMe? p-19 NH2 (CH2 ) 5-Ph tBu NH-tBu p? -20 NH2 (Cn2) 5-Cc? -pF tBu NHMe? P-2i NH2 (C ^ -C ^ -pF tBu NH-tBu 111-22 NH2 (CH2) 5- OPh tBu NHMe 111-23 NH2 (CH2) s-0-C6R4-p- {CH2) 2Me tBu NHMe ip-24 NH2 (CH2) 3-CONHCH2Ph tBu NHMe 111-25 NH2 (CH2) 6-CH3 tBu NHMe ip-26 NH2 (CH2) 6-CH3 tBu NH-tBu 111-27 NH2 (CH2) i4-CH3 tBu NHMe 111-28 NH2 (CH2) 3-C6H4-7-Cl tBu NH-Bu pi-29 NH2 CKz - Cf -pF tBu NH-Bu? P-30 NH2 (CHJa-CA - ^ - e tBu NH-tBu 111-33 NH2 (CH2) 3-C6H4- -C6H4-F tBu NHMe ip-34 NH2 (CH2) 3-C6H4- / r > -C6H4-F tBu NH-tBu 111-35 NMe2 (CH ^ -C? -C-LF tBu NH-tBu ip-36 1 -pyrrolidinyl (CH ^ -C? -P-Ctft-F tBu NH-tBu 111- 37 NHCHjCßHs-z'-OMe (C? 2) 3-C6H4- / C6H4-F tBu NHMe 111-38 NH2 (CH2) 3-C6H4-C6H4-F tBu NHCH2CH2C6H4-p-S02NH2 111-39 NH2 CH2-cyclopentyl tBu NHMe - -? P-40 NH2 CH2-cyclopentyl tBu NH-tBu p? -4i NH2 CH2-cyclopentyl tBu NHCH2CH2CSH4- / j-S02NH2 111-42 NH2 S-CgHs- -OMe tBu NHMe ip-43 NH2 S-Ceüs-p-Cßñs tBu NHMe m-47 NH2 CH2-CH2-s-c6H, - /, - OMe tBu NHMe 111-49 NH2 CH.-S-CeHs- -C? -F tBu NHMe p? -50 NH2 CH2-C6H5- -OMe tBu NHMe ip-52 NH2 CH2-S02-C6H4 - ^ - OMe tBu NHMe 111-53 NH2 CH2-S02-C6H4-p-OMe tBu NH-tBu 111-54 NH2 CHz-SOi-dl-CdHrF tBu NHMe 111-55 NH2 CH2-SO2-C6H4-ip-C0H4-OMe tBu NHMe 111-57 NH2 (CH2) 6-CH3 cyclohexyl NH-tBu 111-58 NH2 (CH2) H-CH3 cyclohexyl NH-tBu HI-59 NH2 (CH2) 6- CH3 cyclohexyl NHCHaCHC ^ -p-SOzNHz ffl-60 NH2 CH2-cyclopentyl cyclohexyl NH-tBu? P-6i NMe2 CH2-cyclopentyl cyclohexyl NH-tBu 111-62 NH2 CH2-cyclopentyl cyclohexyl NHCH2CHAH4-P-SO2NH2 III-63 NH2 (CH2) 3-C6H4-OMe cyclohexyl NH-tBu ffl-64 NMe2 (CH2) 3-C6H4-OMe cyclohexyl NH-tBu III-65 NH2 (CH2) 3-C6H4-OMe cyclohexyl NHCH2CH2Cr3? 4-P -S02NH2 111-66 NH2 (CH2) 3-C6H4 - ^ - C6H4-F cyclohexyl NHMe pi-67 NH2 (CH2) 3-C6H4- -C6H4-F Cichorhexyl NH-tBu 111-68 NH2 S02-C6H4-P-C6H4-F cyclohexyl NHMe pi-69 NH2 cyclohexyl NHMe? p-7o NH2 (CH2) 3-C6H4-OMe CH2-cyclohexyl NHMe? p-7i NH2 (CH2) 3-C6H4-OMe CH2-cyclohexyl NH-tBu 111-72 NH2 (CH2 ) 3-C6H4-OMe CH2-cyclohexyl NHCH2CH2C6H4- -S02NH2 111-73 NH2 (CH ^ -CeíL- -Qft-F CH2-cyclohexyl NHMe pi-74 NH2 (CE2) 3-CfjLÍ4-p-C6H4-F CH2-cyclohexyl NH-tBu ip-75 NH2 CE rCßRA-p-Ct? - CH2-cyclohexyl NHCH2CH2C6H4- -S02NH2 111-76 NH2 (CH2) 3-C6H4-OMe C (Me2) SMe NHMe 111-77 NH2 (CH2) 3-C6H4 -OMe C (Me2) S02Me NHMe 111-78 NH2 (CH2) 3-C5H4-OMe C (Me2) S02Me NHMe 111-79 NH2 (CH2) 3-C6H4-F-CH2- (3, l-indolylene) - ( CH2) 6-NH-111-80 NH2 (CH ^ QHr ^ -QIL-F-CH2- (3, l-indolylene) - (CH2) 6-NH-? P-8i NH2 (CH2) 3-C6H4-OMe -CH2- (3, l-indolylene) - (CH2) 5-NH- 111-82 NH2 CH2-cyclopentyl-CH2- (3, l-indolylene) - (CH2) 6-NH-pi-83 NH2 S02-C6 H4-OMe-CH2- (3, l-indolylene) - (CH2) 6-NH-111-84 NH2 SOz-C? -Ph -CH2- (3, l-indolen) - (CH2) 6-NH-111 -85 NH2 CH2-S02-C6H4-OMe-CH2- (3,1-indoluene) - (CH2) 5-NH-111-86 NHCOOCMe3 CH2CH2CH2Ph CH2Ph NH-CH2-CH2- (4-morpholino) IH-87 NHCOOCMe3 CH2CH2CH2Ph CH2Ph NHMe 111 -88 NH2 CH2CH2CH2Ph CH2Ph NHMe 111-89 NH2 CH2CH2CH = CHPh tBu NHMe p? -90 NMe2 CH2CH2CCPh cyclohexyl NH-tBu Another group of compounds that is preferred particularly of the present invention comprises the compounds of the above-mentioned formula (I '), in which: "R4 is NH-aryl or NH-heterocyclyl, where aryl and heterocyclyl are as defined above, either unsubstituted or substituted by between one and three substituents which are selected from methyl, ethyl, fluoro, chloro and methoxy; or R4 is o-alkyl, where alkyl is a linear or branched C1-C4 alkyl group, especially methyl, ethyl and t-butyl, or is o- phenyl, and derivatives thereof substituted by between one and three substituents which are selected from straight or branched C1-C4 alkyl, chloro and methoxy, and W, R, Ri, R2 and R3 are as defined above. Some representative examples within this group of compounds that are particularly preferred are those listed in Table IV, which is presented below: Table IV IV- 1 NH2 iBu CH2Ph NH- (4-pyridyl) IV-2 NH2 ¡Bu tBu NH- (4-pyridyl) IV-3 NH2 iBu cyclohexyl NH- (4-pyridyl) IV-4 NH2 iBu CH2-cyclohexyl NH- (4-pyridyl) IV-5 NH2 CH2-cyclopentyl CH2Ph NH- (4-pyridyl) IV-6 NH2 CH2-cyclopentyl CU2-C ^ -p-F NH- (4-pyridyl) IV-7 NH2 CH2-cyclopentyl tBu NH- (4-pyridyl) IV-8 NH2 CH2-cyclopentyl cyclohexyl NH- (4-pyridyl) IV-9 NH2 CH2-cyclopentyl CH2-cyclohexyl NH- (4-pyridyl) IV-10 NH2 (CH2) 6-Me tBu NH- (4-pyridium) IV- 1 1 NH2 (CH2) 6-Me ciciohexyl NH- (4-pyridyl) IV-12 NH2 (CH2) 3-CeH5 tBu NH- (4-pyridyl) IV- 13 NH2 (CH2) 3-C6H4 - / -'- OMe tBu NH- (4-pyridyl) IV- 14 NH2 (CH2) 3-C6H4- / 7-OMe cyclohexyl NH- (4-pyridyl) IV- 15 NH2 tBu NH- (4-pyridyl) IV- 16 NH2 (CH2) 3-C6H4-p-C6H4-p-F tBu NH- (4-pyridyl) IV- 17 NH2 (CH2) 3-C0H4-Jp-C (, H4-Jp-F cyclohexyl NH- (4-pyridyl) IV-18 NH2 iBu CH2Ph NH- (4-F-Ph) IV- 19 NH2 iBu tBu NH- (4-F-Ph) IV-20 NH2 iBu cyclohexyl NH- (4-F-Ph) IV-21 NH2 iBu CH2-cyclohexyl NH- (4-F-Ph) IV-22 NH2 CH2-cyclopentyl CH2Ph NH- (4-F-Ph) IV-23 NH2 CH2-cyclopentyl CHz-C? - ^ - F NH- (4-F-Ph) IV-24 NH2 CH2-cyclopentyl tBu NH- (4-F-Ph) IV-25 NH2 CH2-cyclopentyl cyclohexyl NH- (4-F-Ph) IV-26 NH2 CH2-cyclopentyl CH2-cyclohexyl NH- (4-F-Ph) IV-27 NH2 (CH2) 6-Me tBu NH- (4-F-Ph) rv-28 NH2 (CH2) 6-Me cyclohexyl NH- (4-F-Ph) IV-29 NH2 (CH2) 3-C6H5 tBu NH- (4-F-Ph) IV-30 NH2 (CH2) 3-C6H4 - / .- OMe tBu NH- (4- F-Ph) IV-31 NH2 (CH2) 3-C6H4-p-OMe cyclohexyl NH- (4-F-Ph) IV-32 NH2 (CH ^ -C? - ^ - Cl tBu NH- (4-F- Ph) GV-33 NH2 (CH2) 3-C6H4-Jp-C6H4-PF tBu NH- (4-F-Ph) IV-34 NH2 (CH2) 3-C0H4-p-C6H4-pF cyclohexyl NH- (4- F-Ph) IV-35 NH2 tBu CH2Ph NH- (3,4-methylene dioxyphenyl) IV-36 NH2 tBu tBu NH- (3,4-methylene glyoxyphenyl) IV-37 NH2 tBu cyclohexyl NH- (3,4-methylenedioxyphenyl) IV-38 NH2 tBu CH2-cyclohexyl NH- (3,4-memenodioxiferulo) IV-39 NH2 CH-cyclopentyl CH2Ph NH- (3,4-methylenedioxyphenyl) IV-40 NH2 CH2-cyclopentyl C? 2-C? -p-F NH- (3,4-methylenedioxyphenyl) IV-41 NH2 CH2-cyclopentyl tBu NH- (3,4-methylenedioxyphenyl) IV-42 NH2 CH2-cyclopentyl cyclohexyl NH- (3,4-methylenedioxyphenyl) IV-43 NH2 (CH2) 6-Me tBu NH- (3,4-methylenedioxyphenyl) IV-44 NH2 (CH2) 6-Me-cyclohexyl NH- (3,4-methylenedioxyphenyl) IV-45 NH2 (CH2) 3-C6H5 tBu NH- (3,4-methylenedioxyphenyl) IV-46 NH2 (CH2) 3-C6H4 - ^ - OMe tBu NH- (3,4-methylenedioxyphenyl) IV-47 NH2 (CHJs-CeHt- -OMe cyclohexyl NH- (3,4-methylenedioxy-phenyl) IV-48 NH2 (CH2) 3-C6H4-.P-C1 tBu NH- (3,4-metdenedioxy-phenyl) IV-49 NH2 (CH? -Cft ^? - p-F tBu NH- (3,4-methylenedioxyphenyl) IV-50 NH2 (CH2) 3-CaH4-p-C6H4-pF cyclohexyl NH- (3,4-methylenedioxyphenyl) IV-51 NH2 tBu tBu NH- (2-thiazolyl) IV-52 NH2 tBu cyclohexyl NH- (2- thiazolyl) IV-53 NH2 CH2-cyclopentyl tBu NH- (2-thiazolyl) IV-54 NH2 CH2-cyclopentyl cyclohexyl NH- (2-thiazolyl) IV-55 NH2 (CH2) 6-Me tBu NH- (2-thiazolyl) - - IV-56 NH2 tBu NH- (2-thiazoliu) PV-57 NH2 (CH ^ s-CíHr ^ -OMe ciciohexilo NH- (2-thiazohlo) rv-58 NH2 (CH ^ -CJ -p-Cl tBu NH - (2-thiazolfio) IV-59 NH2 (CH? -C? -C? -pF tBu NH- (2-thiazolium) IV-60 NH2 (CH2) 3-C6H4-y, -C6H4-pF cyclohexyl NH- ( 2-thiazolyl) rv-6i NH2CH2-cyclopentyl tBu NH- (5-Me-l, 3,4-thiadiazole-2-ü) IV-62 NH2 CH2-cyclohexyl cyclohexyl NH- (2-thienyl) IV-63 NH2 (CH2) 3-C6H4 ^ -OMe tBu NH- (2-furyl) IV-64 NHCOOCMe3 tBu tBu O-Me IV-65 NH2 tBu tBu O-Me IV-66 NH2 tBu CH2-cyclopentyl O-tBu IV-67 NH2 CH2-cyclopentyl cyclohexyl O-tBu IV-68 NH2 CH2-cyclopentyl cyclohexyl 0- (2,4,6-trimethylphenyl) IV-69 NH2 (CH2) 3-C6H4-p-OMe tBu O-tBu IV-70 NH2 CH2-cyclopentyl 7-isoquinofylmethyl NH- (2,3-methylenedioxy) phenyl IV-71 NH2 CH2-cyclopentyl - (CH2) 3OH NH- (23-methylenedioxy) phenyl The compounds of the general formula (I) can be prepared by any suitable method known in the art and / or method detailed below, which constitute another aspect of the invention. In the description and the formulas that follow, the groups W, R, R > , R2, R3 and F are as defined above. It will be understood that any functional group (for example, carboxyl, hydroxyl or amino) can be covered in the procedures listed below, if necessary or if so desired, by conventional methods and later discovered at the end. when it is convenient.

For those skilled in the art, said protection groups for said functionalities will become apparent and they are described in detail in the chemical literature (see, for example: "Protective Groups in Organic Synthesis" [Protective groups in organic synthesis] , by TW Greene, Wiley Interscience). Likewise, it will be understood that any of the groups W, R, Ri, R2, R3 and R4 can be converted, following conventional methods in different W, R, Ri, R2, R3 and R, which have any meaning that was previously defined, if so it is desired, at the end or at any stage of the procedures that appear later. These conversions are known or will become apparent to those skilled in the art and are described in detail in the chemical literature (see, for example: "Comprehensive organic Transformation" by R.C. Larock, VCH Publishers). A process for carrying out the preparation of a compound of the formula (I), according to what was defined above, comprises: (a) reacting a beta-lactam compound of the general formula (II) where Ri and R2 are as defined above, and W 'is COOH, CONHOH or protected derivatives thereof, with an amine of the formula (III): where R3 and R4 are as defined above, and b) converting the compound thus obtained of the formula (IV): where W ', R-., R2, R3 and R4 are as defined above, in a compound of the formula (I): where W, R, Ri, R2, R3 and R4 are as defined above. It is evident that compounds having a desired configuration can be prepared starting from the compounds (II) and (III) with the appropriate configurations. Thus, a process for carrying out the preparation of the preferred compounds of the formula (II) comprises: (a) reacting a beta-lactam compound of the general formula (II '): where Ri and R2 are as defined above, and W 'is COOH, CONHOH or protected derivatives thereof, with an amine of the formula (III'): where R3 and R4 are as defined above, and b) converting the compound of the formula (IV) obtained in that way: (IV) where W ', Ri, R2 / R3 and R4, are as defined above, in a compound of the formula (I'): where W, Ri, R2, R3 and R4, are as defined above. The reaction between the beta-lactam of the formula (II) and the amine of the formula (III) in step (a) which was mentioned above can be carried out in organic solvents, in particular in dimethylformamide (hereinafter , DMF), tetrahydrofuran (hereinafter, THF), acetonitrile, and toluene, or in aqueous organic solvents, especially in aqueous THF, aqueous DMF, and aqueous acetonitrile, at temperatures ranging from 0 to 120 ° C, either in the absence or in the presence of external bases, or nucleophiles (NuH or the salts thereof, where Nu will be defined below) that fragment the beta-lactam of the formula (II) more easily than the amine of the formula (III), which gives rise to activated carboxylic acid derivatives of the formula (Ha) where W ', Ri and R2 are as defined above, Nu is selected from the group consisting of azido, ylidazole, cyano, lower alkylthio, pyridylthio, phenylthio, benzylthio; said activated carboxylic acid derivative of the formula (Ha) which reacts, in the same manner and under the same reaction conditions, with an amine of the formula (III), which gives rise to the product of the formula (IV). The external nucleophiles that are particularly preferred are sodium azide, imidazole and sodium and potassium cyanide. A solvent that is particularly preferred is DMF. When it is found in compounds of the formula (II), (Ha) and (IV) mentioned above, W 'is a protected derivative of COOH, preferably it is benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl tert-butoxycarbonyl , benzhydryloxycarbonyl trityloxycarbonyl, trimethylsilyloxycarbonyl, tere- - nurlialmethylsilyloxycarbonyl, pheny1-dimethylsilyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl and ethoxycarbonyl. When it is found in the aforementioned compounds of the formula (II), (Ha) and (IV), W 'is a protected derivative of CONHOH, preferably, it is a group of the formula CONHOR10, or CON (Rp) OR10 where Rio and Rn are, respectively, hydroxy- and amino- protection groups, known per se which can be extracted by hydrogenolysis or hydrolysis. The Rio and Ru groups, which are preferred, which may be the same or different, include benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, tert-butoxycarbonyl, tetrahydropyranyl, and trityl. The conversion of a compound of the formula (IV) into a compound of the formula (I) in step (b) that was mentioned above may include any or all of the steps detailed below in any order: - (b ') ): the conversion of the group W, which is a protected derivative of W, into a group W, which is COOH or CONHOH. This conversion is carried out by methodologies that are well known in the art, as generally referred to above. A conversion of this type which is preferred is hydrogenolysis, in particular in the presence of a palladium catalyst, in an inert organic solvent such as ethanol or DMF, or else similar, in particular at room temperature and under pressure atmospheric or moderate pressure, which is suitable for the conversion, for example, of esters of benzyl and p-nitrobenzyl in the parent carboxylic acids, or of hydroxamates of O-benzyl and 0, N-bis-benzyl in the parent hydroxamic acids . Another conversion of this type that is preferred is acid hydrolysis, in particular by trifluoroacetic acid or aluminum trichloride, in the presence or absence of anisole, in inert organic solvents such as, for example, THF, acetonitrile and also other similar, in particular, between -20, and + 30 ° C, which is suitable for the conversion, for example, of the tert-butyl esters and p-methoxybenzyl esters into the parent carboxylic acids, or of o- (p-methoxybenzyl) and 0, N-bis (p-methoxybenzyl) hydroxamates in the parent hydroxamic acids; - (b "): the conversion of the group W ', which is COOH or an activated derivative thereof into a group W, which is CONHOH This conversion involves the condensation of said compounds of the formula (IV) with hydroxylamine or a salt thereof or with a hydroxylamine protected by 0 of the formula R? or ~ NH2, or a hydroxylamine deprotected by N, O of the formula Rio-NRp, in which Rio and Ru are such - as defined above, or a salt thereof and, subsequently, the removal of the protection groups R10 and Rp, if they are present, said condensation is carried out in accordance with the general methodologies for the conversion of the carboxylic acids or the activated derivatives of the same in hydroxamic acids, which are well known in the art In particular, the activated derivatives of the COOH group are the acid chloride, the mixed anhydrides, and the esters, In particular, the acid chloride is obtained by means of the acid reaction or a salt thereof with reagents such as, for example, oxalyl chloride or thionyl chloride; the mixed anhydrides are obtained by reaction of the acid or a salt thereof with chlorocarbonates such as, for example, ethyl chlorocarbonate, or with acid halides, such as, for example, pivaloyl chloride; the esters, which are preferably the esters of methyl, ethyl, pentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl, are obtained by means of the reaction of acid with the corresponding alcohols in the presence of a dehydration agent, for example dicyclohexyl carbodiimide ( hereafter, DCC), N, N-dimethylaminopropyl-N'-ethyl carbodiimide (EDC), and 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydro-quinoline (EEDQ).

- An O-protected hydroxylamine is, preferably, 0-benzyl-hydroxylamine, 0- (4-methoxybenzyl) -hydroxylamine, O-trimethylsilyl-hydroxylamine, and 0- (tert-butoxycarbonyl) hydroxylamine. An N, O-deprotected hydroxylamine is, preferably, N, 0-bis (benzyl) -hydroxylamine, N, 0-bis (4-methoxybenzyl) -hydroxylamine, N, 0-bis (tert-butoxycarbonyl) -hydroxylamine, N- (tert-butoxycarbonyl) -0- (tert-butyldimethylsilyl) -hydroxylamine, and N- (tert-butoxycarbonyl) -0- (tetrahydropyranyl) -hydroxylamine. Preferably, the condensation reaction with hydroxylamine, O-protected hydroxylamines, N, O-deprotected hydroxylamines, and salts thereof, is carried out in an inert organic solvent such as, for example, DMF, THF, acetonitrile, dichloromethane, toluene and the like, at temperatures ranging from -20 to + 60 ° C, optionally, in the presence of a tertiary organic base. When resorting to the use of protected hydroxylamines, the protection groups are extracted after proceeding with the condensation reaction, under the conditions known per se. By way of example, the benzyl and 4-methoxybenzyl groups can be extracted, preferably, by catalytic hydrogenation, according to what is described in the above-mentioned step (b '); the tetrahydropyranyl and tert-butoxycarbonyl groups can be extracted, preferably, by mild acid hydrolysis; the trimethylsilyl and tert-butyldimethylsilyl groups are cleaved during the reaction or by aqueous processing or mild acid treatment; - b "1): the conversion of the NHRj group, where Rj is different from hydrogen, in an NH2 group This reaction can be carried out in compounds of the formula (I) or the intermediates of the formula (IV) where Rj is an amino protecting group, in accordance with methods that are well known per se, for example, by means of the extraction methods of the amino protecting groups that are part of the peptide chemistry techniques. The R groups which are particularly preferred for said conversion are the groups which extract electrons, in particular the alkoxy- or benzyloxycarbonyl groups such as, for example, tert-butoxycarbonyl, benzyloxycarbonyl and 4-nitro or 4-ethoxy and the derivatives thereof, since the same particular R groups contribute, efficiently, in the fragmentation reaction of the beta-lactam between a compound of the formula (II) and a compound of the formula (III), such as it was defined before, to ob have a compound of the formula (IV). In a preferred embodiment of the present invention, Ri is tere- -butoxycarbonyl, which can be extracted by treatment with trifluoroacetic acid (TFA), optionally, in the presence of anisole, in an inert organic solvent; in another preferred embodiment, Ri, is benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, which can be extracted by means of catalytic hydrogenation; - (blv): the conversion of the NHRi group, including the special case in which Ri is hydrogen, into a NRRi group, which will be selected within the previously mentioned specifications. The R and Ri groups that are preferred are the same groups as were detailed for the preferred compounds of the formula (I). Said conversion comprises functionalizations of the amino groups that are well known in the art, such as alkylation, acylation, sulfonylation and the like, and is carried out according to methods that are well known per se. In a preferred embodiment of the present invention, said conversion is carried out in compounds of the formula (IV) in which W 'is protected carboxy and, subsequently, removal of the protecting group to obtain a compound of the formula (I) in which W is COOH, by means of the use of the general methodology described in the above-mentioned point (b) and, optionally, by means of the conversion of the compound of the formula (I) obtained in this way, where W is COOH, in the corresponding compound, where W is CONHOH, by means of the application of the general methodology described in point (b ") above: - (b): the conversion of any Group R, Ri, R2, R3 and R4, in a different group Ri, R2, R3 and R4, which will be selected according to the specifications established above, by applying methodologies known per se. The resulting compounds of the formula (I) can be converted into the salts, prodrugs, hydrates or solvates thereof which are desired by means of the application of well-known reactions, including the preparation of salts by reaction with a pharmaceutically acceptable acid, or the preparation of esters by means of condensation with a pharmaceutically acceptable alcohol or with a pharmaceutically acceptable carboxylic acid, and mixing with an aldehyde of the general formula T-CHO or a ketone of the general formula TT'CO , where T and T 'are as defined above, and water extraction by evaporation. The amines of the formula (III) which were mentioned above are known compounds or can be prepared from known compounds by the use of known methods. The beta-lactams of the formula (II) mentioned above constitute known compounds or can be prepared from known compounds, by means of the application of methodologies known per se or by analogy with the specific preparative examples of the present invention. In particular, a preferred preparation of the compounds of the formula (II) includes: - (i): the cyclization of an aspartic acid derivative to obtain a compound of the formula (II), in which R2 is hydrogen, by means of the reaction with a suitable condensing agent; - (ii): the conversion of a compound of the formula (II), in which R2 is hydrogen, into a compound of the formula (II), in which R2 is as described above, by means of the deprotonation with a strong base and the alkylation of the resulting beta-lactam enolate with an agent of the formula R2-X, in which X is halo, for example chlorine, bromine or iodine, or sulfonyloxy, for example triflate, mesylate or others similar. The general conditions for the above-mentioned step (i) are described in the literature, and the aspartic acid derivative which is preferred is generally dibenzyl aspartate or di (4-nitro) benzyl aspartate. Some of the resulting azetidinones (II) are also available in place. A compound that is preferred in step (ii) is a compound of the formula (II), in which R2 is hydrogen, Ri is tert-butyldimethylsilyl, and W is COOH; said compound is obtained from the product of step (i), in which Ri is hydrogen and W is benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl by using conventional methods, in particular, by means of catalytic hydrogenolysis and silylation by means of tert-butyldimethyl chlorosilane. It is evident that the conditions that were previously described for the reaction of a beta-lactam of the formula (II) and an amine of the formula (III), to effect the conversion of a compound of the formula (IV) into a compound of the formula (I), and to effect the conversion of the resulting compounds of the formula (I) into the salts, the prodrugs or the solvates thereof, also apply to the preferred helicity analogs, ie, respectively , for the reaction of a beta-lactam of the formula (II ') and an amine of the formula (III'), for the conversion of a compound of the formula (IV) into a compound of the formula (I '), and for the conversion of the resulting compounds of the formula (I ') into the salts, the prodrugs or the solvates thereof, since said conditions do not cause epimerization or racemisation. Similarly, the conditions that were previously described for the preparation of the beta-lactams of the formula (II) are also applied for the preparation of the helicity analogues "which are preferred of the formula (II '), when the derivative of the aspartic acid in the aforementioned step (i) in an l-aspartic acid derivative In fact, in step (i), which comprises the intramolecular condensation of the W carboxy group of the aspartic derivative or a derivative thereof, i.e. , a halide, ester or acid anhydride, with the amino group thereof, or a trimethylsilyl derivative thereof, retains the helicity of the carbon atom In step (ii), said helicity induces the configuration of the adjacent stereocenter, that is to say, those of the carbon atom carrying the group R. As is well known, in the chemistry of azetidinone, the alkylation of the 3-unsubstituted, 4-substituted azetidinones allows to obtain products in which the substituents C-3 and C-4 are in a transoid relationship with each other. In this manner, the azetidinones of the formula (II '), in which R2 is a hydrogen atom, which are obtained from the l-aspartic acid derivatives, are subjected to the alkylation with reactants of the formula R2- X mentioned above to provide azetidinones (II ') with the configurations presented in the two helicity centers. Said configurations of the two helicity centers are the same as those observed in the compounds of the formula (I ') which are specifically preferred herein. Accordingly, it will be appreciated that steps (i) and (ii) mentioned above constitute an essential part of a completely original stereo-controlled route of the compounds of the formula (I '), which are characterized by having a (S) and (R) configuration, in accordance with the Cahn- Ingold-Prelog, in the carbon atoms that carry the groups NRRi and R2, respectively.

The compounds of the formula (I) which are provided by the present invention are characterized by a high inhibition activity in the matrix metalloproteinases (MMPs), in particular, of the collagenases, the gelatinous ones and the stromelysins. By way of example, the protocol presented below was used to evaluate the biochemical activity of the compounds of the formula (I) against MMP-1, MMP-2, and MMP-3 (respectively, human interstitial collagenase). , gelatinous A, and stromelysin-1).

- BIOCHEMICAL ANALYSIS (Protocol A) The in vi tro potency of the compounds of the present invention as competitive inhibitors of the selected matrix metalloproteinases was determined in accordance with what will be described below. Human collagenase (MMP-1) was obtained as a truncated recombinant enzyme comprising the residues 101-269 and did not require activation. Human gelatinase-A (MMP-2) was obtained as a pro-enzyme (72 kDa) and was activated with 1 mM of 4-aminophenylmercuric acetate for 30 minutes at 37 ° C immediately before proceeding with its use. Human stromelysin-1 1-255 (MMP-3) was obtained as a recombinant pro-enzyme isolated from E. coli and activated by heat (1 h, 55 ° C). Some measurements were also made, for which a recombinant human MMP-3 pro-enzyme was used isolated from a bacul ovirus infected with Sf9 insect cells and activated with 5 mg / l trypsin (30 minutes, 37 ° C, finally extracted by the agarose-soybean trypsin inhibitor). All enzyme analyzes to determine the dissociation values of the enzyme inhibitor constants were carried out using the substrate peptide (7-methoxycoumarin-4-yl) Acetyl-Pro-Leu-Glv-Leu- (3- [ 2, 4-dinitrophenyl-1-2, 3-diaminopropionyl) -Ala-Arg-NH2 (Mea-Pro- -Glv-Leu-Dpa-Ala-Arg-NH,) [CG Knight, F. Willenbrock and G. Murphy. FEBS Lett. (1992) 296, 263-266]. The enzyme fragment in the Gly-Leu link extracts the group Dpa that internally tunes. The release of the highly fluorescent Mca-Pro-Leu peptide was followed fluorimetrically, for which a Fluorescence spectrophotometer Perkin Elmer LS-50 equipped with a cell changer with four position stirring with thermostat. The excitation wavelength was set at 326 nm (bandwidth, 5 nm) and the emission at 392 nm (bandwidth, 20 nm). All other environments were optimized to obtain the best signal-to-noise ratio. All the experiments were carried out at 37 ° C. The concentration of the substrate was 2 micromolar in the tests, so that they could approximate to join the term (1 + [substrate] / km) in the calculations, the Km values are 70 micromolar or higher for the three MMPs (Knight, Willenbrock and Murphy). The substrate remained stable for more than 60 minutes under the conditions of analysis, which does not give an appreciable increase in fluorescence. The total response against 200 nM of Mca-Pro-Leu-OH (the fluorescent peptide released) was adjusted and the instrument was calibrated within the range between 0-100 nM Mca-Pro-Leu-OH, corresponding to a degree of hydrolysis between 0 and a % of the 2 micromolar substrate. The aqueous analysis buffer was 50 mM Tris / HCl pH = 7.4 containing 0.15 M NaCl, 10 mM CaC12, 0.01 mM ZnC12 and 0.05% Brij 35. In general, the inhibitors were dissolved in DMSO and added at a ratio of 1: 100. The same was for the substrate, in such a way that the actual concentration of DMSO in the tests remained at 2% (v / v). The enzyme concentrations in the tests were, in general, 1.0 nM of collagenase, 0.04 nM of gelatinase-A and 3.0 nM of stromelysin. Under our analysis conditions we have made measurements of k cat / Km values of 26,900, 669,000 and 9,740 l / (M * s) for MMP-1, MMP-2 and MMP-3, respectively. It was observed that these three enzymes remained stable for more than three hours under the conditions of analysis.

Preliminary investigations were carried out on some representative inhibitors through continuous fluorescence. In detail, 1.94 ml of the assay buffer was preheated to 37 ° C and 0.02 ml of the inhibitor was added to DMSO (or DMSO only), 0.02 ml of 0.2 mM of substrate, and 0.02 ml of 100 nM of MMP1 or 4 nM of MMP2 or 300 nM of MMP3. The increase in fluorescence was, in general, monitored after 30 minutes. It was observed that the enzymes remained stable for a period that ranged between 15 and 30 minutes of preincubation under the same conditions. The concentrations of the inhibitors ranged between 0.01 and 50,000 nM, according to the enzyme and potency. The degree of hydrolysis of the substrate was found to be within 5% of the total concentration. We observed that such representative inhibitors were reversible competitive inhibitors and the simplest competitive slow-narrow bond inhibition model representing the observations was a two-step mechanism E + I < = > The < = > The * in which the step for the determination of the speed is the conversion of the enzyme inhibitor complex The initial in the El * more stable. The dissociation and rate constants of the enzyme inhibitor complexes could be obtained by analyzing the progress curve data for the inhibition of slow stray binding as described by Morrison and Walsh [J.F. Morrison and C.T. Walsh, Adv. Enzymol. Reran. Areas Mol. Biol. (1988) 61, 201-301]. Additionally, in order to rapidly monitor large amounts of inhibitors, we have also carried out experiments to determine only the global dissociation constant Ki * = [E] free x [I] free / [El + El *] (Morrison and Walsh) , that is, the Ki value measured in constant state, in the preincubation experiments. All the concentrations and conditions were the same as those mentioned above, but in this case only the value of Vo, the initial velocity in the absence of the inhibitor, and the value of Vs, the constant state velocity, were measured at different concentrations of inhibitors. in the region if its enzyme inhibitor dissociation constants are present. On a routine basis, 1.94 ml of the 37 ° C assay buffer in a flask, 0.02 ml of the inhibitor in DMSO (or DMSO only) were preheated, and 0.02 ml of 100 nM of MMP-1 or 4 nM of MMP-2 or 300 nM of Mmp-3 were mixed and the bottle was kept at 37 ° C for a period of 5-180 minutes. Subsequently, 0.02 ml of 0.2 mM of substrate was added, mixed and transferred in a preheated cell. The sample was allowed to equilibrate in a test tube for 3-5 minutes at 37 ° C against small changes in temperature and changes in the enzyme inhibitor equilibria related to the substrate aggregate. After having monitored the linear increase in fluorescence during a period of 3-5 minutes, the curve (Vo or Vs) was obtained. The concentrations of the inhibitor were changed to collect data about the Vs / Vo ratio, which ranged between 0.05 and 0.95. The values of Ki * were calculated by means of the non-linear weighted regression to the narrow-link equation (Morrison and Walsh): Vs / Vo = [1 / (2 x Et)] x SQR [(K¡ * + lt - Et)? 2 + 4 x K * x Et] - (Ki * + lt -Et) in which Et and It constitute the concentrations of the total enzyme and inhibitor. The lower limits of the determination of the Ki * value were dictated by the concentrations of the enzyme: even if the regression to the narrow link equation takes into account Et, which were known by preliminary titration, and in general, reliable estimates of Ki * values less than - 1/4 of Et could not be obtained. In our case, this means approximately 200-500 pM of Ki * with collagenase, 10-2 pM of Ki * with gelatinase-A or 0.8-1.5 nM of Ki * with stromelysin. By definition, measurements must be carried out under "constant state" conditions. When the Ki * value is very low, which approaches Et, and It is modified in the region of its Ki * value, then it may take a few minutes to establish the equilibrium between the complexes of the enzyme, the inhibitor and the inhibitor. enzyme (Morrison and Walsh). For this reason, the experiments were repeated by extending the preincubation time of the enzyme and the inhibitor (5 minutes, default value) up to three hours every time that measurements were made of Ki * values in the low nanomolar range or inferiors However, with the inhibitors of the present invention examined to date, differences have rarely been found by extending the preincubation time from 5 minutes to three hours or more, even though the inhibitors have very low Ki * values. By way of example, Table V presents the inhibition constants, Ki in constant state, as determined by the aforementioned protocol (A) for 14 compounds of the present invention.

TABLE V. CONSTANTS OF INHIBITION (Ki in constant state, all nanomolar) EXAMPLE # COMPOSITE MMP-1 MMP-2 MMP-3 2 1 1--2255 3 3..66 1 1..66 5.0 4 1 1--22 0 0..88 1 1..77 5.4 6 1 1--4444 1 1..11 1 100 9.5 1- 61 0. 7 1. 2 31 10 1 1--7722 1 1..66 6 6..66 14 12 I IVV - 6644 1 14400 8 855 450 13 IV-65 14 57 930 16 111-87 38 0.16 2.3 17 111-88 7.8 0.012 1.1 18 1-21 1.2 1.3 16 20 11-122 1.9 10 11 21 IV-2 0.6 1.1 1.7 22 IV-41 < 0.2 0.6 0.5 23 11-102 0.5 1.3 3.9 It has also been shown that the compounds of the formula (I) have a high activity in the inhibition of TNF release from different cell lines, under different stimulation conditions. For example, the cell-based analysis that is detailed below was used to evaluate this activity: CELL ANALYSIS (Protocol B) The in vitro potency of the compounds of the present invention as inhibitors of TNF release from cells was determined according to what will be described below. THP-1 cells, cultured in RPM1 1640 supplemented with 10% FCS in 24-well plates, 1 mL of a suspension of lxlO6 cells / mL in each well were distributed. The compounds were added to proba,., Dissolved in DMSO and diluted with the culture medium (1% final concentration of DMSO). Plates were incubated for 30 minutes at 37 ° C in 5% C02, and lipopolysaccharide (LPS 0111: 840 5 microg / mL) was added as a stimulant. After proceeding with the incubation for another 4 h, the cells were harvested, centrifuged (2,000 rpm, 7 minutes), and the supernatant was collected and frozen (-20 ° C) until analysis was performed. The analysis was carried out following the classical ELISA methodology (monoclonal anti-TNF-α antibody, polyclonal rabbit capture antibody, and peroxidase anti-rabbit antibody). Dichloroisocoumarin was used as standard. By way of example, Table VI presents the IC 50 values (all micromolar), as determined by the aforementioned protocol (B) for 7 compounds of the present invention.

TABLE VI. INHIBITING THE RELEASE OF TNF-alpha OF THP-1 CELLS EXAMPLE # COMPOSITE IC50 (μM) 2 1-25 9.9 6 1-44 1.2 8 1-61 25.1 12 IV-64 40.5 13 IV-65 127.8 16 111-87 12.8 17 111-88 1.9 The amino functionality or amino substitution to the carboxy or hydroxamic function that characterizes the compounds of the present invention, not only contributes to improve the biochemical potency but also, in many cases, also contributes to improve the aqueous solubility and properties pharmacokinetics The poor aqueous solubility constitutes an important limitation of the more potent hydroxamate-based MMP inhibitors of the prior art. The compounds of the formula (I), in which the group -NRRi a primary, secondary or tertiary amino group, exists in protonated form at a physiological pH; consequently, its aqueous solubility is high (> 5 mM) or moderate (> 1 nM), even when one or more of the R groups, Ri-R * is of a high lipophilic nature. This characteristic contributes to improve the absorption through the gastrointestinal wall. By way of example, Table VII shows the solubility of 12 compounds of the present invention in physiological saline at 25 ° C.

TABLE VII. SOLUBILITY IN SALINE, 25 ° C EXAMPLE # COMPOSITE Soluble to (mg / mL): 4 1-2 > 7 6 1-44 0.05 10 1-72 0.03 12 IV-64 0.25 13 IV-65 > 9 16 111-87 0.01 17 111-88 2.4 18 1-21 > 8 20 11-122 > 5 21 IV-2 > 13 22 IV-41 > 10 23 11-102 0.5 The compounds of the formula (I), accordingly, can be used in human or veterinary medicine in the form of pharmaceutical preparations containing them, in association with a compatible pharmaceutical carrier material. Thus, a distinctive aspect of the present invention is the preparation of pharmaceutical compositions which carry a compound of the formula (I) as the active ingredient., and a method of control (i.e., treatment or prophylaxis) of diseases or conditions mediated, both in humans and in warm-blooded animals, by MMPs and / or TACE, said method comprising administering to the mammal an effective amount of a compound of the formula (I) mentioned above, or a pharmaceutically acceptable salt thereof in humans as well as in animals. In particular, the compounds of the formula (I) can be administered: A) Orally, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions intended to be used orally can be used. prepared according to any method known in the art for the manufacture of pharmaceutical compositions and, said compositions may contain one or more agents that are selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives for to provide pharmaceutically elegant and tasty preparations. The tablets contain the active ingredient in combination with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; the granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be coated or uncoated by the use of known techniques that delay disintegration and adsorption in the gastrointestinal tract and, consequently, provide a sustained action over a prolonged period. For example, a time-delay material such as, for example, glyceryl monostearate or glyceryl distearate may be employed. Formulations for use in oral form can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as capsules of soft gelatine in which the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in combination with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; the dispersing or wetting agents may be naturally occurring phosphatides, for example lecithin, or the condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or the condensation products of ethylene oxide. with long-chain aliphatic alcohols, such as heptadecaethylene oxide, or the condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as, for example, polyoxyethylene sorbitol monooleate, or the condensation products of the ethylene oxide with partial esters derived from fatty acids and hexitdl anhydrides, for example, polyoxyethylene sorbitan monooleate. Said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as, for example, sucrose or Saccharin An oily suspension can be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those mentioned above, and flavoring agents can be added in order to provide a tasty oral preparation. These compositions can be preserved by the addition of an antioxidant such as, for example, ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, a suspending agent and one or more preservatives. The dispersing or wetting agents and the suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example soy, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example the polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. The syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Said formulations may also contain a demulcent, a preservative and flavoring and coloring agents; B) Parenterally, either, subcutaneously, or intravenously, or intramuscularly, or intramuscularly, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. This suspension can be formulated according to the known art resorting to the use of suitable dispersing and wetting agents and of the suspending agents that were previously mentioned. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, conventionally, sterile fixed oils are used as a solvent or suspension medium. For this purpose, any soft fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use for the preparation of injectables; C) By inhalation, in the form of aerosols or solutions for nebulizers; D) Rectally, in the form of suppositories that are prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperature but liquid at the rectal temperature and, consequently, will melt in the rectum to release the drug . These materials are cocoa butter and polyethylene glycols; E) Topically, in the form of creams, ointments, jellies, solutions or suspensions. The daily dosages are within a range of approximately 0.1 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the individual to be treated. , the type and severity of the disease, and the frequency and route of administration; preferably, the daily dosage levels for humans are within the range between 10 mg and 2 g. The amount of the active ingredient that can be combined with the carrier materials to produce a single dosage form will vary according to the host in question and the particular mode of administration. For example, a formulation which is intended for oral administration in humans, may contain between 5 mg and 2 g of the active agent, which is composed of an appropriate and convenient amount of the carrier material, which may vary between about 5 and 95 percent of the total composition. The dosage unit forms will, generally, contain between about 5 mg and 500 mg of the active ingredient. Pharmaceutical compositions containing a compound of the formula (I) can be used in medicine to effect the treatment of disease states characterized by an imbalance of the active MMPs and their natural inhibitors, tissue inhibitors of metalloproteinases (from hereunder TIMPS). When the local TIMP levels are insufficient, or the MMPs are expressed in excess or activated in excess of their inactive secretory zymogens (pro-MMPs), degradation of the extracellular matrix occurs. This degradation can be slow and progressive, as observed, for example, for the loss of cartilage matrix in rheumatoid arthritis.

(L.A. Walakovits and his collaborators, Arthritis Rheum. : 35-42, 1992) and osteoarthritis (DD Dean et al., J. Clin. Invest., 84: 678-685, 1989), and for the degradation of the bone matrix in osteoporosis (PA Hill et al. collaborators, Biochem. J., 308: 167-175, 1995). In other situations, with congestive heart failure, rapid degradation of the extracellular matrix of the heart occurs (P. W. Armstrong et al, Canadian J. Cardiol 10: 214-20 220, 1994). Cancer cells use MMPS, either expressed by themselves or by the surrounding tissues to achieve rapid remodeling of the extracellular matrix. There is considerable evidence that MMPs are compromised in at least 3 aspects of the growth and expansion of tumors (for example, see A.H. Davidson et al., Chemistry & Industry, [Chemistry and Industry] 258-261, 1997, and references therein). In the process of tumor metastasis, MMPs are used to break down the extracellular matrix, which allows cancer cells of the primary tumor to invade nearby blood vessels from where they are transported to different organs and settle secondary tumors. The invasive growth of these secondary sites also needs MMPs to assist in tissue breakdown. Additionally, MMP activity contributes to the invasive internal growth of new blood vessels (angiogenesis) necessary for tumors to grow above a certain size. The criteria for the use of MMP inhibitors in medicine is well described in the recent literature; see, for example, D.E. Levy & A.M. Ezrin, "Matrix Metalloproteinase Inhibitor Drugs", in: Emerging Drugs: The Prospect for Improved Medicines, [Emerging Drugs: Prospects for Improved Medicines], Chapter Ten (pages 205-230), Ashley Publications Ltd., 1997. According to this criterion and the proof of concept already established with other MMP inhibitors, the compounds of the present invention can be used, in particular, to effect the treatment of: inflammatory and autoimmune diseases, in particular rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, and multiple sclerosis; - cancer, including tumor growth and metastasis, with particular reference to breast cancer, small cell lung cancer, non-small cell lung cancer, brain tumors, prostate cancer, colorectal tumors and the Kaposi sarcoma; - other angiogenic conditions, especially diabetic retinopathies and macular diseases; - cardiovascular diseases, especially congestive heart failure and vascular restenosis; wound healing, including ocular inflammation, ulceration of the cornea or tissues, soft tissue or bone diseases; - other conditions in which the MMPs or the release of TNF-alpha are compromised, in particular, psoriasis, shock syndromes and rejection al-transp ante. The present invention also includes the use of the compounds of the formula (I), to effect the treatment of any of the aforementioned diseases, as auxiliaries for other conventional treatments; for example, together with anti-inflammatory or immunosuppressive drugs for the treatment of rheumatoid arthritis and multiple sclerosis, and together with cytotoxic or cytostatic drugs for the treatment of tumor diseases.

EXAMPLE 1 (3S-tert-Butoxycarbonylamino-4-hydroxy-2R-isobutyl) -succinyl-1-phenylalanine-N-methylamide (Compound 1-24).

-Step (a): A solution of l-tert-butyldimethylsilyl-4S-carboxyzetidinone (6.2 g) in dry THF (100 ml) at 0-5 ° C was treated in drops with 2M of an LDA solution (28.4 ml) in the same solvent, to obtain an orange solution of the di-anion. After 15 minutes, a solution of isobutyl iodide (6.8 ml) in THF was added at 0 ° C under stirring, and the resulting green solution was left at the same temperature overnight. Tempering with aqueous KHSO iM (300 ml) was followed by extraction with ETOAC, which allowed to obtain crude 1-tert-butyldimethylsilyl-4S-carboxy-3R-isobutylazetidinone in the form of an orange syrup (7). g). The aforementioned material was dissolved in DMF (20 ml) and treated dropwise, in that order, with triethylamine (5.85 ml) and benzyl bromide (4.8 ml). After 4 h at room temperature, the mixture was partitioned between water and ETOAC. The organic phase, after washing with saturated aqueous NaCl, was dried and evaporated to obtain crude 4S-benzyloxycarbonyl-l-tert-butyldimethylsilyl-3R-isobutylazetidinone in l <; form of an orange oil, which was dissolved in THF (10 ml) and then left overnight in the presence of tetrabutylammonium fluoride (2.6 g) and acetic acid (1.7 ml). The mixture was partitioned between saturated aqueous NaHCO 2 and EtOAc, and the organic phase was dried and evaporated. Flash chromatography on silica gel (n-hexane / EtOAc) allowed to obtain 4S-benzyloxycarbonyl-3R-isobutyl azetidinone (4.7 g) in the form of white needles. FT-IR (Kbr) 3229 (NH), 1744-1750 br (CO) cm "1. NMR (200 MHZ, CDCl,) 0.94 (d, 3 H, J 6.5), 0.87 (d, 3 H, J = 6.5), 1.57-1.82 (m, 3 H), 3.32 (m, 1 H), 3.90 (d, 1 H, J = 2.4), 5.22 (Abq, 2 H), 5.96 (br s, 1 H) 7.36 (m, 5 H) ppm.

-Step (b): A solution of 4S-benzyloxycarbonyl-3R-isobutylazetidinone (1 g) from step (a), mentioned above, in MeCN (15 ml) with DMAP (4-dimethylamino inopyridine, 46 mg) and BOC2O (di-tert-butyl dicarbonate, 1.67 g) at 40 ° C for 30 minutes and then at room temperature All night long. After extracting the solvent in vacuo, the residue was dissolved in EtOAC and washed in sequences with 1 M aqueous KHSO2, saturated NaHCO3, and brine. Drying over Na 2 SO 2 and evaporation gave crude 4S-benzyloxycarbonyl-l-tert-butoxycarbonyl-3R-isobutylazetidinone (0.83 g) in the form of a yellow oil. FT-IR (CHC13) 1820 (azetidinone CO), 1750 (ester CO), 1728 (carbamate CO) cm "1 Step (c): 4S-benzyloxycarbonyl-l-tert-butoxycarbonyl-3R-isobutylazetidinone was dissolved from step (b), mentioned above, (145 mg) in dry DMF (4 ml). To this solution, sequences 1-phenylalanine-N-methylamide (p-toluenesulfonate salt, 280 mg), N-methylmorpholine (0.1 ml), and sodium azide (25 mg) were added in sequence. After proceeding with stirring overnight at room temperature, the solvent was partially removed in vacuo and the residue, extracted in ETOAC, was washed in sequences with water and brine. Drying over Na 2 S 4, evaporation and flash chromatography on silica. allowed to obtain (4-benzyloxy-3S-tert-butoxycarbonylamino-2R-isobutyl) succinyl-1-phenylalanine-N-methylamide in the form of a white powder (150 mg). FT-IR (KBr) 3312 br (NH), 1735-1695 br and 1647 (CO) c "1. FAB-MS 484 (MH) +, 384 (MH-BOC) +, 120.91 m / z.

-Step (d): A mixture of (4-benzyloxy-3S-tert-butoxycarbonylamino-2R-isobutyl) -succinyl-1-phenylalanine-N-methylamide (146 mg) and 10% Pd / C (50 mg) in 1 was exposed. 1: EtOH / THF (20 ml) at a hydrogen atmosphere for 3 h. The catalyst was removed by filtration (Celite filter aid), washed with additional ethanol, and the solvent removed in vacuo, to obtain a titration compound (100 mg) in the form of a white solid. FT-IR (KBr) 3321 br (NHOH), 1718-1697 br and 1646 (CO). NMR (200 MHz, DMSO-d6) 0.79 (d, 6 H, J = 6.4), 1.10-1.50 (m, 3 H), 1.34 (s, 9 H), 2.46 (d, 3H, J = 4.8) ), 2.82 (m, 2 H), 3.94 (dd, 1 H, J = 8.8 and 6.2), 4.39 (, 1 H), 6.52 (d, 1 H, J = 8.8), 7.20 (m, 5 H) , 7.75 (m, 1 H), 8.22 (d, 1 H, J = 7.9), 12.60 (br s, 1 H) ppm.

EXAMPLE 2 (3S-tert-Butoxycarbonylamino-4-hydroxyamino-2R-isobutyl) -succinyl-1-phenylalanine-N-netylamide (Compound 1-25).

-Step (a): (3S-tert-butoxy-carbonylamino-4-hydroxy-2R-isobutyl) succinyl-1-phenyl-alanine-N-methylamide (300 mg) was suspended, prepared according to what was described in Example 1, in dry MeCN (30 ml) and treated under nitrogen with 0-benzyl hydroxylamine hydrochloride (117 mg) and N-methylmorpholine (0.16 ml). After 10 minutes elapsed, TBTU was added (0-lH-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate, 258 mg) was added to the resulting clear solution, and the mixture was allowed to stir for 3 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed several times with water, dried and evaporated to obtain a white solid, collected after trituration with diisopropyl ether, consisting of (4-benzyloxyamino-3S-tert-butoxycarbonylamino-2R-isobutyl) - Succinyl-1-phenylalanine-N-methylamide (320 mg).

-Step (b): The material from step (a), mentioned above, (85 mg) was dissolved in DMF (5 ml) and treated under a hydrogen atmosphere for 30 minutes in presence of 10% Pd / C (60 mg). The catalyst was extracted by filtration (Celite filter aid), most of the solvent was removed in vacuo, and the residue was triturated with ethyl ether to obtain the titration compound in the form of a white powder (56 mg). FT-IR (KBr) 3314 (NHOH), 1686, 1662, and 1640 (CO) cm "1. NMR (200 MHz, DMSO-ds) 0.70 (two d, 6 H, J = 6.3), 0.84 (m, 1 H), 1.27 (s, 9 H) J, 1.18-1.48 (m, 2 H), 2.41 (d, 3 H), 2.60 (, 1 H), 2.80 (M, 2 H), 3.79 1 H), 4.35 (m, 1 H). 6.50 (d, 1 H, J = 8.6), 7.06-7.21 (m, 5 H), 7.75 (m, 1 H), 7.98 (d, 1 H, J = 8.8), 8.80 (br s, 1 H) , 10.70 (br s, 1 H) ppm. FAB-MS 465 (MH) +, 365, 304, 179, 120 m / z.

EXAMPLE 3 (3S-Amino-4-hydroxy-2R-isobutyl) succinyl-1-phenylalanine-N-methylamide (Compound 1-1). (3S-tert-butoxycarbonylamino-4-hydroxy-2R-isobutyl) succinyl-1-phenylalanine-N-methylamide (20 mg), prepared according to what was described in Example 1, was dissolved in 95% acid aqueous trifluoacetic acid (2 ml), and the solution was allowed to stand overnight at 0 ° C. Toluene was added and evaporated in vacuo, this procedure was repeated several times. The residue was triturated with ethyl ether to obtain the titration compound, trifluoacetate salt, in the form of a pale yellow powder. FT-IR (KBr) 3400-3300 br, 3294, 1745-1664 br cm "1. NMR (400 Mhz, DMS0-d6) 0.77 (d, 6 H, J = 6.1), 1.25-1.45 (, 3 H), 2.52 (d, 3 H, J = 4. 6), 2.76 (m, 1 H), 2.84 (dd, 1 H, J = 13.9 and 8.8), 3.01 (dd, 1 H, J = 13.9 and 5.7), 3.73 (d, 1 H, J = 2.6), 4.36 (M, 1 H), 7.20 (m, 5 H), 7.99 (bt s, 1 H), 8.64 (d, 1 H, J = 7.0) ppm.

EXAMPLE 4 (3S-Amino-4-hydroxyamino-2R-isobutyl) succinyl-L-phenylalanine-N-methylaraide (Compound 1-2).

Poured (3S-tert-butoxycarbonylamino-4-hydroxyamino-2R-isobutyl) succinyl-1-phenylalanine-N-methylamide (30 mg), obtained according to what was described in Example 2, into 95% acid aqueous trifluoacetic acid (3 ml) and stirred for 2 h at 4 ° C. After proceeding with filtration (Celite filter aid) and washing with fresh TFA, the solution was evaporated in vacuo repeatedly with the aid of toluene to obtain the titration product, trifluoroacetate salt, in the form of a powder. FT-IR (KBr) 3292 (NHOH), 1722-1644 br (CO) cm "1. NMR - (200 MHz, DMSO-d,) 0.69-0.73 (two d, 6 H, J = 6.4), 0.77- 1.41 (m, 3 H), 2.47 (d, 3H, J = 4.6), 2.60 (m, 1 H), 2.95 (, 2 H), 3. 38 (m, 1 H), 4.34 (, 1 H), 7.20 (, 5 H), 7.60-8.00 (br s, NH3 *), 7.95 (m, 1 H), 8.25 (d, 1 H, J = 7.5), 9.25 (br s, 1 H), 11.00 (br s, 1 H) ppm. FAB-MS 365 (MH) +, 179, 120 m / z.

EXAMPLE 5 (4-Hydroxy-2R-isobutyl-3S-p-toluenesulfonylamino) -succinyl-L-phenylalanine-N-methylamide (Compound 1-43).

-Step (a): A solution of 4S-benzyloxycarbonyl-3R-isobutylazetidinone (400 mg) was obtained, obtained according to what was described in Example 1, step (a), in dichloromethane (10 ml) with DMAP (4-dimethylaminopyridine, 25 mg) and p-toluenesulfonyl chloride (219 mg) at room temperature overnight under a nitrogen atmosphere. After quenching with saturated aqueous NaHCO, the organic layer was collected, washed with 1M aqueous NH 4 Cl, brine, and dried over Na 2 SO 4. Evaporation and fractionation by flash chromatography on silica (n-hexane / EtOAC) allowed to obtain a portion of unreacted starting material (50 mg) and subsequently pure 4S-benzyloxycarbonyl-3R-isobutyl-1- (p-toluenesulfonyl) azetidinone ( 100 mg) in the form of an oil. FT-IR (CHC13) 1802 (azetidinone CO), 1752 (ester CO) cm "1. NMR (400 MHz, CDC13) 0.79 (d, 3H, J = 6.4), 0.88 (d, 3 H, J = 6.4), 1.54-1.72 (m, 3 H), 2.44 ( s, 3 H), 3.20 (m, 1 H), 4.32 (d, 1 H, J = 3.2), 5.19 (s, 2 H), 7.31 (d, 2 H, J = 8.5), 7.33 (m, 5 H), 7.87 (d, 2 H, J = 8.5) ppm.

Step (b): 4S-benzyloxycarbonyl-3R-isobutyl- (p-toluenesulfonyl) -azetidinone was dissolved from step (a), mentioned above, (290 mg) in dry DMF (15 ml). To this solution were added, in sequence, 1-phenylalanine-N-methylamide (p-toluenesulfonate salt, 486 mg), N-methylmorpholine (0.17 ml), and sodium azide (30 mg). After proceeding with stirring overnight at room temperature, the solvent was partially removed in vacuo and the residue, extracted in EtOAC, was washed in sequences with saturated aqueous NaHS? 4 and brine. Drying over Na2SO4, evaporation, flash chromatography on silica, and trituration in ethyl ether allowed to obtain (4-benzyloxy-2R-isobutyl-35- (p-toluenesulfonyl) amino) succinyl-L-phenylalanine-N-methylamide in the form of a white powder (200 mg). FT-IR (KBr) 3330, 3255, 1750, 1721, 1650 cm "1.

Step (c): (4-Benzyloxy-2R-isobutyl-35- (p-toluenesulfonyl) amino) succinyl-1-phenyl-alanine-N-methylamide (140 mg) was dissolved from step (b), mentioned above, in a mixture of THF (20 ml) and DMF (2 ml). The resulting solution was subjected to treatment with 10% Pd / C (100 mg) and exposed to a hydrogen atmosphere for 5 h. The catalyst was removed by filtration (Celite filter aid), washed with additional THF, and the solvent removed in vacuo to obtain the titration compound (110 mg) in the form of a white solid. NMR (400 MHz, DMSO-d6) 0.60 (d, 3 H, J = 6.8), 0.64 (d, 3 H, J = 6.8), 0.86 (m, 1 H), 1.07 (m, 1 H), 1.34 (, 1 H), 2.28 (s, 3 H), 2.46 (d, 3 H, J = 4.7), 2.53 (m, 1 H), 2.70 (dd, 1 H, J = 13.7 and 8.1), 2.88 ( dd, 1 H, J = 13.7 and 6.8), 3.71 (m, 1 H), 4.31 (m, 1 H), 7.18 (m, 5 H), 7.27 (d, 2 H, J = 8.1), 7.57 ( d, 2 H, J = 8.1), 7.60 (br s, 1 H), 8.06 (d, 1 H, J = 8.1), 12.60 (br s, 1 H) ppm.

EXAMPLE 6 (4-Hydroxyamino-2R-isobutyl-3S- (p-toluenesulfonyl) amino) -succinyl-1-f-enylalanine-N-methylamide (Compound 1-44).

-Step (a): Suspended (4-hydroxy-2R-isobutyl-35- (p-toluenesulfonyl) amino) succinyl-1-phenyl-alanine-N-methylamide (170 mg), prepared according to what was described in Example 5, in dry MeCN (15 ml) and treated under nitrogen with O-benzyl hydroxylamine hydrochloride (64.7 mg) and N-methylmorpholine (0.1 ml).

After 10 minutes elapsed, TBTU was added (0-lH-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate, 131 mg) was added to the resulting clear solution, and the mixture was allowed to stir for 5 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed sequentially with aqueous NH4CI, water and brine, dried, filtered and evaporated to obtain (4-benzyloxyamino-2R-isobutyl-3S- (p-toluenesulfonyl) amino) -succinyl-L-phenylalanine- Crude N-methylamide.

- Step (b): The material from step (a), mentioned above, was dissolved in THF (15 ml) and treated under a hydrogen atmosphere for 5 h in the presence of 10% Pd / C (100 mg ). The catalyst was extracted by filtration (Celite filter aid), the solvent was removed in vacuo, and the residue was triturated with a mixture of ethyl ether and dichloromethane to obtain the titration compound in the form of a white powder. (50 mg). FT-IR (KBr) 3298 (NHOH), 1640 br (CO) cm "1. NMR (400 MHz, DMSO-d6) 0.64 (two d, 6 H, J = 6. 4), 0.75 (m, 1 H), 1.12 (m, 1 H), 1.30 (M, 1 H), 2.27 (s, 3 H), 2.45 (s, 3 H), 2.65 (m, 1 H), 2.82 (m, 1 H), 3.62 (d, 1 H, J = 8.7), 4.25 (m, 1 H) , 7.11-7.23 (m, 7 H), 7. 55 (d, 2 H, J = 8.2) ppm.

Example 7 (4-Hydroxy-2R-isobutyl-35- (4-morpholinocarbonyl) anLino) succinyl-L-phenylalanine-N-methylamide (Compound I-60). Step (a): A solution of 4S-benzyloxycarbonyl-3R-isobutylazetidinone (200 mg), obtained according to that described in Example 1, step (a), in dichloromethane (10 ml) was treated with triethylamine ( 0.44 ml), DMAP (4-dimethylaminopyridine, 10 mg) and 4-morpholinocarbonyl chloride (0.26 ml) at room temperature overnight under a nitrogen atmosphere. After annealing with saturated aqueous NaHCO3, the organic layer was collected, washed with 1M aqueous KHSO4, brine, and dried over NaHCO3. Evaporation and fractionation by flash chromatography on silica (n-hexane / EtOAC) allowed to obtain 4S-benzyloxycarbonyl-3R-isobutyl-1 (4-motfolinocarbonyl) azetidinone (170 mg) in the form of a waxy solid. FT-IR (CHCI3) 1787 (azetidinone CO), 1748 (ester CO), 1678 (urea CO) c "1.

NMR (400 MHz, CDCl 3) 0.85 (d, 3 H, J = 6.4), 0.93 (d, 3 H, J = 6.4), 1.60-1.83 (, 3 H), 3.19 (m, 1 H), 3.53 (, 2 H), 3.67 (m, 6 H), 4.36 (d, 1 H, J = 3.2), 5.16 (d, 1 H, J = 12.1); 5.28 (d, 1 H, J = 12.1), 7.35 (, 5 H) ppm.

Step (b): 4S-Benzyloxycarbonyl-3R-isobutyl-1- (4-morphinocarbonyl) azetidinone was dissolved from step (a), mentioned above, (170 mg) in dry DMF (10 ml). To this solution were added, in sequence form, L-phenylalanine-N-methylamide (salt-p-toluenesulfonate; 317 mg), N-methylmorpholine (0.11 ml), and sodium azide (20 mg) under a nitrogen atmosphere. After 6 h at room temperature and standing overnight in the refrigerator, the solvent was partially extracted in vacuo and the residue was washed, extracted in EtOAC, in sequences with water and brine. Drying over Na 2 SO 4 and evaporation allowed obtaining (4-benzyloxy-2R-isobutyl-3S- (4-morpholinocarbonyl) amino) succinyl-1-phenyl-alanine-N-methylamide in the form of a yellowish foam (207 mg). FT-IR (KBr) 3312 br, 1743, 1641 cm "-Pass (c): It was dissolved (4-benzyloxy-2R-isobutyl-3S (4-morpholinocarbonyl) amino) succinyl-1-phenylalanine-N-methyl amide ( 200 mg) of step (b), mentioned above, in ethanol (10 ml) The resulting solution was treated with 10% Pd / C (100 mg) and exposed to a hydrogen atmosphere for 6 h. the catalyst was removed by filtration (Celite filter aid), the additional ETOH was washed and then the solvent was removed under vacuum to obtain the titration compound (170 mg) in the form of a white solid. (200 MHz, DMSO-de) 0.72 (two d, 6 H, J = 6.2), 1.00-1.60 (m, 3 H), 2.44 (d, 3 H, J = 3.9), 2.60-2.95 (m, 3 H), 3.16 (m, 4 H), 3.48 (m, 4 H), 4.02 (dd, 1 H, J = 7.3 and 6.4), 4. 33 (m, 1 H), 6.52 (d, 1 H, J = 7.9), 7.20 (m, 5 H), 7.87 (br s, 1 H), 8.38 (br s, 1 H) ppm.

EXAMPLE 8 (4-Hydroxyamino-2R-isobutyl-3S- (4-morpholinocarbonyl) -amino) succinyl-L-phenylalanine-N-methylamide (Compound 1-61).

-Step (a): (4-Hydroxy-2R-isobutyl-3S- (4-morpholinocarbonyl) amino) succinyl-1-phenylalanine-N-methylamide (120 mg) was prepared, prepared according to what was described in Example 7, in dry MeCN (20 ml) and treated under nitrogen with O-benzyl hydroxylamine chloride (41 mg) and N-methylmorpholine (0.06 ml). After 10 minutes, TBTU (0-lH-benzotriazole-1-yl-N, N, N ', N'-tetramethyluronium, 100 mg) was added to the resulting clear solution, and the mixture was allowed to stir for 5 minutes. h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was washed in sequences with aqueous NH2C1, water and brine, dried, filtered and evaporated to obtain (4-benzyloxyamino-2R-isobutyl-3S- (4-morpholinocarbonyl) amino) -succinyl-L-phenylalanine- Crude N-methylamide (130 mg) in the form of a white solid.

Step (b): The material of step (a), mentioned above, was dissolved in ethanol (15 ml) and THF (5 ml) and treated under a hydrogen atmosphere for 3 h in the presence of 10% Pd / C (100 mg). The catalyst was removed by filtration (Celite filter aid), the solvent was removed in vacuo, and the residue was triturated with ethyl ether to obtain the crude titration compound in the form of a pink solid (92 mg), which it was further purified by chromatography on silica gel (9: 1 dichloromethane-methanol). FT-IR (KBr) 3313 (NHOH), 1694 and 1628 br (CO) -cm "1 NMR (400 MHz, DMSO-d6) 0.72 (d, 3 H, J = 6.4), 0.73 (d, 3 H, J = 6.4), 0.87 (m, 1 H), 1.28 (m, 1 H), 1.45 (m, 1 H), 2.41 (d, 3 H, J = 4.7), 2.69 (m, 1 H), 2.73 (dd, 1 H, J = 13.6 and 6.5), 2.83 (dd, 1 H, J = 13.6 and 7.8), 3.08-3.24 (m, 4 H), 3.42-3.51 (M, 4 H), 3.98 (dd, 1 H, J = 8.7 and 8.7), 4.36 (m, 1 H), 6.40 (d, 1 H), 7.05-7.22 (m, 5 H), 7. 64 (q, 1 H, J = 4.7), 7.92 (d, 1 H, J = 8.1), 8.78- (br s, 1 H), 10, .0 (br s, 1 H) ppm.

EXAMPLE 9 (3S-Benzamido-4-hydroxy-2R-isobutyl) succinyl-L-phenylalanine-N-methylamide (Compound 1-71).

Step (a): A solution of 4S-benzyloxycarbonyl-3R-isobutylazetidinone (300 mg) was obtained, obtained in accordance with what was described in Example 1, step (a), in dichloromethane (10 ml) with triethylamine ( 0.5 ml) and benzoyl chloride (0.4 ml) at 0 ° C and then at room temperature overnight under a nitrogen atmosphere. The reaction mixture was diluted with dichloromethane, washed several times with aqueous NaHCO3, and subsequently with 1M KHSO4 and brine. After drying over Na2SO4, evaporation and fractionation by flash chromatography on silica (n-hexane / EtOAC), l-benzoyl-4S-benzyloxycarbonyl-3R-isobutylazetidinone (235 mg) was obtained in the form of a powder.

FT-IR (KBr) 1801, 1749, 1678 cm "1. NMR (200 MHz, CDC13) 0. 86 (d, 3 H, J = 6.0), 0.94 (d, 3 H, J = 6.0), 1.60-1.90 (m, 3 H), 3.30 (, 1 H), 4.37 (d, 1 H), 5.22 -5.31 (7Abq, 2 H, J = 12.0), 7.35-7.64 (, 8 H), 8.05 (, 2 H) ppm.

- Step (b); L-Benzoyl-4S-benzyloxycarbonyl-3R-isobutylazetidinone was dissolved from step (a), mentioned above, (235 mg) in dry DMF (10 ml). To this solution were added, in sequence, L-phenylalanine-N-methylamide (salt of p-toluenesulfonate, 450 mg), N-methylmorpholine (0.16 ml), and sodium azide (20 mg) lowered a nitrogen atmosphere. After 6 h at room temperature, the solvent was partially removed in vacuo and the residue, extracted in EtOAC, was washed in sequences with 1 N aqueous NH 4 Cl and brine. After drying over Na 2 SO 4 and evaporation of the solvent, the residue was purified by flash chromatography on silica (n-hexane / EtOAC) to obtain (3S-benzamido-4-benzyloxy-2R-isobutyl) succinyl-L-phenylalanine -N-methylamide in the form of a white powder (330 mg). FT-IR (KBr) 3299, 1734, 1655-1639 br cm "1.

Step (c): (3S-benzamido-4-benzyloxy-2R-isobutyl) succinyl-L-phenylalanine-N-methylamide (330 mg) was dissolved from step (b), mentioned above, in ethanol 1: 1 THF (10 ml). The resulting solution was treated with 10% Pd / C (150 mg) and exposed to a hydrogen atmosphere for 4 h. The catalyst was removed by filtration (Celite filter aid) and washed. on Additional EtOH and the solvent was removed in vacuo to obtain the titration compound (250 mg) in the form of a white solid. FT-IR (KBr) 3297, 1719, 1635 br cm "1. NMR (200 MHz, DMSO-25 d6) 0.63 (d, 3 H, J = 6.3), 0.72 (d, 3 H, J = 6.3), 1.20 (m, 2 H), 1.41 (m, 1 H), 2.51 (d, 3 H, J = 4.7), 2.80 (m, 2 H), 2.99 (m, 1 H), 4.30 (, 2 H) , 7.20 (m, 4 H), 7.50 (, 4 H), 7.72 (m, 2 H), 8.10 (d, 1 H, J = 5.9), 8.27 (m, 1 H), 8.76 (d, 1 H , J = 8.3) ppm.

EXAMPLE 10 (3S-Benzainido-4-hydroxyamino-2R-isobutyl) succinyl-L-phenylalanine-N-methylamide (Compound 1-72).

The titration compound was obtained by the same procedure as described in Example 2, steps (a) and (b), starting from (3S-benzamido-4-hydroxy-2R-isobutyl) succinyl-L-phenylalanine- N-methylamide (prepared in accordance with that described in Example 9). FAB-MS 469 (27, (MH) +), 436 (20, (MH-NHOH) +, 179 (45, (PheNHme + H) +), 105 (100, (PhC0) +) m / z.

EXAMPLE 11 (3S-tert-Butoxycarbonylamino-4-hydroxyamino-2R-phenylpropyl) succinyl-L-phenylalanine-N-2- (4-morpholino) -ethyl-amide (Compound 111-86).

Step (a): A solution of l-tert-butyldimethylsilyl-4S-carboxyzetidinone (0.7 g) in dry THF (20 ml) at 0-5 ° C with 2M of LDA solution (3.2 ml) was treated as drops. ) in the same solvent to obtain an orange solution of the di-anion. After 10 minutes elapsed, a solution of cinnamyl bromide was added (1.4 g) in THF (2 ml) at 0 ° C under stirring, and the resulting solution was left at the same temperature overnight.

Annealing with 1 M aqueous KHSO 4 (300 ml), followed by extraction with EtOAC, allowed to obtain crude 1-tert-butyldimethylsilyl-4S-carboxy-3R-cinnamyl azetidinone in the form of a syrup. The aforementioned material was dissolved in dry DMF (5 ml) and treated in the form of drops in this order, with triethylamine (0.5 ml) and benzyl bromide (0.46 ml). After 4 h at room temperature, the mixture was partitioned between water and EtOAC. The organic phase, after washing with saturated aqueous NaCl, was dried and evaporated to obtain crude 4S-benzyloxycarbonyl-l-tert-butyldimethylsilyl-3R-cinnamylazetidinone, which was dissolved in THF (5 ml) and then left for 3 h in the presence of tetrabutylammonium fluoride trihydrate (1.1.6 g) and acetic acid (0.84 ml). The mixture was partitioned between NaHCO 3, saturated aqueous and EtOAc, the organic phase was collected, washed with brine, dried over Na 2 SO 4 and evaporated. Flash chromatography on silica gel (n-hexane / EtOAc) allowed to obtain 4S-benzyloxycarbonyl-3R-cinnamylazetidinone (0.45 g) in the form of a white powder. NMR (200 MHz, CDC13) 1.45 (S, 9 H), 2.70 (m, 2 H), 3.30 (m, 1 H), 4.22 (d, 1 H, J = 3.1), 5.15 and 5.25 (two d, 2 H, J = 12.1), 6.20 (m, 1 H), 6.60 (m, 1 H), 7.2-7.3 (m, 10 H) ppm.

Step (b): A solution of 4S-benzyloxycarbonyl-3R-cinnamylazetidinone (0.44 g) was treated from step (a), mentioned above, in MeCN (10 ml) with DMAP (0.2 g) and E. : 20 (0.75 g) at 40 ° C for 1 h. A second portion of BOC20 (0.35 g) was added, and after an additional 10 minutes at 40 ° C the mixture was diluted with ethyl acetate and washed in sequences with 1M aqueous KHSO4, saturated NaHC 3 3 and brine. . Drying over Na2SO4, and evaporation gave crude 4S-benzyloxycarbonyl-l-tert-butoxycarbonyl-3R-cinnamylazetidinone (0.7 g) in the form of a syrup.

Step (c): Crude 4S-benzyloxycarbonyl-l-tert-butoxycarbonyl-3R-cinnamyl azetidinone was dissolved from step (b), above, (0.28 g) in dry DMF (3 ml). To this solution was added, in sequence form, L-phenylalanine-N2- (4-morpholino) ethylamide (425 mg), N-methylmorpholine (0.19 ml), and sodium azide (35 mg). After the course of the whole night under stirring at room temperature, the solvent was extracted partially in vacuo and the residue, extracted in EtOAC, was washed in sequences with water and brine. Drying over Na 2 SO 4, evaporation and flash chromatography on silica allowed to obtain (4-benzyloxy-3-S-tert-butoxycarbonylamino-2-R-cinnamyl) -succinyl-L-phenylalanine-N-2- (4- morpholino) ethylamide (300 mg). NMR (400 MHz, DMSO-de) 1.36 (s, 9 H), 2.15 (m, 2 H), 2.25 (m, 4 H), 2.30 (m, 2 H), 2.75 and 2.90 (two m, 2 H), 2.90-3.1 (m, 3 H), 3.50 (m, 4 H), 4.20 (m, 1 H), 4.45 (m, 1 H), 4.95 (m, 2 H), 6.10 (m, 1 H), 6.30 (m, 1 H), 6.70 (d, 1 H, J = 7.5), 7.0-7.4 (m, 15 H), 7.76 (s broad, 1 H), 8.40 (s broad, 1 H) ppm.

Step (d): A mixture of (4-benzyloxy-3S-tert-butoxycarbonylamino-2R-cinnamyl) -succinyl-L-phenylalanine-N-2- (4-morpholino) ethylamide (300 mg) and a mixture was exposed. % Pd / C (100 mg) in 1: 1 EtOH / THF (40 ml) at a hydrogen atmosphere for 3 h. The catalyst was removed by filtration (Celite filter aid), washed with additional ethanol, and the solvent was removed in vacuo, to obtain (3S-tert-butoxycarbonylamino-4-hydroxy-2R-phenylpropyl) succinyl-L-phenylalanine -N-2- (4-morpholino) ethylamide crude in the form of a white solid.

Step (e): The crude material of step (d), mentioned above, was treated with O-benzyl hydroxylamine hydrochloride, N-methylmorpholine and TBTU in the same manner as described in Example 2, step (a). The study and chromatography allowed to obtain (4-benzyloxyamino-3S-tert-butoxycarbonylamino-2R-phenylpropyl) succinyl-L-phenylalanine-N-2- (4-morpholino) ethylamide (220 mg).

Step (f): The material from step (e), mentioned above, (145 mg) was dissolved in DMF (5 ml) and treated under a hydrogen atmosphere for 30 minutes in the presence of 10% Pd / C (60 mg). The filter was removed by filtration (filter aid) Celite), most of the solvent was removed in vacuo, and the residue was triturated with ethyl ether to obtain the titration compound in the form of a white powder (90 mg). FT-IR (KBr) 3315 (NHOH), 1685, 1660, and 1640 (CO) cm "1.

E "TEMPLE 12 (3S-tert-Butoxycarbonylamino-4-hydroxyamino-2R-isobutyl) succinyl- (S) -tert-butylglycine methyl ester (Compound IV-64).

Step (a): 4S-Benzyloxycarbonyl-l-tert-butoxycarbonyl-3R-isobutylazetidinone (200 mg) was dissolved, obtained according to what was described in Example 1, step (b), in dry DMF (4 ml). To this solution were added, in sequence, (S) -tert-butylglycine methyl ester (160 mg), N-methylmorpholine (0.05 ml), and sodium azide (25 mg). After stirring overnight at room temperature, the solvent was partially removed in vacuo and the residue, extracted in ETOAC, was washed in sequences with water and brine. Drying over Na2SO4, evaporation and flash chromatography on silica allowed to obtain (4-benzyloxy-3S-tert-butoxycarbonylamino-2R-isobutyl) succinyl- (S) -tert-butylglycine methyl ester in the form of a white powder (260 mg). FT-IR (KBr) 3375 br (NH), 1737, 1718, and 1664 (CO) cm "1.

- Step (b): A mixture of (4-benzyloxy-3S-tert-butoxycarbonylamino-2R-isobutyl) succinyl- (S) -tert-butylglycine methyl ester (260 mg) and 10% Pd / C was exposed ( 100 mg) in 1: 2 EtOH / THF (10 ml) at a hydrogen atmosphere for 5 h. The catalyst was removed by filtration (Celite filter aid), washed with additional ethanol, and the solvent was removed in vacuo, to obtain (3S-tert-butoxycarbonylamino-4-hydroxy-2R-isobutyl) succinyl (S) -terc. butylglycine methyl ester (210 mg) in the form of a yellowish waxy solid. FT-IR (KBr) 3372 (OH), 1720, 1686, and 1655 (CO) cm "1. NMR (200 MHz, DMSO-25 d6) 0.81 (d, 3 H, J = 6.4), 0.83 (d, 3 H, J = 6.4), 0.91 (s, 9 H), 1.00-1.60 (m, 3 H), 1.33 (s, 9 H), 2.96 (, 1 H), 3.59 (s, 3 H), 3.89 (dd, 1 H, J = 8.8 and 6. 9), 4.12 (d, 1 H, J = 8.3), 6.46 (d, 1 H, J = 8.8), 8.13 (s broad, 1 H), 12.67 (s broad, 1 H) ppm.

Step (c): The material from step (b), mentioned above, (195 mg) was dissolved in dry MeCN (5 ml) and treated under nitrogen with O-benzyl hydroxylamine hydrochloride (90 mg) and N- methylmorpholine (0.13 ml). After 10 minutes, TBTU (180 mg) was added, and the mixture was allowed to stir for 6 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and 0. N aqueous HO. The organic oil was washed with brine, it was dried and evaporated to obtain a residue, which was purified by chromatography on silica gel, whereby (4-benzyloxyamino-3S-tert-butoxycarbonylamino-2R-isobutyl) succinyl- (S) tert-butylglycine methyl was obtained. ester (170 mg) in the form of a white solid. Step (d): The material from step (C), mentioned above, (170 mg) was dissolved in ethanol (5 ml) and treated under a hydrogen atmosphere for 2 h in the presence of 10% Pd / C (100 mg). The catalyst was removed by filtration (Celite filter aid), washed with additional ethanol, and the combined solution was evaporated to dryness, whereby the titration product was obtained in the form of a white powder ( 90 mg). NMR (200 MHz, DMSO-de) 0.76 (d, 6 H, J = 6.4), 0.92 (s, 9 H), 1.29 (s, 9 H), 1.20-1.60 (, 3 H), 2.80 (m, 1 H), 3.58 (s, 3 H), 3.72 (dd, 1 H, J = 8.8 and 8.8), 4.14 (d, 1 H, J = 8.6), 6.47 (d, 1 H, J = 8.8), 7.73 (d, 1 H, J = 8.6), 8.89 (broad s, 1 H), 10.70 broad s, 1 H) ppm.

EXAMPLE 13 (3S-Amino-4-hydroxyamino-2R-isobutyl) succinyl- (S) -tert-butylglycine methyl ester (Compound IV-65). (3S-tert-butoxycarbonylamino-4-hydroxyamino-2R-isobutyl) succinyl- (S) -glycine methyl ester (40 mg), prepared according to what was described in Example 12, was dissolved in 95% acid aqueous trifluoacetic (3 ml). After 20 minutes elapsed, the mixture was evaporated. Toluene was added and evaporated twice. The residue was triturated in ethyl ether to collect the titration compound, trifluoacetate salt, in the form of a pale pink powder (40 mg). FT-IR (KBr) 3363 (NHOH), 1717, 1685 br (CO) cm "1). NMR (400 MHz, DMSO-de) 0.78 and 0.82 (each d, 6) H, J = 6.4), 0.91 (s, 9 H), 1.10-1.5 (m, 3 1), 2.95 (m, 1 H), 3.45 (m, 1 H), 3.54 (s, 3 H), 3.99 (d, 1 H, J = 7.0), 8.08 (d, 1 H, J = 7.0), 8.10 (broad s, 1 H), 9.30 and 9.50 (respectively, s broad, s greater, and s, less, 1 H ), 10.70 and 11.03 (respectively, lower and higher, each s, 1 H) ppm. Note: the compound exists in DMSO solution as a mixture of two rotamers; the signals of minor and major are indicated. In the Examples presented below, other compounds were prepared analogously: EXAMPLE 14 (3S-tert-Butoxycarbonylamino-4-hydroxy-2R-phenylpropyl) -succinyl-L-phenyl-alanine-N-methyl amide. White powder NMR (200 MHz, DMSO-de) 1.46 (s, 9 H), 1.60 4 H), 2.58 (t, 2H, J = 6.7), 2.64 (d, 3 H, J = 4. 8), 2.93 2H), 3.14 (dd, 1 H, J = 13.4 and 5.4), 4.34 (dd, 1 H, J = 2.5 and 6.1), 4.44 (, 1 H), 5.30 (m, 1 H), 5.98 (d, 1 H, J = 6.1), 7.1-7.3 (m, 10 H) ppm.

EXAMPLE 15 (3S-Amino-4-hydroxy-2R-phenylpropyl) succinyl-L-phenylalanine-N-methyl amide. Obtained as the trifluoroacetate salt; white powder. NMR (200 MHz, DMSO-de) 1.2-1.5 (m, 4 H), 2.39 (t, 2H, J = 7.9), 2.50 (d, 3 H, J = 4.4), 2.52 (, 1 H), 2.79 (dd, 1 H, J = 13.4 and 10.8), 3.09 (dd, 1 H, J = 3.5 and 13.4), 3.46 (d, 1 H, J = 2.6), 4.26 (m, 1 H), 7.1-7.3 (m, 10 H), 8.46 (s broad, 1 H), 9.00 (d, 1 H, J = 8.4) ppm.

EXAMPLE 16 (3S-tert-Butoxycarbonylamino-4-hydroxyamino-2R-phenylpropyl) succinyl-L-phenylalanine-N-methyl amide (Compound 111-87). White powder NMR (400 MHz, DMSO-de) 1-28 (s, 9 H), 1.1-1.5 (m, 4 H), 2.35 (m, 2H), 2.38 (d, 3 H, J = 4. 3), 2.57 (m, 1 H), 2.82 (m, 2 H), 3.83 (dd, 1 H, J = 8.7 and 8.7), 4.34 (m, 1 H), 6.52 (d, 1 H, J = 8.7), 7.1-7.2 (m, H), 7.72 (q, 1 H, J = 4.3), 8.01 (d, 1 H, J = 8.1), 8.85 (s, 1 H), 10.71 (_, 1 H) ppm.

EXAMPLE 17 (3S-Amino-4-hydroxyamino-2R-phenylpropyl) succinyl-L-phenylalanine-N-methyl amide (Compound 111-88). Obtained as the trifluoroacetate salt; white powder. NMR (400 MHz, DMSO-d6) 1.40 (m, 4 H), 2.4-2.5 (m, 3 H), 2.44 (s, 3 H), 4.34 (m, 1 H), 7.20 (m, 10 H) , 7.9-8.4 (broad 3 s, 5 H: CONH, CONHMe and NH3 +), 9.2 (broad s, 1 H), 10.9 (broad S, 1 H) ppm.

EXAMPLE 18 (3S-Amino-4-hydroxyamino-2R-isobutyl) succinyl-L-phenylalanine-N-tert-butylamide (Compound 1-21). Obtained as the trifluoroacetate salt; white powder. NMR (400 MHz, DMSO-de) 0.78 and 0.80 (each d, 6 H, J = 6.8), 1.10 and 1.5 (each m, 2 H), 1.11 (s, 9 H), 1.40 (m, 1 H), 2.7 (m, 1 H), 2.89 (d, 2 H, J = 7.3), 3.50 (m, 1 H), 4.47 (dt, H, J = 7.3, 7.3 and 8.6), 7.20 (m, 5 H), 7.40 (s, 1 H), 8.20 broad, 1 H), 8.23 (d, 1 H, J = 8.6), 9.37 and 9.5 (respectively, s broad, greater, and s, less; 1 H), 10.7 and 11.09 (respectively, minor and major, each s, 1 H) ppm Note: the compound exists in DMSO solution as a two-rotate mixture (ca 5: 1); the minor and major signals are indicated.

EXAMPLE 19 (3S-Amino-4-hydroxyamino-2R-isobutyl) succinyl-L-phenylalanine-N-methyl amide, cyclic acetone diamine.

Obtained (trifluoroacetate salt) from the compound of Example 18 by stirring with pure acetone, and evaporation to dryness in vacuo. White powder NMR (400 MHz, DMSO-de) 0.75 and 0.80 (each d, 1 H, J = 6.8), 1.13 and 1.19 (each s, 6 H), 1.14 (s, 9 H), 1.2- 1.6 (m, 3 H), 2.55 (m, 1 H), 2.78 (dd, 1 H, J = 8.1 and 13. 7), 2.88 (dd, 1 H, J = 6.0 and 13.7), 2.99 (d, J = 8.5), 3. 30 (m, 1 H, superimposed by water), 4.40 (ddd, 1 H, J = 6.0, 8.1 and 8.1), 7.21 (m, 6 H), 8.13 'd, 1 H, J = 8.1), 9. 53 (s, 1 H) ppm.

EXAMPLE 20 (3S-Dimethylamino-4-hydroxyamino-2R-isobutyl) succinyl- (S) -tert-butylglycine-N-methyl amide (Compound 11-122).

Obtained as the free base; white powder. NMR (400 MHz, DMSO-de) 0.73 and 0.81 (each d, 6 H, J = 6.5), 0.88 (s, 9 H), 0.9-1.4 (m, 3 H), 2.18 (S, 6 H), 2.53 (d, 3 H, J = 4.4), 2.80 (m, 2 H), 4.22 (d, 1 H, J = 9.4), 7.26 (d, 1 H, J = 9.4), 7.79 (q, 1 H , J = 4.4), 8.78 (s, 1 H), 10.41 (s, 1 H) ppm.

EXAMPLE 21 (3S-Amino-4-hydroxyamino-2R-isobutyl) succinyl (S) -tert-butylglycine-N- (4-pyridyl) amide (Compound IV-2).

Obtained as the double trifluoacetate salt; white powder. NMR (400 MHz, DMSO-de) 0.76 and 0.83 (each d, 6 H, J = 6.5), 0.96 and 0.99 (respectively, lower and higher, each 9 H), 1.1-1.5 (m, 3 H) , 3.03 and 3.30 (respectively, major and minor, each m, 1 H), 3.58 and 4. 20 (respectively, greater, d, J = 6.4, and smaller, broad s, 1 H), 4.27 and 4.30 (respectively, major and minor, each d, J = 7.3), 7.88 (d, 2 H, J = 6.8 ), 8.15 (s broad, 3 H), 8.60 (d, 2 H, J = 6.8), 9.32 and 9.55 (respectively, greater, s broad, and smaller, s; 1 H), . 77 and 11.03 (respectively, major and minor, each s, 1 H), 11.12 (s, 1 H) ppm. Note: the compound exists in DMSO solution as a mixture (ca 4: 1) of two rotamers; Signs of minor and major are indicated.

EXAMPLE 22 (3S-Am.ino-2R-cyclopentylmethyl-4-hydroxyazaino) succinyl (S) -tert-butylglycine-N- (3,4-netylenedioxyphenyl) amide (Compound IV-41).

Obtained as the trifluoroacetate salt; white powder. NMR (400 MHz, DMSO-de) 0.89 and 0.92 (respectively, minor and major, each s, 9 H), 1.2-1.8 (m, 11 H), 2.93 (m, 1 H), 3.58 (m, 1 H), 4.28 (d, J = 9. 4), 5.92 (m, 2 H), 6.80 (d, 1 H, J = 8.2), 6.88 (dd, 1 H, J = 2.0 and 8.2), 7.20 (d, 1 H, J = 2.0), 7.85 and 8.10 (respectively, minor and major, each s broad, 3 H of NH ^), 7.90 and 7.97 (respectively, smaller, d, J = 9.0, and greater, d, J = 9.4, 1 H of CONHCH), 9.26 and 9.35 (respectively, major and minor, each s, 1 H of CONHOH), 9. 93 and 10.01 (respectively, major and minor, each s, 1 H of CONHAR), 10.72 and 10.96 (respectively, minor and major, each s, 1 H of CONHOH) ppm. Note: the compound exists in DMSO solution as a mixture (ca 4: 1) of two rotamers; Signs of minor and major are indicated.

EXAMPLE 23 10 (S) - [(3S-Amino-4-hydroxyamino-2R-isobutyl) succinyl] amino-1, 8-diazatricyclo- [10, 6, 1, 0 ') -nonadeca-12 (19), 13 (18), 14, 16-tetraen-9-one (Compound II-102).

Obtained as the trifluoroacetate salt; white powder. NMR (400 MHz, DMSO-d6) -0.03 and 0.49 (each m, 2 H of N- (CH2) 3-CH2- (CH2) 2-NHCO), 0.81 and 0.83 (each d, J- 6.8, 6 H), 1.0-11.4 (m, 4 H of N- (CH2) 2-CH2-CH2-CH2-CH2-NHCO), 1. 10 and 1.50 (each, 2 H), 1.40 (m, 1 H), 1.60 and 1.80 (each m, 2 H of N-CH2-CH2- (CH2) 2-NHCO) 2.30 and 3.30 (each m, 2 H of N- (CH2) 5-CH2-NHCO), 2.85 (m, 2 H of CH -iBu and CHH-indanyl), 3.08 (dd, J = 3.8 and 13.7, 1 H of CHH-indanyl), 3. 60 (, 1 H of CHNH3 +), 4.00 and 4.28 (each m, 2 H of N-CH2- (CH2) 5-NHCO), 4.50 (m, 1 H, 7.02 and 7.11 (each m, 2 H of 6- and 7-indanyl), 7.07 (s, 1 H of 2-indanyl), 7.37 (m, 1 H of N- (CH2) 6-NHCO), 7.41 (, 1 H of 8-indanyl), 7. 61 (m, 1 H of 5-indanyl), 8.00 and 8.20 (respectively, minor and major, each s broad, 3 H of NH3 +), 8.37 (d, J = 8.1), 9.37 and 9.50 (respectively, major and minor, each S, 1 H of CONHOH), 10.84 and 11.09 (respectively, minor and major, each s, 1 H of CONHOH) ppm . Note: the compound exists in DMSO solution as a mixture (ca 84:16) of two rotamers; Signs of minor and major are indicated.

Claims (10)

1. A compound, which is a succinic amine derivative of the formula (I) where W is a group COOH or -CONHOH; R is hydrogen, d-Cé alkyl, phenyl, or benzyl; Ri is hydrogen or: lower alkyl, especially methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl; aryl, especially phenyl and naphthyl; and aryl- (lower alkyl), especially benzyl; these groups may be unsubstituted or substituted by one or more substituents, which may be the same or different, which are selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy , methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or a group - (CH2) m-heterocyclyl or - (CH2) m-cyclopropyl, where m is zero or an integer ranging from one to three, and a heterocyclyl represents a closed chain of heterocyclyl possessing between 3 and 6 members, simple or condensed with a closed chain of benzene or naphthalene, containing at least one nitrogen atom; more preferably succinimido, phthalimido, saccharin, hydantoin, indolyl, oxyindolyl, 2-oxo-isoindolinyl, imidazolyl, pyridyl, morpholino, pyrrolidino, 2-oxopyrrolidino, piperazino; and wherein said heterocyclyl group is unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or - a group - (CH2) nCOOH or a group - (CH2,) m COOR1, in which n can be 1, 2 or 3, m can be 0, 1, 2 or 3, and R1 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, phenyl, benzyl, allyl, styryl, 1-naphthyl, 2-naphthyl, whether unsubstituted or substituted by one to three substituents selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or - a group that is selected from - (CH2) m SO2R1, - (CH2) mS02NH2, - (CJH2) mS02 (Me) 2, - (CH2) mS02NHRI, where m, R1 and the possible substituents of said group R1 are as defined above, or a group (CH2) mS02- (4-morpholino), - (CH2) raS02- (1-piperazino), (CH2) mS02- (4-methyl-l-piperazino); or - a group - (CH2) nS? 3H, where n is as defined above; acyl, especially acetyl, or benzoyl, or phenacetyl, either unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo , carboxy, and nitro; or a group -C (O) -Rp-C (O) Rm, where -Rp- is selected from a chemical bond, -CH2-, CH2 (CH2) m CH2- where m is as defined above, -CH = CH-, -CH2CH = CH-, phenylene (ie, -C6H4-), CH2CH = CH-CeH4-, -CH2CH2CH = CH-, -CH2-CC-, -CH2CH2-CC-, -CH2CH2CH = CH-CeH4-, -CH2-CC-CeH4-, -CH2CH2-CC-C6H4-, and R is selected from methyl, ethyl, phenyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, and morpholino; or a -c (o) -heterocyclyl group, in which heterocyclic is as defined above, and in which said heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or - a -C (0) -Rp-heterocyclyl or -C (0) -Rparyl group, wherein R, heterocyclyl, aryl and the possible substituents of said heterocyclyl or aryl are as described above; or R and Rl? taken together with the nitrogen atom to which they are attached, they represent morpholino, pyrrolidino, piperazino, N-methylpiperazino, succinimido, or phthalimido; R2 is C3-C15 linear or branched alkyl, either unsubstituted or substituted by a C3-C7 cycloalkyl group; or R2 is C3-C15 linear or branched alkyl, either unsubstituted or substituted by a C3-C7 cycloalkyl group; or R2 is a group -Rp-H, where Rp is as defined above, either unsubstituted or substituted by one to three substituents that are selected from methyl, ethyl, linear or branched C3-C4 alkyl, fluoro , chloro, d-C4 alkoxy, -nitro, amino, dimethylamino, carboxy, carboxymethyl; or R2 is a group -Rp-X-RIV, where R11 is as defined above, Rw is Ci-Ce alkyl, C2-C6 alkenyl, phenyl, phenyl-alkyl (Ci-Cß), or phenyl-alkenyl (C2-) Cß) / either unsubstituted or substituted by a group selected from F, Cl, Br, d-C4 alkyl, C2-C4 alkoxy, and X is a direct bond, or an oxygen atom, a sulfur atom , or a sulfinyl -S (o) -, sulfonyl -S (o) 2 or a carbamoyl group -CONH- or -NHCO-; R3 is the group that characterizes a natural or non-natural alpha-amino acid in which any functional group, if present, may be protected; R4 is o-alkyl, where alkyl is a linear or branched C1-C4 alkyl group, especially methyl, ethyl and t-butyl, or is o-phenyl, and derivatives thereof substituted by between one and three substituents they are selected from linear or branched C1-C4 alkyl, chloro and methoxy; or R 4 is -NH 2, -NH (C 1 -C 6 alkyl) -NH-aryl, -NH-heterocyclyl; or R 4 is -NH (Ci-Cß alkyl) substituted by phenyl or heterocyclyl; or R4 is -NH (alkylCe) substituted by a group selected from -CONH2, -NHCONH2, -S02NH2, -NHSO2NH2, or the derivatives thereof, in which the terminal nitrogen atom is substituted by one or two methyl groups, or derivatives thereof in which the terminal nitrogen atom is part of a closed chain of morpholino, pyrrolidino, piperazino, or N-methylpiperazino; or R 4 is -NH (d-Cß alkyl) substituted by amino, protected amino, mono alkylamino (C 1 -C 6), di alkylamino (Ci-Cβ) guanidm, morpholino, piperazino or N-methylpiperazino; or R3 and R4, taken together, are a group of the formula - (CH2) m ~ NH-, where m ranges from 5 to 12, optionally, interrupted by a group -NR5-, where R5 is selected from from hydrogen, alkyl (Ci-Cß), alkoxycarbonyl (Ci-Ce), aryl, aryl (d-Cß) alkyl, or aryl alkoxycarbonyl (Ci-Cß), or interrupted by a -C6H4-0- group, or interrupted by a closed chain of indole bound by its C-3 and its nitrogen atoms; and wherein alkyl, alkenyl, phenyl, cycloalkyl, heterocyclyl, and the characterizing groups of any of the aforementioned definitions of, R, Ri, R2, R3, R4 and A may be unsubstituted or substituted by one or more substituents, and the salts , the prodrugs, solvates and hydrates thereof, provided that, when -NRRi is -NH2, amino or protected acylamino, R3 is tert-butyl and R4 is amino or alkylamino, then R2 is other than isobutyl.

2. A compound, according to claim 1, which has the formula (I * '): where: W is a group -COOH or -CONHOH; R is hydrogen, methyl, ethyl, or benzyl; Ri is hydrogen, or: lower alkyl, especially methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl; aryl, especially phenyl and naphthyl; and aryl- (lower alkyl), especially benzyl; these groups may be unsubstituted or substituted by one or more substituents, which may be the same or different, which are selected from methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy , methoxy, ethoxy, acetyl, acetamide, carboxy, carboxymethyl; or a group - (CH2) m-heterocyclyl or - (CH2) m cyclopropyl, where m is zero, or an integer ranging from one to three, and a heterocyclyl represents a closed chain of heterocyclyl possessing between 3 and 6 members, simple or condensed with a closed chain of benzene or naphthalene, containing at least one nitrogen atom; more preferably, succinimido, phthalimido, saccharin, hydantoin, indolyl, oxyindolyl, 2-oxo-isoindolinyl, imidazolyl, pyridyl, morpholino, pyrrolidino, 2-oxopyrrolidino, piperazino; and wherein said heterocyclyl group is unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenol, hydroxy, oxo, carboxy, and nitro; or - a group - (CH2) nCOOH or a group - (CH2) m COOR1, in which n can be 1, 2 or 3, m can be 0, 1, 2 or 3, and R1 is methyl, ethyl, propyl , isopropyl, isobutyl, tert-butyl, phenyl, benzyl, allyl, styryl, 1-naphthyl, 2-naphthyl, whether unsubstituted or substituted by one to three substituents selected from methyl, ethyl, isopropyl, tertiary, -butyl, fluoro, chloro, bromo, nitro, amino, dimethylamino, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, carboxymethyl; or - a group that is selected from (CH2) mS02RI, (CH2) mS02NH2, - (CH2) mS02N (Me) 2, - (CH2) mSO ^ HR1, where m, R1 and the possible substituents of said group R are as defined above, or a group - (CH2) mS02- (4-methyl-l-piperazino), - (CH2) mS02- (1-piperazino), (CH2) mS? 2- (4-methyl-l-piperazino); or - a group - (CH2) nS03H, where n is as defined above; acyl, especially acetyl, or benzoyl, or phenacetyl, either unsubstituted or substituted by one or more substituents which are selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or a group -C (0) -Rp-C (0) R, where -Rp- is selected from a chemical bond, -CH2-, -CH2 (CH2) m CH2- where m is as defined before, -CH = CH-, -CH2CH = CH-, phenylene (ie, -C6H4-), -CH2CH = CH-C6H4-, -CH2CH2CH = CH-, -CH2-CC-, -CH2CH2-CC-, -CH2CH2CH = CH-C6H4-, -CH2-CC-C6H4-, -CH2CH2-CC-C6H4-, and R is selected from methyl, ethyl, phenyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, and morpholino; or a -C (0) -heterocyclyl group, in which heterocyclic is as defined above, and in which said heterocyclyl group is either unsubstituted or substituted by one or more substituents selected from bromine, chlorine, fluoro, methoxy, ethoxy, methyl, ethyl, benzyl, phenyl, hydroxy, oxo, carboxy, and nitro; or - a -C (O) -Rp-heterocyclyl or -C (O) -Rp-aryl group, wherein R11, heterocyclyl, aryl and the possible substituents of said heterocyclyl or aryl are as described above; or R and Ri, taken together with the nitrogen atom to which they are attached, represent morpholino, pyrrolidino, piperazino, N-methylpiperazino, succinimido, or phthalimido; R2 is C3-C1 linear or branched alkyl, either unsubstituted or substituted by a C3-C7 cycloalkyl group; or R2 is a group Rp-H, where R is as defined above, either unsubstituted or substituted by one to three substituents selected from methyl, ethyl, linear or branched C3-C4 alkyl, fluoro, chloro, C 1 -C 4 alkoxy, nitro, amino, dimethylamino, carboxy, carboxymethyl; or R2 is a group -Rp-X-Rrv, where -Rp- is as defined above, -X- is a direct bond, -0-, -S-, -SO-, -SO2-, -CONH - or -NHCO-, and Rv is Ci-Ce alkyl, alkenyl -Cé, methyl, ethyl, propyl, butyl, phenyl, or benzyl, the closed benzene chain of the phenyl and benzyl groups is substituted or unsubstituted by one or more substituents that are selected from methyl, ethyl, propyl, butyl, hydroxy, methoxy, ethoxy, chloro, fluoro, trifluoromethyl or nitro; - R3 is phenylmethyl, cyclohexylmethyl, isobutyl, tertbutyl, -C (CH3) 2C6H5, -C (CH3) 2SCH3, C (CH3) 2SCH3, C (CH3) 2S0CH3 C (CH3) 2S02CH3 -CH (C6H5) 2, CH ( CH3) 0H, -CH (CH4) 0Me, -CH (CH4) 0-isopropyl, -CH (CH2) or-tert-butyl, -CH (CH3) OPh, -CH (CH3) OCH2Ph, (4-methoxy) phenylmethyl, (4-hydroxy) -phenylmethyl, indolylmethyl, (N-ethyl) indonylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, (4-carboxy-methoxy) -phenylmethyl, cyclohexyl, phenyl, pyridyl, thiazolyl, thienyl, pyridylmethyl, thiazolimethyl , thienylmethyl, and derivatives thereof, wherein the phenyl, pyridyl groups; thiazolyl, and thienyl are substituted by chloro, fluoro, methoxy, or C3-alkyl; R4 is O-alkyl, where alkyl is a linear or branched alkyl group dd., Especially methyl, ethyl and t-butyl, or is O-phenyl, and derivatives thereof substituted by between one and three substituents which are they select from linear or branched alkyl d-, chloro and methoxy; or R 4 is -NH 2, -NH-alkyl, where alkyl is selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, such as for example linear or branched alkyl groups which are unsubstituted or substituted by a group selected from phenyl, benzyl, 2-pyridyl, 3-pyridyl, 1, 3, 4-thiadiazolyl-2-yl, 2-thiazolyl, these groups in turn are unsubstituted or substituted by a substituent selected from methyl, ethyl, methoxy, amino, methylamino, dimethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, -S02NH2, S02NHCeH5, -S0-morpholino, -S02CH3, -CO-morpholino; or R4 is a group -NHCH2CH2Y, -NHCH2CH2CH2Y, NHCH2CH2CH2CH2Y, -NHCH2CH (CH3) Y or -NHCH2C (CH3) 2Y, where Y is amino, methylamino, dimethylamino, morpholino, pyrrolidino, piperazino, N-methylpiperazino, hydroxy, methoxy, ethoxy , methylthio, 2- (dimethylamino) ethylthio, 2- (morpholino) ethylthio, Cl, F, Br, phenoxy or phenylthio, wherein the closed phenyl chain may be substituted by hydroxy or methoxy; or R 4 is -NH-aryl, -NH-heterocyclyl; NH-CH-aryl, -NH- (CH2) 2-aryl, -NH-CH2-heteroaryl, or -NH- (CH2) 2-heterocyclyl, wherein the aryl group is selected from phenyl, 4-fluorophenyl, -methoxyphenyl, 1,3-benzodioxolyl, 4-tolyl, 1-indanyl, 5-indanyl, and the heterocyclyl group is selected from 2-benzimidazolyl, 2-benzothiazolyl, 1-benzotriazolyl, 2, 5-dimethyl-l-pyrrolidinyl, 2,6-dimethylpiperidinyl, 2-imidazolyl, 1-indolyl, 5-indolyl, 5-indazolyl, 1-isoquinolyl, 5-isoquinolyl, 2-methoxy-5-pyridyl, 1- methyl-2-benzimidazolyl, 4-methyl-7-coumarinyl, 3-methyl-5-isothiazolyl, 5-methyl-3-isoxazolyl, pyrazinyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 3-quinolyl, 5-tetrazolyl, 1-methyl-5-tetrazolyl, 1, 3, 4-thiadiazol-2-yl, 2-thiazolyl, 1,2,4-triazin-3-yl, and 1 2, 4-triazol-3-yl; or R4 is -NH (C2-Ce alkyl), wherein the alkyl group is substituted by a substituent selected from -CONH2, -CONHMe, -NHCONH2, NHCONMe2, -NHCO- (4-morpholino), -NHCO - (4-methyl-l-piperazino), -NHS02NH2, -NHS02NMe2, -NHS02- (4-morpholino) and -NHSO2- (4-methyl-l-piperazino); or R3 and R4, taken together, are a group of the formula - (CH2)? or ~ NH-, or a group of the formula - (CH2) 4 ~ NH- (CH2) 5-NH-; or R3 and R4, taken together, are a group of the formula (B) which is presented below: or a group of the formula (C) that is detailed below: (C) where n is an integer that ranges from 3 to 6; and pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof, in accordance with what was previously described, provided that when -NRRi is -NH2, amino or protected acylamino, R3 is tert-butyl and R4 is amino or alkylamino, then R2 is other than isobutyl.

3. A compound, according to the claim 2, characterized in that R2 is isobutyl; R3 is phenylmethyl; and W, R, Ri and R4 are as defined in claim 2.

4. A compound, according to claim 2, characterized by R2 is isobutyl; R3 is 4-fluorophenylmethyl, 4-hydroxyphenylmethyl, 4-methoxyphenylmethyl; or R3 is selected from phenyl, pyridyl, thiazolyl, thienyl, pyridylmethyl, thiazolylmethyl, thienylmethyl, quinolylmethyl, isoquinolylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, indolylmethyl, N-methylindolylmethyl, imidazolylmethyl, and includes the derivatives thereof substituted in the Closed chain of phenyl, pyridyl, thiazolyl, thienyl, quinolyl or isoquinolyl by one or two substituents which are selected from chlorine, fluon, hydroxy, methoxy, methyl, ethyl, t-butyl, OCH2COOH; or R3 is cyclohexyl or cyclohexylmethyl; or R3 is selected from -C (CH3) 2OCH3, C (CH3) 2SCH3, -C (CH3) 2SOCH3, -C (CH3) 2S02CH3, -CH (CH3) 0H, CH (CH3) OMe, -CH ( CH 3) o-isopropyl-CH (CH 3) O-tert-butyl-C (CH 3) 2 CH 20 H, - (CH 2) 30 H; or R3 is a group that is selected from -CH (C6H5) 2, -C (CH3) 2C6H5, -CH (CH3) OPh, -CH (CH3) OCH2Ph, including the derivatives thereof substituted in the / the closed chain (s) of phenyl by one or two substituents which are selected from chloro, fluoro, hydroxy, methoxy, methyl, ethyl, propyl or t-butyl; or R3 and R4, taken together, constitute a group of the formula - (CH2) 10-NH-, or a group of the formula (B) or (C) mentioned above, where n is 6; and W, R, Ri and R4 are as defined in claim 2.

5. A compound, according to claim 2, characterized in that R is a linear C-7-C15 alkyl; or R2 is cyclopentylmethyl; or R2 is cinnamyl, benzyl, (phenyl) ethyl, (phenyl) propyl, (phenyl) butyl, 4-phenyl-3-butenyl, 4-phenyl-3-butynyl, (phenyl) pentyl, (phenoxy) methyl, (phenoxy) ethyl, (phenoxy) propyl, (phenoxy) butyl, (phenoxy) pentyl, (benzylaminocarbonyl) propyl, phenylthio, (phenylthio) _methyl, (phenylthio) ethyl, (phenylthio) propyl, phenylsulfonyl, (phenylsulfonyl) methyl, (phenylsulfonyl) -ethyl, (phenylsulfonyl) propyl, including derivatives in which the closed chain of benzene of said The groups are preferably substituted in the para position by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hydroxy, methoxy, chloro, fluoro, trifluoromethyl phenyl, fluorophenyl, methoxyphenyl, ethylphenyl, ethylphenyl, propylphenyl, butylphenyl.; and W, R, Ri, R3 and R4 are as defined in claim 2.

6. A compound, according to claim 2, characterized in that R4 is NH-aryl or NH-heterocyclyl, wherein aryl and heterocyclyl are as defined in claim 2, either unsubstituted or substituted by between one and three substituents they are selected from methyl, ethyl, fluoro, chloro and methoxy; or R4 is O-alkyl, where alkyl is a C1-C4 linear or branched alkyl group, especially methyl, ethyl and t-butyl, or is O-phenyl, and derivatives thereof substituted by between one and three substituents which are selected from linear or branched alkyl dd, chloro and methoxy; and W, R, R, R2 and R3 are as defined in claim 2.

7. A process for carrying out the preparation of a compound of the formula (I) as defined in claim 1, said process comprising (a) reacting a beta-lactam compound of the general formula (II): where Ri and R2 are as defined above, and W 'is COOH, CONHOH or protected derivatives thereof, with an amine of the formula (III): (III) where R3 and R are as defined above, and b) converting the compound thus obtained of the formula (IV): where W ', Rj., R2, R and R4 are as defined above, in a compound of the formula (I): where W, R, Ri, R2, R3 and R4, are as defined in claim 1, and if necessary, the protection groups are removed and, if desired, any of the W groups is converted , R, Ri, R2, R3 and R4, at the end or at any stage of the procedure.

8. A process for carrying out the preparation of a compound of the formula (II) as defined in claim 2, said process comprising (a) reacting a beta-lactam compound of the general formula (II '). where Ri and R2 are as defined above, and W 'is COOH, CONHOH or protected derivatives thereof, with an amine of the formula (III'): where R3 and R4 are as defined in claim 2, and b) converting the compound of the formula (IV) obtained in this manner: where W ', Ri, R2, R3 and R4, are as defined above, in a compound of the formula (I'): where W ', Ri, R2, R3 and R4, are as defined above, and if necessary, the protection groups are removed and, if desired, any of the W groups is converted, R, Ri, R2, R3 and R4 in different groups W, R, Ri, R2, R3 and R4 at the end or at any stage of the process.

9. A method, according to claim 7 or 8, for carrying out the preparation of a compound of the formula (I) or (II) as defined in claims 1 or 2, which additionally comprises the conversion of said compounds into their pharmaceutically acceptable salts, prodrugs, hydrates or solvates by means of known reactions.

10. A pharmaceutical composition comprising a compound, according to any of claims 1 to 7, and a pharmaceutically acceptable diluent or carrier.