MXPA00001147A - Acyclic metalloprotease inhibitors - Google Patents

Abstract

The invention provides compounds of formula (I) as described in the claims, or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof are useful as inhibitors of metalloproteases. Also disclosed are pharmaceutical compositions and methods of treating diseases, disorders and conditions characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

Description

ACICLIC METALOPROTEASE INHIBITORS TECHNICAL FIELD This invention relates to compounds that are useful for treating diseases, conditions and disorders associated with unwanted metalloprotease activity.

BACKGROUND OF THE INVENTION Several structurally related metalloproteases [MP] carry out the degradation of structural proteins. Usually, these metalloproteinases act on the intercellular matrix and, in this way, they are related to the degradation and remodeling of the tissues. These proteins are called metalloproteases or MP. There are several different MP families, classified by sequence homology. Several known MP families are described in the art, as well as examples thereof. These MPs include matrix metalloproteases [MMP], zinc metalloproteases, many of the membrane-bound metalloproteases, TNF conversion enzymes, angiotensin converting enzymes (ACE), disintegrins, including ADAM (See Wolfsberg et al, 131 J. Cell Bio, 275-78, October 1995), and enkephalinases. Examples of MP include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecanase and gelatinase and human stromelysin. It is believed that collagenase, stromelysin, aggrecanase and related enzymes are important in mediating the symptomatology of several diseases. Potential therapeutic indications of MP inhibitors have been mentioned in written materials. See, for example, US patent. 5,506,242 (Ciba Geigy Corp); patent of E.U.A. 5,403,952 (Merck &Co); PCT published application WO 96/06074 (British Bio Tech Ltd); PCT publication WO 96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British Bio Tech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); WO 95/26989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Ins. Opthamology); WO 95/23790 (SmithKine Beecham); WO 95/22966 (Sanofi Winthrop); WO 95/19965 (Glycomed); WO 95 19956 (British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd); WO 95/13289 (Chiroscience Ltd.); WO 95/12603 (Syntex); WO 95/09633 (Florida State Univ); WO 95/09620 (Florida State Univ); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 (Celltech); WO 93/14112 (Merck); WO 94/0019 (Glaxo); WO 93/21942 (British Bio Tech Ltd); WO 92/22523 (Res. Corp. Tech. Ine); WO 94/10990 (British Bio Tech Ltd); WO 93/09090 (Yamanouchi); and British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd); published applications of European patent EP 95/684240 (Hoffman LaRoche); EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); published Japanese applications JP 08053403 (Fujusowa Pharm. Co. Ltd.); JP 7304770 (Kanebo Ltd.); and Bird et.al J. Med Chem vol. 37, pp. 158-69 (1994). Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritis (Mullins, D.E., et.al, Biochem. Biophvs. Acta. (1983) 695: 117-214); osteoarthritis (Henderson, B., et.al, Druqs of the Future (1990) 15: 495-508); the metastasis of tumor cells (ibid, Broadhurst, MJ, et.al, European patent application 276,436 (published in 1987), Reich, R., et.al, 48 Cancer Res. 3307-3312 (1988), and various ulcerations or ulcerative tissue conditions, for example, ulcerative conditions may originate in the cornea as a result of alkali burns or as a result of infection by Pseudomonas aeruginosa, Acanthamoeba, herpes simplex and vaccinia virus Other examples of conditions characterized by activity of unwanted metalloprotease include periodontal disease, bullous epidermolysis, fever, inflammation and scleritis (Cf. DeCicco et.al, WO 95 29892, published November 9, 1995.) In view of the intervention of said metalloproteases in various disease conditions Attempts have been made to prepare inhibitors for these enzymes Several of these inhibitors are described in written materials Examples include US Patent No. 5,183, 900, issued on February 2, 1993 to Galardy; the patent of E.U.A. No. 4,996,358, issued February 26, 1991 to Handa et.al; the patent of E.U.A. No. 4,771, 038, issued September 13, 1988 to Wolanin et.al; the patent of E.U.A. No. 4,743,587, issued May 10, 1988 to Dickens et al .; European Patent Publication No. 575,844, published December 29, 1993 by Broadhurst et al .; International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura et al .; World Patent Publication No. 92/17460, published October 15, 1992 by Markwell et.al; and European Patent Publication No. 498,665, published August 12, 1992 by Beckett et.al. Metalloprotease inhibitors are useful in the treatment of diseases caused, at least in part, by structural protein degradation. Although a variety of inhibitors have been prepared, there is a continuing need for potent matrix metalloprotease inhibitors, useful in the treatment of such diseases. Applicants have surprisingly discovered that the lactam-containing acyclic compounds of the present invention are potent metalloprotease inhibitors.

OBJECTIVES OF THE INVENTION Therefore, an object of the invention is to provide compounds useful in the treatment of conditions and diseases that are characterized by unwanted MP activity. It is also an object of the invention to provide potent inhibitors of metalloproteases. Another objective of the invention is to provide pharmaceutical compositions that include those inhibitors. It is also an object of the invention to provide a method of treatment for diseases related to metalloproteases.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds that are useful as inhibitors of metalloproteases and that are effective in treating characterized conditions by the excessive activity of these enzymes. In particular, this invention relates to a compound having a structure according to formula (I) (i) where, A is S02Ar, COAr, CONHAr, PORAr, where Ar is a portion monocyclic or bicyclic aromatic or a monocyclic or bicyclic heteroaromatic portion, substituted or unsubstituted; Ri is alkyl or hydrogen; R2, R3 and R4 are each independently, chosen from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, alkoxyalkyl, alkyl heterocycle, heterocyclealkyl, and these substituents may be substituted or unsubstituted; rings can be formed by R2 and R3, Ri and R2 or R3 and R4; X is a bond, an alkyl of (C-i-Cß) or a heteroatom chosen from O, N, NZ, S, SO or S02; Y is a bond, an alkyl of (C? -C6), CO, C02, CONH, or a heteroatom chosen from O, N, NZ, S, SO or S02; and Z is hydrogen, COR4, COOR4, CONHR4, R4, CSR4, CSNHR4 and S02R4. This structure also includes an optical isomer, diastereomer or enantiomer for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester or imide thereof, an optical isomer, diastereomer or enantiomer for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester or imide thereof. This structure also includes an optical isomer, diastereomer or enantiomer for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester or imide thereof. These compounds have the ability to inhibit at least one mammalian metalloprotease. Accordingly, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of the formula (I), and to methods for treating diseases characterized by unwanted metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

Metalloproteases that are active at a particular unwanted site (e.g., an organ or certain cell types) can be identified by conjugating the compounds of the invention to an identification ligand, specific for a marker at that site, such as an antibody or fragment thereof or a receptor ligand. Methods of conjugation are known in the art. Also, the invention is directed to various methods that take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease. In another aspect, the invention is directed to the compounds of the formula (I) conjugated in a tag. Since the compounds of the invention bind to at least one metalloprotease, the label can be used to detect the presence of relatively high levels of metalloprotease, preferably a cell culture in vivo or in vitro of a matrix metalloprotease. In addition, the compounds of the formula (I) can be conjugated to vehicles that allow the use of these compounds in immunization protocols to prepare antibodies specifically immunoreactive with the compounds of the invention. Typical conjugation methods are known in the art. Then, these antibodies are useful for therapy and to monitor the dosage of the inhibitors.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are inhibitors of mammalian metalloproteases, preferably matrix metalloproteases. Preferably, the compounds are those of the formula (I) or a pharmaceutically acceptable salt or biohydrolyzable amide, ester or imide thereof. In this description reference is made to publications and patents in an effort to fully describe the most advanced state of the art. All references cited herein are incorporated by reference.

Definitions and use of terms The following is a list of definitions for the terms used herein. "Acyl" or "carbonyl" is described as a radical that could be formed by the removal of the hydroxy from a carboxylic acid (ie R-C (= 0) -). Preferred acyl groups include (for example) acetyl, formyl and propionyl. "Acyloxy" is an oxy radical having an acyl substituent (i.e., -O-acyl); for example, -0-C (= 0) -alkyl.

"Alcoxyacyl" is an acyl radical (-C (= 0) -) having an alkoxy substituent (ie, -O-R), for example, -C (= 0) -0-alkyl. This radical can be considered as an ester. "Acylamino" is an amino radical having an acyl substituent (i.e., -N-acyl); for example -NH-C (= 0) -alqu¡lo. "Alkenyl" is a substituted or unsubstituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more preferably from 2 to 8; except where indicated.

Alkenyl substituents have at least one olefinic double bond (including, for example, vinyl, allyl and butenyl). "Alkynyl" is an unsubstituted or substituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more preferably from 2 to 8; except where indicated. The chain has at least one triple carbon-carbon bond. "Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, wherein the hydrocarbon chain is alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include, for example, methoxy, ethoxy, propoxy and allyloxy. "Alkoxyalkyl" is a substituted or unsubstituted alkyl portion, replaced with an alkoxy moiety (ie, -alkyl-O-alkyl). It is preferred that the alkyl have 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms), and the alkoxy 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms).

"Alkyl" is a saturated or unsubstituted or substituted hydrocarbon chain radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms; more preferably 1 to 4; except where indicated. Preferred alkyl groups include, for example, substituted or unsubstituted methyl, ethyl, propyl, isopropyl and butyl. As it is referred to herein, "spirocycle" or "spirocyclic" refers to a cyclic portion that shares one carbon in another ring. Said cyclic portion may be carbocyclic or heterocyclic in nature. Preferred heteroatoms that are included in the main structure of the heterocyclic spirocycle include oxygen, nitrogen and sulfur. Spirocycles can be substituted or unsubstituted. Preferred substituents include oxo, hydroxy, alkyl, cycloalkyl, arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (e.g., benzothiol, cycloalkyl, heterocycloalkyl, benzimidizoles, pyridylthiol, etc., which may also be substituted) and the like. In addition, the heteroatom of the heterocycle can be substituted if its valence allows it. The spirocyclic ring sizes that are preferred include rings of 3 to 7 elements. The term "alkylene" refers to an alkyl, alkenyl or alkynyl that is a diradical, rather than a radical. "Heteroalkylene" is defined similarly as an alkylene (diradical) having a heteroatom in the chain. "Alkylamino" is an amino radical having one (secondary amine) or two (tertiary amine) alkyl substituents (ie, -N-alkyl).

For example, methylamino (-NHCH3), dimethylamino (-N (CH3) 2) and methylethylamino (-N (CH3) CH2CH3). The "amino acid" includes any of the amino acids that occur in nature, its d-amine variants include any amino-carboxylic acid. As such, they are considered pipecolic acid and sarcosine. "Aminoacyl" is an acyl radical having an amino substituent (ie, -C (= 0) -N); for example -C (= 0) -NH2- The amino group of the aminoacyl portion can be unsubstituted (ie, primary amine) or can be substituted with one (secondary amine) or two (ie, tertiary amine) alkyl groups . "Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include, for example, phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl and fluorenyl. Said groups can be substituted or unsubstituted. "Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl, phenylethyl and phenylpropyl. Said groups can be substituted or unsubstituted. "Arylalkylamino" is an amine radical substituted with an arylalkyl group (e.g., -NH-benzyl). Said groups can be substituted or unsubstituted. "Arylamino" is an amine radical substituted with an aryl group (i.e., -NH-aryl). Said groups can be substituted or unsubstituted. "Aryloxy" is an oxygen radical having an aryl substituent (ie, -O-aryl). Said groups can be substituted or unsubstituted.

"Carbocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring radical. The carbocyclic rings are monocyclic or are ring systems fused, bridged spiropolyclic. The monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. The polycyclic carbocyclic rings contain 7 to 17 atoms, preferably 7 to 12 atoms. Preferred polycyclic systems comprise rings of 4, 5, 6 or 7 elements fused to rings of 5, 6 or 7 elements. "Carbocycloalkyl" is a substituted or unsubstituted alkyl radical substituted with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl, more preferably an aryl. Preferred carbocycloalkyl groups include benzyl, phenylethyl and phenylpropyl. "Carbocycloheteroalkyl" is an unsubstituted or substituted heteroarkyl radical replaced with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl; more preferably, an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl or 2-thia-ethyl. "Carboxyalkyl" is an unsubstituted or substituted alkyl radical replaced with a carboxy moiety (-C (= 0) OH). For example, -CH2- C (= 0) OH. "Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include, for example, cyclopropyl, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include, for example, morpholinyl, piperadinyl, piperazinyl, tetrahydrofuryl and hydantoinyl. The "fused rings" are rings that are superimposed on each other so that they share two ring atoms. A certain ring can be fused to more than another ring. The fused rings are contemplated in heteroaryl, aryl and heterocycle radicals, or the like. "Heterocycle-alkyl" is an alkyl radical substituted with a heterocyclic ring. Preferably, the heterocyclic ring is a heteroaryl or cycloheteroalkyl; more preferably, a heteroaryl. Preferred heterocycloalkyl includes C 1 -C 4 alkyl having a preferred heteroaryl attached thereto. For example, pyridylalkyl and the like are more preferred. "Hetero-cycloheteroalkyl" is an unsubstituted or substituted heteroalkyl radical, replaced with a heterocyclic ring. Preferably, the heterocyclic ring is an aryl or cycloheteroalkyl; more preferably, an aryl. A "heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms. "Heteroalkenyl" is an unsubstituted or substituted unsaturated chain radical having 3 to 8 elements comprising carbon atoms and one or two heteroatoms. The chain has at least one carbon-carbon double bond. "Heteroalkyl" is an unsubstituted or substituted saturated chain radical having 2 to 8 elements including carbon atoms and one or two heteroatoms. The "heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical consisting of carbon atoms and one or more heteroatoms in the ring. The heterocyclic rings are monocyclic ring systems or are fused, bridged or spiro-polyclic. The monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7 atoms. The polycyclic rings contain 7 to 17 atoms, preferably 7 to 13 atoms. "Heteroaryl" is a heterocyclic aromatic ring radical, either monocyclic or bicyclic. Preferred heteroaryl groups include, for example, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl, benzothiazolyl, benzofuryl, indolyl, and the like. Said groups can be substituted or unsubstituted. "Halo", "halogen" or "halide" is a radical of chlorine, bromine, fluorine or iodine atom. The preferred halides are bromine, chlorine and fluorine. Also, as referred to herein, a "lower" hydrocarbon portion (e.g., "lower" alkyl) is a hydrocarbon chain consisting of 1 to 6, preferably 1 to 4, carbon atoms. A "pharmaceutically acceptable salt" is a cationic salt formed in any acid group (e.g., carboxyl) or an anionic salt formed in any basic group (e.g., amino). Many of these salts are known in the art, as described in world patent publication 87/05297, Johnston et.al, published on September 11, 1987 (incorporated herein by reference). Preferred cationic salts include the alkali metal salts (such as sodium and potassium) and the alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (as chloride salts). "Biohydrolyzable amides" are amides of the compounds of the invention that do not interfere with the inhibitory activity of the compound, or that a human readily converts in vivo to produce an active inhibitor. A "biohydrolyzable hydroxyimide" is an imide of a compound of the formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds, or that a human readily converts in vivo to produce an active compound of the formula (I). Said hydroxyimides include those which do not interfere with the biological activity of the compounds of the formula (I). A "biohydrolyzable ester" refers to an ester of a compound of the formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds or that a human readily converts in vivo to produce an active compound of the formula (I) . A "solvate" is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water).

See J. Honig et.al, The Van Nostrand Chemist's Dictionary. p. 650 (1953). The pharmaceutically acceptable solvents used in accordance with this invention include those which do not interfere with the biological activity of the metalloprotease inhibitor (eg, water, ethanol, acetic acid, N, N-dimethylformamide and others which are known or determined by those skilled in the art. ease). "Optical isomer", "stereoisomer" and "diastereomer", as they are referred to herein, have the normal meanings recognized in the art (Cf., Hawlev's Condensed Chemical Dictionary, 11th edition). The illustration of specific protected forms and other derivatives of compounds of the formula (I) is not intended to be limiting. The application of other useful protection groups, salt forms, etc., is within the skill of the person skilled in the art. As already defined and used herein, substituent groups can be substituted. That substitution can be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analyzes in Chemistrv and Bioloqy (1979), incorporated herein by reference. Preferred substituents include, for example, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (eg, aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (eg, carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (eg, piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. According to the present invention, "mammalian metalloprotease" means any enzyme containing a metal and found in mammalian sources, which has the ability to catalyze the degradation of collagen, gelatin or proteoglycan under suitable test conditions. Suitable test conditions can be found, for example, in the U.S. patent. No. 4,743,587, which refers to the procedure of Cawston et.al, Anal. Biochem. (1979) 99: 340-345; Weingarten, H., et.al describe the use of a synthetic substrate in Biochem. Biophv. Res. Comm. (1984) 139: 1184-1187. Of course, it is possible to resort to any normal method to analyze the degradation of these structural proteins. The metalloprotease enzymes mentioned herein are all zinc-containing proteases that are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of the candidate compounds to inhibit metalloprotease activity can, of course, be analyzed in the tests described above. The isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or raw extracts containing the scale of enzymes capable of degrading tissues can be used.

Compounds: The compounds of the invention are described in the Brief Description of the Invention. The preferred element A is S02Ar, where Ar is a monocyclic or bicyclic aromatic portion or a monocyclic or bicyclic heteroaromatic portion. This portion can be substituted or unsubstituted and can be carbocyclic or heterocyclic; the preferred heteroatoms include oxygen, sulfur and nitrogen, the most preferred being nitrogen. With nitrogen it is meant that the valence of nitrogen is preferred, so that if the preferred aromatic portion is benzimidazole, the nitrogen includes NH, to preserve the valence. The most preferred aromatic compounds include phenyl and pyridyl, even more preferably, phenyl. Element Ar includes substituted Ar; the substitution may be any number of substituents and at any position in the aromatic portion. The most preferred substituents are alkoxy, aryloxy, aryl, alkyl and halo. Where the Ar portion is monocyclic it is preferred that the substitution be in the 2 or 4 position as to the binding of the Ar to the sulfur, phosphorus, oxygen, nitrogen or coal of the carbonyl of the portion A. Ri includes alkyl, hydrogen, more preferably, hydrogen. R2, R3 and R4 are independently selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle, heterocycloalkyl, and these substituents can be substituted or unsubstituted. X includes a bond or a heteroatom chosen from O, N or S. Of course, the valence of nitrogen leaves room for = N = and -NZ-, and both are considered herein. Z includes COR4, COOR, CONHR and In addition, the rings can be formed by R2 and R3, to thereby form a "spirocyclic ring system", and R1 and R2 or R3 and R can form rings. Preferably, those rings are 5-7 elements in size.

Preparation of the compound: The hydroxamic compounds of the formula (I) can be prepared by the use of a variety of procedures. The general schemes include the following. The hydroxamic compounds of the formula (I) can be prepared by the use of a variety of procedures. The preferred methods in general for making the compounds include the following: A) Preparation of the NHA portion of the molecule and preparation of the hydroxamic acid: It is preferable that this portion of the synthesis proceed through different courses depending on the desired substituent. Where A is S02Ar, COAr, or PORAr, the synthesis proceeds through the use of amide chemistry. However, where A is CONHAr, it is preferable that the amino acid derivative react with the isocyanate ArNCO, as illustrated below. To make it easier, R1 and the portion of C (R2, R3, X-Y-R) is replaced with Q in this scheme: A = SO2Ar, COAr, PORAr NHAr A = CONHAr R 'is alkyl, alkoxy, hydrogen or any other portion with which an acyl halide or the like may then be made which can be used in the synthesis of hydroxamic acid. Then, the hydroxamic acid portion is prepared by normal methods, preferably by the preparation of an acyl halide and the hydroxylamine treatment.

B) Preparation of the "Q portion" rC (R2.R3, XY-R4) 1 Q [C (R2, R3, XY-R4)] can be added by a strong base, using for example metal hydrides with carbonyl compound, in an acidic carbon, which would be present in the alpha position for the carbonyl. Of course, the person skilled in the art would recognize that any free amine in an amino acid would require coverage for reasonable yields, as illustrated below. To make it easier, Ri is illustrated as H, and A is different from CONHAr. The person skilled in the art will be able to elaborate molecules with different substitution based on this illustrative scheme: M is a metal, preferably an alkali metal or alkaline earth metal R1 is an alkyl, benzyl, lower aryl or similarly saponified group X is preferably a halide or suitable leaving group, suitable for an acyl halide synthesis, more preferably is fluorine chlorine; or if the amidation is adequate it can be OH 1 AX, organic base, 2 (CF3CO) 2 ?, 3 ROH d-aspartic acid -R4 AHN 1 Hydrolysis of ester 2 Preparation of hydroxamic acid HO X "Y -R4 The compounds of this invention can also support base synthesis, such as in a column, or in a combination synthesis.

The supports for said synthetic methods are already in the commercial market and the methods for using them are known in general. The organic bases are used in the synthesis, almost always these are nitrogenous bases, and the preferred bases include piperidine, triethylamine (TEA), diisopropylamine (DIPEA), and the like. For illustrative purposes, two common materials and related general procedures are described: a) Chlorotrityl-polystyrene resin 1 pipepdine, 2 reactive coupling c c NHFmoc A = SC ^ Ar, COAr, PORAr, NHCONHAr TFA is trifluoroacetic acid or another suitable acid that will break the molecule from the resin, and does not react with the finished product. b) Wanq resin The compounds of the formula (I) are easily prepared from amino acids, amino acid derivatives and the like. Preferably, alpha-amino reacts with a compound having halo or a suitable leaving group. Of course, where the amino acid is not available, functionality can be reversed in the reagents, i.e., a leaving group of alphacarbonyl can be reacted with an amino group. Preferably, a primary amino compound under basic conditions displaces the halide or the leaving group. Amino acids include not only the twenty commonly occurring amino acids and their derivatives (for example, sarcosine, hydroxyproline, 2-aminobutyric acid, pipicolic acid and the like) and any of those d-amino acids, but also any alpha-amino acid. Many are known or available in the market, such as, from Sigma (St. Louis, MO) or Aldrich (Milwaukee, Wl). For those amino acids that are not available, variants of the amino acids can be made by any of the various methods known in the art. By the use of the following examples and the foregoing explanation, one skilled in the art can generate a variety of compounds in a similar manner, using the above scheme as a guide. These steps can be varied to increase the performance of the desired product. The person skilled in the art will also recognize that the judicious choice of reagents, solvents and temperatures is an important component in a successful synthesis. While determining the optimal conditions, etc. it is routine, it will be understood that to elaborate a variety of compounds these can be generated in a similar way by means of the guide of the previous scheme. The starting materials used in the preparation of the compounds of the invention are known, are manufactured by known methods or are commercially available as a starting material.

It is recognized that one skilled in the art of organic chemistry can easily perform normal manipulations of organic compounds without further direction; that is, it is within the scope and practice of the expert to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyl and similiar, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification and the like. Examples of these manipulations are described in standard texts, such as March, Advanced Orqanic Chemistrv, (Wiley), Carey and Sundberg, Advanced Orqanic Chemistry (Vol. 2). The skilled artisan will readily appreciate that certain reactions are best performed when hides or protects another functionality in the molecule, thereby avoiding any unwanted side reactions and / or increasing the reaction yield. Often, the person skilled in the art uses protective groups to achieve the increase of said yields or to avoid unwanted reactions. These reactions are found in written material and are also within the reach of the person skilled in the art. Examples of many of these manipulations can be found, for example, in T. Greene, Protectinq Groups in Orqanic Synthesis. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to avoid unwanted side reactions.

The compounds of the invention may have one or more chiral centers. As a result, an optical isomer, including diastereomer and enantiomer, can be selectively prepared on others; for example, by means of chiral starting materials, catalysts or solvents, or stereoisomers or optical isomers can be prepared, including diastereomers and enantiomers (a racemic mixture). Since the compounds of the invention can exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers or stereoisomers can be separated using known methods, such as for example chiral salts, chiral chromatography and the like. Furthermore, it is recognized that an optical isomer, including diastereomer and enantiomer, or stereoisomer, may have favorable properties over others. Thus, when describing and claiming the invention, when describing a racemic mixture, it is clearly observed that optical isomers are also described and claimed, including diastereomers and enantiomers, or stereoisomers basically without the others.

Methods of use Metalloproteinases (MP) found in the body function, in part, by degrading the extracellular matrix, which comprises proteins and extracellular glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of the tissue in the body. Metalloprotease inhibitors are useful in the treatment of diseases caused, at least in part, by the degradation of these proteins. It is known that MPs are intimately related to tissue remodeling. As a result of this activity, it has been mentioned that they are active in many disorders that include either: tissue degradation; including degenerative diseases, such as arthritis, multiple sclerosis and the like, metastasis or mobility of tissues in the body: tissue remodeling, including fibrotic disease, scarring, benign hyperplasia and the like. The compounds of the present invention treat diseases, disorders and / or undesired conditions that are characterized by an undesired or elevated activity of that class of proteases. For example, the compounds can be used to inhibit proteases that: destroy structural proteins (ie, proteins that maintain the stability and structure of tissues); interfere with intracellular / intracellular signaling, including those involved in cytokine regulation and / or cytokine processing and / or inflammation, tissue degradation and other diseases [Mohler KM, et.al, Nature 370 (1994) 218-220; Gearing AJH, et.al, Nature 370 (1994) 555-557; McGeehan GM, et.al, Nature 370 (1994) 558-561], and / or facilitate unwanted processes in the subject being treated, for example, the processes of sperm maturation, ovule fertilization and the like.

As used herein, a "disorder related to MP "or" MP-related disease "is that which has to do with an unwanted or elevated MP activity in the biological manifestation of the disease or disorder, in the biological cascade leading to the disorder, or as a symptom of the disorder. This "intervention" of MP includes: the activity of unwanted or elevated MP as a "cause" of the disorder or biological manifestation, whether the activity has been genetically elevated, by infection, by autoimmunity, trauma, biomechanical causes, quality of life [eg, obesity] or for some other cause, MP as part of the observable manifestation of the disease or disorder, that is, the disease or disorder can be measured in terms of the increase in MP activity, or from a certain point Clinically, unwanted or elevated MP levels indicate the disease MPs do not need to be the "hallmark" of the disease or disorder, unwanted or elevated MP activity is part of the biochemical cascade or cell which results or relates to the disease or disorder. In this regard, the inhibition of MP activity disrupts the cascade and thus controls the disease. Fortunately, many MPs are not evenly distributed in the body. Therefore, the distribution of MP expressed in various tissues is often specific for these tissues. For example, the distribution of metalloproteases involved in the degradation of joint tissues is not the same as the distribution of metalloproteases found in other tissues. Accordingly, although not essential for activity or efficacy, certain disorders are preferably treated with compounds that act on specific MPs found in the affected tissues or regions of the body. For example, a compound that exhibits a greater degree of affinity and inhibition for MP found in the joints (e.g., chondrocytes) would be preferred than other compounds that are less specific for the treatment of a disease found there. In addition, certain inhibitors have greater bioavailability than others for certain tissues, and this judicious choice of inhibitor, with the selectivity described above provides a specific treatment of the disorder, disease or unwanted condition. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. In this way, the compounds can be selected to produce mediated effects through MP found specifically outside the central nervous system. The determination of the specificity of an MP inhibitor of a certain MP is within the ability of the expert in that field. Proper test conditions can be found in written material. There is a specific knowledge of the tests for stromelysin and collagenase. For example, the patent of E.U.A. No. 4,743,587 refers to the procedure of Cawston et.al, Anal Biochem (1979) 99: 340-345. Weingarten, H., et.al describe the use of a synthetic substrate in a test in Biochem Biophv Res Comm (1984) 139: 1184-1187. Of course, any standard method for analyzing the degradation of structural proteins by MP can be used. The ability of the compounds of the invention to inhibit the activity of metalloproteases, of course, can be proven in the tests found in the written material or variations thereof. The isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or crude extracts containing the scale of enzymes that can degrade the tissues can be used. As a result of the inhibitory effect of MP of the compounds of the invention, these are also useful in the treatment of the following disorders by virtue of their metalloprotease activity. The compounds of this invention are also useful for prophylactic or acute treatment. They are administered in the way that experts in the fields of medicine or pharmacology wish. It is immediately apparent to the person skilled in the art that the preferred routes of administration will depend on the state of the disease being treated, as well as on the chosen dosage form. Preferred routes for systemic administration include peroral and parenteral administration. However, one skilled in the art will readily appreciate the convenience of administering the MP inhibitor directly to the affected area for many disorders. For example, it may be convenient to administer MP inhibitors directly to the area of the disease or condition, such as in an area affected by surgical trauma (eg, angioplasty), an area affected by scarring or burns (eg, topical to the skin). ). Since bone remodeling is related to MP, the compounds of the invention are useful to prevent prosthesis from loosening. In the art it is known that with the passage of time the prostheses become loose, become painful and can cause another injury to the bone, which would require a replacement. The need for replacement of such prostheses includes such as in, joint replacements (for example, hip, knee and shoulder replacements), dentures, including dentures, bridges and prostheses secured to the maxilla and / or mandible. MP are also active in the remodeling of the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons why angioplasty has a higher-than-expected rate of long-term insufficiency (reobstruction with time) is because MP activity is not desired or is high in response to what the body can do. recognize as "injury" to the base membrane of the blood vessel. Thus, regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, restenosis by angioplasty and aortic aneurysm may increase the success of long term of any other treatment, or it can be a treatment in itself. In the care of the skin, the MPs participate in the remodeling or "renewal" of the skin. As a result, MP regulation improves the treatment of skin conditions, including but not limited to, repair, regulation and prevention of wrinkles, as well as repair of skin damage caused by ultraviolet rays. Such treatment includes prophylactic treatment or treatment before the physiological manifestations are evident. For example, MP can be applied as a pre-exposure treatment to prevent damage by ultraviolet rays and / or during or after exposure to prevent or minimize post-exposure damage. In addition, MPs are involved in disorders and skin diseases related to abnormal tissues resulting from an abnormal manifestation, including metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of "normal" skin injuries, including scarring or "shrinkage" of tissues, for example, after burns. Inhibition of MP is also useful in skin-related surgical procedures to prevent scar formation and the promotion of normal tissue growth, including in those applications reattaching the limb and refractory surgery (either by laser or incision ). In addition, MPs are related to disorders that include irregular remodeling of other tissues, such as bone, for example, in otosclerosis and / or osteoporosis, or for specific organs, such as liver cirrhosis and pulmonary fibrotic disease. Similarly, in diseases such as multiple sclerosis, PM can intervene in the irregular modeling of the blood-brain barrier and / or nerve tissue myelin sheaths. In this way, the regulation of MP activity can be used as a strategy in the treatment, prevention and control of these diseases. Likewise, it is thought that MPs are involved in many infections, including cytomegalovirus.; retinitis [CMV]; HIV and the resulting syndrome, AIDS. MP can also intervene in extravascularization, where the surrounding tissue needs to be degraded to allow new blood vessels, as in angiofibrone and hemangioma. Since MPs degrade the extracellular matrix, it is observed that inhibitors of these enzymes can be used as agents for birth control, for example to prevent ovulation, to prevent the penetration of sperm into and through the extracellular environment of the ovule, as well as the implantation of the fertilized ovum and to prevent sperm maturation. In addition, it is also observed that they are useful to prevent or stop premature labor and delivery. Since MPs are involved in the inflammatory response and in cytokine processing, the compounds are also useful as anti-inflammatories for use in diseases in which inflammation prevails, including, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout and Reiter's syndrome.

When autoimmunity is the cause of the disorder, the immunological response often triggers the activity of MP and cytokine. The regulation of MPs in the treatment of said autoimmune disorders is a useful treatment strategy. Accordingly, PM inhibitors can be used for the treatment of disorders including, lupus erimatosus, ankylosing spondylitis and autoimmune keratitis. Sometimes side effects of autoimmune therapy result in exacerbation of other conditions mediated by MP; inhibitory therapy of MP is also effective here, for example, in fibrosis induced by autoimmune therapy. In addition, other fibrotic diseases lend themselves to this type of therapy, including lung disease, bronchitis, emphysema, cystic fibrosis, acute respiratory fatigue syndrome (especially the acute phase response). When MPs intervene in the unwanted degradation of tissue by exogenous agents, they can be treated with MP inhibitors. For example, they are effective as an antidote for rattlesnake bite, as antivesics, in the treatment of allergic inflammations, septicemia and shock. In addition, they are useful as antiparasitic (e.g., in malaria) and anti-infectious. For example, they are believed to be useful in the treatment or prevention of viral infections, including infection that would result in herpes, "cold" (e.g., rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS.

It is also believed that MP inhibitors are useful in the treatment of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications derived from or that originate from diabetes, especially those that include loss of tissue viability. , coagulation, Graft disease vs. Host, leukemia, cachexia, anorexia, proteinuria and perhaps the regulation of hair growth. For some diseases, conditions or disorders, the inhibition of MP is contemplated as a preferred method of treatment. Said diseases, conditions or disorders include arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or control of growth and tumor metastasis), eye disorders (especially corneal ulceration, lack of corneal healing, macular degeneration and pterygium); and diseases of the gums (especially periodontal disease and gingivitis). Preferred compounds for, but not limited to the treatment of arthritis (including osteoarthritis and rheumatoid arthritis) are those compounds that are selective for metalloproteases and disintegrin metalloproteases. Preferred compounds for, but not limited to the treatment of cancer (especially the prevention or combating of growth and tumor metastasis) are those compounds that preferably inhibit gelatinases or type IV collagenases. Preferred compounds for, but not limited to the treatment of ocular disorders (especially corneal ulceration, lack of healing of the cornea, macular degeneration and pterygium) are those compounds that broadly inhibit metalloproteases. Preferably, these compounds are administered topically, more preferably in a drop or gel. Preferred compounds for, but not limited to the treatment of gum diseases (especially periodontal disease and gingivitis) are those compounds that preferably inhibit collagenases.

Compositions: The compositions of the invention comprise: (a) a safe and effective amount of a compound of the formula (I); and (b) a pharmaceutically acceptable carrier. As already mentioned, it is known that numerous diseases are mediated by excessive or unwanted metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammations of the skin, ulcerations, particularly of the cornea, reactions to infections, periodontitis and the like. In this manner, the compounds of the invention are useful in therapy with respect to conditions related to this undesired activity. Therefore, the compounds of the invention can be formulated into pharmaceutical compositions useful for the treatment or prophylaxis of these conditions. Normal techniques of pharmaceutical formulation are employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., Most recent edition. A "safe and effective amount" of a compound of the formula (I) is an amount that is effective to inhibit metalloproteases at the site (s) of activity, in a mammal, without undue adverse side effects (such as toxicity, irritation or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention. Of course, the specific "safe and effective amount" will vary with factors such as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form. which will be used, the vehicle employed, the solubility of the compound of the formula (I) therein and the desired dosage regimen for the composition. In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more one or more compatible solid or liquid filler or encapsulating substances or diluents that are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition can be mixed with the present compound and with each other, such that there is no interaction that could substantially reduce the pharmaceutical efficacy of the composition under certain conditions. of ordinary use. Of course, pharmaceutically acceptable carriers should have sufficiently high purity and toxicity low enough to make them suitable for administration to the animal, preferably the mammal under treatment. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose.; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; jelly; talcum powder; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as TWEENS, "wetting agents such as sodium laurisulfate, coloring agents, flavoring agents, tabletting agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline and phosphate buffer solutions. The pharmaceutically acceptable carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound will be administered.If the present compound will be injected, the pharmaceutically acceptable carrier that is preferred is a sterile physiological saline solution with a blood-compatible suspension, whose pH has been adjusted to about 7.4.In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, oils synthetics, polyols, alginic acid co, Phosphate pH regulating solutions, emulsifiers, isotonic saline and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier in compositions for parenteral administration comprises at least about 90% by weight of the total composition. Preferably, the compositions of this invention are provided in unit dosage form. As used herein, a "unit dose form" is a composition of this invention that contains an amount of a compound of the formula (I) that is suitable for administration to an animal, preferably a mammal, in a single dose, according to the proper medical practice. These compositions preferably contain from about 5 mg (milligrams) to about 1000 mg, more preferably from about 10 mg to about 50 mg, still more preferably from about 10 mg to about 300 mg of a compound of the formula (I) . The compositions of this invention can be in any variety of suitable forms (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Depending on the specific route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be employed. These include liquid or solid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Optional pharmaceutically active materials may be included, which do not substantially interfere with the inhibitory activity of the compound of the formula (I). The amount of vehicle employed together with the compound of the formula (I) is sufficient to provide a practical amount of material for administration per unit dose of the compound of the formula (I). Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated herein by reference: Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et.al, Pharmaceutical Dosaqe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosaqe Forms 2nd. edition (1976). In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable vehicle"as used herein, means one or more compatible solid or liquid filling or encapsulating substances or diluents that are suitable for administration to an animal, preferably a mammal. The term "compatible" as used herein, means that the components of the composition can be mixed with the present compound and with each other, such that there is no interaction that could substantially reduce the pharmaceutical efficacy of the composition under normal situations of use. Of course, pharmaceutically acceptable carriers should have sufficiently high purity and toxicity low enough to make them suitable for administration to the animal, preferably a mammal under treatment. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose.; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; jelly; talcum powder; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEENS®; wetting agents such as sodium laurisulfate; coloring agents; flavoring agents; tabletting agents, stabilizers; antioxidants; conservatives; water without pyrogens; isotonic saline solution and phosphate buffer solutions. The choice of a pharmaceutically acceptable carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound will be administered. If the present compound is to be injected, the preferred pharmaceutically acceptable carrier is sterile physiological saline with a blood-compatible suspension agent, whose pH has been adjusted to about 7.4. Various oral dosage forms can be employed, including solid forms such as tablets, capsules, granules and powders. These oral forms comprise a safe and effective amount, usually at least about 5% and preferably about 25% to about 50%, of the compound of the formula (I). The tablets can be compressed, comminuted, enteric-coated, sugar-coated, film-coated or multiple-compressed, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and lubricants. appropriate fusion. The liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, fusion agents, coloring agents and flavoring agents. The pharmaceutically acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well known in the art. Almost always, the tablets comprise, as inert diluents, pharmaceutically compatible and conventional adjuvants, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch; alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Slip agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents such as FD &C dyes can be added to improve appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint and fruit flavors are also useful adjuvants for chewable tablets. Almost always, the capsules include one or more of the solid diluents already described. The selection of the components of the vehicle depends on secondary considerations such as taste, cost and shelf stability, which are not decisive for the purposes of the present invention and which one skilled in the art can elaborate with ease. Peroral compositions also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate.; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents and colorants described above. Said compositions can also be coated by conventional methods, usually with pH or time sensitive coatings, such that the present compound is released into the gastrointestinal tract, close to the desired topical application, or repeatedly to prolong the desired action. Almost always, said dosage forms include, but are not limited to, one or more of the following: cellulose acetate phthalate, polyvinylacetate phthalate, dihydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and lacquer. The compositions of the present invention may optionally include other drug actives. Other compositions useful for achieving systemic delivery of the present compounds include sublingual, buccal and nasal dosage forms. Almost always said compositions comprise one or more soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. They are also described above and may include slip agents, lubricants, sweeteners, colorants, antioxidants and flavoring agents. The compositions of the present invention can also be administered topically to a subject, e.g., by direct placement or dispersion of the composition on the epidermal or epithelial tissue of the subject, or transdermally by means of a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. Preferably these topical compositions comprise a safe and effective amount, usually at least about 0.1% and preferably about 1% to about 5%, of the compound of the formula (I). Vehicles suitable for topical administration preferably remain in place on the skin as a continuous film, and are resistant to removal by transpiration or immersion in water. In general, the carrier is of an organic nature and the compound of formula (I) can be dispersed or dissolved therein. The vehicle may include emollients, emulsifiers, thickening agents and pharmaceutically acceptable solvents, and the like.

Methods of administration This invention also provides methods for treating or preventing disorders associated with excessive or undesired activity of the metalloprotease in an animal, preferably a mammal, by administering a safe and effective amount of a compound of the formula (I) to said mammal. subject. As used herein, the phrase "a disorder associated with excessive or unwanted metalloprotease activity" is any disorder characterized by protein degradation. The methods of the invention are useful in the treatment of disorders, such as, for example, osteoarthritis, periodontitis, corneal ulceration, tumor invasion and rheumatoid arthritis. The compounds and compositions of the formula (I) of this invention can be administered topically or systemically. Systemic application includes any method for introducing a compound of formula (I) into body tissues, eg, intra-articular administration (especially in the treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal , subcutaneous, sublingual, rectal and oral. Preferably, the compounds of the formula (I) of the present invention are administered orally. The specific dose of inhibitor to be administered, the duration of treatment and treatment whether topical or systemic are independent. The dosage and treatment regimen will also depend on factors such as the specific compound of the formula (I) that is used, the indication of the treatment, the ability of the compound of the formula (I) to reach minimal inhibitory concentrations at the metalloprotease site. which will be inhibited, the subject's personal attributes (such as weight), cooperation with the treatment regimen and the presence and severity of any side effects of the treatment. Almost always, for a human adult (weighing about 70 kilograms), about 5 mg to about 3,000 mg, more preferably about 5 mg to about 1,000 mg, more preferably about 10 mg to about 300 mg of the compound of the formula (I) per day for systemic administration. It is understood that these dosing scales are by way of example only and that daily administration can be adjusted depending on the factors mentioned above. A preferred method of administration for the treatment of rheumatoid arthritis is oral or parenteral by intra-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans (assuming an approximate body weight of 70 kilograms), individual doses of about 10 mg to about 1000 mg are preferred. A preferred method of systemic administration is oral. Individual doses of about 10 mg to about 1000 mg, preferably about 10 mg to about 300 mg, are preferred. It is possible to resort to topical administration to deliver the compound of the formula (I) systemically or to treat a subject locally. The amounts of the compound of the formula (I) that will be administered topically depend on factors such as skin sensitivity, type and location of the tissue to be treated; the composition and the vehicle (if any) to be administered; the compound of the specific formula (I) to be administered, as well as the particular disorder to be treated and the degree to which the systemic effects are desired (different from the local ones).

The inhibitors of the invention can be directed to specific sites where the metalloprotease is accumulated by selection ligands. For example, to target the inhibitors to the metalloprotease contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof that is immunoreactive with a tumor marker, as is commonly understood in the preparation of immunotoxins in general. The selection ligand may also be a suitable ligand for a receptor that is in the tumor. Any selection ligand that specifically reacts with a marker for the target tissue can be used. The methods for coupling the compound of the invention to the selection ligand are already known and are similar to those described below for coupling to the vehicle. The conjugates are formulated and administered as described above. For localized conditions, topical administration is preferred. For example, to treat ulcerated cornea, direct application to the affected eye can use a formulation such as eye drops or spray. For the treatment of the cornea, the compounds of the invention can also be formulated as gels, drops or ointments, or they can be incorporated into collagen or a hydrophilic polymer shell. The materials can also be inserted as a contact lens or reservoir, or as a subconjunctive formulation. For the treatment of inflammations of the skin, the compound is applied locally and topically, in gel, paste, ointment or ointment. Therefore, the mode of treatment reflects the nature of the condition, and suitable formulations for any selected route are available in the art. Of course, in all of the foregoing, the compounds of the invention may be administered alone or as mixtures, and the compositions may additionally include additional drugs or excipients, as appropriate for the indication. Some of the compounds of the invention also inhibit bacterial metalloproteases, although generally at a level lower than that shown by mammalian metalloproteases. Some bacterial metalloproteases appear to be less dependent on the stereochemistry of the inhibitor, while substantial differences are found between the diastereomers in their ability to inactivate mammalian proteases. In this way, this pattern of activity can be used to distinguish between mammalian and bacterial enzymes.

Preparation and use of antibodies The compounds of the invention can also be used in immunization protocols to obtain immunospecific antisera for the compounds of the invention. Since the compounds of the invention are relatively small, they are conveniently coupled to antigenically neutral vehicles, such as the limpet hemocyanin (KLH) that is commonly used or whey albumin vehicles. For those compounds of the invention having a carboxyl functionality, coupling to the carrier could be performed by methods generally known in the art. For example, the carboxyl residue can be reduced to an aldehyde and coupled to vehicle via reaction with side chain amino groups in protein-based vehicles, optionally followed by reduction of the imino bond formed. The carboxyl residue can also be reacted with side chain amino groups by condensation agents, such as dicyclohexylcarbodiimide or other carbodiimide dehydration agents. The linker compounds can also be used to effect the coupling; Pierce Chemical Company, Rockford, Ill provides the homobifunctional and heterobifunctional linkers. The resulting immunogenic complex can then be injected into suitable mammals, such as mice, rabbits and the like. Suitable protocols include the repeated injection of the immunogen in the presence of adjuvants according to a program that promotes the production of antibodies in the serum. Immune serum concentrations can be easily measured using immunoassay methods, now common in the art, using the compounds of the invention as antigens. The obtained antisera can be used directly or monoclonal antibodies can be obtained by culturing lymphocytes from the peripheral blood or spleen of the immunized animal and immortalizing the antibody producing cells, followed by identification of the appropriate antibody producers by normal immunoassay techniques.

Then, polyclonal or monoclonal preparations are useful for monitoring therapy regimens or prophylaxis relative to the compounds of the invention. Suitable samples, such as those derived from blood, serum, urine or saliva can be tested to verify the presence of the inhibitor administered on several occasions during the treatment protocol by normal immunoassay techniques employing the antibody preparations of the invention. The compounds of the invention can also be coupled to labels such as scintigraphic labels, e.g., technetium 99 or 1-131, through normal coupling methods. The labeled compounds are administered to subjects to determine sites of excessive amounts of one or more metalloproteases in vivo. The ability of the inhibitors to selectively bind to metalloproteases to capture the distribution of these enzymes in situ is then exploited. The techniques can also be employed in histological procedures and the labeled compounds of the invention can be used in competitive immunoassays. The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.

EXAMPLES The compounds are analyzed using 1 H and 13 C NMR, elemental analysis, mass spectrum and / or IR spectrum, as appropriate.

Inert solvents are almost always used, preferably in dry form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and the rest of the solvents are purchased to the appropriate degree. Chromatography is performed on silica gel (70-230 mesh, Aldrich) or (230-400 mesh, Merck) as appropriate. Thin-layer chromatography (TLC) analysis is performed on glass-mounted silica gel plates (200-200 mesh; Baker) and visualized with UV or 5% phosphomolybdic acid in EtOH.

EXAMPLE 1 Preparation of N-hydroxy-2-r (4-methoxyphenylsulfonyl) aminol-3,3-dimethyl-3-methylthio-propanamide S-methyl-D-penicillamine: A suspension of D-penicillamine (10.0 g, 67.01 mmol) in 0.4N solution of barium hydroxide octrahydrate (330 ml, 67.01 mmol) is cooled in an ice water bath. Dimethyl sulfate (6.6 ml, 70.36 mmol, 1.05 equivalent) is added dropwise over a period of 30 minutes. The suspension is stirred for 18 hours at room temperature. A solution of 1 N sulfuric acid is added to the solution (pH ~ 2) to precipitate the barium sulfate. The supernatant is decanted and the precipitate is washed several times in water. The pH of the supernatant is adjusted to 6 with concentrated ammonium hydroxide and the water is evaporated to yield a pure white solid (10.9 g, 100% yield). 2 - [(4-Methoxyphenyl-sulphonyl) amino-1,3-dimethyl-3-methylthio-propionic acid: The penicillamine adduct (10.9 g, 67.01 mmol) is dissolved in dioxane (100 ml) and water (100 ml) and The resulting mixture is then stirred at room temperature. Triethylamine (50 ml, 670 mmol) is added to the reaction mixture followed by 4-methoxyphenylsulfonyl chloride (16.62 g, 80.41 mmol). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified to pH ~ 2 with 1 N HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts are dried (MgSO) and concentrated to an oil under reduced pressure. Purification is carried out on a column of silica gel eluting with 15% methanol and 85% chloroform to produce a solid (73%).

N-hydroxy-2 - [(4-methoxy-phenylsulfonyl) amino] -3,3-d-methyl-3-methylthio-propanamide: The carboxylic acid (7.9 g, 23.7 mmol) in dichloromethane ( 100 ml) is stirred at room temperature and then oxalyl chloride (6.17 g, 48.6 mmol, 2.05 equivalent) and DMF (1.73 g, 23.7 mmol) are added. The resulting solution is stirred at room temperature for 15 minutes. In a separate flask, the hydroxylamine hydrochloride (6.5 g, 94.8 mmol, 4 equivalent) in THF (35 ml) and water (10 ml) is stirred at 0 ° C. Triethylamine (14.3 g, 142.2 mmol, 6 equivalent) is added and the resulting solution is stirred at 0 ° C for 10 minutes. The acid chloride solution is added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is acidified with 1 N HCl and then extracted with dichloromethane. The organic extracts are dried (Na2SO) and concentrated to a solid under reduced pressure. The solid is recrystallized from chloroform to produce a white powder (65%). MS (ESI): 349 (M + N +).

EXAMPLE 2 The following compounds are prepared in a manner similar to Example 1: N-hydroxy-2 - [(4-bromophenylsulfonyl) amino] -3,3-dimethyl-3-methylthio-propanamide MS (ESI): 397.399 (M + N +). N-hydroxy-2 - [(4-butoxyphenylsulfonyl) amino] -3,3-dimethyl-3-methylthio-propanamide MS (ESI): 391 (M + N +).

EXAMPLE 3 Preparation of N-hydroxy-S, S-dioxo-2-r (4-methoxyphenylsulfonyl) amino-1,3-dimethyl-3-methylthio-propanamide N-hydroxy-S, S-dioxo-2-f (4-methoxy-phenylsulfonyl) amino] -3,3-dimethyl-3-methylthio-propanamide: Hydroxamic acid sulfide (4.0 g, 11.5 mmol) it is dissolved in chloroform (50 ml). The suspension is cooled to 0 ° C and then the peracetic acid (32% solution of Aldrich) is added (7.24 ml, 34.4 mmol, 3.0 equivalent). The solution becomes transparent when peracetic acid is added. Then, the reaction mixture is heated to room temperature and the solution becomes a suspension again (cloudy). After several hours, the reaction is verified by HPLC to monitor the completion. Upon completion, the peracetic acid is removed by evaporation under reduced pressure and the resulting solid is purified by recrystallization with chloroform. MS (ESI): 381 (M + N +).

EXAMPLE 4 Preparation of N-hydroxy-2-r (4-methoxybenzenesulfonyl) amino-1,3-dimethyl-3- (p-methoxybenzene) -propanamide S- (4-methoxybenzyl) -D-penicitylamine: The Nt-butoxycarbonyl-S- (4-methoxybenzyl) -D-penicillamine (5.0 g, 13.5 mmol) is dissolved in 40 ml of methylene chloride and cooled to 0 ° C in an ice bath. The trifluoroacetic acid (18.5 g, 162 mmol) is then added, and the resulting mixture is stirred at 0 ° C for 1 hour. The reaction mixture is warmed to room temperature and stirred until the starting material disappears by TLC and mass spectrum (3 h.). The trifluoroacetic acid and methylene chloride are evaporated under reduced pressure to give the desired product.

N - [(4-methoxyphenyl) sulfonyl) -S- (4-methoxybenzyl) -D-penicillamine: Then, the penicillamine adduct (3.65 g, 13.5 mmol) is dissolved in dioxane (50 ml) and water (50 ml). ml) and stirred at room temperature. Triethylamine (9.42 ml, 67.7 mmol) is added to the reaction mixture followed by 4-methoxyphenylsulfonyl chloride (3.37 g, 16.32 mmol). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified to pH ~ 2 with 1 N HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts are dried (MgSO 4) and concentrated to an oil under reduced pressure. Purification is carried out on a column of silica gel eluting with 15% methanol and 85% chloroform to produce a solid (73%).

N-hydroxy-2 - [(4-methoxy-benzenesulfonyl) amino] -3,3-dimethyl-3- (p-methoxybenzene) -propanamide: The carboxylic acid (2.5 g, 5.6 mmol) in dichloromethane (30 ml) is stirred at room temperature and then oxalyl chloride (1.0 ml, 11.48 mmol, 2.05 equivalent) and DMF (0.4 ml, 5.6 mmol) are added. The resulting solution is stirred at room temperature for 15 minutes. In a separate flask, hydroxylamine hydrochloride (1.55 g, 22.4 mmol, 4 equivalent) in THF (15 ml) and water (5 ml) are stirred at 0 ° C. The triethylamine (3.39 g, 33.6 mmol, 6 equivalent) is added and the resulting solution is stirred at 0 ° C for 10 minutes. Next, the acid chloride solution is added to a solution of hydroxylamine at 0 ° C and the resulting mixture is allowed to stir overnight (although it is usually ready in 1-2 hours) at room temperature. Then, the reaction mixture is acidified with 1 N HCl and then extracted with dichloromethane. The organic extracts are dried (Na2SO) and concentrated to a solid under reduced pressure. The solid is purified on reverse phase HPLC. MS (ESI): 455 (M + H +).

EXAMPLE 5 Preparation of N-hydroxy-a-f (4-methoxyphenyl) sulforylaminol-tetrahydro-4-methylthio-cyclohexane-4-acetamide í | i ° 1 M.SNa. MeOH A ° / NH2 1 ArtSC-CI. Et Q 02S x Cyf Ethyl N-formyl-α-cyclohexylidene glycinate: A suspension of sodium hydride (4.07 g, 60%, 101 mmol) in THF (100) is cooled to 0 ° C. Two addition flasks are charged with ethyl isocyanoacetate (10.0 g, 88.4 mmol) in THF (10 mL) and cyclohexanone (9.67 g, 88.4 mmol) in THF (10 mL). The solutions are added dropwise to a reaction mixture over a period of 30 minutes. The resulting mixture is then allowed to warm to room temperature and stir overnight. The reaction mixture is quenched by the addition of a saturated solution of ammonium chloride. The layers are separated, and the aqueous layer is washed with ethyl acetate (3 x 100 ml). The combined organic extracts are washed with brine (200 ml), dried (MgSO4) and then concentrated to an oil under reduced pressure. Ethyl acetate (40 ml) is added to the mixture followed by hexane until the mixture becomes turbid. The resulting solution is cooled to 0 ° C and the desired product is crystallized from the solution.

Ethyl N-formyl-a-amino-1-methylthio-cyclohexane-acetate: Cyclohexylidene (1 g, 4.74 mmol) in methanol (25 ml) is stirred at room temperature and then sodium thiomethoxide (0.66 g, 9.5 mmol, 2 equivalent). The resulting mixture is stirred at room temperature overnight. The reaction is quenched by the addition of a saturated solution of sodium bicarbonate. The resulting mixture is extracted with methylene chloride (3 x 100 ml). The organic extracts are dried (MgSO) and then concentrated to an oil under reduced pressure. The product is purified by chromatography on silica gel (7/3 EtOAC / hexane as eluent) to obtain the desired product as a clear and colorless oil.

A-amino-1-methytho-cyclohexaneacetic acid: Formate ester (0.6 g, 2.44 mmol) is stirred in 4 N HCl (50 ml) and heated at reflux overnight. The reaction mixture is subsequently cooled to room temperature and then the solvent is removed under reduced pressure to leave the desired product as a white solid. Α- (Methoxyphenyl) sulfonylamino] -tetrahydro-1-methylthio-cyclohexaneacetic acid: The amino acid (0.59 g, 2.44 mmol) in dioxane (20 ml) and water (20 ml) are stirred at room temperature and subsequently triethylamine is added. by 4-methoxyphenylsulfonyl chloride (0.53 g, 2.56 mmole, 1.05 equivalent). The resulting mixture is stirred at room temperature overnight. The reaction mixture is acidified with 1 N HCl and subsequently extracted with methylene chloride. The organic extracts are dried (MgSO4) and then concentrated to an oil under reduced pressure. The oil is purified by chromatography on silica gel using 1/1 hexane / EtOAc as the eluent. The product is obtained as a colorless oil.

N-hydroxy-4- (4-methoxy-phenyl) sulfonylamino] -tetrahydro-4-methylthio-cyclohexane-4-acetamide: The carboxylic acid (0.47 g, 1.26 mmol) is stirred at room temperature. dichloromethane (10 ml) and then oxalyl chloride (0.33 g, 2.58 equivalent) and DMF (92 mg, 1.26 mmol) are added. The resulting solution is stirred at room temperature for 15 minutes. In a separate flask, hydroxylamine hydrochloride (0.35 g, 5.04 mmol, 4 equivalent) in THF (15 ml) and water (5 ml) are stirred at 0 ° C. Triethylamine (0.76 g, 7.56 mmol, 6 equivalent) is added and the resulting solution is stirred at 0 ° C for 10 minutes. The acid chloride solution is subsequently added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is subsequently acidified with 1 N HCl and subsequently extracted with dichloromethane. The organic extracts are dried (Na 2 SO) and concentrated to a solid under reduced pressure. The product is recrystallized from chloroform. MS (ESI): 389 (M + H +).

EXAMPLE 6 The following compounds are prepared in a manner similar to Example 5: N-hydroxy-a - [(4-methoxyphenyl) sulfonylamino] -tetrahydro-4-methylthio-2H-pyran-4-acetamide MS (ESI): 391 (M + H + ). N-hydroxy-a - [(4-methoxyphenyl) sulfonylamino] -tetrahydro-4-methylthio-2H-thiopyran-4-acetamide MS (ESI): 407 (M + H +). N-hydroxy-a - [(4-methoxyphenyl) sulfonylamino] -tetrahydro-4-methylthio-1-methyl-piperidine-4-acetamide MS (ESI): 404 (M + H +). N-hydroxy-a - [(4-bromophenyl) sulfonylamino] -tetrahydro-4-methylthio-cyclohexane-4-acetamide MS (ESI): 437.439 (M + H +). N -hydroxy- [(4-butoxyphenyl) sulfonylamino] -tetrahydro-4-methyl-cyclohexane-4-acetamide MS (ESI): 431 (M + H +).

EXAMPLE 7 Preparation of N-Hydroxy-S-dioxo-a-r (4-methoxyphenyl) sulfonylamino-1-tetrahydro-4-methylthio-cyclohexane-4-acetamide S.S-Dioxo - - [(4-methoxyphenyl) sulfonylamino] -tetrahydro-4-methylthio-cyclohexaneacetic acid: Dissolve hydroxamic acid sulfide (0.5 g, 1.34 mmol) in chloroform (50 ml). The suspension is cooled to 0 ° C and then peracetic acid (32% of Aldrich's solution) is added (1.3 ml, 5.04 mmol, 4.0 equivalent). The solution becomes clear upon the addition of the paracetylic acid. The reaction mixture is subsequently heated to room temperature and the solution becomes a suspension again (turbid). After a few hours the reaction is verified by HPLC to monitor its completion. Upon completion, the peracetic acid is removed by vaporation under reduced pressure to leave the desired product as a white solid.

NHdroxy-S, Sd-Oxo-a - [(4-methoxy-phenyl) sulfonyl-lane] -tetrahydro-4-methylthio-cyclohexane-4-acetamide: The carboxylic acid is stirred at room temperature. (0.5 g, 1.24 mmol) in dichloromethane (10 ml) and then oxalyl chloride (0.32 g, 2.53 mmol, 2.05 equivalent) and DMF (90 mg) are added., 1.24 mmoles). The resulting solution is stirred at room temperature for 15 minutes. In a separate flask, hydroxylamine hydrochloride (0.35 g, 4.96 mmol, 4 equivalent) is stirred at 0 ° C, THF (15 ml) and water (5 ml). Triethylamine (0.75 g, 7.44 mmol, 6 equivalent) is added and the resulting solution is stirred at 0 ° C for 10 minutes. The acid chloride solution is subsequently added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is subsequently acidified with 1 N HCl and subsequently extracted with dichloromethane. The organic extracts are dried (Na2SO) and concentrated to a solid under reduced pressure. The product recrystallizes from chloroform. MS (ESI): 421 (M + H +).

EXAMPLE 8 The following compounds are prepared in a manner similar to Example 7: N-hydroxy-S.S-dioxo-a-^ -methoxyphenylJsulfonylamino-tetrahydro-methyl-2-pyran-4-acetamide MS (ESI): 423 (M + H +). N-hydroxy-S, S, S, S-tretraoxo-a - [(4-methoxyphenyl) sulfonylamino] -tetrahydro-4-methylthio-2H-thiopyran-4-acetamide MS (ESI): 455 (M + H +). N-hydroxy-S, S-dioxo-a - [(4-methoxyphenyl) sulfonylamino] -tetrahydro-4-methylthio-1-methyl-piperidine-4-acetamide MS (ESI): 436 (M + H +).

N-hydroxy-S, S-dioxo-a - [(4-bromophenyl) sulfonylamino] -tetrahydro-4-methylthio-cyclohexane-4-acetamide MS (ESI): 469, 471 (M + H +). N-hydroxy-S, S-dioxo-a - [(4-butoxyphenyl) sulfonylamino] -tetrahydro-4-methylthio-cyclohexane-4-acetamide MS (ESI): 463 (M + H +).

EXAMPLE 9 Preparation of propyl ester of N-hydroxy acid 2R-f (4-methoxypheniOsulfonylaminolsuccinnamic acid D-aspartic acid? -alkyl ester hydrochloride: D-aspartic acid (4g) is suspended in allyl alcohol (100 ml) and trimethylsilyl chloride (9.5 ml) is added dropwise and the reaction mixture is stirred at room temperature for 20 hours. Ether (600 ml) is added and the white precipitate is collected by filtration, washed with ether and dried to give D-aspartic acid α-alkyl ester hydrochloride.

Nf (4-methoxyphenyl) -sulfonyl-D-aspartic acid ester: Dissolve D-aspartic acid α-alkyl ester hydrochloride (1.6 g) is dissolved in dioxane-water (1: 1 v / v, 40 ml) and the solution is cooled to 0 ° C. Triethylamine (2.8 ml) is added followed by p-methoxysulfonyl chloride (1.65 g) and the reaction mixture is stirred at 0 ° C for 15 minutes and then at room temperature for 4 hours The reaction mixture is concentrated and the residue is partitioned between 1N hydrochloric acid and ethyl acetate.The aqueous phase is washed with ethyl acetate.The combined organic phases are washed with aqueous sodium bicarbonate, with brine, Dry (Na2SO4) and concentrate under reduced pressure to give N - [(4-methoxyphenyl) sulfonyl-D-aspartic acid? -alicylate as a white solid.

N-Benzyloxy 2R - [(4-methoxyphenyl) sulfonylaminolsuccinnamic acid allyl ester: N - [(4-methoxyphenyl) sulfonyl-D-aspartic acid ester (3.43 g) is dissolved in N, N-dimethylformamide ( 20 ml) and the solution is cooled to 0 ° C. Sequentially, 1-hydroxybenzotriazole (4.6 g), N-methylmorpholine (3.3 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.3 g) were added followed, after 20 minutes, by O-benzylhydroxylamine hydrochloride (1.6 g). The reaction mixture is stirred at room temperature for 20 hours and water is added slowly. The precipitate is collected and washed with water and dried under vacuum. The crude product is purified by crystallization from aqueous methanol to give N-benzyloxy 2R - [(4-methoxyphenyl) sulfonylamino] succinnamic acid allyl ester as a white solid.

Propyl ester of N-hydroxy2R [(4-methoxyphenyl) sulfonylaminolsuccinnamic acid: The allyl ester of N-Hydroxy 2R [(4-methoxyphenyl) sulfonylamino] succinamic acid (150 mg) is dissolved in methanol (10 ml) and palladium is added a carbon catalyst (20 mg). The reaction mixture is stirred under atmospheric hydrogen pressure for 1.5 hours. The catalyst is removed by filtration through celite, the solvents are removed under reduced pressure and the crude product is purified by crystallization from ethyl acetate to give N-hydroxy 2R - [(4-methoxyphenyl) sulfonylamino] succinnamic acid propyl ester. . MS (ESI): 361 (M + H +), 378 (M + NH 4 +).

EXAMPLE 10 Preparation of 2-r (4-methoxyphenyl) sulfonylamino-isobutyric acid hydroxamic acid Methyl ester of 2 - [(4-methoxyphenylDsuyphonylamino-isobutyric acid: 2-Amino-isobutyric acid (15 g, 0.15 mol) was taken in 500 ml and treated with SOCI2 (37 ml, 50 mmol), and stirred for 18 hours, then the mixture was evaporated to dry to give 74 g (81%) of a white solid The above solid (5.0 g, 43 m moles) was dissolved in water: dioxane (1: 1, 40 ml) with triethylamine (15 ml, 107 moles). 4-Methoxyphenylsulfonyl chloride (9.7 g, 0.47 moles) was added and the mixture was stirred 14 hours at room temperature. The mixture was then partitioned between EtOAc and 1N HCl. Layers were separated and the organic layer was washed 1x with 1 N HCl, 1x with brine, dried over MgSO, filtered and evaporated to give 8 g of a yellow oil. The mixture was then subjected to chromatrography on flash silica with hexane: EtOAc (8: 2) to give 2.8 g (23%) of white powder. MS (Cl) 288 (M ++ H, 100%), 305 (62), 228 (71), 171 (26), 118 (15). 2 - [(4-Methoxyphenyl-sulfonyl-1-isobutyric hydroxamic acid: The starting ester (500 mg, 1.74 mmol) was taken in dioxane: water (1: 1.5 ml) and treated with LiOH (146 mg, 3.5 mmol) ) and stirred 18 hours at room temperature The mixture was subsequently partitioned between 1N HCl and EtOAc, then the organic layer was washed with brine, dried over MgOC, filtered and concentrated to give a white solid. in 18 ml of CH 2 Cl 2 at room temperature and treated with (COCI) 2 and catalytic DMF and stirred for 1 h In a separate flask, hydroxylamine HCl (512 mg, 7.32 mmol) was stirred in water: THF (3: 8, 11 ml), cooled to 0 ° C, and treated with triethylamine The acid chloride solution was added to the hydroxylamine solution at 0 ° C, allowed to rise to room temperature and stirred for 15 minutes. The mixture was partitioned between 1 N HCl and CH2Cl2, the organic layer was then dried over MgSO4. filtered and evaporated to give a crude material which was subjected to flash chromatography on silica with EtOAc to give 154 mg of desired hydroxamic acid. MS (ESI) 274 (M ++ H, 58), 291 (100).

EXAMPLE 11 Preparation of 2-f (N) - (4-methoxyphenyl) sulfonyl- (N) -alylamino-1-isobutyric acid hydroxamic acid Methyl ester of 2-r (N) - (4-methoxyphenyl) sulfonyl- (N) -alilaminol-isobutyric acid: The starting sulfonamide (600 mg, 2.09 mmol) was taken in 10 ml of dry THF at room temperature and it was treated with tert-butoxide (2.3 ml, 1 M in THF, 2.3 mmol) and stirred for 1 hour which resulted in the formation of a coarse precipitate. Allyl bromide (271 ml, 3.2 mmol) was added and the mixture was heated at 50 ° C for 3 hours which resulted in the formation of a larger and a smaller product. The mixture was partitioned between 1 N HCl and ether. The organic layer was dried over MgSO, filtered and evaporated. The residue was subjected to flash silica chromatography with hexane: EtOAc (3: 1 to 1: 1) to give 413 mg of the desired alkylated sulfonamide as well as 91 mg of the same product that had been subjected to transesterification to an ester allyl MS (Cl) 288 (M + + H). 2 ((N) - (4-methoxyphenyl) sulfonyl- (N) -alylamine-isobutyryohydroxamic acid: The starting ester (257 mg, 0.782 mmol) was taken in dioxane: water (1: 1, 3 ml) and treated with LiOH (73 mg, 1.7 mmol) and stirred for 18 hours at room temperature. The mixture was subsequently partitioned between 1 N HCl and EtOAc. The organic layer was subsequently washed with brine, dried over MgSO4 filtered and concentrated to give a white solid. The above acid was dissolved in 3 ml of CH2Cl2 at room temperature and treated with (COCI) 2 (140 ml, 1.6 mmol) and catalytic DMF and stirred for 1 hour. In a separate flask, hydroxylamine HCl (512 mg, 7.32 mmol) in water: THF (1: 3, 4 mL) was stirred, cooled to 0 ° C, and treated with 653 mL of triethylamine. The acid chloride solution was added to the hydroxylamine solution at 0 ° C, allowed to warm to room temperature and stirred for 18 hours. The mixture was separated between 1 N HCl and CH 2 Cl 2. The organic layer was subsequently dried over MgSO4, filtered and evaporated to give a crude material which was chromatographed on flash silica with EtOAc to give 26 mg of the desired hydroxamic acid. MS (ESI) 289 (M + + H, 44), 306 (100).

EXAMPLE 12 Preparation of N-Hydroxy-2 - [(4-methoxyphenyl) sulfonylamino] -4-phthalimidobutanamide N-r4-Methoxyphenyl) sulfonyl-1-D-aspartic acid: D-Aspartic acid (2.66 g) is suspended in 2N NaOH (30 ml) and 4-methoxyphenylsulfonyl chloride (4.12 g) is added. The mixture is stirred at 70 ° C for 5 hours (clear solution), cooled to room temperature and extracted with methylene chloride. The aqueous phase after acidification with 12 N HCl is extracted with ethyl acetate. The combined organic phases are with brine, dry (Na2SO4) and concentrated under reduced pressure to give N- [4-methoxyphenyl) sulfonyl] -D-aspartic acid as a white solid.

Nr (4-Methoxyphenyl) sulfonyl-D-aspartic acid a-benzyl ester: N- [4-Methoxyphenyl] sulfonyl] -D-aspartic acid (4.55 g) is dissolved in dry tetrahydrofuran (40 ml) and added trifluoroacetic anhydride (20 ml). The reaction mixture is stirred for 20 hours and the volatiles are removed under reduced pressure. The crude anhydride is dissolved in benzyl alcohol (32 ml) and the mixture is stirred for 20 hours at room temperature. Saturated sodium bicarbonate is added and the mixture is vigorously stirred and subsequently extracted with ethyl ether. The aqueous phase is acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with aqueous sodium bicarbonate, brine, dried (Na 2 SO 4) and concentrated under reduced pressure to give the N- [(4-methoxyphenyl) sulfonyl-D-aspartic acid a-benzyl ester as a white solid. .

Benzyl 2-r (4-methoxy-phenyl) sulfonylamino-1-4-phthalimido-butanoate: N- [(4-Methoxyphenyl) sulfonyl-D-aspartic acid (400 mg) a-benzyl ester is dissolved in dimethoxyethane (2 ml) and allowed to cool to 0 ° C. Sequentially N-methylmorpholine (112 μl) and isobutyl chloroformate (132 μl) are added followed by sodium borohydride (115 mg) and water (25 ml). The product is extracted with ethyl acetate and the combined organic phases are washed with aqueous sodium bicarbonate, brine, dried (Na 2 SO) and concentrated under reduced pressure. The crude alcohol, phthalimide (197 mg) and triphenylphosphine (352.5 mg) are dissolved in dry tetrahydrofuran (11 ml). The solution is cooled to 0 ° C and diethyl azadicarboxylate (212 μl) is added. The cooling bath is removed and the solution is stirred for 18 hours. Ethyl acetate is added and the mixture is washed with brine, dried (Na 2 SO) and concentrated under reduced pressure. The crude product is purified by crystallization to give benzyl 2 - [(4-methoxyphenyl) sulfonylamino] -4-phthalimidobutanoate as a colorless solid. MS (ESI) 509 (M + H) +.

N-Hydroxy-2-r (4-methoxyphenyl) sulfonylamino-4-phthalimido-butanamide: 2 - [(4-Methoxy-phenyl) sulfonylamido] -4-phthalimidobutanoate (199 mg) is dissolved in a mixture of ethyl acetate-methanol (6 ml, 2: 1 v / v) and a palladium (10% Pd / C). The mixture is stirred under the hydrogen atmosphere for 3 hours, filtered through a plug of celite and the volatiles are removed under reduced pressure to give the crude carboxylic acid. Following the procedure described in example 9, it is converted to the corresponding hydroxamic acid to give N-hydroxy-2 - [(4-methoxyphenyl) sulfonylamino] -4-phthalimido-butanamide as a colorless solid. MS (ESI) 434 (M + H) +.

EXAMPLE 13 Preparation of hydroxamic acid from amino acid 1 25% pipecine DMF, 2 DIC DMF c 1"NHFmoc Deprotection with Fmoc of N- (Fmoc) hydroxylamine (1) bound to resin: The 2-chlorotritylpolystyrene resin functionalized with N- (Fmoc) hydroxylamine (1) (5.2 g, 4.0 mmol) was washed several times with dichloromethane (DCM). The resin was suspended in DCM (50 ml) and thereto was added to a 25% piperidine solution in dimethylformamide (DMF) (15 ml). The resin suspension was stirred for 30 minutes and subsequently filtered. The resin was washed with DMF (4 x 75 ml). The resin was again treated with 25% piperidine in DMF in a similar manner to the previous one. After filtration, the resin was washed first with DMF (4x75 ml) subsequently with DCM (2x75 ml) and methanol (MTH) (3x75 ml) alternately. The resin was dried under vacuum for 1 hour. The resin deprotected with Fmoc was suspended in 1: 1 DMF / DCM and was filled by volume to 96 wells of the ACT 496 MOS Robot. This gave approximately 0.042 mmoles of substrate per well. All subsequent procedures were performed identically to each of the 96 wells unless otherwise indicated. ' Amino acid coupling to Q- (Resin) hydroxylamine: 0- (Resin) hydroxylamine (0.042 mmol) was treated with a N- (Fmoc) -protected amino acid solution (6 eq) (Table 1) in DMF (1.5 ml) containing 1,3-diisopropylcarbodiimide (6 eq). The resulting suspension was stirred for 18 hours. The resin was filtered and washed first with DMF (4x3 ml) subsequently with DCM (2x3 ml) and methanol (MTH) (3x3 ml) in an alternating manner.

Deprotection with a-N-Fmoc of resin-bound amino acid hydroxamate (2): 0- (Resin) hydroxylamine-amino acid (a-N-Fmoc) (0.042 mmol) was suspended in a 25% piperidine solution in DMF (1.5 ml). The resin suspension was stirred for 30 minutes and subsequently filtered. The resin was washed with DMF (4x3 ml). The resin was again treated with 25% piperidine in DMF in a similar manner to the previous one. After filtration, the resin was washed first with DMF (4x3 ml) subsequently with DCM (2x3 ml) and MTH (3x3 ml) alternatingly.

Functionalization with -aN- (R) of resin-bound amino acid hydroxamate (3): Formation of sulfonamides 0- (Resin) hydroxylamine-amino acid (3) (0.042 mmol) was treated with the appropriate sulfonyl chloride (Table 1) ) (3 eq) as a solution in 2: 1 1, 2-dichloroethane / diisopropylethylamine (1.5 ml) for 3 hours. The resin was filtered and washed first with DMF (4x3 ml) then with DCM (2x3 ml) and methanol (MTH) (3x3 ml) in an alternating manner.

Formation of caproic acid amides 0- (Resin) hydroxylamine-amino acid (3) (0.042 mmol) was treated with a solution of n-caproic acid (5 eq.), Benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (5 eq.), and triethylamine (10.5 eq.) in DMF (1.5 ml). This suspension was allowed to stir for 18 hours, then filtered. After filtration, the resin was washed first with DMF (4 x 3 ml) then with DCM (2 x 3 ml) and MTH (3 x 3 ml) in an alternating manner.

Formation of nicotinic and benzoic acid amides. 0- (Resin) hydroxylamine-amino acid (3) (0.042 mmol) was treated with a solution of the appropriate acid (5 eq.) And 1,3-diisopropylcarbodiimide in DMF (1.5 ml). The resulting suspension was stirred for 18 hours and subsequently filtered. After filtration, the resin was washed first with DMF (4 x 3 ml) subsequently with DCM (2 x 3 ml) and MTH (3 x 3 ml) alternately.

Urea formation 0- (Resin) hydroxylamine-amino acid (3) (0.042 mmol) was treated with a solution of p-tolyl isocyanate (5 eq.) In 2: 1 DMF / diisopropylethylamine. The resulting suspension was stirred for 18 hours and subsequently filtered. After filtration, the resin was washed first with DMF (4 x 3 ml) subsequently with DCM (2 x 3 ml) and MTH (3 x 3 ml) in an alternating manner.

Rupture of hydroxamic acid (4) of the solid support: The aN-substituted resin bound to amino acid hydroxamate (0.042 mmol) was treated with a solution of 25% trifluoroacetic acid in 1,2-dichloroethane (2 ml) for 20 minutes after from which the resin was filtered and the filtrate was collected in pre-weighed containers. The resin was washed with MTH (3 ml) and the washing was combined with the original filtrate. The containers were evaporated until dry, then the content of the containers was transferred to a deep well microtiter plate using dimethylsulfoxide (1 ml / well). The following compounds are prepared using the method described above: N-hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -acetamide EM (ESI): 261 (M + H +). N-hydroxy-2 - [(4-butoxyphenylsulfonyl) amino] -acetamide EM (ESI): 303 (M + H +). N-hydroxy-2 - [(4-bromophenylsulfonyl) amino] -acetamide EM (ESI): 309 (M + H +). N-hydroxy-2- [octanylamino] -acetamide EM (ESI): 217 (M + H +).

N-hydroxy-2- [nicotinoylamino] -acetamide EM (ESI): 196 (M + H +). N-hydroxy-2- [benzoylamino] -acetamide EM (ESI): 195 (M + H +). N-Hydroxy-2 - [[(4-methylphenylamino) carbonyl] amino] -acetamide EM (ESI): 224 (M + H +). (2R) -N-Hydroxy - [(4-methylphenylsulfonyl) amino] -proponamide EM (ESI): 275 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -propionamide MS (ESI): 317 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -propionamide MS (ESI): 323 (M + H +). (2R) -N-Hydroxy- [octanoylamino] -propionamide MS (ESI): 231 (M + H +). (2R) -N-Hydroxy- [nicotinoylamino] -propionamide MS (ESI): 210 (M + H +). (2R) -N-Hydroxy- [benzoylamino] -propionamide MS (ESI): 209 (M + H +). (2R) -N-Hydroxy - [[(4-methylphenylamino) carbonyl] amino] -propionamide MS (ESI): 238 (M + H +). (2R) -N-Hydroxy - [(4-methoxyphenylsulfonyl) amino] -3-methylbutanamide MS (ESI): 303 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -3-methylbutanamide MS (ESI): 345 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -3-methylbutanamide MS (ESI): 351 (M + H +). (2R) -N-Hydroxy- [octanoylamino] -3-methylbutanamide MS (ESI): 259 (M + H +). (2R) -N-Hydroxy- [nicotinoylamino] -3-methylbutanamide MS (ESI): 238 (M + H +). (2R) -N-Hydroxy- [benzoylamino] -3-methylbutanamide MS (ESI): 237 (M + H +). (2R) -N-Hydroxy - [[(4-methylphenylamino) carbonyl] amino] -3-methylbutanamide MS (ESI): 266 (M + H +). (2R) -N-Hydroxy - [(4-methoxyphenylsulfonyl) amino] -3-phenylpropionamide MS (ESI): 351 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -3-phenylpropionamide MS (ESI): 393 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -3-phenylpropionamide MS (ESI): 399 (M + H +). (2R) -N-Hydroxy- [octanoylamino] -3-phenylpropionamide MS (ESI): 307 (M + H +). (2R) -N-Hydroxy- [nicotinoylamino] -3-phenylpropionamide MS (ESI): 286 (M + H +). (2R) -N-Hydroxy- [benzoylamino] -3-phenylpropionamide MS (ESI): 285 (M + H +). (2R) -N-Hydroxy - [[(4-methyphenylphenylamino) carbonyl] amino] -3-phenylpropionamide MS (ESI): 314 (M + H +). (2R) -N-Hydroxy - [(4-methoxyphenylsulfonyl) amyrio] -3-methylpropionamide MS (ESI): 289 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -3-methylpropionamide MS (ESI): 331 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -3-methylpropionamide MS (ESI): 337 (M + H +). (2R) -N-Hydroxy- [nicotinoylamino] -3-methylpropionamide MS (ESI): 224 (M + H +). (2R) -N-Hydroxy - [(4-methoxyphenylsulfonyl) amino] -4-methylthiobutanamide MS (ESI): 335 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -4-methylthiobutanamide MS (ESI): 377 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -4-methylthiobutanamide MS (ESI): 383 (M + H +). (2R) -N-Hydroxy- [octanoylamino] -4-methylthiobutanamide MS (ESI): 291 (M + H +). (2R) -N-Hydroxy- [nicotynoylamino] -4-methylthiobutanamide MS (ESI): 270 (M + H +). (2R) -N-Hydroxy- [benzoylamino] -4-methylthiobutanamide MS (ESI): 269 (M + H +). (2R) -N-Hydroxy - [[(4-methylphenylamino) carbonyl] amino] -4-methylthiobutanamide MS (ESI): 298 (M + H +). (2R) -N-Hydroxy - [(4-methoxyphenylsulfonyl) amino] -6-aminocapronamide MS (ESI): 332 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -6-aminocapronamide MS (ESI): 374 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -6-aminocapronamide MS (ESI): 380 (M + H +). (2R) -N-Hydroxy- [octanoylamine] -6-aminocapronamide MS (ESI): 288 (M + H +). (2R) -N-Hydroxy- [nicotinoylamino] -6-aminocapronamide MS (ESI): 267 (M + H +). (2R) -N-Hydroxy- [benzoylamino] -6-aminocapronamide MS (ESI): 266 (M + H +). (2R) -N-Hydroxy - [[(4-methylphenylamino) carbonyl] amino] -6-aminocapronamide MS (ESI): 295 (M + H +). N-Hydroxy-2- [nicotinoylamino] -cyclohexanecarbonamide MS (ESI): 264 (M + H +). N-Hydroxy-2 - [(4-bromophenylsulfonyl) amino] -2,3-dihydro-1 H-indene-2-carbonamide MS (ESI): 411 (M + H +). N-Hydroxy-2- [nicotinoylamino] -2,3-dihydro-1 H -ndedan-2-carbonamide MS (ESI): 298 (M + H +). (2R) -N-Hydroxy - [(4-methoxyphenylsulfonyl) amino] -3- (3-pyridine) propionamide MS (ESI): 352 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -3- (3-pyridine) propionamide MS (ESI): 394 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -3- (3-pyridine) propionamide MS (ESI): 400 (M + H +). (2R) -N-Hydroxy- [octanoylamino] -3- (3-pyridine) propionamide MS (ESI): 308 (M + H +). (2R) -N-Hydroxy- [nicotinoylamino] -3- (3-pyridine) propionamide EM (ESI): 287 (M + H +). (2R) -N-Hydroxy- [benzoylamino] -3- (3-pyridine) propionamide MS (ESI): 286 (M + H +). (2R) -N-Hydroxy - [[(4-methylphenylamino) carbonyl] amino] -3- (3-pyridine) propionamide MS (ESI): 315 (M + H +). (2R) -N-Hydroxy - [(4-methoxyphenylsulfonyl) amino] -3-amidopropionamide MS (ESI): 318 (M + H +). (2R) -N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -3-amidopropionamide MS (ESI): 360 (M + H +). (2R) -N-Hydroxy - [(4-bromophenylsulfonyl) amino] -3-amidopropionamide MS (ESI): 366 (M + H +). (2R) -N-Hydroxy- [octanoylamino] -3-amidopropionamide MS (ESI): 274 (M + H +). (2R) -N-Hydroxy- [nicotinoylamino] -3-amidopropionamide MS (ESI): 253 (M + H +). (2R) -N-Hydroxy- [benzoylamino] -3-amidopropionamide MS (ESI): 252 (M + H +). (2R) -N-Hydroxy - [[(4-methylphenylamino) carbonyl] amino] -3-amidopropionamide MS (ESI): 281 (M + H +). (2R, 3S) - N-Hydroxy - [(4-methoxyphenylsulfonyl) amino] -3-hydroxybutanamide MS (ESI): 305 (M + H +). (2R, 3S) - N-Hydroxy - [(4-butoxyphenylsulfonyl) amino] -3-hydroxybutanamide MS (ESI): 347 (M + H +). t (2R, 3S) - N-Hydroxy - [(4-bromophenylsulfonyl) amino] -3-hydroxybutanamide MS (ESI): 353 (M + H +). (2R, 3S) -N-Hydroxy- [octanoylamino] -3-hydroxybutanamide MS (ESI): 261 (M + H +). (2R, 3S) -N-Hydroxy- [nicotinoylamino] -3-h! Droxybutanamida EM (ESI): 240 (M + H +). (2R, 3S) -N-Hydroxy- [benzoylamino] -3-hydroxybutanamide MS (ESI): 239 (M + H +). (2R, 3S) - N-Hydroxy - [[(4-methylphenylamino) carbonyl] amino] -3-hydroxybutanamide MS (ESI): 268 (M EXAMPLE 14 Preparation of substituted 2,3-diaminopropionic hydroxyamic acid Loading of Wang resin with Na- (Fmoc)) - Nß- (Dde) -diaminopropionic acid: The Wang resin (Advanced Chemtech, 0.84 mmol / g, 5.0 g, 4.2 mmol) was suspended in dry dichloromethane (75 ml). To this was added Na- (Fmoc)) - Nß- (Dde) -diaminopropionic acid (3.1 g, 6.3 mmol) followed by triethylamine (0.9 ml, 6.3 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. (1.2 g, 6.3 mmol). The mixture was stirred until all the components were dissolved, at which point hydroxybenzotriazole (0.1 g, 0.63 mmol) was added and the suspension was stirred for 23 hours. The resin was filtered and washed with various portions of dichloromethane and methanol. The resin was dried under vacuum for 16 hours. The production and the new load values were determined by separating a small amount of the derived resin (0.036 g) with 95% TFA / H20. Production 10 mg (95%), MS m / z 491 [M + H] +. The new load value was determined as 0.601 mmoles / g. The previously loaded resin was transferred to a 96-well reaction block of the Advanced Chemtech 496 MOS robot. Functionalized resin (0.050 g, 0.03 mmol) was added to each of the 80 wells. All subsequent procedures were developed in each of the 80 wells.

Deprotection with Fmoc: The resin was suspended in N, N-dimethylformamide (0.5 ml) and a 20% solution of piperidine in DMF (1.5 ml) was added thereto. The reaction was stirred for 20 minutes and subsequently the resin was filtered. This protocol was repeated once again. After the final filtration, the resin was washed with DMF (2x2 ml). The resin was again washed twice with DCE (1x2 ml) and MTH (1x2 ml) in an alternating manner.

Formation of alpha sulfonamide (Ri): The resin was suspended in THF (0.5 ml) and to this was added a 0.5 M solution of the sulfonyl chloride in THF (1.0 ml) (see table 1) followed by a 1.0 M solution of DiPEA in THF (0.5 ml). The reaction was stirred for 20 hours and then filtered. The resin was washed with DCE (2x2 ml) followed by methanol (2x2 ml) and DCE (2x2 ml) in an alternating manner.

Deprotection with Dde: The resin was treated with 2% hydrazine in DMF (1.5 ml). The resin was stirred for 25 minutes and then filtered. Following the final filtration, the resin was washed with DMF (2x2 ml). The resin was subsequently washed twice each with DCE (1x2 ml) and MTH (1x2 ml) in an alternating manner.

Formation of Beta sulfonamide (R?): The resin was suspended in THF (0.5 ml) and a 0.5 M solution of sulfonyl chloride in THF (1.0 ml) was added (see table 1) followed by a 1.0 M solution. of DiPEA in THF (0.5 ml). The reaction was stirred 20 hours and then filtered. The resin was washed with DCE (2x2 ml) followed by methanol (2x2 ml) and DCE (2x2 ml) in an alternating manner.

Hydroxylamine separation: Hydroxylamine hydrochloride (9.2 g) was dissolved in methanol (50 ml) by heating. In a separate flask, potassium hydroxide (10.3 g) was dissolved in hot methanol (25 ml). Both solutions were allowed to cool to almost room temperature before the KOH solution was slowly added to the hydroxylamine solution. The exothermic reaction produced a white precipitate which was removed by filtration. The filtrate was collected and stored in an ice box for 72 hours. After 72 hours, the filtrate was again filtered, placed in an amber container and stored in the refrigerator. The resin was suspended in THF (1.25 ml) and the separation mixture (0.250 ml) was added thereto. The reaction was allowed to stir for 72 hours at which time the resin was filtered and the filtrate was collected. The resin was washed once with methanol (0.5 ml) and this wash was added to the filtrate. A solution of 1N HCl (0.170 ml) was added to the filtrate and all volatiles were removed by evaporation.

EXAMPLE 15 The following compounds are prepared using the method described above: N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 460 (M + H +). N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide MS (ESI): 504 (M + H +). N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(1-naphthalenylsulfonyl) amino] -propanamide MS (ESI): 480 (M + H +). N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 466 (M + H +). N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(2,4,6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 472 (M + H +). N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(4-y-butylphenylsulfonyl) amino] -propanamide MS (ESI): 486 (M + H +). N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 499 (M + H +). N-Hydroxy-2 - [(4-methoxyphenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 464 (M + H +). N-Hydroxy-2 - [(camphorsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 504 (M + H +). N-Hydroxy-2 - [(camphor-sulfonyl) amino] -3 - [(alkanophsulfonyl) amino] -propanamide MS (ESI): 548 (M + H +). N-Hydroxy-2 - [(camphorsulfonyl) amino] -3 - [(1-naphtalenylsulfonyl) amino] -propanamide MS (ESI): 524 (M + H +). N-Hydroxy-2 - [(camphorsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 510 (M + H +). N-Hydroxy-2 - [(camphorsulfonyl) amino] -3 - [(2,4,6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 516 (M + H +). N-Hydroxy-2 - [(camphor-sulfonyl) amino] -3 - [(4-y-butylphenylsulfonyl) amino] -propanamide MS (ESI): 530 (M + H +). N-Hydroxy-2 - [(camphorsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 543 (M + H +). N-Hydroxy-2 - [(camphor-sulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 508 (M + H +). N-Hydroxy-2 - [(1-naphtalenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 480 (M + H +). N-Hydroxy-2 - [(1-naphthalenylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide (MS (ESI): 524 (M + H +). N-Hydroxy-2 - [(1-naphthalenylsulfonyl) ) amino] -3 - [(1-naphthalenylsulfonyl) amino] -propanamide MS (ESI): 500 (M + H +). N-Hydroxy-2 - [(1-naphthalenylsulfonyl) amino] -3 - [(2,4 -difluorophenylsulfonyl) amino] -propanamide MS (ESI): 486 (M + H +). N-Hydroxy-2 - [(1-naphthalenylsulfonyl) amino] -3 - [(2,4,6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 492 (M + H +).

N-Hydroxy-2 - [(1-naphtalenylsulfonyl) amino] -3 - [(4-y-butylphenylsulfonyl) amino] -propanamide MS (ESI): 506 (M + H +). N-Hydroxy-2 - [(1-naphtalenylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 519 (M + H +). N-Hydroxy-2 - [(1-naphtalenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 484 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 466 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide MS (ESI): 510 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(1-naphtalenylsulfonyl) amino] -propanamide MS (ESI): 486 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 472 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(2,4,6-trimertylphenylsulfonyl) amino] -propanamide MS (ESI): 478 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(4-f-butylphenylsulfonyl) amino] -propanamide MS (ESI): 492 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 505 (M + H +). N-Hydroxy-2 - [(2,4-difluorophenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 470 (M + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 472 (M + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide MS (ESI): 516 (M + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3 - [(1-naphtalenylsulfonyl) amino] -propanamide MS (ESI): 492 (m + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide EM (ESI); 478 (m + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3- [2,4,6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 484 (M + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3 - [(4-y-butylphenylsulfonyl) amino] -propanamide MS (ESI): 498 (M + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 511 (M + H +). N-Hydroxy-2 - [(2,4,6-trimethylphenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 476 (M + H +). N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 486 (M + H +). N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide MS (ESI): 530 (M + H +). N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(1-naphthalenylsulfonyl) amino] -propanamide MS (ESI): 506 (M + H +). N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 492 (M + H +).

N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(2,4) 6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 498 (M + H +). N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(4-y-butylphenylsulfonyl) amino] -propanamide MS (ESI): 512 (M + H +). N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 525 (M + H +). N-Hydroxy-2 - [(4-t-butylphenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 490 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 499 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3 - [(camphorsulfonyl) aminoj-propanamide MS (ESI): 543 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3 - [(1-naphthalenylsulfonyl) amino] -propanamide MS (ESI): 519 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amimo] -propanamide MS (ESI): 505 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3 - [(2,4,6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 511 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3 - [(4---butylphenylsulfonyl) amino] -propanamide MS (ESI): 525 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3- [2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 538 (M + H +). N-Hydroxy-2 - [(2,5-dichlorophenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 503 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 464 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide MS (ESI): 508 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(1-naphthalenylsulfonyl) amino] -propanamide MS (ESI): 484 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 470 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(2,4,6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 476 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(4-f-butylphenylsulfonyl) amino] -propanamide MS (ESI): 490 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 503 (M + H +). N-Hydroxy-2 - [(4-chlorophenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propamide EM (ESI): 469 (M + H +). N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) aminoj-propanamide MS (ESI): 444 (M + H +). N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide MS (ESI): 488 (M + H +). N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(1-naphthalenylsulfonyl) amino] -propanamide MS (ESI): 464 (M + H +).

N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 450 (M + H +). N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(2,4,6-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 456 (M + H +). N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(4---butylphenylsulfonyl) aminoj-propanamide MS (ESI): 470 (M + H +). N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 483 (M + H +). N-Hydroxy-2 - [(4-methylphenylsulfonyl) amino] -3 - [(4-chlorophenylsulfonyl) amino] -propanamide MS (ESI): 448 (M + H +). N-Hydroxy-2 - [(n-decylsulfonyl) amino] -3 - [(4-methoxyphenylsulfonyl) amino] -propanamide MS (ESI): 522 (M + H +). N-Hydroxy-2 - [(n-decylsulfonyl) amino] -3 - [(camphorsulfonyl) amino] -propanamide MS (ESI): 566 (M + H +). N-Hydroxy-2 - [(n-decylsulfonyl) amino] -3 - [(1 -naphthalenylsulfonyl) amino] -propanamide MS (ESI): 542 (M + H +). N-Hydroxy-2 - [(n-decylsulfonyl) amino] -3 - [(2,4-difluorophenylsulfonyl) amino] -propanamide MS (ESI): 528 (M + H +). N-Hydroxy-2 - [(n-decylsulfonyl) amino] -3 - [(2,4,6-trimethylphenylsulfonyl) amino] -propanamide MS (ESI): 534 (M + H +). N-Hydroxy-2 - [(n-decylsulfonyl) amino] -3 - [(4-f-butylphenylsulfonyl) amino] -propanamide MS (ESI): 548 (M + H +). N-Hydroxy-2 - [(n-decylsulfonyl) amino] -3 - [(2,5-dichlorophenylsulfonyl) amino] -propanamide MS (ESI): 561 (M + H +).

EXAMPLE 16 The following compounds are prepared using the methodology described herein and that of the patent application of E.U.A. 60 / 024,675, and the methodology thereof is incorporated herein by reference. In the following compounds, A is PORAr, and R is hydroxy. 16 S02C6H4-p-OPh H H CO NH Ph B 16 S02C6H4-p-C6H4-p- H S _ -Pr -CH2CH2CH2CH2- C Br 16 S? 2C6H4-p-C6H4-p- H Me Me CO NMe.

D Br N 16 COC6H4-p-OPh H Me H O CH2 Ph AND 16 POMePh H Me Me - - H G 16 POMe2 Me H H - - H H 161 S02C6H4-p-OMe H H H _ _ 6J S02C6H4-p-OMe H H H 0 X? 16 S02C6H4-p-OMe H H H - _ K v 16 S02C6H4-p-OMe H H H CH2 NHC »w? 0 L 0 16 S02C6H4-p-OPh H H H CH2 NHC 0 M 0 16 S02C6H4-p-OC6H4- H H H S Me 0 p-CI 6P S02C6H4-p-OC6H4- HHH S02 Me pF 16 SO2C6H4-P-OC6H4- H Me Me S Me Q p-Br 16 S02C6H4-p-OMe H -CH2CH2CH2CH I2- S CH2 Ph R 6S S02C6H4-p -OC6H4- HS CH2 CH (CH3) p-CI CH2CH2CH2CH2CH2- 16 S02C5H4-p-OMel HHH CH2 T • ~ yO 6 S02C6H4-p-OMe H H H CH2 - 0 / 2S- V NX METHODS Example prepared by Examples _ prepared in a manner analogous to Example 1. These examples provide the skilled person with sufficient guidance for carrying out the present invention and not limiting it in any way.

EXAMPLES OF USE OF COMPOSITIONS AND METHODS The compounds of the invention are useful for preparing compositions for the treatment of ailments and the like. The following examples of composition and method do not limit the invention, but provide a guide for those skilled in the art to prepare and use the compounds, compositions and methods of the invention. In each case, the compounds of formula I can be substituted by the compound of the example shown below with similar results. The exemplified methods of use do not limit the invention, but provide a guide for those skilled in the art to use the compounds, compositions and methods of the invention. The skilled practitioner will appreciate that the examples provide guidance and can be varied based on the condition and the patient.

EXAMPLE A A tablet composition for oral administration is made according to the present invention, comprising: Component Quantity Example 9 15. mg Lactose 120. mg Corn starch 70. mg Talc 4. mg Magnesium stearate 1. mg Other compounds having a structure according to formula (I) are used with substantially similar results. A female human subject weighing 60 kg and suffering from rheumatoid arthritis is treated with a method of this invention. Specifically, a regimen of three tablets per day for two years is administered orally to said subject. At the end of the treatment period, the patient is examined and found to have reduced inflammation and improved mobility without concomitant pain.

EXAMPLE B A capsule is made for oral administration according to the present invention, which comprises: Component Quantity (% w / w) Example 3 15% Polyethylene glycol 85% Other compounds having a structure according to formula I are used with substantially similar results. A male human subject weighing 90 kg and suffering from osteoarthritis is treated with a method of this invention. Specifically, a capsule containing 70 mg of the compound of Example 3 is administered daily for said subject for five years. At the end of the treatment period, the patient is examined orthoscopically and it is found that there is no additional advance in the erosion / fibrillation of the articular cartilages.

EXAMPLE C A composition is made from saline for local administration according to the present invention, which comprises: Component Quantity (% w / w) Example 13 5% Polyvinyl alcohol 15% Saline 80% Other compounds having a structure according to formula (I) are used with substantially similar results. A patient who has deep corneal abrasion applies the drops to each eye twice a day. Healing is accelerated without visual sequelae.

EXAMPLE D A topical composition for local administration is prepared in accordance with the present invention, which comprises: Component Composition (% w / v) Compound of example 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbitol 5.00 Glycine 0.35 Aromatic ingredients 0.075 Purified water q.s.

Total = 100.00 Total = 100.00 Any of the other compounds having a structure according to formula (I) is used with substantially similar results. A patient who presents chemical burns applies the composition at each change of clothes (b.i.d). The formation of scars is substantially reduced.

EXAMPLE E An aerosol composition for inhalation is manufactured in accordance with the present invention, which comprises: Component Composition (% w / v) Compound of example 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Saccharin sodium 0.2 Propellant (F12, F114) CS Total = 100.0 Any other compound having a structure in accordance with the formula is used (I) with substantially similar results. A patient suffering from asthma sprinkles 0.01 ml by means of a pumping activator in the mouth while inhaling. The symptoms of asthma are reduced.

EXAMPLE F A topical ophthalmic composition is prepared in accordance with the present invention, which comprises: Component Composition (% w / v) Compound of Example 5 0.10 Benzalkonium Chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL M GM 0.50 Sodium Metabisulfite 0.10 Sodium Chloride (0.9%) q.s. Total = 100.0 Any of the other compounds having a structure according to formula (I) is used with substantially similar results. A male human subject weighing 90 kg and suffering from ulcerations in the cornea is treated with a method of this invention.

Specifically, said subject is administered a saline solution containing 10 mg of the compound of Example 5 twice daily in the affected eye for two months.

EXAMPLE G A composition for parenteral administration is made comprising: Component Quantity Example 4 100 mg / ml vehicle Vehicle pH regulator of sodium citrate with (percentage by weight of vehicle): Lecithin 0.48% Carboxymethylcellulose 0.53 Povidone 0.50 Methylparaben 0.11 Propylparaben 0.011 The above ingredients are mixed to form a suspension. Approximately 2.0 ml of the suspension is administered, by injection, to a human subject with a premetastatic tumor. The site of the injection is juxtaposed with that of the tumor. This dose is repeated twice a day, for approximately 30 days. After 30 days the symptoms of the disease are reduced and the dose is gradually decreased to maintain the patient. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE H A composition for mouthwash containing: Component% p / v Example 1 3.00 Alcohol SDA 40 8.00 Flavor 0.08 Emulsifier 0.08 Sodium fluoride 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide 0.20 Dye 0.04 Water balance at 100% A patient with gum disease uses 1 ml of mouthwash three times a day to prevent further oral degeneration. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE I A trocisco composition is prepared: Component% p / v Example 3 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor 11.70 Color 0.10 Corn syrup balance at 100% A patient takes the trocus to prevent loosening of an implant in the maxilla. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE J Composition for chewing gum Component% p / v Example 1 0.03 Sorbitol crystals 38.44 Base for Paloja-T * chewing gum 20.00 Sorbitol (70% aqueous solution) 22.00 Mannitol 10.00 Glycerin 7.56 Flavor 1.00 A patient chews the rubber to prevent loosening of the denture. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE K Components% w / v Water USP 54,656 Methylparaben 0.05 Propylparaben 0.01 Xanthan gum 0.12 Guar gum 0.09 Calcium carbonate 12.38 Antifoam 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 Benzyl alcohol 0.2 Citric acid 0.15 Coolant 0.00888 Flavor 0.0645 Colorant 0.0014 Example 1 is prepared by first mixing 80 kg of glycerin and all of the benzyl alcohol and heating to 65 ° C, then adding slowly and mixing methyl paraben, propyl paraben, water, xanthan gum and guar gum. These ingredients are mixed for approximately 12 minutes in a Silverson in-line mixer. The following ingredients are then added slowly in the following order: the remaining glycerin, sorbitol, antifoam C, calcium carbonate, citric acid and sucrose. Separately combine flavorings and refrigerants and then slowly added to the other ingredients. Mix for approximately 40 minutes. The patient ingests the formulation to prevent the activation of colitis. All references described herein are incorporated herein by reference. Although particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications may be made to the present invention without departing from the spirit and scope thereof. However, attempts are made to cover all the modifications within the scope of this invention in the appended claims.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound having the structure in accordance with formula (I) (I) where A is SO2Ar, COAr, CONHAr, PORAr, where Ar is a monocyclic or bicyclic aromatic portion or a monocyclic or bicyclic heteroaromatic portion, substituted or unsubstituted; Ri is alkyl or hydrogen; R2, R3 and R4 are each independently, chosen from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, alkoxyalkyl, heterocycle, heterocyclic alkyl, and these substituents may be substituted or unsubstituted; rings can be formed by R2 and R3, R1 and R2 or R3 and R4; X is a bond, an alkyl of (C C6) or a heteroatom chosen from O, N, NZ, S, SO or S02; Y is a bond, an alkyl of (C C6), CO, C02, CONH, or a heteroatom chosen from O, N, NZ, S, SO or S02; and Z is hydrogen, COR4, COOR4, CONHR4 > R4, CSR4, CSNHR4 and S02R4. This structure also includes an optical isomer, diastereomer or enantiomer for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester or imide thereof, an isomer, diastereomer or optical enantiomer, for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester or imide thereof.

2. The compound according to claim 1, further characterized in that A is S02Ar, and Ar is phenyl, substituted phenyl or substituted biphenyl and the substitution is with hydroxy, alkoxy, phenoxy, nitro, halo or phenyl.

3. The compound according to claim 1, further characterized in that Ar is substituted in the ortho or para moiety in relation to the binding of Ar to the molecule.

4. The compound according to claim 1, further characterized in that Ri is H, and R2 and R3 can form a ring with the elements 3 to 9 substituted or unsubstituted containing 0 to 4 heteroatoms, chosen from O, N , NZ, S, SO or S02.

5. The compound according to claim 4, further characterized in that the ring can be carbocyclic or heterocyclic in nature.

6. The compound according to claim 4, further characterized in that the ring can include tetrahydropyran, tetrahydrothiopyran, piperidino, or cyclohexyl.

7. The compound according to claim 1, further characterized in that R2 and R3 are CH3, and X is NH or S.

8. The compound according to claim 1, further characterized in that Ri is H, X is S , R2 and R3 are CH3, Y is a bond, and R4 is alkyl.

9. A pharmaceutical composition comprising: a) a safe and effective amount of a compound according to any of the preceding claims; and b) a pharmaceutically acceptable vehicle.

10. The use of a compound according to any of the preceding claims for the manufacture of a medicament for preventing or treating a disease associated with the undesired activity of the metalloprotease in a mammalian subject.