MXPA00010053A - Substituted pyrrolidine hydroxamate metalloprotease inhibitors - Google Patents

Abstract

The invention provides compounds which are potent inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to compounds having a structure according to Formula (I):wherein R1, R2, X, Z, m, and n, are defined below. This invention also includes optical isomers, diastereomers and enantiomers of Formula (I), and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof. The compounds of the present invention are useful for the treatment of diseases and conditions which are characterized by unwanted metalloprotease activity. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for metalloprotease-related maladies using these compounds or the pharmaceutical compositions containing them.

Description

INHIBITORS OF METALOPROTEASE BASED ON PIRROLIDIN HIDROXAMATQ REPLACED TECHNICAL FIELD The invention is directed to compounds that are useful in the treatment of diseases associated with metalloprotease activity, particularly zinc metalloprotease activity.

BACKGROUND OF THE INVENTION The degradation of structural proteins is effected by a number of structurally related metalloproteases. These metalloproteases frequently act on the intercellular matrix, and are thus involved in the degradation and remodeling of tissue. Such proteins are known as 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 (MMPs); zinc metalloproteases; vanes of membrane-bound metalloproteases; enzymes for TNF conversion; enzymes for angiotensin conversion (ACE); disintegrins, including ADAM (See Wolfsberg et al, 131 J. Cell Bio, 275-78, October 1995); and the enkephalinases. The examples of MP they 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 a number of diseases. The potential therapeutic indications of MP inhibitors have been discussed in the literature. See, for example, patent E.U.A. 5,506,242 (Ciba Geigy Corp.); patent 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 (Institute of Ophthalmology); WO 95/23790 (Smithkline 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 University); WO 95/09620 (Florida State University); 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. Inc.); WO 94/10990 (British Bio Tech Ltd); WO 93/09090 (Yamanouchi); and British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd); patent applications European published EP 95/684240 (Hoffman LaRoche); EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); Japanese applications published 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., Biochim, Biophvs. Acta. (1983) 695: 117-214); osteoarthritis (Henderson, B., et al., Druqs of the Future (1990) 15: 495-508); cancer (Rasmussen and McCann, Pharmacol Ther .. vol 75 no.1, pp. 69-75 (1997)); 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), multiple sclerosis ( Gijbels et al, J. • 'Clin. Invest., Vol 94, pp. 2177-2182 (1994)), and various ulcers or ulcerating conditions of tissue, for example, ulcerative conditions may result in the cornea as a result of burns with alkali or as a result of infection caused by Pseudomonas aeruginosa, Acanthamoeba, Herpes simplex and vaccinia viruses Other examples of conditions characterized by unwanted metalloprotease activity include periodontal disease, vesicular epidermolysis, fever, inflammation and scleritis (Cf. DeCicco et al. al, WO 95 29892 published November 9, 1995.) In view of the involvement of such metalloproteases in a number of disease conditions, attempts have been made to prepare inhibitors for these enzymes. write a number such inhibitors. Examples include patent E.U.A. No. 5,183,900, issued on February 2, 1993 to Galardy; patent E.U.A. No. 4,996,359, issued February 26, 1991 to Handa, et al .; patent E.U.A. No. 4,771, 038, issued September 13, 1988 to Wolanin, et al .; patent 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 92/17460, published October 15, 1992 by Markwell et al .; and European Patent Publication Number 498,665, published August 12, 1992 by Beckett, et al. It could be advantageous to inhibit these metalloproteases in the treatment of diseases related to unwanted metalloprotease activity. Although a variety of inhibitors have been prepared, there is a continuing need for potent and useful matrix metalloprotease inhibitors to treat diseases associated with metalloprotease activity.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds that are potent inhibitors of metalloproteases and that are effective to treat conditions characterized by an excess of activity of these enzymes. In particular, the present invention relates to compounds having a compliance structure with the following formula I: in which Ri, R2, X, Z, m, and n are defined later. This invention also includes optical isomers, diastereomers and enantiomers of the above formula, and pharmaceutically acceptable biohydrolyzable salts, amides, esters and imides thereof. The compounds of the present invention are useful for the treatment of diseases and conditions that are characterized by unwanted metalloprotease activity. Accordingly, the invention also provides pharmaceutical compositions containing these compounds. The invention also provides methods of treatment for metalloprotease-related conditions using these compounds or the pharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are inhibitors of mammalian metalloproteases.

Terms and definitions The following is a list of definitions for the terms used in the present invention: "Alkyl" is a saturated or unsaturated hydrocarbon chain having from 1 to 5 carbon atoms, preferably from 1 to 10, more preferred from 1 to 4 carbon atoms. The alkyl chains can be straight or branched. Preferred branched alkyl have one or two branches, preferably a branch. The preferred alkyl is saturated. The unsaturated alkyl has one or more double bonds and / or one or more triple bonds. Preferred unsaturated alkyls have one or two double bonds or a triple bond, the most preferred ones having a double bond. The alkyl chains may be unsubstituted or substituted with 1 to 4 substituents. Preferred substituted alkyls are mono-, di- or trisubstituted alkyls. The alkyl may be substituted with halogen, hydroxy, aryloxy (eg, phenoxy), heteroaryloxy, acyloxy (eg, acetoxy), carboxy, aryl (eg, phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano or any combination thereof. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl and exomethylene. Also, as referred to in the present invention, a "lower" hydrocarbon portion (eg, "lower alkyl") is a hydrocarbon chain containing from 1 to 6, preferably from 1 to 4, atoms (carbon and heteroatoms if they are present).

"Aryl" is an aromatic hydrocarbon ring. The aryl rings are monocyclic or fused bicyclic ring systems. The monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also known as phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably from 9 to 12 carbon atoms in the ring. Bicyclic aryl rings include ring systems in which one ring is aryl and the other ring is aryl, cycloalkyl or heterocycloalkyl. Preferred bicyclic aryl rings comprise 5-, 6- or 7-membered rings fused with 5-, 6-, or 7-membered rings. The aryl rings may be unsubstituted or may be substituted with 1 to 4 substituents on the ring. The aryl may be substituted with halogen, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, heteroaryloxy or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. The most preferred aryl ring radical is phenyl. "Cycloalkyl" is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are not aromatic. The cycloalkyl rings are monocyclic, or are fused, spiro or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms in the ring. The bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms in the ring. The Rings Preferred bicyclic cycloalkyl include 4-, 5-, 6- or 7-block rings fused with 5-, 6-, or 7-link rings. Cycloalkyl rings may be unsubstituted or may be substituted with 1 to 4 substituents on the ring. The cycloalkyl may be substituted with halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl. "Halogen" is fluoro, chloro, bromo or iodo. Preferred halogens are fluoro, chloro and bromo; most preferred are chlorine and fluoro, especially fluoro. "Halogenoalkyl" is a branched or cyclic straight hydrocarbon substituted with uho or more halogen substituents. Preferred halogenoalkyl are C Ci2; more preferred are Ci-Cß; more preferred are still C1-C3. Preferred halogen substituents are fluoro and chloro. The most preferred halogenoalkyl is trifluoromethyl. "Heteroalkyl" is a saturated or unsaturated chain containing carbon and at least one heteroatom, in which two heteroatoms are not adjacent. Heteroalkyl chains contain from 2 to 15 atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferred 2 to 5. For example, the alkoxy radicals (ie, -O-alkyl or -O-heteroalkyl) they are included in heteroalkyl. Heteroalkyl chains can be straight or branched. The preferred branched heteroalkyl has one or two branches, preferably one branching. The heteroalkyl Preferred is saturated. The unsaturated heteroalkyl has one or more double bonds and / or one or more triple bonds. The preferred unsaturated heteroalkyl has one or two double bonds or a triple bond, more preferred a double bond. The heteroalkyl chains may be unsubstituted or substituted with 1 to 4 substituents. The preferred substituted heteroalkyl is a mono-, di- or trisubstituted heteroalkyl. The heteroalkyl can be substituted with lower alkyl, halogen, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioke, cyano or any combination thereof. same. "Heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms. "Heteroaryl" is an aromatic ring that contains carbon and 1 to about 6 heteroatoms in the ring. The heteroaryl rings are monocyclic or are fused bicyclic ring systems. Mopocyclic heteroaryl rings contain from about 5 to about 9 atoms (carbon and heteroatoms), preferably 5 or 6 ring atoms. Bicyclic heteroaplo rings contain from 8 up to 17 atoms in the structure, preferably from 8 to 12 structural atoms in the ring. Bicyclic heteroaryl rings include ring systems in which one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. The preferred bicyclic heteroaryl ring systems they comprise rings of 5-, 6- or 7-links fused with rings of 5-, 6- or 7-links. Heteroaryl rings can be unsubstituted or substituted with 1 to 4 substituents on the ring. The heteroaryl may be substituted by halogen, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, heteroaryloxy or any combination thereof. Preferred heteroaryl rings include thienyl, thiazole, imidazil, purinyl, pyrimidyl, pyridyl and furanyl. "Heterocycloalkyl" is a saturated or unsaturated ring containing carbon and from 1 to 4 (preferably 1 to 3) heteroatoms in the ring, in which two heteroatoms are not adjacent to the ring and no carbon in the ring has a heteroatom that has a hydroxyl radical attached to itself, amino or thiol. The heterocycloalkyl rings are not aromatic. The heterocycloalkyl rings are monocyclic, or are fused, bridged or spiro bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 4 to about 9 structural atoms (carbon and heteroatoms), preferably from 5 to 7 ring structural atoms. Bicyclic heterocycloalkyl rings contain from 7 to 17 structural atoms, preferably 7 to 12 structural atoms in the ring. The bicyclic heterocycloalkyl rings may be fused, spiro or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. The heterocycloalkyl rings may be unsubstituted or substituted to 4 substituents on the ring. The heterocycloalkyl can be substituted by halogen, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amidoalkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents on the heterocycloalkyl include halogen and haloalkyl. "Spirocycle" is a double radical substituent of alkyl or heteroalkyl of alkyl or heteroalkyl in which said double radical substituent is geminally linked and in which said double radical substituent forms a ring, said ring containing from 4 to 8 structural atoms (carbon or heteroatom) preferably 5 or 6 structural atoms. Although the alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups may be substituted with hydroxy, amino and amido as indicated above, the following list is not contemplated by the invention: 1. Enols (OH attached to a carbon carrying a double bond) 2. Amino groups attached to a carbon atom carrying a double bond (except for the vinyl type amides) 3. More than one hydroxy, amino or amido group attached to a single carbon atom (except when two nitrogen atoms are attached to an individual carbon and the three atoms are structural atoms within a heterocycloalkyl ring). 4. Hydroxy, amino or amido attached to a carbon atom that also has a heteroatom attached thereto.

. Hydroxy, amido or amido bonded to a carbon atom that also has a halogen attached to it. A "pharmaceutically acceptable salt" is a cationic salt formed in any of the acid groups (for example a hydroxamic acid), or an anionic salt formed in any of the basic groups (for example amino). Many such salts are known in the art, such as described in World Patent Publication 87/05297, Johnston et al., Published September 11, 1987, incorporated by reference in the present invention. 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 the organic salts. Preferred anionic salts include halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like. In such salts are clearly contemplated addition salts that can provide an optical center where none existed. For example, a chiral salt of tartrate can be prepared from the compounds of the invention, and this definition includes said chiral salts. Said salts are well understood by the person skilled in the art, and he can prepare any number of salts given the knowledge in the field. Furthermore, it is recognized that one skilled in the art may prefer one salt over the other for reasons of solubility, stability, ease of formulation and the like. The determination and optimization of such salts is within the scope of the practice of the person skilled in the art.

A "biohydrolysable amide" is an amide of metalloprotease inhibitor that does not interfere with the inhibitory activity of the compound, or that is easily converted in vivo by an animal, preferably a mammal, more preferred a human subject to give a metalloprotease inhibitor active. A "biohydrolyzable hydroxyimide" is an imide of a metalloprotease inhibitor that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo to an animal, preferably a mammal, more preferred a human subject for give an active metalloprotease inhibitor. A "biohydrolyzable ester" is an ester of a metalloprotease inhibitor that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to an active metalloprotease inhibitor. A "solvate" is a complex formed by a combination of a solute (for example, a metalloprotease inhibitor) and a solvent (for example water). See J. Honig et al., The Van Nostrand Chemist's Dictionarv. 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 known or that can be readily determined by the skilled in the art). "Optical isomer", "stereoisomer", and "diastereomer" such as are referred to in the present invention have the normal meanings recognized in the art (see, Hawlev's Condensed Chemical Dictionarv, 11th Ed.). The illustration of specific protected forms and other derivatives of the compounds of the present invention is not intended to be limiting. The application of other useful protective groups, salt forms, etc., is within the skill of the person skilled in the art. As used in the present invention, "mammalian metalloprotease" refers to the proteases described in the "background of the invention" section of this application. Preferred "mammalian metalloproteases" include any metal containing enzyme (preferably containing zinc) found in animal sources, preferably mammals that can catalyze fe degradation of collagen, gelatin or proteoglycan under appropriate test conditions. Suitable test conditions can be found, for example, in patent E.U.A. No. 4,743,587, which refers to the procedure of Cawtson, et al., Anal. Biochem. (1979) 99: 340-345, the use of synthetic substrate is described by Weipgarten, H., et al., Biochem. Biophv. Res. Comm. (1984) 139: 1184-1187. Of course, any of the standard methods can be used to analyze the degradation of these structural proteins. The most preferred metalloprotease enzymes are zinc-containing proteases which are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit metalloprotease activity can, of course, be evaluated in the tests described previously. Isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or raw extracts containing the range of enzymes that can degrade the tissue can be used.

Compounds The present invention relates to compounds having the following structure: O X-R2 RA Fía Formula (I) In the above structure, Ri is OH, alkoxy or NR3OR3, in which each R3 is independently selected from the group consisting of hydrogen, lower alkyl, and acyl. The preferred R1 is OH and NR3OR3. More preferred R1 is NHOH. In the above structure, X is S02, CO, C02, CONR5, POR5, or a covalent bond, in which R5 is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, or heteroaryloxy. The preferred R5 is hydrogen and lower alkyl. The preferred X is S02 and POR5. The most preferred X is SO2. In the above structure R2 is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy or heteroaryloxy. The preferred R 2 is aryl and heteroaryl. In the above structure, Z is (i) N-W, wherein N is at least 1 and W is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; (I) N-OR4, N-SR4, N-NR4-R4, or N-CR4R4R4, in which N is at least 1 and each R4 is, independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; Q (iii) N- c- Q- R4 in which n is at least 1 and each Q is independently S or O; Q (v) N_Q_p ^, in which n is at least 1; (v) CRβRβ, in which each Re is independently hydrogen, halogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; (vi) a ring, wherein said ring is cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; (vii) , wherein V is cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl. The preferred Z is N-OR4, N-SR4, N-NR4R4, N-CR4R4R4, Q N_C_F ^. where n is P ° r at least 1; CR6R6; and a ring, wherein said ring is cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl. In the above structure, m and n are integers selected independently from 0 to about 4 and m + n is from about 2 to about 7. The preferred m is 1 and the preferred n is 1. The most preferred m + p is 2. The invention also includes pharmaceutically acceptable optical isomers, diastereomers and enantiomers and pharmaceutically acceptable salts, solvates, amides, esters or biohydrolyzable midas thereof.

Preparation of the Compound The Compounds of the invention can be prepared using a variety of methods. The starting materials used in the preparation of the compounds of the invention are known, are prepared by known methods or are commercially available. Particularly preferred syntheses are the following two general reaction schemes: SCHEME 1 R '= OH or OMe' R '? NHOH Q = a derivative group compatible with the N of the imido which can be further manipulated, with the proviso that this finally results in a compound of the invention. In scheme 1, Ri, R2 and X are as defined above. The 4-hydroxyproline (S1a) shown as starting material for scheme 1 can be obtained commercially (for example from Aldrich). In Scheme 1 above, the 4-hydroxyproline (S1a) is coupled with a desired acyl derivative of the choice using any of the methods commonly known to give (S1b). The subsequent oxidation step can be performed using a number of well-known methods by the experts in the field using Jones oxidation and Swern type manipulations to give the S1c type ketones. The conversion of the S1c ketone into compounds of the S1d type is achieved by a variety of well-known methods depending on the specific compound that is desired. For example, when Q = OH, the depot hydroxylamine (O-substituted or unsubstituted) is condensed with the ketone S1c under conditions in acid medium to give the desired oxime derivatives. In the case where Q = N, the hydrazones of the type R "R" N-NH2 are condensed with the ketone S1c to give the hydrazones of the S1d type. The final conversion to S1e can be achieved using many coupling procedures well known to those skilled in the art including treatment of the methyl ester with basic hydroxylamine.

SCHEME 2 V = hydrogen, lower alkyl Y = halogen U = hydrogen, alkyl, heteroalkyl, aryl, heteroaryl. The ketone S1c from scheme 1 above can also be converted into compounds of the type S2e, S2f, S2g, and S2h. Compounds of the S2e type are prepared from the ketone S1c using a Wettig, Peterson olefination method, or other commonly used olefination procedure. Compounds of the type S2f are prepared from the ketone S1c using well known methods such as those described in J. Chem. Soc, Chem. Commun. 1972, 443 and Tetrahedron Lett. 1990, 31, 5571. Compounds of the type S2g and S2h are prepared from the S1c ketopa using well-known condensation methods with malonate-type structures such as those described in Svnthesis. 1978, 385 and Tetrahedron, 1993, 49, 6821. The compounds in which m + n > 2 can be made according to the above reaction scheme wherein S1a, S1b or S1c are substituted with a known compound of appropriate ring size. For example 4-ketopipecolic acid can be prepared as described by J-P. Obrecht et. to the. in Oraanic Svnthesis (1992), p.200. A variety of compounds can be generated in a similar way, using the guides in the previous scheme. It is recognized that it is preferable to use a protecting group for any reactive functional group such as a carboxyl, hydroxyl group and similar, during the formation of the sultamic ester. This is a normal practice, which is within the normal practice of the person skilled in the art. In the above scheme, in which R is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are obtained from the final compounds using a standard dealkylation process (Bhatt, et al., "Cleavage of Ehers." Svnthesis. , pp. 249-281). These steps can be varied to increase the performance of the desired product. The person skilled in the art will recognize that the reasoned choice of reagents, solvents and temperatures is an important component in any successful synthesis. The determination of optimal conditions, etc., is routine. In this way the person skilled in the art can make a variety of compounds using the guide of the above scheme. It is recognized that one skilled in the art in the field of organic chemistry can easily perform normal manipulations of organic compounds without further instructions; that is, it is within the scope and practice of the person skilled in the art to perform such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterifications and saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Orqanic Chemistrv (Wiley), Carey and Sundberg, Advanced Oraanic Chemistry (Vol. 2) and others known to the person skilled in the art.

The skilled artisan will readily appreciate that certain actions are best performed when other potentially reactive functional groups on the molecule are masked or protected, thereby avoiding any of the unwanted side reactions and / or increasing the reaction yield. The expert often uses protective groups to achieve such increased yields or to avoid unwanted reactions. These reactions are found in the literature and are within the scope 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 Svnthesis. Of course, the amino acids used as the starting materials with reactive secondary chains are preferably blocked to avoid unwanted side reactions. The compounds of the invention may have one or more chiral centers. As a result, one optical isomer, including diastereomer and enantiomer, can be selectively prepared on the other, for example by chiral starting materials, catalysts or solvents, or both stereoisomers or both optical isomers, including diastereomers and enantiomers, can be prepared same time (a racemic mixture). Because 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 the use of 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 the other. In this way, when the invention is described and claimed, when a racemic mixture is described, it is clearly contemplated that both optical isomers, including diastereomers and enatomers, or stereoisomers substantially free of the other are described and claimed in the same manner.

Methods of use The metalloproteinases (MP) found in the body function, in part, by degrading the extracellular matrix, which is constituted by extracellular proteins and glycoproteins. Inhibitors of metalloproteases are useful for treating diseases caused, at least in part, by the degradation of such proteins and glycoproteins. These proteins and glycoproteins play an important role in maintaining the shape, size, structure and stability of the tissue in the body. Therefore, MPs are intimately involved in tissue remodeling. As a result of this activity, it has been said that MPs are active in many disorders that involve either: (1) tissue degradation, including degenerative diseases, such as arthritis, multiple sclerosis and the like; and the metastasis or mobility of tissues in the body; or (2) tissue remodeling including fibrotic diseases, scars, benign hyperplasia and the like. The compounds of the present invention treat disorders, diseases and / or undesired conditions that are characterized by high or undesired activity of MP. For example, the compounds can be used to inhibit MPs that: 1. destroy structural proteins (i.e., proteins that maintain tissue stability and structure); 2. interfere in inter / intracellular signaling, including those involved in the regulation of cytokine, and / or cytokine processing and / or inflammation, tissue degradation and other conditions [Mohier 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; 3. facilitate processes that are undesirable in the subject being treated, for example, the processes of sperm maturation, fertilization of the ovule and the like. As used in the present invention, an "MP-related disorder" or "MP-related disease" is one that involves unwanted or elevated MP activity in the biological manifestation of the disease or disorder; in the biological cascade that leads to the disorder; or as a symptom of the disorder. This "involvement" of MP includes: 1. The activity of unwanted or elevated MP as a "cause" of the disorder or biological manifestation, whether the activity is genetically elevated, by infection, by autoimmunity, trauma, causes biomechanics, lifestyle (for example obesity) or for some other reason; 2. MP as part of the observable manifestation of the disease or disorder. That is, the disease or disorder can be measured in terms of increased MP activity. From a clinical point of view, the unwanted or elevated levels of MP indicate the disease, however, it is not necessary that the MPs are the "characteristic mark" of the disease or disorder; or 3. The unwanted or elevated activity of MP is part of the biochemical or cellular cascade that results or that is related to the disease or disorder. In this sense, the inhibition of MP activity interrupts the cascade, and therefore controls the disease. Advantageously, many of the MPs are not evenly distributed throughout the body. Therefore, the distribution of MP expressed in various tissues are frequently specific to these tissues. For example, the distribution of the metalloproteases involved in the degradation of tissues in the joints is not the same as the distribution of metalloproteases found in other tissues. Although not essential for activity or efficacy, certain diseases, disorders, and unwanted conditions are preferably treated with compounds that act on specific MPs found in the affected tissues or affected body regions. For example, a compound that shows a greater degree of affinity and inhibition for an MP found in the joints (for example in chondrocytes) will be preferred over another compound that is Less specific when treating a disease, disorder or unwanted condition involving the joints. In addition, certain inhibitors are more bioavailable to certain tissues than others. By choosing an MP inhibitor that is more bioavailable to a certain tissue and that acts on the specific MPs found in this tissue, specific treatment of the disease, disorder or unwanted condition is provided. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. Therefore, the compounds can be selected to produce mediated effects through the MPs found specifically outside the central nervous system. The termination of the specific character of an inhibitor of a specific MP is within the skill of the person skilled in the art. The appropriate test conditions can be found in the literature. Specifically, tests for stromelysin and collagenase are known. For example, the patent E.U.A. No. 4,743,587 refers to the procedure of Cawston, et al., Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate in a test is described by Weingarten, H., et al., Biochem Biophv Res Comm (1984) 139: 1184-1187. Of course, any standard method can be used to analyze the degradation of structural proteins caused by MP. The ability of the compounds of the invention to inhibit the metalloprotease activity can, of course, be tested in the analyzes found in the literature, or variations of the same. Isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or crude extracts can be used which contain the range of enzymes capable of tissue degradation. The compounds of this invention are also useful for prophylactic or acute treatment. These are administered in any way desired by the person skilled in the art in the fields of medicine or pharmacology. It is quite apparent to the person skilled in the art that the preferred routes of administration will depend on the disease state being treated and the dosage form chosen. Preferred routes for systemic administration include peroral or parenteral administration.

However, one skilled in the art will readily appreciate the advantage of administering the MP inhibitor directly to the affected area for many diseases, disorders or unwanted conditions. For example, it may be advantageous to administer the MP inhibitors directly to the area of the disease, disorder or unwanted condition such as in the area affected by surgical trauma (eg, angioplasty), scars or burns (eg, topically to the skin). ). Because MPs are involved in the remodeling of bone tissue, the compounds of the invention are useful to prevent prosthesis loss. It is known in the art that over time the prostheses become loose, becoming painful, and can result in additional damage to the bone tissue, thus necessitating replacement. The need to replace such prostheses include those such as joint replacements (eg hip, knee and shoulder), 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 for which angioplasty has a higher than expected long-term failure rate (which closes again over time) is that MP activity is not desired or is elevated in response to what could be recognized by the body as "damage" to the basal 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, arrhythmia, angioplasty restenosis and aortic aneurysm can increase the long-term success of any other treatment, or it can be a treatment by itself. In skin care, the MPs are involved in the remodeling or "replacement" of the skin. As a result, MP regulation improves the treatment of skin conditions including, but not limited to, wrinkle repair, regulation and prevention and repair of skin damage induced by ultraviolet radiation. Such treatment includes prophylactic treatment or treatment before the physiological manifestations are evident. For example, PM can be applied as a pre-treatment to exposure to avoid damage by ultraviolet radiation and / or during or after exposure to prevent or minimize post-exposure damage. In addition, MPs are involved in skin disorders and diseases related to abnormal tissues resulting from abnormal turnover, which includes metalloprotease activity, such as vesicular epidermolysis, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of "normal" damage to the skin including the healing or "contraction" of tissue, for example after burns. MP inhibition is also useful in surgical procedures involving the skin to prevent scarring, and the promotion of normal tissue growth including applications such as re-fixation of the extremities and refractory surgery (either by laser or by incision) . In addition, MPs are related to disorders that involve irregular remodeling of other tissues, such as bone tissue, for example, in otosclerosis and / or osteoporosis, or to specific organs, such as liver cirrhosis and fibrotic lung disease. Similarly in diseases such as multiple sclerosis, MPs may be involved in the irregular modeling of the blood-brain barrier and / or the myelin sheaths of nervous tissue. Therefore, the regulation of MP activity can be used as a strategy in the treatment, prevention and control of such diseases. It is also believed that MPs are involved in many infections, including cytomegalovirus; CMV retinitis; HIV, and the resulting AIDS syndrome. MP may also be involved in extravascularization in which the surrounding tissue needs to be degraded to allow new blood vessels such as angiofibroma and hemangioma. Because MPs degrade the extracellular matrix, it is contemplated that inhibitors of these enzymes can be used as agents for birth control, for example to prevent ovulation, to prevent penetration of sperm into and through the extracellular medium of the ovule, the implantation of the fertilized ovum and to prevent sperm maturation. It is also contemplated that these may also be useful to avoid or stop labor and premature delivery. Because MPs are involved in the inflammatory response, and in the processing of cytokines, the compounds are also useful as anti-inflammatory agents, to be used in diseases in which inflammation is a condition including inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung diseases, rheumatoid arthritis, gout and Reiter's syndrome. In situations in which autoimmunity is the cause of the disorder, the immune response often triggers the activity of MP and cytokine. The regulation of MPs in the treatment of such autoimmune disorders is a useful treatment strategy. Therefore, MP inhibitors can be used to treat disorders including lupus erythematosus, ankylosing spondylitis and autoimmune keratitis. Sometimes the side effects of the autoimmune therapy result in an increase of other conditions mediated by the MP, in this situation the therapy with MP inhibitor is also effective, for example in fibrosis induced by autoimmune therapy. In addition, other fibrotic diseases lead to this type of therapy by themselves, including lung disease, bronchitis, emphysema, cystic fibrosis, acute respiratory dysfunction syndrome (especially the acute phase test). In situations in which MPs are involved in unwanted tissue degradation by exogenous agents, they can be treated with MP inhibitors. For example, these are effective as antidotes for rattlesnake bite, as antivesiculating agents, in the treatment of inflammation, allergy, septicemia and shock. In addition, they are also useful as antiparasitics (for example in malaria) and as anti-infective agents. For example, it is believed that these are useful for treating or preventing viral infection, including infection that could result in herpes, "cold" (eg, rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS. It is also believed that MP inhibitors are useful for treating Alzheimer's disease, lateral amyotrophic sclerosis (ASL), muscular dystrophy, complications resulting from or arising from diabetes, especially those that involve loss of tissue viability, coagulation, graft-versus-host disease, 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. Such diseases, conditions or disorders include, arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or suppression of growth and tumor metastasis), ocular disorders (especially corneal ulceration, lack of corneal scarring, degeneration). macular and pterygium), and gum disease (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 matrix metalloproteases and disintegrin metalloproteases. Preferred compounds for, but not limited to, the treatment of cancer (especially the prevention or suppression of growth and tumor metastasis) are those compounds that preferentially inhibit gelatinases or collagenases of type IV. Preferred compounds for, but not limited to, the treatment of eye disorders (especially corneal ulceration, the lack of scarring of the cornea, macular degeneration and ptepgio) are those compounds that widely inhibit metalloproteases. Preferably these compounds are administered topically, more preferably as a drop or gel. Preferred compounds for, but not limited to, the treatment of gum disease (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 invention; and > '(b) a pharmaceutically acceptable vehicle. As discussed above, it is known that numerous diseases are mediated by an excess of unwanted metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammation of the skin, ulcerations, particularly of the cornea, reaction to infection, periodontitis and the like. Therefore, the compounds of the invention are useful in therapy with respect to conditions involving this undesired activity. The compounds of the invention can, therefore, be formulated as pharmaceutical compositions that are used in the treatment or prophylaxis of these conditions. Techniques are used standard pharmaceutical formulation, such as those described in Reminoton's Phramaceutical Sciences. Mack Publishing Company, Easton, PA, latest edition. A "safe and effective amount" of a compound of the formula (I) is an amount that is effective to inhibit the metalloproteases at the site or sites of activity, in an animal, preferably a mammal, more preferred a human subject, 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. The "specific safe and effective amount" will obviously vary with factors such as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of the concurrent therapy (if any), the specific dosage form to be used, the vehicle used, 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 in the present invention, means one or more compatible solid or liquid fillers or encapsulating substances that are suitable for administration to an animal, preferably a mammal, more preferably a human. The term "compatible", as used in the present invention, means that the components of the composition can be mixed with the present compound, and with each other, in such a way that there is no interaction that could substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. The pharmaceutically acceptable carriers should, of course, be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the animal, preferably a mammal, more preferably a human being being treated. 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 lauryl sulfate; coloring agents; flavoring agents; tabletting agents, stabilizers; antioxidants; conservatives; pyrogen-free water; isotonic saline, 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 way in which the compound is to be administered. If the present compound is to be injected, the preferred pharmaceutically acceptable carrier is sterile physiological saline, with up to blood compatible suspending agent, whose pH has been adjusted to approximately 7.4. In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, solution isotonic saline, and pyrogen-free water. Preferred vehicles for parenteral administration include propylene glycol, ethyl oleate, plrrolidone, ethanol and sesame oil. Preferably, the pharmaceutically acceptable carrier, in the compositions for parenteral administration, comprises at least about 90% by weight of the total composition. The compositions of this invention are preferably provided in unit dosage form. As used in the present invention, a "unit dosage form" is a composition of this invention that contains an amount of a compound of formula (I) that is suitable for administration to an animal, preferably a mammal, more preferred a human subject, in an individual dose, in accordance with good medical practice. These compositions preferably contain from about 5 mg (milligrams) to about 1000 mg, more preferred from about 10 mg to about 500 mg, more preferred even from about 10 mg to about 300 mg of a compound of the formula (I). The compositions of this invention can be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers known in the art may be used. These include solid or liquid fillers, dilipients, 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 used together with the compound of formula (I) is sufficient to provide a practical amount of material for administration per unit dose of compound of formula (I). Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference in the present invention: Modem Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosaqe Forms 2a. edition (1976). Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and bulk powders.

These oral forms comprise a safe and effective amount, usually of at least about 5%, and preferably from about 25% to about 50%, of the compound of the formula (I). The tablets can be compacted, crushed tablets, enteric coated, sugar-coated, film-coated or multiple-compacted materials containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and agents of fusion. 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 solvents, preservatives, emulsifying agents, suspending agents, diluents , sweeteners, fusion agents, coloring agents and appropriate flavoring agents. The pharmaceutically acceptable carrier suitable for preparing unit dosage forms for peroral administration is known in the art. The tablets typically comprise conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscaramellose, lubricants such as magnesium stearate, stearic acid and talc. Slippers such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as FD &C dyes can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, mint essence and fruit flavors, are useful adjuvants for chewable tablets. The capsules typically comprise one or more solid diluents described above. The choice of vehicle components depends on secondary considerations such as flavor, cost and shelf stability, which are not important for the purposes of the present invention, and can be easily made by one skilled in the art. The peroral compositions also include liquid solutions, emulsions, suspensions and the like. Suitable pharmaceutically acceptable carriers for preparing 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, sodium carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate.; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include ethylparaben and sodium benzoate. The liquid peroral compositions may also contain one or more components such as sweeteners, flavoring agents and colorants described above. Such compositions can also be coated by conventional methods, typically with time or pH dependent coatings, such that the compound of the present invention is released into the gastrointestinal tract near the desired topical application, or at various times to prolong the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac. The compositions of the present invention in optional form may include other active drugs. Other compositions useful for obtaining the systemic delivery of the compound of the present invention include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more soluble fillers such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Slides, lubricants, sweeteners, colorants, antioxidants and flavoring agents described above may also be included. The compositions of the invention can also be administered topically to a subject, for example, by direct deposition on or disseminating the composition on the epidermal or epithelial tissue of the subject, or transdermally via a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solid These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1%, and preferably from about 1% to about 5%, of the compound of the formula (I). Suitable vehicles for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by transpiration or immersion in water. Generally, the carrier is of an organic nature and may have dispersed or dissolved therein the compound of formula (I). The vehicle may include pharmaceutically acceptable emollients, emulsifiers, thickeners, solvents and the like.

Methods of administration The invention also provides methods for treating or preventing disorders associated with excess or unwanted metalloprotease activity in a human or other animal subject by administering a safe and effective amount of a compound of the formula (I) to said subject. As used in the present invention, "a disorder associated with excess or unwanted metalloprotease activity" is any disorder characterized by degradation of the matrix proteins. The methods of the invention are useful for treating disorders described above. The compositions of this invention may be administered topically or systemically. Systemic application includes any method of introducing the compound of formula (I) into body tissues, for example, by intra-articular administration (especially in the treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral. The compounds of formula (I) of the present invention are preferably administered orally. The specific dose of inhibitor to be administered, as well as the duration of treatment, and whether the treatment is topically or systemically are dependent on each other. The dose and the treatment regimen will also depend on factors such as the specific compound of formula (I) used, the indication of treatment, the ability of the compound of formula (I) to reach minimal inhibitory concentrations at the metalloprotease site. it will inhibit, the subject's personal attributes (such as weight), acceptance of the treatment regimen, and the presence and severity of any side effects of the treatment. Typicallyn. , for an adult human (weighing approximately 70 kilograms), from about 5 mg to about 300 mg, more preferably from about 5 mg to about 1000, more preferably from about 10 mg to about 100 mg of the formula compound will be administered ( I) per day for systemic administration. It is understood that these dosage ranges are by way of example, and that daily administration can be adjusted depending on the factors indicated above. A preferred method of administration for the treatment of Rheumatoid arthritis is orally or parenterally by intra-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (considering an approximate body weight of 70 kilograms) individual doses are preferred from about 10 mg to about 1000 mg. A preferred method of systemic administration is oral administration. The preferred individual doses are from about 10 mg to about 1000 mg, preferably from about 10 mg to about 300 mg. Topical administration can be used to deliver the compound of formula (I) systemically, or to treat a subject locally. The amounts of compound of formula (I) to be administered topically depend on factors such as skin sensitivity, type and location of the tissue to be treated, the composition and vehicle (if any) that the particular compound of formula (I) to be administered is to be administered, as well as the particular disorder to be treated and the degree to which the systemic effects are desired (as distinguished from local effects). The inhibitors of the invention can be directed to specific sites in which metalloprotease is accumulated using steering ligands. For example, to focus the inhibitors towards the metalloproteases contained in a tumor, the inhibitor is conjugated with a antibody or fragment thereof which is immunoreactive with a tumor marker as generally understood in the preparation of immunotoxins in general. The targeting ligand may also be an appropriate ligand for a receptor that is present on the tumor. Any targeting ligand that specifically reacts with a marker for the intended target tissue can be used. The methods for coupling the compound of the invention with the targeting ligand are known and are similar to those described below for coupling the vehicle. The conjugates are formulated and administered as described above. For localized conditions, topical administration is preferred. For example, to treat the ulcerated cornea, direct application to the affected eye may use a formulation such as eye drops or aerosol. 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 contact lenses or as a reservoir or as a subconjunctive formulation. For the treatment of inflammation of the skin, the compound is applied locally and topically, in a gel, paste, balm or ointment. In this way the mode of treatment reflects the nature of the condition, and the appropriate formulations for any selected route are available in the art. In all of the above, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions can be also include additional drugs or excipients as appropriate for the indication. Some of the compounds of the invention also inhibit bacterial metalloproteases. Some bacterial metalloproteases may be less dependent on the stereochemistry of the inhibitor, while substantial differences are found between the diastereomers in their ability to deactivate mammalian proteases. Therefore, this pattern of activity can be used to distinguish between mammalian and bacterial enzymes.

Preparation and use of antibodies The active metalloproteases in a particularly undesired location (for example an organ with certain cell types) can be targeted by conjugating the compounds of the invention to a specific targeting ligand for a marker at that location, such as an antibody or fragment thereof or a receptor ligand. Methods of conjugation are known in the art. The invention is also directed to some other methods that take advantage of the unique properties of these compounds. Therefore, 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 compounds of formula (I) conjugated with a label. Because 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 in vivo or in cell culture in vitro. In addition, the compounds of formula (I) can be conjugated with carriers that allow the use of these compounds in immunization protocols to prepare antibodies specifically immuno reactive with the compounds of the invention. Typical conjugation methods are known in the art. These antibodies are then useful both in therapy and in the inspection of the dose of the inhibitors. The compounds of the invention can also be coupled with labels such as scintigraphic labels, for example, technetium 99 or I-131, using standard coupling methods. The labeled compounds are administered to subjects to determine the locations of excessive amounts of one or more metalloproteases in vivo. The ability of the inhibitors to selectively bind metalloprotease is then considered as an advantage to map the distribution of these enzymes in situ. The techniques can also be used in histological procedures and the labeled compounds of the invention can be used in competitive immunological tests. 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. Typically tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and all other solvents are purchased to the appropriate degree. Chromatography is performed on silica gel (70-230 mesh, Aldrich) or (230-400 Merk mesh) as appropriate. Thin-layer chromatography (TLC) analysis is performed on glass-mounted silica gel plates (200-300 mesh, Baker) and developed with UV or 5% phosphomolybdic acid in EtOH.

EXAMPLES 1-13 The following table shows the structure of the compounds shown in Examples 1-13: phenyl. -O-B corresponds to t in the formula (I) when Z is N-OR4.

EXAMPLE 1 Preparation of / V-hydroxy-1 / V- (4-methoxyphenyl) sulfonyl-4- (Z, E- < V-hydroxyiminoipyrrolidine-2R-carboxamide to. 1? / - (4-methoxyphen? Lsulfonip-4 (R) -hydroxypyrrolidin-2 (R) -methylcarboxylate (1a) cis-hydroxy-D-proline (50 g, 0.38 moles) was dissolved in water: dioxane ( 1: 1, 300 mL) with triethylamine (135 mL, 0.96 mole) 4-methoxyphenylsulfonyl chloride (87 g, 0.42 mole) was added together with 2,6-dimethylaminopyridine (4.6 g, 0.038 mole) and the mixture was stirred for 14 hours at room temperature, then the mixture was concentrated and diluted with EtOAc. The layers were separated and the organic layer was washed twice with 1 N HCl, once with brine, dried with MgSO 4, filtered and the solid material which was dissolved in MeOH (500 mL) was evaporated. Thionyl chloride (50 mL) was added dropwise and the resulting mixture was stirred for 14 hours. The mixture was then evaporated to dryness and triturated with CHCl3 to give 1a which is sufficiently pure to proceed without purification. b. Methyl 1? / - (4-methoxyphenylsulfonyl) -4-oxo-pyrrolidin-2 (f?) Carboxylate (1 b) A 0.76 M batch of Jones reagent was prepared. Alcohol 1a (10.0 g, 31.7 mmol) was dissolved in 175 mL of acetone and cooled to 0 ° C. Jones's reagent (20 mL, 317 mmol) was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were washed three times with water and once with sodium chloride, dried with MgSO and evaporated. Purification of the product by chromatography on silica gel using EtOAc: hexane (1: 1) provides the ketone 1b.

Compound 1b (0.2 g, 0.6 mmol) was mixed with NH2OK (3 mL, 5.1 mmol, 1.7 M in methanol as described in Fieser and Fieser, Vol 1, p 478) and stirred overnight at room temperature . It was acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The layer of Combined EtOAc was dried with MgSO 4 and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC (60A40B, A, 95% H20, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% H20, preparative C18 column waters Symmetry 19 x 5 300 mm) to give example 1.

EXAMPLE 2 Preparation of Hydroxy 1 / V- (4-n-butoxyphenyl) sulfonyl-4- (Z, E-) V-hydroxyimine) pyrroline-2R-carboxamide 0 a. 1? / - (4-n-Butoxyphenylsulfonyl- (4R) -hydroxypyrrolidin- (2RV methyl carboxylate (2a) cis-4-hydroxy-D-proline (14.8 g, 112.95 mmol) was mixed with water: dioxane (1: 1, 90 mL), triethylamine (39.3 mL, 282 mmol) and N-5 dimethylaminopyridine (1.3 g, 11.3 mmol). 4- (n-Butoxy) phenylsulfonyl chloride (29.5 g, 118.6 mmol) was added and the mixture was mixed. The mixture was then concentrated and diluted with EtOAc and 1 N HCl. The layers were separated and the organic layer was washed twice with 1 N HCl, once with brine, dried over MgSO 4, filtered and evaporated to give a solid which was dissolved in MeOH (200 ml) Thionyl chloride (20 ml, 272 mmol) was added dropwise, and the resulting mixture was stirred for 14 hours. The mixture was then evaporated to dryness to give 2a, which is sufficiently pure to be continued using without purification. b. 1? - (4-Butoxyphenylsulfonyl) -4-oxo-pyrrolidin-2 (f?) -methyl carboxylate (2b): An 8N solution of Jones's reagent was prepared (see, for example, Oxidations in Organic Chemistry, P273 ). The alcohol 2a (40 g, 112 mmol) was dissolved in 300 ml of acetone and cooled to 0 ° C. Jones reagent (120 ml, 960 mmol) was added (the color changed from orange-red to green), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were washed three times with water and once with sodium chloride, dried over MgSO4 and evaporated. The product was crystallized from EtOAc to give 2b.

The compound of 2b (0.29 g, 0.8 mmol) was mixed with NH2OK (4 mL, 6.4 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by inverted phase preparative HPLC (60A40B, A, 95% H20, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% H20, 19 x SymmetryPrep C18 column). 300 mm) to give example 2.

EXAMPLE 3 Preparation of / V-hydroxy 1 N- (4-methoxyphenyl) sulfonyl-4- (Z, E-N-methoxyimino) pyrrolidine-2R-carboxamide to. 1N- (4-methoxyphenyl) sulfonyl-4- (Z, E- / V-methoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (3a): To a solution of 1 to (15.0 g, 47.88 mmol) in dioxane (140 ml ), methanol (70 ml) and water (40 ml), methoxylamine hydrochloride (12.2 g, 144 mmol) and sodium acetate (39.2 g, 479 mmol) were added. The mixture was stirred overnight at room temperature, and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give a mixture of the (Z / E) isomers of 3a. b The compound of 3a (16.3 g, 47.8 mmol) was mixed with NH2OK (125 mL, 225 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with CH 2 Cl 2: CH OH (95: 5) to give example 3.

EXAMPLE 4 Preparation of? 1M- (4-ethoxy-phenol) -sulfonyl-4- (Z.E-? > - methoxyimino) pyrrolidine-2R-carboxamide to. 1? / - (4-Ethoxyphenylsulfonyl) -4-oxo-pyrrolidin-2 (f?) -methyl carboxylate (4a): Intermediate 4a was prepared using a method substantially similar to the previous one for the preparation of intermediate 1a, substituting the Starting material. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can use protecting groups to "block secondary reactions, or increase the yields, as appropriate. Such modifications can be easily carried out by the person skilled in the art of organic chemistry, and thus are within the scope of the invention. b. ? / - (4-Ethoxyphenyl) sulfonyl-4- (ZE-V-methoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (4b): To a solution of the ketone 4a (1.2 g, 3.67 mmol) in dioxane (10 g). ml) and methanol (5 ml) and water (5 ml), methoxylamine hydrochloride was added. (0.77 g, 9.16 mmoles) and sodium acetate (2.9 g, 36 mmoles). The mixture was stirred overnight at room temperature, and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined layer of EtOAc was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a mixture of the (Z / E) isomers of 4b.

S-. The compound of 4b (1.2 g, 3.37 mmol) was mixed with NH20K (11.0 mL, 18.7 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with EtOAc / hexane (7: 3) to give example 4.

EXAMPLE 5 Preparation of / V-hydroxy 1? V- (4-propoxyphenyl) sulfonyl-4- (Z, E- / V-methoxy-amino) pyrrolidine-2R-carboxamide to. 1? / - (4-propoxyphenylsulfonyl) -4-oxo-pyrrolidin-2 (R) -methylcarboxylate (5a): Intermediate 5a was prepared using a method substantially similar to the above for the preparation of intermediate 1a, substituting the material of appropriate departure. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, the person skilled in the art can use protecting groups to block side reactions, or increase yields, as appropriate. Such modifications can be easily carried out by the person skilled in the art of organic chemistry, and thus are within the scope of the invention. b. 1 ? - (4-n-Propoxyphenyl) sulfonyl-4- (ZE -? / - methoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (5b): To a solution of the ketone 5a (0.8 g, 2.34 mmol) in dioxane (8 ml. ) and methanol (4 ml), methoxylamine hydrochloride (2 ml, 7 mmol, 30% solution in water) and sodium acetate (1.9 g, 23.4 mmol) were added. The mixture was stirred overnight at room temperature, and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a mixture of the (Z / E) isomers of 5b. c. The compound of 5b (0.9 g, 2.43 mmol) was mixed with NH20K (7.2 mL, 12.1 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with EtOAc / hexane (2: 1) to give Example 5.

EXAMPLE 6 Preparation of JV-hydroxy 1A / - (4-n-butoxyphenyl) sulfonyl-4- (Z, E -? / - methoxyimino) pyrrolidin-2R-carboxamide to. 1? - (4-n-butoxyphenyl) sulfonyl-4- (ZE -? / - methoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (6a): To a solution of 2a (2.0 g, 5.63 mmol) in dioxane (20 ml. ), and methanol (5 ml) and water (5 ml), methoxylamine hydrochloride (1.41 g, 16.9 mmol) and sodium acetate (4.6 g, 56.3 mmol) were added. The mixture was stirred overnight at room temperature and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a mixture of the (Z / E) isomers of 6a. b. Compound 6a (1.0 g, 4.95 mmol) was mixed with NH20K (13.8 mL, 24.7 mmol 1.7 M in methanol) and stirred overnight at room temperature. It was acidified with 1 N HCl, and the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The pure product was purified by column chromatography eluting with CH2Cl2: CH3? H (95: 5) to give Example 6.

EXAMPLE 7 Preparation of W-hydroxy 1W- (4-phenoxyphenyl) sulfonyl-4- (Z, E- / V-methoxyimino) pyrrolidine-2R-carboxyamide to. 1? / - (4-Phenoxyphenyl) sulfonyl-4R-hydroxy-pyrrolidine-2R-carboxylic acid (7a): To a solution of cis-4-hydroxy-D-proline (5.85 g, 44.7 mmoles in dioxane (20 ml) , water (20 ml, triethylamine (15.6 ml, 111.7 mmol, and 4-dimethylaminopyridine (0.54 g, 4.4 mmol) at 0 ° C, 4-phenoxybenzenesulfonyl chloride (11.5 g, 43 mmol) was slowly added in. The mixture was stirred for overnight at room temperature and diluted with 1N HCl. The reaction mixture was extracted three times with EtOAc The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 7a. b. 1? / - (4-phenoxyphenyl) sulfonyl-4R-hydroxy-pyrrolidin-2R-carboxylic acid methyl ester (7b): To a solution of 7a acid (14.6 g, 40.19 mmole) in methanol (75 ml), thionyl chloride (7.3 ml, 100 mmol) was added dropwise. The mixture was stirred for 1 hour at 45 ° C, and overnight at room temperature. The solvent was removed under reduced pressure to give 7b as a dense oil. c. 1 A / - (4-phenoxyphenyl) sulfonyl-4-oxo-pyrrolidin-2R-carboxylic acid methyl ester (7c): To a solution of the alcohol 7b (14.8 g, 39.2 mmol) in acetone (110 ml), reagent was added. Jones (28 ml, 224 mmol), 8 N solution prepared as described in Oxidation in Org. Chem., Vol 186, P273). The mixture was stirred overnight at room temperature. The green solid formed was removed by filtration, and the solvent was removed under reduced pressure. The reaction mixture was then dissolved in water and extracted three times with EtOAc. The combined EtOAc layer was washed twice with water, once with brine, dried over MgSO4 and concentrated under reduced pressure to give 7c. d. 1? - (4-phenoxyphenyl) sulfonyl-4- (ZE -? / - methoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (7d): To a solution of the ketone 7c (1.5 g, 4 mmol) in dioxane (15 ml. ) and methanol (5 ml) and water (5 ml), methoxylamine hydrochloride (1.02 g, 12 mmol) and sodium acetate (3.28 g, 40 mmol) were added. The mixture was stirred overnight at room temperature and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with hexane: EtOAc (4: 1) to give a mixture of the (Z / E) isomers of 7d.

The compound of 7d (0.6 g, 1.49 mmol) was mixed with NH20K (4.2 mL, 7.4 mmol, 1.7 M in methanol solution prepared as described in Fieser and Fieser, Vol 1, p 478) and stirred overnight room temperature. It was acidified with 1 N HCl, and the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (55A45B, A, H20 at 95%, acetonitrile at 5%, formic acid at 0.1%, B, acetonitrile at 80%, H20 at 20%; SymmetryPrep C18 column at 19 x 300 mm) to give example 7.

EXAMPLE 8 Preparation of 1α-M (4-fluorophenoxy) -phenylsulfonyl-4- (Z, E -? / - methoxyimino) pyrrolidine-2R-carboxamide to. Acid 1? -r4- (4-fluorophenoxy) phenylsulfonyl-4R-hydroxy-pyrrolidin-2R-carboxylic acid (8a): To a solution of cis-4-hydroxy-D-proline (4.97 g, 37.9 mmol) in dioxane ( 20 ml), water (20 ml), triethylamine (23 ml, 165 mmol) and 4-dimethylaminopyridine (0.43 g, 3.6 mmol) at 0 ° C, 4-phenoxybenzenesulfonyl chloride (10 g, 36.1 mmol) was slowly added. The mixture was stirred overnight at room temperature and diluted with 1 N HCl. The reaction mixture was extracted three times with EtOAc. The combined layer of EtOAc was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 8a. b. 1? / - r4- (4-fluorophenoxy) phenylsulfonyl-4R-hydroxy-pyrrolidin-2R-carboxylic acid methyl ester (8b): To a solution of the acid 8a (11.5 g, 30.1 mmol) in methanol (100 ml), thionyl chloride (13 ml, 180 mmol) was added dropwise. The mixture was stirred for 1 hour at 50 ° C and overnight at room temperature. The solvent was removed under reduced pressure to give 8b. c. 1A 4- (4-fluorophenoxy) phenylbuffoyl-4-oxo-pyrrolidin-2R-carboxylic acid methyl ester (8c): To a solution of the alcohol 8b (10 g, 25.3 mmol) in acetone (80 ml), reagent was added of Jones (13 ml, 101 mmol, 8 N solution prepared as described in Oxidation in Org Chem., Vol 186, P273). The mixture was stirred overnight at room temperature. The green solid formed was removed by filtration, and the solvent was removed under reduced pressure. The reaction mixture was then dissolved in water, and extracted three times with EtOAc. The combined EtOA layer was washed twice with water, once with brine, dried over MgSO4 and concentrated under reduced pressure to give 8c. d. 1? / -r4- (4-fluorophenoxy) phenylsulfonyl-4- (ZE -? / - methoxyimino) -pyrrolidin-2R-carboxylic acid methyl ester (8d): To a solution of the ketone 8c (0.9 g, 2.29 mmol) in dioxane (8 ml), methanol (5 ml) and water (5 ml), methoxylamine hydrochloride (0.6 g, 6.86 mmol) and sodium acetate (1.9 g, 22.9 mmol) were added. The mixture was stirred overnight at room temperature and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with hexane: EtOAc (3: 1) to give a mixture of the (Z / E) isomers of 8d.

The compound of 8d (0.63 g, 1.46 mmol) was mixed with NH20K (8 mL, 7.4 mmol, 1.7 M in methanol), and stirred overnight at room temperature. It was acidified with 1 N HCl, and the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with CH2Cl2: CH3? H to 5% / CH2Cl2 to give example 8.

EXAMPLE 9 Preparation of < V-hydroxy-1 N- (4-pyridyloxyphenyl) sulfonyl-4- (Z, E-? V-methoxyimino) pyrrolidine-2R-carboxamide to. Methyl ester of cis-hydroxy-D-proline (9a): To a solution of cis-hydroxy-D-proline (6 g, 45.8 mmol) in methanol (50 ml), thionyl chloride (17 ml) was added dropwise. , 229 mmol). The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to give 9a. b. 1A - (4-pyridyloxyphenyl) sulfonyl-4R-hydroxy-pyrrolidin-2R-carboxylic acid methyl ester (9b): To a solution of cis-4-hydroxy-D-proline methyl ester 9a (8.5 g, 45.8 mmol) in dioxane (50 ml), water (50 ml) and triethylamine (26 ml, 184 mmol) at 0 ° C, 4-pyridyloxybenzenesulfonyl chloride (13.0 g, 48 mmol) was added slowly. The mixture was stirred overnight at room temperature and diluted with 1 N HCl. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 9b. c. 1? / - (4-pyridroxyphenyl) sulfonyl-4-oxo-pyrrolidin-2R-carboxylic acid methyl ester (9c): To a solution of the alcohol 9b (1.0 g, 2.6 mmol) in acetone (10 ml), Jones reagent (2 ml, 16 mmol, 8 N solution prepared as described in Oxidation in Org. Chem. Vol 186, P273) was added. The mixture was stirred overnight at room temperature. The green solid formed was removed by filtration, and the solvent was removed under reduced pressure. The reaction mixture was then dissolved in aqueous NaHCO 3 solution, and extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 9c. d. 1 / V- (4-pyridyloxyphenyl) sulfonyl-4- (Z.E-? / -methoxyimino) pyrrolidin-2-methylcarboxylate (9d): To a solution of the ketone 9c (0.35 g, 0.93 mmole) in dioxane (5 ml), methanol (2 ml) and water (2 ml), methoxylamine hydrochloride (0.35 g, 2.79 mmoles, 30% w / w in H20) and sodium acetate (0.76 g, 9.3 mmoles) were added. The mixture was stirred overnight at room temperature, and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 9d as a white solid.

The compound of 9d (0.38 g, 0.93 mmol) was mixed with NH20K (4.4 mL, 7.4 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (90A10B, A, 95% H20, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% H20, 19 x SymmetryPrep C18 column). 300 mm) to give example 9 as a white foaming solid.

'! EXAMPLE 10 Preparation of < V-hydroxy-1 N- (4-n-butoxyphenyl) sulfonyl-4- (Z, E- / V-ethoxyimino) pyrrolidin-2R-carboxamide to. 1? / - (4-n-butoxyphenyl) sulfonyl-4- (Z, E -? / - ethoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (10a): To a solution of 2a (1.0 g, 2.82 mmol) in dioxane (10 ml) and methanol (5 ml), o-ethylhydroxylamine hydrochloride (0.82 g, 8.45 mmol) and sodium acetate (2.3 g, 28.2 mmol) were added. The mixture was stirred overnight at room temperature and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure give a mixture of the isomers (Z / E) of 10a. b. The 10a compound (0.5 g, 1.26 mmol) was mixed with NH20K (6.7 mL, 10 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (45A55B, A, H20 at 95%, acetonitrile at 5%, formic acid at 0.1%, B, acetonitrile at 80%, H20 at 20%; SymmetryPrep C18 column at 19 x 300 mm) to give example 10.

EXAMPLE 11 Preparation of V-hydroxy-1 V- (4-methoxyphenyl) sulfonyl-4- (Z, E-? V-re-butoxyimino) pyrrolidine-2R-carboxamide to. 1N- (4-methoxyphenyl) sulfonyl-4- (Z, E -? / - tert-butoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (11a): To a solution of 1a (5.0 g, 15.96 mmol) in dioxane (50 ml) and methanol (5 ml) and water (5 ml), o- (εe-butyl) hydroxylamine hydrochloride was added. (5.0 g, 40 mmol) and sodium acetate (13 g, 160 mmol). The mixture was stirred overnight at room temperature and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined layer of EtOAc was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a mixture of the (Z / E) isomers of 11a. b, The compound of 11a (0.4 g, 1.04 mmol) was mixed with NH20K (6 mL, 8 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (45A55B, A, H20 at 95%, acetonitrile at 5%, formic acid at 0.1%, B, acetonitrile at 80%, H20 at 20%; SymmetryPrep C18 column at 19 x 300 mm) to give example 11.

EXAMPLE 12 Preparation of / V-hydroxy-1 N- (4-n-butoxyphenyl) sulfonyl-4- (Z, E-N-t-butoxyimino) pyrrolidin-2R-carboxamide to. 1 ? - (4-n-butoxyphenyl) sulfonyl-4- (ZE -? / - t-butoxyimino) pyrrolidin-2R-carboxylic acid methyl ester (12a): To a solution of 2a (1.50 g, 4.23 mmoles) in 1, 4- dioxane (15 ml), methanol (5 ml) and water (5 ml), t-butoxylamine hydrochloride (1.59 g, 12.7 mmol) and sodium acetate (3.49 g, 42.5 mmol) were added. This mixture was stirred overnight at room temperature. The reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 15% EtOAc / hexanes) to give the desired product as a mixture of the (Z / E) isomers of 12a.

. The compound of 12a (1.07 g, 2.51 mmol) was treated with NH20K solution (11.1 ml, 20 mmol, 1.8 M in methanol) and stirred for 4 hours at room temperature. The reaction was cooled in an ice bath, acidified with 1 N aqueous HCK and extracted three times with EtOAc. The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 4% CH3OH / CH2Cl2 to give Example 12 as a mixture of the isomers (Z / E).

EXAMPLE 13 Preparation of ?? hydroxyl < V-4 - (4-fluorophenoxy) phenylsulfonyl-4- (Z, E -? / - tert-butoxyimino) -pyrrolidine-2R-carboxamide to. 1N-f4- (4-fluorophenoxy) -phenylsulfonyl-4- (Z, E -? / - fer-butoxyimino) -pyrrolidin-2R-carboxylic acid methyl ester (13a): To a solution of 8c (0.82 g, 2.08 mmol) in dioxane (8 ml), methanol (5 ml) and water (5 ml), 0- (fer-butyl) hydroxylamine hydrochloride (0.78 g, 6.25 mmol) and sodium acetate (1.7 g, 20.8 mmol) were added. The mixture was stirred overnight at room temperature, and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a mixture of the (Z E) isomers of 13a. b. The 13a compound (0.95 g, 2.08 mmol) was mixed with NH20K (10 mL, 16.6 mmol, 1.7 M in methanol) and stirred at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with 5% CH3OH / CH2Cl2 to give example 13.

EXAMPLES 14 TO 15 The following table shows the structure of the compounds exemplified in examples 14 and 15: -O-C corresponds to a substituent of R2 in the formula (I) when R2 is phenyl. D corresponds to a member of the heterocycloalkyl ring radical when Z of the formula (I) is N-W and W is heterocycloalkyl.

Gaaak EXAMPLE 14 Preparation of JV-hydroxy-1α / - (4-n-butoxyphenyl) sulfonyl-4- (Z.E - γ / - piperidinoimino) pyrrolidin-2R-carboxamide to. 1? / - (4-n-butoxyphenyl) sulfonyl-4- (Z, E -? / - piperidinoimino) pyrrolidin-2R-carboxylic acid methyl ester (14a): To a solution of 2a (2.5 g, 7.04 mmol) in dioxane (20 ml) and methanol (15 ml), was added 1-aminopiperidine (1.14 ml, 10.56 mmol) and sodium acetate (5.7 g, 70 mmol). The mixture was stirred overnight at room temperature and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSOi, and concentrated under reduced pressure to give 14a. b, The compound of 14a (0.65 g, 1.49 mmol) was mixed with NH2OK (4.4 mL, 7.45 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Acidified with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with CH3OH / CH2Cl2 (5:95) to give example 14.

EXAMPLE 15 Preparation of N-hydroxy 1fV- (4-n-butoxyphenyl) sulfonyl-4- (Z, E- / V- morpolinoimino) pyrrolidine-2R-carboxamide to. 1 ? - (4-n-butoxyphenyl) sulfonyl? -4- (ZE-? V-morpolinoimino) pyrrolidin-2R-carboxylic acid methyl ester (15a): To a solution of 2a (1.5 g, 4.2 mmol) in dioxane (20 ml) , methanol (5 ml) and water (5 ml), was added 1-aminomorpholine (0.52 ml, 5.04 mmol) and sodium acetate (3.4 g, 42 mmol). The mixture was stirred overnight at room temperature, and diluted with water. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 15a. b. The 15a compound (2 g, 4.2 mmol) was mixed with NH2OK (13 mL, 22 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Neutralized with 1 N HCl at pH of about 7, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography eluting with CH3? H / CH2Cl2 (5:95) to give example 15.

EXAMPLES 16 TO 49 The following table shows the structure of the compounds exemplified in examples 16 to 49: E corresponds to R2 in Formula (I). F corresponds to R4 in Formula (I) when Z is N-OFÍ4. It corresponds to methyl (CH3). Examples 16 to 49 were prepared using substantially the same procedures described in Examples 3 to 13, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can use protecting groups to block side reactions, or increase the yields, as appropriate. Such modifications can be easily carried out by the person skilled in the art of organic chemistry, and thus are within the scope of the invention.

EXAMPLES 50 TO 72 The following table shows the structure of the compounds exemplified in examples 50 to 72: G corresponds to R2 in Formula (I). H and I independently correspond to F in Formula (I) when Z is N-NR4R4.

Examples 50 to 72 were prepared using substantially the same procedures described in Examples 14 and 15, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can use protecting groups to block side reactions, or increase the yields, as appropriate. These modifications can be JUMMíJ? iam easily carried out by the person skilled in the art of organic chemistry, and thus are within the scope of the invention.

EXAMPLES 73 TO 83 The following table shows the structure of the compounds exemplified in examples 73 to 83: J corresponds to R2 in Formula (I). K corresponds to R4 in Formula (I) when Z is N-NR4R4, and an R4 is hydrogen.

Examples 73 to 83 were prepared using substantially the same procedures described in Examples 14 and 15, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can use protecting groups to block side reactions, or increase the returns, as appropriate. Such modifications can be easily carried out by the person skilled in the art of organic chemistry, and thus are within the scope of the invention.

EXAMPLE 84 Preparation of JV-hydroxy 1 N- (4-methoxyphenyl) sulfonyl-4-methylene-pyrrolidine-2R-carboxamide to. 1? / - (4-methoxyphenyl) sulfonyl-4-methylene-pyrrolidine-2R-carboxylic acid methyl ester (84 a): To a solution of methyltriphenylphosphonium bromide (1.75 g, 4.78 mmol) in 10 ml of anhydrous THF at 0 ° C under argon, lithium bis (trimethylsilyl) amide (5.74 mL, 5.74 mmol, 1.0 M solution in THF) was added dropwise, and stirred for 15 minutes. Then, a solution of 1a (1.5 g, 4.78 mmol) in THF (25 ml) was slowly added thereto. The mixture was stirred overnight at room temperature and diluted with ammonium chloride. The reaction mixture was extracted three times with EtOAc. The combined EtOAc layer was washed with 1 N HCl, water, aqueous NaHCO 3, brine, dried on MgSO4 and concentrated under reduced pressure to an oil which was purified by column chromatography eluting with EtOAc / hexane (3/7) to give exomethylene 84a. b. The 84a compound (0.26 g, 0.83 mmol) was mixed with NH2OK (3.7 mL, 6.64 mmol, 1.7 M in methanol) and stirred overnight at room temperature. Neutralized with 1 N HCl, the mixture was extracted three times with EtOAc. The combined EtOAc layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with CH2Cl2: CH30H (95: 5) to give example 84.

EXAMPLES 85 TO 91 The following table shows the structure of the compounds exemplified in examples 85 to 91: -O-L corresponds to a substituent of R2 in the formula (I) when R2 is phenyl. M corresponds to Re in the formula (I) when Z is CRβRβ- Examples 85 to 87 were prepared using substantially the same procedure described in Example 84, substituting the appropriate starting material: The person skilled in the art can change the temperature , pressure, atmosphere, solvents or the order of reactions, as appropriate. In addition, one skilled in the art can use protecting groups to block side reactions, or increase the yields, as appropriate. Such modifications can be easily carried out by the person skilled in the art of organic chemistry, and thus are within the scope of the invention. Example 88 was prepared using a sequence including an olefinization process (described in J. Chem. Soc. Chem. Commun., 1972, 443). Example 89 was prepared using a sequence including an olefinization process (described in Tetrahedron Lett, 1990, 31, 5571). Example 90 was prepared using a sequence including a procedure of olefination (described in Tetrahedron, 1993, 49, 6821). Example 91 was prepared using a sequence including an olefinization process (described in J. Am. Chem. Soc. 1962, 84, 3370).

EXAMPLES 92 TO 96 The following table shows the structure of the compounds exemplified in examples 92 to 96: -O-P corresponds to a Z-member atom in formula (1) when Z is a ring.

Examples 92 to 96 were prepared using substantially the same procedure described in example 84, using the yluride precursor appropriately functionalized which is derived from the related bromide precursor. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can use protecting groups to block side reactions, or increase the yields, as appropriate. Such modifications can be easily carried out by the person skilled in the art of organic chemistry, and thus are within the scope of the invention.

EXAMPLES 97 TO 98 The following table shows the structure of the compounds exemplified in examples 97 and 98: -O-T corresponds to a substituent of R2 in the formula (I) when R2 is phenyl.

Examples 97 and 98 were prepared using a sequence including an olefinization process (described in Synthesis, 1978, 385).

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 within the invention can be substituted by the compound of the example shown below with similar results. The skilled person will appreciate that the examples provide guidance and that they can be varied based on the condition and the patient.

EXAMPLE A A tablet composition for oral administration is made in accordance with the present invention, comprising: Component Quantity The compound of example 2 15 mg Lactose 120 mg Corn starch 70 mg Talc 4 mg Magnesium stearate 1 mg 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 in accordance with the present invention, which comprises: Component Quantity (% w / w) The compound of example 3 15% Polyethylene glycol 85% A male human subject weighing 90 kg and suffering from osteoarthritis is treated with a method of this invention. Specifically, it administered daily to said subject a capsule containing 70 mg of the compound of Example 3 for five years. At the end of the treatment period, the patient is examined by orthoscopy, and it is found that there is no further advance in the erosion / fibrillation of the articular cartilage.

EXAMPLE C A composition based on saline for local administration is prepared in accordance with the present invention, which comprises: Component Quantity (% in o / p) The compound of example 6 5% Polyvinyl alcohol 15% Saline 80% 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 9 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbitol 5.00 Glycine 0.35 Aromatic ingredients 0.075 Purified water C.S. Total = 100.00 A patient who has chemical burns applies the composition at each change of clothes (twice a day). 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 14 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Sodium saccharin 0.2 Propellant (F12, F114) C.S Total = 100.0 A patient suffering from asthma sprinkles 0.01 ml by means of a pumping actuator 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 84 0.10 Benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL M) 0.50 Sodium metabisulfite 0.10 Sodium chloride (0.9%) is. Total = 100.0 A male human subject who weighs 90 kg and who suffers 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 84 twice daily in the affected eye for two months.

EXAMPLE G A composition for parenteral administration is made comprising: Component Quantity The compound of example 53 100 mg / ml of vehicle Sodium Citrate pH Regulator Vehicle 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.

EXAMPLE H A composition for mouthwash containing: Component% in o / v Compound in example 73 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 Coloring 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.

EXAMPLE I A trocisco composition is prepared: Component% in p / v The compound of example 92 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Sabonzante 11.70 Color 0.10 Corn syrup balance at 100% '"'" * - *** A patient takes the trocus to prevent loosening of an implant in the maxilla.

EXAMPLE J Composition for chewing gum: Component% in w / v The compound of example 2 1.00 Sorbitol crystals 38.44 Base for chewing gum 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.

EXAMPLE K Components% in w / v The compound in Example 3 4.0 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 0.0088 Flavor 0.064 Colorant 0.0012 The composition is prepared by first mixing 80 kg of glycerin and all the benzyl alcohol and heating to 65 ° C, then slowly adding and mixing methylparaben, propylparaben, water, xanthan gum and guar gum. These ingredients are mixed for approximately 12 minutes in an in-line mixer. Silververson. The following ingredients are then added slowly in the following order: the remaining glycerin, sorbitol, antifoam C, calcium carbonate, citric acid and sucrose. Separately, flavorings and refrigerants are combined 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 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 to the present invention can be made 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 (5)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the following structure: characterized in that (a) Ri is OH, alkoxy or NR3OR3, wherein each R3 is independently selected from the group consisting of hydrogen, lower alkyl and acyl; (b) rX is S02, CO, C02, CONR5, POR5, or a covalent bond, wherein R5 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy and heteroaryloxy; (c) R2 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy and heteroaryloxy; (d) Z is selected from the group consisting of: (i) N-W, wherein N is at least 1, and W is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; (ii) N-OR 4, N-SR 4, N-NR R 4 or N-CR 4 R 4 R, wherein n is at least 1, and each R 4 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl , cycloalkyl and heterocycloalkyl; (iii) N- C- Q- R4, wherein n is at least 1 and each Q is selected independently of the group consisting of S and O; (iv) N- C- R4, wherein n is at least 1; (v) CR6R6, wherein each R6 is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and cyano; (vi) a ring, said ring being selected from the group consisting of cycloalkyl and heterocycloalkyl; (ix) C = CR4R; and (x) C = V, wherein V is a ring, said ring being selected from the group consisting of cycloalkyl and heterocycloalkyl; (e) m and n are selected integers independently from 0 to about 4, and m + n is from about 2 to about 7; and any optical isomer, diastereomer or enantiomer, or pharmaceutically acceptable salt, solvate, biohydrolyzable amide, ester or prodrug thereof.

2. The compound according to claim 1, further characterized in that m and n are integers independently selected from 1 to about 4, and m + n is from about 2 to about 7.

3. The compound according to claim 1 or 2, further characterized in that Z is N-OR and R 4 is hydrogen or alkyl.

4. The compound according to claim 1 or 2, further characterized in that Z is CRßRe and each Re is independently hydrogen, halogen or lower alkyl.

5. The compound according to claim 1 or 2, further characterized in that Z is a ring, said ring being selected from the group consisting of cycloalkio and heterocycloalkyl. 6- The compound according to any of the preceding claims, further characterized in that R 2 is aryl or heteroaryl. 7. The compound according to any of the preceding claims, further characterized in that R1 is NHOH and X is S02. 8. 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 carrier. 9. The use of a compound as claimed in claims 1, 2, 3, 4, 5, 6 or 7, in the manufacture of a medicament for preventing or treating a disease associated with unwanted metalloprotease activity in a mammalian subject. 10. The use as claimed in claim 9, wherein the Disease associated with unwanted metalloprotease activity is selected from the group consisting of arthritis, cancer, multiple sclerosis, cardiovascular disorders, skin disorders, eye disorders, inflammation, skeletal muscle disease, cachexia and gum disease.