MXPA99002067A - Heterocyclic metalloprotease inhibitors - Google Patents

Abstract

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

Description

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

BACKGROUND A number of structurally related metalloproteases [MPs] carry out the degradation of structural proteins. These metalloproteinases act commonly on the intercellular matrix, and in this way they are involved in the degradation and remodeling of the tissues. These proteins are called metalloproteases or MPs. There are several different families of MPs, classified by sequence homology. In the art several families of known MPs are described, as well as examples thereof. These MPs include matrix metalloproteases [MMPs], zinc metalloproteases, many of the membrane-bound metalloproteases, TNF conversion enzymes, angiotensin converting enzymes (ACEs), disintegrins, including ADAMs (See Wolfsberg et al., 131 J .Cell Bio, 275-78, October 1995), and enkephalinases. Examples of MPs 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. Potential therapeutic indications of MP inhibitors have been mentioned in the literature. See, for example, US patent. 5,506,242 (Ciba Geigy Corp); US patent 5,403,952 (Merck &Co); PCT application published WO 96/06074 (British Bio Tech Ltd); PCT publication WO 96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British Bio Tech Ltd); Wo 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); WO 95/26989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Ins. Opthamology); WO 95/23790 (SmithKIine Beecham); WO 95/22966 (Sanofi Winthrop); WO 95/19965 (Glycomed); WO 95 19956 (British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd); WO 95/13289 (Chiroscience Ltd); WO 95/12603 (Syntex); WO 95/09633 (Florida State Univ), - WO 95/09620 (Florida State Univ); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 (Celltech); WO 93/14112 (Merck); WO 94/0019 (Glaxo); WO 93/21942 (British Bio Tech Ltd); WO 92/22523 (Res. Corp. Tech. Ine); WO 94/10990 (British Bio Tech Ltd); WO 93/09090 (Yamanouch); and British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd); European patent applications published EP 95/684240 (Hoffman LaRoche); EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); published Japanese applications JP 08053403 (Fujusowa Pharm. Co. Ltd); JP 7304770 (Kanebo Ltd); and Bird and others 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., and others, Druqs of the Future (1990) 15: 495-508); metastasis of tumor cells (ibid, Broadhurst, MJ, et al., application for European female patient 276,436 (published in 1987), Reich, R., et al., 48 Cancer Res. 3307-3312 (1988), and various ulcerations or conditions Tissue ulceratives For example, ulcerative conditions may originate in the cornea as a result of alkali burns or as a result of infection by Pseudomonas aeruginosa, acanthamoeba, herpes simplex and vaccinia virus, and other examples of conditions characterized by metalloprotease activity. unwanted include periodontal disease, bullous epidermolysis, fever, inflammation and scleritis (Cf. DeCicco et al., WO 95 29892, published November 9, 1995.) In view of the involvement of said metalloproteases in a number of disease conditions, Attempts have been made to prepare inhibitors for these enzymes A number of such inhibitors are described in the literature Examples include US Patent No. 5 , 183,900, issued on February 2, 1993 to Galardy; US patent No. 4,996,358, issued February 26, 1991 to Handa et al .; US patent No. 4,771,038, issued September 13, 1988 to Wolanin et al .; US patent No. 4,743,587, issued May 10, 1988 to Dickens, et al .; European Patent Publication No. 575,844, published December 29, 1993 by Broadhurst et al .; International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura et al .; World Patent Publication No. 92/17460, published October 15, 1992 by Markwell et al .; and European Patent Publication No. 498,665, published August 12, 1992 by Beckett et al. Metalloprotease inhibitors are useful for treating diseases caused, at least in part, by the decomposition of structural proteins. Although a variety of inhibitors have been prepared, there is a continuing need for potent metalloprotease inhibitors useful in treating such diseases. Applicants have surprisingly found that the compounds of the present invention are potent metalloprotease inhibitors.

OBJECTS OF THE INVENTION Thus, it is an object of the present invention to provide compounds useful for the treatment of conditions and diseases that are characterized by undesired MP activity. It is also an object of the invention to provide potent metalloprotease inhibitors. A further object of the invention is to provide pharmaceutical compositions comprising said inhibitors. Another object of the invention is to provide a method of treatment for diseases related to metalloproteases.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds that are useful as inhibitors of metalloproteases, and that are effective to treat conditions characterized by excessive activity of these enzymes. In particular, the present invention relates to a compound having a structure according to the formula (I) where R is H; R2 is hydrogen, alkyl or acyl; Ar is COR3 or SO2R4; and R3 is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R 4 is alkyl, heteroalkyl, aryl, or heteroaryl, substituted or unsubstituted; X is CH2, 0, S, SO, S02, or NR5, wherein R5 is independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R5, C0R7, CSRg, PO (R9) 2 or can optionally form a ring with W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino; R7 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, and alkylarylamino; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, - Rg is alkyl, aryl, heteroaryl, heteroalkyl; W is hydrogen or one or more lower alkyl portions, or is an alkylene, arylene, or heteroarylene bridge between two adjacent or non-adjacent carbons (thereby forming a fused ring); And it is independently one or more of hydrogen, hydroxy, SRIQ, SOR4, SO2R4, alkoxy, amino, wherein amino is of formula NR] _] _, R? 2 / where R_? And R-12 are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R6, COR7, CSR8, PO (R9) 2; and R ?? is hydrogen, alkyl, aryl, heteroaryl; Z is zero, a spiro portion or an oxo substituted group on the heterocyclic ring; n is 1-3. This structure also includes an optical isomer, diastomer or enanomer for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester or imide thereof. These compounds have the ability to inhibit at least one mammalian matrix metalloprotease. Accordingly, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of the formula (I) and to methods for treating diseases characterized by the undesired activity of matrix metalloprotease using these compounds or the pharmaceutical compositions containing them. Metalloproteases active at a particularly undesired site (eg, an organ or certain cell types) can be identified by conjugating the compounds of the invention to a specific identification ligand for a label at that site, 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 several other methods that take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease. In another aspect, the invention is directed to the compounds of the formula (I) conjugated to a marker. As 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 metalloproteases, preferably a matrix metallopropease in vivo or in vitro in cell cultures. In addition, the compounds of the formula (I) can be conjugated to vehicles that allow the use of these compounds in immunization protocols to prepare antibodies specifically immunoreactive with the compounds of the invention. Typical conjugation methods are known in the art. These antibodies are then useful both in therapy and in the monitoring of the dosage of the inhibitors.

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

Definitions and use of the terms The following is a list of definitions for the terms used herein. "Acyl" or "carbonyl" is described as a radical that could be formed by removing the hydroxyl from a carboxylic acid (ie R-C (= 0) -). Preferred acyl groups include (for example) acetyl, formyl and propionyl. "Acyloxy" is an oxy radical having an acyl substituent (i.e., -O-acyl); for example, -O- (= 0) -alkyl. "Alcoxyacil" is an acyl radical (-C (= 0) -) having an alkoxy substituent (ie, -0-R), for example, -C (= 0) -0-alkyl. This radical can be considered as an ester. "Acylamino" is an amino radical having an acyl substituent (i.e., -N-acyl); for example -NH-C (= 0) -alkyl. "Alkenyl" is a substituted or unsubstituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; very preferably from 2 to 8; except when indicated. Alkenyl substituents have at least one olefinic double bond (including, for example, vinyl, allyl and butenyl). "Alkynyl" is an unsubstituted or substituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms, - most preferably from 2 to 8, except where indicated. The chain has at least one triple carbon-carbon bond. "Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, wherein the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy. "Alkoxyalkyl" is a substituted or unsubstituted alkyl portion, replaced with an alkoxy moiety (ie, -alkyl-O-alkyl). It is preferred when the alkyl has 1 to 6 carbon atoms (most preferably 1 to 3 carbon atoms) and the alkyloxy has 1 to 6 carbon atoms (most preferably 1 to 3 carbon atoms). "Alkyl" is a saturated or unsubstituted or substituted hydrocarbon chain radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms; very preferably 1 to 4; except when indicated. Preferred alkyl groups include (for example) substituted or unsubstituted methyl, ethyl, propyl, isopropyl and butyl.

As referred to herein, "spirocycle" or "spirocyclic" refers to a cyclic portion that shares a carbon in another ring. Said cyclic portion may be carbocyclic or heterocyclic in nature. Preferred heterogeneous atoms included in the base structure of the heterocyclic spirocycle include oxygen, nitrogen and sulfur. Spirocycles can be substituted or unsubstituted. Preferred substituents include oxo, hydroxyl, alkyl, cycloalkyl, arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (e.g., benzothiol, cycloalkyl, heterocycloalkyl, benzimidizoles, pyridyl thiol, etc., which may also be substituted ) and similar. In addition, the heterogeneous atom of the heterocycle can be substituted if its valence allows it. Preferred spirocyclic ring sizes include rings of 3 to 7 members. The term "alkylene" refers to an alkyl, alkenyl or alkynyl that is a diradical, rather than a radical. "Heteroalkylene" is likewise defined herein as a (diradical) alkylene having a heterogeneous atom in its chain. "Alkylamino" is an amino radical having one (secondary amine) or two (tertiary amine) alkyl substituents (ie, -N-alkyl). For example, methylamino (-NHCH3), dimethylamino (- (CH3) 2) and ethylethylamino (-N (CH3) CH2CH3).

"Aminoacyl" is an acyl radical having an amino substituent (ie., -C (= 0) -N); for example -C (= 0) -NH2 • The amino group of the aminoacyl portion can be unsubstituted (ie, primary amine) or can be substituted with one (secondary amine) or two (ie, tertiary amine) alkyl groups . "Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl and fluorenyl. Said groups can be substituted or unsubstituted. "Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl, phenylethyl and phenylpropyl. Said groups can be substituted or unsubstituted. "Arylalkylamino" is an amine radical substituted with an arylalkyl group (e.g., -NH-benzyl). Said groups can be substituted or unsubstituted. "Arylamino" is an amine radical substituted with an aryl group (i.e., -NH-aryl). Said groups can be substituted or unsubstituted. "Aryloxy" is an oxygen radical having an aryl substituent (i.e., -O-aryl). Said groups can be substituted or unsubstituted. "Carbocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring radical. The carbocyclic rings are monocyclic or are ring systems fused, bridged spiropolyclic. The monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. The polycyclic carbocyclic rings contain 7 to 17 atoms, preferably 7 to 12 atoms. Preferred polycyclic systems comprise rings of 4, 5, 6 or 7 members fused to rings of 5, 6 or 7 members. "Carbocycloalkyl" is a substituted or unsubstituted alkyl radical substituted with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl, most preferably an aryl. Preferred carbocycloalkyl groups include benzyl, phenylethyl and phenylpropyl. "Carbocycloheteroalkyl" is an unsubstituted or substituted heteroarkyl radical replaced with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl; most preferably an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl or 2-thia-ethyl. "Carboxyalkyl" is an unsubstituted or substituted alkyl radical replaced with a carboxy moiety (-C (= 0) 0H). For example, -CH2-C (= 0) OH.

"Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) morpholinyl, piperadinyl, piperazinyl, tetrahydrofuryl and hydantoinyl. "Fused rings" are rings that are superimposed on each other in such a way that they share two ring atoms. A certain ring can be fused to more than another ring. The fused rings are contemplated in heteroaryl, aryl and heterocycle radicals, or the like. "Heterocycle-alkyl" is an alkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably a heteroaryl or cycloheteroaryl; most preferably a heteroaryl. Preferred heterocycloalkyl includes C 1 -C 4 alkyl having a preferred heteroaryl attached thereto. More preferred is, for example, pyridyl-alkyl and the like. "Hetero-cycloheteroalkyl" is an unsubstituted or substituted heteroalkyl radical, replaced with a heterocyclic ring. The heterocyclic ring is preferably an aryl or cycloheteroalkyl; most preferably an aryl.

"Heterogeneous atom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heterogeneous atoms may contain different heterogeneous atoms. "Heteroalkenyl" is an unsaturated chain radical, unsubstituted or substituted having 3 to 8 members comprising carbon atoms and one or two heterogeneous atoms. The chain has at least one carbon-carbon double bond. "Heteroalkyl" is an unsubstituted or substituted saturated chain radical having 2 to 8 members comprising carbon atoms and one or two heterogeneous atoms. "Heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprising carbon atoms and one or more heterogeneous atoms in the ring. The heterocyclic rings are monocyclic ring systems or are fused, bridged or spiro-polyclic. The monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7 atoms. The polycyclic rings contain 7 to 17 atoms, preferably 7 to 13 atoms. "Heteroaryl" is an aromatic heterocyclic radical, whether monocyclic or bicyclic radical. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl, benzothiazolyl, benzofuryl, indolyl, and the like. Said groups can be substituted or unsubstituted.

"Halo", "halogen" or "halide" is a radical of chlorine, bromine, fluorine or iodine atom. The halides that are preferred are bromine, chlorine and fluorine. Likewise, as will be mentioned herein, a "lower" hydrocarbon portion (e.g., "lower" alkyl) is a hydrocarbon chain comprising 1 to 6, preferably 1 to 4, carbon atoms. A "pharmaceutically acceptable sai" is a cationic salt formed in any acid group (e.g., carboxyl) or an anionic salt formed in any basic group (e.g., amino). Many of these salts are known in the art, as described in world patent publication 87/05297, Johnston and others, published on September 11, 1987 (incorporated herein by reference). Preferred cationic salts include the alkali metal salts (such as sodium and potassium) and the alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides (such as chloride salts). "Biohydrolyzable amides" are amides of the compounds of the invention that do not interfere with the inhibitory activity of the compound, or that are easily converted in vivo by a mammalian subject to produce an active inhibitor. A "biohydrolyzable hydroxyimide" is an imide of a compound of formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by a human or lower animal subject to producing an active compound of the formula (I). Said hydroxyimides include those which do not interfere with the biological activity of the compounds of the formula (I). A "biohydrolyzable ester" refers to an ester of a compound of the formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to produce a compound of the formula (I) active . A "solvate" is a complex formed by the combination of a solute (e.g., a hydroxamic acid) and a solvent (e.g., 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 hydroxamic acid (e.g., water, ethanol, acetic acid, N, N-dimethylformamide and others known or readily determined by the person skilled in the art. The technique) . "Optical isomer", "stereoisomer" and "diastereomer", as mentioned herein, have the normal meanings recognized in the art (Cf., Hawleys Condensed Chemical Dictionary, Uva Ed.). It is not desired that the illustration of specific protected forms and other derivatives of compounds of the formula (I) be limiting. The application of other useful protective groups, salt forms, etc., is within the ability of the person skilled in the art. As mentioned above and as used herein, the substituent groups may in turn be substituted. Said substitution can be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Sustituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated herein by reference. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxyl, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyaceil (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholino, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. As used herein, the term "mammalian matrix metalloprotease" means any enzyme containing a metal found in mammalian sources, and which is capable of catalyzing the degradation of collagen, gelatin or proteoglycan under suitable test conditions. Proper test conditions can be found, for example, in the US patent. No. 4,743,587, which refers to the procedure of Cawston et al., Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate is described by Weingarten, H. et al., Biochem Biophy Res Comm (1984) 139: 1184-1187. Of course, any normal method can be used to analyze the degradation of these structural proteins. The matrix metalloprotease enzymes mentioned herein are all zinc-containing proteases and which are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit matrix metalloprotease activity can, of course, be tested in the assays described above. The isolated matrix metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or raw extracts containing the scale of enzymes capable of tissue degradation can be used.

Compounds: The compounds of the invention are described in Brief description of the invention. Preferred compounds of the invention are those in which Z is heteroespyrocaryalkylene, preferably having heteroatoms adjacent to the original ring structure, more preferably such spiroheteroalkylenes have from 4 to 5 members. The preferred heteroatoms are divalent. The invention provides compounds which are useful as inhibitors of metalloproteases, preferably a matrix of metalloproteases, and which are effective in the treatment of conditions characterized by excess activity of these enzymes. In particular, the present invention relates to a compound having a structure according to formula (I) where Rl is H; R2 is hydrogen, alkyl or acyl; Ar is COR3 or SO2R4; and R3 is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R 4 is alkyl, heteroalkyl, aryl, or heteroaryl, substituted or unsubstituted; X is CH, O, S, SO, S02, or NR5, wherein R5 is independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S02Rg, COR7, CSRg, P0 (R9) 2 or can optionally form a ring with W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino; R7 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, and alkylarylamino; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino; Rg is alkyl, aryl, heteroaryl, heteroalkyl; W is hydrogen or one or more lower alkyl portions, or is an alkylene, arylene, or heteroarylene bridge between two adjacent or non-adjacent carbons (thereby forming a fused ring); And it is independently one or more of hydrogen, hydroxy, SRIQ, SOR4, SO2R4, alkoxy, amino, wherein amino is of formula NRn, R12 'wherein Rn and R12 are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R6, COR7, CSRg, PO (Rg) 2; and R10 is hydrogen, alkyl, aryl, heteroaryl; Z is zero, a spiro portion or an oxo substituted group on the heterocyclic ring; n is 1-3. This structure also includes an optical isomer, diastereomer, or enanomer for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable ester, amide, or imide thereof.

Preparation of the compound The hydroxamic compounds of formula (I) can be prepared using a variety of procedures. The general schemes include the following: PREPARATION OF THE PORTION AND For the manipulation of Y it is understood that the skilled artisan can choose to prepare Y before, after or concurrently with the preparation of the heterocyclic ring. For clarity, the W and Z portions are not shown below. More than one Y and Z may be present in the compounds of formula (I). For compounds where Y is not adjacent to the nitrogen ring, a preferred method for making the compound is: SCHEME 1.

Where R is a derivable group or can be manipulated or substituted, such compounds are known or are prepared by known methods. (A) is converted to its analogous sultamic ester and R is manipulated to give (B) during this or a subsequent step. Y and Z can be added or altered, followed by appropriate reaction to provide R. For example, this step can include treatment with hydroxyl amine under basic conditions to give a compound of formula I (C).

For the preparation and preparation of the heterocyclic ring it is understood that the skilled person can choose to prepare And before, after or concurrent with the preparation of the heterocyclic ring. For clarity, the portions W, Y, and Z are not shown below. More than one W, Y and Z may be present in the compounds of formula (I). For compounds where X is nitrogen, the preferred method for handling R5 is shown. In the scheme below, L is any acceptable residual group, and B is a blocking group as above, Boc is an example of a preferred blocking group, recognized in the art. The expert will recognize that the choice of blocking group is within the technique of the expert working in organic chemistry. In this way the choice of Boc is not required, but preferred.

SCHEME II For compounds containing a sulfur in the heterocyclic ring the preferred methods of ring formation are shown. For the preparation and preparation of the heterocyclic ring it is understood that the skilled person can choose to prepare Y before, after or concurrently with the preparation of the heterocyclic ring. For clarity, the W, Y and Z portions are not shown below. More than one W, Y and Z may be present in the compounds of formula (I) ESOUEMA III Another acceptable strategy for making the invention having X as sulfur includes the following scheme. The method allows the formation of the sultamic ester and the subsequent reaction with a bifunctional portion. Preferably the OH described in the scheme below is a primary hydroxyl. The ring lock uses normal methods. The functionalization and elaboration of the molecule proceeds as described above.

SCHEME IV Where X is sulfur, further elaboration of the heterocyclic ring can be achieved after the ring has been formed. For example, oxidation of the sulfur ring atom using known methods can provide the corresponding sulfoxides and sulfonates as shown.

SCHEME V For compounds containing an oxygen in the heterocyclic ring the preferred methods of ring formation are shown. A bifunctional portion, for example a hydroxy halo species, is reacted with an aziridine as shown below. The halo portion serves as a residual group, useful in the ring closure reactions. With the formation of the ring, the working up of the invention proceeds as described above.

SCHEME VI PREPARATION OF THE Z PORTION Of course the skilled artisan will recognize that the schemes applicable to the preparation of Y may be useful in the preparation of Z as noted above. Other preferred methods are provided for the reader. Where Z is a ketal or thioketal the compounds of the invention can be prepared from a compound having a carbonyl in the ring. Such compounds are prepared by known methods, and many such compounds are known or commercially available. In this way the skilled person will appreciate that a hydroxy, amino, imino, alkoxy, oxo or any other group can be handled within a carbonyl compound. The order of elaboration of ketal, R or the sultamic ester can be changed. A preferred method for making the spiro compounds of the invention is through a carbonyl compound, using "protecting group" technology known in the art, such as a thioketal or ketal, and the like. Ketals, acetals and the like are prepared from carbonyl compounds by methods known in the art. Such carbonyl compounds can be made from hydroxy alkylene cyclic amines through oxidation to an acetone, or from lactams, which provide 2-amino spiro functionality.

A variety of compounds can be generated in a similar way, using the guide of the previous scheme. In the above schemes, wherein Rb is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derivatives of final compounds using a standard dealkylating process (Bhatt, et al., "Cleavage of Ethers", Synthesis, 1983, pp 249-281). These steps may vary to increase the performance of the desired product. The expert will recognize that the judicious choice of reactants, solvents and temperatures is an important component in the successful synthesis. Although the determination of optimal conditions, etc. it is routine, it will be understood that a variety of compounds can be generated in a similar way, using the guides of the previous scheme. The starting materials used to prepare the compounds of the invention are known, are manufactured by known methods or are commercially available as a starting material. It is recognized that one skilled in the art of organic chemistry can easily perform normal manipulations of organic compounds without additional guidance; that is, it is within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification and the like. Examples of these manipulations are described in normal texts, such as March, Advanced Orqanic Chemistry, (Wiley), Carey and Sundberg, Advanced Orqanic Chemistry (Vol. 2) and Keeting, Heterocvclic Chemistrv (all 17 volumes). The person skilled in the art will readily appreciate that certain reactions are best carried out when another functionality is masked or protected in the molecule, thereby avoiding any undesirable side reactions and / or increasing the yield of the reaction. Commonly, those skilled in the art use protecting groups to achieve said increased yields or to avoid unwanted reactions. These reactions are found in the literature and are also within the scope of the person skilled in the art. Examples of many of these manipulations can be found, for example, in T. Greene, Protectin Groups in Organics Synthesis. Of course, the amino acids used as starting materials with reactive side chains are preferably blocked to avoid unwanted side reactions. The compounds of the invention may have one or more chiral centers. As a result, one optical isomer, including diastereomer and enantiomer, can be selectively prepared on others; for example, by chiral starting materials, catalysts or solvents, or both stereoisomers or both optical isomers can be prepared at the same time, including diastereomers and enantiomers (a racemic mixture). Since the compounds of the invention can exist as racemic mixtures, mixtures of optical isomers including diastereomers or enantiomers or stereoisomers can be separated, using known methods such as chiral salts, chiral chromatography and the like. Furthermore, it is recognized that an optical isomer, including diastereomer and enantiomer or stereoisomer, may have favorable properties over others. Thus, when describing and claiming the invention, when describing a racemic mixture, it is clearly contemplated that both optical isomers are also described and claimed, including diastereomers and enantiomers or stereoisomers substantially free of the others.

Methods of use The metalloproteinases (MPs) found in the body function, in part, by degrading the extracellular matrix, which comprises proteins and extracellular glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of the tissue in the body. Metalloprotease inhibitors are useful for treating diseases caused, at least in part, by the degradation of said proteins. It is known that MPs are intimately involved in tissue remodeling.

As a result of this activity, it has been mentioned that they are active in many disorders that include either: tissue degradation; including degenerative diseases such as arthritis, multiple sclerosis and the like; Metastasis or mobility of tissues in the body: - tissue remodeling, including fibrotic disease, scar prevention, benign hyperplasia and the like. The compounds of the present invention treat disorders, diseases and / or undesired conditions that are characterized by undesired or elevated activity of this class of proteases. For example, the compounds can be used to inhibit proteases that: - destroy structural proteins (ie, the proteins that maintain the stability and structure of the tissues); - interfere in inter / intracellular signaling, including those involved in cytokine upregulation and / or cytokine processing and / or inflammation, tissue degradation and other diseases [Mohler KM. and others, Nature 370 (1994) 218-220; Gearing AJH et al., Nature 370 (1994) 555-557; McGeehan GM et al., Nature 370 (1994) 558-561], and / or - facilitate unwanted processes in the subject being treated, for example, the processes of sperm maturation, egg fertilization and the like. As used herein, an "MP-related disorder" or "MP-related disease" is one that includes undesired or high 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 "implication" of the PM includes.- - the activity of unwanted or elevated MP as a "cause" of the disorder or biological manifestation, whether the activity has been genetically elevated, by infection, by autoimmunity, trauma, biomechanical causes, quality of life [eg, obesity] or for some other reason; - MP as part of the observable manifestation of the disease or disorder. That is, the disease or disorder is measurable in terms of increased MP activity, or from a clinical point of view, unwanted or elevated MP levels indicate the disease. MPs do not need to be the "hallmark" of the disease or disorder; - the activity of unwanted or elevated MP is part of the biochemical or cellular cascade that originates or is related to the disease or disorder. In this regard, the inhibition of MP activity disrupts the cascade and thus controls the disease.

Advantageously, many MPs are not distributed evenly throughout the body. In this way, the distribution of MPs expressed in various tissues is commonly specific for these tissues. For example, the distribution of metalloproteases involved in the degradation of joint tissues is not the same as the distribution of metalloproteases found in other tissues. Thus, although not essential for activity or efficacy, certain disorders are preferably treated with compounds that act on specific MPs found in the affected tissues or regions of the body. For example, a compound that exhibits a higher degree of affinity and inhibition for an MP found in the joints (e.g., chondrocytes) would be preferred for the treatment of a disease found there, than other compounds that are less specific. In addition, certain inhibitors are more bioavailable for certain tissues than others, and this judicious choice of the inhibitor, with the selectivity described above, provides a specific treatment of the disorder, disease or undesired condition. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. In this way, the compounds can be selected to produce mediated effects through MPs found specifically outside the central nervous system.

The determination of the specificity of an MP inhibitor of a certain MP is within the ability of the expert in that field. Proper test conditions can be found in the literature. Tests for stromelysin and collagenase are specifically known. For example, the US patent. 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 normal method can be used to analyze the degradation of structural proteins by the MPs. The ability of the compounds of the invention to inhibit metalloprotease activity can, of course, be tested in assays found in the art or variations thereof. The isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or crude extracts containing the scale of enzymes capable of tissue degradation can be used. As a result of the MP inhibitory activity of the compounds of the invention, they are also useful for treating the following disorders by virtue of their metalloprotease activity. The compounds of this invention are also useful for prophylactic or acute treatment. They are administered in any way that experts in the fields of medicine or pharmacology desire. It is immediately apparent to the person skilled in the art that the preferred routes of administration will depend on the disease state being treated, as well as on the dosage form chosen. Preferred routes for systemic administration include peroral and 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 disorders. For example, it may be advantageous to administer MP inhibitors directly to the area of the disease or condition, such as in an area affected by surgical trauma (eg, angioplasty), an area affected by scarring or burn. (e.g., topical to the skin). Since the remodeling of the bones includes the MPs, the compounds of the invention are useful to prevent loosening of prostheses. It is known in the art that with the passage of time the prostheses become loose, become painful and can cause an additional injury to the bone, thus demanding a replacement. The need for replacement of such prostheses includes those such as in, joint replacements (for example hip, knee and shoulder replacements), dentures, including dentures, bridges and prostheses secured to the maxillium and / or jaw. MPs are also active to reshape the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons why angioplasty has a higher-than-expected long-term insufficiency index (reobstruction with time) is because MP activity is not desired or is high in response to what could be recognized by the body as "injury" to the base membrane of the blood vessel. Thus, the regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, restenosis by angioplasty and aortic aneurysm can increase the success of long term of any other treatment, or it may be a treatment in itself. In skin care, MPs are involved in the remodeling or "renewal" of the skin. As a result, the regulation of MPs improves the treatment of skin conditions, including but not limited to, wrinkle repair and regulation, prevention and repair of skin damage induced by ultraviolet rays. Such treatment includes prophylactic treatment or treatment before the physiological manifestations are obvious. For example, PM can be applied as a pre-exposure treatment to prevent ultraviolet damage and / or during or after exposure to prevent or minimize post-exposure damage. In addition, MPs are involved in disorders and skin diseases related to abnormal tissues that result from an abnormal manifestation which includes metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of "normal" skin injuries, including scarring or "shrinkage" of tissues, for example, after burns. Inhibition of MP is also useful in surgical procedures that include the skin for the prevention of scar formation and the promotion of normal tissue growth, including applications such as limb refraction and refractory surgery (either by laser or incision). In addition, MPs are related to disorders that include irregular remodeling of other tissues, such as bone, for example, in otosclerosis and / or osteoporosis, or 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 nerve tissue myelin sheaths. In this way, the regulation of MP activity can be used as a strategy in the treatment, prevention and control of said diseases. It is also believed that MPs are implicated in many infections, including cytomegalovirus; [CMV] retinitis; HIV and the resulting syndrome, AIDS.

MPs may also be involved in extravascularization where the surrounding tissue needs to be degraded to allow new blood vessels such as angiofibrone and hemangioma. Since MPs degrade the extracellular matrix, it is contemplated that the inhibitors of these enzymes can be used as agents for birth control, for example to prevent ovulation, to prevent the penetration of sperm into and through the extracellular environment of the egg, in the implantation of the fertilized egg and to avoid the maturation of the sperm. In addition, it is also contemplated that they are useful in preventing or stopping premature labor and delivery. Since MPs are involved in inflammatory responses and cytokine processing, the compounds are also useful as anti-inflammatories for use in diseases in which inflammation prevails, including, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout and Reiter's syndrome. When autoimmunity is the cause of the disorder, the immune response commonly triggers the activity of MP and cytokine. The regulation of MPs to treat such autoimmune disorders is a useful treatment strategy. In this way, MP inhibitors can be used to treat disorders including lupus erythema, ankylosing spondylitis and autoimmune keratitis. Sometimes the side effects of autoimmune therapy lead to the exacerbation of other conditions mediated by MPs, and MP inhibitor therapy is also effective here, for example, in fibrosis induced by autoimmune therapy. In addition, other fibrotic diseases lead to this type of therapy, including lung disease, bronchitis, emphysema, cystic fibrosis, acute respiratory distress syndrome (especially the acute phase response). When MPs are involved in unwanted tissue degradation by exogenous agents, it can be treated with MP inhibitors. For example, they are effective as an antidote to rattlesnake bite, as antivesics, to treat allergic inflammations, septicemia and shock. In addition, they are useful as antiparasitic (e.g., in malaria) and anti-infective. For example, they are believed to be useful for treating or preventing viral infections, including infection that would result in herpes, "cold" (e.g., rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS. It is also believed that MP inhibitors are useful for treating Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from, or originating from diabetes, especially those that include loss of viability. tissues, coagulation, Graft's disease vs. Host, leukemia, cachexia, anorexia, proteinuria and perhaps the regulation of hair growth. For some diseases, conditions or disorders, the inhibition of MP is contemplated as a preferred treatment method. Said diseases, conditions or disorders include arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or combating of the growth and metastasis of tumors), ocular disorders (especially corneal ulceration, lack of healing of the cornea, macular degeneration and pterygium); and gum diseases (especially periodontal disease and gingivitis). Compounds that are preferred 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. The compounds that are preferred for, but not limited to, the treatment of cancer (especially the prevention or combating of growth and tumor metastasis) are those compounds that preferably inhibit gelatinases or type IV collagenases. The compounds that are preferred for, but not limited to, the treatment of eye disorders (especially ulceration of the cornea, lack of healing of the cornea, macular degeneration and pterygium) are those compounds that widely inhibit mechaloproteases. Preferably, these compounds are administered topically, most preferably as a drop or gel. Compounds that are preferred for, but not limited to, the treatment of gum diseases (especially periodontal disease and gingivitis) are those compounds that preferentially inhibit collagenases.

Compositions; The compositions of the invention comprise: (a) a safe and effective amount of a compound of the formula (I); and (b) a pharmaceutically acceptable carrier. As mentioned above, it is known that numerous diseases are mediated by excessive or unwanted matrix destruction metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammations of the skin, ulcerations, particularly of the cornea, reactions to infections, periodontitis and the like. In this manner, the compounds of the invention are useful in therapy with respect to conditions that include this undesired activity. Therefore, the compounds of the invention can be formulated into pharmaceutical compositions useful for the treatment or prophylaxis of these conditions. Normal pharmaceutical formulation techniques are used, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., Most recent edition. A "safe and effective amount" of a compound of the formula (I) is an amount that is effective to inhibit matrix metalloproteases at the site or sites of activity, in a human or lower animal subject, without undue adverse side effects ( such as toxicity, irritation or allergic response), congested 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 patient's physical condition, the duration of the treatment, the nature of the concurrent therapy (if any), the form of specific dosage to be used, the vehicle employed, the solubility of the compound of the formula (I) therein and the desired dosage regimen for the composition. In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible solid or liquid filler or encapsulant substances that are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the composition are capable of being mixed with the present compound and with each other, such that there is no interaction that could substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. The pharmaceutically acceptable carriers must, of course, have a high enough purity and a toxicity low enough to make them suitable for administration to the human or lower animal 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; rattlers, stabilizers; antioxidants; conservatives; pyrogen-free water; isotonic saline solution and phosphate buffer solutions.

The choice of a pharmaceutically acceptable carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound will be administered. If the present compound will be injected, the pharmaceutically acceptable carrier that is preferred is a sterile physiological saline solution with a blood-compatible suspension agent, whose pH has been adjusted to about 7.4. In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and their derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers , isotonic saline solution and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier, in 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 herein, 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 a human or lower animal, in a single dose , according to the proper medical practice. These compositions preferably contain about 5 mg (milligrams) to about 1000 mg, most preferably about 10 mg to about 50 mg, more preferably 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 or parenteral administration. Depending on the particular administration route desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. These include liquid or solid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Optional pharmaceutically active materials may be included, which do not substantially interfere with the inhibitory activity of the compound of the formula (I). The amount of vehicle employed in conjunction with the compound of formula (I) is sufficient to provide a practical amount of material for administration per unit dose of the 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 herein by reference: Modern Pharmaceutics, Chapters 9 and 10. (Banker &; Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd. edition (1976). In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible solid or liquid filler or encapsulant substances that are suitable for administration to a human or lower animal. The term "compatible" as used herein, means that the components of the composition are capable of being mixed with the present compound and with each other, such that there is no interaction that could substantially reduce the pharmaceutical efficacy of the composition under certain conditions. of normal use. The pharmaceutically acceptable carriers must, of course, have a high enough purity and a sufficiently low toxicity to make them suitable for administration to the human or lower animal 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 carboxymethylcellulose, ethylcellulose and methylcellulose; 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 thiobroma 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; rattlers, stabilizers; antioxidants; conservatives; pyrogen-free water; isotonic saline solution and phosphate buffer solutions. The choice of a pharmaceutically acceptable carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound will be administered. If the present compound will be injected, the preferred pharmaceutically acceptable carrier is sterile physiological saline with a blood-compatible suspension agent, whose pH has been adjusted to about 7.4. Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and powders. These oral forms comprise a safe and effective amount, usually at least about 5% and preferably about 25% to about 50%, of the compound of the formula (I). The tablets can be compressed, comminuted, enteric-coated, sugar-coated, film-coated or multiple-compressed, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and preservatives. appropriate fusion. The liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, fusion agents, coloring agents and flavoring agents. The pharmaceutically acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well known in the art. The tablets typically comprise conventional pharmaceutically compatible adjuvants such as inert diluents, calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.; binders such as starch, gelatin and sucrose; disintegrants such as starch; alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Slip agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents such as FD &C dyes can be added to improve appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint and fruit flavors are also useful adjuvants for chewable tablets. The capsules typically comprise one or more of the solid diluents described above. The selection of vehicle components depends on secondary considerations such as flavor, cost and stability at the counter, which are not critical 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. Pharmaceutically acceptable carriers useful for the preparation of such compositions are well known in the art. Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, carboxymethylcellulose, AvicelRRC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. The peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents and colorants described above. Said compositions can also be coated by conventional methods, typically with pH or time dependent coatings, such that the present compound is released into the gastrointestinal tract, in the vicinity of the desired topical application or several times to extend the desired action . Said dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, dihydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and lacquer. The compositions of the present invention may optionally include other drug actives. Other compositions useful for achieving systemic delivery of the present compounds include sublingual, buccal and nasal dosage forms. Said compositions typically comprise one or more soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Also described above and may include slip agents, lubricants, sweeteners, colorants, antioxidants and flavoring agents. The compositions of the present invention can also be administered topically to a subject, e.g., by direct placement or dispersion of the composition on the epidermal or epithelial tissue of the subject, or transdermally by means of a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1% and preferably about 1% to about 5%, of the compound of the formula (I). 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. In general, the vehicle is of an organic nature and capable of having the compound of the formula (I) dispersed or dissolved therein. The vehicle may include emollients, emulsifiers, thickening agents and pharmaceutically acceptable solvents, and the like.

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

The inhibitors of the invention can be sent to specific sites where the matrix tr.etaloprotease is accumulated using selection ligands. For example, to target inhibitors to matrix metalloproteases contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof that is immunoreactive with a tumor marker as it is generally understood in the preparation of immunotoxins in general. The selection ligand may also be a suitable ligand for a receptor that is present in the tumor. Any selection ligand that specifically reacts with a marker for the target tissue can be used. The methods for coupling the compound of the invention to the selection ligand are well known and are similar to those described below for coupling to the vehicle. The conjugates are formulated and administered as described above. For localized conditions, topical administration is preferred. For example, to treat ulcerated cornea, direct application to the affected eye can use a formulation such as eye drops or spray. For the treatment of the cornea, the compounds of the invention can also be formulated as gels or ointments, or they can be incorporated into collagen or a hydrophilic polymer shell. The materials can also be inserted as a contact lens or reservoir, or as a subconjunctive formulation. For the treatment of inflammations of the skin, the compound is applied locally and topically, in gel, paste, ointment or ointment.

The mode of treatment then reflects the nature of the condition, and suitable formulations for any selected route are available in the art. In all of the foregoing, of course, the compounds of the invention may be administered alone or as mixtures, and the compositions may further include additional drugs or excipients, as appropriate for the indication. Some of the compounds of the invention also inhibit bacterial metalloproteases, although generally at a level lower than that exhibited with respect to mammalian metalloproteases. Some bacterial metalloproteases appear to be less dependent on the stereochemistry of the inhibitor, while substantial differences are found between the diastereomers in their ability to inactivate mammalian proteases. In this way, this pattern of activity can be used to distinguish between mammalian and bacterial enzymes.

Preparation and use of antibodies: The compounds of the invention can also be used in immunization protocols to obtain immunospecific antisera for the compounds of the invention. Since the compounds of the invention are relatively small, they are advantageously coupled to antigenically neutral vehicles such as conventionally used lockhead hemocyanin (KLH) or whey albumin vehicles. For those compounds of the invention having a carboxyl functionality, coupling to the carrier could be done by methods generally known in the art. For example, the carboxyl residue can be reduced to an aldehyde and coupled to the carrier by reaction with side chain amino groups in protein-based vehicles, optionally followed by the reduction of the imino bond formed. The carboxyl residue can also be reacted with side chain amino groups using condensing agents such as dicyclohexylcarbodiimide or other carbodiimide dehydration agents. Binding compounds can also be used to carry out the coupling; Both ob-functional and heterobifunctional linkers are available from Pierce Chemical Company, Rockford, III. The resulting immunogenic complex can then be injected into suitable mammalian subjects, such as mice, rabbits and the like. Suitable protocols include the repeated injection of the immunogen in the presence of adjuvants according to a program that promotes the production of antibodies in the serum. Immune serum concentrations can be easily measured using immunoassay methods, now common in the art, using the compounds of the invention as antigens. The antisera obtained can be used directly or monoclonal antibodies can be obtained by culturing peripheral blood lymphocytes or the spleen of the immunized animal and immortalizing the antibody producing cells, followed by identification of the appropriate antibody producers using normal immunoassay techniques. Polyclonal or monoclonal preparations are then useful for monitoring therapy or prophylaxis regimens that include the compounds of the invention. Suitable samples such as those derived from blood, serum, urine or saliva can be tested to verify the presence of the inhibitor administered several times during the treatment protocol using normal immunoassay techniques employing the antibody preparations of the invention. The compounds of the invention can also be coupled to markers such as scintigraphic labels, e.g., technetium 99 or 1-131, using normal coupling methods. The labeled compounds are administered to subjects to determine the sites of excessive amounts of one or more matrix metalloproteases in vivo. The ability of the inhibitors to selectively bind to matrix metalloproteases to map the distribution of these enzymes in situ is then exploited. The techniques can also be employed in histological procedures and the labeled compounds of the invention can be used in competitive immunoassays. The following non-limiting examples illustrate the compounds, compositions and uses of the present invention EXAMPLESCompounds are analyzed using iH and 13C NMR, elemental analysis, mass spectrum and / or RI spectrum, as desired. Typically, inert solvents are used, preferably in dry form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and all other solvents are purchased as the proper gradation. Chromatography is carried out on silica gel (70-230 sieve, Aldrich) or (sieve 230-400, Merck) as desired. The tin layer chromatography analysis is carried out on glass-mounted silica gel plates (200-300 sieve, Baker) and visualized with UV or with phosphomolybdic acid in EtOH.

EXAMPLE I Preparation of N-hydroxy-2,2-dimethyl-S, S-dioxo-4- [(4'-methoxyphenyl) sulfonyl] thiazepine-3 (S) -carboxamide the. Methyl N- [(4-methoxyphenyl) sulfonyl] -S- (2-hydroxypropyl) -D-penicillamine: D-penicillamine (29.8 g, 0.2 mol) in 2N NaOH (135 ml., 0.27 mol, 1.35 equiv.) Is stirred at 0 ° C under an argon atmosphere. A solution of 2-bromopropanol (36.1 g, 0.26 mol, 1.3 equiv) in ethanol (200 ml) is slowly added dropwise at 0 ° C. The resulting solution is stirred overnight at room temperature and then the mixture is acidified to pH -6 with IN HCl. The solvent is removed under reduced pressure to leave a thick oil. The penicillamine adduct is then dissolved in dioxane (200 ml) and water (200 ml) and stirred at room temperature. Triethylamine (58.6 g, 0.58 mol, 3 equiv) is then added to the reaction mixture followed by 4-methoxyphenylsulfonyl chloride (40.0 g, 0.193 mol). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified to pH -2 with IN HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts were dried (MgSO 4) and concentrated to an oil under reduced pressure. The resulting oil is diluted in methanol (30 ml) and enough diazomethane in diethyl ether is added to form a yellow solution. The mixture is concentrated under reduced pressure to leave an oil without color. The purification of the resulting methyl ester is achieved by chromatography on silica gel using 1/1 hexane / EtOAc as the eluent. The desired product is obtained as a clear, colorless oil. lb. 4-N- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxylic acid methyl ester: The methyl ester (30.0 g, 76.6 mmol) in THF (400 mL) is stirred at room temperature. and then triphenylphosphine (24.1 g, 91.9 mmol, 1.2 equiv) followed by diethyl azodicarboxylate (14.7 g, 84.3 mmol, 1.1 equiv) is added. The resulting solution is stirred at room temperature for 2 hours. The solvent is removed and then the coarse yellow oil is diluted with methylene chloride and silica gel (60 g) is added. The solvent is removed to leave a white powder. This powder is placed on a chromatography column and levigated with 8/2 hexane / EtOAc. The desired product is obtained as a colorless oil. MS (ESI): 374 (M + + H), 391 (M + + NH 4). you. Acid. 4- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxylic acid: The methyl ester Ib (26.7 g, 71.5 mmol) in pyridine (400 ml) is stirred at room temperature under an argon atmosphere . Lithium iodide (115 g, 858 mmol, 12 equiv) is added and the resulting solution is heated to reflux for 3 hours. The reaction mixture is cooled to room temperature and then the solution is acidified with IN HCl. The mixture is extracted with methylene chloride and then the organic layers were dried (Na2 =? 4) and concentrated to an oil under reduced pressure. The oil is purified by column chromatography using 1/1 hexane / EtOAc as the eluent to provide the desired product as a light yellow oil. MS (ESI): 360 (M + + H), 377 (M + + NH 4). ld. N-hydroxy-4- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxyamide: The carboxylic acid (14.9 g, 41.6 mmol) in dichloromethane (200 ml) is stirred at room temperature and then oxalyl chloride (10.8 g, 85.2 mmol, 2.05 equiv) and DMF (3.04 g, 4.6 mmol) are added. The resulting solution is stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (11.6 g, 166 mmol, 4 equiv) in THF (50 ml) and water (10 ml) is added at 0 ° C. Triethylamine (25.3 g, 249.6 mmol, 6 equiv) is added and the resulting solution is stirred at 0 ° C for 15 minutes. The hydrochloric acid solution is then added to the hydroxylamine solution at 0 ° and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is then acidified with IN HCl and then extracted with dichloromethane. The organic extracts were dried (Na 2 S 4) and concentrated to a solid under reduced pressure. The solid is recrystallized from CH3CN to give a white powder. MS (ESI): 392 (M + + NH 4), 375 (M + + H).

EXAMPLE 2 Preparation of N-hydroxy-S, S-dioxo-4- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxamide 2a. N-hydroxy-S, S-dioxo-4- [(4-methoxyphenyl) sulfonyl] -2-dimethyl-thiazinespine-3-carboxamide: Hydroxamic acid ld (47. g, 12.55 mmol) is dissolved in chloroform (50 ml ) at 0 ° C in an ice bath. A solution of 32% peracetic acid (7.9 ml, 37.65 mmol, 3.0 equiv in acetic acid) is added and the mixture is then stirred at room temperature. A 32% equivalent peracetic acid of 3 is added after 3 hours and the resulting mixture is stirred overnight. Once the reaction is complete, the peracetic acid is removed under reduced pressure. The white solid is recrystallized from acetonitrile to give a white powder. MS (ESI): 407 (M + + H).

EXAMPLE 3 Preparation of 3 (S) -N-Hidoxy-N-methyl-2,2-dimethyl-4N- [(4-methoxyphenyl) sulfonyl] -thiazepine-3-carboxamide 1c 3a 3a. 3 (S) -N-hydroxy-N-methyl-2,2-dimethyl-4N- [(4-methoxyphenyl) sulfonyl] -thiazepine-3-carboxamide:? L carboxylic acid (1.10 g, 3.06 mmol) in dichloromethane (25 ml) is stirred at room temperature and then oxalyl chloride (0.80 g, 6.27 mmoles, 2.05 equiv) and DMF (0.22 g, 3.06 mmoles) are added. The resulting solution is stirred at room temperature for 30 minutes. In a separate flask, N-methylhydroxylamine hydrochloride (1.02 g, 12.24 mmol, 4 equiv) in THF (8 ml) and water (2 ml) are stirred at 0 ° C. Triethylamine (1.85 g, 18.4 mmol, 6 equiv) is added and the resulting solution is stirred at 0 ° C for 15 minutes. The hydrochloric acid solution is then added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is acidified with IN HCl and then extracted with dichloromethane. The organic extracts are dried (a2S? 4) and concentrated to a solid under reduced pressure. The solid is purified by reverse phase chromatography (Ci) HPLC to give a white powder. MS (ESI): 389 (M + + H).

EXAMPLE 4 Preparation of N-hydroxy-S, S-dioxo-2,2-dimethyl-4- [(4-bromophenyl) sulfonyl] thiazepine-3 (S) -carboxamide 4a 'Methyl N- [(4-bromophenyl) sulfonyl] -S- (2-hydroxypropyl) -D-penicillamine: Q-penicillamine (20.9 g, 134.0 mmol) in 2N NaOH (88 ml, 174.2 mmol, 1.35 equiv) is stir at 0 ° C under an argon atmosphere. A solution of 2-bromopropanol (26.0 g, 187.7 mmol, 1.3 equiv) in ethanol (150 ml) is slowly added dropwise at 0 ° C. The resulting solution is stirred overnight at room temperature and then the mixture is acidified to pH -6 with 1N HCl. The solvent is removed under reduced pressure to leave a thick oil. The penicillamine adduct is then dissolved in dioxane (150 ml) and water (150 ml) and stirred at room temperature. Triethylamine (40.6 g, 402 mmol, 3 equiv) is then added to the reaction mixture followed by 4-bromophenylsulfonyl chloride (41.1 g, 160.8 mmol). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified to pH -2 with IN HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts were dried (MgSO4) and concentrated to an oil under reduced pressure. The resulting oil is diluted in methanol (30 ml) and enough diazomethane in diethyl ether is added to form a yellow solution. The mixture is concentrated under reduced pressure to leave an oil without color. The purification of the resulting methyl ester is achieved by chromatography on silica gel using 40% ethyl acetate / 60% hexane as the eluent. The desired product is obtained as a clear, colorless oil. MS (ESI): 440.442 (M + + H), 457.459 (M * + NH4). 4b 4N- [(4-bromophenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxylic acid methyl ester: The methyl ester 4a (31.0 g, 70.6 mol) in THF (400 ml) is stirred at room temperature and then triphenylphosphine (22.2 g, 84.7 mmoles, 1.2 equiv) followed by diethyl azodicarboxylate (13.5 g, 77.7 mmoles, 1.1 equiv) is added. The resulting solution is stirred at room temperature for 2 hours. The solvent is removed and then the coarse yellow oil is diluted with methylene chloride and silica gel (60 g) is added. The solvent is removed to leave a white powder (the compound absorbs on silica gel). This powder is placed on a chromatography column and eluted with 9/1 hexane / EtOAc. The desired product is obtained as a colorless oil. EM (IEA): 422,424 (M + + H), 439.441 (M + + NH4). 4c. 4- [(4-Bromophenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxylic acid: The methyl ester 4b (24.8 g, 58.9 mmol) in pyridine (350 ml) is stirred at room temperature under an argon atmosphere . Lithium iodide (107 g, 706 mmol, 12 equiv) is added and the resulting solution is heated to reflux for 3 hours. The reaction mixture is cooled to room temperature and then the solution is acidified with IN HCl. The mixture is extracted with methylene chloride and then the organic extracts were dried (N2SO4) and concentrated to an oil under reduced pressure. The oil is purified by column chromatography using 1/1 hexane / EtOAc as the eluent to provide the desired product as a light yellow oil. MS (ESI): 408.410 (M + + H), 425.427 (M + + NH4). 4d. N-Hydroxy-4- [(4-bromophenyl) sulfonyl] -2, 2, dimethyl-thiazepine-3-carboxamide: The carboxylic acid 4c (14.65 g, 36.0 mmol) in dichloromethane (200 ml) is stirred at room temperature and then oxalyl chloride (9.4 g, 73.8 mmol, 2.05 equiv) and DMF (2.63 g, 360 mmol) were added. The resulting solution is stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (10.0 g, 144.0 mmol, 4 equiv) in THF (50 ml) and water (10 ml) is stirred at 0 ° C. Tritylamine (21.8 g, 216 mmol, 6 equiv) is added and the resulting solution is stirred at 0 ° C for 15 minutes. The Doric acid solution is then added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is then acidified with 1 N HCl and then extracted with dichloromethane. The organic extracts were dried (Na 2 S 4) and concentrated to a solid under reduced pressure. The solid is recrystallized from acetonitrile to give a white powder. MS (ESI): 423, 425 (M + + H).

EXAMPLE 5 Preparation of N-hydroxy-S, S-dioxo-4 - [(4-bromo-enyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboximide 6a F. P .29 fig 5a. N-hydroxy-S, S-dioxo-4- [(4-bromophenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxamide: the hydroxamic acid (4.2 g, 9.9 mmol) is added to chloroform (50 ml ). The suspension was cooled to 0 ° C followed by the addition of peracetic acid (32% Aldrich's solution) (6.4 ml, 29.7 mmoles, 3.0 equiv). The solution becomes clear with the addition of peracetic acid. The resulting solution is then heated to room temperature. After being stirred overnight, the peracetic acid is removed under reduced pressure and the resulting solid is recrystallized from acetonitrile. MS (ESI): 455, 457 (M + + H).

EXAMPLE 6 Preparation of N-hydroxy-4- [(4-butoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxamide 6a. Methyl N- t (4-butoxyphenyl) sulfonyl] -S- (2-hydroxypropyl) -D-phenycylamine: D-Penicillamine (2.5 g, 16.7 mmol) in 2N NaOH (18 mL, 1.35 equiv) is stirred at 0 ° C under an Argon atmosphere. A solution of 2-bronopropanol (3.24 g, 23.4 mmol, 1.4 equiv) in ethanol (20 ml) is slowly added dropwise at 0 ° C. The resulting solution is stirred overnight at room temperature and then the mixture is acidified to pH-6 with IN HCl. The solvent is removed under reduced pressure to leave a thick oil. The penicillamine adduct is then dissolved in dioxane (30 ml) and water (30 ml) and stirred at room temperature. Triethylamine is then added to the reaction mixture followed by 4-n-butoxyphenylsulfonyl chloride (7.0 ml, 50.1 mmoles, 3 equiv). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified to pH-2 with 1H HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts are dried (MgSO4) and concentrated to an oil under reduced pressure. The resulting oil is diluted in methanol (30 ml) and enough diazomethane in diethyl ether is added to form a yellow solution. The mixture is concentrated under reduced pressure to leave an oil without color. The purification of the resulting methyl ester is achieved by chromatography on silica gel using 3/2 hxan / EtOAc as the eluent. The desired product is obtained as a clear, colorless oil. MS (ESI): 434, (M + + H), 451 (M + + NH 4). 6b. 4N- [(4-Butoxyphenyl) sulfonyl] -, 2-dimethyl-thiazepine-3-carboxylic acid methyl ester: The methyl ester 6a (3.3 g, 7.6 mmol) in THF (30 ml) is stirred at room temperature and then triphenylphosphine ( 2.39 g, 9.12 mmol, 1.2 equiv) followed by diethyl azodicarboxylate (1.45 ml, 8.36 mmol, 1.1 equiv) is added. The resulting solution is stirred at room temperature for 2 hours. The solvent is removed and then the coarse yellow oil is diluted with methylene chloride and silica gel (10 g) is added. The solvent is removed to leave a white powder. This powder is placed on a column chromatography and levigated with 9/1 hexane / EtOAc. The desired product is obtained as a colorless oil. MS (ESI): 416, (M + + H) 433 (M + + NH 4). 6c. 4- [(4-Butoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxylic acid: The methyl ester 6b (2.1 g, 5.06 mmol) in pyridine (50 ml) is stirred at room temperature under an atmosphere of argon. Lithium iodide (8.13 g, 60.7 mmol, 12 equiv) is added and the resulting solution is heated to reflux for 3 hours. The reaction mixture is cooled to room temperature and then the solution is acidified with IN HCl. The mixture is extracted with methylene chloride and then the organic extracts are dried (Na 2 S 4) and concentrated to an oil under reduced pressure. The oil showed 95.5% purity on HPLC analysis using a solvent system of 4% A (95% water, 5% acetonitrile 0.1% formic acid) and 60% B (20% water, 80% acetonitrile). The product is a colorless oil, which did not require further purification. MS (ESI): 4402, (M + + H), 419 (M ++ NH4). 6d. N-hydroxy-4- [(4-butoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepin-3-carboxamide:? Carboxylic acid (1.65 g, 4.15 mmol) in dichloromethane (20 ml) is stirred at room temperature and then oxalyl chloride (1.08 g, 8.5 mmol, 2.05 equiv) and DMF (0.3 g, 4.15 mmol) are added. The resulting solution is stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (1.25 g, 18.0 mmol, 4 equiv) in THF (20 ml) and water (5 ml) is stirred at 0 ° C. Triethylamine (2.5 g, 24.9 mmol, 6 equiv) is added and the resulting solution is stirred at room temperature for 15 minutes. The Doric acid solution is then added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is then acidified with IN HCl and then extracted with dichloromethane. The organic extracts are dried (a2S? 4) and concentrated to a solid under reduced pressure. The solid is recrystallized from CH3CN / H2O to provide a white powder. MS (IA?): 417 (M + + H) 434 (M ++ NH4).

EXAMPLE 7 Preparation of N-hydroxy-S, S-dioxo-2,2-dimethyl- [4- (4-butoxyphenyl) sulfonyl] -thiazepine-3-carboxamide 7a 7a. N-hydroxy-S, S-dioxo-2,2-dimethyl- [4- (4-butoxyphenyl) sulfonyl] -thiazepine-3-carboxamide:? Hydroxamic acid (0.50 g, 1.2 mmol) is dissolved in chloroform (10 ml) to form a suspension. Peracetic acid (0.855 g, 3.6 mmol, 3.0 equiv) is added afterwards, and the resulting clear solution is stirred overnight. The solvents are removed under reduced pressure to leave a white solid. The purification is achieved by recrystallization with acetonitrile to form a white powder. MS (ESI): 449 (M + + H), 466 (M ++ NH4).

EXAMPLE 8 Preparation of N-hydroxy-4- [(2-methyl-4-bromophenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxamide 8a. Methyl N- [(2-methyl-4-bromophenyl) sulfonyl] -S- (2-hydroxypropyl) -D-penicillamine: D-penicillamine (3.0 g, 20.1 mmol) in 2N NaOH (18 mL, 1.35 equiv) is stirred at 0 ° C under an Argon atmosphere. A solution of 2-bromopropanol (3.91 g, 28.1 mmol, 1.4 equiv) in ethanol (20 ml) is slowly added dropwise at 0 ° C. The resulting solution is stirred overnight at room temperature and then the mixture is acidified to PH-6 with IN HCl. The solvent is removed under reduced pressure to leave a thick oil. The penicillamine adduct is then dissolved in dioxane (30 ml) and water (30 ml) and stirred at room temperature. Triethylamine (8.3 ml, 60.0 mmol, 3 equiv) is then added to the reaction mixture followed by 2-methyl-4-bromophenylsulfonyl chloride (6.5 g, 24.1 mmol). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified to pH-2 with IN HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts are dried (MgSO4) and concentrated to an oil under reduced pressure. The resulting oil is diluted in methanol (30 ml) and enough diazomethane in diethyl ether is added to form a yellow solution. The mixture is concentrated under reduced pressure to leave an oil without color. The purification of the resulting methyl ester is achieved by chromatography on silica gel using 1/1 hexane / EtOAc as the eluent. The desired product is obtained as a clear, colorless oil. M (IEA): 456, 458 (M + + H), 473, 475 (M + + NH 4). 8b. Methyl 4N- [2-methyl-4-bromophenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxylate:? L methyl ester 8a (4.2 g, 9.4 mmol) in THF (30 ml) is stirred at room temperature environment and then triphenylphosphine (2.95 g, 10.3 mmol, 1.2 equiv) followed by diethyl azodicarboxylate (1.63 ml, 11.3 mmol, 1.1 equiv) is added. The resulting solution is stirred at room temperature for 2 hours. The solvent is removed and then the coarse yellow oil is diluted with methylene chloride and silica gel (10 g) is added. The solvent is removed to leave a white powder. This powder is placed on a column of chromatography and levigated with 9/1 hexane /? tOAc. The desired product is obtained as a colorless oil. MS (ESI): 436, 438 (M + + H), 453, 455 M + + NH 4). 8c. 4- [(2-Methyl-4-bromphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxylic acid:? L Methyl ester 8b (2.4 g, 5.45 mmol) in pyridine (75 ml) is stirred at room temperature environment under an atmosphere of Argon. Lithium iodide (8.69 g, 65.4 mmol, 12 equiv) is added and the resulting solution is heated to reflux for 3 hours. The reaction mixture is cooled to room temperature and then the solution is acidified with IN HCl. The mixture is extracted with methylene chloride and then the organic extracts are dried (NaS04) and concentrated to an oil under reduced pressure. The oil showed 97% purity on HPLC analysis using a solvent system of 40% A (95% water, 5% acetonitrile, 0.1% formic acid) and 60% B (20% water, 80% acetonitrile), the product had a retention time of 9.58. The product is a colorless oil, which did not require further purification. M (IEA): 422, 424 (M + + H), 439, 441 (m + + NH 4). 8d. N-hydroxy-4- [(2-methyl-4-brromophenyl) sulfonyl] -2,2-dimethyl-thiazepin-3-carboxamide: The carboxylic acid 8c (1.65 g, 3.9 mmol) in dichloromethane (20 ml) is stirred at room temperature and the hoxalyl chloride (1.01 g, 7.9 mmoles, 2.05 equiv) and DMF (0.28 g, 3.9 mmoles) are added. The resulting solution is stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (1.1 g, 15.6 mmol, 4 equiv) in THF (20 ml) and water (5 ml) is stirred at 0 ° C. Triethylamine (2.4 g, 23.4 mmol, 6 equiv) is added and the resulting solution is stirred at 0 ° C for 15 minutes. The Doric acid solution is then added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is then acidified with IN HCl and then extracted with dichloromethane. The organic extracts are dried (Na2SO4) and concentrated to a solid under reduced pressure. The solid is recrystallized from CH3CN / H2O to provide a white powder. MS (ESI): 437, 439 (M + + H), 454, 456 (M + + NH 4).

EXAMPLE 9 Preparation of N-hydroxy-6-hydroxy-2,2-dimethyl-S, S-dioxo-4- [(4-methoxyphenyl) sulfonyl] -thiazepine-3 (S) -carboxamide •• M 9a. Methyl N- [(4-methoxyphenyl) sulfonyl] -S- [(2,2-diethyl-l, 3-dioxolan-4-yl) methyl] -D-penicillamine: D-Penicillamine (9.56 g, 64.1 mmol) in 2N NaOH (41.7 mL, 83.3 mmol, 1.3 equiv) is stirred at 0 ° C under an Argon atmosphere. A solution of (S) -4- (bromomethyl) -2,2-dimethyl-l, 3-dioxolane (15.0 g, 76.9 moles, 1.2 equiv, Ref: Ka akami et al., J. Org. Cem. 1982, 47 , 3581) in ethanol (30 ml) is slowly added dropwise to the reaction mixture at 0 ° C. The resulting solution is stirred overnight at room temperature and then the mixture is acidified to pH-6 with IN HCl. The solvent is removed under reduced pressure to leave a thick oil. The penicillamine adduct is then dissolved in dioxane (75 ml) and water (75 ml) and stirred at room temperature. Triethylamine (19.5 g, 192.3 mmol, 3 equiv) is then added to the reaction mixture followed by 4-methoxyphenylsulfonyl chloride (15.9 g, 76.9 mmol). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified at pH-2 with IN HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts are dried (MgSO 4) and concentrated to an oil under reduced pressure. The resulting oil is diluted in methanol (30 ml) and enough diazomethane in diethyl ether is added to form a yellow solution. The mixture is concentrated under reduced pressure to leave an oil without color. The purification of the resulting methyl ester is achieved by chromatography on silica gel using 8/2 hexane / EtOAc as the eluent. The desired product is obtained as a clear oil, colorless. MS (ESI): 448 (M + + H), 465 (M + + NH). 9b. Methyl 2 (S) -N- [(4-methoxyphenyl) sulfonyl] -S- (2,3-dihydroxypropyl) -D-penicillamine: acetonide 9a (11.1 g, 24.8 mmol) in THF (50 mL) is stirred at Room temperature and the IN HCl is added. The resulting mixture is stirred overnight at room temperature until all the starting material is consumed. The reaction mixture is concentrated to remove the THF and then the aqueous layer is. extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated to an oil under reduced pressure. No further purification was performed. The product (10.0 g, 99%) is obtained as a colorless oil. 9c. Methyl N- [(4-methoxyphenyl) sulfonyl] -S- (2 (S) -hydroxy-3-t-butyldimethylsiloxypropyl) -D-penicillamine: diol 9b (10.0 g, 24.5 mmolar) in methylene chloride (150 mL ) is stirred at room temperature and then triethylamine (2.73 g, 27 mmol), 1.1 equiv) and dimethylaminopyridine (100 mg, 0.04 equiv) is added. The t-butyldimethylsilyl chloride (3.7 g, 24.5 mmolar) is added and the resulting mixture is stirred at room temperature overnight. The reaction mixture is poured into dilute sodium bicarbonate solution and extracted with methylene chloride. The organic extracts are dried (Na 2 SO 4) and then concentrated to an oil under reduced pressure. The purification of the oil is achieved by chromatography on silica gel using 7/3 hexane / EtOSc as the eluent. The product is obtained as a clear oil, without color. 9d. Methyl N [(4-methoxyphenyl) sulfonyl] -S- (2 (S) -methoxymethoxy-3-t-butyldimethylsiloxypropyl) -D-penicillamine: sodium iodide (12.0 g, 80 mmol, 4 equiv) is stirred in dimethoxyethane ( 120 mL) at room temperature and then chloromethyl methyl ether (8.2 g, 102 mmol, 5. 1 equiv) is added. A formed brown suspension that is heated on contact. The resulting mixture is stirred for 10 minutes and alcohol 9c (10.5 g, 20 mmol) and diisopropylethylamine (14.3 g, 110 mmol, 5.5 equiv) in dimethoxyethane (30 mL) is added. The mixture is stirred at room temperature for one hour and then heated to reflux for 4 hours. The reaction mixture is poured into saturated sodium bicarbonate solution and then extracted with methylene chloride. The organic extracts are dried (Na2 =? 4) and then concentrated to an oil under reduced pressure. The oil is purified by chromatography on silica gel using 8/2 hexen /? TOAc as the eluent. The product is obtained as a yellow oil. 9e. Methyl N- [(4-methoxyphenyl) sulfonyl] -S- (2 (S) -methoxymethoxy-3-hydroxypropyl) -D-penicillamine: Silyl ether 9d (3.16 g, 5.58 mmolar) in THF (25 mL) is cooled to 0 ° C and then tetrabutylammonium fluoride (1.0 M in THF, 14 mL, 2.5 equiv) is added. The resulting mixture is stirred at 0 ° C for 30 minutes and heated to room temperature. The reaction mixture is stirred for an additional 3 hours. The reaction mixture is poured into saturated sodium bicarbonate solution and then extracted with methylene chloride. The organic extracts are dried (Na 2 S 4) and then concentrated to an oil under reduced pressure. The oil is purified by chromatography on silica gel using l / l hexane / EtOAc as the eluent. The product is obtained as a clear oil, without color. 9f. Methyl 6 (S) -methoxymethyl-4N- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3 (S) -carboxylic acid methyl ester:? L methyl ester 9c (1.9 g, 4.3 mmolar) in THF (15 mL) is stirred at room temperature and then triphenylphosphine (1.35 g, 5.16 mmol, 1.2 equiv) followed by diethyl azodicarboxylate (0.82 g, 4.73 mmol, 1.1 equiv) is added. The resulting solution is stirred at room temperature for 2 hours. The solvent is removed and then the coarse yellow oil is diluted with methylene chloride and silica gel (20 g) is added. The solvent is removed to leave a white powder. This powder is placed on a chromatography column and levigated with 8/2 hexane / EtOAc. The desired product is obtained as a colorless oil. EM (IEA): 434 (M ++ H), 451 (M ++ NH4). 9g. 6-Methoxymethyl-4- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3 (S) -carboxylic acid: methyl ester 9f (2.2 g, 5.07 mmol) in pyridine (40 mL) is stirred at room temperature under an argon atmosphere. Lithium iodide (8.15 g, 61.9 mmol, 12 equiv) is added and the resulting solution was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and then the solution was acidified with IN HCl. The mixture was extracted with methylene chloride and then the organic layers were dried (Na 2 SO 4) and concentrated to an oil under reduced pressure. The oil was purified by column chromatography using 1/1 hexane /? TOAc as the eluent to provide the desired product as a light yellow oil. M (IEA): 420 (M + + H), 437 (M + + NH4), 442 (M + + Na). 9h N-Hydroxy-6-methoxymethyl-4- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboximide: The carboxylic acid 9g (2.35 g, 5.6 mmolar) in acetonitrile (15 mL) is stirred at room temperature and then oxalyl chloride (1.46 g, 11.5 mmolar, 2.05 equiv) and DMF (0.41 g, 5.6 mmolar) are added. The resulting solution is stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (1.56 g, 22.4 mmol, 4 equiv) in THF (10 mL) and water (2 mL) is stirred at 0 ° C. Triethylamine (3.40 g, 33.6 mmolar, 6 equiv) is added and the resulting solution is stirred at 0 ° C for 15 minutes. The chloride acid solution is then added to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is acidified with IN HCl and then extracted with dichloromethane. The organic extracts are dried (Na 2 S 4) and concentrated in a solid under reduced pressure. The solid is purified by reverse phase HPLC using 60/40 water / acetonitrile as the eluent to give a white powder. MS (ESI): 373 (M + + H).

EXAMPLE 10 Preparation of N-Hydroxy-S, S-dioxo-6-hydroxy -4 - [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-thiazepine-3-carboxamide 10a. N-Hydroxy-S, S-dioxo-6-hydroxy-4- [(4-methoxyphenyl) sulfonyl] -2, 2-dimethyl-thiazepine-3-carboxamide: Hydroxamic acid 9h (1.30 g, 2.99 mmolar) is dissolved in chloroform (50 mL) and the mixture is stirred at room temperature. A 32% solution of peracetic acid (3.03 mL, 11.97 mmol, 4.0 equiv) is added and the resulting mixture is stirred at room temperature. The solvent and remaining peracetic acid is removed under reduced pressure to leave the desired product as a white solid. The solid is recrystallized from acetonitrile to provide the product as a white crystalline solid. MS (ESI): 423 (M + H +).

EXAMPLE 11 Preparation of 3 (S) -N-hydroxy-2,2-dimethyl-4- [(4-methoxyphenyl) sulfonyl] octahydro-1,4-thiazinone-3-carboxamide 11b 11c n lia Methyl N- [(4-methoxyphenyl) sulfonyl] -S- (2-hydroxypentyl) -D-penicillamine: D-penicillamine (5.0 g, 33.5 mmolar) in 2N NaOH 821.8 mL, 43.6 mmolar, 1.3 equiv) is stirred at 0 ° C under an argon atmosphere. A solution of 1-chlorofentanol (4.92 g, 40.2 mmolar, 1.2 equiv) in ethanol (30 mL) is added slowly by dripping at 0 ° C. The resulting solution is stirred overnight at room temperature and then the mixture is acidified to pH-6 with IN HCl. The solvent is removed under reduced pressure to leave a thick oil.

The penicillamine adduct is then dissolved in dioxane (100 mL) and water (100 mL) and stirred at room temperature. Triethylamine (10.2 g, 100 mmolar, 3 equiv.) Is then added to the reaction mixture followed by 4-methoxyphenylsulfonyl chloride (7.62 g, 36.9 mmolar, 1.1 equiv). The resulting homogeneous solution is stirred at room temperature for 18 hours and then acidified to pH-2 with 1 N HCl. The solution is poured into water and extracted with methylene chloride. The organic extracts are dried (MgSO4) and concentrated to an oil under reduced pressure. The resulting oil is diluted in methanol (20 mL) and enough diazomethane in diethyl ether is added to form a yellow solution. The mixture is concentrated under reduced pressure to leave an oil without color. The purification of the resulting methyl ester is achieved by chromatography on silica gel using 6/4 hexane / EtOAc as the eluent. The desired product is obtained as a clear, colorless oil. ? M (IEA): 420 (M ++ H), 437 (M ++ NH4). llb. 3 (S) -N-hydroxy-2, 2-dimethyl-4- [(4-methoxyphenyl) sulfonyl] octahydro-1,4-thiazonine-3-methylcarboxylate: the methyl ester lia (2.1 g, 5.0 mmolar ) in THF (50 mL) is stirred at room temperature and then triphenylphosphine (1.58 g, 6.0 mmolar, 1.2 equiv) followed by diethyl azodicarboxylate (0.96 g, 5.50 mmol), 1.1 equiv) is added. The resulting solution is stirred at room temperature for 18 hours. The solvent is removed and then the coarse yellow oil is diluted with methylene chloride and silica gel (15 g) is added. The solvent is removed to leave a white powder. This powder is placed on a chromatography column and levigated with 8/2 hexane /? TOAc. The desired product is obtained as a colorless oil. ? M (I? A): 402 (M ++ H), 419 (M ++ NH4). 11c. 3 (S) -N-Hydroxy-2,2-dimethyl-4- [(4-methoxyphenyl) sulfonyl] octahydro-1,4-thiazonine-3-carboxylic acid: The methyl ester llb (0.44 g, 1.10 mmol) in pyridine (10 mL) is stirred at room temperature under an argon atmosphere. Lithium iodide (1.76 g, 13.1 mmol, 12 equiv) is added and the resulting solution is heated to reflux for 5 hours. The reaction mixture is cooled to room temperature and then the solution is acidified with IN HCl. The mixture is extracted with methylene chloride and then the organic extracts are dried (Na2SO4) and concentrated to an oil under reduced pressure. The oil is purified by column chromatography using 1/1 hexane / EtOAc as the eluent to provide the desired product as a light yellow oil. ? M (IEA): 388 (M + + H), 405 (M + + NH4). fight. 3 (S) -N-hydroxy-2,2-dimethyl-4- [(4-methoxyphenyl) sulfonyl] octahydro-1,4-thiazonine-3-carboxy-ida: carboxylic acid 11c (392 mg, 1.01 mmol) in dichloromethane (10 mL) is stirred at room temperature and then oxalyl chloride (0.263 g, 2.07 mmol, 2.05 equiv) and DMF (73.9 mg, 1.01 mmol) are added. The resulting solution is stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (3.3 g, 47.5 mmolar, 4 equiv) in THF (50 mL) and water (10 mL) is stirred at 0 ° C. Triethylamine (615 mg, 6.06 mmolar, 6 equiv) is added and the resulting solution is stirred at 0 ° C for 15 minutes. The chloride acid solution is added immediately to the hydroxylamine solution at 0 ° C and the resulting mixture is allowed to stir overnight at room temperature. The reaction mixture is then acidified with IN HCl and then extracted with dichloromethane. The organic extracts are dried (Na2S4) and concentrated to a solid under reduced pressure.The solid is recrystallized from CH3CN to provide a white powder. ? M (IEA): 378 (M + + NH), 361 (M + + H).

EXAMPLE 12 Preparation of N-hydroxy-2-methyl-4N- [(4-methoxyphenyl) sulfonyl-thiazepine-3-carboxamide 12g. "2h 12a.4 (S) -Methyl 2-tert-butyl-1,3-thiazolidine-4-carboxylate (1): D-cysteine methyl ester hydrochloride (12.9 g, 75.2 mmol) and trimethylacetaldehyde (7.12 g, 82.7 mmoles) in petroleum ether (150 ml) was stirred at room temperature and then triethylamine (8.37 g, 82.7 mmoles) was added dropwise over a period of 5 minutes.The resulting homogeneous mixture was stirred for 16 hours at reflux and stirred The reaction mixture was cooled to room temperature and then filtered, the residue was washed with diethyl ether, the resulting filtrate was concentrated to leave 14.87 g (97%) of the product. desired as a light yellow oil. 12b. 2S, 4S-Methyl 2-tert-butyl-l, 3-thiazolidine-3-formyl-4-carboxylate (2): Thiazolidine (14.8 g, 72.8 mmol) in formic acid (110 ml) and sodium form (5.45) g, 80 mmol, 1.1 equiv) was stirred at 0 ° C and then acetic anhydride (22.3 g, 218 mmol, 3 equiv) was added dropwise over a period of 45 minutes. The resulting solution was then heated to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to leave a yellow oil. The oil was carefully neutralized with saturated sodium bicarbonate solution and then extracted with diethyl ether (3 x 200 ml). The combined ether extracts were dried (Na 2 SO 4) and then concentrated to an oil under reduced pressure. The oil (13.2 g, 79%) crystallized under rest. 12c. 2S, 4S-Methyl 2-tert-butyl-l, 3-thiazolidine-3-formyl-4-methyl-4-carboxylate (3): A solution of n-butyllithium (1.6 M, 25.8 ml, 41.2 mmol, 1.06 equiv ) was added dropwise to a cold solution (-78 ° C) of diisopropylamine (5.9 g, 58.4 mmol, 1.5 equiv) in THF (180 ml). The resulting solution was stirred at -78 ° C for 10 minutes. The DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone, 27 ml) was added immediately and the now blue solution was stirred at -78 ° C for 1 hour. The reaction mixture was cooled to -90 ° C and then the thiazolidine (9.0 g, 38.9 mmol) in THF (10 ml) was added slowly. The mixture was stirred for an additional 0.75 hours at -90 ° C and then methyl iodide (6.63 g, 46.7 mmol, 1.2 equiv) was added for 5 minutes. The reaction mixture was stirred at -90 ° C for 2 hours and then warmed to room temperature. The solvent was removed to leave an oil that was poured into brine (200 ml) and extracted with diethyl ether (3 x 200 ml). The combined organic extracts were dried (Na2S?) And then concentrated to an oil under reduced pressure. Purification of the oil was achieved by chromatography on silica gel using 9/1 hexane / EtOAc as the eluent. The product (5.90 g, 62%) was obtained as a clear, colorless oil. 12d. (S) -2-methylcysteine hydrochloride (4): The methyl ester (6.0 g, 24.6 mmol) was added to 5N HCl (110 mL) and the resulting mixture was heated to reflux for 3 days. The mixture was then cooled to room temperature and the solvent was removed under reduced pressure to leave 3.62 g. (87%) of a yellow solid. 12e. Methyl N- [(4-methoxyphenyl) sulfonyl] -S- (2-hydroxyethyl) -2-methyl-D-cysteine (5): D-Penicillamine (14.9 g, 0.1 moles) in 2N NaOH (65 ml, 0.13 moles) 1.2 equiv) was stirred at 0 ° C under an argon atmosphere. A solution of 2-bromopropanol (15 g, 0.12 mol, 1.2 equiv) in ethanol (100 ml) was slowly added dropwise at 0 ° C. The resulting solution was stirred overnight at room temperature and then the mixture was acidified to pH-6 with IN HCl. The solvent was removed under reduced pressure to leave a thick oil. The penicillamine adduct was then dissolved in dioxane (200 ml) and water (200 ml) and stirred at room temperature. Triethylamine (29.8 g, 0.295 moles, 3 equiv) was then added to the reaction mixture followed by 4-methoxyphenylsulfonyl chloride (22.3 g, 0.108 moles, 1.1 equiv). The resulting homogeneous solution was stirred at room temperature for 18 hours and then acidified to pH-2 with IN HCl. The solution was poured into water and extracted with methylene chloride. The organic extracts were dried (MgSO 4) and concentrated to an oil under reduced pressure. The resulting oil was diluted in methanol (30 ml) and enough diazomethane in diethyl ether was added to form a yellow solution. The mixture was concentrated under reduced pressure to leave an oil without color. Purification of the resulting methyl ester was achieved by chromatography on silica gel using 1/1 hexane / EtOAc as the eluent. The desired product was obtained as a clear, colorless oil. 12f. 2-Methyl-4N- [(4-methoxyphenyl) sulfonyl] -thiazepine-3-carboxylic acid methyl ester (6): The methyl ester (10.8 g, 28.6 mmol) in THF (200 ml) was stirred at room temperature and then triphenylphosphine (9.0 g, 34.3 mmol, 1.2 equiv) followed by diethyl azodicarboxylate (5.48 g, 31.5 mmol, 1.1 equiv) was added. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed and then the coarse yellow oil was diluted with methyl chloride and silica gel (30 g) was added. The solvent was removed to leave a white powder. This powder was placed on a column of chromatography and levigated with 8/2 hexane / EtOAc. The desired product was obtained as a colorless oil. MS (ESI): 360 (M + + H), 377 (M + + NH4). 12g. 2-Methyl-4N- [(4-methoxyphenyl) sulfonyl] -thiazepine-3-carboxylic acid: The methyl ester (9.5 g, 26.4 mmole) in pyridine (150 ml) was stirred at room temperature under an argon atmosphere. Lithium iodide (42.4 g, 317 mmol, 12 equiv) was added and the resulting solution was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and then the solution was acidified with IN HCl. The mixture was extracted with methylene chloride and then the organic extracts were dried (Na2 =? 4) and concentrated to an oil under reduced pressure. The oil was purified by column chromatography using 1/1 hexane / EtOAc as the eluent to provide the desired product as a light yellow oil. 12h N-Hydroxy-2-methyl-4N- [(4-methoxyphenyl) sulfonyl] -thiazepine-3-carboxamide:? L carboxylic acid (4.1 g, 11.8 mmol) in dichloromethane (50 ml) was stirred at room temperature and then chloride Oxalyl (3.09 g, 24.3 mmol, 2.05 equiv) in DMF (0.87 g, 11.8 mmol) was added. The resulting solution was stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (3.3 g, 47.5 mmol, 4 equiv) in THF (50 ml) and water (10 ml) was stirred at 0 ° C. Triethylamine (7.16 g, 70.8 mmol, 6 equiv) was added and the resulting solution was stirred at 0 ° C for 15 minutes. The Doric acid solution was then added to the hydroxylamine solution at 0 ° C and the resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was then acidified with IN HCl and then extracted with dichloromethane. The organic extracts were dried (Na 2 SO 4) and concentrated to a solid under reduced pressure. The solid was recrystallized from CH3CN / H2O to provide a white powder. MS (IA?): 378 (M ++ NH4), 361 (M + + H).

EXAMPLE 13 Preparation of N-hydroxy-1- (4-methoxyphenylsulfonyl) -3,3-dimethyl-hexahydro-1H-azepine-2-carboxamide 13 * 13f 3a 13a. Methyl 7-methyl-3-oxo-6-octenoate: In a dry flask, sodium hydride (17.44 g, 436 mmol) was added under argon and rinsed several times with hexane to remove the mineral oil. A solution of dimethylcarbonate (35.66 g, 396 mmol) in ether (60 ml) was added. The suspension was stirred and heated to reflux. Then, 6-methyl-5-hepten-2 -one (25.2 g, 198 mmol) was added dropwise until the hydrogen started to evolve. The remaining ketone was added very slowly over a period of several hours at reflux. Once the addition was complete, the solution was stirred for two additional hours, and then allowed to stand at room temperature overnight. The mixture was cooled in an ice bath and a solution of methanol (40 ml) in ether (200 ml) was added carefully. The reaction mixture remained in the ice bath for 1 hour until all the bubbling was over. The reaction mixture was then stirred at room temperature for 2 hours. The resulting suspension was poured onto ice (320 g) and concentrated HCl (80 ml). The solution was extracted several times with ether, the organic layers were washed with sodium bicarbonate and dried over magnesium sulfate and concentrated under reduced pressure to form an oil. The purification was achieved through distillation, the product distilled at 75 ° C to 90 ° C. The product was obtained as a light pale yellow oil. MS (ESI): 185 (M + + H), 202 (M + + NH4). 13b. Methyl 2,2-dimethyl-6-oxo-cyclohexanecarboxylate: Methyl ester 13a (16.3 g, 88.6 mmol) was dissolved in methylene chloride (600 ml) and cooled to 0 ° C, followed by the addition of sodium chloride (34.5 g, 132.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with ether (1000 ml) and washed with IN HCl several times and some water, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified on silica gel using hexane ethyl acetate (95: 5). ? M (IEA): 185 (M + + H), 202 (M + + NH4). 13c. 6, 6-Dimethyl-7-carbomethoxy-tetrahydro-2 (3H) -azepinone: The keto ester 13b (7.3 g, 39.7 mmol) is dissolved in chloroform (180 ml) and cooled to 0 ° C. Methanesulfonic acid (38.1 g, 397 mmol) was added followed by the addition of sodium azide. The reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux for 5 hours. Ice was added to the reaction mixture and stirred for several minutes, this was followed by the addition of ammonium hydroxide until the reaction became basic. The mixture is then extracted with methylene chloride, and the organic layers are dried (MgSO 4) and concentrated under reduced pressure to an oil. MS (ESI) 200 (M + + H). 13d. 2-Hydroxymethyl-3,3-dimethyl-hexahydro-1H-azepine: Ketone 13c (3.75 g, 18.9 mmol) is dissolved in THF (100 ml) under an argon atmosphere at room temperature. Lithium aluminum hydride (1.5 g, 37.7 mmol, 2 equiv) was then added slowly to the reaction mixture. The reaction mixture was heated to reflux for 5 hours. The mixture was quenched by the slow, dropwise addition of ethyl acetate until the bubbling of the reaction mixture ended.

Then, water (1.5 ml) was added to the solution. A 15% NaOH (1.5 ml) was added followed by water (3.0 ml). The resulting heterogeneous mixture is then filtered, and the resulting organic layer is diluted with water and extracted with ether. The organic layers are dried over sodium sulfate and concentrated under reduced pressure. ? M (I? A): 158 (M + + H). 13e. 1- [(4-Methoxyphenyl) sulfonyl] -2-hydroxymethyl-3, 3-dimethyl-hexahydro-1H-azepine:? L alcohol 13d (2.9 g, 18.9 mmol) was dissolved in a 1: 1 mixture of water and p -dioxane (100 ml), followed by the addition of 4-methoxyphenylsulfonyl chloride (4.7 g, 22.6 mmol) and triethylamine (7.86 ml, 56.5 mmol). The reaction mixture was stirred overnight. The reaction was quenched and acidified with IN HCl at pH-2. The mixture was then diluted with water and extracted with methylene chloride. The organic layers were dried over magnesium sulfate, and concentrated under reduced pressure. The compound was purified by silica gel chromatography using hexane: ethyl acetate (3: 2) as the eluent. ? M (IEA): 328 (M + + H), 345 (M + + NH4). 13f. 1- [(4-Methoxyphenyl) sulfonyl] -3,3-dimethyl-hexahydro-1H-azepine-2-carboxylic acid: Alcohol 13e (0.40 g, 1. 22 mmol) is dissolved in acetone (50 ml) and fresh 8N Jones reagent is added until the solution holds an orange / brown color as opposed to a green color.

The reaction mixture is then stirred overnight. Isopropanol is added to quench Jones' excess reagent and a green solid is precipitated out of the solution. The solid is filtered through celite, and the liquid is concentrated under reduced pressure. The residue is then dissolved in chloroform and washed with water several times. The organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The product is carried forward without further purification. MS (ESI): 342 (M + + H), 359 (M + + NH4). 13g. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3,3-dimethyl-hexahydro-1H-azepine-2-carboxamide: The carboxylic acid 13f (0.37 g, 1.07 mmol) in dichloromethane (10 ml) was stirred at room temperature and then oxalyl chloride (0.28 g, 2.2 mmoles, 2.05 equiv) and DMF (0.08 g, 4.15 mmoles) were added. The resulting solution was stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (0.3 g, 4.28 mmol, 4 equiv) in THF (10 ml) and water (2 ml) were stirred at 0 ° C. Triethylamine (0.65 g, 6.42 mmol, 6 equiv) was added and the resulting solution was stirred at 0 ° C for 15 minutes. The hydrochloric acid solution was added immediately to the hydroxylamine solution at 0 ° C and the resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was then acidified with IN HCl and then extracted with dichloromethane. The organic extracts were dried (Na2SO4) and concentrated to a solid under reduced pressure. The solid was recrystallized from CH3CN / H2O to provide the desired product as a white powder. MS (ESI): 357 (M + + H).

EXAMPLE 14 Preparation of N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -hexahydro-1H-azepine-2-carboxamide 1 * and i4 14 # 14 to. 7-Carboxymethoxy-tetrahydro-2 (3H) -azepinone: The ethyl carboxylate 2-cyclohexanone (15.0 g, 88.12 mmol) is dissolved in chloroform (200 mL) and cooled to 0 ° C. Methanesulfonic acid (84.7 g, 881.2 mmol) was added followed by the addition of sodium azide. The reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux for 5 hours. Ice was added to the reaction mixture and the resulting solution was stirred for several minutes. Ammonium hydroxide was added until the reaction was made basic. The mixture is extracted with methylene chloride, and the organic layers are dried (MgSO4) and concentrated under reduced pressure to an oil. MS (IA?): 186 (M + + H). 14b. 2-Hydroxymethyl-hexahydro-1H-azepine: Amide 14a (5.0 g, 27.0 mmol) is dissolved in THF (100 mL) under an argon atmosphere at room temperature. Lithium aluminum hydride (2.0 g, 54.0 mmol, 2 equiv) was then added carefully. The reaction mixture was heated to reflux for 5 hours. The mixture was quenched by the slow, dropwise addition of ethyl acetate until the bubbling of the reaction mixture ended. Then, water (2.0 mL) was added to the solution. A 15% NaOH (2.0 mL) was added immediately followed by water (5.0 mL). The resulting homogeneous solution is filtered, and the remaining organic layer is diluted with water and extracted with ether. The organic layers are dried over sodium sulfate and concentrated under reduced pressure. 14c. 1- (4-Methoxyphenyl) sulfonyl-2-hydroxymethyl-hexahydro-H-azepine:? L alcohol 14b (3.0 g, 23.5 mmol) was dissolved in a 1: 1 mixture of water and p-dioxane (100 mL) followed by the addition of 4-methoxyphenylsulfonyl chloride (5.8 g, 28.2 mmol) and triethylamine (9.8 mL, 70.5 mmol). The reaction mixture was allowed to stir overnight. The reaction was quenched and acidified with IN HCl at pH -2. The reaction mixture was then diluted with water and extracted with methylene chloride. The organic layers were dried over magnesium sulfate, and concentrated under reduced pressure. The compound was purified by silica gel chromatography using hexane: ethyl acetate (2: 1) as the eluent. ? M (I? A): 300 (M + + H), 317 (M + + NH4). 14d. 1- [(4-Methoxyphenyl) sulfonyl] -hexahydro-1H-azepine-2-carboxylic acid:? L alcohol 14c (1.3 g, 4.35 mmol) is dissolved in acetone (100 mL) at 0 ° C and Jones 8N reagent Freshly prepared is added until the solution holds an orange-brown color as opposed to a green color. The resulting mixture is then stirred overnight. Isopropanol is added to quench Jones' excess reagent and a green solid is precipitated out. The solid is filtered through celite, and the liquid is concentrated under reduced pressure. The residue is then dissolved in chloroform and washed with water several times. The organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The product is carried forward without further purification. ? M (IEA): 314 (M ++ H), 331 (M ++ NH4). 14e. N-hydroxy-1- [(4-methoxyphenyl) sulfonyl-hexahydro-1H-azepine-2-carboxamide: The carboxylic acid 14d (1.11 g, 3.56 mmol) in dichloromethane (25 mL) was stirred at room temperature and then chloride. oxalyl (0.93 g, 7.2 mmol, 2.05 equiv) and DMF (0.260 g, 3.56 mmol) were added. The resulting solution was stirred at room temperature for 30 minutes. In a separate flask, hydroxylamine hydrochloride (0.99 g, 14.24 mmol, 4 equiv) in THF (15 mL) and water (8 mL) were stirred at 0 ° C. Triethylamine (2.15 g, 21.4 mmol, 6 equiv) was added and the resulting solution was stirred at 0 ° C for 15 minutes. The Doric acid solution was then added to the hydroxylamine solution at 0 ° C and the resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was then acidified with IN HCl and then extracted with dichloromethane. The organic extracts were dried (Na2 =? 4) and concentrated to a solid under reduced pressure. The solid was recrystallized from CH3CN / H2O to provide a white powder. EM (IEA): 429 (M ++ H).

EXAMPLES 15-101 The following compounds (where it is null) are made using the methods described and exemplified above.

Methods Examples 15-50 are prepared analogously to Example 1 using suitably functionalized sulfonyl chloride. The sulfonyl chlorides which are used to prepare the above examples are purchased from commercial sources or prepared by known methods. For example, the 4-phenoxyphenylsulfonyl chloride used for the preparation of Example 17 was prepared as described by R. J. Cremlyn et al in Aust. J. Chem., 1979, 32, 445, 52. Examples 15-90 are prepared by oxidation of the corresponding sulfide (discovered in Examples 15-50). The oxidation proceeds in a manner analogous to Example 2. Examples 91-101 are prepared analogously to Example 13 using suitably functionalized sulfonyl chloride. these examples provide a person skilled in the art with sufficient guidance to make the present invention and not limit it in any way.

COMPOSITION AND EXAMPLES OF THE METHOD OF USE 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 guidance to one skilled in the art to prepare and use the compounds, compositions and methods of the invention. In each case the compounds of formula I can be substituted by the compound of the example shown below with similar results. The exemplified methods of use do not limit the invention, but provide guidance to one skilled in the art to use the compounds, compositions and methods of the invention. The expert will appreciate that the examples provide guidance and can be varied based on the condition and the patient.

EXAMPLE A A tablet composition for oral administration, according to the present invention, is made up of: Component Quantity Example 2a 15. mg Lactose 120. mg Corn starch 70. rng Talc 4. mg Magnesium stearate 1. mg Other compounds having a structure according to formula (I) are used with substantially similar results. A human female subject weighing 60 kg (132 lbs), suffering from rheumatoid arthritis, is treated by a method of this invention. Specifically, for 2 years, a regimen of three tablets per day is administered orally to said subject. At the end of the treatment period, the patient is examined and discovered to have reduced inflammation, and improved mobility without concomitant pain.

EXAMPLE B A capsule for oral administration, according to the present invention, is made up of: Component Quantity (% w / v) Example 1 15% Polyethylene glycol 85% Other compounds having a structure according to formula (I) are used with substantially similar results. A male human subject weighing 90 kg (198 lbs), suffering from osteoarthritis, is treated by a method of this invention. Specifically, for 5 years, a capsule containing 70 mg of Example 3 is administered daily to said subject. At the end of the treatment period, the patient is examined through orthoscopy, and it is discovered that there is no further advancement of erosion / fibrillation of the articular cartilage.

EXAMPLE C A composition based on saline for local administration, according to the present invention, is made up of: Component Quantity (% w / v) Example 1 5% Polyvinyl alcohol 15% Saline solution 80% Other compounds having a structure according to formula (I) are used with substantially similar results. A patient who has deep corneal abrasion applies the drop to each eye twice a day. Healing is accelerated, with no visual sequelae.

EXAMPLE D A topical composition for local administration, in accordance with the present invention, is made up of: Component Quantity (% w / v) Compound example 2b 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbitol 5.00 Glycine 0.35 Aromatics 0.075 Purified water ce. Total = 100.00 Total = 100.00 Any of the other components having a structure in accordance with formula (I) are used with substantially similar results. A patient suffering from chemical burns applies the composition at each change of clothes (twice a day). The healing is substantially reduced.

EXAMPLE E A composition for aerosol inhalation, according to the present invention, consists of: Component Quantity (% w / v) Compound example 2c 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Saccharin sodium 0.2 Propellant (F12, F114) ce. Total = 100.0 Any of the other components having a structure in accordance with formula (I) are used with substantially similar results. An asthma patient sprays 0.01 ml through a pump actuator into the mouth while inhaling. The symptoms of asthma are diminished.

EXAMPLE F A topical ophthalmic composition, in accordance with the present invention, consists of: Component Quantity (% w / v) Compound example 1 0.10 Benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL M ™) 0.50 Sodium metabisulfite 0.10 Sodium chloride (0.9%) c .e. Total = 100.0 Any of the other components having a structure in accordance with formula (I) are used with substantially similar results. A male human subject weighing 90 kg (198 lbs), suffering from corneal ulcerations, is treated by a method of this invention. Specifically, for 2 months, a saline solution containing 10 mg of Example 5 is administered to the subject's affected eye twice a day.

EXAMPLE G A composition for parenteral administration is made up of: Component Quantity Example 2b 10 mg / ml carrier Sodium citrate buffer carrier with (weight percent carrier): lecithin 0.48% carboxymethylcellulose 0.53 povidone 0.50 methylparaben 0.11 propylparaben 0.011 The above ingredients are mixed, forming a suspension. Approximately 2.0 ml of the suspension is administered, via injection, to a human subject with a pre-metastatic tumor. The injection site is juxtaposed to the tumor. This dosage is repeated twice a day, for approximately 30 days. After 30 days, the symptoms of the disease subside, and the dosage is gradually decreased to maintain the patient. Other compounds having a structure according to formula I are used with substantially similar results.

EXAMPLE H A mouthwash composition is prepared: Component% p / v Example 2c 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 Ink 0.04 Water remaining at 100% A patient with gum disease uses 1 ml of mouthwash three times a day to prevent further oral degeneration.

Other compounds having a structure according to formula I are used with substantially similar results.

EXAMPLE I A composition in tablets is prepared: Component% p / v Example 2a 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor 11.70 Color 0.10 Corn syrup rest at 100% A patient uses the pill to prevent loosening of an implant in the maxilla. Other compounds having a structure according to formula I are used with substantially similar results.

EXAMPLE J Chewing gum composition Component% p / v Example 1 0.03 Sorbitol crystals 38.44 Sodium-T base gum * 20.00 Sorbitol (70% aqueous solution 70%) Mannitol 10.00 Glycerin 7.56 Taste 1.00 A patient chews on the rubber to prevent loosening of dentures. Other compounds having a structure according to formula I are used with substantially similar results.

EXAMPLE K Components P /% v Water USP 54,656 Methylparaben 0.05 Propylparaben 0.01 Xanthan gum 0.12 Guar gum 0.09 Calcium carbonate 12.38 Antifoam 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 Benzyl alcohol 0.2 Citric acid 0.15 Cooler 0.00888 Flavor 0.0645 Colorant 0.0014 Example 1 is prepared by first mixing 80 kg of glycerin and all of the benzyl alcohol and heating to 65 ° C, then adding slowly and mixing together methylparaben, propylparaben, water, xanthan gum and guar gum. Mix these ingredients for 12 minutes with a Silverson in-line mixer. Then slowly add the following ingredients in the following order: the rest of the glycerin, sorbitol, antifoam C, calcium carbonate, citric acid, and sucrose. Combine the flavors and chillers separately and then add slowly to the other ingredients. Mix for 40 minutes. The patient takes the formulation to prevent the widening of colitis. All references described herein are incorporated herein by reference. Although particular embodiments of the present invention have been described, it will be obvious to the person skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all of these modifications that are within the scope of this invention.

Claims (30)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound having a structure according to the formula (I) where Ri is H; R2 is hydrogen, alkyl or acyl; Ar is COR3 or SO2R4; and R3 is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R 4 is alkyl, heteroalkyl, aryl, or heteroaryl, substituted or unsubstituted; X is CH2, O, S, SO, SO2, or NR5, wherein R5 is independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R6 / COR7, CSRg, PO (Rg) 2 or can optionally form a ring with W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R7 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino, - Rg is alkyl, aryl, heteroaryl, heteroalkyl; W is hydrogen or one or more lower alkyl portions, or is an alkylene, arylene, or heteroarylene bridge between two adjacent or non-adjacent carbons (thereby forming a fused ring), - Y is independently one or more of hydrogen, hydroxy , SRig, SOR4, SO2R4, alkoxy, amino, wherein amino is of the formula Rn, Ri2 < wherein Rn and R 2 are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R6, COR7, CSRg, PO (Rg) 2; And Rio is hydrogen, alkyl, aryl, heteroaryl; Z is zero, a spiro portion or an oxo group substituted on the heterocyclic ring; n is 1-3; This structure also includes an optical isomer, diastereomer or enantiomer for the formula (I) or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester, or imide thereof.

2. The compound according to claim 1, further characterized in that X is O, S, SO, SO2 or NR5, wherein R5 is independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S? 2R7, CORg, CSR9

3. The compound according to claim 1, further characterized in that Ar is SO2R4 and R4 is alkyl, heteroalkyl, aryl, or heteroaryl, substituted or unsubstituted.

4. - The compound according to claim 1, further characterized in that Ar is phenyl or substituted phenyl.

5. The compound according to claim 4, further characterized in that Ar is substituted phenyl and the substitution is with hydroxy, alkoxy, nitro or halo.

6. The compound in accordance with the claim 5, further characterized in that Ar is substituted with methoxy, bromine, nitro and butoxy.

7. - The compound in accordance with the claim 6, further characterized in that Ar is substituted in the ortho or para position in relation to the sulfonyl.

8. The compound according to claim 1, further characterized in that it is one or more of hydrogen or Ci to C4 alkyl.

9. The compound according to claim 1, further characterized in that it is Ci-C4 geminal alkyl.

10. The compound according to claim 1, further characterized in that Z is an oxo substituted portion on the heterocyclic ring.

11. A pharmaceutical composition comprising: a) a safe and effective amount of a compound according to claim 1; and b) a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising: a) a safe and effective amount of a compound according to claim 4; and b) a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising: a) a safe and effective amount of a compound according to claim 5; and b) a pharmaceutically acceptable carrier

14. A pharmaceutical composition comprising: a) a safe and effective amount of a compound according to claim 9; and b) a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising: a) a safe and effective amount of a compound according to claim 10; and b) a pharmaceutically acceptable carrier.

16. The use of a compound according to claim 1, for the manufacture of a medicament for preventing or treating a disease associated with unwanted metalloprotease activity in a mammalian subject.

17. The use of a compound according to claim 4, for the manufacture of a medicament for preventing or treating a disease associated with unwanted metalloprotease activity in a mammalian subject.

18. The use of a compound according to claim 5, for the manufacture of a medicament for preventing or treating a disease associated with unwanted metalloprotease activity in a human or other animal subject.

19. The use of a compound according to claim 9, for the manufacture of a medicament for preventing or treating a disease associated with intrasseda metalloprotease activity in a mammalian subject.

20. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for preventing or treating a disease modulated by metalloproteases, wherein the disorder is chosen from the group consisting of arthritis, cancer, cardiovascular disorders, skin disorders, eye disorders, inflammation and gum disease in a mammal.

21. The use according to claim 20, wherein the alteration is arthritis, and is chosen from the group consisting of osteoarthritis and rheumatoid arthritis.

22. The use according to claim 20, wherein the alteration is cancer, and the treatment prevents or stops tumor growth and metastasis.

23. The use according to claim 20, in which the disorder is a cardiovascular disorder chosen from the group consisting of dilated cardiomyopathy, congestive heart failure, arteriosclerosis, plaque rupture, reperfusion wound, ischemia, chronic obstructive pulmonary disease, restenosis of angioplasty and aortic aneurysm.

24. The use according to claim 20, wherein the alteration is an ocular alteration, and is chosen from the group consisting of corneal ulceration, lack of corneal health, macular degeneration, and pterygoma.

25. The use according to claim 20, wherein the alteration is gum disease, and is chosen from the group consisting of periodental disease, and gingivitis.

26. The use according to claim 20, wherein the condition is skin condition chosen from the group consisting of repair and prevention of wrinkling, skin damage by U.V. , bullous epidermolysis, psoriasis, sclerodema, atopic dermatitis and scarring.

27. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for preventing the loosening of prosthetic devices chosen from the group consisting of replacements of joints and dental prostheses in a mammal.

28. The use according to claim 20, wherein the disease is chosen from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, inflammation of acne, osteomyelitis, bronchitis, arthritis, asthma.

29. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for the treatment of multiple sclerosis in a mammal.

30. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for the treatment of skeletal muscle disease or cacexia in a mammal.