MXPA99002064A - 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 as inhibitors of metalloproteases. Also disclosed are pharmaceutical compositions and methods of treating diseases, disorders and conditions characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

Description

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

BACKGROUND OF THE INVENTION A number of structurally related metalloproteases [MPs] effect the breaking down of structural proteins. These metalloproteases commonly act in the intercellular matrix, and thus are involved in tissue breakdown and remodeling. These proteins are known as metalloproteases or MPs. There are several different families of MPs, classified by sequence homology. Several families of known MPs, as well as examples thereof, are described in the art. These MPs include matrix metalloproteases [MMPs], zinc metalloproteases, many of the membrane-bound metalloproteases, TNF conversion enzymes, TNF conversion enzymes, angiotensin conversion enzymes (ACEs), disintegrins including ADAMs (See Wolfsberg et al. others, 131 J. Cell Bio. 275-78 October, 1995), and, enkephalinases. Examples of MPs include skin fibroblast collagenase human, human skin fibroblast gelatinase, human sputum collagenase, aggrecanase and gelatinase and human elicina estrus. It is believed that collagenase, stromelicin, 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, e.g., U.S. Patent. 5,506,242 (Ciba Geigy Corp); Patent E.U.A. 5,403,952 (Merck &Co); published PCT application WO 96/06074 (British Bio Tech Ltd), PCT publication WO 96/00214 (Ciba Geigy), * WO 95/35275 (British Bio Tech Ltd), - WO 95/35276 (British Bio Tech Ltd); Wo 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); WO 95/26989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Ins. Optha ology); WO 95/23790 (SmithKline Beecham); WO 95/22966 (Sanofi Winthrop); WO 95/19965 (Glycomed); WO 95 19956 (British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd); WO 95/13289 (Chiroscience Ltd); WO 95/12603 (Syntex), - WO 95/09633 (Florida State 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. Inc); WO 94/10990 (British Bio Tech Ltd), - WO 93/09090 (Yamanouch); and British patents 2282598 (Merck) and GB 2268934 (Britis.h 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, Biophys. Acta. (1983) 695: 117-214); osteoarthritis (Henderson, B., et al., Drugs of the Future (1990) 15: 495-508); metastasis of tumor cells (ibid, Broadhurst, MJ, et al., European Patent Application 276,436 (published 1987), Reich, R., et al., m 48 Cancer Res. 3307-3312 (1988), and various ulcerations or conditions. ulcers of tissue 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 Other examples of conditions characterized by undesirable metalloprotease activity include disease periodontal, 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 for preparing inhibitors for these enzymes A number of such inhibitors are described in the literature Examples include US Patent No. 5,183,900 issued l February 2, 1993 to Galardy; Patent E.U.A. No. 4,996,358, issued on February 26, 1991 to Handa, and others; Patent E.U.A. No. 4,771,038, issued September 13, 1988 to Wolanin, and others; Patent E.U.A. No. 4,743,587, issued May 10, 1988 to Dickens, et al .; European Patent Publication No. 575,844, published December 29, 1993 by Broadhurst, et al., International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura, et al .; World Patent Publication No. 92/17460, published October 15, 1992 by Markwell et al .; and European Patent Publication No. 498,665, published August 12, 1992 by Beckett, et al. Metalloprotease inhibitors are useful in the treatment of diseases caused, at least in part, by the breakdown of structural proteins. Although a variety of inhibitors have been prepared, there is a continuing need for potent and useful metalloprotease matrix inhibitors to treat such diseases. Applicants have surprisingly found that the compounds of the present invention are potent metalloprotease inhibitors.

OBJECTS OF THE INVENTION Therefore, an object of the present invention is to provide compounds useful for the treatment of diseases and conditions that are characterized by MP activity not desired. It is further 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 which are effective to treat 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: R - * _ is H; R2 is hydrogen, alkyl, or acyl; 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 O, S, SO, S02, or NR5, where R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2 6, COR7, CSRβ, PO (R9) 2 or may optionally form a ring with W or Y; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino; R7 is hydrogen, alkoxy, aryloxy, heteroatyloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylkamino, dialkylamino, arylamino, and alkylarylamino; Rβ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, -R9 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, SR_Q / SOR4, SO2R4, alkoxy, amino, wherein the amino is of the formula NR] _ ?, R] _2 / wherein R -_] _ and R -_2 are independently chosen from hydrogen, alkyl, heteroalkyl , heteroaryl, aryl, SO2 6, COR ^ SRg, PO (Ro,) 2; Y RIQ is hydrogen, alkyl, aryl, heteroaryl; Z is nothing, a spiro portion or an oxo substituted group on the heterocyclic ring; n is 1-4. This structure further includes an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically acceptable salt or a biohydrolyzable amide, ester or imide thereof. These compounds have the ability to inhibit at least one mammalian metalloprotease. Accordingly, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of the formula I and to methods for treating diseases characterized by unwanted metalloprotease activity using these compounds or the pharmaceutical compositions containing them. Metalloproteases that are active at a particularly undesired site (e.g., an organ or certain cell types) can be identified by conjugating the compounds of the invention to a specific identification ligand for a marker at that location such as an antibody or fragment thereof or a receptor ligand. Methods of conjugation are known in the art. The invention is also directed to several other methods that take advantage of the unique properties of those compounds. Thus, in another aspect, the invention is directed to the compounds of the formula I conjugated to solid support. These conjugates can be used as an affinity reagent for the purification of a desired metalloprotease. In another aspect, the invention is directed to the compounds of the formula I conjugated to markers. 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 metalloprotease, preferably a matrix metalloprotease in vivo or in cell cultures in vitro. 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 methods of conjugation 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 matrix metalloproteases. Preferably, the compounds are those of the formula I or a pharmaceutically acceptable salt or a biohydrolyzable amide, ester or imide thereof.

Publications and patents are referred to throughout this description in an effort to fully describe the condition of the technique. All references cited herein are therefore incorporated for reference.

Definitions and uses of terms The following is a list of definitions for terms used herein. "Acyl" or "Carbonyl" is described as a radical that could be formed by the removal of 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 (ie, -O-acyl), for example, -0-C (= 0) -alkyl. "Alkoxycyl" is an acyl radical (-C (= 0) -) having an alkoxy substituent (ie, -O-R), for example, -C (= 0) -0-alkyl. This radical can be called an ester. "Acylamino" is an amino radical having an acyl substituent (ie, -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. The Alkenyl substituents have at least one double or letinic 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; very preferably from 2 to 8; except when 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 3 carbon atoms) and the alkyloxy has 1 to 6 carbon atoms (most preferably 1 to 3 carbon atoms) and the alkyloxy has 1 to 6 carbon atoms (very preferably 1 to 3 carbon atoms). "Alkyl" is an unsubstituted or substituted saturated 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) methyl, ethyl, propyl, isopropyl and butyl or substituted. not replaced. As referenced herein, "Spirocycle" or "spirocyclic" refers to a cyclic portion that shares one carbon in another ring. Said cyclic portion may be carbocyclic or heterocyclic in nature. The heterogeneous atoms that are preferred included in the base structure of the etoricyclic spirocycle include oxygen, nitrogen and sulfur. Spirocycles can be substituted or not substituted. Preferred substituents include oxo, hydroxyl, alkyl, cycloalkyl, arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused ring (e.g., benzothiol, cycloalkyl, ethercycloalkyl, benzimidizoles, pyridithiol, etc., which may be substituted) and similar. In addition, the heterogeneous atom of the heterocycle can be replaced if the valence allows it. Preferred spirocyclic ring sizes include rings of 3 to 7 members. "Alkylene" refers to an alkyl, alkenyl, or alkynyl that is a diradical, rather than a radical. "Heteroalkylene" is defined in the same way as a (diradical) alkylene having a heterogeneous atom in its chain. "Alkylamino" is an amino radical having 1 (secondary amine) or 2 (tertiary amine) alkyl substituents (ie, -N-alkyl). For example, methylamino (-NHCH3), dimethylamino (-N (CH3) 2), methylethylamino (-N (CH3) CH2CH3). "Aminoacyl" is an acyl radical that has an amino substituent (ie., -C (= 0) -N), *. for example C (= 0) -NH2. The amino group of the aminoacyl moiety may be substituted (i.e., primary amine) or can be substituted with 1 (secondary amine) or 2 (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 not substituted. "Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl. Said groups can be substituted or not substituted. "Arylalkylamino" is an amine radical substituted with an arylalkyl group (e.g., -N-H-benzyl). Said groups can be substituted or not substituted. "Arylamino" is an amine radical substituted with an aryl group (i.e., -NH-aryl). Said groups can be substituted or not substituted. "Aryloxy" is an oxygen radical having an aryl substituent (i.e., -O-aryl). Said groups can be substituted or not substituted. "Carbocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring radical. The carbocyclic rings are monocyclic or are fused, bridged or spiro-polycyclic ring systems. The monocyclic carbocyclic rings they generally contain 4 to 9 atoms, preferably 4 to 7 atoms. The polycyclic carbocyclic rings have 7 to 17 atoms, preferably 7 to 12 atoms. Preferred polycyclic systems comprise 4- to 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. "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 carbocycle-alkyl groups include benzyl, phenylethyl, diphenylethyl. "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) OH For example, -CH2 ~ C (= 0) OH. "Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring.The cycloheteroalkyl groups that are preferred they 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 cycloheteroarylalkyl; 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 unsubstituted or substituted unsaturated chain radical having 3 to 8 members comprising carbon atoms and 1 or 2 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 1 or 2 heterogeneous atoms. "Heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical of carbon atoms and one or more heterogeneous atoms in the ring. Heterocyclic rings are monocyclic ring systems or are fused, bridged or spiro-polycyclic. 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 not substituted. "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 salt" is a salt cationic formed in any acid group (e.g., carboxyl) or an anionic salt formed in any basic group (e.g., amino). Many of these salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., Published 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 human subject to give an active inhibitor. A "biohydrolyzable hydroxyimide" is an imide of a compound of the formula I that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted in vivo by a human subject to produce a compound of the active 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 which does not interfere with the metalloprotease inhibitory activity of these compounds or which easily converted by an animal to produce a compound of active formula I. A "solvate" is a complex formed by the combination of a solute (e.g., a metalloprotease) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist 's Dictionary, p. 650 (1953). The pharmaceutically acceptable solvents used in accordance with this invention include those which do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N, N-dimethylformamide and others known or readily determined by the skilled artisan. in the technique). "Optical isomer", "stereoisomer", "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 may be with one or more substituents. Said substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Bioloqy (1979), incorporated herein by reference. The Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxyl, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyaceyl (e.g., carboethoxy) , etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. As used herein, the term "mammalian matrix metalloprotease" means any metal-containing enzyme found in mammals that is capable of catalyzing the breakdown of collagen, gelatin or proteoglycan under suitable test conditions. Suitable test conditions can be found, for example, in the patent E.U.A. No. 4,743,587, which refers to the Cawston procedure, and others, Anal Biochem (1979) 99: 340-345, the use of a synthetic substrate 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 breakdown of these structural proteins. The metalloprotease enzymes mentioned herein are all zinc-containing proteases which are similar in structure to, for example, human stromelicynin or skin fibroblast collagenase. The ability of the candidate compounds to inhibit the metalloprotease activity can, of course, be tested in the. assays described above. The isolated metalloprotease enzymes can used to confirm the inhibitory activity of the compounds of the invention, or crude extracts containing the scale of enzymes capable of breaking tissue can be used.

Compounds The compounds of the invention are described in the brief description of the invention. Preferred compounds of the invention are those in which Z is heteroespyrocaryalkylene, preferably having heteroatoms adjacent to the structure of the parent ring, more preferably said spiroheteroalkylenes having 4 to 5 members. The preferred heteroatoms are divalent. The invention provides compounds which are useful as inhibitors of metalloproteases, preferably matrix 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 O, S, SO, SO2, or NR5, where R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S? 2, COR7, CSR8, PO (R9) 2 or can optionally form a ring with W or Y; 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; R9 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 (forming thereof) mode a fused ring); And it is independently one or more of hydrogen, hydroxy, SR or SOR4, SO2 4, alkoxy, amino, wherein the amino is of the formula NRH'R12 'wherein R-_- and R12 are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R6, COR7, CSR8, PO (R9) 2; Y R 10 is hydrogen, alkyl, aryl, heteroaryl; Z is zero, a spiro portion or an oxo substituted group on the heterocyclic ring; n is 1-4. This structure further includes an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically acceptable salt, a biohydrolyzable amide, ester or imide thereof.

Preparation of the compound The hydroxamic compounds of the formula (I) can be prepared using a variety of process. The general schemes include the following.

PREPARATION OF THE PORTION AND For the manipulation of Y it is understood that the person skilled in the art must choose to prepare Y before, after or concurrent with the preparation of the ring, heterocyclic. For clarity, portions W and Z are not shown below.

More than one portion Y and Z may be present in the compounds of the formula (I). For compounds where Y is not adjacent to the ring nitrogen, a preferred method of working for this compound is SCHEME 1 (A) (B) (C) wherein R is a derivatizable group or that can be manipulated or substituted, such compounds are known or are prepared by known methods. (A) is converted to its analogous sulfanamide and R is manipulated to give (B) during this step or a subsequent step. Y and Z can be added or altered, followed by the appropriate reaction to give Ri. For example, this step can include treating with hydroxylamine 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 person skilled in the art can choose to prepare Y before, after or concurrent with the preparation of the heterocyclic ring. For clarity the portions W, Y and Z are not shown ahead. More than one W, Y and Z may be present in the compounds of the formula (I).

For compounds where X is nitrogen, the preferred method for handling R5 is shown. In the scheme that follows, L is any acceptable leaving group, and B is a blocking group like the previous one. The person skilled in the art will recognize that the choice of blocking group is within the skills of the expert working in organic chemistry.

SCHEME 2 For compounds containing two different groups attached to the nitrogen of the amide, the preferred method of ring formation is shown below. For the preparation and preparation of the heterocyclic ring it is understood that the person skilled in the art can choose to prepare Y before, after or concurrent with the preparation of the heterocyclic ring. For clarity, the W, Y and Z portions are not shown. More than one W, Y and Z may be present in the compounds of the formula (I) The formation of the amide with an amino alcohol will leave a free hydroxyl group which can undergo a normal ring closure to give the heterocyclic ring. Once the ring has been formed, the preparation of the invention proceeds as such. as described above.

SCHEME III A convenient method of preparing the compounds of the invention is via alkylation of an alpha-carbonyl with activated carbon of a compound shown in the following scheme, under basic conditions. Preferably the alkylation occurs with an alpha halo ester, depending on the desired functionality, or any compound where L represents a potential anion or a good leaving group. In this first step, it is preferred that an alpha isocyano carbonyl compound be used, since the isocyano group is easily converted to an amine under acidic conditions. Using the amine prepared from the isocyano compound, it is preferred that the sulfanamide proceed via a similar route as that shown in Scheme I and the like. In the following scheme, B and P represent protection and blocking groups respectively, and L represents a leaving group. The person skilled in the art will recognize these groups from standard works in the art. In addition, the expert in the art it will recognize that these groups are chosen with the reaction conditions and reaction routes in mind, so the specific choice of the group is left to the expert, and is well within the domain of the practice of the person skilled in the art. For convenience, the radicals W, Y and Z are not shown, and the person skilled in the art can proceed as indicated above in preparing them. The last step of the synthesis, closed of the ring system, proceeds as in scheme II and / or scheme III above.

SCHEME IV An additional method of ring formation with two nitrogens within the ring is shown below. For the preparation and preparation of the heterocyclic ring it is understood that the person skilled in the art can choose to prepare the heterocyclic ring before, after or concurrent with the preparation. For clarity, the W, Y and Z portions are not shown More than one W, Y and Z may be present in the compounds of the formula (I). In the following scheme, L is any acceptable leaving group, and B is a blocking agent as previously indicated, Boc is an example of a preferred blocking group recognized in the art. The person skilled in the art will recognize that the choice of the blocking group is within the skill of the expert working in organic chemistry. Therefore the choice of Boc is not required, but preferred. A bifunctional portion, for example a diamine, is allowed to react with an appropriate dihalo compound as shown below. The halo portion serves as a leaving group. After the formation of the ring, the working up of the invention proceeds as described above.

SCHEME V PREPARATION OF THE Z PORTION The person skilled in the art will of course 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 by 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. Therefore, the person skilled in the art will appreciate that a hydroxy, amino, imino, alkoxy, oxo group or any other group that can be manipulated in a carbonyl compound. The order of preparation of ketal, Ri or sulfanamide can be changed. A preferred method of making spiro compounds of the invention is via a carbonyl compound, using "protective group" technology known in the art, such as the thioketal or ketal and the like. Cetals, acetals and the like are prepared from carbonyl compounds by methods known in the art. Such carbonyls can be made from cyclic hydroxyalkyleneamines via oxidation to a ketone, or from lactams, which provide the 2-aminospiro functionality. A variety of compounds can be generated in a similar way, using the guidance of the previous scheme.

In the above schemes, where R 'is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derived from the final compounds using a standard dealkylation process (Bhart, et al., "Cleavage of Ethers", Synthesis, 1983, pp. 249-281). These steps can be varied to increase the performance of the desired product. The person skilled in the art will also recognize that the judicious choice of reagents, solvents and temperatures is an important component in a successful synthesis. Although the determination of optimal conditions, etc., is routine, it will be understood that to make a variety of compounds can be generated in a similar manner, using the guide of the above 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 direction; 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 of hydroxyls and the like, 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 Organic Chemistrv, (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and Keeting, Heterocyclic Chemistry (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, the person skilled in the art uses protective 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, Protecting 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, including diastereomers and enantiomers at the same time (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. In addition, it is recognized that an optical isomer, including diastereomer and enantiomer or stereoisomer may have favorable properties over the other. Thus, when the invention is described and claimed, when a racemic mixture is described, it is clearly contemplated that both optical isomers, including diastereomers and enantiomer or styreoisomers substantially free of the others are described and claimed as well.

Methods of use The metalloproteinases (MPs) found in the body operate, 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 breakdown 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 including either: tissue degradation, - including degenerative diseases such as arthritis, multiple sclerosis and the like; Metastasis or mobility of tissues in the body: tissue remodeling, including fibrotic disease, scarring, benign hyperplasia and the like. The compounds of the present invention treat disorders, diseases and / or undesired conditions that are characterized by undesired or elevated activity by that class of said proteases. For example, the compounds can be used to inhibit proteases that: destroy structural proteins (i.e., proteins that maintain tissue stability and structure); 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 that is 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 a which includes an unwanted or elevated MP activity in the biological manifestation of the disease or disorder; in the biological cascade that leads to the disorder; or as a symptom of the disorder. This "involvement" of the MP includes: the activity of unwanted or elevated MP as a "cause" of the disorder or biological manifestation, whether the activity has been genetically elevated, by infection, by autoimmunity, trauma, biomechanical causes, lifestyle [eg, obesity] or by some other cause; 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; unwanted or elevated MP activity 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 interrupts 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 said tissues. For example, the distribution of metalloproteases involved in the degradation of tissues in the joints is not the same as the distribution of the 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 to certain tissues than others, and this judicious choice of inhibitor, with the selectivity described above, provides specific treatment of the disorder, disease or unwanted condition. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. In this way, the compounds can be selected to produce mediated effects through 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. The appropriate test conditions can be found in the literature. Specific tests are known for stromelicin and collagenase. For example, Patent E.U.A. No. 4,743,587 makes reference to the procedure of Cawston, and others, Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate in a test is described by Weingarten, H., and others, Biochem Biophy Res Corara (1984) 139: 1184-1187. Of course, any normal method can be used to analyze the degradation of structural proteins by 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 raw 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, these compounds 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. Routes that are preferred 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. By 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 burn or irritation (eg, topical). the skin) . Since the remodeling of the bones includes MPs, the compounds of the invention are useful to prevent loosening of the prosthesis. 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 maxillary and / or mandible. 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 rate of long-term insufficiency (reobstruction over time) is because MP activity is not desired or is high in response to what might be recognized by the body as "injury" to the base membrane of the baso. In this way, the regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, repercussion injury, ischemia, disease Chronic obstructive pulmonary restenosis due to angioplasty and aortic aneurysm may increase the long-term success of any other treatment or may be a treatment by 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, regulation and 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 damage by ultraviolet rays and / or during or after exposure to prevent or minimize post-exposure damage. In addition, MPs are involved in disorders and skin diseases related to abnormal tissues resulting from an abnormal manifestation 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 "contraction" of tissues, for example, after burns. MP inhibition is also useful in surgical procedures that include the skin for prevention of scarring and the promotion of normal tissue growth including in such applications as limb refraction and refractory surgery (either by laser or incision). In addition, MPs are related to disorders that include the remodeling and regulation 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 in myelin sheaths of nerve tissue. 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] rhinitis; 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 inhibitors of these enzymes can be used as agents for birth control, for example, to prevent ovulation, to prevent sperm penetration into and through the extracellular envelope of the egg. , implantation of the fertilized egg and to prevent maturation of 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 is prevalent 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 MP and cytokine activity. 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 erimatosus, ankylosing spondylitis and autoimmune keratitis. Some of the side effects of autoimmune therapy result in the exacerbation of other conditions mediated by MPs, here the inhibitory therapy of MP is also effective, 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, they can be treated with MP inhibitors. For example, they are effective as an antidote to rattlesnake bite, as antidesics, to treat allergic inflammations, septicemia and attacks. 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 could result in herpes, "catarrh" (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 arising from diabetes, especially those that include loss of tissue viability. , coagulation, Graft disease vs. Host, leukemia, cachexia, anorexia, proteinuria and perhaps the regulation of hair growth. For some diseases, conditions or disorders, the inhibition of MP is contemplated as a preferred 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 ulceration of the cornea, lack of healing of the cornea, macular degeneration and terigo); and gum diseases (especially periodontal disease and gingivitis). The compounds that are preferred for, but not limited to, the treatment of arthritis (including rheumatoid arthritis and osteoarthritis) are those compounds that are selective for the metalloproteases and the 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. Compounds which are preferred for, but not limited to, the treatment of ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration and tergium) are those compounds that broadly inhibit metalloproteases. 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 vehicle. As mentioned before, it is known that numerous diseases are mediated by excess or unwanted metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammation of the skin as ulcerations, particularly of the cornea, reactions to infections, periodontitis and the like. In this manner, the compounds of the invention are useful for therapies with respect to conditions that include this undesired activity. The compounds of the invention can therefore 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. , recent edition. A "safe and effective amount" of a compound of formula I is an amount that is effective to inhibit metalloproteases at the site of activity, in a human 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 "safe and effective amount" specific will vary, of course, with factors such as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of the concurrent therapy (if any), the specific dosage form that will be used, the vehicle employed, the solubility of the compound of formula I therein, as well as the desired dosage regimen for the composition. In addition to the compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein means one or more solid or liquid filler diluents compatible with encapsulating substances that are suitable for administration to a human. 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 conditions of ordinary use. The pharmaceutically acceptable carriers must, of course, have a sufficiently high purity and a toxicity low enough to make them suitable for administration to the human 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 starch dad; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malta, - gelatin; talc, - 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 pH regulating solutions. The choice of a pharmaceutically acceptable carrier that is used in conjunction with the present compound is basically determined by the manner in which the compound will be administered. If the present compound is injected, the preferred pharmaceutically acceptable carrier is a sterile physiological saline solution with a blood-compatible suspension agent, whose pH has been adjusted to approximately 7.4. In particular, pharmaceutically acceptable vehicles for systemic administration. they include sugars, starches, cellulose and their drifts, malt, gelatin, talc, Calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier, in 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. In accordance with 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 formula I. The compositions of this invention they 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 formula I. The amount of carrier 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. The techniques of 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., Pharraaceutical Dosage Forras: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forras 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 diluents or encapsulating 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 some -with others, so that there is no interaction that could reduce substantially the pharmaceutical efficacy of the composition under normal use situations. 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 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; talc, - 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 pH regulating solutions. The choice of a pharmaceutically acceptable carrier to be used in conjunction with the present compound is It basically determines by the way in which the compound will be administered. If the present compound is 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 formula I. The tablets can be compressed, comminuted, enteric coated, coated with sugar, film-coated or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents. 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 vehicle suitable for the preparation of unit dosage forms for peroral administration are 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 croscaramellose, - 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 sparta, saccharin, menthol, peppermint, and fruit flavors are also useful adjuvants for chewable tablets. The capsules typically comprise one or more solid diluents described above. The selection of vehicle components depends on secondary considerations such as taste, 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 components of vehicles for syrups, Elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants described above. Said compositions may also be coated by conventional methods, typically with pH coatings or time dependent, such that the present compound is released from 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. Slip agents, lubricants, sweeteners, colorants, antioxidants and flavoring agents are also described above and may be included. 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 typical 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 formula I. Vehicles suitable for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by transpiration or emersion in water. In general, the carrier is of an organic nature and capable of having dispersed or dissolved therein the compound of formula I. The carrier may include emollients, emulsifiers, thickening agents, pharmaceutically acceptable solvents and the like.

Methods of administration This invention also provides methods for treating or preventing disorders associated with metalloprotease activity excessive or unwanted in a human or other animal subject, administering a safe and effective amount of a compound of formula I to said subject. As used herein, a "disorder associated with excess or unwanted metalloprotease activity" is any disorder characterized by protein degradation. 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 of the formula I and compositions of this invention can be administered topically or systematically. Systemic application includes any method for introducing compound of formula I into body tissues, e.g., intra-articular (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, depend mutually. The dosage regimen under treatment will also depend on factors such as the compound of the specific 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 matrix metalloprotease. which will be inhibited, the subject's personal attributes (such as weight), acceptance of the treatment regimen and the presence and severity of any side effects of the treatment. 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 per day. It is understood that these dosage ranges 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 deliver the compound of formula I systemically or for 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 vehicle (if any) to be administered, the compound of the formula I in particular that it will be administered, as well as the particular disorder that will be treated and the degree to which systemic effects (such as those that differ from local) are desired. The inhibitors of the invention can be sent to specific locations where the metalloprotease is accumulated using selection ligand. For example, to detect matrix metalloprotease inhibitors contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof that is immunoreactive with a tumor marker as 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 desired target tissue can be used. The methods for coupling the compound of the invention with the selection ligand are well known and are similar to those described below for coupling it to the vehicle. The conjugates are formulated and administered as described above. For localized conditions, the topical administration. For example, to treat ulcerated cornea, direct application to the affected eye may employ a formulation such as eye drops or aerosol. For the treatment of corneas, the compounds of the invention can also be formulated as gels or ointments or 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 inflammation of the skin, the compound is applied locally and topically, in a gel, paste, cream or ointment. The treatment mode 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 is suitable for 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 between diastereomers are found 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 use 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 lock limmo hemocyanin (KLH) or whey albumin vehicles. For those compounds of the invention having 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 base 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 dicyclohexyl carbodiimide or other carbodiimide dehydration agents. Binding compounds can also be used to carry out the coupling; Homobifunctional 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 immunoprecipitation methods, now common in the art, using the compounds of the invention as antigens. The obtained antisera can be used directly or monoclonal antibodies can be obtained by cultivating the peripheral blood lymphocytes or the vessel of the immunized animal and immortalizing the antibody producing cells, followed by the 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 markers, e.g., technetium 99 or 1-131, using standard coupling methods. The labeled compounds are administered to subjects to determine sites of excessive amounts of one or more metalloproteases in vivo. The ability of inhibitors to Selectively bind to metalloproteases is then used to map the distribution of these enzymes in situ. The techniques can also be employed in histological procedures and the labeled compounds of the invention can be used in competitive immunoprotes. The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.

EXAMPLES The compounds are analyzed using 13 C NMR, elemental analysis, mass spectroscopy and / or IR spectroscopy, as appropriate. Inert solvents are typically 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 to the appropriate degree. Chromatography is performed on silica gel (Aldrich, mesh 70-230) or (Merck, mesh 230-400) as appropriate. The analysis by fi ber-layer chromatography (TLC) is carried out on glass-mounted silica gel plates (Baker, 200-300 mesh) and visualized with UV or with 5% phosphomolybdic acid in EtOH.

EXAMPLE 1 Synthesis of N-hydroxy l-benzyl-3- [(4-methoxy-phenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxamide (lf) Ó-Benzyl N- [(4-methoxyphenyl) sulfonyl] -D-aspartate (la): O-benzyl D-aspartate (10.48 g, 47.0 mmol) is suspended in a p-dioxane: water 1: 1 mixture (600 ral) ), and it is cooled to 0 ° C in an ice bath. To this is added 4-methylmorpholine (12.9 ml, 117.4 mmoles) and 4-methoxybenzenesulfonyl chloride (10.67 g, 51.7 mmoles) and the reaction is stirred for one hour at room temperature. The pH of the mixture is adjusted to 6 with 1 M aqueous hydrochloric acid and then water (300 ml) is added. The product is extracted with ethyl acetate (3x). The combined organic phases are washed with water (2x), dried (Na2S?), And concentrated under reduced pressure to give O-benzyl N- [(4-methoxyphenyl) sulfonyl] -D-aspartate as an oil. Benzyl ester of N-benzyl-2 (R) - [(4-methoxyphenyl) sulfonylamino] -succinnamic acid (lb): O-benzyl N- [(4-methoxyphenyl) sulfonyl] -D-aspartate (1.92 g, 4.9 mmol) in N, N-dimethylformamide (250 ml) and cooled to 0 ° C. to this is added 1-hydroxybenzotriazole (1.98 g, 14.6 mmol), 4-methylmorpholine (1.6 ml, 14.6 mmol) and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.12 g, 5.86 mmol) followed, after 20 minutes , with benzylamine (0.59 ml, 5.4 mmol). The reaction is stirred for 16 hours at room temperature, water (400 ml) is added and the product is extracted with ethyl acetate (3x). The combined organic phases are washed with water (3x), dried (Na 2 SO 4) and concentrated under reduced pressure to give the benzyl ester of N-benzyl-2 (R) - [(4-methoxyphenyl) sulfonylamino] -succinamic acid as an oil . Benzyl l-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxylate (le): to the benzyl ester solution of N-benzyl-2 (R) acid - [(4-methoxyphenyl) sulfonylamino] -succinnamic acid as an oil (2.10 g, 4.4 mmol) in 200 ml of dichloromethane is added, with stirring, 1, 3, 5-trioxane (1.57 g, 17.4 mmol) followed by two drops of sulfuric acid. The reaction is heated to reflux for 3 hours at which time the mass spectroscopy (MS) indicates that the reaction is complete. The reaction is allowed to cool to room temperature, diluted with dichloromethane (250 ml), and washed with water (2x). The product is purified by flash chromatography on silica gel (hexanes-ethyl acetate 1: 1), to give benzyl l-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxylate.

L-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxylic acid (id): a mixture of benzyl l-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxylate (518 mg, 1.0 mmol) and 10% Pd / C (50 mg) in methanol (25 ml) is stirred under a hydrogen atmosphere for 45 minutes . The mixture is filtered over celite and the filtrate is collected and concentrated under reduced pressure to give l-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxylic acid. as a crystalline solid. N-benzyloxy l-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxamide (le): l-benzyl-3- [(4-) acid is dissolved methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxylic acid (206 mg, 0.5 mmol), in N, N-dimethylformamide (20 ml) and cooled to 0 ° C. To this is added 1-hydroxybenzotrisol (203 mg, 1.5 mmol), 4-methylmorpholine (0.16 ml, 1.5 mmol) and l-ethyl-3- (3-dimethylaminopropyl) carbodiimine (117 mg, 0.61 mmol), followed, after 20 minutes with O-benzylhydroxylamine hydrochloride. (889 mg, 0.56 mmol). The reaction is stirred for 4 hours at room temperature, water (50 ml) is added and the product is extracted with ethyl acetate (3x). The combined organic phases are washed with water (2x), dried (Na2SC > 4) and concentrated under reduced pressure to give N-benzyloxy 1-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydroxy. pyrimidin-4 (R) -carboxamide.

N-hydroxy l-benzyl-3 - [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxamide (lf): a mixture of N-benzyloxy l-benzyl-3- [( 4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxamide (213 mg, 0.4 mmol) and 10% of Pd / C (50 mg) in methanol (25 ml) is stirred under an atmosphere of hydrogen for 3 hours. The mixture is filtered on celite and the filtrate is collected and concentrated under reduced pressure to give an oil. The crude product is purified by flash chromatography on silica gel (200: 1 ethyl acetate-formic acid) to give N-hydroxy-1-benzyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro- pyrimidin-4 (R) -carboxamide as a white solid. MS (ESI): 420 (M + H +), 437 (M + NH 4 +).

EXAMPLE 2 The following compounds are prepared in a manner similar to Example 1: N-Hydroxy l-methyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R) -carboxamide MS (IEA): 344 (M + H +), 361 (M + NH 4 +); N-Hydroxy 1- (1-methylethyl) -3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexa-hydro-pyrimidin-2 (R) -carboxamide. MS (ESI): 372 (M + H +), 389 (M + NH +): N-Hydroxy 1- (1,1-dimethylethyl) -3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-2 (R) -carboxamide. MS (ESI): 386 (M + H +), 403 (M + NH 4 +): N-Hydroxy 1- (2-methoxyethyl) -3 - [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-2 (R) -carboxamide. MS (ESI): 388 (M + H +), 405 (M + NH +): N-Hydroxy-l-cyclohexyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexa-hydro-pyrimidin-2 ( R) -carboxamide. MS (ESI): 412 (M + H +), 429 (M + NH 4 +): EXAMPLE 3 Synthesis of N-hydroxy-l-benzyl-5,5-dimethyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R. S) -carboxamide (3e) Ester 1-allyl 4-ethyl ester of 3-isocyano-2,2-dimethyl-succinic acid (3a): ethyl isocyanoacetate (2.19 g, 19.4 mmol) and allyl 2-bromo-2-methylpropionate (4.40 g, 21.3) are dissolved mmoles) in diethyl ether (50 ml) and methyl sulfoxide (50 ml) with stirring. Sodium hydride (775 mg of a dispersion in 60% mineral oil) is rinsed in a separate flask with hexane and suspended in diethyl ether (10 ml). The suspension is added dropwise to the solution under stirring and additional methyl sulfoxide (50 ml) is added to the mixture. The reaction is stirred for 2 hours at room temperature. The mixture is diluted with diethyl ether (250 ml) and washed several times with water. The organic phase is dried over sodium sulphate and evaporated to give the 3-ethyl-3-ethyl ester of 3-isocyano-2-allyl ester., 2-dimethyl-succinic. Ester 1-allyl 4-ethyl ester of 3-amino-2,2-dimethyl-succinic acid (3b): the 3-isocyan-2, 2-dimethyl-succinic acid ester 1-allyl ester (3.75 g) , 15.5 mmol) is dissolved in methanol (100 ml), and the mixture is cooled to 0 ° C in an ice bath. To this is added, drop by drop, 37% aqueous hydrochloric acid (1.58 g). The reaction is stirred 20 minutes and neutralized with 1 M aqueous sodium hydroxide. The volatiles are removed in vacuo and then the product is extracted with ethyl acetate (2x) and washed with water (2x). The combined organic phases are dried over sodium sulfate and evaporated to give the 3-amino-2,2-dimethyl-succinic acid 1-allyl ester ester as a yellow oil. 3 - [(4-Methoxy-phenyl) -sulfonylamino] -2, 2-dimethyl-succinic acid ester 3-allyl ester (3c): the 3-amino-2-1-allyl ester of 4-ethyl ester , 2-dimethyl-succinic (2.10 g, 9.2 mmol) is dissolved in a 1: 1 mixture of p- dioxane.-water (250 ml) and cooled to 0 ° C in an ice bath. To this solution is added 4-methylmorpholine (2 ml, 18.2 mmol) followed by 4-methoxybenzenesulfonyl chloride (1.90 g, 9.2 mmol). The reaction is stirred at room temperature for 30 minutes. The mixture is diluted with water (200 ml) and the product is extracted with ethyl acetate (3x). The combined organic phases are washed with water (3x), dried over sodium sulfate, and evaporated to give the 3- [(4-methoxy-phenyl) sulfonylamino] -2, 2-yl ester of 4-ethyl ester dimethyl-succinic. 3- [(4-Methoxyphenyl) -sulfonyl-amino) -2, 2-dimethyl-succinic acid (3d): 4-ethyl ester: to a solution of the 3-ethyl ester of 4-ethyl ester of 1-allyl ester -methoxyphenyl) sulfonylamino] -2,2-dimethyl-succinic acid (1.50 g, 3.8 mmol) in dichloromethane (150 ml) is added tetrakis (triphenylphosphine) palladium (0) (109 mg, 0.09 mmol), triphenylphosphine (61 mg, 0.23 mmoles), and pyrrolidine (0.47 ml, 5.6 mmoles). The reaction is stirred for 15 minutes, then 1 M aqueous hydrochloric acid (200 ml) is added and the product is extracted into dichloromethane (3x). The combined organic phases are washed with water (lx) dried over sodium sulfate and evaporated to give the 3 - [(4-methoxyphenyl) sulfonylamino] -2,2-dimethyl-succinic acid 4-ethyl ester as a brown oil.

N-hydroxy-l-benzyl-5,5-dimethyl-3- [(4-methoxyphenyl) sulfo-nyl] -6-oxo-hexahydro-pyrimidin-4 (R, S) -carboxamide (3e). Following the example and using sodium hydroxide-methanol to hydrolyse the ethyl ester instead of the hydrogenolytic elimination of the benzyl ester to make Id, the 4 - ethyl ester of 3 - [(4-methoxyphenyl) sulfonylamino] -2, 2- dimethyl-succinic is converted to N-hydroxy-l-benzyl-5,5-dimethyl-3- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-4 (R, S) -carboxa-mide as a solid white. MS (ESI): 448 [M + H] +, 465 (M + NH 4 +).

EXAMPLE 4 Synthesis of N-hydroxy 1- (1-methylethyl) -4- [(4-methoxy-phenyl) sulfonylamino] -7-oxo-l, 4-diazepin-5 (R) -carboxamide (4e) alpha-benzyl N- (4-methoxyphenyl) sulfonyl-D-aspartate (4a): alpha-benzyl D-aspartate (10.48 g, 47.0 mmol) is suspended in p-dioxane: water 1: 1 (600 ml) and is cooled at 0 ° C in an ice bath. To this suspension are added 4-methylmorpholine (12.9 ml, 117.4 mmol) and 4-methoxybenzenesulfonyl chloride (10.67 g, 51.7 mmol) and the reaction is stirred for one hour at room temperature. The pH of the mixture is adjusted to 6 with 1 M aqueous hydrochloric acid and then water (300 ml) is added. The product is extracted with ethyl acetate (3x). The combined organic phases are washed with water (2x) dried (Na2SO4), and concentrated under reduced pressure to give alpha-benzyl N- (4-methoxyphenyl) sulfonyl-D-aspartate as an oil. N- (2-Hydroxyethyl) -N- (1-methylethyl) -2- (R) - [(4-methoxyphenyl) sulfonylamino] -succinnamic acid benzyl ester (4d): alpha-benzyl N- (4-methoxyphenyl) sulfonyl-D-aspartate (1.04 g, 2.6 mmol) is dissolved in N, -dimethylformamide (75 ml) and cooled to 0 ° C. To this solution is added 1-hydroxybenzotriazole (1.07, 7.9 mmoles), 4-methylmorpholine (0.87 ml, 7.9 mmoles) and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.55 g, 2.9 mmol) followed, after 10 minutes, with 2- (isopropylamino) ethanol (0.33 ml, 2.9 mmol). The reaction is stirred for 60 hours at room temperature, water (150 ml) is added and the product is extracted with ethyl acetate (3x). The combined organic phases are washed with water (3x), dried (Na2S? 4) and concentrated under reduced pressure to give the ester N- (2-hydroxyethyl) -N- (1-methylethyl) -2- [(4-methoxyphenyl) sulfonylamino] -succinnamic acid benzyl ester as an oil. Benzyl 1- (1-methylethyl) -4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-l, 4-diazepin-5 (R) -carboxylate (4c): to the benzyl ester solution of N- (2-hydroxyethyl) -N- (1-methylethyl) -2- [(4-methoxyphenyl) sulfonylamino] -succinnamic acid (500 mg, 1.0 mmol) in tetrahydrofuran (10 ml) is added, with stirring, triphenylphosphine (328 g, 1.3 mmol) followed by diethyl azodicarboxylate (0.18 ml, 1.2 mmol). The reaction is stirred for 16 hours at room temperature and concentrated under deduced pressure. The product is purified by flash chromatography on silica gel to give benzyl 1- (1-methylethyl) -4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-l, 4-diacepin-5 (R) -carboxylate. . 1- (1-Methylethyl) -4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-l, 4-diazepin-5- (R) -carboxylic acid: a mixture of benzyl 1- (1-methylethyl) - 4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-l, 4-diacepin-5 (R) -carboxylate (253 mg, 0.6 mmol) and 10% Pd / C (40 mg) in methanol (10 ml) ) is stirred under a hydrogen atmosphere for 45 minutes. The mixture is filtered over celite and the filtrate is collected and concentrated under reduced pressure to give the acid 1-1 (1-methylethyl) -4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-l, -diazepine- 5 (R) -carboxylic acid as a crystalline solid.

N-hydroxy 1- (1-methylethyl) -4- [(4-methoxyphenyl) sulfo-nylamino] -7-oxo-1,4-diazepin-5 (R) -carboxamide (4e): acid 1 is dissolved (1-Methylethyl) -4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-1,4-diazepin-5 (R) -carboxylic acid (95 mg, 0.26 mmol) in dichloromethane and cool to 0 ° C. Oxalyl chloride (46 ml, 0.53 mraole) is added, followed by N, N-dimethylformamide (20 ml, 0.26 mmol) and the reaction is stirred for 30 minutes at room temperature. In addition, hydroxylamine hydrochloride (71 mg, 1.0 mmol) is dissolved in water (1 ml) and tetrahydrofuran (3 ml), the solution is cooled to 0 ° C and triethylamine (0.21 ml, 1.5 mmol) is added. The prepared mixture of acid chloride is added dropwise. The reaction mixture is stirred for four hours, water is added, and then the product is extracted into dichloromethane (3x). The combined organic phases are washed with water (50 ml, 2x), dried (Na 2 S 4), and evaporated under reduced pressure to give the crude product. The hydroxamic acid is purified by flash chromatography on silica gel (ethyl acetate) to give N-hydroxy 1- (methylethyl) -4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-1,4-diazepine -5 (R) -carboxamide. MS (ESI): 386 (M + H +), 403 (N + NH4 +).

EXAMPLE 5 The following compounds are prepared in a manner similar to Example 4: N-hydroxy 1- (1-phenylmethyl) -4- [(4-methoxyphenyl) sulfonylamino] -7-oxo-l, 4-diazepin-5 (R) -carboxamide. MS (ESI): 434 (M + H +), 451 (N + NH 4 +); N-hydroxy 1- (1-methylethyl) -4- [(4-methoxyphenyl) sulfonyl] -6-oxo-hexahydro-pyrimidin-2 (R) -carboxamide. MS (ESI): 372 (M + H +), 389 (N + NH 4 +); N-hydroxy 2-oxo-5- [(4-methoxyphenyl) sulfonyl] -1,5-diaza [5.3.0] 1'-bicyclodecane-4-carboxamide. MS (ESI): 384 (M + H +), 401 (N + NH 4 +); EXAMPLE 6 Synthesis of N-hydroxy-1,5-di- [(4-methoxyphenyl) -sulfonyl] -diacepin-2-carboxamide. t-Butyl 1, 5-bis (phenylmethyl) -diacepin-2-carboxylate (6a): N, N-dibenzylethylenediamine (20.0 g, 83.2 mmol), triethylamine (25.3 g, 250 mmol, 3 equiv) and t- are heated. butyl 1,3-dibromobutyrate (25.1 g, 83.2 mmol) in benzene (150 ml) at reflux for 12 hours. The resulting mixture is cooled to room temperature and the solution is washed with saturated sodium bicarbonate solution. The product is purified on a column of silica gel using a mixture hexane / ethyl acetate 85/15 as eluent to obtain the desired product as a yellow oil. t-Butyl 1,5-diazepin-2-carboxylate (6b): The t-butyl 1,5-bis (phenylmethyl) -diacepin-2-carboxylate (4.6 g, 12.1 mmol) in ethanol was placed in a Parr bottle and 10% Pd / C (1.0 g) was added. The resulting mixture was placed under 50 psi of hydrogen and stirred for 24 hours. The hydrogen was removed and the solution filtered through celite. The solvent was removed until leaving a pale yellow oil which was used without further purification EM (Cl): 201 (M + H +). t-Butyl 1, 5-di- [(4-methoxyphenyl) sulfonyl] -diacepin-2-carboxylate (6c): The t-butyl 1,5-diazepine-2-carboxylate (1.15 g, 5.74 mmole) in p- dioxane (30 ml) and water (30 ml) is stirred at room temperature and then triethylamine (2.32 g, 22.9 mmol) and 4-methoxyphenylsulfonyl chloride (2.61 g, 12.6 mmol) are added and the reaction is stirred overnight . The The resulting solution is acidified to a pH close to 1 with IN hydrochloric acid, poured into water and extracted with methylene chloride. The organic extracts are dried Na 2 S 4) and concentrated under reduced pressure to an oil. The oil is purified on a column of silica gel using hexane / ethyl acetate 7/3 as eluent to obtain the desired product as a pale yellow oil. MS (Cl): 541 (M + H +), 558 (M + NH 4 +). 1, 5-Di- [(4-methoxyphenyl) sulfonyl] -diacepin-2-carboxylic acid (6d): The t-butyl 1,5-di- [(4-methoxyphenyl) sulfonyl] - Diacepin-2-carboxylate (0.45 g, 0.8 mmol) is dissolved in methylene chloride (1.5 ml) and cooled in an ice bath. Trifluoroacetic acid (1.5 ml) is added, 19.0 mmol) and the resulting solution is stirred at 0 ° C for 3 hours. The reaction mixture is warmed to room temperature and an additional 1 ml of trifluoroacetic acid is added. The resulting solution is stirred for a further hour and the mixture is concentrated under reduced pressure. The residue is used subsequently without further purification. MS (ESI): 485 (M + H +), 502 (M + NH). N-hydroxy-1, 5-di- [(4-methoxyphenyl) sulfonyl] -diace-phenyl-2-carboxamide (6e): 1,5-di- [(4-methoxyphenyl) sulfonyl] -diacepin-2 acid -carboxylic acid (0.60 g, 1.24 mmol) is dissolved in methylene chloride (15 ml) at room temperature followed by the addition of oxalyl chloride (0.32 ml, 2.54 mmol) and slow addition of DMF (0.09 g, 1.24 mmol). This solution is stirred for 30 minutes at room temperature. In a separate flask, hydroxylamine hydrochloride (0.34 g, 5.0 mmol) in water (5 ml) and THF (7 ml) are stirred at 0 ° C, and then triethylamine (1.0 ml, 6 equiv) is added. This solution is stirred for 15 minutes. The acid chloride solution is added to the hydroxylamine solution at 0 ° C and then heated to room temperature and stirred for 3 hours. The solution is acidified to pH ~ 1 with IN hydrochloric acid, poured into water and extracted with methylene chloride. The organic extracts are dried (Na2 =? 4) and concentrated until an oil is obtained. The oil is purified by HPLC with a column of Reverse phase using 65% (95% water, 5% acetonitrile, 0.1% formic acid) and 35% (80% acetonitrile, 20% water) as eluent. MS (ESI): 500 (M + H +), 517 (M + NH 4).

EXAMPLE 7 Synthesis of N-hydroxy-1- [4-methoxyphenyl) sulfonyl] -5- (1-methyl-lH-imidazol-4-sulfonyl-diazepin-2-carboxamide) t-Butyl- [(4-methoxyphenyl) sulfonyl] -5- (t-butoxysarbonyl) -diacepin-2-carboxylate (7a): T-butyl 1,5-diazepine-2-carboxylate (2.0 g, 9.98 mmoles) in p-dioxane (100 ml) and water (100 ml) are stirred at room temperature and then aqueous sodium hydroxide (0.399 g, 50% w / w, 9.98 mmol) is slowly added. Then, the di-t-butyl bicarbonate (2.18 g, 9.98 mmol) is added and the reaction mixture is stirred overnight. To the solution with stirring are added triethyl amine (4.17 ml, 29.9 mmol), 4-dimethylaminopyridine (0.1 equivalent) and 4-methoxybenzenesulfonyl chloride (2.47 g, 12.0 mmol), and the reaction is stirred overnight. The resulting mixture is acidified to pH ~ 1 with IN HCl, poured into water, and extracted with methylene chloride. The organic extracts are extracted with (Na2S? 4) and concentrated under reduced pressure to obtain an oil. The oil is purified on a column of silica gel using hexane / ethyl acetate 5/1 as eluent to obtain the desired product as a solid. 1- [(4-Methoxyphenyl) sulfonyl] -diazepine-2-carboxylic acid (7b): The t-butyl l - [(4-methoxyphenyl) sulfonyl] -5- (t-butoxycarbonyl) -diacepin-2- is dissolved carboxylate (0.45 g, 0.95 mmol) in methylene chloride (1.5 ml) and cooled to 0 ° C in an ice bath. Trifluoroacetic acid (1.5 mL, 19.0 mmol) was added and the resulting mixture was stirred at 0 ° C for three hours. The reaction mixture is warmed to room temperature and 1 ml of TFA is added. The reaction mixture is again stirred for an additional hour and the mixture is then concentrated in vacuo. The waste is used without further purification. The product is obtained as a TFA salt. Acid 1, [(4-methoxyphenyl) sulfonyl] -5- (1-methyl-lH-imidazole-4-sulfoni) -diacepin-2-carboxylic acid (7c): 1- [(4-methoxyphenyl) sulfonyl] - Diacepin-2-carboxylic acid (0.150 g, 0.48 mmol) is dissolved in water (10 ml) and p-dioxane (10 ml).

Then triethylamine (0.27 ml, 1.9 mmol) and l-methyl-lH-imidazole-4-sulfonyl chloride (0.104 g, 0.58 mmol) are added. The reaction mixture is stirred overnight at room temperature and then the solution is acidified with HCl IN to pH ~ 1, poured into water, and extracted with methylene chloride. The organic extracts are dried (Na2S? 4) and concentrated to an oil. The oil is purified by HPLC with a reverse phase column using 70% (95% water, 5% acetonitrile, 0.1% formic acid) and 30% (80% acetonitrile, 20% water) as eluent. N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -5- (1-methyl-lH-imidazole-4-sulfonyl) -diacepin-2-carboxamide (7d): 1- [(4-methoxyphenyl)] sulfonyl] -5- (l-methyl-lH-imidazole-4-sulfonyl) -diazepine-2-carboxylic acid (0.35 g, 0.76 mmol) is dissolved in methylene chloride (10 ml) at room temperature followed by the addition of chloride of oxalyl (0.14 ml, 1.56 mmol) and the slow addition of DMF (0.058 ml, 0.76 mmol). This mixture is stirred for 30 minutes at room temperature. In a separate flask, hydroxylamine hydrochloride (0.21 g, 1.56 mmol) in water (2 ml) and THF (5 ml) are stirred at 0 ° C, and then triethylamine (0.634 ml, 4.56 mmol) is added. This mixture is stirred for 15 minutes. The acid chloride solution is added to the hydroxylamine solution at 0 ° and the resulting solution is warmed to room temperature and stirred for 3 hours. The solution is acidified to pH ~ 1 with IN HCl, poured into water, and extracted with methylene chloride. The organic extracts are dried (Na2 =? 4) and concentrated to an oil. The oil is purified by HPLC with a reverse phase column using 80% (95% water, 5% acetonitrile, 0.1% formic acid) and 20% (80% acetonitrile, 20% water) as eluent.

EXAMPLE 8 Synthesis of N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -5-benzyloxycarbonyl-diazepine-2-carboxamide 1- [(4-Methoxyphenyl) sulfonyl] -5-benzyloxycarbonyl-2-carboxylic acid (8a): l - [(4-methoxyphenyl) sulfonyl] -diazepine-2-carboxylic acid (0.570 g, 1.33 mmoles) is dissolved in water (5 ml) and p-dioxane (10 ml). Then add triethyl amine (0.74 ml, 5.32 mmol) and benzyl chloroformate (0.228 ml, 1.59 mmol). The reaction mixture is stirred overnight at room temperature and then the solution is acidified with IN HCl to pH ~ l and poured into water and extracted with methylene chloride. The organic extracts are dried (Na2S? 4) and concentrated to an oil. The oil is purified by HPLC with a reverse phase column using 70% (95% water, 5% acetonitrile, 0.1% formic acid) and 30% (80% acetonitrile, 20% water) as eluent. N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -5-benzyloxy-sarbonyl-diazepin-2-carboxamide (8b): l - [(4-) methoxyphenyl) sulfonyl] -5-benzyloxycarbonyl-diazepine-2-carboxylic acid (0.70 g, 1.56 mmole) is dissolved in methylene chloride (15 ml) at room temperature followed by the addition of oxalyl chloride (0.28 ml, 3.20 mmol) and slow addition of DMF (0.12 ml, 1.56 mmol). This solution is stirred for 30 minutes at room temperature. In a separate flask, hydroxylamine hydrochloride (0.43 g, 6.24 mmol) in water (5 ml) and THF (7 ml) are stirred at 0 ° C, and then triethylamine (1.3 ml, 9.12 mmol) is added. The solution is stirred for 15 minutes. The acid chloride solution is added to the hydroxylamine solution at 0 ° C and then warmed to room temperature and stirred for 3 hours. The solution is acidified to pH ~ l with IN HCl, poured into water and extracted with methylene chloride. The organic extracts are dried with (Na 2 SO 4) and concentrated to an oil. The oil is purified by HPLC with a reverse phase column using 65% (95% water, 5% acetonitrile, 0.1% formic acid) and 35% (80% acetonitrile, 20% water) as the eluent.

EXAMPLE 9 Synthesis of N-Hydroxy-4- [(4-methoxyphenyl) sulfonyl] -thiazepine-5-carboxamide Methyl N- [(4-methoxyphenyl) sulfonyl] - (2-hydroxyethyl) -homocysteine (9a): Stir at 0 ° CD, L-homocysteine (6.0 g, 44.3 mraole) in 2N NaOH (28.8 ral, 57.7 mmol, 1.3 equiv) under an argon atmosphere. A solution of 2-bromopropanol (6.66 g, 53. 3 mmol, 1.2 equiv) in ethanol (50 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 with 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. Then triethylamine (13.5 g, 133.2 mmol, 3 equiv) is added to the reaction mixture followed by 4-methoxyphenylsulfonyl chloride (10.0 g, 48. 8 mmol, 1.1 equiv). 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 a colorless oil. The purification of the resulting methyl ester is completed by chromatography on silica gel using hexane / ethyl acetate 1/1 as the eluent. The desired product is obtained as a clear, colorless oil. MS (ESI): 364 (M + H +), 381 (M + NH +). Methyl 4- [(4-methoxyphenyl) sulfonyl] -thiazepine-5-carboxylate (9b): Methyl N- [(4-methoxyphenyl) sulfonyl] - (2-hydroxyethyl) -homocysteine (5.23 g, 14.4 g. mmoles) in THF (100 ml) at room temperature and then triphenylphosphine is added (4.52 g, 17.3 mmol, 1.2 equiv) followed by diethyl azodicarboxylate (2.76 g, 15.8 mraols, 1.1 equiv). The resulting solution is stirred at room temperature for 2 hours. The solvent is removed and then the thick yellow oil is diluted with methylene chloride and silica gel (30 g) is added. The solvent is removed to leave a white powder. This powder is placed on a chromatography column and eluted with > hexane / ethyl acetate 8/2. The desired product is obtained as a colorless oil. MS (ESI): 346 (M + H +), 363 (M + NH 4 +). N-Hydroxy-4- [(4-methoxyphenyl) sulfonyl] -thiazepine-5-carboxamide (9c): Methyl 4- [(4-methoxyphenyl) sulfonyl] -thiazepine-5-carboxylate (1 g, 2.90 mmol) in methanol (50 ml) is stirred at room temperature and the solution of potassium hydroxide, hydroxylamine (Fieser &Fieser Vol. 1) (5 equiv.) is added. The resulting solution is stirred at room temperature for 6 hours. The reaction mixture is acidified with IN HCl and then extracted with dichloromethane. The organic extracts were dried (Na2SO4) and concentrated to a solid with reduced pressure. The solid is recrystallized from CH3CN / H2O to give a white powder. MS (ESI): 347 (M + H +), 364 (M + NH 4 +).

EXAMPLES 10-65 The following compounds are prepared using methods described and exemplified above.

Methods: Examples 10-54 are prepared analogously to Examples 1-9 using appropriately functionalized sulfonyl chloride. The sulfonyl chlorides which are used to prepare the above examples are either purchased from commercial sources or prepared by known methods. For example, the 4-phenoxyphenylsulfonyl chloride used for the preparation of Example 10 was prepared as described by R. J. Cremlyn et al. In Aust. J. Chem., 1979,32,445.52. These examples give a person skilled in the art sufficient guidance to make the present invention and do not limit it in any way.

EXAMPLES OF COMPOSITIONS AND METHODS OF USE The compounds of the invention are useful for preparing compositions for the treatment of diseases 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 formula I of the compounds can be replaced by the example compound shown below with similar results. The exemplified methods of use do not limit the invention, but give a guide to one skilled in the art to use the compounds, compositions and methods of the invention. The practicing expert will appreciate that the examples give guidance and can be varied based on the conditions and the patient.

EXAMPLE A A tablet composition for oral administration, in accordance with the present invention, is made comprising: Component Quantity Example 9 15. mg Lactose 120. mg Corn starch 70. mg Talc 4. mg Magnesium stearate 1. mg Other compounds having a structure according to formula I are used with substantially similar results. A human female subject weighing 60 kg (132 lbs), suffering from rheumatoid arthritis, is treated by a method of this invention. Specifically, for two years, a regimen of 3 tablets daily is administered orally to said subject. At the end of the treatment period, the patient is examined and found to have reduced inflammation, and improved mobility without concomitant pain.

EXAMPLE B A capsule for oral administration, according to the present invention, is made comprising: Component Quantity (% W / W) Example 3 15% Polyethylene glycol 85% Other compounds having a structure according to formula I are used with substantially similar results. A human male 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 via orthoscopy, and it is found that there is no further advancement of erosion / fibrillation of the articular cartilage.

EXAMPLE C A composition based on saline for local administration, in accordance with the present invention, is made comprising: Component Quantity (% W / W) Example 13 5% Polyvinyl alcohol 15% Saline 80% Other compounds having a structure according to formula I are used with substantially similar results. A patient who has deep corneal abrasion applies the drop to each eye twice a day. Recovery is accelerated, with no visual sequelae.

EXAMPLE D A topical composition for local administration, in accordance with the present invention, is made of the following: Component Composition (% P / P) Compound of example 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbj.tol 5.00 Glycine 0.35 Aromatics 0.075 Purified water c.b.p.

Total = 100.00 Total = 100.00 Any of the other compounds having a structure according to formula I are used with substantially similar results. A patient suffering from burns with chemical products is applied the composition to each change of clothes (b.i.d.). The scars are substantially diminished.

EXAMPLE E An aerosol composition for inhalation, according to the present invention, is made comprising: Component Composition (% P / P) Compound of example 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Saccharin sodium 0.2 Propellant (F12, F114) c.b.p.

Total = 100.

Any of the other compounds having a structure according to formula I are used with substantially similar results. A patient suffering from asthma is sprayed 0.01 ml via a pump actuator in the mouth while inhaling. The symptoms of asthma are diminished.

EXAMPLE F A topical ophthalmic composition, in accordance with the present invention, is made comprising: Component Composition (% P / P) Compound of Example 5 0.10 Benzalkonium Chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL M ™) 0.50 Sodium Metabisulfite 0.10 Sodium Chloride (0.9%) c.b.p.

Total 100.0 Any of the other compounds having a structure according to formula I are used with substantially similar results. A human male 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 affected eyes of said subject twice a day.

EXAMPLE G A composition for parenteral administration is made comprising: Component Quantity Example 4 100 mg / ml vehicle Vehicle Sun regulator of sodium citrate (% by weight of the vehicle) with 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 dose is repeated twice daily, for approximately 30 days. After 30 days, the symptoms of the disease subside, and the dose is gradually decreased to maintain the patient. Other compounds that have a structure of according to formula I are used with substantially similar results.

EXAMPLE H A mouthwash composition is prepared; Component% P / P Example 1 3.00 Alcohol SDA 40 8.00 Flavor 0.08 Emulsifier 0.08 Fluoride 'sodium 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide 0.20 Dye 0.04 Water the rest for 100% A patient with gingivitis uses 1 ml of mouthwash three times daily to prevent further oral degeneration. Other compounds having a structure according to formula I are used with substantially similar results EXAMPLE I A composition for pills is prepared; Component% P / P Example 3 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor 11.70 Color 0.10 Corn syrup the rest for 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 / P Example 1 0.03 Sorbitol crystals 38.44 Paloja-T gum base 20.00 Sorbitol (70% aqueous solution) 22.00 Mannitol 10.00 Glycerin 7.56 Taste 1.00 A patient chews the gum to prevent loosening of the dentures. Other compounds having a structure according to formula I are used with substantially similar results.

EXAMPLE K Component% P / P Water USP 54,656 Methylparaben 0.05 Propylparaben 0.01 Gum xantan 0.12 Guar gum 0.09 Calcium carbonate 12.38 Defoamer 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 Benzyl alcohol 0.2 Citric acid 0.15 Freshener 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 slowly adding and mixing together methylparaben, propylparaben, water, xanthan gum, and guar gum. Those ingredients are mixed for about 12 minutes with a Silverson in-line mixer. After slowly adding the following ingredients in the following order: the rest of glycerin, sorbitol, antifoam C, calcium carbonate, citric acid, and sucrose. Separately combine the flavorings and cooling agents and then slowly add to the other ingredients. They mix for about 40 minutes. The patient takes the formulation to prevent colitis attacks. All references described hereinafter are incorporated for reference. While the particular embodiments of the subject of the invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the subject matter of the invention can be made without departing from the essence and scope of the invention. It is intended to cover, in the appended claims, all modifications that are within the scope of this invention.

Claims (4)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound that has a structure according to the formula (I) where Ri is H; R2 is hydrogen, alkyl, or acyl; Ar is COR3 or SO2 4; 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 0, S, SO, SO2 or NR5, wherein R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SÜ2Rg, COR7, CSRβ, PO (R) 2 or may optionally form a ring with W or Y; 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; R3 is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R9 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, SR Q, SOR4, SO2 4, alkoxy, amino, wherein amino is of the formula NRn, R12 / wherein Rn and R12 are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl , aryl, S? 2 g, COR7, CSR?, PO (R9) 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 1-4. This structure also includes an optical isomer, diastereomer, or enantiomer for formula I, or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester, or imide thereof.
2. 2. The compound of claim 1 characterized in that X is O, S, SO, SO2, or NR5, wherein R5 is independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S02R7, CORβ, CSR.
3. 3. The compound of claim 1 characterized in that Ar is SO2 4 and R4 is unsubstituted or substituted heteroalkyl, aryl, or heteroaryl alkyl.
4. 4. The compound of claim 1, characterized in that Ar is phenyl or substituted phenyl. 5. - The compound of claim 4, wherein Ar is substituted phenyl and the substitution is with hydroxy, alkoxy, nitro or halo. 6. The compound of claim 5, characterized in that Ar is substituted with methoxy, bromine, nitro and butoxy. 1 . - The compound of claim 6, characterized in that Ar is substituted in the ortho or para position relative to the sulfonyl. 8. The compound of claim 1, characterized in that W is 1 or more of hydrogen or Ci to C4 alkyl. 9. The compound of claim 1, characterized in that W is a Ci-C4 alkyl geminal. 10. The compound of claim 1 characterized in that Z is an oxo substituted portion in the heterocyclic ring. 11. A pharmaceutical composition comprising: an effective and safe amount of a compound of claim 1; and a pharmaceutically acceptable vehicle. 12. A pharmaceutical composition comprising: an effective and safe amount of a compound of claim 4; and a pharmaceutically acceptable vehicle. 13. A pharmaceutical composition comprising: an effective and safe amount of a compound of claim 5; and a pharmaceutically acceptable vehicle. 14. - A pharmaceutical composition comprising: an effective and safe amount of a compound of claim 9; and a pharmaceutically acceptable vehicle. 15. A pharmaceutical composition comprising: an effective and safe amount of a compound of claim 10; and a pharmaceutically acceptable vehicle. 16. The use of a compound of claim 1, for the manufacture of a medicament for the prevention or treatment of a disease associated with unwanted metalloprotease activity in a mammalian subject. 17. The use of a compound of claim 4, for the manufacture of a medicament for the prevention or treatment of a disease associated with unwanted metalloprotease activity in mammalian subjects. 18. The use of a compound of claim 5 for the manufacture of a medicament for the prevention or treatment of a disease associated with unwanted metalloprotease activity in a human or other subject. 19. The use of a compound of claim 9, for the manufacture of a medicament for the prevention or treatment of a disease associated with unwanted metalloprotease activity in a mammal. 20. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for the -prevention or treatment of a disorder modulated by metalloproteases, characterized in that the disorder it is chosen from the group comprising arthritis, cancer, cardiovascular disorders, skin disorders, eye disorders, gum disease and inflammation in a mammal. 21. The use according to claim 20, characterized in that the disorder is arthritis, and is chosen from the group comprising osteoarthritis and rheumatoid arthritis. 22. The use according to claim 20, characterized in that the disorder is cancer, and the treatment prevents or suppresses tumor growth and metastasis. 23. The use according to claim 20, characterized in that the disorder is a cardiovascular disorder chosen from the group that compromises dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion damage, ischemia, chronic obstructive pulmonary disease , angioplasty restenosis and aortic aneurysm. 24. The use according to claim 20, characterized in that the disorder is an ocular disorder, and is chosen from the group comprising ulceration of the cornea, lack of sanitation in the cornea, macular degeneration and pterygium. 25. The use according to claim 20, characterized in that the disorder is gum disease, and is chosen from the group comprising periodontal disease and gingivitis. 26. Use according to claim 20, characterized in that the condition is a condition of the skin chosen from the group that includes repair and prevention of wrinkles, skin damage by U.V. rays, epidermolysis bullosa, psoriasis, sclerodema, atopic dermatitis, and scars. 27. The use of a metalloprotease inhibitor according to claim 1 for the manufacture of a medicament for the prevention of loosening of prosthetic devices chosen from the group comprising replacement of joints and dental prostheses in a mammal. 28. The use according to claim 20, characterized in that the disease is chosen from the group comprising inflammatory bowel disease, Crohn, 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 treating multiple sclerosis in a mammal. 30. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for treating musculoskeletal disease or cachexia in a mammal.