MXPA99002066A - 1,3-diheterocyclic 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

INHIBIDORBS DB MBTALOPROTKASAS 1.3-PIHETEROCICLICOS This invention is directed to compounds that are useful for treating diseases, disorders and conditions associated with unwanted metalloprotease activity.

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

OBJECTS OF THE INVENTION Thus, it is an object of the present invention to provide compounds useful for the treatment of conditions and diseases that are characterized by undesired MP activity. It is also an object of the present 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 matrix metalloproteases, and which are effective to treat conditions characterized by excessive activity of these enzymes. In particular, the present invention relates to a compound having a structure according to formula (I) where R! it's 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, 0 NR5, where R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S02Rg, COR7, CSRβ, P0 (Rg) 2 or may optionally form a ring with Y or W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, 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 moieties, or a heterocycle or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbons (in this way a fused ring is formed); And it is independently one or more of hydrogen, hydroxy, SR ^ Q / SOR-4, SO2 4 / alkoxy, amino, where amino is of the formula NR _] _, R12 'wherein R ^ and R ^ 2 are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R6' COR7, CSRg, PO (R9) 2; and R 5 O 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 isomer, diaesteromer or optical enantiomer of Formula (I) or a pharmaceutically acceptable salt or amide, ester or imide thereof. These compounds have the ability to inhibit at least one mammalian matrix metalloprotease. Accordingly, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of the formula (I) to methods for treating diseases characterized by matrix metalloprotease activity using these compounds or the pharmaceutical compositions containing them. Metalloproteases that are active at a particularly undesired site (eg, an organ or certain cell types) can be identified by conjugating the compounds of the invention to a specific identification ligand for a label at that site, such as an antibody or fragment thereof or a receptor ligand. Methods of conjugation are known in the art. The invention is also directed to several other methods that take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease. In another aspect, the invention is directed to the compounds of the formula (I) conjugated to a marker. As the compounds of the invention bind to at least one metalloprotease, the label can be used to detect the presence of relatively high levels of matrix metalloproteases in vivo or in vitro in cell cultures. In addition, the compounds of the formula (I) can be conjugated to vehicles that allow the use of these compounds of immunization protocols to prepare antibodies specifically immunoreactive with the compounds of the invention. Typical conjugation methods are known in the art. These antibodies are then useful both in therapy and in the monitoring of the dosage of the inhibitors.

DETAILED DESCRIPTION The compounds of the present invention are inhibitors of mammalian metalloproteases, preferably mammalian metalloproteases. Preferably, the compounds are those of the formula (I) or a pharmaceutically acceptable salt or biohydrolyzable amide, ester or imide thereof.

Throughout this description, publications and patents are mentioned in an effort to fully describe the state of the art. All references cited herein are incorporated herein by reference.

Definitions and use of terms The following is a list of definitions for the terms used herein. "Acyl" or "carbonyl" is described as a radical that could be formed by removing the hydroxyl from a carboxylic acid (ie R-C (= 0) -). Preferred acyl groups include (for example) acetyl, formyl and propionyl. "Acyloxy" is an oxy radical having an acyl substituent (i.e., -O-acyl); for example, -O- (= 0) -alkyl. "Alcoxyacil" is an acyl radical (-C (= 0) -) having an alkoxy substituent (ie, -0-R), for example, -C (= 0) -0-alkyl. This radical can be considered as an ester. "Acylamino" is an amino radical having an acyl substituent (i.e., -N-acyl); for example -NH-C (= 0) -alkyl. "Alkenyl" is a substituted or unsubstituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; very preferably from 2 to 8; except when indicated. Alkenyl substituents have at least one olefinic double bond (including, for example, vinyl, allyl and butenyl). "Alkynyl" is an unsubstituted or substituted hydrocarbon chain radical having 2 to 15 carbon atoms, preferably 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 1 to 3 carbon atoms) and the alkyloxy has 1 to 6 carbon atoms (most preferably 1 to 3 carbon atoms). "Alkyl" is a saturated or unsubstituted or substituted hydrocarbon chain radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms; very preferably 1 to 4; except when indicated. Preferred alkyl groups include (for example) substituted or unsubstituted methyl, ethyl, propyl, isopropyl and butyl. As referred to herein, "spirocycle" or "spirocyclic" refers to a cyclic portion that shares a carbon in another ring. Said cyclic portion may be carbocyclic or heterocyclic in nature. Preferred heterogeneous atoms included in the base structure of the heterocyclic spirocycle include oxygen, nitrogen and sulfur. Spirocycles can be substituted or not replaced. Preferred substituents include oxo, hydroxyl, alkyl, cycloalkyl, arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (e.g., benzothiol, cycloalkyl, heterocycloalkyl, benzimidizoles, pyridyl thiol, etc., which may also be substituted ) and similar. In addition, the heterogeneous atom of the heterocycle can be replaced if its valence allows it. Preferred spirocyclic ring sizes include rings of 3 to 7 members. The term "alkylene" refers to an alkyl, alkenyl or alkynyl that is a diradical, rather than a radical. "Heteroalkylene" is likewise defined herein as a (diradical) alkylene having a heterogeneous atom in its chain. "Alkylamino" is an amino radical having one (secondary amine) or two (tertiary amine) alkyl substituents (ie, -N-alkyl). For example, methylamino (-NHCH3), dimethylamino (-N (CH3) 2) and methylethylamino (-N (CH3) CH2CH3). "Aminoacyl" is a radical acyl that has an amino substituent (ie., -C (= 0) -N); for example -C (= 0) -NH2. The amino group of the aminoacyl moiety can be unsubstituted (ie, primary amine) or can be substituted with one (secondary amine) or two (ie, tertiary amine) alkyl groups. "Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl and fluorenyl. Said groups can be substituted or 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., -NH-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 ring systems fused, bridged spiropolyclic. The monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. The polycyclic carbocyclic rings contain 7 to 17 atoms, preferably 7 to 12 atoms. Preferred polycyclic systems comprise rings of 4, 5, 6 or 7 members fused to rings of 5, 6 or 7 members. "Carbocycloalkyl" is a substituted or unsubstituted alkyl radical substituted with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl, most preferably an aryl. Preferred carbocycloalkyl groups include benzyl, phenylethyl and phenylpropyl. "Carbocycloheteroalkyl" is an unsubstituted or substituted heteroarkyl radical replaced with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl; most preferably an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl or 2-thia-ethyl. "Carboxyalkyl" is an unsubstituted or substituted alkyl radical replaced with a carboxy moiety (-C (= 0) 0H). For example, -CH2 ~ C (= 0) 0H. "Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) morpholinyl, piperadinyl, piperazinyl, tetrahydrofuryl and hydantoinyl.

"Fused rings" are rings that are superimposed on each other in such a way that they share two ring atoms. A certain ring can be fused to more than another ring.

The fused rings are contemplated in heteroaryl, aryl and heterocycle radicals, or the like. "Heterocycloalkyl" is an alkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably a heteroaryl or cycloheteroaryl; most preferably a heteroaryl. Preferred heterocycloalkyl includes C 1 -C 4 alkyl having a preferred heteroaryl attached thereto. More preferred is, for example, pyridyl-alkyl and the like. "Hetero-cycloheteroalkyl" is an unsubstituted or substituted heteroalkyl radical, replaced with a heterocyclic ring. The heterocyclic ring is preferably an aryl or cycloheteroalkyl; most preferably an aryl. "Heterogeneous atom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heterogeneous atoms may contain different heterogeneous atoms. "Heteroalkenyl" is an unsubstituted, unsubstituted or substituted chain radical having 3 to 8 members comprising carbon atoms and one or two heterogeneous atoms. The chain has at least one carbon-carbon double bond. "Heteroalkyl" is an unsubstituted or substituted saturated chain radical having 2 to 8 members comprising carbon atoms and one or two heterogeneous atoms.

"Heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprising carbon atoms and one or more heterogeneous atoms in the ring. The heterocyclic rings are monocyclic ring systems or are fused, bridged or spiro-polyclic. The monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7 atoms. The polycyclic rings contain 7 to 17 atoms, preferably 7 to 13 atoms. "Heteroaryl" is an aromatic heterocyclic radical, whether monocyclic or bicyclic radical. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl, benzothiazolyl, benzofuryl, indolyl, and the like. Said groups can be substituted or 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 cationic salt formed in any acidic 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). "Biohydrolysable amide" 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 mammal to produce an active inhibitor. A "biohydrolyzable hydroxyimide" is an imide of a compound of the formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by a mammal to produce an active compound of the formula (I) ). Said hydroxyimides include those which do not interfere with the biological activity of the compounds of the formula (I). A "biohydrolyzable ester" refers to an ester of a compound of the formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to produce a compound of the formula (I) active . A "solvate" is a complex formed by the combination of a solute (v.gr., a hydroxamic acid) and a solvent (e.g., water). See J. Hónig et al., The Van Nostrand Chemist's Dictionarv, p. 650 (1953). The pharmaceutically acceptable solvents used in accordance with this invention include those which do not interfere with the biological activity of the hydroxamic acid (e.g., water, ethanol, acetic acid, N, N-dimethylformamide and others known or readily determined by the person skilled in the art. The technique) . "Optical isomer", "stereoisomer" and "diastereomer", as mentioned herein, have the normal meanings recognized in the art (Cf., Hawlevs 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 can 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 Biology (1979), incorporated herein by reference. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxyl, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyaceil (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholino, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. As used herein, the term "mammalian matrix metalloprotease" means any enzyme containing a metal found in mammalian sources, and which is capable of catalyzing the degradation of collagen, gelatin or proteoglycan under suitable test conditions. Suitable test conditions can be found, for example, in the US patent. No. 4,743,587, which refers to the procedure of Cawston et al., Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate is described by Weingarten, H. et al., Biochem Biophv Res Comm (1984) 139: 1184-1187. Of course, any normal method can be used to analyze the degradation of these structural proteins. The matrix metalloprotease enzymes mentioned herein are all zinc-containing proteases and which are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit matrix metalloprotease activity can, of course, be tested in the assays described above. The isolated matrix metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or raw extracts containing the scale of enzymes capable of tissue degradation can be used.

Compounds; The compounds of the invention are described in the Brief Description of the Invention. Preferred compounds of the invention are where Z is heteroespyrocaryalkylene, preferably having heterogeneous atoms adjacent to the ring matrix structure, more preferably said spiroheteroalkylenes have 4 to 5 members. The preferred heterogeneous atoms are divalent. The invention provides compounds that are useful as inhibitors of metalloprotease, preferably of matrix metalloproteases and which are effective to treat conditions characterized by excessive activity of these enzymes. In particular, the present invention relates to a compound having a structure according to formula (I) where R] _ 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 O, S, SO, SO2, or NR5, where R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S? 2R, COR7, CSRg, PO (Rg) 2 or may optionally form a ring with Y or W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, 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 moieties, or a heterocycle or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbons (in this way a molten ring is formed); And it is independently one or more of hydrogen, hydroxy, SRiQ SOR-4, SO2 4, alkoxy, amino, where amino is of formula NR] _] _, R12 'where R] _? and R12 are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S? 2, COR7, CSRg, PO (R9) 2 and R] _0 is hydrogen, alkyl, aryl, heteroaryl; Z is zero, a spiro portion or an oxo group substituted on the heterocyclic ring; n is 1-4. The structure also includes an isomer, diastereomer or optical enantiomer for Formula (I) or a pharmaceutically acceptable salt or biohydrolyzable ester, amide or imide thereof.

Preparation of Compounds The hydroxamic compounds of Formula (I) can be prepared using a variety of procedures. The general schemes include the following.

PREPARATION OF PORTION AND For Y-manupulation it is understood that the person skilled in the art can choose to prepare Y before, after or concurrent with the preparation of a heterocyclic ring. For clarity, the W and Z portions are not presented later. More than one Y and Z may be present in the compounds of formula (I). For compounds where Y is not adjacent to the ring nitrogen, a preferred method of making the compounds is; (A) (B) (C) SCHEME I When R is a derivable group or can be manipulated or substituted, said compounds are known or prepared by known methods. (A) is converted to its analogous sultanic ester and R is manipulated to give (B) during this or a subsequent step.

Y and Z may be added or altered, followed by an appropriate reaction to provide R_. For example, this step may include treatment 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 those skilled in the art can choose to prepare Y before, after or concurrent with the preparation of a heterocyclic ring. For clarity, the portion of W, Y and Z is not presented later, more than one W, Y and Z are present in the compounds of formula (I). For compounds where X is nitrogen, the preferred method for handling R5 is presented. In the subsequent scheme, L is an acceptable residual group and B is a blocking group as mentioned above. The person skilled in the art will recognize that the choice of blocking group is within the skill of the art which works with organic chemistry.

SCHEME II For compounds containing two different groups attached to the ring nitrogens, the preferred methods of ring formation are presented. 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 presented later. More than one W, Y and Z are present in the compounds of formula (I). The protected diamine is treated with sulfonyl halide. The removal of the protected group followed by the addition of R5L. The addition of a pyruvate or glycoxylate group under standard conditions closes the ring to form the heterocycle. Until the formation of the ring, in the elaboration of the invention proceeds as described above.

SCHEME III For compounds containing an oxygen or a sulfur in the heterocyclic ring, preferred methods of ring formation are presented. 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 presented later. More than one W, Y and Z may be present in the compounds of formula (I). A bifunctional moiety, for example an aminoalcohol or an aminothiol reacts with a sulfonyl halide as it is subsequently presented. The halo portion serves as a residual group. The addition of a pyruvate or glycoxylate group under standard conditions closes the ring to form the heterocycle. Until the formation of the ring, the development of the invention proceeds as described above.

SCHEME IV PREPARATION OF THE Z PORTION Of course, those skilled in the art will recognize that schemes applicable to the preparation of Y may be useful in the preparation of Z as described above. Other preferred methods are provided for the reader. When Z is a ketal 9 thioketal the compounds of the invention can be prepared from a compound having a carbonyl in the ring. Said compounds are prepared by known methods and much of said compounds are known or commercially available. In this way, the person skilled in the art will appreciate that a hydroxy, amino, imino, alkoxy, oxo or any other group can be manipulated in a carbonyl compound. The order to elaborate the ketal, R_ or the sultamic ester can change. A preferred method of making the spiro compounds of the invention is by a carbonyl compound, using "protecting group" technology known in the art, such as triocetal or ketal and the like. Cetals, acetals and the like are prepared from carbonyl compounds by methods known in the art. Said carbonyl compounds can be made from hydroxycyclic alkylene amines by oxidation of a ketone, or lactam, which provide 2-amino spiro functionality. The variety of compounds can be generated in a similar way, using the guide 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 by using a standard dealkylator process (Bhart et al., "Cleavage of Ethers", Svnthesis, 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. it is routine, it will be understood that to make a variety of compounds these can be generated in a similar way, using the guide of the previous scheme. The starting materials used to prepare the compounds of the invention are known, are manufactured by known methods or are commercially available as a starting material. It is recognized that one skilled in the art of organic chemistry can easily perform normal manipulations of organic compounds without additional guidance; that is, it is within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification and the like. Examples of these manipulations are described in normal texts, such as March, Advanced Organic Chemistry, (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and Keeting, Heterocyclic Chemistrv (all 17 volumes). The person skilled in the art will readily appreciate that certain reactions are best carried out when another functionality is masked or protected in the molecule, thereby avoiding any undesirable side reactions and / or increasing the yield of the reaction. Commonly, those skilled in the art use protecting groups to achieve said increased yields or to avoid unwanted reactions. These reactions are found in the literature and are also within the scope of the person skilled in the art. Examples of many of these manipulations can be found, for example, in T. Greene, 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 at the same time, including diastereomers and enantiomers (a racemic mixture). Since the compounds of the invention can exist as racemic mixtures, mixtures of optical isomers including diastereomers or enantiomers or stereoisomers can be separated, using known methods such as chiral salts, chiral chromatography and the like. Furthermore, it is recognized that an optical isomer, including diastereomer and enantiomer or stereoisomer, may have favorable properties over others. Thus, when describing and claiming the invention, when describing a racemic mixture, it is clearly contemplated that both optical isomers are also described and claimed, including diastereomers and enantiomers or stereoisomers substantially free of the others.

Methods of use The metalloproteinases (MPs) found in the body function, in part, by degrading the extracellular matrix, which comprises proteins and extracellular glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of the tissue in the body. Metalloprotease inhibitors are useful for treating diseases caused, at least in part, by the degradation of said proteins. It is known that MPs are intimately involved in tissue remodeling. As a result of this activity, it has been mentioned that they are active in many disorders that include either: tissue degradation; including degenerative diseases such as arthritis, multiple sclerosis and the like; Metastasis or mobility of tissues in the body: - tissue remodeling, including fibrotic disease, scar prevention, benign hyperplasia and the like. The compounds of the present invention treat disorders, diseases and / or undesired conditions that are characterized by undesired or elevated activity of this class of proteases. For example, the compounds can be used to inhibit proteases that: destroy structural proteins (i.e., proteins that maintain the stability and structure of tissues); - interfere in inter / intracellular signaling, including those involved in cytokine upregulation and / or cytokine processing and / or inflammation, tissue degradation and other diseases [Mohler KM. and others, Nature 370 (1994) 218-220; Gearing AJH et al., Nature 370 (1994) 555-557; McGeehan GM et al., Nature 370 (1994) 558-561], and / or - facilitate unwanted processes in the subject being treated, for example, the processes of sperm maturation, egg fertilization and the like. As used herein, an "MP-related disorder" or "MP-related disease" is one that includes undesired or high MP activity in the biological manifestation of the disease or disorder; in the biological cascade that leads to the disorder, or as a symptom of the disorder. This "involvement" of MP includes: - the activity of unwanted or elevated MP as a "cause" of the disorder or biological manifestation, whether the activity has been genetically elevated, by infection, by autoimmunity, trauma, biomechanical causes, quality of life [eg, obesity] or for some other cause; - MP as part of the observable manifestation of the disease or disorder. That is, the disease or disorder is measurable in terms of increased MP activity, or from a clinical point of view, unwanted or elevated MP levels indicate the disease. MPs do not need to be the "hallmark" of the disease or disorder; - the activity of unwanted or elevated MP is part of the biochemical or cellular cascade that originates or is related to the disease or disorder. In this regard, the inhibition of MP activity disrupts the cascade and thus controls the disease. Advantageously, many MPs are not distributed evenly throughout the body. In this way, the distribution of MPs expressed in various tissues is commonly specific for these tissues. For example, the distribution of metalloproteases involved in the degradation of joint tissues is not the same as the distribution of metalloproteases found in other tissues. Thus, although not essential for activity or efficacy, certain disorders are preferably treated with compounds that act on specific MPs found in the affected tissues or regions of the body. For example, a compound that exhibits a higher degree of affinity and inhibition for an MP found in the joints (e.g., chondrocytes) would be preferred for the treatment of a disease found there, than other compounds that are less specific.

In addition, certain inhibitors are more bioavailable for certain tissues than others, and this judicious choice of the inhibitor, with the selectivity described above, provides a specific treatment of the disorder, disease or undesired condition. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. In this way, the compounds can be selected to produce mediated effects through MPs found specifically outside the central nervous system. The determination of the specificity of an inhibitor of MP of certain MP is within the ability of the expert in that field. Proper test conditions can be found in the literature. Tests for stromelysin and collagenase are specifically known. For example, the US patent. No. 4,743,587 refers to the procedure of Cawston et al., Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate in a test is described by Weingarten, H. et al., Biochem Biophy Res Comm (1984) 139: 1184-1187. Of course, any normal method can be used to analyze the degradation of structural proteins by the MPs. The ability of the compounds of the invention to inhibit metalloprotease activity can, of course, be tested in assays found in the art or variations thereof. The isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or crude extracts containing the scale of enzymes capable of tissue degradation can be used. As a result of the MP inhibitory activity of the compounds of the invention, they are also useful for treating the following disorders by virtue of their metalloprotease activity. The compounds of this invention are also useful for prophylactic or acute treatment. They are administered in any way that experts in the fields of medicine or pharmacology desire. It is immediately apparent to the person skilled in the art that the preferred routes of administration will depend on the disease state being treated, as well as on the dosage form chosen. Preferred routes for systemic administration include peroral and parenteral administration. However, one skilled in the art will readily appreciate the advantage of administering the MP inhibitor directly to the affected area for many disorders. For example, it may be advantageous to administer PM inhibitors directly to the area of the disease or condition, such as in an area affected by surgical trauma (e.g., angioplasty), an area affected by scarring or burning (Fig. gr., topical to the skin). Since the remodeling of the bones includes the 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 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 long-term insufficiency index (reobstruction with time) is because MP activity is not desired or is high in response to what could be recognized by the body as "injury" to the base membrane of the blood vessel. Thus, the regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, restenosis by angioplasty and aortic aneurysm can increase success at long term of any other treatment, or it may be a treatment in itself. In skin care, MPs are involved in the remodeling or "renewal" of the skin. As a result, the regulation of MPs improves the treatment of skin conditions, including but not limited to, wrinkle repair and regulation, prevention and repair of skin damage induced by ultraviolet rays. Such treatment includes prophylactic treatment or treatment before the physiological manifestations are obvious. For example, MP can be applied as a pre-exposure treatment to prevent damage by ultraviolet rays and / or during or after exposure to prevent or minimize post-exposure damage. In addition, MPs are involved in disorders and diseases of the skin related to abnormal tissues that result from an abnormal manifestation which includes metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of "normal" skin injuries, including scarring or "shrinkage" of tissues, for example, after burns. Inhibition of MP is also useful in surgical procedures that include the skin for the prevention of scar formation and the promotion of normal tissue growth, including applications such as limb refraction and refractory surgery (either by laser or incision). In addition, MPs are related to disorders that include irregular remodeling of other tissues, such as bone, for example, in otosclerosis and / or osteoporosis, or to specific organs, such as liver cirrhosis and fibrotic lung disease. Similarly, in diseases such as multiple sclerosis, MPs may be involved in the irregular modeling of the blood brain barrier and / or nerve tissue myelin sheaths. In this way, the regulation of MP activity can be used as a strategy in the treatment, prevention and control of said diseases. It is also believed that MPs are implicated in many infections, including cytomegalovirus; [CMV] retinitis; HIV and the resulting syndrome, AIDS. MPs may also be involved in extravascularization where the surrounding tissue needs to be degraded to allow new blood vessels such as angiofibrone and hemangioma. Since MPs degrade the extracellular matrix, it is contemplated that the inhibitors of these enzymes can be used as agents for birth control, for example to prevent ovulation, to prevent the penetration of sperm into and through the extracellular environment of the egg, in the implantation of the fertilized egg and to avoid the maturation of the sperm. In addition, it is also contemplated that they are useful in preventing or stopping premature labor and delivery. Since MPs are involved in inflammatory responses and cytokine processing, the compounds are also useful as anti-inflammatories for use in diseases in which inflammation prevails, including, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout and Reiter's syndrome. When autoimmunity is the cause of the disorder, the immune response commonly triggers the activity of MP and cytokine. The regulation of MPs to treat such autoimmune disorders is a useful treatment strategy. In this way, MP inhibitors can be used to treat disorders including, lupus erimatosus, ankylosing spondylitis and autoimmune keratitis. Sometimes the side effects of autoimmune therapy lead to the exacerbation of other conditions mediated by MPs, and MP inhibitor therapy is also effective here, for example, in fibrosis induced by autoimmune therapy. In addition, other fibrotic diseases lead to this type of therapy, including lung disease, bronchitis, emphysema, cystic fibrosis, acute respiratory distress syndrome (especially the acute phase response). When MPs are involved in unwanted tissue degradation by exogenous agents, it can be treated with MP inhibitors. For example, they are effective as an antidote to rattlesnake bite, as antivesics, to treat allergic inflammations, septicemia and shock. In addition, they are useful as antiparasitic (e.g., in malaria) and anti-infective. For example, they are believed to be useful for treating or preventing viral infections, including infection that would result in herpes, "cold" (e.g., rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS. It is also believed that MP inhibitors are useful for treating Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from, or originating from diabetes, especially those that include loss of viability. tissues, coagulation, Graft disease vs. Host, leukemia, cachexia, anorexia, proteinuria and perhaps the regulation of hair growth. For some diseases, conditions or disorders, the inhibition of MP is contemplated as a preferred treatment method. Said diseases, conditions or disorders include arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or combating of the growth and metastasis of tumors), ocular disorders (especially corneal ulceration, lack of healing of the cornea, macular degeneration and pterygium); and gum diseases (especially periodontal disease and gingivitis). Compounds that are preferred for, but not limited to, the treatment of "arthritis (including osteoarthritis and rheumatoid arthritis) are those compounds that are selective for matrix metalloproteases and disintegrin metalloproteases.

The compounds that are preferred for, but not limited to, the treatment of cancer (especially the prevention or combating of growth and tumor metastasis) are those compounds that preferably inhibit gelatinases or type IV collagenases. The compounds that are preferred for, but not limited to, the treatment of ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration and pterygium) are those compounds that broadly inhibit metalloproteases. Preferably, these compounds are administered topically, most preferably as a drop or gel. The compounds that are preferred for, but not limited to, the treatment of gum diseases (especially periodontal disease and gingivitis) are those compounds that preferably inhibit collagenases.

Compositions; The compositions of the invention comprise: (a) a safe and effective amount of a compound of the formula (I); and (b) a pharmaceutically acceptable carrier. As mentioned above, it is known that numerous diseases are mediated by excessive or unwanted metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammations of the skin, ulcerations, particularly of the cornea, reactions to infections, periodontitis and the like. In this manner, the compounds of the invention are useful in therapy with respect to conditions that include this undesired activity. Therefore, the compounds of the invention can be formulated into pharmaceutical compositions useful for the treatment or prophylaxis of these conditions. Normal pharmaceutical formulation techniques are used, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., Most recent edition. A "safe and effective amount" of a compound of the formula (I) is an amount that is effective to inhibit metalloproteases at the site or sites of activity, in a mammal, without undue adverse side effects (such as toxicity, irritation or allergic response), congested with a reasonable benefit / risk ratio when used in the manner of this invention. The specific "safe and effective amount" will obviously vary with factors such as the particular condition being treated, the patient's physical condition, the duration of the treatment, the nature of the concurrent therapy (if any), the form of specific dosage to be used, the vehicle employed, the solubility of the compound of the formula (I) therein and the desired dosage regimen for the composition. In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible solid or liquid filler or encapsulant diluent substances that are suitable for administration to a mammal. 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 would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. The pharmaceutically acceptable carriers must, of course, have a high enough purity and a sufficiently low toxicity to make them suitable for administration to the mammal being treated. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; jelly; talcum powder; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Tweens, • wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; rattlers, stabilizers; antioxidants; conservatives; pyrogen-free water; isotonic saline solution and phosphate buffer solutions. The choice of a pharmaceutically acceptable vehicle that will be used in batch with the present compound is basically determined by the manner in which the compound will be administered. If the present compound will be injected, the preferred pharmaceutically acceptable carrier is a sterile physiological saline solution with a blood-compatible suspension agent, whose pH has been adjusted to about 7.4. In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and their derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers , isotonic saline solution and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier, in the compositions for parenteral administration, comprises at least about 90% by weight of the total composition.

The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention that contains an amount of a compound of formula (I) that is suitable for administration to a mammal, in a single dose, in accordance with the proper medical practice. These compositions preferably contain about 5 mg (milligrams) to about 1000 mg, most preferably about 10 mg to about 50 mg, more preferably about 10 mg to about 300 mg of a compound of the formula (I). The compositions of this invention can be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal or parenteral administration. Depending on the particular administration route desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. These include liquid or solid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Optional pharmaceutically active materials may be included, which do not substantially interfere with the inhibitory activity of the compound of the formula (I). The amount of vehicle used in batch with the compound of the formula (I) is sufficient to provide a practical amount of material for administration per unit dose of the compound of the formula (I). Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated herein by reference: Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd. edition (1976). In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible solid or liquid filler or encapsulant substances that are suitable for administration to a human or lower animal. The term "compatible" as used herein, means that the components of the composition are capable of being mixed with the present compound and with each other, such that there is no interaction that could substantially reduce the pharmaceutical efficacy of the composition under certain conditions. of normal use. The pharmaceutically acceptable carriers must, of course, have a high enough purity and a sufficiently low toxicity to make them suitable for administration to the human or lower animal being treated. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose.; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; jelly; talcum powder; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and thiobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as Tweens, • wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; rattlers, stabilizers; antioxidants; conservatives; pyrogen-free water; isotonic saline solution and phosphate buffer solutions. The choice of a pharmaceutically acceptable vehicle that will be used in batch with the present compound is basically determined by the manner in which the compound will be administered. If the present compound will be injected, the preferred pharmaceutically acceptable carrier is sterile physiological saline with a blood-compatible suspension agent, whose pH has been adjusted to about 7.4. Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and powders. These oral forms comprise a safe and effective amount, usually at least about 5% and preferably about 25% to about 50%, of the compound of the formula (I). The tablets can be compressed, comminuted, enteric-coated, sugar-coated, film-coated or multiple-compressed, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and preservatives. appropriate fusion. The liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, fusion agents, coloring agents and flavoring agents. The pharmaceutically acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well known in the art. The tablets typically comprise conventional pharmaceutically compatible adjuvants such as inert diluents, calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch; alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Slip agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents such as FD &C dyes can be added to improve appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint and fruit flavors are also useful adjuvants for chewable tablets. The capsules typically comprise one or more of the solid diluents described above. The selection of vehicle components depends on secondary considerations such as flavor, cost and stability at the counter, which are not critical for the purposes of the present invention and can be easily made by one skilled in the art. The peroral compositions also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers useful for the preparation of such compositions are well known in the art. Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate.; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. The peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents and colorants described above.

Said compositions can also be coated by conventional methods, typically with pH or time dependent coatings, such that the present compound is released into the gastrointestinal tract, in the vicinity of the desired topical application or several times to extend the desired action . Said dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, dihydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and lacquer. The compositions of the present invention may optionally include other drug actives. Other compositions useful for achieving systemic delivery of the present compounds include sublingual, buccal and nasal dosage forms. Said compositions typically comprise one or more soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Also described above and may include slip agents, lubricants, sweeteners, colorants, antioxidants and flavoring agents. The compositions of the present invention can also be administered topically to a subject, e.g., by direct placement or dispersion of the composition on the epidermal or epithelial tissue of the subject, or transdermally by means of a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1% and preferably about 1% to about 5%, of the compound of the formula (I). Suitable vehicles for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by transpiration or immersion in water. In general, the vehicle is of an organic nature and capable of having the compound of the formula (I) dispersed or dissolved therein. The vehicle may include emollients, emulsifiers, thickening agents and pharmaceutically acceptable solvents, and the like.

Methods of administration This invention also provides methods for treating or preventing disorders associated with excessive or undesired activity of the metalloprotease a human or other animal subject, by administering a safe and effective amount of a compound of the formula (I) to said subject. As used herein, the phrase "a disorder associated with excessive or undesired activity of the metalloprotease" is any disorder characterized by degradation of the matrix proteins. The methods of the invention are useful for treating disorders such as, (for example) osteoarthritis, periodontitis, corneal ulceration, tumor invasion and rheumatoid arthritis.

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

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

Preparation and use of antibodies; The compounds of the invention can also be used in immunization protocols to obtain immunospecific antisera for the compounds of the invention. Since the compounds of the invention are relatively small, they are advantageously coupled to antigenically neutral vehicles such as conventionally used lockhead hemocyanin (KLH) or whey albumin vehicles. For those compounds of the invention having a carboxyl functionality, coupling to the carrier could be done by methods generally known in the art. For example, the carboxyl residue can be reduced to an aldehyde and coupled to the carrier by reaction with side chain amino groups in protein-based vehicles, optionally followed by the reduction of the imino bond formed. The carboxyl residue can also be reacted with side chain amino groups using condensing agents such as dicyclohexylcarbodiimide or other carbodiimide dehydration agents. Binding compounds can also be used to carry out the coupling; Both 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 immunoassay procedures, now common in the art, employing the compounds of the invention as antigens. The antisera obtained can be used directly or monoclonal antibodies can be obtained by cultivating peripheral blood lymphocytes or the spleen of the immunized animal and immortalizing the antibody producing cells, followed by identification of the appropriate antibody producers using normal immunoassay techniques. Polyclonal or monoclonal preparations are then useful for monitoring therapy or prophylaxis regimens that include the compounds of the invention. Suitable samples such as those derived from blood, serum, urine or saliva can be tested to verify the presence of the inhibitor administered several times during the treatment protocol using normal immunoassay techniques employing the antibody preparations of the invention. The compounds of the invention can be copied to markers such as scintigraphic labels, e.g., technetium 99 or 1-131, using normal coupling methods. The labeled compounds are administered to subjects to determine the sites of excessive amounts of one or more matrix metalloproteases in vivo. The ability of the inhibitors to selectively bind to matrix metalloproteases to map the distribution of these enzymes in situ is then exploited. The techniques can also be employed in histological procedures and the labeled compounds of the invention can be used in competitive immunoassays. The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.

EXAMPLES The compounds are analyzed using - ^ H and 13C NMR. Elemnetal analysis, mass spectrum and / or IR spectra are appropriate. Typically, the inert solvents are used, preferably in dry form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and other solvents are purchased to the appropriate degree. Chromatography is performed on silica gel (70-230 mesh, Aldrich) or (200-400 mesh, Merck). The layer chromatography (CCD) analysis is performed on glass-mounted silica gel plates (200-300 mesh, Baker) and visualized with UV rays or 5% phosphomolybdic acid in EtOH.

EXAMPLE 1 Synthesis of N-hydroxy-1,3-di- [(4-methoxyphenyl) sulfonyl] -5,5-diptethyl-hexahydro-pyrimidine-2-carboxamide (le). 1,3-Di- [(4-methoxyphenyl) sulfonyl] -2, 2-dimethyl-propane (la); 2,2-Dimethyl-1,3-propanediamine (502 mg, 4.9 mmol) is dissolved in 1: 1 water: dioxane (80 mL). To this is added 4-methoxyphenylsulfonyl chloride (2.03 g, 9.8 mmol) followed by 4-methylmorpholine (2.4 mL, 21.6 mmol). The mixture is stirred 30 minutes at room temperature, where the CCD time (7: 3 ethyl acetate: hexane) indicated the reaction to complete. The reaction was diluted with 150 mL of water and the product was extracted into ethyl acetate, dried and evaporated to give 1,3-di- [(4-methoxyphenyl) sulfonyl] -2,2-dimethylpropane as an off-white solid. from: mp 115-117 ° C.

Methyl 1,3-di- [(4-methoxyphenyl) sulfonyl] -5,5-dimethyl-hexahydro-pyrimidine-2-carboxylate (Ib); 1, 3-Di - [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-propane (991 mg, 2.2 mmol) is combined with 0.55M solution of methyl glyoxylate (12.2 mL, 6.7 mmol) in ether and the Ether is removed under reduced pressure. Subsequently, benzene (75 mL) is added followed by a catalytic amount of sulfuric acid and the mixture is heated under reflux with Dean-Stark removal of water / benzene for 15 minutes, in which time CCD (1: 1 acetate) of ethyl: hexane) indicates that the reaction is complete. The mixture is cooled, washed with water, dried (Na 2 SO 4) and concentrated in vacuo to give methyl 1,3-di [(4-methoxyphenyl) sulfonyl] -5,5-dimethyl-hexahydro-pyrimidin-2-methyl. carboxylate as an oil.

N-hydroxy-1,3-di- [(4-methoxyphenyl) sulfonyl-5. 5 ^ dimethyl-hexahydro-pyrimidine-2-carboxamide (le); Methyl 1,3-di- [(4-methoxyphenyl) sulfonyl] -5,5-dimehexahydro-pyrimidine-2-carboxylate (826 mg, 1.6 mmol) is treated with 4.6 mL of NH2OK (1.76 M in methanol, solution prepared as described in Fieser and Fieser, Vol. 1, p 478). The reaction is stirred for 16 hours at room temperature and neutralized with IN aqueous hydrochloric acid. The volatile components are removed under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo to give a white solid. The crude product is purified by crystallization from ethanol to give N-hydroxy-1,3-di- [(4-methoxyphenyl) sulfonyl] -5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide. MP 125-126 ° C. MS (EA): 514 [M + H] +.

EXAMPLE 2 The following compounds are prepared in a similar manner to Example 1: N-Hydroxy-1,3-di- [(4-methoxyphenyl) sulfonyl] -1,3-imidazolidine-2-carboxamide, MS (EA): 472 [M + H] +; N-Hydroxy-1,3-di- [(4-methoxyphenyl) sulfonyl] -hexahydro-pyrimidine-2-carboxamide, MS (EA): 486 [M + H] +; N-Hydroxy-l, 3-di- [(4-methoxyphenyl) sulfonyl] -1,3-diazepine-2-carboxamide, MS (EA): 500 [M + H] +; N-Hydroxy-l, 3-di- [(4-methoxyphenyl) sulfonyl] -5-hydroxy-hexahydro-pyrimidine-2-carboxamide, MS (EA): 502 [M + H] +; N-Hydroxy-3- [(4-methoxyphenyl) sulfonyl] -2H-tetrahydrooxazine-2 (R, S) -carboxamide, MS (EA): 317 [M + H] +; N-Hydroxy-3- [(4-methoxyphenyl) sulfonyl] -2H-1,4-dihydro-3, l-benzooxazine-2-carboxamide, MS (EA): 365 [M + H] +.

EXAMPLE 3 Synthesis of N-hydroxy 1- [(4-methoxyphenyl) sulfonyl] -3- [methylaulfonyl] -hexahydro-pyrimidin-2 (R.sup.S) -carboxamide (3d). 1- [(4-Methoxyphenyl) sulfonyl] -3- [t-butyloxy-carbonyl] -1,3-diamino-propane (3a): N-BOC-1,3-diaminopropane (4.5 g, 25.8 mmol) is dissolved in 100 mL of dichloromethane and cooled to 0 ° C with an ice bath. To this is added, carefully, 4-methoxyphenylsulfonyl chloride (5.37 g, 26 mmol) followed by 4-methylmorpholino (7.2 mL, 65 mmol). The reaction is stirred for 45 minutes, heating it to room temperature. The mixture is diluted with an additional 100 mL of dichloromethane and washed with water. The solvents are evaporated and the residue is taken up in 50 mL of ethyl acetate. The crystals formed until the addition of hexane are collected to give 1- [(4-methoxyphenyl) sulfonyl] -3- [t-butyloxy-carbonyl] -1,3-diamino-propane. 1- [(4-Methoxyphenyl) sulfonyl] -1,3-diamino-propane (3b): 1- [(4-Methoxyphenyl) sulfonyl] -3- [t-butyloxy-carbonyl] -1,3-diamino-propane (3 g, 8.7 mmol) is dissolved in 20 mL of dichloromethane and to this is added 7 mL (90.9 mmol) of trifluoroacetic acid. This reaction is stirred for 3 hours at this time CCD (100% ethyl acetate) indicates that the reaction is complete. The volatile components are removed by azeotropism with toluene to give 1- [(4-methoxyphenyl) sulfonyl] -1,3-diamino-propane trifluoroacetate salt as a colorless solid. 1- [(4-Methoxyphenyl) sulfonyl] -3-rmethylsulfonyl] -1,3-diamino-propane: salt of 1- (3c): 1- [(4-Methoxyphenyl) sulfonyl] -1,3-diamino-propane Trifluoroacetate (500 mg, 1.4 mmol) is dissolved in 15 mL of dichloromethane and cooled to 0 ° C with ice bath. To this is added 4-methylmorpholino (0.46 mL, 4.2 mmol) followed by chloride of sulfonyl chloride (0.11 mL, 1.5 mmol). The reaction is stirred for 30 minutes at this time the CCD (1: 1 hexane: ethyl acetate) indicated that the reaction is complete. The reaction was washed with water, dried and evaporated. The crude product was purified by flash chromatography (7: 3 ethyl acetate: hexane) to give 1- [(4-methoxyphenyl) sulfonyl] -3- [methylsulfonyl] -1,3-diamino-propane as a colorless solid MS (EA): 394 [M + H] +.

N-Hydroxy 1- \ (4-methoxyphenyl) sulfonyl-3-rmethylsulfonyl-hexahydro-pyrimidin-2 (R.sup.S) -carboxamide (3d).

Following the example 1 1- [(4-methoxyphenyl) sulfonyl] -3- [methylsulfonyl] -1,3-diamino-propane is converted to N-hydroxy 1- [(4-methoxyphenyl) sulfonyl] -3- [methylsulfonyl] -hexahydro-pyrimidin-2 (R, S) -carboxamide. MS (EA): 448 [M + H] +.

EXAMPLE 4 The following compounds are prepared similarly to Example 3: N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3-acetyl-hexahydro-pyrimidin-2 (R, S) -carboxamide, MS (EA): 358 [M + H] +; N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3-benzoyl-hexahydro-pyrimidin-2 (R, S) -carboxamide, MS (EA): 420 [M + H] +.

EXAMPLE 5 Synthesis of N-hydroxy-1,5-dithia-8,10-diaza-spiro [5.5] t-ndecane-9-carboxamide (5c). 1,3-Di- [(4-methoxyphenyl) sulfonyl] -2-oxo-propane (5a): 1, 3-Di- [(4-methoxyphenyl) sulfonyl] -2-hydroxy-propane (1.0 g, 2.3 mmol), prepared from 2-hydroxy-1,3-propanediamine according to Example 1, is dissolved in 20 mL of acetone and the solution is cooled to 0 ° C with an ice bath. The Jones reagent is added later until the orange color persists and the reaction is allowed to stir overnight at room temperature. The reaction is diluted with 100 mL of water and the product is extracted into ethyl acetate (3x). The organic extracts are washed with water (Ix) and 10% sodium bicarbonate solution (lx), dried over sodium sulfate, and concentrated under reduced pressure. The crude product is purified by flash silica gel chromatography (6: 4 ethyl acetate: hexanes) to give 1,3-di- [(4-methoxyphenyl) sulfonyl] -2-oxo-propane.

Methyl 1, 5-dithia-8, 10-diaza-spiro [5.5] undecane-9-carboxylate (5b): methyl ester (105, ng, 0.2 mmol), prepared from 1,3-di- [(4-methoxyphenyl) ) sulfonyl] -2 -oxo-propane according to example 1, dissolved in 20 ml of dichloromethane and to the solution is added 1, 3-propandithiol (0.042 mL, 0.4 mmol) followed by boron trifluoride diethyl etherate (0.01 mL, 0.08 mmol). The reaction is stirred for 40 hours at room temperature, the pH is adjusted to a pH of 8 with aqueous sodium hydroxide to the IM and the mixture is washed with ethyl acetate (2x). The combined organic phases are washed once with 10% ammonium chloride solution, dried (Na2SO4), and concentrated under reduced pressure. The crude product is purified by flash silica gel chromatography (6: 4 ethyl acetate: hexanes) to give l, 5-dithia-8,10-diazaspiro [5.5] undecane-9-carboxylate methyl.

N-Hydroxy-1, 5-dithia-8, 10-diaza-spiro [5.5] undecane-9-carboxamide (5c): Methyl 1,5-dithia-8,10-diaza-spiro [5.5] undecane-9- The carboxylate is converted to the target hydroxamic acid in a similar manner to Example 1. ES (EA): 590 [M + H] +.

EXAMPLE 6 Synthesis of 3- [(4-methoxyphenyl) sulfonyl] - [1,3] thiazine-2 (R, S) -carboxamide (6e). 0M * _ ^^, 0M »_ _, 0M- u« D MiCI / EtiW ° 2Í NH./ M.OH ° 2? H < 0O X 2) KSAe / 0MF "S *" 'HO. Sb • MOiCCHO. H * M 3- [(4-Methoxyphenyl) sulfonyl-propan-1-ol (6a): 3-aminopropanol (8.0 g, 106.5 mmol). triethylamine (21.6 g, 213 mmol, 2.0 equiv.) in 1,4-dioxane (75 ml) and water (75 ml) are stirred at room temperature and subsequently 4-methoxyphenylsulfonyl chloride (23.1 g, 111.8 mmol, 1.05 equiv.). The resulting solution is stirred at room temperature for 24 hours and subsequently the solution is acidified to pH -1 with an IN HCl. The solution is poured into water and then extracted with CH2Cl2. The organic extracts are dried (Na2S4) and concentrated in an oil. The oil is purified by chromatography (1/1 hexane / EtOAc) to give 3- [(4-methoxyphenyl) sulfonyl] -propan-1 as a colorless oil. lS-Acetyl-3- [(4-methoxyphenyl) sulfonyl-propane (6b): 3- [4-methoxyphenyl) sulfonyl] -propan-1-ol (26.0 g, 106 mmol) in CH 2 Cl 2 (250 ml) is stirred at At room temperature, methanesulfonyl chloride (13.4 g, 117 mmol, 1.1 equiv.) and triethylamine (16.0 g, 159 mmol, 1.5 equiv.) were added. The resulting solution is stirred for 1 hour at room temperature and subsequently emptied into water. The solution is extracted with EtOAc and the organic extracts are dried (Na 2 SO 4) and concentrated in an oil under reduced pressure. The oil is dissolved in DMF (300 ml) and then potassium thioacetate (18 g, 159 mmol, 1.5 equiv.) Is added. The resulting solution is stirred overnight at room temperature and subsequently emptied in water. The mixture is extracted with EtOAc, the organic extracts are dried (Na 2 S 4) and then concentrated in an oil under reduced pressure. The resulting oil is purified by chromatography on silica gel (7/3 hexane / EtOAc) to give lS-acetyl-3- [(4-methoxyphenyl) sulfonyl] -propane as a light yellow oil which solidifies to solidify at prolonged rest . IM (Cl): 304 [M + H] +. 3- [(4-Methoxyphenyl) sulfonyl] -propane-1-thiol (6c): 1-S-acetyl-3- [(4-methoxyphenyl) sulfonyl] -propane (8.91 g, 29.4 mmol) in methanol (125 ml. ) is stirred under an argon atmosphere at room temperature. Subsequently the solution bubbles with ammonia gas for 20 minutes at room temperature and then the solution is purged with argon gas. The solvent is removed under reduced pressure to leave a colorless oil. Purification of the oil is accomplished by chromatography (8/2 hexane / EtOAc) to give 3 - [(4-methoxyphenyl) sulfonyl] -propane-1-thiol as a colorless oil. EM (EA): 262 [M + H] +.

Methyl-1- [(4-methoxyphenyl) sulfonyl] - [1,3] thiazine-2 (R, S) -carboxylate (6d): 3- [(4-Methoxyphenyl) sulfonyl] -propane-1-thiol (6.90 g, 26.4 mmoles) and methyl glyoxylate (158 ml, 79.2 mmoles, 3.0 equiv 0.5 M in Et2?) is concentrated for an oil for reduced pressure. The resulting thick oil subsequently diluted with benzene (100 ml) and 0.1 g-p-TsOH is added. The solution is heated to reflux and the water is removed in the reaction mixture with the aid of a Dean-Stark trap. The solution is cooled to room temperature, then it is poured into a diluent solution NaHC 3 (50 ml). The solution is extracted with EtOAc, the organic extracts are dried (Na 2 S 4), and then concentrated to an oil under reduced pressure. The product is purified by chromatography on silica gel (8/2 hexane / EtOAc) to give l - [(4-methoxyphenyl) sulfonyl] - [1,3] thiazine-2 (R, S) -carboxylate methyl as a colorless oil that solidifies to rest. MS (CI): 332 [M + H] +. 1- [(4-methoxyphenyl) sulfonyl] - [1, 3] thiazine-2 (RS) -carboxylate (6e): Methyl 1- [(4-methoxyphenyl) sulfonyl] - [1,3] thiazine-2 (R, S) -carboxylate (0.5 g, 1.51 mmol) in methanol (15 ml) is stirred at room temperature and then a solution of KONH2 (0.868 M in MeOH, 3.5 ml, 3.02 mmol, 2 equiv.) is added. The resulting solution is stirred at room temperature for 24 hours and subsequently a pH ~ 2 is acidified with 1 N HCl. The solution is poured into water and subsequently extracted with CH 2 Cl 2. The organic extracts are dried (Na 2 S 4) and concentrated under reduced pressure to give l - [(4-methoxyphenyl) sulfonyl] - [1,3] thiazine-2 (R, S) -carboxamide as a white solid. MS (EA): 333 [M + H] +.

EXAMPLE 7 Synthesis of N-hydroxy-3- [(4-methoxyphenyl) sulfonyl] -2,5,5- trimethyl-thiazolidine-2 (R, S) -carboxamide (7d).

Te 7d Ethyl 2.5.5 '-trimethyl-thiazolidine-2 (R.S) -carboxylate (7a): l-Amino-2-methyl-2-propantiol (25.11 g, 177 mmol) and ethyl pyruvate (20.58 g, 177 mmol) are suspended in benzene (300 ml) and heated to reflux in a flask equipped with a Dean-Stark trap. Two drops of sulfuric acid are added. The reaction is allowed to stir at reflux for 3 hours. Volatile components are removed to give 2,5,5'-trimethyl-thiazolidine-2 (R, S) -carboxylate ethyl as a white solid.

Ethyl 3- [(4-methoxyphenyl) -2,5,5'-trimethyl-iazolidine-2 (R, S) -carboxylate (7b): Ethyl 2, 5, 5 '-trimethyl-thiazolidine-2R, S) - carboxylate (40.39 g, 168 mmol) and a 4-methoxyphenylsufonyl chloride (35.13 g, 170 mmol) are dissolved in pyridine (138 ml) and heated at reflux for 1 hour. After cooling to room temperature, the solution is diluted with aqueous hydrochloric acid to IM and the product is extracted into diethyl ether (3x). The combined organic phases are dried (a2 =? 4) and concentrated under reduced pressure to give ethyl 3- [(4-methoxyphenyl) sulfonyl] -2,5,5'-trimethyl-thiazolidine-2 (R, S) - carboxylate as red oil.

Nt-Butyloxy-3- [(4-methoxyphenyl) sulfonyl] -2,5,5'-trimethyl-thiazolidine-2 (R, S) -carboxamide (7c): Ethyl 3 - [(4-methoxyphenyl) sulfonyl] - 2,5,5'-trimethyl-thiazolidine-2 (R, S) -carboxylate (53.26 g, 143 mmol) is dissolved in aqueous sodium hydroxide to the IM (285 ml) and ethanol (500 ml) is heated to reflux for 5 hours. The reaction is cooled to room temperature and the mixture is stirred further for 16 hours. Subsequently, the reaction is neutralized with aqueous hydrochloric acid to IM and the volatile components are removed under reduced pressure to give 3- [(4-methoxyphenyl) sulfonyl] -2,5,5'-trimethyl-thiazolidine-2 (R) acid. , S) -carboxylic. The acid is dissolved in N, N-dimethylformamide (500 ml) and the solution is cooled to 0 ° C with an ice bath. To these is added 1-hydroxybenzotriazole (38.3 g, 284 mmol), 4-methylmorpholine (46.7 ml, 425 mmol) and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (40.8 g, 213 mmol) followed, after 30 minutes, with O-tert-butylhydroxylamine hydrochloride hydrochloride (18 g, 143 mmol). The reaction is stirred for 16 hours at room temperature, water (750 ml) is added, the product is extracted with ethyl acetate (2x). The combined organic salts are washed with 10% sodium bicarbonate (2x), dried (Na2S? 4) and concentrated under reduced pressure to give Nt-butyloxy-3- [(4-methoxyphenyl) sulfonyl] -2.5 , 5'-trimethyl-thiazolidine-2 (R, S) -carboxamide as an oil.

N-Hydroxy-3- [(4-methoxyphenyl) sulfoni11 -2,5,5'-trimethyl-thiazolidine-2 (R, S) -carboxamide (49.0 g, 118 mmol) is dissolved in dichloroethane (700 ml). and the solution is cooled to 0 ° C. The hydrochloride gas bubbles through the solution for 20 minutes. Subsequently, the reaction is sealed and stirred for 16 hours. The hydrochloride gas again bubbles through the reaction for 1 hour. The reaction is dried and stirred for 72 hours. The volatile components are removed under reduced pressure to give a dark and thick oil. The crude product is purified by flash chromatography on silica gel to give N-hydroxy-3 - [(4-methoxyphenyl) sulfonyl] -2,5,5'-trimethyl-thiazolidine-2 (R, S) -carboxamide as a solid white. IM (EA): 361 [M + H] +.

EXAMPLE 8 The following compounds are prepared similarly to Example 7 N-Hydroxy-3- [(4-methoxyphenyl) sulfonyl] -5,5'-trimethyl-thiazolidine-2 (R, S) -carboxamide, MS (EA) 347 [M + H] +; N-Hydroxy-3- [(4-methoxyphenyl) sulfonyl] -trimethyl-2 (R, S) -carboxamide, MS (IA) 319 [M + H] + EXAMPLE 9 Synthesis of N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3-phenylmethyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide (9d); 3- [(4-Methoxyphenyl) sulfonyl] -2, 2-dimethyl-propanol (9a): 3-amino-2,2-dimethylpropanol (5.16 g, 50 mmol) is dissolved in 1: 1 dioxane-water (500 ml), cooled to 0 ° C followed by the addition of triethylamine (17.4 ml, 125 mmol) and 4-methoxybenzenesulfoniyl chloride (10 g, 48.39 mmol). The reaction is stirred for 1 hour, water (250 ml) is added and the mixture is extracted with ethyl acetate (2x). The combined organic phases are washed with brine, dried (Na 2 S 4) and concentrated under reduced pressure to give 3- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl-propanol as a white solid. 3- [(4-Methoxyphenyl) sulfonyl] -2,2-dimethyl-3-aminopropionic acid (9b): 3- [(4-Methoxyphenyl) sulfonyl] -2, 2-dimethyl-propanol (5 g, 18.3 mmol) it is dissolved in acetone (150 ml). The Jones reagent is then added until an orange color persists and the reaction is allowed to stir overnight at room temperature. The reaction is diluted with 300 ml and water and the product is extracted into ethyl acetate (3x). The organic extracts are washed with water (lx) and 10% sodium bicarbonate solution (lx), dried over sodium sulfate and concentrated under reduced pressure to give 3- [(4-methoxyphenyl) sulfonyl] - 2, 2-dimethyl-3-aminopropionic. 3- [(4-Methoxyphenyl) sulfonyl] -2,2-dimethyl-3-aminopropionic acid phenylmethylamide (9c): 3- [(4-Methoxyphenyl) sulfonyl] -2,2-dimethyl-3-aminopropionic acid ( 863 mg, 3 mmol). 1-hydroxybenzotriazole (1.37 g, 9 mmol) and 4-methylmorpholine (1 ml, 9 mmol) are dissolved in N, N-dimethylformamide (10 ml). The solution is cooled to 0 ° C and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (690 mg, 3.6 mmol). The solution is stirred for 30 minutes, benzylamine (322 mg, 3 mmol) is added and the solution is stirred for 2 hours at room temperature. Water (10 ml) is added and the product is extracted with ethyl acetate (2x). The combined organic phases are washed with 10% sodium bicarbonate and brine, dried (Na 2 S 4) and concentrated under reduced pressure to give 3- [(4-methoxyphenyl) sulfonyl] -2,2-dimethyl- phenylmethylamide. 3-aminopropionic.

N-Hydroxy-1- [(4-methoxyphenyl) sulfoni1] -3-phenylmethyl-4-oxo-5,5-dimethyl-hexachido-pyrimidin-2-carboxamide (9d): phenylmethylamide of 3- [(4-methoxyphenyl ) sulfonyl] -2,2-dimethyl-3-aminopropionic acid is converted to the hydroxamic acid in a similar manner to Example 1. MS (EA): 448 [M + H] +.

EXAMPLE 10 The following examples are prepared similarly to Example 9: N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3-phenylmethyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide MS (EA) : 372 [M + H] +; N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3- (2-phenylethyl) -4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide MS (EA): 462 [M + H ] +; N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3-isopropyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide MS (EA): 400 [M + H] +; N-Hydroxy-1- [(4-butoxyphenyl) sulfonyl] -3-isopropyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide MS (EA): 442 [M + H] +; N-Hydroxy-1- [(4-butoxyphenyl) sulfonyl] -3-phenyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide MS (EA): 476 [M + H] +; N-Hydroxy-1- [(4-butoxyphenyl) sulfonyl] -3- (2-thienylmethyl) -4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide MS (EA): 496 [M + H] ] +; N-Hydroxy-1- [(4-methoxyphenyl) sulfonyl] -3-methyl-4-oxo-diazolidine-2-MS (EA): 330 [M + H] +; EXAMPLE 11 Synthesis of N-hydroxy-2,4-dioxo-3-methyl-9 - [(4-methoxyphenyl) isulfonyl] -1,3,9-triaz [3.5. Ol - ^ - ^ bicyclodecane-10-carboximide (l).

Methylamide of 2S-amino-5- [(4-methoxyphenyl) sulfonylamino] -caproic acid (bundle) N- (tert-butoxycarbonyl) -L-ornithine (4.5 g, 19.4 mmol) is dissolved in 1: 1 v / v 1 , 4-dioxane and water (200 mL). The mixture is cooled to 0 ° C with an ice bath, triethylamine (3.6 mL, 28 mmol) is added followed by 4-methoxybenzenesulfonyl chloride (4.2 g, 20 mmol). The ice bath is removed and the solution allowed to stir for one hour. Subsequently, the solution is acidified to a pH of 5 with 1 M aqueous hydrochloric acid and the product is extracted into ethyl acetate (500 mL). The ethyl acetate mixture is washed with water (2 X 150 mL). The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give the desired sulfonamide as a white solid. IM (EAI) 403 (M + H) +. The sulfonamide is dissolved in N, N-dimethylformamide (250 mL) and this solution is cooled to 0 ° C. To this is added (1-hydroxybenzothiazole (2.84 g, 21 mmol), 4-methylmorpholino (3.1 mL, 28 mmol), and 1-ethyl-3- (3-dimethylaminopropyl) carboximide (1.59 g, 8.3 mmol). The reaction is stirred 10 minutes and then methylamine hydrochloride (500 mg, 7.4 mmol) is added. The ice bath is removed and the mixture is stirred at room temperature for 16 hours. Subsequently, water (200 mL) is added and the product is extracted with ethyl acetate (500 mL). The ethyl acetate solution is washed with water (every 3 X 150 mL). The ethyl acetate mixture is dried over sodium sulfate and concentrated under reduced pressure to give the desired methylamide as a white solid. IM (EAI) 416 (M + H) +. The amide (2.247 g.l micron .4 mmole) is dissolved in dichloromethane (25 mL) and to this is added trifluoroacetic acid (1.7 mL, 22 mmol). The reaction is stirred for four hours and then the volatile components are removed under reduced pressure to give an oil. The crude product is further dried in a vacuum pump for 16 hours to give 2S-amino-5- [(4-methoxyphenyl) sulfonylamino] -caproic acid methylamide. IM (EAI) 316 (M + H) +. 3-Methyl-5S- [3- [(4-methoxyphenyl) sulfonylamino] propyl] -hydantoin acid methylamide (Ilb). 2S-amino-5- [(4-methoxyphenyl) sulfonylamino] -caproic acid (1.7 g, 5.4 mmol) is dissolved in dichloromethane (150 mL) and cooled to -20 ° C. To this is added N, N-disopropylethylamine (2.5 mL, 14 mmol) followed by triphosgene (964 mg, 3.3 mmol). The bath at -20 ° C is replaced with an ice bath and the reaction is stirred for 45 minutes. The mixture is emptied into ice and the product is extracted with ethyl acetate. The ethyl acetate solution is washed with water and brine, then dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by flash silica gel chromatography to give 3-methyl-5S- [3- [(4-methoxyphenyl) sulfonylamino] propyl] -hydantoin. IM (EAI) 416 (M + H) +.

N-Hydroxy 2,4-dioxo-3-methyl-9 - [(4-methoxyphenyl) sulfonyl] -1,3,9-triaza [3.5.0] bicyclodecane-10-carboxamide (lie). 3-Methyl-5S- [3- [(4-methoxyphenyl) sulfonylamino] propyl] -hydantoin (200 mg, 0.6 mmol) is dissolved in benzene (75 mL) in a round bottom flask equipped with a Dean-Stark trap . To this is added methyl glyoxylate (287 mg, 3.68 mmol) followed by a catalytic amount of sulfuric acid. The mixture is refluxed for 30 minutes with water removal by the Dean-Stark trap. The reaction is allowed to cool to room temperature and the reaction mixture is diluted with ethyl acetate (100 mL). The ethyl acetate mixture is washed once with water (25 mL) and then dried over sodium sulfate and the desired crude methyl ester is evaporated under reduced pressure. IM (EAI) 411 (M + H) +. The methyl ester (220 mg, 0.53 mmol) is treated with 2. 1 mL of NH2OK (1.76 M in methanol, solution prepared as described in Fieser and Fieser, Vol. L, p 478). The reaction is stirred for 3 hours at room temperature. The reaction is neutralized with aqueous HCl to the IM and the distereomers are extracted into ethyl acetate. The organic components are dried over sodium sulfate and the volatile components are removed under reduced pressure. The crude product is purified by high pressure liquid chromatography to give N-hydroxy 2,4-dioxo-3-methyl-9 - [(4-methoxyphenyl) sulfonyl] -1,3,9-triaza [3.5.0] - L-3-bicyclodecane-10-carboxamide as a colorless solid. IM (EAI) 413 (M + H) +, 430 (M + NH 4) +, 435 (M + Na) +.

EXAMPLES 12-65 The following compounds are made by using the methods described and illustrated above.

Method Examples 12-65 are prepared analogously to Examples 1,3,5 and 9 using appropriately functionalized sulfonyl chloride. The sulfonyl chlorides used to prepare the above examples are purchased from commercial sources or prepared by known methods. For example, the 4-phenoxyphenylsufonyl chloride used for the preparation of Example 12 was prepared as described in R. J. Cremlyn and others Aust. J. Chem., 1979, 32, 445.52. These examples provide a person skilled in the art with sufficient guidance on how to make the present invention and not limit it in any way.

COMPOSITION AND METHOD OF EXAMPLES OF USE The compounds of the invention are useful for preparing compositions for the treatment of diseases and the like. The following composition and examples of the method do not limit the invention, but provide guidance to those skilled in the art for preparing and using the compounds, compositions and methods of the invention. In each case, the compounds of formula I can be substituted by the compound of the example presented below with similar results. The illustrated methods of use do not limit the invention, but provide guidance to those skilled in the art for using the compounds, compositions and methods of the invention. The person skilled in the art will appreciate that the examples provide guidance and may vary based on the condition and the patient.

EXAMPLE A A tablet composition for oral administration, in accordance with the present invention, is made including: 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 woman who weighs 60 kg (132 lbs), suffers from rheumatoid arthritis, is treated by a method of this invention. Specifically, for 2 years, a regimen of three tablets per day is administered orally to said patient. At the end of the treatment period, the patient is examined and it is found that inflammation has been reduced and mobility has been improved without concomitant pain.

EXAMPLE B A capsule for oral administration, in accordance with the present invention, is made including: 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 man who weighs 90 kg (198 lbs), suffers 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 individual. At the end of the treatment period, the patient is examined by orthoscopy and it is found that there is no erosion / fibrillation progression of the articular cartilage.

EXAMPLE C A composition based on saline for local administration, in accordance with the present invention is made including: 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 a deep corneal abrasion applies the drop to each eye twice a day. Recovery is rapid without visual sequelae.

EXAMPLE D A topical composition for local administration, in accordance with the present invention is made including: Component Composition (% w / v) Compound of Example 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbitol 5.00 Glacin 0.35 Aromatic Compounds 0.075 Purified water c.b. Total = 100.00 Total »100.00 Any other compound having a structure in accordance with formula (I) are used with substantially similar results. A patient who suffers from burns due to chemical compounds applies the composition at each bandage change (twice a day). The scars diminish substantially.

EXAMPLE E An aerosol composition for inhalation, in accordance with the present invention, is made including: Component Composition (% w / v) Compound of Example 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Sodium saccharin 0.2 Propellant (F12, F114) c.b. Total »100.0 Any other compound having a structure in accordance with formula (I) are used with substantially similar results. A patient suffering from asthma, sprinkles O.Olml by a pump actuator in the mouth while inhaling it. The symptoms of asthma decrease.

EXAMPLE F A topical ophthalmic composition, in accordance with the present invention, is made including: Component Composition (% w / v) Compound of Example 5 0.10 Benzacolium Chloride 0.01 EDTA 0.05 Hydroxyethylcellulose 0.50 Sodium Metabisulfite 0.10 Sodium Chloride (0.9%) c.b. Total »100.0 Any of the other compounds having a structure according to formula (I) are used with substantially similar results. A man who weighs 90kg (198 lbs) suffers from corneal ulcers, is treated by a method of that invention specifically, for two months, a saline solution containing 10 mg of Example 5 is administered to said affected eye of the individual twice a day. .

EXAMPLE G A composition for parenteral administration is made including: Component Quantity Example4 100 mg / ml vehicle Vehicle pH regulator sodium citrate with (Percent by weight of vehicle) Lecithin 0.48% Carboxymethylcellulose 0.53 Povidone 0.50 Methylparaben 0.11 Propylparaben 0.011 The ingredients mentioned above are mixed, forming a suspension. Approximately 2.0 ml of suspension is administered, by injection, to a human individual with a premetastatic tumor. The site of injection is juxtaposed to the tumor. This dose is repeated twice a day, for approximately 30 days. After 30 days, the symptoms of the disease decrease and the dose is gradually reduced to maintain the patient. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE H A composition for mouthwash is prepared; Component% p / y Example 1 3.00 Alcohol SDA 40 8.00 Flavor 0.08 Emulsifier 0.08 Sodium fluoride 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide 0.20 Dye 0.04 Water balance at 100% A patient with gum disease uses 1 ml of mouthwash three times a day to prevent further oral degeneration.

Other compounds having a structure according to formula (I) are used with substantially similar results EXAMPLE I A composition of a tablet is prepared; Component% p / v Example 3 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor 11.70 Color 0.10 Corn syrup 100% balance 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 1 COMPOSITION OF MASK RUBBER Component w / v% Example 1 0.03 Sorbitol crystals 38.44 Paloja-T rubber base 20.00 Sorbitol (70% aqueous solution 22.00 Mannitol 10.00 Glycerin 7.56 Flavor 1.00 A patient chews the gum to prevent the loosening of teeth. Other compounds having a structure according to the formula of (I) are used with substantially similar results.

EXAMPLE K Components w / v% Water USP 54,656 Methylparaben 0.05 Propylparaben 0.01 Xanthan gum 0.12 Guar gum 0.09 Cacio carbonate 12.38 Defoaming 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 Benzyl alcohol 0.2 Citric acid 0.15 Cooler 0.00888 Flavor 0.0645 Colorant 0.0014 Example 1 is prepared by first mixing 80 kg of glycerin and all of the benzyl alcohol and heating to 65 ° C. Subsequently, it is added slowly and mixed together with methylparaben, propylparaben, water, xanthan gum and guar gum. These ingredients are mixed for approximately 12 minutes with an in-line Silverson mixer. Subsequently, the following ingredients are slowly added in the following order: residual glycerin, sorbitol, antifoam C, calcium carbonate, citric acid and sucrose. Separately, flavors and chillers are combined and then slowly added to the other ingredients. Mix for approximately 40 minutes. The patient takes the formulation to prevent the appearance of colitis.

All references described herein are incorporated herein by reference. Although the particular embodiments of the invention in question have been described, it will be obvious to those skilled in the art that various changes and modifications may be made to the invention without departing from the essence and scope in the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of the invention.

Claims (31)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound having a structure in accordance with formula (1) where R 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 O, S, SO, SO2, or NR5, where R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S? 2R, COR7, CSRg, PO (Rg) 2 or may optionally form a ring with Y or W; and Rg is alkyl, aryl, heteroaryl, heteroalkyl, 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 moieties, or a heterocycle or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbons (in this way a fused ring is formed); And is independently one or more of hydrogen, hydroxy, SR or, SOR-4, SO2 4, alkoxy, amino, where amino is of formula NR? f R 2, where R? and R 2 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, S 2 R, COR 7, CSR g, PO (R g) 2; and R? 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 isomer, diastereomer or optical enantiomer for formula (I) or a pharmaceutically acceptable salt or biohydrolyzable amide, ester, or imide thereof. 2. The compound according to claim 1, wherein X is O, S, SO, SO2, or NR5, wherein R5 is independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl SO2 7, CORg, CSRg.

3. The compound according to claim 1, wherein Ar is SO2 and R4 is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted.

4. - The compound in accordance with the claim 1, wherein Ar is phenyl or substituted phenyl.

5. The compound according to claim 4, wherein Ar is substituted phenyl and the substitution is with hydroxy, alkoxy, nitro or halogen.

6. The compound according to claim 5, wherein Ar is substituted with methoxy, bromine, nitro and butoxy.

7. The compound according to claim 6, wherein Ar is substituted in the ortho or para position relative to the sulfonyl.

8. The compound according to claim 1, wherein W is one or more of hydrogen or C_ to C alkyl.

9. The compound according to claim 1, wherein W is C4 to C4 geminal alkyl.

10. The compound according to claim 1, wherein Z is an oxo-substituted moiety in the heterocyclic ring.

11. The compound according to claim 1, wherein Z is a substituted spiro portion in the heterocyclic ring.

12. A pharmaceutical composition that includes: (a) a safe and effective amount of a compound according to claim 1 and (b) a pharmaceutically acceptable carrier.

13. A pharmaceutical composition that includes: (a) a safe and effective amount of a compound according to claim 4 and (b) a pharmaceutically acceptable carrier.

14. - A pharmaceutical composition that includes: (a) a safe and effective amount of a compound according to claim 5 and (b) a pharmaceutically acceptable carrier.

15. A pharmaceutical composition that includes: (a) a safe and effective amount of a compound according to claim 9 and (b) a pharmaceutically acceptable carrier.

16. A pharmaceutical composition that includes: (a) a safe and effective amount of a compound according to claim 10 and (b) a pharmaceutically acceptable carrier.

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

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

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

20. The use of a compound according to claim 9 for the manufacture of a medicament for preventing or treating a disease associated with the metalloprotease activity of a mammal.

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

22. The use according to claim 21, wherein the disorder is arthritis and is selected from the group consisting of osteoarthritis and rheumatoid arthritis.

23. The use according to claim 21, wherein the disorder is cancer and the treatment prevents or decreases the growth and metastasis of the tumor.

24. The use according to claim 21, wherein the disorder is a cardiovascular disorder chosen from the group that includes dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reflux injury, ischemia, chronic obstructive pulmonary disease, restenosis by angioplasty and aortic aneurysm.

25. The use according to claim 21, wherein the disorder is an ocular disorder and is selected from the group consisting of corneal ulceration, lack of corneal healing, macular degeneration and pterión.

26. The use according to claim 21, wherein the disorder is a disease of the gums and is chosen from the group that includes periodontal disease and gingivitis.

27. - The use according to claim 21, wherein the condition is the skin condition that is chosen from the group that includes repair and prevention of wrinkles, skin damage by UV rays, epidermolysis bullosa, psoriasis, scleroderma, atopic dermatitis and scars

28. The use of a metalloprotease inhibitor according to claim 1 for the manufacture of a medicament for preventing loosening of prosthetic devices chosen from the group that includes joint replacements and dental prostheses in a mammal.

29. The use according to claim 21, wherein the disease is selected from the group that includes inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, acne inflammation, osteomyelitis, bronchitis, arthritis and asthma.

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

31. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for treating musculoskeletal diseases or cahexia in a mammal.