MXPA99002068A - Spirocyclic 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

ESPIROCICLIC METALOPROTEASE INHIBITORS TECHNICAL FIELD The present invention relates to compounds that are useful in the treatment of diseases, disorders and conditions associated with unwanted metalloprotease activity.

BACKGROUND A number of structurally related metalloproteases [MPs] carry out the degradation of structural proteins. These metalloproteinases act commonly on the intercellular matrix, and in this way they are involved in the degradation and remodeling of the tissues. These proteins are called metalloproteases or MPs. There are several different families of MPs, classified by sequence homology. In the art several families of known MPs are described, as well as examples thereof. These MPs include matrix metalloproteases [MMPs], zinc metalloproteases, many of the membrane-bound metalloproteases, TNF conversion enzymes, angiotensin converting enzymes (ACEs), disintegrins, including ADAMs (See olfsberg et al., 131 J .Cell Bio, 275-78, October 1995), and enkephalinases. Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecanase and gelatinase and human stromelysin. It is believed that collagenase, stromelysin, aggrecanase and related enzymes are important in mediating the symptomatology of a number of diseases. Potential therapeutic indications of MP inhibitors have been mentioned in the literature. See, for example, US patent. 5,506,242 (Ciba Geigy Corp); US patent 5,403,952 (Merck &Co); PCT application published WO 96/06074 (British Bio Tech Ltd); PCT publication WO 96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British Bio Tech Ltd); Wo 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); WO 95/26989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Ins. Opthamology); WO 95/23790 (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 (Yamanouch); and British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd); European patent applications published EP 95/684240 (Hoffman LaRoche); EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); published Japanese applications JP 08053403 (Fujusowa Pharm. Co. Ltd); JP 7304770 (Kanebo Ltd); and Bird and others J. Med Chem vol, 37, pp. 158-69 (1994). Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritis (Mullins, D.E., et al., Biochim, Biophvs. Acta. (1983) 695: 117-214); osteoarthritis (Henderson, B., et al., Drugs of the Future (1990) 15: 495-508); metastasis of tumor cells (ibid, Broadhurst, MJ, et al., application for European female patient 276,436 (published in 1987), Reich, R., et al., 48 Cancer Res. 3307-3312 (1988), and various ulcerations or conditions For example, ulcerative conditions may originate in the cornea as a result of alkali burns or as a result of infection by Pseudomonas aeruqinosa, acanthamoeba, Herpes simplex and vaccinia virus, etc. 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 U.S. 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 the treatment of diseases caused, at least in part, by the decrease of structural proteins. Although a variety of inhibitors have been prepared, there is a continuing need for potent and useful metalloprotease inhibitors. .-to treat these diseases. Applicants have discovered that, surprisingly, the spirocyclic compounds of the present invention are potent metalloprotease inhibitors.

OBJECTS OF THE INVENTION It is an object of the present invention to provide compounds useful for the treatment of conditions and diseases which are characterized by the desired MP activity.

It is also an object of the invention to provide potent metalloprotease inhibitors. A further object of the invention is to provide pharmaceutical compositions comprising said inhibitors. Another object of the invention is to provide a method of treatment for diseases related to metalloproteases.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds that are useful as inhibitors of metalloproteases, and 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) (I) wherein Ar is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted; R ^ is H; R2 is hydrogen, alkyl acyl; W is zero or one or more lower alkyl portions, or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbons (thereby forming a fused ring); And it is independently one or more of hydrogen, hydroxy, SR3, SOR4, SO2R5, alkoxy, amino, wherein the amino is of the formula NRg, R7, wherein Rg and R7 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, OR3, S02R8 COR9, CSRIQ. PO (Rn) 2; and R3 is hydrogen, alkyl, aryl, heteroaryl; R 4 is alkyl, aryl heteroaryl; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R9 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, "dialkylamino, arylamino and alkylarylamino; R_0 is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, dialrylamino and alkylarylamino Rll is alkyl, aryl, heteroaryl, heteroalkyl, Z is a spiro portion, n is 1-3, This structure also udes an otic isomer, diastereomer or enantiomer for formula (I), or a pharmaceutically acceptable salt, or biohydrolysable amide , ester, or imide thereof.

These compounds have the ability to inhibit at least one mammalian metalloprotease. Accordingly, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of the formula (I) and to methods for treating diseases characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them. Metalloproteases active at a particularly undesired site (eg, an organ or certain cell types) can be identified by conjugating the compounds of the invention to a specific identification ligand for a label at that site, such as an antibody or fragment thereof or a receptor ligand. Methods of conjugation are known in the art. The invention is also directed to several other methods that take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease. In another aspect, the invention is directed to the compounds of the formula (I) conjugated to a marker. As the compounds of the invention bind to at least one metalloprotease, the label can be used to detect the presence of relatively high levels of metalloproteases 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, the compounds are those of the formula (I) or a pharmaceutically acceptable salt or alkoxyamide, acyloxyamide or imide biohydrolyzable thereof.

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.

"Alkoxycyl" is an acyl radical (-C (= 0) -) having an alkoxy substituent (ie, -O-R), for example, -C (= 0) -0-alkyl. This radical can be considered as an ester. "Acylamino" is an amino radical having an "acyl substituent (ie, -N-acyl), for example -NH-C (= 0) -alkyl." Alkenyl "is a substituted or unsubstituted hydrocarbon chain radical. having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, most preferably 2 to 8, except where indicated.Alkenyl substituents have at least one olefinic double bond (including, for example, vinyl, allyl and butenyl) "Alkynyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to 15 carbon atoms, preferably from 2 to 10 carbon atoms, most preferably from 2 to 8, except where indicated. The chain has at least one carbon-carbon triple 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 (by 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. "The spirocycles may be substituted or unsubstituted Preferred substituents include oxo, hydroxyl, alkyl, cycloalkyl, arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (e.g., benzothiol, cycloalkyl, heterocycloalkyl, benzimidizoles, pyridylthiol, etc., which can also be substituted) and the like, In addition, the heterogeneous atom of the heterocycle can be substituted if its valence allows it.The preferred spirocyclic ring sizes include 3 to 7 membered rings. refers to an alkyl, alkenyl or alkynyl which is a diradical, instead of 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 (-NHCH 3), dimethylamino (-N (CH 3) 2) and metilet ila ino (-N (CH3) CH2CH3). "Aminoacyl". is an acyl radical that has an amino substituent (ie., -C (= 0) -N); for example -C (= 0) - NH2 • The amino group of the aminoacyl portion can be unsubstituted (ie, primary amine) or can be substituted with one (secondary amine) or two (ie, tertiary amine) alkyl groups . "Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl and fluorenyl. Said groups can be substituted or unsubstituted. "Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl, phenylethyl and phenylpropyl. Said groups can be substituted or unsubstituted. "Arylalkylamino" is an amine radical substituted with an arylalkyl group (e.g., -NH-benzyl). Said groups can be substituted or unsubstituted. "Arylamino" is an amine radical substituted with an aryl group (i.e., -NH-aryl). Said groups can be substituted or unsubstituted.

"Aryloxy" is an oxygen radical having an aryl substituent (i.e., -O-aryl). Said groups can be substituted or unsubstituted. "Carbocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring radical. The carbocyclic rings are monocyclic or are ring systems fused, bridged spiropolyclic. The monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. The polycyclic carbocyclic rings contain 7 to 17 atoms, preferably 7 to 12 atoms. Preferred polycyclic systems comprise rings of 4, 5, 6 or 7 members fused to rings of 5, 6 or 7 members. "Carbocycloalkyl" is a substituted or unsubstituted alkyl radical substituted with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl, most preferably an aryl. Preferred carbocycloalkyl groups include benzyl, phenylethyl and phenylpropyl. "Carbocycloheteroalkyl" is an unsubstituted or substituted heteroarkyl radical replaced with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl; most preferably an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl or 2-thia-ethyl.

"Carboxyalkyl" is an unsubstituted or substituted alkyl radical replaced with a carboxy moiety (-C (= 0) OH). For example, -CH2-C (= 0) OH. "Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) morpholinyl, piperadinyl, piperazinyl, tetrahydrofuryl and hydantoinyl. "Fused rings" are rings that are superimposed on each other in such a way that they share two ring atoms. A certain ring can be fused to more than another ring.

The fused rings are contemplated in heteroaryl, aryl and heterocycle radicals, or the like. "Heterocycle-alkyl" is an alkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably a heteroaryl or cycloheteroaryl; most preferably a heteroaryl. Preferred heterocycloalkyl includes C 1 -C 4 alkyl having a preferred heteroaryl attached thereto. More preferred is, for example, pyridyl-alkyl and the like. "Hetero-cycloheteroalkyl" is an unsubstituted or substituted heteroalkyl radical, replaced with a heterocyclic ring. The heterocyclic ring is preferably an aryl or cycloheteroalkyl; most preferably an aryl.

"Heterogeneous atom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heterogeneous atoms may contain different heterogeneous atoms. "Heteroalkenyl" is an 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. Heterocyclic rings are monocyclic ring systems or are fused, bridged or spiro polycyclic The monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7 atoms The polycyclic rings contain 7 to 17 atoms, preferably 7 to 13 atoms. "Heteroaryl" is an aromatic heterocyclic radical, whether monocyclic or bicyclic radical Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl, benzothiazolyl, benzofuryl, indolyl and the like, said groups may be substituted or unsubstituted.

"Halo", "halogen" or "halide" is a radical of chlorine, bromine, fluorine or iodine atom. The halides that are preferred are bromine, chlorine and fluorine. Likewise, as will be mentioned herein, a "lower" hydrocarbon portion (e.g., "lower" alkyl) is a hydrocarbon chain comprising 1 to 6, preferably 1 to 4, carbon atoms. A "pharmaceutically acceptable salt" is a cationic salt formed in any acid group (e.g., carboxyl) or an anionic salt formed in any basic group (e.g., amino). Many of these salts are known in the art, as described in world patent publication 87/05297, Johnston et al., Published 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 amides" are amides of the compounds of the invention that do not interfere with the inhibitory activity of the compound, or that are easily converted in vivo by a mammalian subject to produce an active inhibitor. A "biohydrolyzable hydroxyimide" is an imide of a compound of formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by a human or lower animal subject to producing an active compound of the formula (I). Said hydroxyimides include those which do not interfere with the biological activity of the compounds of the formula (I). A "biohydrolyzable ester" refers to an ester of a compound of the formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to produce a compound of the formula (I) active . A "solvate" is a complex formed by the combination of a solute (e.g., a hydroxamic acid) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Che ist'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., Ha l s Condensed Chemical Dictionar, 1 I Ed.). It is not desired that the illustration of specific protected forms and other derivatives of compounds of the formula (I) be limiting. The application of other useful protective groups, salt forms, etc., is within the ability of the person skilled in the art. As mentioned above and as used herein, the substituent groups may in turn be substituted. Said substitution can be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Sustituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated herein by reference. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxyl, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyaceil (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholino, pyrrolidinyl, etc.), imino, thioxo, "hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof. here, 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., 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 those in which Z is heteroespyrocaryalkylene, preferably heteroatoms adjacent to the ancestor ring structure, most preferably said spiroheteroalkylenes have from 4 to 5 members. The preferred heteroatoms are divalent. The invention provides compounds which are useful as inhibitors of metalloproteases, preferably matrix metalloproteases, and which are effective under treatment conditions characterized by the excess activity of said enzymes. In particular, the present invention relates to a compound having a structure according to formula (I): wherein W Ar is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted; R] _ is H; R2 is hydrogen, alkyl acyl; W is zero or one or more lower alkyl portions, or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbons (thereby forming a fused ring); And it is independently one or more of hydrogen, hydroxy, SR3, SOR4, SO2R5, alkoxy, amino, wherein the amino is of the formula NRg, R7, wherein Rg and R7 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, 0R3, S02Rs, C0R9, CSR10, PO (Rn) 2; and R3 is hydrogen, alkyl, aryl, heteroaryl; R 4 is alkyl, aryl heteroaryl; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; Rg is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R 10 is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, dialrylamino and alkylarylamino; Rll is alkyl, aryl, heteroaryl, heteroalkyl; Z is a spiro portion; n is 1-3. The structure also includes an optical isomer, diastereomer or enantiomer for the formula (I), or a pharmaceutically acceptable salt, or biohydrolyzable ester, amide or imide thereof. Preparation of the compound: J The hydroxamic compounds of the formula (I) can be prepared using a variety of procedures. The general schemes include the following.

PREPARATION OF THE PORTION AND For the manipulation of Y it is understood that the person skilled in the art can select to prepare Y before, after or together with the preparation of Z, the spiro portion. For clarity, the W and Z portions are not shown later. More than one portion Y and Z may be present in the compounds of the formula (I). Pair the compounds where Y is not adjacent to the nitrogen ring, a preferred method of manufacturing the compounds is; (A) (B) (C) SCHEME I Where R is a group that can be derived or can be manipulated or substituted, said compounds are known or are prepared by known methods. For example, where R is OH and n is 1, a commercially available hydroxyproline (A) is converted to its analogous estersic and the hydroxyl is then manipulated to provide (B) during this or a subsequent step. Y and Z can be added or altered, followed by treatment with hydroxylamine under basic conditions to provide (C). Where Y is adjacent to the nitrogen ring, a preferred method for preparing the compounds of the following formula I. For clarity, the W and Z portions are not shown; (D) (E) (F) SCHEME II Obviously, this route is also preferred to prepare compound with Z as heteroalkylene with Z adjacent to the nitrogen ring. The transformations to manufacture the spiro portion, Z, are known in the art. Obviously, for this and other schemes, the person skilled in the art will appreciate that the order of the steps can be altered. Where the amide D is known or commercially available, or made by known methods from known materials, and converted to the corresponding esteric E using known techniques, such as described in scheme I above, with proper handling to prepare And, then elaborating Rid, a compound of the formula I, shown in F. Obviously, the steps can be rearranged or altered to provide the acceptable yield and the desired products.

PREPARATION OF THE Z PORTION Obviously the person skilled in the art will recognize that the schemes that can be applied to the preparation of Y can be useful in the preparation of Z as mentioned above. Other preferred methods are provided for the reader.

Where Z is a compound or thiochetal of the compounds of the invention, they can be prepared by the following method. Again W and Y are not shown for clarity; (O) (H) SCHEME III Where R is hydroxy, amino, imino, alkoxy, oxo or any other group that can be manipulated in a carbonyl compound, and R "is hydrogen or any other group can be displaced in the formation of the sultamic ester. A preferred method of making the compounds of the invention with Z as a carbocycle or a heterocycle that is not prepared by the formation of a cannae is shown below, The portion, Z, shown below. it is described as a carbocycle, but heteroatoms can occur interspersed anywhere in the hope cycle.In the following, Z is described as a carbocyclic spirocycle, but one or more heteroatoms can be interspersed in the base structure of the spirocyclic ring. The omission of the heteroatoms is intended to help the voter.It is not intended to limit the claims, again W and Y are not shown for clarity: R is any group that can give rise to W or Y. B is a group that can be manipulated in Ri (or in the case of alkoxy it is Rl). Evidently the achievement of Ri, the sultamic ester, and the other groups proceed as illustrated previously. In either of said methods W may be present in the starting material or a known starting material may have one or more W portions added using known methodologies. It is recognized that it is preferable to use a protecting group for any reactive functionality such as a carboxyl, hydroxyl and the like, during the formation of the sulfamic ester. The above is a standard practice, within the normal practice of the person skilled in the art. A preferred method for manufacturing the spiro compounds of the invention is by a carbonyl compound, using the "protection group" technology known in the art, such as a thioquetol or quetalo and the like. The quats, ketals and the like are prepared from carbonyl compounds by methods known in the art. Said carbonyl compounds can be manufactured from cyclic hydroxyalkylene amines by oxidation to a ketone or delactams, which are provided for the 2-aminospiro functionality. A variety of compounds can be generated in a similar way, using the guidance of the previous scheme. 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 direction, ie, it is within the scope and practice of the skilled artisan to carry out such manipulations.These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification and the like Examples of these manipulations are described in normal texts, such as March, Advanced Orqanic Chemistrv, (Wiley), Carey and Sundberg, Advanced Orqanic Chemistry (Vol. 2) and Keeting, Heterocyclic Chemistry (all 17 volumes). The person skilled in the art will readily appreciate that certain reactions are best carried out when another functionality is masked or protected in the molecule, thereby avoiding any undesirable side reactions and / or increasing the yield of the reaction. Commonly, 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, an optical isomer, including diastereomer and enantiomer, can be selectively prepared on other; 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, in 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 metalloproteases (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 to certain tissues than others, and this judicious choice of inhibitor, with the selectivity described above, provides a "specific treatment of the disorder, disease or condition not desired. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. In this way, the compounds can be selected to produce mediated effects through MPs found specifically outside the central nervous system. The determination of the specificity of an MP inhibitor of a certain MP is within the ability of the expert in that field. Proper test conditions can be found in the literature. Tests for stromelysin and collagenase are specifically known. For example, the US patent. No. 4,743,587 refers to the procedure of Cawston et al., Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate in a test is described by Weingarten, H. et al., Biochem 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 MP 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 in, joint replacements (for example hip, knee and shoulder replacements), dentures, including dentures, bridges and prostheses secured to the maxillary and / or mandible. MPs are also active to reshape the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons why angioplasty has a higher-than-expected 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 hulosa, 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 limbal 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 cirrhosis of the liver 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 these diseases, It is also believed that MPs are involved 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." believes that PM 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 tissue viability , coagulation, Graft's disease vs. host, leukemia, cachexia, anorexia, proteinuria and perhaps the regulation of hair growth.For some diseases, conditions or disorders, the inhibition of MP is considered as a preferred treatment method. , conditions or disorders include arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or fight against growth and meta tumor tesis), 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 matrix destruction metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammations of the skin, ulcerations, particularly of the cornea, reactions to infections, periodontitis and the like. In this manner, the compounds of the invention are useful in therapy with respect to conditions that include this undesired activity, Therefore, the compounds of the invention can be formulated into pharmaceutical compositions useful for the treatment or prophylaxis of these conditions. they use normal pharmaceutical formulation techniques, 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 formula (I) is an amount that is effective to inhibit matrix metalloproteases at site or activity sites, in a human or lower animal subject, without undue adverse side effects (such as toxicity, irritation or allergic response), congested with a reasonable benefit / risk ratio when used in the manner of this invention. The specific "safe and effective amount" will obviously vary with factors such as the particular condition being treated, the patient's physical condition, the duration of the treatment, the nature of the concurrent therapy (if any), the form of specific dosage to be used, the vehicle employed, the solubility of the compound of the formula (I) therein and the desired dosage regimen for the composition. In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible solid or liquid filler or encapsulant diluent substances that are suitable for its 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, so that there is no interaction that could substantially reducing the pharmaceutical efficacy of the composition under ordinary conditions of use The pharmaceutically acceptable carriers must, of course, have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the human or lower animal being treated Some examples of susta 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, tableting agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline solution and pH-regulating solutions of phosphate. The selection of a pharmaceutically acceptable carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound will be administered.If the present compound will be injected, the pharmaceutically acceptable carrier that is preferred is a sterile physiological saline solution. with a blood-compatible suspension agent, the pH of which has been adjusted to about 7.4.In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, pH regulating solutions of phosphate, emulsifiers, isotonic saline and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier, in the compositions for parenteral administration, comprises at least about 90% by weight of the total composition. The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention that contains an amount of a compound of the formula (I) that is suitable for administration to a human or lower animal, in a single dose , according to the proper medical practice. These compositions preferably contain about 5 mg (milligrams) to about 1000 mg, most preferably about 10 mg to about 50 mg, more preferably about 10 mg to about 300 mg of a compound of the formula (I).

The compositions of this invention can be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal or parenteral administration. Depending on the particular administration route desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. These include liquid or solid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Optional pharmaceutically active materials may be included, which do not substantially interfere with the inhibitory activity of the compound of the formula (I). The amount of vehicle used in conjunction 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).

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 carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound will be administered. If the present compound will be injected, the preferred pharmaceutically acceptable carrier is sterile physiological saline with a blood-compatible suspension agent, whose pH has been adjusted to approximately 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 (composed of the formula (I) .The tablets can be compressed, crushed, enteric-coated, sugar-coated, film-coated or multiple-compressed, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and suitable melting agents. The liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, fusion agents, coloring agents and flavoring agents. The pharmaceutically acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well known in the art. The tablets typically comprise conventional pharmaceutically compatible adjuvants such as inert diluents, calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.; binders such as starch, gelatin and sucrose; disintegrants such as starch; alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Slip agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents such as FD &C dyes can be added to improve appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint and fruit flavors are also useful adjuvants for chewable tablets. The capsules typically comprise one or more of the solid diluents described above. The selection of vehicle components depends on secondary considerations such as flavor, cost and stability at the counter, which are not critical for the purposes of the present invention and can be easily made by one skilled in the art.

The peroral compositions also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers useful for the preparation of such compositions are well known in the art. Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, carboxymethylcellulose, AvicelRRC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. The peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents and colorants described above. Said compositions can also be coated by conventional methods, typically with pH or time dependent coatings, such that the present compound is released into the gastrointestinal tract, in the vicinity of the desired topical application or several times to extend the desired action . Said dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, dihydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and lacquer.

The compositions of the present invention may optionally include other drug actives. Other compositions useful for achieving systemic delivery of the present compounds include sublingual, buccal and nasal dosage forms. Said compositions typically comprise one or more soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Also described above and may include slip agents, lubricants, sweeteners, colorants, antioxidants and flavoring agents. The compositions of the present invention can also be administered topically to a subject, e.g., by direct placement or dispersion of the composition on the epidermal or epithelial tissue of the subject, or transdermally by means of a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1% and preferably about 1% to about 5%, of the compound of the formula (I). Suitable vehicles for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by transpiration or immersion in water. In general, the vehicle is of an organic nature and capable of having the compound of the formula (I) dispersed or dissolved therein.

The vehicle may include emollients, emulsifiers, thickening agents and pharmaceutically acceptable solvents, and the like.

Methods of administration This invention also provides methods for treating or preventing disorders associated with excessive or undesired activity of the matrix metalloprotease in a human or other animal subject by administering a safe and effective amount of a compound of the formula (I) to said subject. As used herein, the phrase "a disorder associated with excessive or undesired activity of matrix metalloprotease" is any disorder characterized by degradation of 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 formula (I) of this invention may be administered topically or Systemically, the systemic application includes any method for introducing a compound of the formula (I) into the tissues of the body., 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 invention are administered. formula (I) a day. It is understood that these dosing scales are by way of example only and that daily administration can be adjusted depending on the factors listed above. A preferred method of administration for the treatment of rheumatoid arthritis is oral or parenteral by intra-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans (assuming an approximate body weight of 70 kilograms), individual doses of about 10 mg to about 1,000 mg are preferred. A preferred method of systemic administration is oral. Individual doses of about 10 mg to about 1,000 mg, preferably about 10 mg to about 300 mg, are preferred. Topical administration can be used to provide the compound of formula (I) systemically or to treat a subject locally. The amounts of the compound of the formula (I) that will be administered topically depend on factors such as skin sensitivity, type and location of the tissue to be treated, the composition and the vehicle (if any) to be administered, the compound of the particular formula (I) that will be administered, as well as the particular disorder that will be treated and the degree to which the systemic effects are desired (which are distinguished from the local ones). The inhibitors of the invention can be sent to specific sites where the matrix 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 * deposit, 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 the conventionally used lock-step 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 methods, now common in the art, using the compounds of the invention as antigens. The antisera obtained can be used directly or monoclonal antibodies can be obtained by culturing peripheral blood lymphocytes or the spleen of the immunized animal and immortalizing the antibody producing cells, followed by identification of the appropriate antibody producers using normal immunoassay techniques. Polyclonal or monoclonal preparations are then useful for monitoring therapy or prophylaxis regimens that include the compounds of the invention. Suitable samples such as those derived from blood, serum, urine or saliva can be tested to verify the presence of the inhibitor administered several times during the treatment protocol using normal immunoassay techniques employing the antibody preparations of the invention. The compounds of the invention can also be coupled to markers such as scintigraphic labels, e.g., technetium 99 or 1-131, using normal coupling methods. The labeled compounds are administered to subjects to determine the sites of excessive amounts of one or more matrix metalloproteases in vivo. The ability of the inhibitors to selectively bind to matrix metalloproteases to map the distribution of these enzymes in situ is then exploited. The techniques can also be employed in histological procedures and the labeled compounds of the invention can be used in competitive immunoassays. The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.

EXAMPLES Compounds are analyzed using iH and 13 C NMR, elemental analysis, mass spectrum and / or IR spectrum, as appropriate. Typically, inert solvents are preferably used in the dry form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, disopropylamine is distilled from calcium hydrogenide, and all other solvents are purchased to the right degree. Chromatography is carried out on silica gel (70-230 mesh, Aldrich) or (230-400 mesh, Merck) as appropriate. The thin layer chromatography (TLC) analysis is carried out on a glass mounted on the silica gel plates (200-300 mesh; Baker) and visualized with UV or 5% phosphomolybdic acid in EOH.

EXAMPLE 1 la.lN- (4-methoxyphenylsulfonyl) -4 (R) -hydroxy-pyrrolidine-2 (R) -methylcarboxylate: cis-Hydroxy-D-proline (50 g, 0.38 moles) was dissolved in water: dioxane ( 1: 1, 300 ml) with triethylamine (135 ml, 0.96 moles). The 4-methoxyphenylsulfonyl chloride (87 g, 0.42 mole) was added together with 2,6-dimethylaminopyridine (4.6 g 0.038 mole) and the mixture was stirred for 14 hours at room temperature. The mixture was then concentrated and diluted with EtOAc. The layers were separated and the organic layer was washed twice with IN HCl, once with brine, dried with MgSO 4, filtered and evaporated to provide 83 g of solid material which was dissolved in MeOH (500 mL). Thionyl chloride (50 ml) was added dropwise and the resulting mixture was stirred for 14 hours. The mixture was then evaporated to dryness and triturated with CHCl3 'to give a white solid which is sufficiently pure to continue without purification. Ib. Intermediate A-N- (4-methoxyphenylsulfonyl) -4-oxo-pyrrolidine-2 (R) -methylcarboxylate: a batch of 8M of Jones Reagent is prepared. The alcohol (10.0 g, 31.7 moles) was dissolved in 175 ml of acetone and cooled to 0 ° C. The Jones reagent was added until the solution turned orange and the mixture was stirred at room temperature for 14 hours. Isopropanol was added to the solution to quench the excess chromium reagent and the resulting solid was filtered with celite. The filtrate was concentrated under reduced pressure and the residue was dissolved in methylene chloride and washed with water. The resulting solution was dried with magnesium sulfate, concentrated under reduced pressure. Purification of the product by chromatography on silica gel using EtOAc: hexane (1: 1) provides the desired ketone. MS (ESI): 374 (M + + H). lc. 7N- (4-methoxyphenylsulfonyl) 1,4-dithia-7 azaspiro [4.4] nonan-8 (R) -methylcarboxylate: the ketone Ib (1.3g 4.15 mmol) was dissolved in 30 ml of anhydrous dichloromethane and then added 1,2 ethanedithiol (0.300 ml, 8.30 mol) and borane trichloride stearate (0.20 ml, 1.66 mmol). The mixture was stirred at room temperature overnight. The solution was made basic by the addition of IN sodium hydroxide and then the mixtures were extracted three times with EtOAc. The organic layers were washed with water and ammonium chloride, dried with magnesium sulfate, filtered and evaporated to give the title compound. MS (ESI): 39 (M + + H). 407 (M ++ NH4). ld. N-Hydroxy-7N- (4-methoxyphenylsulfonyl) -1,4-dithia-7-azaspiro [4] nonan-8 (R) -carboxylamide: a 1.76M solution of potassium hydroxylamine in methanol was prepared. The 1.76M solution (1.46ml, 2-57mmol) was added directly to the liter methyl ester (0.100 g 0.257mmol) and the reaction mixture was stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by chromatography on silica gel using ethyl acetate: hexane: formic acid (1: 1: 0.1) to give the title compound. MS (ESI): 391 (M ++ H), 408 (M ++ NH4).

EXAMPLE 2 2a. InN- (4-methoxyphenylsulfonyl) -spiro [1,3-benzothiol-24n-pyrrolidine] -2n (R) -methylcarboxylate: The ketone Ib (0.5 g 1.59 mmole) was dissolved in 10 ml of anhydrous dicl? Romethane, then 1,2 benzenedithiol (0.450 g, 3.19 mmole) and borane trifluoride stearate (0.7 ml, 0.63 mmol) were added. The mixture was stirred at room temperature overnight. The solution was made basic by the addition of IN sodium hydroxide and then the mixture was extracted 3 times with ethyl acetate. The organic layers were washed with water and ammonium chloride, dried with magnesium sulfate and evaporated under reduced pressure to provide a solid. MS (ESI): 438 (M ++ H) 2b. N-hydroxy-InN- (4-methoxyphenylsulfonyl) -Espiro [1,3-benzothiol-2,4n-pyrrolidone] -2n (R) -carboxamide: A 1.76M solution of potassium hydroxylamine in methanol is prepared. The "1.76M solution (7.3 ml, 13.0 mmoleS) was added directly , to the methyl ester 2a (0.590 g, 1.3 mmol) and the reaction mixture was stirred overnight. HCl IN was added to the solution to acidify it, and then the solution was extracted three times with ethyl acetate, dried with magnesium sulfate and evaporated under reduced pressure. Purification of the product was achieved by chromatography on silica gel using ethyl acetate / hexane / formic acid (1/1/0) to give the pure compound. EM (IEA): 439 (M + + H).

EXAMPLE 3 3a. 8N- (4-methoxyphenylsulfonyl) -1, 5.Ditia-ß-azaspiri [4.5] nonan-9 (R) -methylcarboxylate: the ketone Ib (1.5g, 4.79 mmol) was dissolved in 30ml of anhydrous dichloromethane and then 1,3-propane dithiol (1.20 ml 11.9 mmole) and borane trifluorine etherane (0.24 ml 1.91 mmol) were added, the mixture was stirred at room temperature overnight. The solution was made basic by the addition of sodium hydroxide IN and then the mixture was extracted 3 times with ethyl acetate.The organic layers were washed with water and ammonium chloride, dried with magnesium sulfate and evaporated under pressure reduced to give a solid MS (ESI): 403 (M ++ H), 420 (M ++ H4), 3b.N-Hydroxy-8N- (4-methoxyphenylsulfonyl) -1,5-Dithia-8-azaspiro [4.5] onan-9 (R) -carboxamide: a 1.76M solution of potassium hydroxylamine in methanol was prepared.The 1.76M solution (1.4 ml, 2.48 mole) was added directly to the methyl ester 3a (0.100 g). 0.248 mmol) and the reaction mixture was stirred overnight, IN HCl was added to acidify it, then the resulting mixture was extracted three times with ethyl acetate, dried with magnesium sulfate and evaporated under reduced pressure. of the product was achieved by chromatography on silica gel using ethyl acetate / hexane / formic acid (1/1 / 0.1) pair to give the pure compound: MS (ESI): 404 (M + + H), 421 (M + + NH4).

EXAMPLE 4 4a. 7N- (4-methoxyphenylsulonyl) -1, -Dioxa-7- azaspiro [4,4,] nonan-8 (R) -carboxylate: Ketone Ib (0.5 g), 1.59 borane triflorane. The ketone Ib (0.5 g, 1.59 mmole) was dissolved in 50 ml of benzene, and then 1.2 g. . tanodiol (0.108 g 1.75 mmoles) and p-toluene sulfuric acid (0.006 g, 0.0160 moles). The reaction mixture was refluxed for 18 hours. The mixture was diluted with ether and neutralized with sodium bicarbonate (10 ml), extracted with ether 3 times and the combined ether layers were washed with ammonium chloride, dried with magnesium sulfate and evaporated. Purification of the resulting oil was achieved by chromatography on silica gel with hexane / ethyl acetate (l / l) to achieve the pure compound. MS (ESI): 438 (M + + H), 455 (M + + NH4). 4b N-Hydroxy-7N- (4-Methoxyphenylsulfonyl) -1,4-Dioxa-7-azaspiro [4,4] nonan-8 (R) carboxylate: A 1.76M solution of potassium hydroxylamine in methanol was prepared. The 1.76M solution (2.0 ml 3.52 mmol) was added directly to the methyl ester 4a (0.146 g 0.408 mmol) and the reaction mixture was stirred overnight. 1N HCl was added to the solution to acidify it, then the remaining solution was extracted three times with ethyl acetate, dried with magnesium sulfate and evaporated with an oil. The purification of the resulting oil was achieved by chromatography on silica gel using ethyl acetate / hexane / formic acid (2/1 / 0.1) to give the pure compound. MS (ESI): 438 (M + + H), 455 (M + + NH4).

EXAMPLE 5 5a. N-Hydroxy-7N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3,3-dimethyl-8-azaspiro [5, 4] decan-9 (R) -methylcarboxylate: Ketone Ib (2) was dissolved g, 3.19 mmoles) in 50 ml of benzene, and then 2,2-dimethyl-1,3-propanediol (0.4 g, 3. 83 mmole) and the p-toluene sulphonic acid monohydrate (57 mg, 0.3 mmol). The mixture was refluxed using a Dean-Stark apparatus overnight. The solution was made basic by the addition of. NaHC03 aqueous and then extracted three times with Et20. The organic layers were washed with ammonium chloride, dried with magnesium sulfate, filtered and evaporated. Purification of the product was achieved by chromatography on silica gel with hexane / EtOAc (7: 3) to achieve the desired product, EM ion spray: m / z 417 (M ++ NH4), 440 (M + + H) . 5b.- N-Hydroxy-8N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3, 3-dimethyl-8-azaspiro [5,4] decan-9 (R) -carboxamide: A solution of 1.5 was prepared M of potassium hydroxylamine in methanol as described in Fieser and Fieser, Vol, l, p 478. The 1.5M solution (5.7ml, 8mmol) was added directly to the methyl ester 5a (0.32 g, 0.8 mmol) and the mixture of reaction was stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by the preparation of the reversed phase HPLC (60A40B, A, 95% H2?, 5% acetonitrile, 0.1% formic acid; B, 80% acetonitrile, 20% H2O; 19 x 300 mm water Symmetri Prep column from 18) to give the title compound as a white foam solid. EM ion spray: m / z 418 (M ++ NH4), 401 (M ++ H).

EXAMPLE 6 6a. 7N- (4-methoxyphenylsulfonyl) -1,4-dioxo- (2S), (3S) -trans-cyclohexyl-7-azaspiro [4,4] nonane-8 (R) -methylcarboxylate: Ketone Ib (1) g, 3.19 mmoles) was dissolved in 50 ml of benzene and then (IS, 2S) -trans-1,2-cyclo-p-exediol (0.45 g, 0.3 mmoles) and p-toluensulfonic acid monohydrate (57 mg 0.3) were added. mmoles). The mixture was refluxed using a Dena-Stark apparatus overnight. The solution was made basic by the addition of aqueous NaHC 3 and then extracted three times with Et 2. The organic layers were They were washed with ammonium chloride, dried over magnesium sulfate, filtered and evaporated. Purification of the product was achieved by chromatography on silica gel with hexane / EtOAc (1: 3) to achieve the desired product. Ion spray EA: m / z 429 (M ++ NH4), 412 (M ++ H). 6b. 7N- (4-methoxyphenylpropyl) -1,4-dioxo- (2S), (3S) -trans-cyclohexyl-7azaspiro [4, 4] nonane-8 (R) -carboxamide of N-Hydroxy: A solution of 1.5M potassium hydroxylamine in methanol as described in Feser and Fieser, Vol 1, p 478. The 1.5M solution (5.7 ml, 8 mmol) was added directly to the methyl ester 6a (0.33 g, 0.8 mmol) and the mixture and reaction were stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by the HPLC reverse phase preparation (60A40B, A, 95% H2O, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% H2O 19 x 300mm Simmetri Prep water from C18 column) to give the title compound as a white foaming solid. Ion spray EA: m / z 430 (M ++ NH4), 413 (M ++ H).

EXAMPLE 7 7a. 7N- (4-methoxyphenylprokyl) -1,4-dioxo- (2RR), (3R) -trans-cyclohexyl-7-azaspiro [4, 4] nonane-8 (R) -methylcarboxylate: Ketone Ib (1) g, 3.19 mmole) was dissolved in 35 ml of benzene, and then (1R, 2R) -trans-1,2-cycloexanediol (0.45g, 3.82mmol) and p-toluensulphonic acid monohydrate (29 mg, 0.15 mmoles). The mixture was refluxed using a Dean-Stark apparatus overnight. The solution was made basic by the addition of aqueous NaHC 3 and then extracted three times with Et 2 ?. The organic layers were washed with ammonium chloride, dried with magnesium sulfate, filtered and evaporated. The purification of the product was achieved by chromatography on silica gel with hexane / EtOAc (1: 3) to achieve the desired product. Ion spray EA: m / z 429 (M ++ NH4), 412 (M ++ H). 7b. 7N- (4-M-methoxyphenylpropyl) -1,4-dioxo- (2R), (3R) -trans-cyclohexyl-7-azaspiro [4,4] nonane-8 (r) -carboxamido of N-hydroxy: a 1.5M solution of potassium hydroxylamine in methanol as described in Fieser and Fieser, Vol. l, p 478. The 1.5M solution (12.8ml, 19.3mmol) was added directly to methyl ester 7a (0.8 g, 1.92 mmol) and the reaction mixture was stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times "with ethyl acetate, dried with magnesium sulfate, filtered and evaporated, the product was purified by the HPLC reverse phase preparation (60A40B to 95% of H2O, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile 20% H2O, 19 x 300 mm water Simmetri Prep from C18 column) to give the title compound as a white foaming solid. Ion spray EA: m / z 430 (M ++ NH4), 413 (M ++ H). is EXAMPLE 8 8a. 8N- (4-Methyphenylsulfonyl) -1,5-dioxo-3-benzyloxy-8-azaspiro [5.4] decan 9 (R) -methylcarboxylate: Ketone Ib (3.4 g 10.98 mmoles) was dissolved in 65 ml of benzene and then 2-benzyloxy-1,3-propanediol (2 g, 10.98 mmol) and p-toluene sulfonic acid monohydrate (104 mg, 0.15 mmol) were added. The mixture was refluxed using a Dean-Stark apparatus overnight. The solution was made basic by the addition of aqueous aHC? 3 and then extracted three times with Et2 ?. The organic layers were washed with ammonium chloride, dried with , magnesium sulfate, filtered and evaporated. Purification of the product was achieved by chromatography on silica gel with hexane / EtOAc (3: 7) to achieve the desired product. Ion spray EA: m / z 495 (M ++ NH4) 478 (M ++ H). 8b. 8N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3-benzyloxy-8-azaspiro [5,4] -decan-9 (R) -carboxamide of N-hydroxy: A solution of 1.5M hydroxylamine was prepared from potassium in methanol as described in Fieser and Fieser, Vol 1, p478. The 1.5M solution (9.3 ml, 13 mmol) was added directly to the methyl ester 8a (0.78 g, 1.63 mmol) and the reaction mixture was stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product is purified by the HPLC phase / reverse preparation (60A40B, A, 95% H 0.5% acetonitrile, 0.1% formic acid B, 80% acetonitrile, 20% H2O, 19 x 300mm Simmetri waters C18 column prep) To give the title compound as a white foaming solid. Ion spray EA: m / z 510 (M ++ Na) 479 (M ++ H).

EXAMPLE 9 9a. 8N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3,3-diethyl-8-azaspiro [5,4] -decan 9 (R) -methylcarboxylate: The ketone Ib (2.0 g 6.39 mmol) was dissolved in methylene chloride (40 ml) followed by the addition of bis (trimethyl siloxy) -2-diethyl-1,3-propanediol (8.8 g, 31.9 mmol). The reaction mixture was cooled to minus 78 ° C in a dry ice / acetone bath and trimethylsilyl trifloromethane sulfonate (0.075 g, 0.31 mmol, 0.048 equiv) was added. The reaction mixture was then warmed to room temperature and stirred overnight. Saturated sodium bicarbonate was added to neutralize the mixture and the mixture was then extracted with water and methylene chloride. The organic layers were dried with sodium sulfate and evaporated under reduced pressure. Purification was achieved by silica gel chromatography using an eluent system of ethyl acetate: hexane 3: 7, EA (IEA): 428 (M + + H), 445 (M + + NH4). 9b. 8N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3,3-diethyl-8-azaspiro [5,4] -decano- (R) -carboxamide of N-hydroxy: The ketal 9a (4.0 g, 9.68 mmoles) ) was added to a solution of 1.5M potassium hydroxylamine solution (77ml, 14 equiv, prepared as described in Fieser and Fieser, Vol. 1, p.478). The reaction was quenched after 4 hours with IN HCL at a pH of 4-5. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layers were dried with sodium sulfate and evaporated under reduced pressure to a foamy solid. Purification was achieved by silica gel chromatography using 3% methanol: 97% chloroform as the eluent. EA (IEA): 429 (M ++ H), 446 (M ++ NH4).

EXAMPLE 10 10a. 8N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3-hydroxy-8-azaspiro [5, 4] decan-9 (R) -methylcarboxylate: Actale 9a (1.2 g, 2.51 mmol) is taken in 20 ml of EtOH and the mixture is charged with 10% palladium on carbon (120 mg) and stirred under a hydrogen atmosphere for 32 hours. TLC (EtOAc / hexane 1: 1) indicates that the reaction is complete. The mixture was filtered with celite and concentrated to give the desired product. Ion spray EA: m / z 405 (M ++ NH4), 388 (M ++ H). 10b. 8N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3-hydroxy-8-azaspiro [5,4] decan-9 (R) -carboxamide of N-hydroxy: A solution of 1.5M of potassium hydroxylamine in methanol was prepared as described in Fieser and Fieser, Vol.l, p 478. The solution of 1.5M 811 ml 16.5 mmoles) was added directly to the ester "methyl 10a (0.8 g, 2.06 mmol) and the reaction mixture was added.

. Agitated during the night. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by HPLC reverse phase preparation (80A20B, A, 95% H2O 5% acetonityl, 0.1% formic acid; B, 80% acetonitrile, 20% H2O; 19 x 300 mm Simmetri Prep waters column C18) to give the title compound as a white foaming solid. Ion spray EA: m / z 406 (M ++ NH4), 389 (M ++ H).

EXAMPLE 11 lia 7N- (4-methoxyphenylsulfonyl) -1,4-dioxo- (2R) -methyl- (3R) -methyl-7-azaspiro [4,4] nonan-8 (R) -methylcarboxylate: Ketone Ib (2) g, 6.38 mmol) was dissolved in 40 ml of benzene, and then (2R, 3R) - (-) -2, 3 -butanediol (0.67g, 7.66mmol) and p-toluene sulfonic acid monohydrate ( 120 mg, 0.63 mmol). The mixture was refluxed using a Dean-Stark apparatus overnight. The solution was made basic by the addition of aqueous NaHC 3 and then extracted three times with Et 2, the organic layers were washed with ammonium chloride, dried with magnesium sulfate, filtered and evaporated to obtain the product. desired EA ion spray: m / z 404 (M + + NH 4), 386 (M + + H), lb 7 N- (4-methoxyphenylsulfonyl) -1,4-dioxo- (2R) -methyl- (3R ) methyl-7-azaspiro [4,4] nonan-8 (R) -carboxamide of N-hydroxy: A solution of 1.5M of potassium hydroxylamine in methanol was prepared as described in Fieser and Fieser, Vol 1, p 478 The 1.5M 832m solution, 48 mmol) was added directly to the methyl ester (2.5 g, 6.7 mmol) and the reaction mixture was stirred overnight.The solution was acidified with IN HCl, then the Mix three times with ethyl acetate, dry with magnesium sulfate, filter and evaporate The product is purified by flash chromatography . { CH2CL2 / EtOAc / hexane, 5: 3: 2 to 5: 4: 1) of silica gel to give the title compound as a white foaming solid. Ion spray EA: m / z 404 (M ++ NH4), 387 (M ++ H).

EXAMPLE 12 12a. 7N- (4-methylphenylsulfonyl) -1,4-dioxo- (2S) -methyl- '(3S) methyl-7-azaspiro [4,4] nona-8 (R) -methylcarboxylate: The Acetone Ib (1.5 g, 4.78 mmol) was dissolved in 45 ml of benzene, and then (2S, 3S) - (+) -2, 3-butanedi (0.52g 5.74mmol) and p-toluene sulphonic acid monohydrate were added. (89 mg, 0.47 mmol). The mixture was refluxed using a Dean and Stark apparatus overnight, the solution made basic by the addition of aqueous NaHC 3 and then extracted three times with Et 2. The organic layers were washed with ammonium chloride, dried with magnesium sulfate, filtered and evaporated to achieve the desired product. Ion Awareness: EA: m / z 403 (M ++ NH4), 386 (M ++ H). 12b- 7N- (4-methoxy-phenylsulphonyl) -1,4-dioxo- (2S) -methyl) -ptethyl-7-azaspiro [4, 4] nona-8 (R) -carboxamide of N-hydroxy: A solution of 1.5M potassium hydroxylamine in methanol was prepared as described in Fieser and Fieser, Voll, p 478. The 1.5M solution (10 ml, 19 mmoles) was added directly to the methyl ester 12a (0.92 g, 2.29 mmoles) and the reaction mixture was stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography (CH2CL2 / CH3OH, 95: 5) silica gel to give the title compound as a white foaming solid. Ion spray: EA: m / z 409 (M + + Na), 387 (M + + H).

EXAMPLE 13 13a. 8N- (4-methoxyphenylsulfonyl) -l, 5-dioxo-3-methylene-8-azaspiro [5.4] decaN- 9 (R) -methylcarboxylate: The ketone Ib (3g, 9.58 mmol) was dissolved in 45 ml of benzene and then 2-methylene-1,3-propanediol (1.04 g, 11.8 mmol) and p-toluene sulfonic acid monohydrate (182 mg, 0.95 mmol) were added.

The mixture was refluxed using a Dean-Stark apparatus overnight. The solution was made basic by the addition of NaHCC > Water was added and then extracted three times with Et2, the organic layers were washed with ammonium chloride, dried with magnesium sulfate, filtered and evaporated. The product purification is achieved by silica gel chromatography with hexane / EtOAc (3: 7 to 4: 6) to achieve the desired product. Ion spray: EA: m / z (intensity reí.) 401 (M ++ NH4), 384 (M ++ H). 13b. 8N- (4-methoxyphenylsulfonyl) -1,5-dioxo-3-methylene-8-azaspiro [5,4] -decan (R) -carboxamide: A solution of 1.5 M potassium hydroxylamine in methanol was prepared as described in Fieser and Fieser Vol 1, p 478. The 1.5 M solution (14 ml, 26 mmol) was added directly to the methyl ester 13a (1.25 g, 3.26 mmol) and the reaction mixture was stirred overnight.

The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography (CH2Cl2 / CH3OH, 95: 5) on silica gel to give the title compound as a white foaming solid. EM ion spray: m / z 407 (M + + Na), 385 (M + + H).

EXAMPLE 14 14 to. IN - [(4-methoxyphenyl) sulfonyl] -1,4-dioxa-azspiro [4.5] nonan-2-carboxylic acid methyl. Ketone Ib (20.0 g 63.9 mmol) was dissolved in methylene chloride (500 ml) followed by the addition of bis (trimethylsiloxy) -1,3-propanediol (51.9 g, 221.9 mmol, 3.5 equiv.). The reaction mixture was cooled to -78 ° C in a dry ice acetone bath, and trimethyl silyl trifluoromethal sulphonate (3.6 g, 3.07 mmol, 0.048 equiv) was added. The reaction mixture was then warmed to room temperature and stirred overnight. Saturated sodium bicarbonate was added to neutralize the mixture, and then the mixture was extracted with water and methylene chloride (3 x 200 ml). The organic layers were dried with sodium sulfate and evaporated under reduced pressure. Purification was achieved by silica gel chromatography using an eluent system of ethyl acetate 1: 1: hexane to achieve the product as a colorless oil. ES (ESI): 372 (M + + H), 389 (M + + NH 4). 14b. N-hydroxy-lN [(4-methoxyphenyl) sulfonyl] -1,4-dioxa-azaspiro [4.5] nonan-2-carboxamide IN (C). Cetal 14a (14.0 g, 37.7 mmol) was added to a solution of 1.5 M potassium hydroxylamine solution (300 ml, 14 equiv prepared as described in Fieser and Fieser, Vol. 1, p 478). The reaction was quenched after 1 hour of IN HCl at pH 4.5. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layers were dried (2SO-4), and evaporated under reduced pressure to a foamy solid. Purification was achieved by silica gel chromatography (eluent: 3% methanol: 97% cloform). The product was obtained as a white powder. MS (ESI): 372 (M + + H), 389 (M + + NH). EXAMPLE 15 15a. [(4-methoxyphenyl) sulfonyl] -2,4,8,14-tetraoxa-ll-azadispiro [4.2.5.2] -pentadecan-2-carboxylic acid methyl ester. Ketone Ib (1.0 g, 3.19 mmol) in benzene (60 ml) was stirred at room temperature and then 1.3 dioxane-5,5 dimethanol (0.56 g, 3.83 mmol) and p-toluenesulfonic acid (0.01 equiv) were added. . The reaction was then equipped with a Dean-Stark trap and a reflux condenser under a nitrogen atmosphere. The reaction was heated to reflux during noqhe. The reaction mixture was quenched and purified with saturated sodium bicarbonate. The resulting mixture was extracted with ethyl acetate and water and the organic layers were dried with sodium sulfate and concentrated under reduced pressure. Purification was achieved by chromatography on silica gel using hexane: ethyl acetate (1: 1). MS (ESI): 444 (M + + H), 461 (M + + NH 4). 15b. [(4-methoxyphenyl) sulfonyl] -2,4,8,14-tetraoxa-l-azadispiro [4.2.5.2] pentadecane-2-carboxylic acid from UN. The ketal 15a (0.90 g, 2.03 mmol) was dissolved in methanol (10 mL) and THF (5 ml). Then the lithium hydroxide (1.0 g, excess) 'was added in water (5 ml), and the resulting mixture was stirred for 1 hour.

The reaction extinguished the addition of HCli ÍN to reach the ph = 2. Then the reaction mixture was extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure to give the product. MS (ESI): 444 (M + + NH 4). 15c. [(4-methoxyphenyl) sufonyl] -2,4,8,14-tetraoxa-l-azadispyrol [4.2.5.2] -pentadecane-2-carboxamide of N-hydroxy-N: carboxylic acid 15b (0.43 g, 1.0 mmol) ) was dissolved in methylene chloride (15 ml), followed by the addition of oxalyl chloride (0.26 g, 2.05 mmol) and then DMF (0.07 g, 1.0 mmol) under nitrogen atmosphere. In a separate flask, hydroxylamine hydrochloride (0.28 g), 4.0 mmol) was dissolved in water (3 ml), followed by the addition of THF (10 ml). The amine solution was cooled in a water bath and triethylamine (0.61 ml, 6.0 mmol) was added. The acid mixture was then added to the hydroxylamine solution at 0 ° C. The reaction mixture was then warmed to room temperature and stirred for 1 hour. To neutralize the solution, IN HCl was added to achieve pH-5. The mixture was then extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure. Purification was achieved by reverse phase chromatography (Waters Symmetry C e) using a solvent system of 40% A (95% water, 5% acetonitrile, 0.1% formic acid) and 60% B (20% water, 80% water). MS (ESI): 445 (M + + NH 4).

EXAMPLE 16 16a. (4-methoxyphenylsulfonyl) -1,5-dioxa-azaspirol [4.5] nonan-2S, 4S-dimethyl-2-carboxylate: Ketone 1b (1.0 g, 3.19 mmol) was dissolved in benzene (60 ml) and then they added 2S, 4S- (+) pentanedio (0.4 g, 3.82 mmoles) and p-toluenesulfonic acid (0.01 equiv.). The reaction was equipped with a Dean-Stark trap and a reflux condenser under a nitrogen atmosphere. The reaction was then heated to reflux overnight. The reaction mixture was quenched and basified with a saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate and water, the organic layers were dried with sodium sulfate and then concentrated under reduced pressure. Purification was achieved by silica gel chromatography using hexane: ethyl acetate (7: 3). 16b. (4-methoxyphenylsulfonyl) -1,5-dioxa-azaspiro [4.51nonano-2S, 4S-dimethyl-2-carboxamide of N-hydroxy IN: The ketal 16a (0.9 g, 2.25 mmol) was added to a solution of 1.5 M of potassium hydroxylamine solution (10.2 ml, 18"mmoles, prepared as described in Fieser and Fieser Vol. 1, p. .478) and the resulting mixture was stirred overnight. The reaction was quenched and neutralized to pH-5 with IN HCl. The solution was diluted with water and extracted with ethyl acetate.

The organic layers were dried with sodium sulfate and concentrated under reduced pressure. Purification was carried out by reverse phase HPLC (Waters Sñymmetry C e) using 60% A (95% water, 5% acetonitrile, 0.1 formic acid) and 40% B (20% water, 80% of acetonitrile) MS (ESI): 368 (M + + H), 403 (M + NH4).

EXAMPLE 17 17a. (4-methoxyphenylsulfonyl) -1,5-dioxa-azaspirol [4.5] nonane-2R, 4R-dimethyl-2-carboxylic acid methyl ester.

The ketone (1.0 g, 3.19 mmol) was dissolved in benzene (60 ml) and then added 2R, 4R- (+) - pentanodium (0.40 g, 3.82 mmol) and p-toluenesulfonic acid (0.01 equiv). The reaction was equipped with a Dean-Stark trap and a reflux condenser under a nitrogen atmosphere. The reaction was heated to reflux overnight. The reaction mixture was quenched and basified with saturated sodium bicarbonate and then extracted with ethyl acetate and water, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. silica gel using hexane: ethyl acetate (7: 3) as eluent EM (IEA): 400 (M + H +), 417 (M + + NH 4). 17b. (4-methoxyphenylsulfonyl) -1,5-dioxa- azaspiro [4.5] nonane-2R, 4R-dimethyl-2-carbomamide of N-hydroxy-IN The ketal (0.9 g, 225 mmol) was added to a solution of 1.5 M of potassium hydroxylamine solution (10.2 ml, mmoles, prepared as described in Fieser and Fieser, Vol. 1, page 478) and the resulting mixture was stirred overnight.The reaction was quenched and neutralized to pH-5 with 1N HCl.The solution was diluted with water and extracted with ethyl acetate, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. achieved by crystallization with acetonitrile. MS (ESI) 40 (M + + H), 418 (M + + NH 4).

EXAMPLE 18 18. [(4-methoxyphenyl) sulfonyl] -1,5-idoxa-azaspiro [4.6] decane-2-carboxylic acid methyl ester. Ketone Ib (1.0 g, 3.19 mmol) was dissolved in methyl chloride (25 ml) followed by the addition of bis (trimethylsiloxy) -1,4-butanediol (3.73 g, 15.9 mmol 50 equiv). The reaction mixture was cooled to -78 ° C in a dry ice acetone bath, and trimethylsilyl trifluoromentansulfan (0.36, 1.53 mmol, 0.048 equiv) was added. The reaction mixture was then warmed to room temperature and stirred overnight. Saturated sodium bicarbonate was added to neutralize the mixture, and then the mixture was extracted with water and methylene chloride (3 x 50 ml). The organic layers were then dried with sodium sulfate and evaporated under reduced pressure. Purification was achieved by silica gel chromatography using an eluent system of ethyl acetate: hexane of 1: 1 to achieve the product. MS (ESI): 368 (M + + H), 403 (M + + NH 4). 18b. [(4-methoxyphenyl) sulfonyl] -1,5-dioxa-azaspiro [4.6] decane-2-carboxamide: Cetal 18a (1.0 g, 2.6 mmol) was added to a solution of 1.5 M potassium hydroxylamine solution ( 12 ml, 8 equiv, prepared as described in Fieser and Fieser, Vol. 1, p.478). The reaction was then removed after 1 hour with IN HCl at pH-4.5. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layers were (? A2SO4) dried, and evaporated under reduced pressure to a foamy solid. Purification was achieved by silica gel chromatography (eluent: 3% methanol: 97% chloroform). The product was obtained as a white powder. MS (ESI): 387 (M + + H), 404 (M + +? H4). EXAMPLE 19 19a. Acid? -methyl-7? - [(4-methoxyphenyl) sulfonyl] -1,4-dithia-7-azaspiro [4.4] nonan-8 (R) -carboxylic: The ketal lc (0.90 g, 2.31 mmol) was dissolved in methanol (10 mL) and THF (5 mL). Then the lithium hydroxide (1.0 g, excess) in water (5 mL) was added, and the resulting mixture was stirred for 1 hour. The reaction was quenched by the addition of IN HCl to reach pH = 2. The reaction mixture was then extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure to give the product MS (ESI): 376 (M + + H), 393 (M + + NH4). 19b. N-Hydroxyl-N-methyl-7N- [(4-methoxyphenyl) sulfonyl] -1,4-dithia-7-azaspiro [4.4.] -nonan-8 (R) -carboxamide: The carboxylic acid 19a (0.5 g, 1.33 mmole) was dissolved in methylene chloride (15 mL), followed by the addition of oxalyl chloride (0.35 g, 2.73 mmol) and then DMF (0.097 g, 1.33 mmol) under nitrogen atmosphere in a separate flask, the hydroxylamine hydrochloride (0.37 g, 5.33 mmol) was dissolved in water (1 mL), followed by the addition of THF (10 mL). The amine solution was cooled in an ice bath and triethylamine (1.1 mL, 8.0 mmol) was added. The acid mixture was then added to the hydroxylamine solution at 0 ° C. The reaction mixture was then warmed to room temperature and stirred for one hour. To neutralize the solution, IN HCl was added to achieve pH = 5. The mixture was then extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure. Purification was achieved by reverse phase chromatography (Waters Symmetry C 3) using a solvent system of 40% A (95% water, 5% acetonitrile, 0.1% formic acid) and 60% B (20% water, 80% water). MS (ESI): 391 (M ++ H), 408 (M ++ NH4).

EXAMPLE 20 l3 a. 6l- (1-pyrrolidine) spiro [cyclohexane-2,5 '(6'H) - [4H-1,2] -oxasin-3'-ethylcarboxylate: 1- (cyclohexylidenemethyl) -pyrrolidine (9.0 g) , 54.4 mmoles) in THF (100 mL) was stirred at room temperature and then ethyl 3-bromo-2-hydroxyiminopropanoate (12.2 g, 57.7 mmol), 1.06 equiv. ref: Ottenheijm, H.C. J .; píate, R.; Noordlik, J. H.; Herscheid, J. D. M. J. Org. Chem. 1982, 47, 2147.) in portions for 15 minutes. The reaction mixture was heated and the resulting mixture was stirred at room temperature for 30 minutes. Then triethylamine (5.9 g, 58.3 mmol, 1.07 eqiiiv) was added. The reaction mixture was heated again, and the resulting solution was stirred for an additional two hours at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic extracts were dried (Na2 =? 4) and concentrated in an oil under reduced pressure. Purification of the oil was achieved by silica gel chromatography using 85/15 hexane / EtAOc as eluent. The product was obtained as a light yellow oil. MS (ESI): 295 (M + + H). 20b. 1-azabicyclo [4.5.0] -decano-2-carboxylic acid ethyl ester: Oxasin (2.0 g, 6.8 mmol) in ethanol (100 mL) was placed in a Parr bottle with Raney nickel (Aldrich, W-2, 2 g) . The reaction mixture was placed under an atmosphere of hydrogen (2,109 kg / cm 2) and stirred until the hydrogen uptake had ceased. The reaction mixture was then stirred with celite and concentrated in a light oil. No other purification was carried out. MS (ESI): 212 (M + + H). 20c. IN- (4-methoxyphenylsulfonyl) -1-azabicyclo [4.5.0] -decano-2-carboxylic acid ethyl ester: The amine (1.4 g, 6.6 mmol) in dioxane (40 mL) and water (40 mL) was stirred at room temperature Then, triethylamine (2.0 g, 19.8 mmol, 3 equiv) was added followed by 4-methoxybenzenesulfonyl chloride (1.51 g, 7.2 mmol, 1.1 equiv.) The resulting solution was stirred at room temperature for 18 hours. The reaction was acidified with IN HCl and then the mixture was poured into water, the solution was extracted with methylene chloride and the combined organic extracts were dried (MgSO 4) and concentrated in an oil under reduced pressure. achieved by chromatography on silica gel using 8/2 hexane / EtOAc as eluent.The product was obtained as a clear oil which solidified on standing 20d.IN- (4-Methoxyphenylsulfonyl) -1-azabicyclo- [4.5. 0] -decan-2-carboxylic acid: The ethyl ester (1.5 g3.93 mmole) in THF (10 mL) and methanol (20 mL) were stirred at room temperature and then the lithium hydroxide (2.0 g) in water (20 mL) was added. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was acidified with IN HCl and then the mixture was poured into water. The solution was extracted with methylene chloride and the combined organic extracts were dried (a2S?) And then concentrated in an oil under reduced pressure. The oil solidified to a white solid during rest. 20e. N-Hydroxy-ÍN- (4-methoxyphenylsulfonyl) -1-azabicyclo- "[4.5.0] -decan-2-carboxamide: The carboxylic acid (1.7 g, 1.98 mmol) in dichloromethane (10 mL) was stirred at room temperature and then the oxalyl chloride (0.52 g, 4.06 mmol, 2.05 equiv) and DMF (0.14 g, 1.98 mmol) were added The resulting solution was stirred at room temperature for 30 minutes In a separate flask, the hydroxylamine hydrochloride ( 0.55 g, 7.92 mmol, 4 equiv) in THF (10 mL) and water (2 mL) were stirred at 0 ° C. Triethylamine (1.2 g, 11.9 mmol, 6 equiv) was added and the resulting solution was stirred at 0 ° C. Then the acid chloride solution was added to the hydroxylamine solution at 0 ° C and the resulting mixture was allowed to stir overnight at room temperature.The reaction mixture was acidified with 1 N HCl and After the solution was extracted with dichloromethane, the organic extracts were dried (Na2SO4) and concentrated in a solid under pressure. The solid was recrystallized from CH3CN / H2O to provide the desired product as a white powder. ES (IEA): 369 (M + + H), 386 (M + + NH4).

EXAMPLE 21 n B J XJ dapiro de J 21fl Boc 21h Boc 211 ßoc 20 ^ 21a. L-t-Butyldicarbonate-4-piperidinecarboxylic acid: Isonipecotic acid (15.0 g, 95.1 mmol) was dissolved in p-dioxane (75 mL), followed by the addition of NaOH (4.0 g, 100 mmol) in water (75 mL). To the stirring solution was added di-t-butyldicarbonate (20.8 g, 95.1 mmol), and the reaction mixture was stirred overnight. The reaction was quenched and acidified with IN HCl to pH = 1-2. The resulting mixture was then diluted with water, and extracted with methylene chloride. The organic layers were dried with sodium sulfate, and concentrated under reduced pressure to give the desired product as a colorless oil. MS (ESI): 230 (M + + H), 247 (M + + NH4). 21b. 1-t-butyldicarbonate-4- (hydroxymethyl) piperidine: Protected carboxylic acid 21a (21.7 g, 95.1 mmol) was dissolved in THF (300 mL) and cooled to 0 ° C in an ice bath. A 1.0 M solution of BH3 THF (237.75 mL, 237.25 mmol) was added to the stirring reaction mixture. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 ° C and water was added - very slowly to quench the reaction until bubbling ceased. Once the reaction was complete, it was acidified with 1N HCl and extracted with ethyl acetate. The organic layers were dried with sodium sulfate and concentrated under reduced pressure to provide the desired product. MS (ESI): 216 (M + + H). 21c. l-t-butyldicarbonate-4-piperidinecarboxylate: The alcohol 21b (20.2 g, 93.9 mmol) was dissolved in methylene chloride (300 mL). To this stirring solution was added pyridinium chlorochromate (20.2 g, 93.9 mmol, 1.0 equiv). The reaction mixture became a dark suspension which was stirred at room temperature for 4 hours. The solution was then decanted from the black residue and the residue was rinsed with ether several times. The combined organic layers were filtered through a plug of silica gel and an extra ether was used as eluent. The resulting solution was concentrated under reduced pressure and purified by chromatography on a silica gel column using hexane: ethyl acetate (1.5: 1). 21d. l-t-butyldicarbonate-4- (pyrrolidonetylene) piperidine: The aldehyde 21c (8.3 g, 39.1 mmol) was dissolved in 150 mL of benzene, followed by the addition of pyrrolidine (4.2 g, 58.6 mmol). The reaction flask was equipped with a Dean-Strak trap and a reflux condenser and refluxed for 5 hours. The solvent was then removed under reduced pressure. No other purification was necessary. MS (ESI): 267 (M + + H). 2le. 6 • - (pyrrolidinyl) spiro [4-t-butyldicarbonate-piperidine-2, 5 '(6'H) - [4H-1, 21-oxazine] -3'-carboxylate: Enamine 21d (8.9g, 33.17 mmoles ) was dissolved in THF (80 mL) and stirred at room temperature. Ethyl 3-bromo-2-hydroxyiminopropanoate (7.42 g, 35.16 mmol, 1.06 equiv, ref: Ottenheijm, HCJ; Piet, R .; Noordlik, JH; Herscheid, JDMJ Org. Chem. 1982, 47, 2147) was added. in portions for 15 minutes. The solution was heated during this procedure. The resulting solution was stirred at room temperature for 30 minutes, and then triethylamine was added. (3.59 g, 35.5 immoles, 1.07 equiv). The reaction mixture was stirred for an additional 2 hours. The reaction was quenched with the addition of water (100 mL) and then extracted with ethyl acetate. The organic layers were dried with sodium sulfate and concentrated under reduced pressure in an oil. Purification was achieved by silica gel chromatography using hexane: ethyl acetate (3: 1) as eluent to obtain a clear oil. MS (ESI): 396 (M + + H). 21f. 8N-t-butylcarbonate-l-8, diazobicyclo- [4.5.0] -decan-2-carboxylic acid ethyl ester: Oxasin 21e (2.033 g, 5.14 mmol) was dissolved in ethanol (100 mL) in a Parr bottle followed by the addition of Raney nickel (wet) (2.0 g, equiv. weight). The Parr bottle was then placed in the hydrogenator under a hydrogen atmosphere (2812 kg / cm2) for 5 hours, the hydrogen was refilled several times. The Raney nickel was then filtered with celite, and the resulting mixture was concentrated under reduced pressure. MS (ESI): 313 (M + + H). 21g. IN - [(4-methoxyphenyl) sulfonyl] -8N-t-butyldicarbonate-1,8-diazabicyclo [4.5.0] -decano-2-carboxylic acid ethyl ester: The ethyl ester 21f (1.7 g, 5.48 mmol) was dissolved in p-dioxane: water (1: 1, 100 mL) and then 4-methoxyphenylsulfonyl chloride (1.36 g, 6.6 mmol) and triethylamine (1.66 g, 16.44 mmol) were added. The reaction mixture was stirred overnight. The reaction was quenched and acidified with IN HCl, diluted with water and extracted with methylene chloride. The organic extracts were dried with sodium sulfate and concentrated or reduced pressure. Purification was achieved by chromatography on silica gel using hexane: ethyl acetate (3: 1). MS (ESI): .483 (M ++ H), 500 (M ++ NH4). 9pm INN- [(4-methoxyphenyl) sulfonyl] -8N-t-butyldicarbonate-1,8-diazobicyclo- [4.5.0] -decano-2-carboxylic acid: The ethyl ester 21 g (1.0 g, 2.07 mmol) was dissolved in methanol (10 mL) and THF (5 mL). Then a solution of lithium hydroxide (1.5 g, excess) in water (5 mL) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was then quenched and acidified with IN HCl. The reaction mixture was extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure to give the product. MS (ESI) 455 (M ++ H), 472 (M ++ NH4). 21i. N-Hydroxy-IN- [(4-M -toxhoxy) sulfonyl] -8N-t-butyldicarbonate-1,8-diazobicyclo- [4.5.0] -decano-2-carboxamide: The 21h carboxylic acid (0.92 g, 2.02 mmol) was dissolved in methylene chloride (20 mL) and then oxalyl chloride (0.525 g, 4.14 mmol) and DMF (0.148 g, 1.0 mmol) were added under a nitrogen atmosphere. In a separate flask, the hydroxylamine hydrochloride (0.56 g, 8.08 mmol) was dissolved in water (5 mL), followed by the addition of THF (15 mL). The reaction was cooled in an ice bath and triethylamine (1.22 mL, 12.12 mmol) was added. The acid mixture was then added to the hydroxylamine solution at 0 ° C. The reaction mixture was then warmed to room temperature and stirred for 1 hour. To neutralize the solution, IN HCl was added to reach a pH of 5.

The mixture was then extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography was carried out in reverse phase HPLC (Waters Symmetry Cig) using a solvent system of 50% A (95% water, 5% acetonitrile, 0.1% formic acid) and 50% B (20% water) , 80% water). MS (ESI) 470 (M ++ H), 487 (M ++ NH4) EXAMPLE 22 22a. IN- (4-n-botoxyphenylsulfonyl] - (4R) -hydroxy-pyrrolidin- (2R) -carboxylic acid methyl ester: cis-4-hydroxy-D-proline (14.8 g, 112.95 mmol) was mixed with water: dioxane (1: 1, 90 mL), triethylamine (39.3 mL, 282 mmol) and N-dimethylaminopyridine (1.3 g, 11.3 mmol). The 4- (n-butoxy) phenylsulfonyl chloride (29.5 g, 118.6 mmol) was added and the mixture was stirred for 14 hours at room temperature. The mixture was then concentrated and diluted with EtOAc and IN HCl. The layers were separated and the organic layer was washed twice with IN HCl, a decombrine, dried with MgSO 4, filtered and evaporated to give 37.4 g of solid material which was dissolved in MeOH (200 mL). Thionyl chloride (20 mL, 272 mmol) was added dropwise and the resulting mixture was stirred for 14 hours. The mixture was then evaporated to dry to give a white solid which is pure enough to continue without purification. EM ion spray m / z 375 (M + + NH4), 358.3 (M + + H). 22b. IN- (4-butoxyphenylsulfonyl) 4-oxo-pyrrolidin-2 (R) -methylcarboxylate: An 8N solution of Jones reagent (oxidations in organic chemistry, P273) was prepared. The alcohol 22a (40 g, 112 mmol) was dissolved in 300 mL of acetone and cooled to 0 ° C. The Jones reagent (120 mL, 960 mmol) was added (color change from orange-red to green) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was dulled with water and extracted three times with EtOAc. The organic layers were washed three times with water and once with sodium chloride, dried with magnesium sulfate and evaporated. The product was crystallized from EtOAc to give the desired product as a solid. EM ion spray m / z 378.3 (M + + Na), 356.3 (M + + H). 22c 8N- (4-butoxyphenylsufonyl) -1,5-dithia-8- / azaspiro [5, 4] decan-9 (R) -methylcarboxylate: The ketone 22b (1.5 g, 4.22 mmol) was dissolved in 30 mL of anhydrous dichloromethane and then 1,3-propanedithiol (0.84 mL, 8.45 mmol) and borane trifluoride etherate (0.42 mL, 3.98 mmol) were added. The mixture was stirred at room temperature overnight. The solution was made basic by the addition of IN sodium hydroxide and then the mixture was extracted three times with EtOAc. The organic layers were washed with water and ammonium chloride, dried with magnesium sulfate, filtered and evaporated to give the title compound as an oil. EM ion spray m / z 463 (M ++ H4), 446 (M + + H). 22d. ? -hydroxy-8? - (4-n-butoxyphenylsulfonyl) -1,5-dithia-8-azaspiro [5, 4] decan-9 (R) -carboxamide: A solution of 1.5M potassium hydroxylamine in methanol is prepared as described in Fieser and Fieser, Vol 1, p 478. The 1.5M solution (10 mL, 14.3 mmol) was added directly to the methyl ester 22c (0.8 g, 1.8 mmol) and the reaction mixture was stirred during the reaction. overnight, the solution was acidified with HCl 1, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated.The product was purified by reverse phase HPLC preparation (40A60B, A, 95% H2O, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% H2O, 19 x 300 mm water column SymmetryPrep of C ^ g) to give the title compound as a white foaming solid, EM ion spray m / z 464 (M ++? H4), 447 (M + + H).

EXAMPLE 23 23a. 8N- (4-Butoxyphenylsulfonyl) -1,5-dioxo-8-azaspiro [5,4] decan-9 (R) -carboxyl methyl: Ketone 22b (1.5 g, 4.22 mmol) was dissolved in 40 mL of benzene , and then 1,3-propandiol (0.32 g, 4.22 mmol) and the p-toluenesulfonic acid monohydrate (8 mg, 0.042 mmol) were added. The mixture was refluxed using the Dean and Stark apparatus overnight. The solution was made basic by the addition of aqueous NaHC 3 and then extracted three times with Et 2 ?. The organic layers were washed with water and ammonium chloride, dried with magnesium sulfate, filtered and evaporated. Purification of the product was achieved by chromatography on silica gel using hexane / EtOAc (4: 1) to achieve the desired product. EM ion spray m / z 431 (M + + NH-4), 414 (M + + H). 23b. N-Hydroxy-8N- (4-n-butoxyphenylsulfonyl) -1,5-dioxo-8-azaspiro [5, 4] decan-9 (R) -carboxamide: A 1.5M solution of postasy hydroxylamine in methanol was prepared as described in Fieser and Fieser, Vol 1, p 478. The 1.5M solution (15 mL, 22.5 mmol) was directly tapped to the methyl ester 23a (0.8 g, 1.9 mmol) and the reaction mixture was stirred during the reaction. night. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by reverse phase HPLC preparation (40A60B, A, 95% H2O, 5% acetonitrile, 0.1% formic acid, B, 80% acetonitrile, 20% H2O, 19 x 300 mm waters SymmetryPrep of column C 3) to give the title compound as a white foaming solid. EM ion spray m / z 432 (M + + NH4), 415 (M + + H).

EXAMPLE 24 24a. 8N- (4-Butoxyphenylsulfonyl) -1,5-dioxo-3,3-dimethyl-8-azaspiro [5, 4] decan-9 (R) -methylcarboxylate: The ketone 22b (1.5g, 4.22mmol) is dissolved in 40 mL of toluene, and then neopentyl glycol (0.44 g, 4.22 mmol) and p-toluenesulfonic acid monohydrate (8 mg, 0.042 mmol) were added. The mixture was refluxed using a Dean and Stark apparatus overnight. The solution was made basic by the addition of aqueous NaHC 3 and then extracted three times with Et 2. The organic layers were washed with ammonium chloride, dried with magnesium sulfate, filtered and evaporated. Purification of the product is achieved by chromatography on silica gel with hexane / EtOAc (7: 3) to achieve the desired product. EM ion spray m / z 459 (M ++ H4), 442 (M + + H). 24b. N-Hydroxy-8N- (4-n-butoxyphenylsulfonyl) -1,5-dioxo-3, 3-dimethyl-8-azaspiro [5,4] decan-9 (R) -carboxamide: A solution of 1.5M was prepared of post-salt hydroxylamine in methanol as described in Fieser and Fieser, Vol 1, p 478. The 1.5M solution (12 mL, 18.1 mmol) was added directly to the methyl ester 24a (1.0 g, 2.27 mmol) and the mixture of reaction was stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (CH2-Cl2 / E OAc, 1: 1) of silica gel to give the title compound as a white foaming solid. EM ion spray m / z 460 (M + + NH4), 443 (M + + H).

EXAMPLE 25 25a. 7N- (4-Butoxyphenylsulfonyl) -1,4-dioxo- (2R) -ethyl- (3R) -methyl-7-azaspiro [4, 4] nonan-8 (R) -methylcarboxylate: Ketone 22b (1.5 g, 4.2 mmol) was dissolved in 40 mL of benzene, and then (2R, 3R) - (-) -2, 3 -butanediol (0.46 g, 5.07 mmol) and the p-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol). The mixture was refluxed using a Dean and Stark apparatus overnight. The solution was made basic by the addition of aqueous NaHC 3 and then extracted three times with Et 2. The organic layers were washed with ammonium chloride, dried with magnesium sulfate, filtered and evaporated to achieve the desired product. EM ion spray m / z 445 (M ++ NH), 428 (M ++ H). 25b. N-Hydroxy-7N- (4-butoxyphenylsulfonyl) -1,4-dioxo- (2R) -methyl- (3R) -methyl-7-azaspiro [4,4] nonan-8 (R) -carboxamide: One was prepared 1.5M solution of postasium hydroxylamine in methanol as described in Fieser and Fieser, Vol 1, p 478. The 1.5M- solution (15 mL, 26 mmol) was added directly to the methyl ester 25a (1.4 g, 3.28 mmol) ) and the reaction mixture was stirred overnight. The solution was acidified with IN HCl, then the mixture was extracted three times with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography (CH2Cl2 / CH3OH, 95: 5) of silica gel to give the title compound as a white foaming solid. EM ion spray m / z 451 (M + + Na), 429 (M + + H).

EXAMPLE 26 26a. IN - [(4-Butoxyphenyl) sulfonyl] -1,5-dioxa-azaspiro [4, 5] onan-2R, 4R-dimethyl-2-carboxylic acid methyl ester: Ketone 22b (1.0 g, 2.82 mmol) was dissolved in benzene (60 mL), and then 2R, 4R- (+) - pentanediol (0.44 g, 4.22 mmol) and the sulfonic acid p-toluene (0.01 equiv) were added. The reaction was equipped with a Dean-Stark trap and a reflux condenser under a nitrogen atmosphere. The reaction was heated under reflux overnight. The reaction mixture was quenched and basified with saturated sodium bicarbonate. The resulting mixture was then extracted with ethyl acetate and water and the organic layers were dried with sodium sulfate and concentrated under reduced pressure. The purification that was carried out was achieved by silica gel chromatography using hexane / ethyl acetate (7: 3) as eluent. MS (ESI) 442 (M ++ H), 459 (M ++ NH4). 26b. INN [(4-butoxyphenyl) sulfonyl] -1,5-dioxa-azaspiro [4,5] nonan-2R, 4R-dimethyl-2-carboxylic acid: The 26a cell (0.7 g, 1.56 mmole) was dissolved in methanol (10 mL) and THF (5 mL) and then lithium hydroxide (1.0 g, excess) in water (5 mL) was added. The reaction mixture was stirred for 1 hour and then was quenched and acidified with IN HCl to achieve a pH 2. The reaction mixture was then extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure to give the product. MS (ESI) 428 (M ++ H), 445 (M ++ NH4). 26c. N-Hydroxy-IN- [(4-butoxyphenyl) sulfonyl] -1,5-dioxa-azaspiro [4, 5] nonan-2R, 4R-dimethyl-2-carboxamide: Carboxylic acid 26b (0.60 g, 1.4 mmol) was dissolved in methylene chloride (15 mL), followed by the addition of oxalyl chloride (0.36 g, 2.87 mmol) and DMF (0.102 g, 1.4 mmol) under a nitrogen atmosphere. In a separate flask, the hydroxylamine hydrochloride (0.39 g, 5.2 mmol) was dissolved in water (3 mL), followed by the addition of THF (10 priL). The amine solution was cooled in an ice bath and triethylamine (1.16 mL, 8.4 mmol) was added. The acid mixture was then added to the hydroxylamine solution at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. To neutralize the solution, IN HCl was added to achieve a pH = 5. The solution was then extracted with methylene chloride and water. The organic layers were dried with sodium sulfate and concentrated under reduced pressure. Purification was achieved by reverse phase chromatography (Waters Symmetry of Cig) using a solvent system of 40% A to (95% water, 5% acetonitrile, 0.1% formic acid) and 60% B (20% water, 80% water). MS (ESI) 443 (M ++ H).

The following table shows the structure of the other examples 27-116 described below: EXAMPLES 27-116 The following compounds (where W is null) are made using the methods described and exemplified above.

Methods Example 27 is prepared by forming acetate with the appropriately functionalized hydroxy proline derivative, described by Ra an Sharma and William D. Lubell in J. Org. Chem. 1996, 61, 202. Examples 28-99 are prepared by forming acid with the suitably functionalized hydroxy proline derivative which is prepared in a manner analogous to Example 1. The sulfonyl chlorides used to prepare the above examples are obtained from commercial sources or are prepared by known methods. For example, the 4-phenoxyphenylsulfonyl chloride used for the preparation of Example 17 is prepared as described by R. J. Cremlvn et al in Aust. J. Chem., 1979, 32, 445.52. Examples 100-102 are prepared by acid formation, reduction and / or nucleophilic substitution of suitably functionalized 4-ketopanic acid described by J.-P. Obrecht et al. In Organic Synthesis 1992, 200.

Examples 103-105 are prepared by forming acétalo, reduction and / or nucleophilic substitution of suitably functionalized 5- quetopipecolic acid described by M. E. Freed and A. R. Day in J. Org. Chem. 1960, 25., 2105 or the adequately functionalized 3-keto-percholic acid described by J. Bosch et al in Tetrahedron 1984, 40, 2505. Examples 106-113 are prepared by cyclization, reduction and / or nucleophilic substitution of enamine suitably functionalized as described by R. Henning and others in Synthesis, 1989. 265 and further manipulated as described in example 5. Example 114 (spirohydantoin) is prepared from the suitably substituted ketone (Ib) and cyanide of potassium and ammonium carbonate as described by Smith et al. - J. Med. Chem. 1995, 38, 3772. Example 115-116 is prepared from the suitably substituted ketone (Ib) by the Wittig reaction and the addition Subsequent Michael's Nitromethane as described by Smith et al. J. Med. Chem. 1995, 38, 3772. Subsequent reduction and nucleophilic substitution provide the desired compounds. Such examples provide a person skilled in the art with sufficient guidance to carry out the present invention and not .l.i.i.i.m. to this (- -e • n ni.nguna form.

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 examples of composition and method do not limit the invention, but provide guidance for the person skilled in the art to prepare and use the compounds, compositions and methods of the invention. In each case, the compounds of the formula I can be replaced by the compound of the example shown below with similar results. The exemplified methods of use do not limit the invention, but provide guidance for those skilled in the art to use the compounds, compositions and methods of the invention. The person skilled in the art will appreciate that the examples' provide guidance and can be varied based on the condition and the patient.

EXAMPLE A A tablet composition for oral administration, according to the present invention, is made comprising: Component Quantity Example: 9 15. mg Lactose 120. mg Corn starch 70. mg Talc 4. mg Magnesium stearate 1. mg Other compounds having a structure according to formula (I) are used with substantially similar results. A female human subject weighing 60 kg who suffers from rheumatoid arthritis is treated by a method of the present invention. Specifically, for 2 years, a regimen of three tablets per day is administered orally said subject. At the end of the treatment period, the patient is examined and discovered to have reduced inflammation, and improved mobility without concommitant pain.

EXAMPLE B A capsule for oral administration, according to the present invention, is made comprising: Component Quantity (% W / W) Example 3 15% Polyethylene glycol 85% Other compounds having a structure according to formula (I) are used with substantially similar results. A male human subject weighing 90 kg who suffers from osteoarthritis is treated by a method of the present invention. Specifically, for 5 years, a capsule containing 70 mg of Example 3 is administered daily to said subject. At the end of the treatment period, the patient is examined by orthoscopy, and it is discovered that he no longer has any erosion / fibrillation advance of the articulated cartilage.

EXAMPLE C A salt-based composition for local administration according to the present invention is made comprising: Component Quantity (% p / p) 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. The healing accelerates, without visual sequels.

EXAMPLE D A topical composition for local administration according to the present invention is made comprising: Component Composition (% w / w) Compound of example 3 0.20 Benzalonium chloride 0.02 Thimerosal 0.002 d-Sorbitol 5.0 -. Glycine 0.35 Aromatics 0.075 Purified water g.s. Total »100.00 Total = 100.00 Any of the other compounds having a structure according to formula (I) is used with substantially similar results. A patient suffering from burn by chemical compounds applies the composition at each bandage change twice a day. The healing is reduced substantially.

EXAMPLE E An inhalation aerosol composition, according to the present invention, is made comprising: Component Composition (% w / w) Compound of example 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Saccharin sodium 0.2 Propellant (F12.F114) g.s. Total * 100.0 Any of the other compounds having a structure according to formula (I) is used with substantially similar results. A patient suffering from asthma sprayed 0.01 ml by a pump activator in the mouth when inhaling. The symptoms of asthma are reduced.

EXAMPLE F A topical ophthalmic composition, according to the present invention, is made comprising: Component Composition (% w / w) Compound of Example 5 0.10 Benzalkonium Chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL M) 0.50 Sodium Metabisulfite 0.10 Sodium Chloride (0.9%) g.s. Total »100.0"Any of the other compounds having a structure according to formula (I) is used with substantially similar results: A male human subject weighing 90 kg (198 lbs), suffering from corneal ulcerations, is treated by a METHOD OF THE PRESENT INVENTION Specifically, for two months, a saline solution containing 10 mg of Example 5 is administered twice daily to said affected subject. ú EXAMPLE G A composition for parenteral administration is made comprising: Component Quantity Example 4 100 mg / ml vehicle Vehicle pH regulator sodium citrate with (weight percent vehicle) Lecithin 0.48% Carboxymethylcellulose 0.53 Polidone 0.50 Methylparaben 0.11 Propylparaben 0.011 The above ingredients are mixed, forming a suspension. Approximately 2.0 ml of the suspension is administered, by injection, to a human subject with a pre-metastatic tumor. The injection site juxtaposes 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 Component% P / v Example 1 3.00 Alcohol SDA 40 8.00 Flavor 0.08 Emulsifier 0.08 Sodium fluoride 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide 0.20 Dye 0.04 Water balance 100% A patient with gum disease uses 1 ml of mouthwash three times a day to prevent another oral degeneration. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE 1 A troche composition is prepared; Component% p / v Example 3 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor 11.70 Color 0.10 Corn syrup rest 100% "A patient uses the trochus to prevent , loss of an implant in the maxilla. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE J Chewing gum composition Component w / v% Example i- 1 0.03 Sorbitol crystals 38.44 Paloja-T rubber base 20.00 Sorbitol aqueous solution 22.00 Mannitol 10.00 Glycerin 7.56 Taste 1.00 A patient chews the softening prevention rubber to prevent softening of the dentures. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE K Components w / v% Water USP 56,656 Methylparaben 0.05 Propiparaben 0.01 Xanthan gum 0.12 Guar gum 0.09 Calcium carbonate 12.38 An. Foam 1.27 Sucrose 15.0 Sorbitol ll.o Glycerin 5.0 Benzyl alcohol 0.2 Citric acid 0.15 Cooler 0.00888 Flavor 0.06445 Colorant 0.0014 Example 1 is prepared by first mixing 80 kg of glycerin and all of the benzyl alcohol and heating to 65 ° C, then slowly adding and mixing with methyl paraben, propyl paraben, water, xanthan gum, and guar gum. These ingredients are mixed for approximately 12 minutes with a Silverson in-line mixer. They are then added slowly in the following ingredients in the following order: remaining glycerin, sorbitol, antifoam C, calcium carbonate, citric acid, and sucrose. Separate the flavors and chillers separately and then add slowly 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 by reference. Although the particular embodiments of the present invention have been described, it will be apparent to those skilled in the art that various changes and modifications of the invention objects can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all modifications that are within the scope of the present invention.

Claims (31)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has a structure according to the formula (I) (i) wherein Ar is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted; R is H; R2 is hydrogen, alkyl or acyl; is zero or one or more lower alkyl portions, or is an alkylene, arylene or heteroarylene bridge between two adjacent or non-adjacent carbons (thereby forming a fused ring); And it is independently one or more portions of hydrogen, hydroxy, SR3, SOR4, SO2, alkoxy, amino, wherein amino is of the formula NRg, R7, wherein Rg and R7 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl , aryl, OR3, SO2R8, COR9, CSR Q PO (R?) 2; and R3 is hydrogen; alkyl, aryl, heteroaryl; R 4 is alkyl, aryl, heteroaryl; Rg is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, dialkylamino and alkylarylamino; R9 is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; RIQ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R ^ is alkyl, aryl, heteroaryl, heteroalkyl; z is a spiro portion; n is 1-3; an optical isomer, diastereomer or enantiomer for formula (I), or a pharmaceutically acceptable salt, or amide, ester or biohydrolyzable or imide thereof.

2. The compound according to claim 1, further characterized in that Y is independently one or more portions of hydrogen, hydroxy, SR3, alkoxy, amino, wherein amino is of the formula NRg, R7, wherein Rg and R7 are independently selected from hydrogen, alkyl, heteroalkyl, SO2 8, COR9; and Rg is alkyl, aryl, heteroaryl, or heteroalkyl.

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

4. The compound in accordance with the claim 3, further characterized in that Ar is substituted phenyl and the substitution is with hydroxy, alkoxy, nitro or halogen.

5. - The compound in accordance with the claim 4, further characterized in that Ar is substituted with methoxy, bromine, nitro and butoxy.

6. - The compound according to claim 5, further characterized in that Ar is substituted in the ortho or para position relative to the sulfonyl.

7. The compound according to claim 1, further characterized in that W is one or more hydrogen or alkyl portions of Cl to C4.

8. The compound according to claim 1, further characterized in that W is C1 to C4 alkyl geminal.

9. The compound according to claim 1, further characterized in that the spiro portion, Z, forms a ring of 5 to 7 members with the carbon to which it is attached.

10. The compound in accordance with the claim 9, further characterized in that the spiro ring is unsubstituted or substituted with a fused ring.

11. The compound in accordance with the claim 10, further characterized in that Z has one or more heteroatoms selected from oxygen or sulfur.

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

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

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

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

16. A pharmaceutical composition comprising: (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 undesired metalloprotease activity in a mammalian subject.

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 mammalian subject.

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

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

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, further characterized in that the disorder is selected from the group comprising arthritis, cancer , cardiovascular disorders, skin disorders, eye disorders such as inflammation and gum disease.

22. The use according to claim 21, further characterized in that the disorder is arthritis, and is selected from the group comprising, osteoarthritis and rheumatoid arthritis.

23. Use according to claim 21, further characterized in that the disorder is cancer, and the treatment prevents or stops tumor growth and metastasis.

24. The use according to claim 21, further characterized in that the disorder is a caridovascular disorder selected from the group comprising dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque fructura, reperfusion injury, ischemia, chronic obstructive pulmonary disease restenosis by angioplasty and aortic aneurysm.

25. The use according to claim 21, further characterized in that the disorder is an ocular disorder, and is selected from the group comprising corneal ulceration, lack of corneal healing, macular degeneration and pterygium.

26. The use according to claim 21, further characterized in that the disorder is gum disease, and is selected from the group comprising periodontal disease and gingivitis.

27. The use according to claim 21, further characterized in that the condition is the condition of the skin selected from the group comprising repair and prevention of wrinkles, UV damage to the skin, epidermolysis bullosa, psoriasis, sclerodema, dermatitis and atopic scarring.

28. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a * medication to prevent the loss of prosthetic devices . selected from the group that includes replacement of dental joints and prostheses.

29. The use according to claim 21, further characterized in that the disease is selected from the group comprising inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, acne inflammation, osteomyelitis, bronchitis, arthritis. 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 disease or cachexia in a mammal. < • '