MXPA99002065A - Bidentate metalloprotease inhibitors - Google Patents

Abstract

The invention provides compounds which are useful as inhibitors of metalloproteases, and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to a compound having a structure according to Formula (I) as described in the claims, or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, or biohydrolyzable alkoxyamide, ester, acyloxyamide, or imide thereof. Also disclosed are compounds, pharmaceutical compositions and methods of treating diseases characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

Description

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

BACKGROUND OF THE INVENTION A number of structurally related metalloproteases [MPs] carry out the degradation of structural proteins. These metalloproteases commonly act on the intercellular matrix, and are thus involved in the degradation and remodeling of tissues. These proteins are called metalloproteases or MPs. There are several different families of MPs, classified by sequence homology. In the art several families of known MPs are described, as well as examples thereof. These MPs include matrix metalloproteases [MMPs], zinc metalloproteases, many of the membrane-bound metalloproteases, TNF conversion enzymes, angiotensin converting enzymes (ACEs), disintegrins, including ADAMs (See Wolfsberg et al., 131 J Cell Bio 275-78, October 1995), and enkephalinases. Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecanase and gelatinase and human stromelysin. It is believed that collagenase, stromelysin, aggrecanase and related enzymes are important in mediating the symptomatology of a number of diseases. Potential therapeutic indications of MP inhibitors have been mentioned in the literature. See, for example, US patent. 5,506,242 (Ciba Geigy Corp); patent of E.U.A. 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 (SmithKline Beecham); WO 95/22966 (Sanofi Winthrop); WO 95/19965 (Glycomed), - WO 95 19956 (British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd); WO 95/13289 (Chiroscience Ltd); WO 95/12603 (Syntex); WO 95/09633 (Florida State Univ); WO 95/09620 (Florida State Univ); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 (Celltech); WO 93/14112 (Merck); WO 94/0019 (Glaxo); WO 93/21942 (British Bio Tech Ltd); WO 92/22523 (Res. Corp. Tech. 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); Japanese applications published JP 08053403 (Fujusowa Pharm. Co. Ltd.); JP 7304770 (Kanebo Ltd); and Bird and others J. Med Chem vol, 37, pp. 158-69 (1994). Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritis (Mullins, D.E. et al., Biochim, Biophys. Acta. (1983) 695: 117-214); Osteoarthritis (Henderson, B. and others, Drugs of the Future (1990) 15: 495-508); metastasis of tumor cells (ibid, Broadhurst, MJ et al., European patent application 276,436 (published in 1987), Reich, R. et al., 48 Cancer Res. 3307-3312 (1988), and various ulcerations or ulcerative conditions of For example, ulcerative conditions may originate in the cornea as a result of alkali burns or as a result of infection by Pseudomonas aeruginosa, Acanthamoeba, Herpes simplex and vaccinia virus Other examples of conditions characterized by unwanted metalloprotease activity 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 to prepare inhibitors for these enzymes A number of such inhibitors are described in the literature Examples include U.S. Patent No. 5,18 3,900, issued on February 2, 1993 to Galardy; patent of E.U.A. No. 4,996,358, issued February 26, 1991 to Handa et al .; patent of E.U.A. No. 4,771,038, issued September 13, 1988 to Wolanin et al .; patent of E.U.A. No. 4,743,587, issued May 10, 1988 to Dickens et al .; European Patent Publication No. 575,844, published December 29, 1993 by Broadhurst et al .; International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura et al .; World Patent Publication No. 92/17460, published October 15, 1992 by Markwell et al., and European Patent Publication No. 498,665, published August 12, 1992 by Beckett et al. Metalloprotease inhibitors are useful in the treatment of diseases caused, at least in part, by the degradation of structural proteins. Although a variety of inhibitors have been prepared, there is a continuing need for potent and useful metalloprotease inhibitors to treat such diseases. Applicants have found that the compounds of the present invention are potent metalloprotease inhibitors.

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

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) where n is an integer of 3, and 0 to 2 additional heteroatoms, selected from O, N or S, can occur in the base structure of the ring instead of carbon, and where S occurs it can be S-shaped, SO or SO2, and where N occurs is in the form of NR5 and R is selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R10 COR ^, CSR] _2, PO (Ri3) 2; Z is independently one or more of (CH2) m (CR? R2) 0SR3; and R] _ is independently hydrogen, alkyl, CH2SR3 or CH2C () R4, and R4 is alkoxy, hydroxy, NR5, alkylthio or thio; and R5 is independently one or more of heterocyclylalkyl, alkyl, aryl, heteroalkyl, heteroaryl, hydrogen, or with W can form a heterocyclic ring; R 2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylene, aryl or heteroaryl, W is O or S, R 3 is hydrogen, alkyl, aryl, heteroaryl; and m and o are integers, independently selected from 0, 1 and 2; And it is independently one or more of hydrogen, hydroxy, oxo, a spiro portion, SOR, SO2R10 alkoxy, aryloxy, alkylaryl, heteroaryl, COR ^, CSR] _2, amino, wherein amino is of formula NR3R9, wherein Rβ and R9 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, OR3, S? 2Ri0 / COR11; CSR12, PO (R13) 2; and g is alkyl, aryl, heteroaryl; R o is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R] - is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R 12 is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R 13 is alkyl, aryl, heteroaryl, heteroalkyl; Ar is alkyl, aryl, carbocyclyl, heterocyclyl, or substituted or unsubstituted heteroaryl; This structure also includes an optical isomer, diastereomer or enantiomer for the formula (I), or a pharmaceutically acceptable salt or alkoxyamide, ester, acyloxyamide or imide thereof biohydrolyzable. 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. Active metalloproteases 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 marker at that site, such as an antibody or fragment of the same 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 metalloprotease 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 OF THE INVENTION 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 biohydrolyzable alkoxyamide, acyloxyamide or imide thereof.

Definitions and use of the terms The following is a list of definitions for the terms used herein.

"Acyl" or "carbonyl" is described as a radical that could be formed by removing the hydroxyl from a carboxylic acid (ie R-C (= 0) -). Preferred acyl groups include (for example) acetyl, formyl and propionyl. "Acyloxy" is an oxy radical having an acyl substituent (i.e., -O-acyl); for example, -0- (= 0) -alkyl. "Alcoxyacil" is an acyl radical (-C (= 0) -) having an alkoxy substituent (ie, -0-R), for example, -C (= 0) -0-alkyl. This radical can be considered as an ester. "Acylamino" is an amino radical having an acyl substituent (i.e., -N-acyl); for example -NH-C (= 0) -alkyl. "Alkenyl" is a substituted or unsubstituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; very preferably from 2 to 8; except when indicated. Alkenyl substituents have at least one olefinic double bond (including, for example, vinyl, allyl and butenyl). "Alkynyl" is an unsubstituted or substituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; most preferably from 2 to 8, - except where indicated. The chain has at least one triple carbon-carbon bond. "Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, wherein the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy. "Alkoxyalkyl" is a substituted or unsubstituted alkyl portion, replaced with an alkoxy moiety (ie, -alkyl-O-alkyl). It is preferred when the alkyl has 1 to 6 carbon atoms (most preferably 1 to 3 carbon atoms) and the alkyloxy has 1 to 6 carbon atoms (most preferably 1 to 3 carbon atoms). "Alkyl" is a saturated or unsubstituted or substituted hydrocarbon chain radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms; very preferably 1 to 4; except when indicated. Preferred alkyl groups include (for example) substituted or unsubstituted methyl, ethyl, propyl, isopropyl and butyl. As referred to herein, "spirocycle" or "spirocyclic" refers to a cyclic portion that shares a carbon in another ring. Said cyclic portion may be carbocyclic or heterocyclic in nature. Preferred heteroatoms included in the base structure of the heterocyclic spirocycle include oxygen, nitrogen and sulfur. Spirocycles can be substituted or not replaced. Preferred substituents include oxo, hydroxyl, alkyl, cycloalkyl, arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (for example, benzothiol, cycloalkyl, heterocycloalkyl, benzimidizoles, pyridyl thiol, etc., which may also be substituted) and Similar. In addition, the heteroatom of the heterocycle can be substituted if its valence allows it. Preferred spirocyclic ring sizes include rings of 3 to 7 members. The term "alkylene" refers to an alkyl, alkenyl or alkynyl that is a diradical, rather than a radical. "Heteroalkylene" is defined in the same way herein as a (diradical) alkylene having one heteroatom 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 (- (CH 3) 2) and methylethylamino (-N (CH 3) CH 2 CH 3). "Aminoacyl" is a radical acyl that has an amino substituent (ie., -C (= 0) -N); for example -C (= 0) -NH2. The amino group of the aminoacyl moiety can be unsubstituted (i.e., primary amine) or can be substituted with one (secondary amine) or two (ie, tertiary amine) alkyl groups. "Aryl" • is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl ,. Naphthyl, biphenyl and fluorenyl. Said groups can be substituted or not substituted. "Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl, phenylethyl and phenylpropyl. Said groups can be substituted or not substituted. "Arylalkylamino" is an amine radical substituted with an arylalkyl group (e.g., -NH-benzyl). Said groups can be substituted or not substituted. "Arylamino" is an amine radical substituted with an aryl group (i.e., -NH-aryl). Said groups can be substituted or not substituted. "Aryloxy" is an oxygen radical having an aryl substituent (i.e., -O-aryl). Said groups can be substituted or not substituted. "Carbocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring radical. The carbocyclic rings are monocyclic or are ring systems fused, bridged spiropolyclic. The monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. The polycyclic carbocyclic rings contain 7 to 17 atoms, preferably 7 to 12 atoms. Preferred polycyclic systems comprise rings of 4, 5, 6 or 7 members fused to rings of 5, 6 or 7 members. "Carbocyclo-alkyl" is a. substituted or unsubstituted alkyl radical replaced with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl, most preferably an aryl. Preferred carbocycloalkyl groups include benzyl, phenylethyl and phenylpropyl. "Carbocycloheteroalkyl" is an unsubstituted or substituted heteroarkyl radical replaced with a carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is preferably an aryl or cycloalkyl; most preferably an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl or 2-thia-ethyl. "Carboxyalkyl" is an unsubstituted or substituted alkyl radical replaced with a carboxy moiety (-C (= 0) 0H). For example, -CH2-C (= 0) OH. "Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) morpholinyl, piperadinyl, piperazinyl, tetrahydrofuryl and hydantoinyl. "Fused rings" are rings that are superimposed on each other in such a way that they share two ring atoms. A certain ring can be fused to more than another ring. The fused rings are contemplated in heteroaryl, aryl and heterocycle radicals, or the like.

"Heterocycle-alkyl" is an alkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably a heteroaryl or cycloheteroaryl; most preferably a heteroaryl. Preferred heterocycloalkyl includes C 1 -C 4 alkyl having a preferred heteroaryl attached thereto. More preferred is, for example, pyridyl-alkyl and the like. "Hetero-cycloheteroalkyl" is an unsubstituted or substituted heteroalkyl radical, replaced with a heterocyclic ring. The heterocyclic ring is preferably an aryl or cycloheteroalkyl; most preferably an aryl. "Heterogeneous atom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms. "Heteroalkenyl" is an unsubstituted, unsubstituted or substituted chain radical having 3 to 8 members comprising carbon atoms and one or two heteroatoms. 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 heteroatoms. "Heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprising carbon atoms and one or more heteroatoms in the ring. The heterocyclic rings are monocyclic ring systems or are fused, bridged or spiro-polyclic. The monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7 atoms. The polycyclic rings contain 7 to 17 atoms, preferably 7 to 13 atoms. "Heteroaryl" is an aromatic heterocyclic radical, whether monocyclic or bicyclic radical. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl, benzothiazolyl, benzofuryl, indolyl, and the like. Said groups can be substituted or not substituted. "Halo", "halogen" or "halide" is a radical of chlorine, bromine, fluorine or iodine atom. The halides that are preferred are bromine, chlorine and fluorine. Likewise, as will be mentioned herein, a "lower" hydrocarbon portion (eg, "lower" alkyl) is a hydrocarbon chain comprising 1 to 6, preferably 1 to 4, carbon atoms. Likewise, as referred to herein, a "lower" hydrocarbon portion (eg, "lower" alkyl) is a hydrocarbon chain comprising from 1 to 6, preferably from 1 to 4, carbon atoms. As used herein, the term "parent ring system" or "parent ring" refers to the ring system that forms the core of the structure described in the brief description of the invention; This ring system is from about 5 to about 7 members, and may contain from 0 to 2 additional heteroatoms selected from 0, S or N, providing rings such as morpholine, diazepine, piperidine, thiamorpholine, and the like. The position of the heteroatom is limited by those rings that are known in the art. A "pharmaceutically acceptable salt" is a cationic salt formed in any acid group (eg, carboxyl) or an anionic salt formed in any basic group (eg, amino). Many of these salts are known in the art, as described in world patent publication 87/05297, Johnston et al., Published September 11, 1987 (incorporated herein by reference). Preferred cationic salts include the alkali metal salts (such as sodium and potassium) and the alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides (such as chloride salts). "Biohydrolyzable alkoxyamide" and "biohydrolyzable acyloxyamide" are amides of a hydroxamic acid that do not interfere essentially with the inhibitory activity of the compound, or which are readily converted in vivo by a human or lower animal subject to producing an active hydroxamic acid. A "biohydrolyzable hydroxyimide" is an imide of a compound of formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by a human or lower animal subject to producing an active compound of the formula (I). Said hydroxyimides include those which do not interfere with the biological activity of the compounds of the formula (I). A "biohydrolyzable ester" refers to an ester of a compound of the formula (I) that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to produce a compound of the formula (I) active . A "solvate" is a complex formed by the combination of a solute (e.g., a hydroxamic acid) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist 's Dictionary, p. 650 (1953). The pharmaceutically acceptable solvents used in accordance with this invention include those which do not interfere with the biological activity of the hydroxamic acid (eg, water, ethanol, acetic acid, N, N-dimethylformamide and others known or readily determined by the person skilled in the art. ). "Optical isomer", "stereoisomer" and "diastereomer", as mentioned in the present, have the normal meanings recognized in the art (Cf., Hawleys Condensed Chemical Dictionary, Uva Ed.). We do not want the illustration of specific protected forms and other derivatives of compounds of the formula (I) is limiting. The application of other useful protective groups, salt forms, etc., is within the ability of the person skilled in the art. As mentioned above and as used herein, the substituent groups may in turn be substituted. Said substitution may be with one or more substituents. Said substituents include those listed in C. Hansch and A. Leo, Sustituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated herein by reference. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxyl, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyaceil (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholino, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. As used herein, the term "mammalian metalloprotease" means any enzyme that contains a metal found in mammalian sources, and that is capable of catalyzing the degradation of collagen, gelatin or proteoglycan under suitable testing conditions. Suitable test conditions can be found, for example, in the patent of E.U.A. No. 4,743,587, which refers to the procedure of Cawston et al., Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate is described by Weingarten, H. et al., Biochem Biophy Res Comm (1984) 139: 1184-1187. Of course, any normal method can be used to analyze the degradation of these structural proteins. The metalloprotease enzymes mentioned herein are all proteases containing zinc and which are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit metalloprotease activity can, of course, be tested in the assays described above. The isolated metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or raw extracts containing the scale of enzymes capable of tissue degradation can be used. Compounds: The compounds of the invention include: s. as described in the brief description of the invention, described above. A class of preferred compounds are of the formula: as described above. Of this class, the preferred Z includes compounds of the formula: Preferably, R3 is hydrogen, and n is 1 or 2. Where R4 appears, it is preferably alkoxy. Another preferred class of compounds include those of the formula: of where Z is SR3. Most preferred compounds have two Z portions at the preferred positions, as shown above.

Preparation of compounds: The compounds of the formula (I) can be prepared using various methods. For ease of illustration, Y is not shown. A preferred method for obtaining the compounds of formula (I) is illustrated by the following scheme: SCHEME I or ual IB) s or an e Ph = phenyl In fact, one of the examples of a Z-portion is exemplified herein, but others can be obtained using known methodologies. It is preferred that the thiol portion is then introduced into the synthesis for reasons that are apparent to the person skilled in the art. In the above scheme, preferably a piperidine, azepine, diazepine, proline or a similar compound (A) is converted to the sulfonamide by standard methods to produce (B), which can be optionally converted to an aldehyde (C) and transformed to the unsaturated O-β carbonyl compound (D). This unsaturated compound is thiolated using standard methods to produce compounds of formula I (E). In fact, Y may be present in (A), masked in (A), or introduced at an appropriate time during the synthesis. The order of synthesis, the reagents used and the methodologies used can be varied, or can be removed from the previous scheme. For example, Y can be introduced by a derivable group which can be manipulated or replaced. Such compounds are known or are prepared by known methods. For example, when R is OH and n is 1, the hydroxyproline (A) is converted to its analogous sulfonamide, and the hydroxyl is then manipulated to give (B), and during this step or a subsequent step, Y can be added or altered . It is to be expected that the expert in the art uses protective groups or any other portion that he prefers, provided that the method ultimately provides the compounds of the invention. Several compounds can be generated in a similar way, using the guide of the previous scheme. It is recognized that it is preferable to use a protecting group for any reactive functionality, such as a carboxyl, hydroxyl and its like, during the formation of the sulfonamide. This is a standard practice and is well within the normal practice of the person skilled in the art. For example, in the above schemes, alkoxy or alkylthio, produce the corresponding hydroxy or thiol compounds by the use of a standard dealkylation process (Bhatt et al., "Cleavage of Ethers", Synthesis, 1983, p.249-281).

Preparation of the Y portion For the manipulation of Y, it is understood that the expert in the. The technique may choose to prepare Y before, after or concurrent with the preparation of Z. It will be understood that more than one Y and Z may be present in the compounds of formula (I). A preferred method for introducing Y includes choosing a starting material with a derivable group that can be manipulated or substituted in Y. Said compounds are known or are prepared by known methods. Preferred derivable groups include hydroxy, alkoxy, oxo, amino, thiol and many others immediately recognizable by the person skilled in the art.

The person skilled in the art will appreciate that the judicious choice of reactions and starting materials is essential to prepare any molecule, including those of the invention. For example, when Y is adjacent to the ring nitrogen, a preferred starting material for the preparation of Y includes a lactam, wherein the derivable group is oxo, adjacent to the nitrogen. Where Y is a ketal or thioketal (including spirocetals), the compounds of the invention can be prepared from the analogous oxo compound using standard protective group methodologies. In fact, the hydroxy, amino, imino, alkoxy, oxo groups and many other groups can be manipulated in a carbonyl compound. A preferred method for obtaining the spiro compounds of the invention is by a carbonyl group, using the "protecting group" technology known in the art, such as a thioketal or ketal, and the like thereof. Ketals, acetals and the like are prepared from carbonyl compounds by methods known in the art. Said carbonyl compounds may be formed from cyclic hydroxyalkyleneamines by oxidation to a ketone, or from lactams, which provides the 2-aminospiro functionality. The order of elaboration of ketal, Z or sulfonamide, can be rearranged to optimize performance and avoid inconvenient reactions. A preferred method for obtaining compounds of the invention with Y as a carbocycle or a heterocycle that does not use ketal formation is shown below. In the following scheme, Y is represented as a carbocyclic spirocycle, but one or more heteroatoms may be intermixed in the base structure of the spirocyclic ring. The omission of heteroatoms is for the purpose of improving clarity and helping the reader. It is not intended to limit the claims: SCHEME II Basfi Reduction R is any group that can give rise to Y or Z. L is a residual group. COB is a group that can be manipulated in Z. In fact, it is possible to make Y, Z, the sulfonamide and any other group, as illustrated above, or as will be apparent to the person skilled in the art.

Preparation of heterocyclic parent ring systems For the preparation and processing of the parent ring system as the heterocyclic ring, it is understood that one skilled in the art can choose to prepare Y before, after, or concurrent with the preparation of the heterocyclic ring. In fact, more than one Y and Z may be present in the compounds of formula (I). For purposes of illustration, these parent ring systems include: wherein X is independently selected from NR5, S, SO, SO2 or O. Also contemplated in this invention are the cyclic sulfonamides, and the like. For compounds where X is NR5, the preferred method for handling R5 is shown. In the following scheme, L is any acceptable residual group, and B is a blocking group as described above, Boc is an example of a preferred blocking group recognized in the art. The person skilled in the art will recognize that the choice of the blocking group is within the capacity of the expert in organic chemistry. Thus, the choice of Boc is not required, but is preferred.

SCHEME III For compounds containing a sulfur in the heterocyclic ring, preferred methods of ring formation are shown. For the preparation and preparation of the heterocyclic ring, it is understood that the person skilled in the art can choose to prepare Y before, after or concurrent with the preparation of the heterocyclic ring.

SCHEME IV ,? rx Another acceptable strategy for carrying out the invention having X as sulfur includes the following scheme. The method allows the formation of the sulfonamide and the subsequent reaction with a bifunctional portion. Preferably, the OH described in the following scheme is a primary hydroxyl. The ring closure uses standard methods. The functionalization and the preparation of the molecule proceed as described above.

SCHEME IV Where x is sulfur, further elaboration of the heterocyclic ring can be achieved after the ring has been formed. For example, oxidation of the ring sulfur atom using known methods can provide the corresponding sulfoxides and sulfones,. as shown. After the oxidation of the ring sulfur, the working up of the invention proceeds as described above SCHEME V For compounds containing an oxygen in the heterocyclic ring, preferred methods of ring formation are shown. A bifunctional moiety, for example, a halohydroxy species is reacted with an aziridine as shown below. The halogen moiety functions as a residual group, and can be any appropriate residual group. After the formation of the ring, the working up of the invention proceeds as described above.

SCHEME VI Preparation of the Z-portion In fact, the person skilled in the art will recognize that some of the schemes applicable to the preparation of Y may be useful for the preparation of Z, as described above. Other preferred methods are provided for the reader. In the above schemes, alkoxy or alkylthio produce the corresponding hydroxy or thiol compounds by the use of a standard dealkylation process (Bhatt et al., "Clevage of Ethers", Synthesis, 1983, pp. 249-281). The order of the steps can be varied to increase the yield 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 the successful synthesis. Although the determination of optimal conditions, etc., is customary, it will be understood that several compounds can be generated in a similar way, using the guidance 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; that is, it is within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification and the like. Examples of these manipulations are described in normal texts, such as March, Advanced Organic Chemistry, (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and other common texts. 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, ae can selectively prepare an optical isomer, including diastereomer and enantiomer, over others; for example, by chiral starting materials, catalysts or solvents, or both stereoisomers or both optical isomers can be prepared at the same time, including diastereomers and enantiomers (a racemic mixture). Since the compounds of the invention can exist as racemic mixtures, mixtures of optical isomers, including diastereomers or enantiomers or stereoisomers, can be separated using known methods such as chiral salts, chiral chromatography and the like. Furthermore, it is recognized that an optical isomer, including diastereomer and enantiomer or stereoisomer, may have favorable properties over others. Thus, when describing and claiming the invention, when describing a racemic mixture, it is clearly contemplated that both optical isomers are also described and claimed, including diastereomers and enantiomers or stereoisomers substantially free of the others.

Methods of use The metalloproteinases (MPs) found in the body function, in part, by degrading the extracellular matrix, which comprises proteins and extracellular glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of the tissue in the body. Metalloprotease inhibitors are useful for treating diseases caused, at least in part, by the degradation of said proteins. It is known that MPs are intimately involved in tissue remodeling. As a result of this activity, it has been mentioned that they are active in many disorders that include either: tissue degradation; including degenerative diseases such as arthritis, multiple sclerosis and the like; Metastasis or mobility of tissues in the body: - tissue remodeling, including fibrotic disease, scar prevention, benign hyperplasia and the like. The compounds of the present invention treat disorders, diseases and / or undesired conditions that are characterized by undesired or elevated activity of this class of proteases. For example, the compounds can be used to inhibit proteases that: - destroy structural proteins (ie, proteins that maintain the stability and structure of tissues), - - interfere with inter / intracellular signaling, including those involved in upregulation of cytokine 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, ovule 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 the PM includes: - unwanted or elevated MP activity 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 [for example, 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 displays 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. further, 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 unwanted condition. For example, the compounds of this invention vary in their ability to penetrate the central nervous system. In this way, the compounds can be selected to produce mediated effects through MPs found specifically outside the central nervous system. The determination of the specificity of an MP inhibitor of a certain MP is within the ability of the expert in that field. Proper test conditions can be found in the literature. Tests for stromelysin and collagenase are specifically known. For example, the patent of E.U.A. No. 4,743,587 refers to the procedure of Cawston et al., Anal Biochem (1979) 99: 340-345. The use of a synthetic substrate in a test is described by Weingarten, H. et al., Biochem 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 (eg, angioplasty), an area affected by scarring or burning (eg, 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 maxilla and / or mandible. MPs are also active to reshape the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons why angioplasty has a higher-than-expected rate of long-term insufficiency (reobstruction 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. In this way, regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemiaChronic obstructive pulmonary disease, restenosis due to angioplasty and aortic aneurysm can increase the long-term success of any other treatment, or it can 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 postexposure damage. In addition, MPs are involved in disorders and diseases of the skin related to abnormal tissues that result from an abnormal manifestation which includes metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of "normal" skin injuries, including scarring or "shrinkage" of tissues, for example, after burns. Inhibition of MP is also useful in surgical procedures that include the skin for the prevention of scar formation and the promotion of normal tissue growth, including applications such as 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 said diseases. It is also believed that MPs are implicated in many infections, including cytomegalovirus; [CMV] retinitis; HIV and the resulting syndrome, AIDS. MPs may also be involved in extravascularization where the surrounding tissue needs to be degraded to allow new blood vessels such as angiofibrone and hemangioma. Since MPs degrade the extracellular matrix, it is contemplated that inhibitors of these enzymes can be used as birth control agents, for example to prevent ovulation, to prevent sperm penetration into and through the extracellular environment of the ovule, in the implantation of the fertilized ovum and to avoid the maturation of the spermatozoon. 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, 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 (for example, 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" (eg, rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS. It is also believed that MP inhibitors are useful for treating Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from, or originating from diabetes, especially those that include loss of viability. tissue, coagulation, disease, graft against host, leukemia, cachexia, anorexia, proteinuria and perhaps the regulation of hair growth. For some diseases, conditions or disorders, the inhibition of MP is contemplated as a preferred treatment method. Said diseases, conditions or disorders include arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or combat of growth and tumor metastasis), ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration and pterygium), - and diseases of the gums (especially periodontal disease and gingivitis). The 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 the metalloproteases and the disintegrin metalloproteases. The compounds that are preferred for, but not limited to, the treatment of cancer (especially the prevention or combating of growth and tumor metastasis) are those compounds that preferably inhibit gelatinases or type IV collagenases. The compounds that are preferred for, but not limited to, the treatment of ocular disorders (especially ulceration of the cornea, lack of healing of the cornea, macular degeneration and pterygium) are those compounds that widely inhibit the metalloproteases. Preferably, these compounds are administered topically, most preferably as a drop or gel. Compounds that are preferred for, but not limited to, the treatment of gum diseases (especially periodontal disease and gingivitis) are those compounds that preferentially inhibit collagenases.

Compositions: The compositions of the invention comprise: (a) a safe and effective amount of a compound of the formula (I); and (b) a pharmaceutically acceptable carrier. As mentioned above, it is known that numerous diseases are mediated by excessive or unwanted matrix destruction metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, inflammations of the skin, ulcerations, particularly of the cornea, reactions to infections, periodontitis and the like. In this manner, the compounds of the invention are useful in therapy with respect to conditions that include this undesired activity. Therefore, the compounds of the invention can be formulated into pharmaceutical compositions useful for the treatment or prophylaxis of these conditions. Normal pharmaceutical formulation techniques are used, such as those descr in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. , most recent edition. A "safe and effective amount" of a compound of the formula (I) is an amount that is effective to inhibit metalloproteases at the site or sites of activity, in a human or lower animal subject, without adverse side effects not due (such as toxicity, irritation or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention. The specific "safe and effective amount" will obviously vary with factors such as the particular condition being treated, the patient's physical condition, the duration of the treatment, the nature of the concurrent therapy (if any), the form of specific dosage to be used, the vehicle employed, the solubility of the compound of the formula (I) therein and the desired dosage regimen for the composition. In addition to the present compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible solid or liquid filler or encapsulant substances that are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the composition are capable of being mixed with the present compound and with each other, so that there is no interaction that could substantially reduce the pharmaceutical efficacy of the composition. composition under ordinary situations of use. The pharmaceutically acceptable carriers must, of course, have a high enough purity and a toxicity low enough to make them suitable for administration to the human or lower animal being treated. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; jelly; talcum powder; solid lubricants such as stearic acid and magnesium stearate, calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic p-acid; emulsifiers, such as Tweens; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; rattlers, stabilizers; antioxidants; conservatives; pyrogen-free water; isotonic saline solution and phosphate buffer solutions. The choice of a pharmaceutically acceptable carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound will be administered. If the present compound will be injected, the pharmaceutically acceptable carrier that is preferred is a sterile physiological saline solution with a blood-compatible suspension agent, whose pH has been adjusted to about 7.4. In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and their derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers , isotonic saline solution and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier, in the compositions for parenteral administration, comprises at least about 90% by weight of the total composition. The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention that contains an amount of a compound of formula (I) that is suitable for administration to a human or lower animal, in a single dose , from. compliance with proper medical practice. These compositions preferably contain from about 5 mg (milligrams) to about 1000 mg, most preferably from about 10 mg to about 50 mg, more preferably from about 10 mg to about 300 mg of a compound of the formula (I). The compositions of this invention can be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal or parenteral administration. Depending on the particular administration route desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. These include liquid or solid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Optional pharmaceutically active materials may be included, which do not substantially interfere with the inhibitory activity of the compound of the formula (I). The amount of vehicle employed in conjunction with the compound of formula (I) is sufficient to provide a practical amount of material for administration per unit dose of the compound of formula (I). Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated herein by reference: Modern Pharmaceutics, chapters 9 and 10 (Banker &Rhodes, editors, 1979), - Lieberman et al., Pharmaceutical 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 normal use situations. The pharmaceutically acceptable carriers must, of course, have a high enough purity and a sufficiently low toxicity to make them suitable for administration to the human 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 p-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 compound of the formula (I). The tablets can be compressed, comminuted, enteric-coated, sugar-coated, film-coated or multiple-compressed, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and preservatives. appropriate fusion. The liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, fusion agents, coloring agents and flavoring agents. The pharmaceutically acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well known in the art. The tablets typically comprise conventional pharmaceutically compatible adjuvants such as inert diluents, calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.; binders such as starch, gelatin and sucrose; disintegrants such as starch; alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Slip agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents such as FD &C dyes can be added to improve appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint and fruit flavors are also useful adjuvants for chewable tablets. The capsules typically comprise one or more of the solid diluents described above. The selection of vehicle components depends on secondary considerations such as flavor, cost and stability at the counter, which are not critical for the purposes of the present invention and can be easily made by one skilled in the art. The peroral compositions also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers useful for the preparation of such compositions are well known in the art. Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methylcellulose, carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. The peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents and colorants described above. Said compositions can also be coated by conventional methods, typically with pH or time dependent coatings, such that the present compound is released into the gastrointestinal tract, in the vicinity of the desired topical application or several times to extend the desired action . Said dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, dihydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and lacquer. The compositions of the present invention may optionally include other drug actives. Other compositions useful for achieving systemic delivery of the present compounds include sublingual, buccal and nasal dosage forms. Said compositions typically comprise one or more soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Also described above and may include slip agents, lubricants, sweeteners, colorants, antioxidants and flavoring agents. The compositions of the present invention can also be administered topically to a subject, for example, by direct placement or dispersion of the composition on the epidermal or epithelial tissue of the subject, or transdermally by means of a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1% and preferably about 1% to about 5%, of the compound of the formula (I). Suitable vehicles for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by transpiration or immersion in water. In general, the vehicle is of an organic nature and capable of having the compound of the formula (I) dispersed or dissolved therein. The vehicle may include emollients, emulsifiers, thickening agents and pharmaceutically acceptable solvents, and the like.

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

The compounds and compositions of the formula (I) of this invention can be administered topically or systemically. Systemic application includes any method for introducing a compound of formula (I) into body tissues, for example, 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. metalloprotease that will be inhibited, the personal attributes of the subject (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 from about 5 mg to about 1,000 mg, more preferably from about 10 mg to about 300 mg of the compound are administered. of the 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 metalloprotease is accumulated using selection ligands. For example, to target inhibitors to 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, such as a contact lens or reservoir, or as a subconjunctive formulation. For the treatment of inflammations of the skin, the compound is applied locally and topically, in gel, paste, ointment or ointment. The mode of treatment then reflects the nature of the condition, and suitable formulations for any selected route are available in the art. In all of the foregoing, of course, the compounds of the invention may be administered alone or as mixtures, and the compositions may further include additional drugs or excipients, as appropriate for the indication. Some of the compounds of the invention also inhibit bacterial metalloproteases, although generally at a level lower than that exhibited with respect to mammalian metalloproteases. Some bacterial metalloproteases appear to be less dependent on the stereochemistry of the inhibitor, while substantial differences are found between the diastereomers in their ability to inactivate mammalian proteases. In this way, this pattern of activity can be used to distinguish between mammalian and bacterial enzymes.

Preparation and use of antibodies: The compounds of the invention can also be used in immunization protocols to obtain immunospecific antisera for the compounds of the invention. Since the compounds of the invention are relatively small, they are advantageously coupled to antigenically neutral vehicles such as conventionally used lockhead hemocyanin (KLH) or whey albumin vehicles. For those compounds of the invention having a carboxyl functionality, coupling to the carrier could be done by methods generally known in the art. For example, the carboxyl residue can be reduced to an aldehyde and coupled to the carrier by reaction with side chain amino groups in protein-based vehicles, optionally followed by reduction of the 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. The linker 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 in accordance with 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 labels such as scintigraphic labels, for example, technetium 99 or 1-131, using standard coupling methods. The labeled compounds are administered to subjects to determine sites of excessive amounts of one or more metalloproteases in vivo. The ability of the inhibitors to selectively bind to metalloproteases is then exploited to map the distribution of these enzymes in situ: The techniques can also be employed in histological procedures and the labeled compounds of the invention can be used in competitive immunoassays.

The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.

EXAMPLES The compounds are analyzed using 1 H and 13 C NMR, elemental analysis, mass spectra and / or R 1 spectra, as appropriate. Inert solvents are typically used, preferably in dry form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride, and all other solvents are purchased to the appropriate degree. Chromatography is carried out on silica gel (70 to 230 mesh, Aldrich, or 230 to 400 mesh, Merck), as appropriate. Thin-layer chromatography (TLC) analysis is carried out on glass-mounted silica gel plates (200-200 mesh, Baker), and visualized with UV light or 5% phosphomolybdic acid in EtOH.

EXAMPLE 1 Synthesis of 2 (R) -thiomethyl-4- (S) -thio-1- [(4-methoxyphenyl) sulfonyl] irrolidine 1- (4-methoxyphenyl) sulfonyl] -cis-4-hydroxy-D-proline (la): cis-4-hydroxy-D-proline (9.0 g, 68.6 mmol) is dissolved in 100 ml of water mixture and p-dioxane (1: 1), and then triethylamine (19.1 ml, 137.3 mmol), 4-methoxyphenylsulfonyl chloride (15.6 g, 75.5 mmol) and 4-dimethylaminopyridine (0.86 g, 6.86 mmol) are added. The solution is stirred at room temperature overnight. The reaction mixture is washed with sodium bicarbonate and extracted once with ether. The aqueous layer is acidified with IN HCl until the pH is about 2, and then the solution is extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, and dried (MgSO 4), filtered and evaporated to give the crude acid. Cl + MS: m / z (relative intensity) 302.0 (M + + H, 100). 1- [(4-methoxyphenyl) sulfonyl] -cis-4-hydroxy-D-prolinol (lb): dissolve the acid (0.60 g, 1.99 mmol) in 10 ml of anhydrous THF followed by the slow addition of borane complex - 1.0 M tetrahydrofuran (3.98 ml, 3.98 mmol) at room temperature. After stirring for 30 minutes, another ml of the borane-THF complex is added, and the solution is stirred for another 1.5 hours. The reaction is quenched by the slow addition of water, and acidified with IN HCl until pH = 2. The resulting solution is extracted three times with ethyl acetate. The combined organic layers are washed with ammonium chloride, dried (MgSO 4), filtered and evaporated to give the crude product. Cl + MS: m / z (relative intensity) 289.0 (M + + H, 100). 2 (R) -acetylthiomethyl-4- (S) -acetylthio-1- [(4-methoxy-phenyl) sulfonyl] pyrrolidine (lc): in flask 1, triphenylphosphine (1.09 g, 4.18 mmol) is dissolved in 25 ml of anhydrous THF at -10 ° C, and stirred. The diethyl azodicarboxylate (0.658 ml, 4.18 mmol) is then added, and the resulting solution is stirred for 30 minutes. In flask 2, the alcohol (0.300 g, 1.04 mmol) and thiolacetic acid (0.373 ml, 5.22 mmol) are dissolved in 7 ml of anhydrous THF. The contents of flask 2 are poured with cannula into flask 1. The resulting solution is stirred at 0 ° C for 4 hours, and then at room temperature overnight. The reaction is treated with sodium bicarbonate until the pH is about 9, and then the solution is extracted three times with ethyl acetate. The organic layers are washed with IN HCl, sodium bicarbonate and ammonium chloride, dried (gSO 4), filtered and evaporated to give a crude solid which is chromatohed on silica gel with hexanes / ethyl acetate / sodium chloride. methylene (4.5 / 1/1) to produce the desired product. Cl + MS: m / z (relative intensity) 403.0 (M + + H, 100). 2 (R) -thiomethyl-4- (S) -thio-1- [(4-methoxyphenyl) -sulfonyl] -pyrrolidine (Id): dithioic acetate (0.085 g, 0.211 mmol) is dissolved in 10 ml of methanol, and the solution is completely degassed. Gaseous anhydrous ammonia is passed through the solution for 8 minutes, and the solution is stirred for 15 minutes. The solution is evaporated to give the crude product which is chromatohed on silica gel with hexanes / ethyl acetate / methylene chloride / formic acid (70/5/6 / 0.1) to give the final product as an oil. Cl + MS: m / z (relative intensity) 320.0 (M + + H, 100).

EXAMPLE 2 Synthesis of (2R) -2-thiomethyl-l- [(4-methoxyphenyl) sulfonyl] pyrrolidine (2a) (2b) (ae) (2d) 1- [(4-methoxyphenyl) sulfonyl] -D-proline (2a): D-proline (15 g, 130.3 mmol) is dissolved in a 1: 1 mixture of water (150 ml) and p-dioxane (150 ml) , and then triethylamine (40 ml, 287 mmol), 4-methoxyphenylsulfonyl chloride (29.0 g, 140.3 mmol) and 4-dimethylaminopyridine (1.5 g, 13.0 mmol) are added. The solution is stirred at room temperature overnight. The reaction mixture is then treated with IN HCl until the solution is acidic. (pH = 2). The resulting solution is extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, they are dried (MgSO 4), filtered and evaporated to give the crude compound. Cl + MS: m / z (relative intensity) (M + H 286, 100). 1- (4-methoxyphenyl) sulfonyl] -D-prolinol (2b): the acid is dissolved (5.0 g, 17.5 mmol) in 100 ml of anhydrous THF followed by the slow addition of 1.0 M borane-tetrahydrofuran complex (26.5 ml, 26.5 yams) at room temperature. The reaction mixture is stirred for 2 hours. The reaction is quenched by the slow addition of water and acidified with IN HCl until pH = 2. The resulting solution is extracted three times with ethyl acetate. The organic layers are washed with ammonium chloride, dried (MgSO), filtered and evaporated to give the crude product. Cl + MS: m / z (relative intensity) (M + H 272, 100). 2R-2-acetylthiomethyl-l- [(4-methoxyphenyl) -sulfonyl] -pyrrolidine (2c): in flask 1, triphenylphosphine is dissolved (0.782 g, 2.98 mmol) in 20 ml of anhydrous THF at -10 ° C, and stirred. The diethyl azodicarboxylate (0.470 ml, 2.98 mmol) is then added, and the resulting solution is stirred for 30 minutes. In flask 2, the alcohol (0.404 g, 1.49 mmol) and thiolacetic acid (0.266 ml, 3.73 mmol) are dissolved in 10 ml of THF anhydrous. The contents of flask 2 are poured with cannula into flask 1. The resulting solution is stirred at 0 ° C for 4 hours, and then at room temperature overnight. The reaction is treated with sodium bicarbonate until the pH is about 9, and then the solution is extracted three times with ethyl acetate. The organic layers are washed with IN HCl, sodium bicarbonate and ammonium chloride, dried (MgSO), filtered and evaporated to give a crude solid. Purification of the solid is achieved by chromatography on silica gel using ethyl acetate / methylene chloride (1.5 / 500) as eluent to produce the desired product. Cl + MS: m / z (relative intensity) (M ++ H 329.9, 100). 2-thiomethyl-l- [(4-methoxyphenyl) sulfonyl pyrrolidine (2d): the thiol acetate (0.110 g, 0.334 mmol) is dissolved in 15 ml of methanol, and the solution is completely degassed. Anhydrous gaseous ammonia is passed through the solution for 8 minutes, and the solution is stirred for another 15 minutes. The solution is evaporated to give the crude product, which is chromatographed on silica gel with hexanes / ethyl acetate / methylene chloride (5/1/1) to provide the final product. Cl + MS: m / z (relative intensity) (M + H 288.0, 100).

EXAMPLE 3 Synthesis of (2R, 4S) -methyl 4-thio-l- [(4-methoxyphenyl) sulfonyl] proline (3c) 1- [(4-methoxyphenyl) sulfonyl] -cis-hydroxy-D-proline methyl (3a): 1- [(4-methoxyphenyl) sulfonyl] -cis-hydroxy-D-proline (5 g, 16.6 mmol) is dissolved ) in 150 ml of ether and 20 ml of p-dioxane, and treated with a 0.7 M solution of diazomethane. The addition is interrupted until the color continues to be yellow. The solution is stirred for another hour. The reaction mixture is diluted with 300 ml of ethyl acetate and washed with sodium bicarbonate and ammonium chloride, and dried over magnesium sulfate. Cl + MS: m / z (relative intensity) 316 (M + + H, 100). 4-acetylthio-l- [(4-methoxyphenyl) sulfonyl proline from (2R.4S) -methyl (3b): in flask 1, triphenylphosphine (5.16 g, 19.68 mmol) is dissolved in 150 ml of anhydrous THF at -10 ° C, and stirred. The diethyl azodicarboxylate (3.1 ml, 19.68 mmol) is added, and the resulting solution is stirred for 30 minutes. In flask 2, alcohol 1 (3.1 g, 9.84 mmol) and thiolacetic acid (1.76 ml, 24.60 mmol) are dissolved in 30 ml of anhydrous THF. The contents of flask 2 are poured with cannula into flask 1. The resulting solution is stirred at 0 ° C for 4 hours, and at room temperature overnight. The reaction mixture is treated with sodium bicarbonate and extracted three times with ethyl acetate. The organic layers are washed with IN HCl, sodium bicarbonate and ammonium chloride, dried (MgSO 4), filtered and evaporated to give a crude solid which is chromatographed on silica gel with ethyl acetate / methylene chloride ( 1/30). Cl + MS: m / z (relative intensity) 374 (M + + H, 100). 4-thio-l- [(4-methoxyphenyl) sulfonyl] proline from (2R.4S) -methyl 3 (c): the thiol acetate (0.120 g, 0.321 mmol) is dissolved in 5 ml of methanol, and the solution degass completely. Anhydrous gaseous ammonia is passed through the solution for 8 minutes, and the solution is stirred for another 15 minutes. The solution is evaporated to a crude product, which is chromatographed on silica gel with hexanes / ethyl acetate / methylene chloride (4/1/1) to give the crude product. Cl + MS: m / z (relative intensity) 331.9 (M + + H, 100).

EXAMPLE 4 Synthesis of 2 (R, S) -thiomethyl-l- [(4-n-butoxyphenyl) sulfonyl] piperidine 1- [4-n-butoxyphenyl) sulfonyl] pipecolinic acid (4a): Pipecolinic acid (0.331 g, 2.56 mmol) is dissolved in 16 ml of water and p-dioxane (1: 1) mixture followed by the addition of triethylamine (0.78 mL, 5.64 mmol), 4-butoxyphenylsulfonyl chloride (0.67 g, 2.69 mmol) and 4-dimethylaminopyridine (0.31 g, 0.25 mmol). The resulting solution is stirred at room temperature overnight. The reaction mixture acidifies with IN HCl and extracted 3 times with ethyl acetate. The combined organic extracts are washed with ammonium chloride, dried (MgSO), filtered and evaporated to give the crude compound. Cl + MS: m / z (relative intensity) 342 (M + + H, 100). 2-hydroxymethyl-l- [(4-n-butoxyphenyl) -sulfonyl] -piperidine (4b): The acid (0.650 g, 1.90 mmol) is dissolved in 15 ml of anhydrous THF followed by the slow addition of borane-complex. 1.0 M tetrahydrofuran (3.8 ml, 3.81 mmol) at room temperature. The reaction is stirred for two hours, and then quenched by the slow addition of water. The resulting solution is acidified with IN HCl until pH = 2 and extracted three times with ethyl acetate. The organic layers are washed with ammonium chloride, dried (MgSO 4) and evaporated to give the crude product. Cl + MS: m / z (relative intensity) 328.1 (M + + H, 100). 2-acetylthiomethyl-l- [(4-n-butoxyphenyl) -sulfonyl] -piperidine (4c): In flask 1, triphenylphosphine (0.650 g, 2.01 mmol) is dissolved in 20 ml of anhydrous THF at -10 ° C, and it is agitated. The diethyl azodicarboxylate (0.317 ml, 2.01 mmol) is then added, and the resulting solution is stirred for 30 minutes. In flask 2, the alcohol (0.325 g, 1.00 mmol) and thiolacetic acid (0.179 ml, 2.51 mmol) are dissolved in 10 ml of anhydrous THF. The contents of flask 2 are poured with cannula into flask 1. The resulting solution is stirred at 0 ° C for 4 hours and at room temperature overnight. The reaction is treated with sodium bicarbonate and extracted 3 times with ethyl acetate. The organic layers are washed with IN HCl, sodium bicarbonate and ammonium chloride, dried (MgSO), filtered and evaporated to give a crude solid which is chromatographed on silica gel with hexane / ethyl acetate / sodium chloride. methylene (7/1/1). Cl + MS: m / z (relative intensity) 386.0 (M + + H, 100). 2 (R.S) -thiomethyl-l- [(4-n-butoxyphenyl) -sulfonyl-1-piperidine (4d): Dissolve in thiol acetate (0.105 g, 0.272 mmol) in 10 ml of methanol, and the solution is completely degassed. Anhydrous gaseous ammonia is passed through the solution for 8 minutes, and the solution is stirred for another 15 minutes. The solution is evaporated to give a crude product which is chromatographed on silica gel with hexanes / ethyl acetate / methylene chloride (10/1/1) to yield 0.070 g (75.0%) of a pure product. Cl + MS: m / z (relative intensity) 344.0 (M + + H, 100).

EXAMPLE 5 Synthesis of 2 (R, S) -thiomethyl-l- [(4-n-methoxyphenyl) sulfonylpiperidine (ße) (M) 1- [(4-methoxyphenyl) sulfonyl] iperidine-2 (methyl R, S-carboxylate (5a) .- Methyl pipecorinium hydrochloride (10.0 g, 55.6 mmol), triethylamine (14.1 g, 19.4 g. ml, 139.2 mmol, 2.5 equivalents), 1,4-dioxane (75 ml) and water (75 ml), and then p-methoxyphenylsulfonyl chloride (13.8 g, 66.8 mmol, 1.2 equivalents) was added.The resulting solution was stirred At room temperature overnight the solution is poured into water and extracted with CH2Cl2, the combined organic extracts are dried (Na2S4) and concentrated to an oil under reduced pressure.The oil purification is achieved by chromatography over silica gel using hexane / EtOAc 7/3 as eluent The product is obtained as a colorless oil which solidifies after standing. 2 (R, S) -1- [(4-methoxyphenyl) sulfonyl] piperidinemethanol (5b): The sulfonamide (4.0 g, 12.7 mmol) in THF (50 ml) is stirred at room temperature, and then diisobutylaluminum hydride in THF (25.5 ml, 25.5 mmol, 2 equivalents) is added. The resulting solution is stirred at room temperature for 2 hours, and then the reaction mixture is quenched by the addition of water. The solution is extracted with CH2Cl2 (3 x 100 ml). The combined organic extracts are dried (Na 2 SO 4) and concentrated to an oil under reduced pressure.

Purification of the oil is achieved by chromatography using hexane / EtOAc I / L as eluent. The product is obtained as a clear colorless oil. 2 (R, S) -acetylthiomethyl-1- [(4-methoxyphenyl) -sulfonyl] -piperidine (5c): The alcohol (2.90 g, 10.1 mmol) in CH 2 Cl 2 (10 mL) is added to a solution of triphenylphosphine (3.19). g, 12.2 mmoles, 1.2 equivalents) and diethyl azodicarboxylate (1.94 g, 11.1 mmoles, 1.1 equivalents) in CH2Cl2 (20) at -78 ° C. The solution is stirred at -78 ° C, and then thiolacetic acid is added (1.55 g, 20.3 mmol, 2.0 equivalents). The resulting solution is concentrated at room temperature, and then stirred for 2 hours. The reaction mixture is concentrated to an oil and silica gel (20 g) is then added. The resulting powder is purified by chromatography on silica gel using hexane / EtOAc 7/3 as eluent to produce the desired thiol acetate as a clear colorless oil. MS (Cl, NH3): 344 (M + H +). 2 (R, S) -thiomethyl-l- [(4-methoxyphenyl) sulfonyl] piperidine (5d): The thiol acetate 3 (0.295 g, 0.86 mmol) in methanol (20 ml) is stirred under an atmosphere of argon at room temperature. ambient. The solution is then bubbled with gaseous ammonia for 20 minutes at room temperature, and then the solution is purged with argon gas. The solvent is removed under reduced pressure to leave a colorless oil. The purification of the oil is achieved by chromatography using hexane / EtOAc 7/3 as eluent. The product is obtained as a colorless oil. MS (electron spray): 302 (M + H +).

EXAMPLE 6 Synthesis of 2 (R) -thiomethyl-4- (S) -thio-1- [(4-n-butoxyphenyl) sulfonylpyrrolidine 1- [(4-Butoxyphenyl) sulfonyl] -cis-4-hydroxy-D-proline (6a): cis-4-hydroxy-D-proline (0.308 g, 2.67 mmol) is dissolved in 16 ml of a mixture 1: 1 of water and p-dioxane, and then triethylamine (0.819 ml, 5.89 mmol), 4-butoxyphenylsulfonyl chloride (0.700 g, 2.81 mmol) and 4-dimethylaminopyridine (0.033 g, 0.268 mmol) are added. The resulting solution is stirred at room temperature overnight. The reaction is then washed with sodium bicarbonate and extracted once with ether. The aqueous layer is acidified with IN HCl until pH = 2 and extracted 3 times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, dried (MgSO 4), filtered and evaporated to give the crude compound. Cl + MS: m / z (relative intensity) 361 (M + + H, 40). 1- [(4-Butoxyphenyl) sulfonyl] -cis-4-hydroxy-D-prolinol (6b): Sulfonamide (0.750 g, 2.18 mmol) is dissolved in 10 ml of anhydrous THF followed by the slow addition of borane complex - 1.0 M tetrahydrofuran (4.4 ml, 4.37 mmol) at room temperature. The solution is stirred for 1.5 hours at room temperature. The reaction is quenched by the slow addition of water, acidified with IN HCl until pH = 2 and extracted 3 times with ethyl acetate. The organic layers are washed with ammonium chloride, dried (MgSO 4), filtered and evaporated to give the crude product. Cl + MS: m / z (relative intensity) 347.1 (M + + H, 40). 2 (R) -acetylthiomethyl-4- (S) -acetylthio-1- (4-butoxy-phenyl) sulfonyl] -rolidolidine (6c): Triphenylphosphine (1.35 g, 5.14 mmol) is dissolved in 25 ml of flask 1. THF anhydrous at -10 ° C, and stirred. The diethyl azodicarboxylate (0.809 ml, 5.14 mmol) is then added, and the resulting solution is stirred for 30 minutes. In the flask 2 the alcohol (0.423 g, 1.28 mmol) and thiolacetic acid (0.459 ml, 6.43 mmol) are dissolved in 10 ml of anhydrous THF. The contents of flask 2 are poured with cannula into flask 1. The resulting solution is stirred at 0 ° C for 4 hours and then at room temperature overnight. The reaction mixture is washed with sodium bicarbonate and extracted 3 times with ethyl acetate. The organic layers are washed with IN HCl, sodium bicarbonate and ammonium chloride, dried (MgSO 4), filtered and evaporated to give a crude solid which is chromatographed on silica gel with hexanes / ethyl acetate / sodium chloride. methylene (8/1/1). Cl + MS: m / z (relative intensity) 446 (M + + H, 100). 2 (R) -thiomethyl-4- (S) -thio-1- [(4-butoxyphenyl) -sulfonyl] -pyrrolidine (6d): The dithioic acetate (0.150 g, 0.337 mmol) is dissolved in 10 ml of methanol, and the solution is completely degassed. Gaseous anhydrous ammonia is passed through the solution for 8 minutes, and the solution is stirred for 15 minutes. The solution is evaporated to the crude product which is chromatographed on silica gel with hexanes / ethyl acetate / methylene chloride / formic acid (10/1/1 / 0.1) to give the desired product as a pure white solid. Cl + MS: m / z (relative intensity) 362 (M + + H, 100).

EXAMPLE 7 Synthesis of 3 (R) -thio-1- [(4-methoxyphenyl) sulfonyl] irroli? Ina (3S) -3-hydroxy-l- [(4-methoxyphenyl) sulfonyl] pyrrolidine (7a): 3 (S) -hydroxy-pyrrolidine (1.0 g, 11.5 mmol), triethylamine (2.32 g, 22.9 mmol, 2.0 equivalents) in 1,4-dioxane (30 ml) and water (10 ml) are stirred at room temperature, and then 4-methoxyphenylsulfonyl chloride (2.61 g, 12.6 mmol, 1.10 equivalents) is added. The resulting solution is stirred at room temperature for 3 hours, and then the solution is acidified to pH of about 1 with IN HCl. The solution is poured into water and then extracted with CH2CI2. The organic extracts are dried (Na2SO4) and concentrated to an oil. The oil is purified by chromatography using hexane / EtOAc I / L as eluent to yield 2.62 g (81%) of the desired product as a colorless oil. (3R) -3-acetylthio-l- [(4-methoxyphenyl) -sulfonyl] -pyrrolidine (7b) .- Add alcohol (1.30 g, 5.05 mmol) in CH2Cl2 (30 mL) to a solution of triphenylphosphine (1.59). g, 6.06 mmoles, 1.2 equivalents) and diethyl azodicarboxylate (0.97 g, 5.56 mmoles, 1.1 equivalents) in CH2Cl2 (30 ml) at 0 ° C. The solution is stirred at 0 ° C, and thiolacetic acid (0.77 g, 10.1 mmol, 2.0 equivalents) is then added. The resulting solution is heated to room temperature, and then stirred for 2 hours. The reaction mixture is concentrated to an oil and silica gel (20 g) is then added. The resulting powder is purified by chromatography on silica gel using hexane / EtOAc 7/3 as eluent to yield 1.18 g (74%) of the desired thiol acetate as a clear, colorless oil. (3R) -3-thio-l- [(4-methoxyphenyl) sulfonium pyrrolidine (7c): The thiol acetate (0.46 g, 1.46 mmol) in methanol (30 ml) and THF (10 ml) are stirred under an atmosphere of Argon at room temperature. The solution is then bubbled with gaseous ammonia for 20 minutes at room temperature, and then the solution is purged with argon gas. The solvent is removed under reduced pressure to leave a colorless oil. The purification of the oil is achieved by chromatography using hexane / EtOAc 8/2 as eluent. The product is obtained as a colorless oil. MS (electron spray): 274 (M + H +).

EXAMPLE 8 Synthesis of 3 (S) -thiomethyl-l- [(4-methoxyphenyl) sulfonyl] pyrrolidine -Oxo-l- (1-phenylethyl) -3-pyrrolidine-carboxylic acid of (1R.3S) methyl (8a): Itaconic acid is heated (16.1 g, 124 mmol), (R) -a-methylbenzylamine (15.0 g, 124 mmol) and xylenes (150 ml) were refluxed for 6 hours. The water is removed from the reaction by a Dean-Stark trap. The reaction mixture is cooled to room temperature, and then the xylenes are removed under reduced pressure. The product, a white solid, is dissolved in methanol (350 ml) and a catalytic amount of H2SO4 (0.7 g) is added. The resulting solution is heated to reflux for 18 hours. The solvent is removed and the product is purified by chromatography on silica gel (hexane / EtOAc 65/35 as eluent) to produce both diastereomers as individual entities. The low Rf material is used in the following sequence of reactions. (IR, 3S) 5-Oxo-l- (1-phenylethyl) -3-hydroxy-methyl-pyrrolidine (8b): The ester (2.27 g, 9.18 mmol) in THF (50 ml) was stirred at room temperature, and then the LIAIH4 is added slowly (0.7 g, 18.3 mmoles, 2.0 equivalents). After the addition is complete, the solution is stirred at reflux for 4 hours. The reaction mixture is cooled to room temperature, and EtOAc (ca. 5 ml) is slowly added. The reaction is quenched by the careful addition of water (0.7 ml), 15% NaOH (0.7 ml) and water (3 ml). The solution is stirred at room temperature for 10 minutes and then filtered. The solvent is removed to leave the desired product as a colorless oil, which does not need further purification. (3S) 3-hydroxymethylpyrrolidine (8c): Place the amine (1.85 g, 9.01 mmol), Pd-C (10%) (185 mg) in methanol (25 ml) under a nitrogen atmosphere (3.515 kg / cm) for 72 hours. The product is filtered over celite with the help of methanol (50 ml), and then the resulting solution is concentrated to yield the desired amine as a light yellow oil. No further purification is carried out. (3S) -3-hydroxymethyl-l- [(4-methoxyphenyl) -sulfonyl] -pyrrolidine (8d): The 3 (S) -hydroxymethylpyrrolidine (0.9 g, 8.90 mmol), triethylamine (1.80 g, 17.8 mmol, 2.0 equivalents) in 1,4-dioxane (30 ml) and water (10 ml) at room temperature, and 4-methoxyphenylsulfonyl chloride (2.02 g, 9.80 mmol, 1.10 equivalents) is then added.

The resulting solution is stirred at room temperature for 3 hours, and then the solution is acidified to pH of about 1 with 1N HCl. The solution is poured into water and then extracted with CH2Cl2. The organic extracts are dried (Na2S? 4) and concentrate to an oil. The oil is purified by chromatography using hexane / EtOAc 1/1 as eluent to produce the desired product as a colorless oil. (3S) -3-acetylthiomethyl-l- [(4-methoxyphenyl) -sulfonyl] -pyrrolidine (8e): The alcohol (0.8 g, 2.95 mmol) in CH2Cl2 (20 ml) is added to a solution of triphenylphosphine (0.93 g). , 3.54 mmol, 1.2 equivalents) and diethyl azodicarboxylate (0.57 g, 3.24 mmol, 1.1 equivalents) in CH2CL2 (20 mL) at room temperature. The solution is stirred for 15 minutes at room temperature, and thiolacetic acid is then added (0.45 g, 5.90 mmoles, 2.0 equivalents). The resulting solution is stirred at room temperature for 2 hours. The reaction mixture is concentrated to an oil and silica gel (20 g) is then added. The resulting powder is purified by chromatography on silica gel using hexane / EtOAc 8/2 as eluent to produce the desired thiol acetate as a clear colorless oil. (3S) -3-thiomethyl-1- (4-methoxyphenyl) -sulfonyl] -pyrrolidine (8f): The thiol acetate (0.45 g, 1.37 mmol) in methanol (30 ml) is stirred under an atmosphere of argon at room temperature. ambient. The solution is then bubbled with gaseous ammonia for 20 minutes at room temperature, and then the solution is purged with argon gas. The solvent is removed under reduced pressure to leave a colorless oil. The purification of the oil is achieved by chromatography using hexane / EtOAc 8/2 as eluent. The product is obtained as a colorless oil. MS (electron spray): 288 (M + H +).

EXAMPLE 9 Synthesis of 2- (1-thiol-1- (2-thiazolymethyl) -1- [(4-methoxyphenyl) sulfonyl] iperidine < «*) (M) 2- (R, S) -1- [(4-methoxyphenyl) sulfonyl] piperidinmetanal (9a): Dissolve 2 (R, S) -1- [(4-methoxyphenyl) sulfonyl] -piperidinemethanol (16.5 g, 57.9 mmol) in 400 mL of dichloromethane at room temperature, followed by the addition of PDC (32.67). g, 86.8 mmoles, 15 equivalents). The reaction is stirred at room temperature overnight. In the morning, another 0.5 equivalents of PDC are added, and the reaction mixture is stirred for another 4 hours. The reaction is diluted with ether and passed through a short plug silica gel column with CH2Cl2 as eluent to remove the color to provide the pure product. Cl + EM: m / z (relative intensity) 284. 0 (M + + H, 100). 2- [1-hydroxy-1- (2-thiazolyl) methyl] -1- [(4-methoxyphenyl) -sulfonyl] piperidine (9b): The thiazole (0.576 ml, 8.13 mmol) is dissolved in 150 ml of THF and it is cooled to -78 ° C in an acetone-dry ice bath. N-Butyl lithium (5.0 mL, 8.13 mmol) is added slowly, and this solution is stirred for 30 minutes. Then, the aldehyde (2.0 g, 7.07 mmol) is dissolved in 15 ml of THF and poured with cannula into the solution at -78 ° C. The resulting solution is stirred at -78 ° C for 1 hour and at room temperature for 2 hours. The reaction is quenched with IN HCl and extracted 3 times with ethyl acetate., and the organic layer is washed with saturated sodium chloride and dried over magnesium sulfate and evaporated. Chromatography is carried out on silica gel using ethyl acetate / hexane (1/1) to give the pure compound. Cl + MS: m / z (relative intensity) 397.0 (M + + H, 100). 2- [1-thioacetyl-l- (2-thiazolyl) methyl] -1- [(4-methoxy-phenyl) sulfonyl] piperidine (9c): In the flask 1, the azeotropically dried alcohol is dissolved (0.270 g, 0.73 mmoles) in 20 ml of anhydrous methylene chloride, followed by the addition of 2,6-lutidine (0.126 ml), 1.08 mmol), and the reaction is cooled to -78 ° C in a dry ice / acetone bath. Then, the trifluoromethanesphonic anhydride (0.135 ml, 0.80 mmol) is added, and the mixture is stirred at -78 ° C for 45 minutes, and then at 0 ° C for 5 minutes. In a separate flask (flask 2), the thiolacetic acid (0.174 ml, 2.44 mmoles) and 2,6-lutidine are dissolved. (0.28 ml, 2.44 mmol) in 10 ml of anhydrous methylene chloride. The contents of flask 2 are poured with cannula into flask 1 at 0 ° C. The reaction is then stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate and water, and then extracted 3 times with ethyl acetate and washed with saturated ammonium chloride, dried over magnesium sulfate, and evaporated. A column of silica gel is run using hexanes / ethyl acetate (3/1) to give the pure compound. 2- [1-thiol-l- (2-thiazolyl) methyl] -1- [(4-methoxyphenyl) -sulfonyl piperidine (9d): The thiol acetate (0.100 g, 0.234 mmol) is dissolved in 8 ml of methanol, and the solution is completely degassed. Anhydrous gaseous ammonia is passed through the solution for 8 minutes, and the solution is stirred for another 15 minutes. The solution is evaporated to a crude product, which is chromatographed on silica gel with hexanes / ethyl acetate (3/1) to give the pure product.

EXAMPLE 10 Synthesis of 2- [1-thiol-2- (5-methyl-1,3,4-thia-iazol-2-yl) thio] ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine 2-ethenyl-l- [(4-methoxyphenyl) sulfonyl] piperidine (10a): Triphenylphosphinmethyl iodide (22.5 g, 55.6 mmol) is suspended in 400 ml of THF, and cooled to 0 ° C in an ice bath, and potassium t-butoxide (8.33 g, 74.2 mmol) is added, and the reaction mixture is stirred for 1 hour. This produces a suspension of a yellow solid in yellow solution. The aldehyde 9a (10.5 g, 37.1 mmoles) is dissolved in 40 ml of THF, and then added to the reaction mixture. The reaction is stirred at 0 ° C for 4 hours. The reaction is quenched with IN HCl and water. This is extracted 3 times with ethyl acetate, and the organic layers are washed with saturated sodium bicarbonate and ammonium chloride, dried over magnesium sulfate, and evaporated to provide the product. Chromatography is carried out on silica gel using hexanes / ethyl acetate (3/1) to give the pure compound. Cl + MS: m / z (relative intensity) 331.9 (M + + H, 100). 2-ethylene oxide-1- (4-methoxyphenyl) sulfonyl] piperidine (10b): The alkene (4.5 g, 16.0 mmol) is dissolved in 200 ml of dichloromethane, followed by the addition of MCPBA (50-75% pure ) (17 g, 64 mmol). The reaction mixture is stirred at room temperature for 26 hours. The reaction is quenched with sodium sulfite (10.1 g, 64.0 mmol) and water, and diluted with saturated sodium bicarbonate. This is extracted 3 times with ethyl acetate, and the organic layers are washed with IN HCl, sodium bicarbonate and ammonium chloride, dried over magnesium sulfate and evaporated. Chromatography is carried out on silica gel using hexanes / ethyl acetate / methylene chloride (11/3/3) to give two different diastereomers as individual pure compounds. Cl + EM (relative intensity) 298 (M + + H, 100). 2- (l-Hydroxy-2- (5-methyl-1,3,4-thiadiazol-2-yl) thio) ethyl-l- [(4-methoxyphenyl) sulfonyl] iperidine (10c): The epoxide is further dissolved polar (0.270 g, 0.908 mmol) in 10 ml of dichloromethane, and cooled to 0 ° C followed by the addition of lithium perchlorate (0.363 ml, 1.81 mmol). This mixture is stirred for 5 minutes, and then 5-methyl-1,3,4-thiadiazole-2-thiol (0.480 g, 3.63 mmol) is added. The reaction mixture is stirred at 0 ° C at room temperature overnight. The reaction is quenched with IN HCl and extracted 3 times with ethyl acetate. The organic layers are washed with ammonium chloride, dried over magnesium sulfate and evaporated. Chromatography is carried out on silica gel using hexanes / ethyl acetate (1/1) to give the pure compound. Cl + MS: m / z (relative intensity) 430 (M + + H, 70). 2- (1-acetylthio-2- (5-methyl-1,3,4-thiadiazol-2-yl) thio) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine (lOd): In flask 1, the azeotropically dried alcohol (0.300 g, 0.968 mmol) is dissolved in 10 ml of anhydrous methylene chloride, followed by the addition of 2,6-lutidine (0.122 ml, 1.04 mmol), and the reaction is cooled to -78 ° C. in a dry ice / acetone bath. Then, the trifluoromethanesulfonic anhydride (0.129 ml, 0.768 mmol) is added, and the mixture is stirred at -78 ° C for 45 minutes and then at 0 ° C for 5 minutes. In a separate flask (flask 2), thiolacetic acid (0.498 ml, 6.93 mmol) and 2,6-lutidine (0.81 ml, 6.93 mmol) are dissolved in 10 ml of anhydrous methylene chloride. The contents of flask 2 pour with cannula into flask 1 to 0 ° C. The reaction is then stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate and water, then extracted 3 times with ethyl acetate, and washed with saturated ammonium chloride, dried over magnesium sulfate, and evaporated. Run a column of silica gel using hexanes / ethyl acetate (1 / 2.5) to give the pure compound. Cl + MS: m / z (relative intensity) (M + + H, 100). 2- (l-fciol-2- (5-methyl-l, 3,4-thiadiazol-2-yl) thio) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine (lOe): The thiol acetate is dissolved (0.050 g, 0.102 mmol) in 5 ml of methanol, and the solution is completely degassed. Anhydrous gaseous ammonia is passed through the solution for 2 minutes, and the solution is stirred for another 5 minutes. The solution is evaporated under reduced pressure to leave a crude product which is chromatographed on silica gel with hexanes / ethyl acetate (1/2) to give the desired thiol. Cl + MS: m / z (relative intensity) (M + + H, 100).

EXAMPLE 11 Synthesis of 2- (R, S) - (2-methoxycarbonyl-1- (R, S) -mercapto) ethyl-1- [(4-methoxyphenyl) sulfonyl] iperidine («B) (11 e) 2- (2-methoxycarbonyl) ethenyl-1- [(4-methoxyphenyl) -sulfonyl] piperidine lia: The aldehyde (450 mg, 1.59 mmol) is dissolved in 20 ml of acetonitrile. It adds (triphenylphosphonarinylidene) methyl acetate (1.06 g, 3.18 mmol). The solution is heated to reflux and stirred for hours. After cooling to room temperature, the solvent is removed by rotary evaporation. Chromatography is carried out on silica gel using hexanes / ethyl acetate (2/1) to give the pure compound. Cl + MS: m / z (relative intensity) 340 (M + + H, 53). 2- (RS) - (2-methoxycarbonyl-1- (R, S) -thiacetyl) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine llb: The a, b-unsaturated ester is dissolved (462 mg, 1.36 mmoles) in 25 ml of thiolacetic acid. The solution is heated to 80 ° C and stirred for 5 days. After cooling to room temperature, the solvent is removed by rotary evaporation. Chromatography is carried out on silica gel using methanol / dichloromethane (3%) to give the pure compound. Cl + MS: m / z (relative intensity) 416 (M + + H, 100). 2- (R, S) - (2-methoxycarbonyl -1- (RS) -mercapto) ethyl-1- [(4-methoxyphenyl) sulfonylpiperidine 11c: The thiol acetate is dissolved in 25 ml of methanol, and the solution is degassed with argon for 20 minutes. The solution is cooled to -50 ° C, and ammonia is bubbled at such a rate to maintain the temperature below -20 ° C. When the addition of ammonia ceases to be exothermic, the flow is stopped and the mixture is stirred under argon at -60 ° C for 1 hour. The mixture is heated to room temperature, and the solvent is removed by rotary evaporation. Chromatography is carried out on silica gel using methanol / dichloromethane (0.5%) to give pure compounds as separable diastereomers. Cl + MS: m / z (relative intensity) 374 (M + + H, 65).

EXAMPLE 12 Synthesis of 2- (R, S) - (2-methylthio-l- (R, S) -mercapto) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine (10b) («•> (1? B) 2- (R, S) - (2-ethylene sulfide) -1- [(4-methoxyphenyl) -sulfonyl piperidine 12a: The epoxide is dissolved (0.124 mg, 0. 415 mmoles) in 3.7 ml of methanol under argon. Thiourea is added (63.3 mg, 0.831 mmol), and the mixture is stirred for 7 days.

The solvent is removed by rotary evaporation. Chromatography is carried out on silica gel using hexanes / ethyl acetate (2/1) to give the pure compound. FAB + MS: m / z (relative intensity) 374 (M + + H, 23). 2- (R, S) - (2-methylthio-1- (R, S) -mercapto) ethyl-l - [(4-methoxyphenyl) sulfonyl] piperidine 12b: The episulfide (25.7 mg, 0.0798 mmol) is dissolved in 4 ml of DMF under argon. Triethylamine (53 ml, 0.383 min) is added, and the mixture is cooled to -55 ° C. Methyl mercaptan is passed through the solution for 15 minutes, and the mixture is stirred at -55 ° C for 4 hours. The bath is removed and the mixture is stirred at room temperature for 16 hours. The solvent is removed by rotary evaporation. The crude product is purified by radial chromatography using hexanes / ethyl acetate (6/1). EM ion spray: m / z (relative intensity) 362 (M + + H, 42).

EXAMPLE 13 Synthesis of 2- (R, S) - (1- (R, S) -methylthio-2-mercapto) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine (Ui) (13 «| (11b) 2- (R, S) - (1- (R, S) -methylthio-2-chloro) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine 13a: Methyl disulfide (32 ml, 0.355 mmol) is dissolved in 5 ml of 1,2-dichloroethane, and cooled to -40 ° C. Sulfuryl chloride is added by syringe (29 ml, 0.355 mmol). The mixture is heated to -10 ° C and cooled to -40 ° C. A solution of the alkene in 1 ml of 1,2-dichloroethane is added by syringe. The cold bath is removed and the mixture is stirred at room temperature for 16 hours. The solvent is removed by rotary evaporation. Chromatography is carried out on silica gel using hexanes / ethyl acetate (4/1) to give the pure compound Cl + MS: m / z (relative intensity) 364 (M + + H, 100). 2- (R, S) - (1- (R, S) -methylthio-2-mercapto) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine 13b: Chlorosulfide (50.0 mg, 0.137 mmol) is dissolved in 5 ml of 95% ethanol. Thiourea (12.6 mg, 0.165 mmol) is added, and the mixture is heated to reflux temperature for 4 hours. After cooling to room temperature, the solvent is removed by rotary evaporation. The residue is treated with 5 ml of concentrated ammonium hydroxide at 85 ° C for 1 hour. The mixture is cooled to room temperature, diluted with water and extracted with two portions of ethyl acetate. The combined organic layers are washed 3 times with water, dried over MgSO 4, filtered, and the solvent is removed by rotary evaporation. The crude product is purified by radial chromatography using hexanes / ethyl acetate (4/1) EM ion spray: m / z (relative intensity) 362 (M + + H, 100).

EXAMPLE 14 Synthesis of 2- (R, S) - (1- (R, S) -2-dithio) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine (1y> (14i) (14 *) 2- (R, S) - (2-thioacetyl-l- (RS) -mercapto) ethyl-1- [(4-methoxyphenyl) sulfonyl] piperidine 14a: The episufide (25 mg, 0.0798 mmol) is dissolved in 2 ml of ethyl acetate. Triethylamine (40 ml, 0.287 mmol) and thiolacetic acid (25 ml, 0.251 mmol) are added, and the mixture is stirred for 16 hours at room temperature and 4.5 hours at 50 ° C. The reaction mixture is diluted with ethyl acetate and washed with 3 portions of 5% NaHCO3. The organic layer is dried over Na 2 SO 4, filtered, and the solvent is removed by rotary evaporation. The crude product is purified by radial chromatography using hexanes / ethyl acetate (4/1). 2- (RS) - (1- (RS) -2 -dithio) ethyl-1- \ (4-methoxyphenyl) -sulfonyl] piperidine 14b: The thiol acetate is dissolved in 25 ml of methanol, and the solution is degassed with Argon for 20 minutes. The solution is cooled to -50 ° C, and ammonia is bubbled at such a rate to maintain the temperature below -20 ° C. When the addition of ammonia ceases to be exothermic, the flow is stopped, and the mixture is stirred under argon at -60 ° C for 1 hour. The mixture is heated to room temperature, and the solvent is removed by rotary evaporation. The crude product is purified by radial chromatography using methanol / dichloromethane (0.5%). Ion spray + MS: m / z (relative intensity) 348 (M + + H, 100). The following compounds are obtained using the methods described and exemplified above. For illustration purposes, Y is shown as R2 and Z is shown as Rl.

Me = methyl, Ph = phenyl; CgH4 = di-radical phenyl. The following compounds are obtained using the methods described and exemplified above. All the compounds exemplified below have Z (or R?) As Me02CCH2CH (SH) -.

These examples provide a person skilled in the art with sufficient guidance to carry out the present invention, and in no way limit it.

Composition and method of use EXAMPLES The compounds of the invention are useful for preparing compositions for the treatment of diseases and the like. The composition and the following method examples do not limit the invention, but serve as a guide 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 formula I can be substituted by the example of compound shown below with similar results. The exemplified methods of use do not limit the invention, but they guide the person 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 serve as a guide, and that they can be varied based on the condition and the patient.

EXAMPLE A A tablet composition for oral administration is formulated, according to the present invention, comprising: Cantida component? Example 9 15 mg Lactose 120 mg Corn starch 70 mg Talc 4 mg Magnesium stearate 1 mg Other compounds having a structure according to formula (I) are used with substantially similar results. A woman who weighs 60 kg and who suffers from rheumatoid arthritis is treated by a method of this invention. Specifically, for 2 years, a regimen of 3 tablets per day is orally administered to said subject. At the end of the treatment period, the patient is examined, and is found to have reduced inflammation and improved mobility without concomitant pain.

EXAMPLE B A capsule for oral administration is formulated, according to the present invention, 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 man who weighs 90 kg and who suffers from osteoarthritis is treated by a method of this invention. Specifically, for 5 years, a capsule containing 70 mg of Example 3 is administered daily to said subject. At the end of the treatment period, the patient is examined by orthoscopy, and it is found that there is no erosion / fibrillation progression in the patient. Articular cartilage.

EXAMPLE C A composition based on saline for local administration is formulated, in accordance with the present invention, comprising: Component Quantity (% w / w) Compound of 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 suffering from deep corneal abrasion is given twice a day the drop in each eye. Healing is accelerated, with no visual sequelae.

EXAMPLE D A topical composition for local administration is formulated, according to the present invention, comprising: Component Composition (% w / v) Compound of example 3 0.20 Benzalkonium chloride 0.02 EXAMPLE D (CONTINUED) Thimerosal 0.002 d-sorbitol 5.00 Glycine 0.35 Aromatic compounds 0.075 Purified water q.s. Total = 100 Total = 100 Any of other compounds having a structure according to formula (I), is used with substantially similar results. A patient suffering from burns by chemical compounds, the composition is applied at each change of bandage (twice a day). Scar formation is substantially diminished.

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

EXAMPLE F A topical ophthalmic composition is formulated in accordance with the present invention, comprising: Component Composition (% w / v) Compound of Example 5 0.10 Benzalkonium Chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL M ™) 0.50 EXAMPLE F (CONTINUED) Sodium metabisulphite 0.10 Sodium chloride (0.9%) c.s Total = 100.0 Any other compounds having a structure according to formula (I) are used with substantially similar results. A man weighing 90 kg who suffers from corneal ulcerations is treated by a method of this invention. Specifically, for two months, a saline solution containing 10 ml of Example 5 is administered twice daily to the affected eye of said subject.

EXAMPLE G A composition for parenteral administration is formulated comprising: Component Quantity Example 4 100 mg / ml of vehicle Vehicle: Sodium citrate pH regulator (% by weight of the vehicle): Lecithin 0.48% Carboxymethylcellulose 0.53 EXAMPLE G (CONTINUED) Povidone 0.50 Methylparaben 0.11 Propylparaben 0.011 The above ingredients are mixed forming a suspension. Approximately 2.0 ml of the suspension is administered by injection to a human suffering from pre-metastatic tumor. The injection site is juxtaposed to the tumor. This dosage is repeated twice a day for approximately 30 days. After 30 days, the symptoms of disease decrease, and the dosage is gradually reduced to maintain the patient. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE H A composition for mouthwash is prepared Component% in p / v Example 1 3.00 Alcohol SDA 40 8.00 Flavor 0.08 EXAMPLE H (CONTINUED) Emulsifier 0.08 Sodium fluoride 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide 0.20 Dye 0.04 Water balance at 100% A patient with gum disease uses 3 ml per day of mouthwash to prevent further oral degeneration. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE I A tablet composition is prepared: Component% in p / v Example 3 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 EXAMPLE I (CONTINUED) Sweetener 1.20 Flavor 11.70 Color 0.10 Corn syrup 100% balance A patient uses the pill to prevent loosening of an implant in the jaw. Other compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE J Chewing gum composition Component% in p / v Example 1 0. .03 Sorbitol crystals 38. .44 Paloja-T gum base 20.. Sorbitol (aqueous solution at 0% L 22. .00 Mannitol 10. .00 Glycerin 7,. 56 Flavoring 1 .00 A patient chews the gum to prevent loosening of the denture. Other compound compounds having a structure according to formula (I) are used with substantially similar results.

EXAMPLE K Components% in w / v Water USP 54., 656 Methylparaben 0. .05 Propylparaben 0. .01 Xanthan gum 0. .12 Guar gum 0, .09 Calcium carbonate 12. .38 Antifoam 1. .27 Sucrose 15. .0 Sorbitol 11. .0 Glycerin 5, .0 Benzyl alcohol 0, .2 Citric acid 0. .15 Refreshing 0 .00888 Flavoring 0, .0645 Dye 0. .0014 Example 1 is prepared by first mixing 80kg of glycerin and all the benzyl alcohol and heating to 65 ° C, then adding slowly and mixing together methylparaben, propylparaben, water, xanthan gum and guar gum. These ingredients are mixed for approximately 12 minutes with a Silverson in-line mixer. The following ingredients are then added slowly in the following order: rest of glycerin, sorbitol, antifoam C, calcium carbonate, citric acid and sucrose. Flavoring and refreshing are combined separately, and then slowly added to the other ingredients. All of the above is mixed for approximately 40 minutes. The patient takes the formulation to prevent the appearance of colitis. All references described herein are incorporated herein by reference. Although particular embodiments of the present invention have been described, it will be obvious to one skilled in the art that various changes and modifications of the present invention can be made without departing from the spirit and scope thereof. It is intended to encompass, in the appended claims, all modifications that are within the scope of this invention.

Claims (34)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound, characterized in that it the structure according to formula (I): (i) where n is an integer of 3, and 0 to 2 additional heteroatoms, selected from O, N or S, can occur in the base structure of the ring instead of carbon, and where S occurs it can be S-shaped, SO or SO2, and where N occurs is in the form of NR5 and R is selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO2R10, COR] _ ?, CSR_2, PO (R) _3) 2; Z is independently one or more of (CH2) m (CR1R2) 0SR3; and R ^ is independently hydrogen, alkyl, CH2SR3 or CH2C (W) R4, and R4 is alkoxy, hydroxy, NR5, alkylthio or thio; and R5 is independently one or more of heterocyclylalkyl, alkyl, aryl, heteroalkyl, heteroaryl, hydrogen, or with W can form a heterocyclic ring; R 2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylene, aryl or heteroaryl, W is O or S, R 3 is hydrogen, alkyl, aryl, heteroaryl; and m and o are integers, independently selected from 0, 1 and 2; And it is independently one or more of hydrogen, hydroxy, oxo, a spiro portion, SORg, SO 2 10 alkoxy, aryloxy, alkylaryl, heteroaryl, COR 4, CSR] _2, amino, wherein amino is of the formula R g R g, wherein R g y R9 are independently selected from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, OR3, S0 R? O, CORllf CSR12, PO (R13) 2; and Rg is alkyl, aryl, heteroaryl; R] o is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R ^ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R] _2 is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R 13 is alkyl, aryl, heteroaryl, heteroalkyl; and Ar is alkyl, aryl, carbocyclyl, heterocyclyl, or substituted or unsubstituted heteroaryl; or an optical isomer, diastereomer, enantiomer, or a pharmaceutically acceptable salt, or biohydrolyzable ester, amide or imide thereof.

2. The compound in accordance with the claim 1, further characterized in that Z is selected from thio, alkylthio, thioalkyl, R3SCH2CH (RS3) - and R C (O) CH2CH (SR3) -.

3. - The compound in accordance with the claim 2, further characterized because it the structure:

4. - The compound according to claim 2, further characterized by having the structure:

5. - The compound in accordance with the claim 1, further characterized in that Ar is phenyl or substituted phenyl.

6. - The compound in accordance with the claim 5, further characterized in that Ar is substituted phenyl and the substitution is with hydroxy, alkoxy, nitro or halogen.

7. The compound in accordance with the claim 6, further characterized in that the substitution is with methoxy, bromine, nitro and butoxy.

8. The compound according to claim 7, further characterized in that the substitution of Ar is ortho or para in relation to the sulfonyl.

9. The compound according to claim 8, further characterized in that n is 1 or 2.

10. The compound according to claim 1, further characterized in that Y is one or more of hydrogen, or C_ to C4 alkyl.

11. The compound according to claim 8, further characterized in that Y is alkyl of geminal Cl to C4.

12. The compound according to claim 9, further characterized in that the compound two Z-portions selected from thio and thiomethyl.

13. The compound according to claim 9, further characterized in that Z is CH3OC (0) CH2CH (SH) -.

14. The compound according to claim 9, further characterized in that Z is R3SCH CH (SH) -, and R3 is heteroaryl.

15. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound according to claim 1; and (b) a pharmaceutically acceptable carrier.

16. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound according to claim 2; and (b) a pharmaceutically acceptable carrier.

17. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound according to claim 3; and (b) a pharmaceutically acceptable carrier.

18. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound according to claim 4; and (b) a pharmaceutically acceptable carrier.

19. A pharmaceutical composition, characterized in that it comprises: (a) a safe and effective amount of a compound according to claim 9; and (b) a pharmaceutically acceptable carrier.

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

21. The use of a compound according to claim 2, for the manufacture of a medicament for preventing or treating a disease associated with undesirable metalloprotease activity in a mammalian subject.

22. The use of a compound according to claim 3, for the manufacture of a medicament for preventing or treating a disease associated with undesirable metalloprotease activity in a human or other animal subject.

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

24. 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, wherein the disorder is selected from the group comprising arthritis, cancer, cardiovascular disorders, skin disorders, eye disorders, inflammation and gum disease in a mammal.

25. The use according to claim 24, wherein the disorder is arthritis, and is selected from the group comprising osteoarthritis and rheumatoid arthritis.

26. The use according to claim 24, wherein the disorder is cancer, and the treatment prevents or counteracts tumor growth and metastasis.

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

28. The use according to claim 24, wherein the disorder is an ocular disorder, and is selected from the group comprising corneal ulceration, lack of corneal scarring, macular degeneration and pterygium.

29. The use according to claim 24, wherein the disorder is gum disease, and is selected from the group comprising periodontal disease and gingivitis.

30. The use according to claim 24, wherein the condition is a condition of the skin selected from the group comprising restoration and prevention of wrinkles, skin damage by light U.V. , 'epidermolysis huullosa, psoriasis, scleroderma, atopic dermatitis and scar formation.

31. The use of a metalloprotease inhibitor according to claim 1, for the manufacture of a medicament for preventing loosening of prosthetic devices selected from the group comprising joint replacements and dental prostheses in a mammal.

32. The use according to claim 24, wherein the disease is selected from the group comprising inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, inflammation due to acne, osteomyelitis, bronchitis, arthritis and asthma.

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

34. 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.