MXPA97007214A - Derivatives of hydroxamic acid containing lactama, compositions containing them and using the mis - Google Patents

Abstract

The present invention relates to compounds that exhibit inhibitory activity against matrix metalloproteases ("MMPs"), since it is known that MMPs play a role in tissue degradation, the compounds of the present invention can be useful for preventing or treating diseases associated with excess MMP activity, in particular, the compounds have a structure according to formula (I), wherein (A) (1) (a) R 1 is hydrogen, alkyl, heteroalkyl, a heterocyclic ring; carbocyclic ring, alkoxy, carbocycle-alkyl, heterocyclealkyl, carbocycle-heteroalkyl, or heterocycle-heteroalkyl, and (b) R2 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, heteroalkyl, a heterocyclic ring, a carbocyclic ring, carbocycle alkyl; heterocyclealkyl; or -OR, wherein R is alkyl, alkenyl or carbocycloalkyl; or (2) R1 and R2 together form a cycloalkyl ring of 3 to 8 ring atoms; (B) R3 is hydrogen;; or carbocycle-alkyl; (C) R4 e s (1) alkyl; (2) carbocycloalkyl; (3) -XC (= Y) -Z-R5 or X-CH2-Z-R5 or -X-CH2-Z-R5, wherein (a) X is a covalent or alkyl bond, (b) Y is O, S or NH, (c) Z is O, S or NH, and (d) R5 is hydrogen, alkyl, alkenyl, carbocycloalkyl, or aryl; 4) -S = 2-R6, wherein R6 is alkyl, carbocycloalkyl, heterocycloalkyl, or aryl, and (D) Q is [-C (R7) 2 -] - n, wherein (I) n is the integer 2, 3 or 4, and (2) each R7 is independently hydrogen or alkyl such that the heteroatom containing Q is saturated, or the portion of R7 in two adjacent carbon atoms is a covalent bond so that the heterocycle containing Q of the formula (I) is unsaturated, or a pharmaceutically acceptable salt, or biohydrolyzable alkoxyamide, acyloxyamide or imide thereof, the invention also relates to pharmaceutical compositions comprising these compounds, and to the use of said compounds and compositions in the preparation of pharmaceutical compositions to prevent or treat associated diseases s with MMP activity you do not want

Description

DERIVATIVES OF HYDROXYLIC ACID CONTAINING LACTAMA, COMPOSITIONS CONTAINING THE SAME AND THE USE THEREOF TECHNICAL FIELD This invention is directed to compounds that are useful in the treatment of diseases associated with excess and / or unwanted rnet-alloprotease activity, in particular the tail action < jenasa and / or is + roioel i s na. More specifically, the invention is directed to compounds containing hydroxanic acid which contain a substituted lactate ring.

BACKGROUND OF THE INVENTION A number of enzymes perform the division of structural proteins and > These include collagenase from human skin fibroblast collagenase, gela + fibroblast nase from human skin collagenase and human sputum gel, and c + r? mel i si ^ < \ human These are rnetaloprotease enzymes that contain pnc, co or are the enzymes that convert angiotensi to and? ,, - n < i? Uina ',, 1,. i < ? < . n < niui 'or l ulniji ii i, .., i t i i i i i -J i, iha and Lt < , related are important to mediate the smtoma + ology of a number of diseases, including reuinatoid arthritis (Riullms, D. E., et al., Biochirn Biophys Acta (1983) 695: 117-214); osteoart pt s (Henderson, B., and o + ros, Dr-ugs of the Future (1990) 15;? -508); metastasis of tumor cells (ibid, Broadhurst, M. 3., et al., 48 Cure Res 3307-3312 (1988); and various ulcerated conditions.The ulcerative conditions can result in the cornea as the result of alkali burns. or as a result of infection by Pseudornonas aeruginosa, ñcantharnoeba, Herpes simplex, and vaccine virus Other carcinogenic conditions due to undesired matrix metal opioid activity include pepodontal disease, epidermoidis blister, and sclerotis. Since matrix etaloproteases involve a number of disease conditions, attempts have been made to prepare inhibitors for these enzymes A number of such inhibitors are described in the literature Examples include US Patent No. 5,183,900 , issued on February 2, 1993 to Galardy, EUD Patent No. 4,996,358, issued on February 26, 1991 to Handa et al .; US Patent No. 4,771,038, issued September 13, e 1988 to Uolarun, and others; patent of F.U.A. No. 4,743,587, issued on April 10, 1988 to Dickens, et al .; European Patent Publication Number 575,844, published December 29, 1993 by Broadhurst, and others; International Patent Publication No. UO 93/09090, published on August 13, 1993 by Isornura, et al .; World Patent Publication 92/17460, published October 15, 1992 by Markwell et al. And European Patent Publication Number 498,665, published August 12, 1992 by Beckett, et al. It is known in the art that matrix metalloprotease inhibitors are useful in the treatment of diseases caused, at least in part, by the division of proteins into proteins. Although many inhibitors have been prepared, there is a continuing need for compounds useful in the treatment of such diseases. It has been found that, surprisingly, the lactam-containing hydroxamic acids of the present invention are bean-type collagenase and / or isomeric inhibitors. The compounds of the present invention can therefore be useful for the treatment of conditions and diseases that are characterized by undesired activity by the class of proteins that destroy the structural proteins.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds which are useful as inhibitors of matrix rnetalloproteases and which are effective in the treatment of conditions characterized by the excess activity of these enzymes. In particular, the present involution will be applied to a module + or a structure according to the formula T (A) (1) (a) R1 is hydrogen; I rent; heteroalk a heterocyclic ring; a carbocyclic ring; a cox; carbocyclic-alkyl; heteroei cío -al qui o; carbocycle-heter-oalkyl; or heterocyclohexyl uilo; and (b) R2 is hydrogen; hydroxy; I rent; alqueni o; alkynyl; heteroalkyl; a hetorocicl co ring; a carbocyclic ring; carbocyloalkyl; het PG? CI cl o- 1 qui 1 o; or -OR, where R is not even, to the uenil, or carbocycium-to the one; or (2) R1 and R2 together form a cycloalkyl ring of 3 to 8 ring atoms; (B) R3 is hydrogen; I rent; or carbocycle-alkyl; (C) R "is (1) alkyl; () carbocycium chloride; (3) -X-C (-Y) -Z- S or -X-CH2-Z-RS, wherein (a) X is a covalent or alkyl bond; (b) Y is 0, S or NH; (c) Z is O, S or NH; and (d) RS is hydrogen; I rent; alkenyl; carbocí clo-al qu lo; or aplo; or (4) -O2-R6, wherein R6 is alkyl, carbocycloalkyl, heterocycle-atylo, or aplo; and (D) 0 is an alkyl chain, an alkemyl chain, a heteroalkyl chain or a heteroalkyl enyl chain; wherein said chain has 2, 3 or 4 atoms of chain and is substituted or unsubstituted with one or more alkyl portions; or a pharmaceutically acceptable salt, or biohydrolizable alkoxy acide, acyloxyamide or iride thereof. These compounds have the ability to inhibit at least one Maricidal matrix opioid target. Therefore, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of the formula (T), and to methods for treating diseases characterized by the activity of matrix etaloprotease using these compounds or the pharmaceutical compositions which they contain them. Matrix metalloproteases at a particular undesired location can be identified by conjugating the compounds of the invention to a specific targeting ligand for a marker at said location such as an antibody or fragment thereof or a receptor ligand. The invention is also directed to several other methods that take advantage of the unique properties of these compounds. Thus, in either aspect, the invention is directed to the compounds of the formula (T) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired matrix metal oprotease. In another aspect, the invention is directed to the compounds of the formula (I) conjugated to a brand. As the compounds of the invention bind to at least one metal oprotease matrix, the label can be used to detect the presence of relatively high levels of matrix rnetalloprotease in the cell culture in vivo or in vivo. In addition, the compounds of the formula (I) can be conjugated to vehicles that allow the use of these compounds in the immunization of protocols for preparing antibodies specifically immunoreactive with the compounds of the invention. These antibodies are then useful both in the therapy and in the control of the dose of the inhibitors.

DETAILED DESCRIPTION The compounds of the present invention are ihibi or '-' '- d met the onrotea'-as de rnat i- * inamífera ^ Preferably, the compounds are those of the formula (I) wherein the heteroeicio containing 0 has a nitrogen atom. These compounds are the following (A) (1) (a) R1 is hydrogen; I rent; heteroal what; a heterocyclic ring; a carbocyclic ring; to the cox i; carbocycyl or -alkyl; he is eroe iclo-alqui 1 o; carbocycloheteroalkyl; or heterocyclohexyl uilo; and (b) R2 is hydrogen; hydroxy; I rent; alkenyl; alkyle heteroalkyl; a heterocyclic ring; a carbocyclic ring; carbocycloalkyl; heterocycle-al ui lo; or -OR, wherein R is alkyl, alkaryl, or carbocyclic o-qui 1; or (2) R and R2 together form a cycloalkyl ring of 3 to 8 ring atoms; (B) R3 is hydrogen; I rent; or carbocycium-1; (C) R * is (1) alkyl; (2) carbocycloalkyl; (3) -X-0 (^ Y) -Z-R5 or -X-CH2- -R5, wherein (a) X is a covalent or alkyl bond; (b) Y is 0, or NH; (c) Z is 0, S or NH; and (d) R5 is hydrogen; I rent; alkenyl; carbocytic-to the quilo; or ap o; or (4) -O2-R6, wherein R * is alkyl, carbocycloalkyl, heterohydrochloroalkyl, or alkyl; and (D) 0 is C-CÍR7) 2 -] - n, wherein (1) n is the integer 2, 3 or 4; and (2) each R7 is independently hydrogen or alkyl such that the heterocycle containing 0 is saturated; or the portion of R7 in two adjacent carbon atoms is a covalent bond so that the heterocycle with Lene Q of the formula (T) is killed. or a pharmaceutically acceptable salt, or alkoxylated biohydrolyzale, acyloxyamide or the like of the same.

DEFINITIONS AND USE OF TERMS: The present is a list of definitions for the termams used herein: "Acyl" or "carbonyl" is a radical formed by the removal of hydroxy from a carboxylic acid (ie, R ~ C (= 0 ) -). Preferred acyl groups include (by e-lim io) acyl, phyllo and propiom. "Acyloxy" is an oxygen radical having an acyl substituent (i.e., -0-acyl); for example, -0- C (= 0) -alkyl.

"Aci lamino" is an arnine radical that has an acyl substi- tant (ie, N ~ ac? Lo); for example, -NH-C (= 0) -aiqu? lo. "To coxy acyl" is an acyl radical (-Ci-0) -) having an alkoxy substituent (i.e., -0-R), for example, -C (= 0) -0-alkyl. "Alkenyl" is a substituted or unsubstituted hydrocarbon chain radical having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms; preferably from 2 to 10 carbon atoms; more preferably from 2 to 8; except where indicated. Preferred are alkerule substituents having at least one olefinic double linkage (including, for example, vimol, allyl, and butenyl). "Alkynyl" is a substituted or unsubstituted hydrocarbon chain radical having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms; preferably from 2 to 10 carbon atoms; more preferably from 2 to 8; except where it is written. 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., -0-alkyl or -0- al queni lo) .. Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy ,. "Alkoxyalkyl" is an alkyl portion substituted or unsubstituted with an alkoxy moiety (ie, -alkyl-0-alkyl). Preferred is where the alkyl has 1, 2, 3, 4, 5 or 6 carbon atoms (most preferred 1 to 3 carbon atoms), and the alkyloxy has 1, 2, 3, 4, 5 or 6 carbon atoms. carbon (most preferred 1 to 3 carbon atoms). "Alkyl" is a substituted or unsubstituted hydrocarbon chain radical having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms; I preferred blernente of 1 to 10 carbon atoms; very preferred from 1 to 4; except where indicated. Preferred alkyl groups include (for example) substituted and unsubstituted methyl, ethyl, propyl, isopropyl and butyl. "Alquilammo" is an arnino radical that has one (secondary amine) or two (tertiary amine) alkyl substituents (ie, N-alkyl) "For example, rhenylamine (-NHOH3), dirneti lamina (-N (CH3) 2), met 1 let 1 lamí na (- N (CH3) 0H2 CH3"Arní noací lo" is an acyl radical having an amino substituent (ie, -0 (= 0) ~ N), for example, -C (= 0) -NH2. The arnino group of the ammoacyl moiety may be unsubstituted (ie, primary amine) or may be substituted with one (secondary amine) or two (ie, tertiary amine) alkyl groups. "Aplo" is a carbocyclic ring radical. Preferred acyl groups include (for example) phenyl, tolyl, xylyl, curnenyl and naphthyl. "Aplalkyl" is an alkyl radical substituted with an aplo group Preferred lanyl groups include benzyl, femlethyl and ferulpropyl. Laquilano "is an amine radical substituted with an aplakchiio group (for example, ~ NH-benzyl)." Aplarnino "is an amine radical substituted with an amino group. (ie, -NH-aryl). "Aploxy" is an oxygen radical that has an aryl substituent (ie, -0-ar? Lo). "Carbicyclic ring" is a substituted or unsubstituted, saturated, saturated or aromatic hydrocarbon ring radical. The carbocyclic rings are monocyclic or are polycyclic ring systems, bridged or spiral. The carbocyclic oncyclic rings generally contain 3, 4, 5, 6, 7, 8 or 9 atoms, preferably from 3 to 6 atoms. Polycyclic carbocyclic rings contain 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 atoms, f >; refor *? bl ement of 7 to 1 volumes. "Carbocycloalkyl" is an alkyl radical substituted or unsubstituted, substituted with a carbocyclic ring. Unless otherwise specified, the carbocyclic ring is preferably an aryl or cycloalkyl; more preferably an aryl. The carbocycle-alkyl groups reported include benzyl, phenylene and femotropyl. "Carbocycloheteroacyl" is a substituted or unsubstituted heteroalkyl radical, substituted with a carbocyclic ring. Unless otherwise specified, the oarbicylic ring is preferably an aplo or cycloalkyl; more preferably an aplo. The heteroalkyl is preferably 2-oxa-prop? lo, 2-oxa-ethylene, 2-thia-propyl or 2- ia- and ilo. "Car boxyalkyl" is an alkyl radical substituted or unsubstituted, substituted with a carboxy (-O (-O) OH) moiety. For example, -CH2 -C (^ = 0) 0H. "Cycloalkyl" is a saturated carbocyclic ring radical. The pr-eferidic cycloalkyl groups include (for example) cyclopropylo, cyclobutyl and cyclohexyl. "Cycloheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) orfolma, piperadma and piperazine. "Fused rings" are the rings that are superimposed together so that they share two ring atoms. A given ring can be fused to more than one other ring "Herocycle-to-which" is a substituted or unsubstituted alkyl radical, substituted with a heterocyclic ring. The ionic ring is preferably an aryl or cycloheteroalkyl; more preferably a heteroaryl. "Hetero-cycloheteroalkyl" is a substituted or unsubstituted heteroalkyl radical, substituted with a heteroaryl ring. The heterocyclic ring is preferably an alkyl or cycloheteroalkyl; More preferably one aplo. "Het eroatorno" is a nitrogen atom, sulfur or oxygen. Groups containing one or more heteroatoms may contain different heteroatoms. "Heteroalquem" is a substituted or unsubstituted unsaturated chain radical having 3, 4, 5, 6, 7 or 8 members comprising carbon atoms and one or two heteroatoms. The chain has at least one carbon-carbon double bond. "Heteroalkyl" is a substituted or unsubstituted saturated chain radical having 2, 3, 4, 5, 6, 7 or 8 members comprising carbon atoms and one or two heteroatoms. "Heterocyclic ring" is a substituted or unsubstituted, saturated, unsaturated or aromatic ring radical composed of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monoclonal or are polycyclic ring systems, bridged or spiral. Heterocyclic ringlets containing 3, 4, 5, 6, 7, 8 or 9 atoms, I prefer 4 to 7 atoms. Polycyclic rings contain 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 atoms, preferably from 7 to 13 atoms. "Heteroap lo" is a heterocyclic aromatic ring radical. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pipdinyl, pyrazinyl, thiazolyl, pi rimidinyl, quinine! i nor Jo and tetrazol ilo. "Halo", "halogen" or "halide" is a radical of chlorine, bromine, fluorine or iodine atom. Preferred halides are chlorine and fluorine. n Also, as referred to herein, a "lower" hydrocarbon portion (eg, "lower" alkyl) is a hydrocarbon chain composed of 1, 2, 3, 4, 5 or 6, preferably 1 to 4, carbon atoms. A "pharmaceutically acceptable salt" is a cationic salt formed in any acid group (eg, carboxyl), or an ammonium salt formed in any basic group (eg, a mo). Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., Published on September 11, 1987 (incorporated herein by reference). Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkali metal salts (such as magnesium and calcium). Preferred ammonium salts include halides (such as or chloruron salts). "Biohydrolyzable coxarynide" and "biohydrolyzable acyloxyarm" are hydroxamic acid amides which do not interfere essentially with the inhibitory activity of the compound, or which are readily converted. I live by a human or lower animal subject to give an active hydroxyl acid. A biohydrolyzable alkoxyarmide derivative of the orbitals the formula (T) is represented by < -? gu? ente: wherein E is an alkyl portion. A biohydrolyzable acyloxyarnide derivative of the compounds of the formula (T) is wherein E is an acyl portion (eg, R-C (-O) -). A "biohydrolyzable hydroxy irnide" is a bond of a compound of the formula (I) that does not interfere with the rnetaloprotease inhibitory activity of these compounds, or that is readily converted alive by a human or lower animal subject to a compound active of the formula (I). Said hydroxy-imides include those which do not interfere with the biological activity of the compounds of the formula (I).

These images have a structure in accordance with the following: ^ n where F is an acyl moiety (eg, -0 (= 0) -R). A "solvate" is a complex formed by the combination of a solute (e.g., a hydroxarnic acid) and a solvent (e.g., water). See 3. Hong and others, The Van Nostrand Chernist's ictionary, 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 hydroxarnic acid (eg, water, ethane, acetic acid, N, N ~ d-rnet-il-pharnamide). The illustration of specific protected forms and other derivatives of the compounds of the formula (I) should not be limiting. The application of other useful protective groups, salt forms, etc., is within the capacity of the skilled in the art. As defined before and as used herein, the substituent groups can be substituted by themselves. Said substitution may be one or more substituents. These substituents include those listed in C. Hansch and A.

Leo, Subst ituent Constants for Cor elation Analysis ín Chemistry and Biology, (1979), incorporated herein by reference. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, arnino, arninoalkyl (e.g., arni ornetium, etc.), cyano, Halo, carboxy, alkoxyaceil (for example, rarhoeloxi, ote), thiol, aplo, cycloalkyl, heteroaryl, heterocycloalkyl (for example, my pipepdi, morpholinyl, pyrrolidium, etc.), L nli I IU, t 1 X, i i d I O A 1, _t 1 q U 1 O,. i r 1 i - > ? 1,? L, laJ 'l l l'j combinations thereof. As it is used in the present, "me loproteasas de matrix rnarní feras" means any enzyme found in rich sources that is capable of catalyzing the division of collagen, gelatin or proteoglycan under suitable test conditions. Suitable test conditions can be found, for example, in the US patent. No. 4,743,587, with references to the Cawston procedure and others, Anal Biochem (1979) 99: 340-345, the use of a synthetic substrate is described by Ueingarten, H. et al., Biochern Biophy Res Cornm (1984) 139: 1184-1187. Of course, any normal method can be used to analyze the division of these structural proteins. The matrix rnetaloprotease enzymes referred to herein are all zinc-containing proteases that are similar in structure to, for example, human stromal cells or skin fibroblast collagenases. Of course, the ability of the candidate compounds to inhibit matrix rnetalloprotease activity can be tested in the tests described above, the isolated matrix metal oprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or can be use crude extracts that contain the scale of enzymes capable of dividing the tissue.

COMPOUNDS: Referring to formula (I), the group subst ítuyen + e Ri is selected from hydrogen; I rent; heteroalkyl; alkenyl; a heterocyclic ring; a car-boc ring? clico alkoxy; carbocycle-alkyl; heterocycloalkyl; carbocycle-het eroalkyl; and heterocycle-heteroalkyl. It is preferred wherein Ri is hydrogen; I rent; alkenyl; a heterocyclic ring; alkoxy; carbocycle-alkyl; or arninoalqui lo. It is more preferred where R1 is hydrogen; C 1 -Ce alkyl; to inoalkyl; or benzyl. It is highly preferred where Ri is hydrogen, methyl, ethyl or proplo. R2 is selected from hydrogen; hydroxy; I rent; alquemlo; alquulo; heteroalk a heterocyclic ring; an earbocicl ring J, co; carbocycle-alkyl; heterocycle-alkyl; and -OR, wherein R is alkyl, alkenyl, or carbocycloalkyl. It is preferred wherein R2 is hydrogen; I rent; or arninoalkyl. It is further preferred wherein R 2 is hydrogen or C 1 -C e alkyl. Particularly preferred is where R2 is n-octyl, n-? Entyl or 2-rnethyl? R-op? The. In an alternative, R1 and R2 together can form a cycloalkyl ring having from 3 to 8 ring atoms; preferably from 5 to 7 ring atoms; very preferred 6 atoms. It is preferred where Rl and R2 do not combine to form an anion. R3 is selected from hydrogen; I rent; and carbocycloalkyl (most preferred C1-C2 alkyl). It is preferred where R3 is hydrogen. R "is selected from alkyl; carbocyc-alkyl; alkoxyalkyl; -X-C (-Y) -Z-R5 or -X-CH2-Z-R5, where (a) X is a covalent or alkyl linkage; (b) Y is 0, S or NH; (c) 2 is O, S or NH; R5 is hydrogen; alkyl, alquer it, carhocycloalkyl, or aryl. When R * is -XC (= Y) -Z-Rs, X is preferably Ci-C3 alkyl (most preferred Ci-C2 alkyl), Y is preferably 0, and Z is preferably NH or 0. When And and Z are 0, R5 is preferably alkyl (preferably methyl or ethyl; rnuy preferred methyl) or carbocycloalkyl (I preferred blernente benzyl); very preferred alkyl. When Y is 0 and Z is NH, R5 is preferably alkyl or carbocyc-alkyl; most preferred is methyl, ethyl, butyl or hencyl. When R 1 is -X-CH 2 -Z-R 5, X is C 1 -C 3 alkyl, Z is preferably 0 or S, and RS is preferably alkyl or carbocycloalkyl (most preferably alkyl). It is particularly preferred where X is Ci, Z is 0 and R5 is Ci-C3 alkyl - When R * os - SO2 R6, R6 is Alkyl, carbocycle-alkyl, hetero-alkyl or alkyl; preferably aplo (preferably fe lo, most preferred 4-rnetil ferulo). As noted above, the particularly preferred compounds of the present invention are those wherein the heterocycle containing 0 has only one ring nitrogen atom. That is, when 0 is -C-CÍR7) 2 -1-n, eri where n is the integer 2, 3 or 4 (rnuy preferred 3 or í). It is particularly preferred where n is 4, so that the heterocycle containing 0 has 7 ring atoms. Each R? is independently hydrogen or alkyl; or the portion of R? in two adjacent carbon atoms it is a covalent bond so that the rock core containing 0 in the formula (T) is more saturated. Preferred compounds are those wherein the heterocycle containing 0 is saturated; very preferred where each R7 is hydrogen. The following illustrates the compounds where the heterocycle containing 0 is unsaturated: In this structure, the heterocycle has seven members (ie, n-4). With reference to formula (I), the carbon atoms a and b represent a portion of -C (R7) 2- where one R7 is hydrogen and the other is a covalonto bond, so that there is a double bond between the atoms b. Two groups of adjacent carbon atoms may have portions of R7 which are covalent bonds, so that the ring of lactate has two points of saturation (ie, two double bonds). The following illustrates these rings where the hot-cycle with 0 and 0 has two points of unsaturation: 2L In this structure, the heterocycle has six members (ie, n = 3). Referring to the formula (T), the carbon atoms a and b represent a portion of -C (R7) 2 ~ where one R7 is hydrogen and the other is a covalent bond, so that there is a double bond between the atoms a b. In addition, c and d represent a portion of -C (R7) 2- where one R7 is hydrogen and the other is a covalent bond, so that there is a double bond between atoms c and d. The following table lists representative preferred compounds within the scope of the invention. The table should not be an exhaustive list of the com ponents within the scope of the invention. With reference to formula (I), 0 is (-CH2-) n, n is 4, and R3 is hydrogen in each case. Cornp. Rl R2 R * 1 hydrogen 2-rnet? 1-CH 2 -C (= 0) -0-CH 3 2 -hydrogen 2-? ne +? lprop? l -CH 2 -C (= 0) -NH-CH 3 3 hydrogen 2-rnet? l propyl -CH 2 -0 (= 0) -0-CÍCH3) 3 4 hydrogen '' -met i 1 propí 1 -CH2-phenMo 5 hydrogen 2-meti 1 propi 1 -CH2 -C (-0) -0-CH2 -femlo 6 hydrogen 2-methyl l propyl -CH2 -C (= 0) -NH-CH2-phenyl 7 hydrogen 2-rnet i 1 propyl -CH2C (= 0) -0-CH3 8 hydrogen - (OH2 CH3 -CH2-C (= 0) -NH- (CH2) 3-CH3 9 hydrogen - (CH2 J7CH3 -CH2-C (= 0) -0-CH3 10 hydrogen - (CH2) 7CH3 -SO2 -ferrum 11 hydrogen - (CH2) 7CH3 -CH2 -CH2 -0-CH3 12 hydro ene - (CH2 ) 7 H3 - (CH2) 3CH3 13 CH3 (fo rma S) 2-rneti lpropi 1 -CH2-C 0) -0-CH3 14 CH3 (form R) 2-metii? Ro? L -CH2-C (= 0) -0-CH3 15 CH3 CH2 CH2-2-methylpropyl • CH2-C (= 0) -0-CH3 16 - (CH2) 2"CH2 OH (forrna cy) 2-methyl ipropyl-CH2-C ( -0-CH3 17 CH3 (S-form) - (CH2) 7CH32 ~ -CH2-C (= 0) -0-CH3 18 CH3 (form R) - (CH2) 7CH32- -CH2-C (= 0 ) -0-CH3 19 CH3 (S-form) - (CH2) 7CH32- -CH2 -CH2 -O-CH3 CH3 (form R) - (CH2) 7CH32- -CH2-CH2 -O-CH3 GENERAL SCHEMES FOR THE PREPARATION OF THE COMPOUND: The hydroxamino compounds of the formula (T) can be prepared using a variety of methods. The general schemes include the following. (Representative examples are described to make specific compounds more than Lante). to. General Scheme 1 1) (BOCbO, DMSO.2A) LNRTMSfe, R4 -X. THF 2B) t-BuOK, R4.X. DMF.3) TFA / CH2CI2 or HCI / EQO 4) L? N (TMS) 2. THF Rl-X. 5) LDA. THF 6) EDAC. HOBT. NMM. DMF. Odtg. C. ") TFA, CH2Cl2, 8A-EDAC, HOBT, NMM, DMF, BnONf HCl, O deg C, li) H.Pd-C, EtOH, 8B- CH2N2; u) NH20HHCW0aMe0H Caprolactane (A) available commercially is given to give (B), followed by the alkylation of the arniic nitrogen under appropriate conditions to give (C) "The lactam (O derived is deprotected under acidic conditions to give the amine salt. (D) which is then used to couple to various succinates as described in schemes 2 and 3. The different alkyl succinates (E) are synthesized following the chiral alkylation method of Evan (DA Evans et al., Synth Org, Voi 86, p. 03 (1991), incorporated herein by reference.) The dianion generated by treating (E) with a hindered base is alkylated to give succinates (F) without dissociates which on further treatment with LD gives the anti-diastereomer (G) desired in reasonable yield (H. 3. Criinrnin, et al., Synlett, 137-138 (1993).) The acid salt (F) or (G) and the amine salt (D) are coupled under a mild condition to give the amide (H) (illustrated without specific stereo- quency), which during Deprotection under acidic conditions gives the corresponding acid (I). A final transformation is carried out to convert the purified acid to the desired inhibitor Cl). b. General Scheme A direct alkylation method can also be used to synthesize the final inhibitors. For example, the tertiary (K) reaction (propagated by reacting Compound a with Compound F or G according to scheme 1) with a base impeded at low temperature followed by an extinction of the anion with an agent of the dilution (L) that during the deprotection under acid conditions and re-esterification provides (M) in good yield .. A direct treatment of this ester with freshly generated hydroxylamina then produces the final inhibitor (N). c. General Scheme 3: The compounds of the present invention having a lactate ring with 5 or 6 members can be prepared from the following inane: 1) (TMS) 2NH. CH3CN: 2) (BOO2O, DMSO 3) L? N (TMSte, THF, BrOftCOOMe; 4) TFA. CH2CI2 For example, L-ormtpna hydrochloride (0) during heating under reflux provides the six-membered lactase (P) which in the additional protection with BOC anhydride produces the desired amide (0) in reasonable yield. This intermediary can then be carried in the final product (S) following a method < As described in the previous schemes. For 5-member lactarines, L-ornithine hydrochloride (Compound (0)) is replaced by (COOH) CH (H2) CH2 CH2 H2 as the starting material. d. General Scheme 4: The modifications of the ring system in the general scheme 3 can also be made by the following method, to provide unsaturation in the ring with ene 0.

Here, a properly substituted pyrimidone (T) is N-alkylated under appropriate conditions to give (U). The resulting product, in this case the m-pipmidone (U), is reduced to provide the desired amine (V). This medium is coupled to the succinate (F) or (G) described in scheme 1 (see scheme I for the synthesis of final products). A variety of ring systems can be generated in a similar manner.

COMPOSITIONS: ! - > < - > The invention also relates to a (a) a safe and effective amount of a compound of the formula (I); and (b) a pharmaceutically acceptable carrier.

As discussed above, numerous diseases are known to be mediated by metalloprotease activity that destroys unwanted or excess matrix. These include tumor metastasis, osteoarthritis, reu atoid arthritis, inflammation of the skin, ulcerations, particularly of the cornea, reaction to infection, pepodontitis and the like. In this manner, the compounds of the invention are useful in therapy with respect to conditions involving this undesired activity. Therefore, the compounds of the invention can be formulated in pharmaceutical compositions for use in the treatment or prophylaxis of these conditions. Normal pharmaceutical formulation techniques are used, such as those described in Pharrnaceutical Sciences of Rern ngton, Macl-Publishmg Company, Easton, Pa., Latest edition. A "safe and effective amount" of a compound of formula (T) is an amount that is effective to inhibit matrix etaloproteases at the site or sites of activity, in a human or lower animal subject, without undue adverse side effects (such such as toxicity, irritation, or allergic response), which coheses with a reasonable benefit / risk ratio when used in this manner of this invention. The specific "safe and effective amount" will obviously vary with such factors as the tra ± ada condition, the physical condition of the patient, the duration of the treatment, the nature of the concurrent therapy (if any), the specific dosage form that the vehicle used is used, the solubility of the compound of the formula (I) in the ism, and the desired dosage regimen for the composition. The compositions of this invention are preferably provided in a unit dosage form. As used herein, a "unit dose 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 subject, in a individual dose, in accordance with good medical practice. These compositions preferably contain from about 5 rng (milligrams) to approximately 1000 rng, more preferably from about 10 rng to about 500 rng, most preferred from about 10 rng to about 300 mg, of a compound of the formula ( T). The compositions of this invention can be in any of a variety of suitable forms (for example) for oral administration., rectal, topical or parenteral. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. These include solid or liquid fillers, diluents, hydrotropes, surfactants, and substances for encapsulation. 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 together with the compound of the formula (I) is sufficient to provide a practical amount of material for administration per unit dose of the compound of the formula (I). The 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 Phar-maceutics, Chapters 9 and 10 (Banker a Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Posage Forms: Tablets (1981); and Ansel, Introduction to Phar-inaceut cal Dosage Forrns 2nd edition (1976). In particular, pharmaceutically acceptable carriers 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, ernulsi ficadores, isotonic salina, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, otyl oleate, pyrrole idone, ethane and sesame oil. Preferably, the pharmaceutically acceptable carrier, in the compositions for administration to the patient, comprises at least about 90% by weight of the total composition. Various forms of oral doses can be used, including l r rma-, solid oino K.u < l < you.,.? L-t, granules > voluminous powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50% of the compound of formula (I). Tablets can be compressed, tablet crushed, fully coated, sugar coated, film coated, or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, color-former agents, flavoring agents, agents flow inductors, and fusion agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, ernulsifying agents, suspending agents , diluents, sweeteners, melting agents, coloring agents and flavoring agents. The compositions of the invention can also be administered to a subject, i.e., by direct placement or spreading of the composition in the epidermal or epithelial tissue of the subject. 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 O.L%, and preferably from about 1% to about 5% of the compound of the formula (I). Suitable vehicles for topical administration preferably remain in place in the skin as a continuous film, and are resistant to being removed by aspiration or immersion in water. Generally, the vehicle is organic in nature and capable of having in it the compound of the formula (T) dispersed or dissolved. The vehicle can include pharmaceutically acceptable emollients, ernulsifiers, thickening agents and solvents.

METHODS OF ADMINISTRATION: This invention also provides m all for the rat or prevention of disturbances associated with excess or unwanted matrix metalloprotease activity 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, a "disturbance associated with excess or unwanted matrix metalloprotease activity" is any disturbance characterized by degradation of matrix proteins. The methods of the invention are useful for treating disturbances such as (for example) oeteoart ritis, pepodontitis, ulceration of the cornea, tumor invasion, rheumatoid arthritis, etc. The compounds of the formula (I) and the compositions of the invention are admixed either topically or systemically The systemic application includes any method for introducing the compound of the formula (I) into the tissues of the body, for example, administration intra-articular (especially in the treatment of rheumatoid arthritis), mthecal, epidural, intramuscular, transderrnal, intravenous, intrapeptoneal, subcutaneous, sublingual, rectal and oral The compounds of the formula (I) of the present invention are preferably administered The specific dose of inhibitor to be administered, as well as the duration of the treatment, are mutually dependent.The dosage and treatment regimen will also depend on such factors as the compound of the specific formula (I) used, the indication of the treatment, the ability of the compound of the formula (I) to reach the minimum inhibitory concentrations at the rnetaloprotease site of matrix to be inhibited, the personal attributes of the subject (such as weight), adherence to the treatment regimen, and the presence and severity of any side effect of the treatment. Typically, for a human adult (weighing approximately 70 kilograms), from about 5 mg to about 3000 rng, more preferably from about 5 mg to about 1000 rng, most preferably from about 10 rng to about 100 mg, of the compound of the formula (I) are administered per day. It is understood that these dose 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 orally or parenterally by intra-articular injection. As is known and practiced in the art, all formulations for arenteral administration must be sterile. For mammals, especially humans, (taking into account an approximate weight of 70 kilograms), individual doses of about 10 ing to about 1000 rng are preferred. A preferred method of systemic administration is oral. Individual doses of about 10 mg to about 1000 mg, preferably about 10 mg to about 300 mg, are preferred. Topical administration can be used to supply the compound of the formula (I) systemically, or to treat a subject locally. The amounts of the compound of the formula (I) to be administered topically depend on such factors as the sensitivity of the skin, the location of the tissue to be treated, the composition and vehicle (if any) that are going to be administered. administering the compound of the formula (T) in particular to be administered, as well as the particular disturbance to be treated and the degree to which systemic effects are desired (as distinguished from local ones). The inhibitors of the invention can be identified at specific locations where the matrix rnetaloprotease is accumulated using target ligands. For example, to target inhibitors to matrix rnetaloprotease contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof that is non-reactive. with a tumor marker as is generally understood in the preparation of immunotoxins in general. The target ligand may also be a suitable ligand for a receptor that is present in the tumor. Any target ligand that specifically reacts with a marker for the desired target tissue can be used. The methods for coupling the compound of the invention to the target ligand are well known and are similar to those described below for coupling to vehicle. The conjugates are formulated and administered as described above. For localized locations, topical administration is preferred. For example, to treat the ulcerated cornea, the direct application to the affected patient may employ a formulation such as eye drops or aerosol. For the treatment of 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 protector. The materials can also be inserted as a contact lens or reserve or co or a subconjunctival formulation. For the treatment of skin inflammation, the compound is applied locally or topically, in a gel, paste, balm or ointment. In this manner, the treatment method reflects the nature of the condition and suitable formulations for any selected route are available in the art.

Of course, in all of the foregoing, the compounds of the invention may be administered alone or as mixtures, and the compositions may also include additional drugs or excipients as appropriate for the indication. Some of the compounds of the invention also inhibit the bacterial metalloproteases although generally at a level lower than that exhibited with respect to the amineous rnetaloproteases. Some bacterial rnetaloproteases seem to be less dependent on the stereochemistry of the inhibitor, while substantial differences are found in the diatherms in their ability to inactivate rnarniferase proteases. In this way, this pattern of activity can be used to distinguish between marine enzymes and bacteria.

PREPARATION AND USE OF ANTIBODIES: The compounds of the invention can also be used in immunization protocols to obtain immunospecific antiserum for the compounds of the invention. Since the compounds of the invention are relatively small, they are advantageously coupled to antigene neutral vehicles, talus romos, lance hornwort vehicles of the genus Fissurella (KLH) or serum albumin. For those compounds of the invention having a carboxyl functionality, it can be made to the vehicle coupling by means of methods generally known in the art. For example, the carboxyl residue can be reduced in an aldehyde and coupled to a carrier through reaction with side chain amino groups in protein-based vehicles, optionally followed by reduction of the irni bond or formed. The carboxyl residue can also be reacted with side chain arnino groups using such condensing agents or dicyclohexyl carbodiimide or other carbodi uni ding agents. The ligand compounds can also be used to perform the coupling; both functional furnace binders and functional heterobiols are available from Pierc Chemical Company, Rockford, III. The resulting immunogenic complex can then be injected into suitable mammalian subjects such as mice, rabbits and the like. Appropriate protocols involve the repeated injection of mrnunogene in the presence of adjuvants in accordance with a program that drives the production of antibodies in the serum. The titres of the immune serum can be readily measured using immunity methods, now standard in the art, which employ the compounds of the invention as anti-enzymes. The obtained anti-urea can be used directly or monoclonal antibodies can be obtained by culturing the peripheral blood cells or the spleen of the immunized animal and immortalizing the cells that produce antibodies, followed by the identification of suitable antibody procedures using normal immunity techniques. Polyclonal or monoclonal preparations are then useful in the control of the therapy or prophylaxis regimens involving the compounds of the invention. Suitable samples such as those derived from blood, serum, urine or saliva can be tested for the presence of the inhibitor administered at different times during the treatment protocol using standard immunity techniques employing the antibody preparations of the invention. The compounds of the invention can also be coupled to labels such as graphical labels, for example, technetium 99 or 1-131, using standard coupling methods. The labeled compounds are administered to subjects to determine the locations of the excess amounts of one or more matrix metalloproteases n vivo, The ability of the inhibitors to selectively bind the rnetaloprotease do ma riz in this way takes advantage to trace the distribution of these enzymes? r? if you. The techniques can also be employed in histological procedures and the labeled compounds of the invention can be used in competitive immunity tests. The following non-limiting examples illustrate the 'ompuo- t o, n? N o < - 1 i nn (, r, friction v u < -o < - the prosen + or invention.

EXAMPLE 1 Synthesis of (2R) - Tsobutyl-3 - (N-hydroxycarboxyamido) -propane ico IN (carbornetoxirnet 11) caprolactam (3S) -amine (1) acid amide 28 Amide acid (2 R) - 1 obut i 1 - 3 - ca rbo - te r - but ox i propioni o caprolact ma- (3S) -auu (25). A mix < acid 23 (2.0 g, 8.70 rnmoles), caprolactarine- [3S3-amine 24 (1.23 g, 9.57 mmolee) and hydrate of 1-H? droxybenzotr? zol ("HOBT") (4.0 g, 26.1 rnrnoles) in 40 L of DMF and 1.6 rnL of N-Metmolum folin ("NMM") is charged with l-Et? l-3 - (-dirnethylaminopropyl) carbodinnide ("EDAC") (2.0 g, 10.44 mrnol.es) and the reaction is stir for 15 hours at room temperature.

The reaction is then partitioned between water and ethyl acetate ("EtOAc"). The organic layer is then washed with 1N HCl, NaHCO 3, and brine, dried over MgSO 4, filtered, evaporated and chromatographed on flash silica with EtOAc to give acid (2R) -isobut? I-3-carbo-tert-buto ipropanoic acid 1N- (carbornetoxy-rnet il) -caprolact arna- (3S) ~ amine (26). The caprolact ama 25 (914 ing, 2.69 nmrnols) is taken in 10 mL of THF and cooled to -78 ° C under argon. To this is added 1 M of b? S (tprnet? Ls? Lil) am? Da of lithium (2.69 rnL, 2.69 rnrnoles) and the reaction is stirred «for 5 minutes. Methyl broacetate (256 μL, 2.69 mmol) is added and stirred for 2 hours. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1N HCl, NaHC 3, and brine, dried over MgSO 4, filtered and evaporated to give the crude material which is then chromatographed on flash silica with hexanes: Et OA (1: 4). par-a »l 26. Amide acid (2R) -Isobut? l-3-carboxypropane? co N- (carbometox? rn? i) - caprolactarna- (3S) -amine (27). T rum luoroa et j co (3 ml.) Acid is added by rubbing a solution of tert-butyl ester 26 (380 mg, 0.922 mmol) in 3 ml of CH2Cl2 under argon and the resulting mixture is stirred for 2 hours. hours at room temperature. The atoi lal e then concentrates to vacuum to give 27 that is carried forward without pupil ication. Amide of acid (2R) -Tsobutyl-3- (0-benzyl) -N- h or ro xi ca r bo xam i do) - p ro pa no i co of 1N- (carbo ethoxyrnethyl) -caprolactar- (3S) -am? na (28) A mixture of acid 27 (345 mg, 0.863 mmol), 0-benzyl hydroxylanine hydrochloride (166 mg, 1.035 mmol) and HOBT (397 mg, 2.59 mmol) in 5 L of N, N-Dimethylformamide ("DMF") ) and 260 μL of NMM is charged with EDAC (199 mg, 1035 mmol) and the reaction is stirred for 15 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1N HCl, NaHCO3, and brine, dried over O, filtered and evaporated to give the crude material which is then chromatographed on flash silica with EtOAc to give the title compound 28. (2R) -Isobutyl l- 3- (N-hydroxycarboxylamino) acid (1N- (carbornetoxymethyl) -caprolaca arna- (3S) -amine (1) acid). The benzyl hydroxamic acid 28 (325 mg, 0.705 mmol) in 6 mL of EtOAc and the loading mixture were treated with 10% palladium on carbon (60 mg) and stirred under a hydrogen atmosphere for 45 minutes. The mixture is then filtered through celite and concentrated to give 240 rng of crude material which; then chromatography on flash silica with EtOAc: formic acid (98: 2) and recrystallize from hexanes: EtOAc (2: 1) to give the desired pure hydroxya1-olic acid.

EXAMPLE 2 Synthesis of (2R) - Tsobutyl acid amide -3- (N-hydro-icoxboxed) -propionic acid of IN- (I-carboxamidomethyl) ca-rolactam- (3S) -amine (2) Acid (2R) -Isobutyl-3- (N-hi-dicarboxarnido) -propionic acid (1N- (rnetylcarboxa idornetyl) -caprolactarna- (3S) -amine (2) acid). The methyl ester 1 (80 ing, .216 mrnol) is converted to 5 rnL of 8M of methyl amine in MeOH and stirred for 15 hours. The solvent is removed and the residue is chromatographed on flash silica with EtOAc: formic acid (97: 3) to give 2.

EXAMPLE 3 Synthesis of acid amule (2R) -Tsobut Ll- 3- (N-hydroxycarboxarnido) -pro-on? Co of 1N- (carbo-butox-1-met-1) caprolactar- (3S) -amine ( 3) 31 Amide of acid (2R) -Isobutyl-3-carboxypropionic acid of caprolactam-i "3S) amine (29) .Tp fluoacetaacetic acid (15 mL) is added via a syringe to an ester solution. butyl 25 (2.2 mg, 6.47 mmol) in 15 mL of CH2Cl2 under argon and the resulting mixture is stirred for 2 hours at room temperature, then the material is concentrated under vacuum to give 29 which is carried forward without purification. (2R) -Isobutyl -3-carborneto-propionirp caprolactarine- (3S) -nane (30) acid. To an acid solution 29 (1.24 g, 4.37 rnrols) in 5 mL of MeOH is added an excess of The excess of diazomethane is then quenched with acetic acid and the solvent is evaporated, the residue is chromatographed on flash silica.

EtOAc to give the desired ester 30. Acid (2R) -Isobutyl-3-carborneto? Pro? On? Co amide of N- (carbo-ter-butoxy-net? L) -cap rol actarna- ( 3S) -amine (31). Caprolact ama 30 (200 rng, 0.67 rnrnols) is added to tetrahydrofuran ("THF") and cooled to -78 ° C under argon. This is added to 1 M b bs (t pmethylsili lithium Darnide (0.67 rnL, 0.67 mmoles) and the reaction is stirred for 5 minutes.T-bromobutyl bromoaceate (99 μL, 0.67 rnmoles) is added and The reaction is then partitioned between water and EtOAc The organic layer is then washed with 1N HCl, NaHC 3, and brine, dried over MgSO 4, filtered and evaporated to give the crude material quo. then chromatographed on flash silica with hexanes: Et? Ac (1: 4) to give the desired ester 31. A da of? acid (2R) - Tsobut i 1 -3- (N-hydroxycarboxaride) -pro-on? co of 1N- (carbo-tert-butoxy-methyl) -caprolactam- (3S) -amine (3) .Step 31 (130 rng, 0.29 immoles) is added to NH2OK (1.3 mL, 1 eq. in MeOH, prepared in accordance with Fieser and Fieser, Reagents for Organic Synthesis, Vol.1, p.478 (1967)) and stirred for 24 hours, the solvent is evaporated and the residue is dissolved in 1N HCl and extract with EtOAc The organic layer is dried over MgS O *, evaporated and the residue was chromatographed on flash silica with EtOAc: formic acid (98: 2) to give -3.

EXAMPLE 4 Synthesis of (2R) -Tsobut 11-3- (N- hydroxycarboxarnide) -propionic acid amide of IN-Benzyl-caprolact arna- (3S) -arn i () 32 A trip of (2R) -Tsobut i l-3-carton) ometo? Prop? On? Co acid from lN-Benc? Lcaprolactarna- (3S) -ar na (32). The caprolactarna 30 (200 mg, 0.67 rnmoles) is converted to 5 mL dry THF and cooled to -78 ° C under argon. To this is added 1 M b bs (tpmethylsiJ ?l) ammonia lithium (0.67 mL, 0.67 rnmoles) and the reaction is stirred for 5 minutes. Benzyl bromide (80 μL, 0.67 mmol) is added and stirred for 2 hours. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1N HCl, NaHC 3, and brine, dried over Mg O 4, filtered and evaporated to give a crude oil which is then chromatographed on flash silica with hexanes: EtOAc (1: 4) to give 32. (2R) -Isobutyl -3- (Nh? drox? carboxam? do) acid amide ~ prop? on? co of lN-Benzyl-ca? rolactam- (3S) -am i na () . Ester 32 (200 ng, 0.52 moJes) is added to NH2OK (1.0 rnL, l eq in MeOH, prepared in accordance with Fieser and Fieser, Vol. 1, p 478) and stirred for 24 hours. The solvent is evaporated and the residue is dissolved in 1N HCl and extracted with EtOAc. The organic layer is dried over MgSO4, evaporated and the residue chromatographed on flash silica with Et? Ac: formic acid (98: 2) to give 4.

EXAMPLE 5 Synthesis of (2R) -Isobutyl-3-N-hydroxy carboxarnidopropiomco acid amide of IN- (carbobenzyl Jox 1 -met.il) - caprolactarna- (3S) -amine (5) ? * 7 38 Ammonium carboxylic acid amide of caprolactane- (3S) -amine (33). A solution of 24 (49.0 g, 383 mol) in 350 rnL of DMSO is charged with di-tert-butyl di carbonate (83.5 g, 383 mmol) and stirred for 5 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1N HCl, and brine, dried over MgSO /; , it filters and evaporates. The residue is re-crystallized from ether: hexanes (2: 1) to give a tert-butoxycarboxylic acid amide of 1N- (carbobenzyloxyrnet j i) -caprolactam- (3S) -amine (34). Aggregate b? S (tnmet? L? J) lithium iron (44.7 mL, 44.7, 1M in THF) to a solution of the cap lac tama 33 (10.2 g, 44.7 mmoles) in THF (100 mL) at -78 ° C under argon and stirred for 15 minutes. Benzyl brioacetate (7.08 ml_, 44.7 rnmoles) is added to the solution by syringe, warmed to room temperature, and stirred for 2 hours. The reaction is then partitioned between H2O and EtOAc. The organic layer is washed with aqueous NaHC 3, aqueous NaCl, and dried over MgSO 4. The crude product is chromatographed on flash silica with hexane: EtOAc (1: 1) to give a salt of trifluoroacetic acid of 1N- (carbobenzyloxyethanol) caprolactam- (3S) -amine (35). 4R is added p-fluoroacetic acid (15 ml.) by syringe to a solution of tert-butyl carboxarnate 34 (5.0 g, 13.2 rnmoles) in 15 ml under argon and the resulting mixture is stirred for 1 hour at room temperature. The material is then concentrated in a vacuum to give it to be carried forward without? Ur? t ation. Acid release (2R) -Tsobut? I-3-carho-ter-butox ipr-opionic of 1N- (carbobenzyloxy-meth j i) -caprol to ct ama - (3S) -aini na (36). A mixture of acid 23 (1.67, 7.25 mole), caprol actarna 35 (2.0 g, 7.25 mole) and HOBT (2.94 g, 21.75 mole) in 15 rnL of DMF and 1.5 rnL of NMM is loaded with EDAC (1.67 g). , 8.70 Rimóles) and the reaction is stirred for 15 hours at room temperature. The reaction is then partitioned between water and EtOAc and then washed with IN HCl, NaHCO 3, and brine, dried over MgSO 4, filtered, evaporated and chromatographed on flash silica with EtOAc: hexanes (2: 1). ) to give the desired pure amide 36. Amide of (2R) -Isobu-3-carbometho- and propionic acid of 1N- (carbobenzyloxymethyl) -caprolac ama- (3S) -amine (38). Trifluoroacetic acid (5 rnL) is added via syringe to a solution of tert-butyl carboxamate 36 (1.2 g, 2.46 rnmoles) in 5 L of CH2CJ2 under argon and the resulting mixture is stirred for 2 hours at room temperature. The material is then concentrated in vacuo to give the acid as a clear oil which is carried forward without purification. To a solution of acid 37 (1.06 g, 2.46 immoles) in 5 40 rnl. of MeOH an excess of diazornethane in ether is added. F? Excess diazotnetane is then quenched with acetic acid and the solvent evaporated. The residue is chromatographed on flash silica gel with EtOAc hexanes (2: 1) to give the desired ester 38. Acid Arn (2R) - Isobutyl-3-N-hydroxycaroni 1N- dopropioni co (carbobenzyl) -rnethyl) -cap ro 1 a ct ama - (3) ami a (5). Ester 38 (420 rnG, 0.94 inol) is added to a solution of H OK (1.3 mL, 1 eq.On MeOH, propagated according to Fieser and Fiesor, Vol. 1, p.48) and stirred for 24 hours. hours. The solvent is evaporated and the residue is dissolved in 1N HCl and extracted with EtOAc. The organic layer is dried over Mg 0 °, evaporated and the residue is chromatographed on flash silica with EtOAc: acid (98: 2) for 5.

EXAMPLE 6 Synthesis of (2R) -Isobutyl-3- (N-hydroxycarboxaride) -amide amide of 1N- (N-Benzyl-1-carboxarnidornethyl) - cap rola ct arna - (3S) -am na (6) Amide of tert-butoxycarboxylic acid of 1N- (carbome oxy rnet? L) -capr-ol actaine- (3S) -a na (39). It was added (t-phenylethylsulfate 1 lithium lime (83.3 rnL, 83.3, 1M in THF) to a solution of caprolactam 33 (J9.0 g, 83.3 mmol) in THF (200 mL) at -78 ° C. C under argon and stir for 15 minutes.Methyl bromoacetate (7.88 mL, 83.3 min) is added to the solution by syringe, warmed to room temperature, and stirred for 1 hour.The reaction is then divided between H2O and EtOAc The organic layer is washed with aqueous NaHCO3, Aqueous NaCl, and dried over MgSO4. The crude product is chromatographed on flash silica with FtOAc to give 39. 1N- (N-benzylcarboxa i orneti 1) -caprolactam- (3S) -amine (40) tert-Butoxycarboxylic acid amide. The methyl ester 39 (2. 5 g, 8.33 rnmoles) is taken in 10 L of MeOH and the mixture is charged with benzyl amine (8.7 L, 79.7 mmol) and stirred for 15 hours. The solvent is removed and the residue is chromatographed on flash silica with EtOAc: hexane (1: 1) to give 40.

Clorhi tl of 1N- (N-Bencí Icarboxami dometi 1) -caprolactam- (3S) -amine (41). amide 40 (2.2 g, 5.87 mol) becomes 50 rnL of ether at 0 ° C and bubbles dry HCl for 10 minutes. The solid is filtered and rinsed with ether to form 41. Acid acid (2R) - Tsobu 11- -c rbooter-butox and 1N-propionic acid (N-benz and read rboxami do -met 11) - caprol actarna- (3S) - ami na (42). A mixture of acid 23 (1.0 g, 4. 35 rnnols), caprolactam 41 (1.35 g, 4.35 mmol) and HOBT < .0 g, 13.0 immoles) in 15 rnL of DMF and 1.3 L of NMM is loaded with EDAC (1.0 g, 5.22 min.) And the reaction is stirred for 15 minutes at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1N HCl, NaHCO3, and brine, dried over MO, filtered and evaporated to give 1.9 crude solid which is chromatographed on flash silica with EtOAc to give 42. Acid Amide ( 2R) -Isobutyl-3-carboxypropionic acid of 1N- (N-benzylcarboxamidorneti 1) -caprolactam- (3S) -arnine (43). T-rifluoroacetic acid (5 rnL) is added via syringe to a solution of tert-butyl carboxarnate 42 (1.51 g, 3.10 rnrols) in 5 L of CH2Cl2 under argon and the resulting mixture is stirred for 2 hours at room temperature. The material is then concentrated in vacuo to give it to carry forward without purification. Amide acid (2R) - Isobuti i-3-carbomethoxy? Ro ?? orne of 1N- (N-eni read rboamido-rnetyl) -caprolactam- (3S) -amine (44). To a solution of acid 43 (1.51 g, 3.50 mol) in 5 mL of MeOH is added an excess of diazonethane in ether. The excess diazomethane is quenched with acetic acid and the solvent evaporated. The residue is chromatographed on flash silica with EtOAc "hexanes (2: 1) to give 44. (2R) -Tsobutyl-3- (N-hydroxy ca boxate) - propionic acid amide of 1 - - (N-benzyl carboxamine dome ii) -caprolactam- (3S) -amine (6). Ol ester 44 (800 mg, 1.80 mmol) is added to a solution of NH2OK (1.5 mL, 1 eq in MeOH, prepared in accordance with Fieser and Fieser-, Voi, L, page 478) and stirred for 24 hours. ., The solvent is evaporated and the residue is dissolved in 1N HCl and extracted with EtOAc. The organic layer is dried over g O ^, evaporated and the residue is chromatographed on flash silica with EtOAc: formic acid (97: 3) to give 6.

EXAMPLE 7 Synthesis of (2R) - Isobutyl-1 -3-N-hydroxycarboxarnidopropionic acid amide of 1N- (-butylcarboxamidornethyl) caprolactarin- (3S) -amine (7) [',3 Amide of tert-Butoxycarboxylic acid 1-N- (n-butylcarboxarnule and L 1) -caprolactam- (3S) -aryn na (45). The ester methyl ester (2.5 g, 8.33 mmol) is converted to 10 mL of MeOH and the mixture is charged with 11-amine (8.1 mL, 79.7 mmol) and stirred for 15 hours. The solven + is removed and the residue is chromatographed on a flash-on silica gel.

EltOAc: hexane (2: 1) to give 45. lN- (n-butylcarboxamidomethyl) - (S) -ain i hydrochloride not ca p ro 1 to c tama (46). Take the amide 45 (2.2 g, 6.43 rnmoles) in 50 L of ether at 0 ° C and bubble dry HCl for 10 minutes. The solid is filtered and washed with ether to yield 46. A (J? Ci do (2R) -Isobut? L- (3) - r-buty-oxypropanoic carbohydrate of f IN) -n-but iicarboxami do- methyl-caprolactane- (3S) -amine (47). A mixture of acid 23 (1.76 g, 7.65 mrnol), 1N- (n-butylcarboxarnidornetil) -ca-rolactarna- (3S) -amine 46 (3.17 g, 11.4 rnmoles) and HOBT (3.08 g, 22.80 rnrnoles) in 20 L of DMF and 2. 36 mL of NMM is charged with EDAC (1.74 g, 9.07 mmol) and the reaction is stirred for 15 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1N HCl, NaHCO 3, brine and dried over MgSO 4, filtered and evaporated to give 4.68 g of crude solid which is chromatographed on flash silica with F tOAc to give 47. Amide acid (2R) - Tsobu 11- () -carboxipropanoi co de (1 N) -n-buty lcar-boxarnidornet? -caprolactam- (3S) -amine (48). Acid t nf 1 uoroacet 1 co (15 rnL) was added via syringe to a solution of tert-butyl ester 47 (2.45 g, 5.40 mol) in The CH2Cl2 under argon is added and the resulting mixture is stirred for 1 hour at room temperature. The material is then concentrated in vacuo to give it to carry forward without pupil. Amide acid (2R) - Isobut ii -3-carbornetox 1 1N- (n-butycarboxarn? Do? Net?) Propionic) ~ caprolactane ~ (3S) -armna (49). The acid 48 (1.23 g, 3.09 rnmoles) is taken up in methane and treated with an excess of diazornetan in ether at 0 ° C and stirred for one hour. Formic acid (3 drops) is added and the mixture is evaporated to dryness to give it to be carried forward without pupil. Am 1 da of (2R) -Isobut il -3-N-hydroxycarboxarnidopropiom of 1N- (n-butycarboxamidornet jp-caprolactam- (3S) -amine (7) Add methyl ester 49 (500 rng, 1.21 mmoles) to a solution of NH2OK (1.4 L, 1 eq.

MeOH, prepared in accordance with Fieser and Fieser, Vol. 1, p. 478) and stirred for 15 hours. The reaction mixture is acidified with acetic acid to pH = 2. The reaction is then divided between ethyl acetate and water. The organic layer is then washed with brine, and dried over magnesium sulfate, filtered and evaporated to give a crude solid which is chromatographed with ethanol: water: ac? or acetic (16: 1: 1) and crystallize again from ethyl acetate to give 7. EXAMPLE 8 Synthesis of acid amide (2R) -Hydroxycarboxamidomet 11 heptanoic N- (carbornetoxunet? \) - caprolact arna - (35) -amine (8) 58 57 3- (l-Oxohept? L) - (4S) -phen Irnet? L-2-oxazole? di nona (52) .. Aggregate n-butyl lithium (58 rnL, 2.5 M in hexanes, 142 immoles) to a solution of (S) -4-benzj 1-2-oxazoJ dina 51 (25 5 g , 141 rnmoles) in THF (250 rnl.) At -78 ° C under argon and stirring for 15 minutes. 50 Heptanoyl chloride (21 g, 141 mmol) is added to the solution as drops and stirred for 40 minutes, then heated at 0 ° C for 24 hours. The reaction is quenched with NH 4 Cl and extracted with EtOAc. The organic layer lf) is washed with IN HCl, aqueous NaHC 3, and dried over M? 4. The crude product is recrystallized from hexane to give 52. 3-Cl-0xo- (2R) - (carbo-1-butoxyirnet-11) -hept in - (4 S) - phen lrnet? I-2 -oxazol idi none (53). It is added bs (t prnetilsi ll 1) lithium arnide (132 rnL, 132, 1M in THF) to a solution of the oxazolidinone 52 (38.0 g, 132 mol) in THF (100 rnL) at -78 ° C under Argon and stirred for 15 minutes. Tert-butyl brornoacetate (26 rnL, 132 rnrols) is added to the solution by syringe, warmed to room temperature, and stirred for 3 hours. The reaction is then heated to 0 ° C and stirred for 1.5 hour. The reaction is quenched with NH 4 Cl and extracted with EtOAc. The organic layer is washed with 1N HCl, aqueous NaHC 3, aqueous NaCl, and dried over MgSO 4. The crude product is chromatographed on flash silica with hexane: EtOAc (2: 1) to give 53. ter-Butyl-t (3R) -carboxy Hoctanoate (54). Oxazoli dinone 53 (10.0 g, 24.9 mol) is dissolved in THF / H2O (100 rnL: 25 L) under argon and cooled to 0 ° C. Hydrogen peroxide (12 rnL, 30%, 106.7 mmol) is added dropwise to the solution, followed by lithium hydroxide (1.8 g, 43.9 mmol) in H2O (40 mL). The reaction is stirred for 3 hours, at which time sodium sulfate (10 g in 40 ml of H 2 O) is added in the form of drops and stirred for 20 minutes. The solution is extracted 3 times with CH2Cl2. The organic extracts are combined, washed with aqueous NaCl, dried over MgSO4, filtered, and the solvent is removed to give 54. Salt of? 1N- r-fluoroacetic acid (carborne oxime il) -cap rola ct arna- (3S) -amine (55). Trifluoroacet LCO acid (15 mL) is added via syringe to a solution of tert-butyl carboxy-ate 39 (10.0 g, 33.3 mmol) in 15 rnL under argon and the resulting mixture is stirred for 1 hour at room temperature. The material is then concentrated in vacuo to give it to carry forward without purification. (2R) -carbo-tert-butoxymethyl-heptanoic acid amide of N-carbornetoxirnetyl-caprylamide (3S) -amine (56). Amine 55(2.16 g, 10.8 mmol) is mixed with acid 54 (2.64 g, 10.8 mol), HOBT (4.4 g, 32.4 mmol), EDAC (2.69 g, 14 mol) in 15 rnL of DMF and 2.4 rnL (21.6 mmol) NMM at 0 ° C, and stirred for 17 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is washed with HCl 1, H 2 O, 1N NaOH, and brine, dried over MgSO 4, filtered and evaporated to give an oil (3.2 g) which was chromatographed on flash silica with hexane: FtOAc (1: 1) to give the product. Arn (acid) (2R) -Q-benc? l-N-hydroxycarboxarnine dornet and heptanoic of N-earhomethoxyrnethyl-caprolac arna- (3S) -amino (58). Ester 56 (1.2 g, 2.64 rnmoles) is dissolved in 15 mL of methylene chloride and cooled to 0 ° C and t rif luoacetic acid (15 i.) Is slowly added. The mixture is stirred for 1.5 hour at room temperature and evaporated to give 57. A mixture of crude acid 57 (1.5 g, 2.64 mmol), 0-benzyl hydroxylanine hydrochloride (0.51 g, 3.17 mmol) and HOBT ( 1.07 g, 7.92 mmoles) in 10 rnL of DMF and 0.99 ml. NMM (9.0 rnmoles) is charged with EDAC (0.61 g, 3.17 mrnol) and the reaction is stirred for 15 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1N HCl, NaHC 3, and brine, dried over MgSO 4. filter, and evaporate to give an oil which is chromatographed on flash silica with EtOAc to give 58. N- (carbornetoxymethyl) -caprolactam (2R) -N-hydroxycarboxarnidohexyl-heptanoic acid (carbamate) - na (8) The benzyl hydroxamic acid 58 (370 mg, 0.78 mrnol) is made in 10 L of EtOH and the mixture is loaded with 10% of carbon dioxide (44 rn) and stirred under a hydrogen atmosphere for 3 hours. The mixture is then filtered through celite and concentrated in an oil. The crude product is crystallized from ethyl acetate par-a to give 8, EXAMPLE 9 S i nt e s s of a c i do (2 R) - N - hydroxycarboxarm darnet i 1 decanoic 1 N- (carbomethoxy irnot 11) caprolactam- (3S) -amine (9) 3- (l-Qxodec? L) - (45) -phenyl-2-oxazoli dinone (60).

Lithium n-butyl (160 L, 2.5 M in hexanes, 398 mmol) is added to a solution of (S) -4-benzyl-2-oxazole-di none 51 (64 g, 362 mmol) in THF (750 mL ) at -78 ° C under argon and stirring for 15 minutes. Decanoyl chloride 59 (69 g, 362 min) is added to the solution as drops and stirred for 40 minutes, then heated at 0 ° C for 2 hours. The reaction is quenched with NH 4 Cl and extracted with EtOAc. The organic layer is washed with 1N HCl, aqueous NaHC 3, and dried over 50 g.

MgSOi "The crude product is recrystallized from hexane to give 60. 3- p-Oxo- (2R) - (cborte- butox rnet? I) -deci 11 (45) -í orulme ij - 2 -oxazole idinone (61). Lithium (t-prnethylsilyl) amide is added (210 ml., 210 rnrols, 1 M TI-IF) to a solution of Ja oxazolidinone 60 (56.6 g, 200 rnrols) on THF (100 ml.) At -78 ° C under argon and stirred for 15 minutes. Brornoacetat or tert-butyl (31 ml, 200 mmol) is added to the solution by syringe and shaken for 3 hours. The reaction is then heated to 0sC and stirred for L.b hour. The reaction is quenched with NH 4 Cl and extracted with EtOAc. The organic layer is washed with IN HCl, aqueous NaHC 3, aqueous NaCl, and dried over MgSO 4. The crude product is chromatographed on flash silica with hexane: Et? Ac (7: 1) to give 61. ter-Buti l-r3R-carboxydecanoate or (62). Oxazole 1-dinone 61 is dissolved in THF / H 2 O (100 mL: 25 ml_) under argon and cooled to 0 ° C. Hydrogen peroxide (13 rnL, 30%, 115.6 mmol) is added in the form of drops to the solution, followed by lithium hydroxide onohydrate (l.Bg, 43.9 rnmoles) in H2O (40 rnL). The reaction is stirred for 3 hours, at which time its sodium phytate (10 g in 40 mL of H2O) is added in the form of drops and stirred for 20 minutes. The solution is extracted 3 times with CH 2 Cl 2 - The organic extracts are combined, washed with aqueous NaCl, dried over MgSO 4. The product is purified on a column of silica gel using EtOAc co or bl The pair is to be given 62. Acid amide (2R) - carbo-ter-but oxi rnet i lde < 1N-anoic acid (c rbome ox i -met 11) -caprolact arna- (35) -amine (63). A mixture of acid 62 (2.5 g, 8.74 mol) and 0.9 ml. NMM is cooled to -20 ° C and charged with isobutyium chloroform (1.45 ml., 8.74 mmol) and stirred for 10 minutes. Amine 55 (1.75 g, 8.74 mol) and 0.9 L of NMM in 2 rnL of DMF are added and stirred for 30 minutes, the organic layer is then washed with 1N HCl, MaHC ™ 3, and brine, is soaked over Mg50. Filter and evaporate to give 2.8 g of crude sol which is chromatized on flash silica with EtOAc: hexanes (1: 1) to give 63. Acid Arn (2R) -O - benzyl 1-N-hydroxycarboxylic acid 1N- (carbornetox nnet l) -caprolact arna- (35) -amine (65) "Addic acid t 1 f (5 mL) by syringe to a solution of butyl ester-63 (1.2 g, 2.55 mmol) in 5 mL of CH2CL2 under argon and the resulting mixture is stirred for 2 hours at room temperature. The material is then concentrated under vacuum to give 64 which is carried forward without purification. A mixture of acid 64 (1.05 g, 2.55 mol), O-benzyl hydroxylamina hydrochloride (165 rn, 2.55 rnmoles) and HOBT (1.2 g, 7.65 rnmoles) in 15 rnL of DMF and 6 mL of NMM is loaded with EDAC (57 μg, 2.55 rnmoles) and the reaction is stirred for 15 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1101 1N, NaHC? 3, and brine and dried over MgSO4, filtered, evaporated and chromatographed on flash silica with EtOAc to give 65. Acid acid (2R) -N-hydroxycarboxarnide decanoic lN- (carbomethoxy -rnet i D-ca p ro ct arna - (35) - arn i na (9). It turns the benzyl hydroxaric acid 65 (428 rng, .828 mmoles) into 15 rnL of EtOH and the mixture is loaded with 10% palm on carbon (60 mg) and stirred under a hydrogen atmosphere for 45 minutes, then the mixture is filtered through eelite and concentrated and chromatographed over it. of flash vaporization with Et? Ac: formic acid (99: 1) and then recrystallized from EtOAc to give 9.

EXAMPLE 10 Synthesis of acid (2R) -N-hi droxycarboxaini domet 11-decanoic acid of N-p-t.oluensulfonyl-caprolactarna- (3S) -amine (10) 68 5 (35) - or-Buto? Carbon? La? N no-N-t l uensul fo i 1 < : aprolactama (66). (35) -ter ~ Bu o? -carbom larní no caprolact ama 33 (2.0 g, 8.8 mol) is dissolved in THF (20 ml.) And cooled to 0 ° C. A solution of b? S (t pmet ilsilil) arn? The amount of litter (10 ml, 10.6 mrnol, 1 M in THF) is added in the form of drops. After do L5 minutes, add toluensuifoni chloride (2.0 g, 10.56 mrnol). The resulting mixture is stirred at 0 ° C for 10 minutes and at room temperature for 30 minutes, the reaction is washed with water and the acetate is extracted, the organic layer is then washed with 0.1 N HCl, H 2 O, and brine. Dried on M SOu, filtered and evaporated to give an oil which is chromatographed on flash silica with hexanes: Et? Ac (3: 1) to give the product. 66. Acid amide (2R) -carbohydrate -ter-hutox 1rnet.1l decanoic of N- t oluensul fon 1 -caprolactam- (35) -amine (68). (3S) - ter ~ Butoxy carbo la í no ~ N-toluensulfon? 1-caprolactarine 66 (2.2 g, 5.8 mmol) is dissolved in 10 L of full methylene chloride and trifluoroacetic acid is slowly added (10 rnL). The mixture is stirred for 30 minutes and evaporated to give 67. The caprol ctarna 67 amine (1.6 g, 5.7 min) is mixed with 62, HOBT (2.31 g, 17.1 mmol), EDAC (1.34 rng, 7 mrnol) in 25 rnL of DMF and 1.26 rnL (11.4 mmoles) of NMM at 0 ° C, and stir for 17 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is washed with 1N HCl, NaHCO3, and brine, dried over gSOii, filtered and evaporated to give an oil (3.1 g) which is chromatographed on anhydrous basis. instant vaporization with FtOAc to give 68. Amide of? Acid (2R) -O-benzyl-N-hydroxycarboxyne decanoic of N-toluensulfon 1-caprolactam- (35) -amine (70). (5) ~ terbutoxycarboxylane-N-toluene fucilcaprolactane 68 (2.1 g, 3.8 rnnols) is dissolved in 10 ml of rnetylene chloride, cooled to 0 ° C, and acid is slowly added. rit 1 uo roa ce tico (10 rnL). The mixture is stirred for 1.5 h at ambient temperature and evaporated to give 69. A mixture of crude acid 69 (2 g, 3.8 mmol), hydrochloride of 0-benzyl hydroxylamine (0.73 g, 4.56 mmol) and HOBT (1.54 g, 11.4 mmol) in 20 μL of DMF and 1.4 μL of NMM (12.9 mmol) is charged with EDAC (0.87 g, 4.56 mmol) and the reaction is stirred for 15 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is washed with 1N HCl, 1N NaOH, and brine, dried over MgSO4, filtered and evaporated to give a semisolid (2.2 g) which is chromatographed. on flash silica with FtOAc: hexane (1: 1) to give 70. Amide of (2R) -N-Hydroxycarboxarnidene decanoic acid of N-tololuensul fonylcaprolactane- (35) -amine (10). The hydroxyl acid of benzyl 70 (680 g, 1.13 mmol) is made in 10 ml of EtOH and the mixture is loaded with 10% palladium on carbon (68 mg) and stirred under a hydrogen atmosphere for 2.5 hours The mixture is filtered through ceLit and concentrated to give a solid, which is purified by flash chromatography (if ice, 1-tOAe) to give 10. EXAMPLE 11 Amide Synthesis (2R) -N-Hydroxycarboxamidornet and decanoic acid N-1"(2-rneto) and 11 l-caprolac rna- (35) -amine (11) 11 73 (35) -ter-But-oxycarbonylamino-N-r (2-rneto?) And 111-caprolactane (71). (35) - non-caprolactane-tert-Butoxycarbonylane (2.0 g, 8.8 mmol) is dissolved in DMF (10 mL). Potassium tert-butoxide (1.25 g, 10.6 mmol) is added in drops and stirred for 45 minutes. Bromine methyl ether (0.99 mL, 10.6 mmol) is then added. The resulting mixture is stirred for 3 hours, at which time the reaction is quenched by water and extracted with ethyl acetate. The organic layer is then washed with IN HCl, H 2 O, and brine, dried over MgSO / j, 56 filter and evaporate to give an oil which is chromatographed on flash silica gel with hexanes: Et? Ac (1: 1) to give 71. Acid Amide (2R) -Carbo-? er-butoximeti l decanoic of N-C (2-rnetp ??) et? 11-caprolactarna- (3S) -am? na (73) .. (3 S) - 1 e r ~ Butoxy car-bomlarnino-Nr (2-methoxy) et i 11-caprolac arna 71 (1.46 g, 5.L immoles) is dissolved in 15 mL of methylene chloride, cooled to 0 ° C, and acid is added slowly tp lu roacót i co (15 mL). The mixture is stirred for 2 hours at room temperature and evaporated to give 72. The caprolactam amine 72 is mixed with (2R) -tert-but-icarboxyrnethyl decanoic acid (1.5 g, 5.2 mmol), HOBT ( 2.07 g, 15.3 rnmoles), EDAC (1.17 g, 6.1 immoles) in 15 rnL of DMF and 14.3 inL (13 mmoles) of NMM at 0 ° C, and stir for 17 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is washed with 1N HCl, H 2 O, IN NaOH, and brine, dried over MgSO 4, filtered and evaporated to give an oil which is chromatographed on flash silica with EtOAc to give 73. Acid Amide ( 2R) -0-benzyl-N-hydroxycarboxarnidohexyl decanoic acid of Nf (-methoxy 1) and i-caprolactarine- (35) -arnine (75). (35) -ter-Butoxycarboni lami no-N-C (2- rnetoxy) etip caprolact ama 73 (1.2 g, 2.64 mrnol) is dissolved in 15 rnL of methylene chloride, cooled to 0 ° C, and added slowly, rifluoroacetic acid (15 inL). The mixture is stirred for 1.5 hour at room temperature and evaporated to b? give- 74. A mixture of crude acid 74 (1.5 g, 2.64 immoles), hydrochloride 0-benzyl hydroxylamina (0.5L g, 3.17 immoral) and HOBT (1.07 g, 7.92 immoles) in 10 ml. of DMF and 0.99 ml of NMM (9.0 rnrnolee) is loaded with EDAC (0.61 g), 3.17 rnmoles) and the reaction is stirred for 15 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is washed with HCl LN, IN NaOH, and brine, dried over MgSO4, filtered and evaporated to give an oil which is chroma or raffia on flash silica with r-LOAc to give 75. Ami a of (2R) -N-hydroxycarboxarnide dornet il decanoic of N ~ L "(2-methox?) Et i p-caprolactarna- (35) -ar ma (11). (700 rng, 1.39 rnmoles) in 10 rnL of EtOH and the mixture is charged with 10% palm on carbon (70 rn) and stirred under a hydrogen atmosphere for 1.5 hours. The mixture is concentrated to give a solid, which is purified by flash chromatography (silica gel, 4% formic acid in EtOAc) to give 11.

EXAMPLE 12 Synthesis of (2R) -N-hi-hydroxycarboxainidomethalandelic acid amide of 1-N-n-butyl 1-c: aprolactane- (35) -nane (12) 58 (35) -ter-- Buto i car'bonilami no-N-n-but l-caprol act arna (76). (35) -ter-- ut ox L-carbon? Jarnino caprolactam 33 (2.0 g, 8.8 rnnols) is dissolved in DMF (8 rnl.). Potassium tert -butoxide (1.25 g, 10.6 mmol) is added dropwise and stirred for 50 minutes. Then add l-bro? Not butane (J. 13 rnL, 10.6 mmoles). The resulting mixture is stirred for 3 hours, at which time the reaction is quenched by water and extracted. with ethyl acetate. The organic layer is then washed with 1N HCl, H2O, and brine, dried over MgSO4, filtered and evaporated to give an oil which was chromatographed on flash silica with hexanes: Et? Ac (1: 1) to give 76. Acid Amide (2R) ) -carbo-ter-butoxi and il decanoico 2b of N-n-butyl-ca-rolactarna- (3S) -amina (78). 76 (2.37 g, 8.3 < • rnnols) is dissolved in 15 mL of methylene chloride, cooled 59 at 0 ° C, and slowly add t-acid 11 uoroacetic acid (15 i.). The mixture was stirred for 2 hours at room temperature and evaporated to 77. The caprol amine 77 was mixed with 62 (1.5 g, 5.2 rnrols), HOBT (3.36 g, 24.9 rnmoles), EDAC (1.92). g, 10 immoles) in 15 ml of DMF and 2.3 ml (20.8 mrnols) of 'NMM ap ° C, and stirred for 17 hours at room temperature. The reaction was then partitioned between water and EtOAc. The organic layer was washed with H01 1N, H2O, NaOH LN, and brine, and the residue was treated with MgSO4, filtered and evaporated to give an oil which was subjected to flash chromatography with EtOAc to give 78. Amide of acid (2R) -O-benzylhydroxycarboxy dometyl-decanoic of Nn-butycamprolactam- (35) -armna (80). It dissolved 78 (1.4 g, 3.1 rnrols) in 15 rnl of methylene chloride and cooled to 0 ° C and trifluoroacetic acid was added slowly (15 ml), the mixture was stirred for 1.5 hours at room temperature and evaporated to give 79. A mixture of crude acid 79 (1.5 g, 3.1 mmol), 0-benzylhydroxyl hydrochloride? N? na (0.6 g, 3.72 immoles) and HOBT (1.26 g, 9.3 min) in 10 ml of DMF and 1.16 mln of NMM (10.5 mmol) was charged with EDAC and the reaction was stirred for 15 hours at room temperature. Then, the reaction was divided between water and FtOAc. The organic layer was washed with HCl LN, NaOH 1N and brine, dried over MgSO, filtered and evaporated to give an oil which was subjected to flash chromatography with EtOAc to give 80.

A acid (2R) -N-hydroxy carboxarnidomet-1-decanoic acid of 1-N-n-but 11 caprolactarine - (35) -arnine (12). The acid boncil hi droxárnico 80 (900 mg, 1.8 rnmoles) was converted into 10 ml of EtOH and the mixture was loaded with 10% palladium on carbon (90 rng) and stirred under a hydrogen atmosphere for 2 hours, the mixture It was filtered through celite and concentrated to give a sol, which was purified by flash chromatography (silica, 2% formic acid in EtOAc). After the p? Oducte was crystallized from ethyl acetate to give 12.

EXAMPLE 13 Amide of (2R) -isobutyl- (3S) -CN-idroxycarboxa-idolbutanoic acid (lN) -carbomethoxymethyl-caprolactam- (3S) -amine (13) EXAMPLE 14 Amide of (2R) -isobutyl acid 1- (3R) -TN-- hydroxycarboxarnide] butanoic acid (lN) -carbometho-rnet 11-caprolactam- (35) -amine (14).

Amide acid (2R) -i sobut l- (3R, 5) --- arbo-tert-butoxy butanoi co (IN) -carbometox unet lcaf) rolactam- (95) -arn ina (82). A mixture of acids 81 (3R: 35 - 8: 1, 720 g, 2.95 min), 55 (757 mg, 3.84 mol) and HOBT (1.39 g, 10.33 mol) in 4 rnl of DMF and 4 rnJ of NMM charged with EDAC (737 mg, 3.84 mmol) and the reaction was stirred for 15 hours at room temperature. The reaction was then partitioned between water and FtOAc. The organic layer was then washed with 1 N HCl, NaHCO 3, and brine, dried over MgSO, filtered and evaporated to give a crude solid which was chromatographed on flash silica with hexane: EtOAc (3: 1). 1: 2) to give 82 (3R: 3S = 8: 1). Amide of acid (2R) - i sobu 11 - (R, 5) -CO-benzyl-N-hydroxycarboxylamino- (35) -amine (84). Esters 82 (3R: 3S = 8: 1: 560 rng, 1.31 immole), were dissolved in 4 ml of CH2Cl2 under argon and 4 ml of tnfluoroacetic acid was added to this mixture by syringe. The mixture was stirred for 30 minutes at the end of which the mixture was concentrated to give 83. A mixture of the resulting crude acid 83 (560 g, 1.51 mmol), O-benzylhydroxylanine hydrochloride (314 mg, 1. 96 mrnols) and HOBT (917 mg, 6.80 mmol) in 4 ml DMF and 4 ml NMM was charged with EDAC (376 rng, 1.96 min) and the reaction was stirred for 15 hours at room temperature. The reaction was then partitioned between water and EtOAc. The organic layer was then washed with 1N HCl, NaHC 3, and brine, dried over MgSO 4, filtered and evaporated. The crude solid was filtered through a gel pad of ice and then recrystallized to give the (3R) diaster gold 84. The mother liquor was then chromatographed through silica gel with hexane: EtOAc (1: 1 0: 1) pair to give 84 (35). Acid Arn (2 R) - 1 sobu 111 ~ (35) - L ~ Nh dr-oxi carboxarnidol-hutanoic of (1 N) - ca rborneto i met 11 -caprolactarna- (35) -arní na (1) . The benzyl hydroxarnide acid 84 (35) (45 ing, 0.095 mol) was converted to 95% EtOH and the mixture was charged with 5 mg of palladium on 10% carbon and stirred into an atmosphere. of hydrogen for 12 hours. The mixture was then filtered through celite and concentrated to give a crude oil which was crystallized from EtOAc to give anhydrous acid (2R) -isobutyl- (3R) -L "N-hydroxycarboxa ido] -butanoi Co (1N) -carhomethoxyrnethyl-caprolactarine- (3S) ~ arni na (1). (3R) (100 rng, 0.211 mmol) was added in 1.5 ml of 95% EtOH and the mixture was loaded with palladium on 10% carbon-bonded (10 mg) and stirred under a hydrogen atmosphere for 15 hours. The mixture was then filtered through celite and concentrated to give 14.

EXAMPLE 15 Synthesis of (2R) -isobutyl- (3S) - [N-hydroxycarboxamido-3-hexanoic acid (lN) -carbomethoxy ethylcaprolactam- (3S) -amine amide (15) Amide acid (2R) - i sobut ii - (35) - Ccarbo-ter-butoxy] -hex-5-eneco of (IM) -carbo-ethoxymethiicaprolactam- (35) -amine (86). A mixture of the acid 85 (1.91 g, 7.07 rnmoles), 55 (1.84 g, 9.20 rnmoles) and HOBT (2.77 g, 20.5 immoles) in 2 ml of DMF and 2 ml of NMM was charged with FDAC (2.04 g, 10.6 mmol) ) and the reaction was stirred for 15 hours at room temperature. Then the reaction was partitioned between water and EtOAc. The organic layer was then washed with 1 N HCl, NaHCO 3 and brine dried over MgSO 4, filtered and evaporated to give a crude solid which was chromatographed on flash silica with hexane: Et 2 Ac (3: 1).

J: 2) to give 86. (2R) -isobutyl- (R, 5) -carboxyl-hex-5-enoic acid (lN) -carbometho-methylamide acid amide? l -caprolactam- (35) -amine (87).

Tp fluoroacetic acid (15 rnl) was added via syringe to a solution of ter-butyl esters 86 (3R: 3R = 2: 3; 1.51 g, 3. 34 rnmoles) in 15 ml of CH 2 Cl 2 under argon and the resulting mixture was stirred for one hour at room temperature. It was then concentrated under vacuum to give 87 as a diastereomeric mixture (3R: 35 = 2: 3) which was carried forward without a pupil. Amide acid (2R) - isobutyJ - (35) - [Q-benzyl-Nh 1 drox 1 carboxarnido] - hex-5-ene 1 co of (1N) -carhorr? Et or jinet.il -caprol c ma- ( 35) - ar í na (88). A mixture of the acids 87 (3R: 35 = 2: 3, 1.32 g, 3.34 rnrols), 0-benzyl hydroxylamine hydrochloride (0.693 g, 4.34 mmol) and HOBT (1.26 g, 9. 35 mmol) in 7 rnL of DMF and 7 rnl of NMM was charged with EDAC (0.962 tng, 5.01 rnmoles) and the reaction was stirred for 15 hours at room temperature. Then the reaction was partitioned between water and EtOAc. The organic layer was then washed with 1N HCl, NaHCO 3, and brine, dried over MgSO 4, and evaporated to give a crude solid which was filtered through a plug of silica gel with EtOAc and then recrystallized from 2 × hexane: EtOAc (2: 1) give 88. (2R) - isobutyl amide 1- (3S) - L ~ Nh 1 hydroxylcarboxamide] -hexane (1N) -carbo-ethoxymethyl-caprolactane- (35) -amine (15). Benzylhydroxanilic acid 88 (176 g, 0.351 mmol) was taken up in 1 ml of 95% EtOH and the mixture was charged with 30 mg of 10% palladium on carbon and stirred under a hydrogen atmosphere for 12 hours. Then the mixture was filtered through celite and concentrated to give 15, EXAMPLE 16 (2R) -isobutyl- (3S) - [N-hydroxycarboxamide] -6-hydroxyl exanoic acid (lN) -carbomethoxymethyl-l-caprolactam- (3S) amine acid amide (16) Amide acid (2R) - i sobut ii- (3S) ~ L ~ 0-honc? L ~ N ~ h? Dr-ox? Carboxarn? Do] -6-hydroxyhexanoic acid (1N) - carbornetox i -rneil caprolact arna- (35) -arni na (89). The starting olefma 88 (3R: 3S = ~ 1: 1, -240 rng, 0.49 rnmoles) became n 5 rnl of dry THF under argon and cooled to 0 ° C and then 9-borabicyclononane ("9") was added. -BBN ") (3.45 rnl, 0.5 M in THF 1.73 immoles)) by syringe and the solution was stirred at 0 ° C for 2 hours at the end of which NaOH (2 ml, 1M) and H2O2 ( 2 rnl, 30%) and the resulting solution was stirred for 5 minutes. After the mixture was partitioned between EtOAC and water and the organic layer was washed with saturated NH1C1 and brine, was added over g5? , it was filtered and evaporated to give a crude oil. This diastereophase mixture was chromatographed twice over flash silica with EtOAc: Et? H (20: 1) to give 15-89. Amide acid (2R) - isobut i i- (3S) -L "N'Hydroxycarboxarn? Do1 ~ 6 -hydroxy-hoxanoic d (1N) ~ car-l)? Ineto? Imet 11 -ca rol ct ama- (35 ) -arn i na (16) "FL cido ben í Lhi droxarm co 89 (45 mg, 0.351 immoles) was layed in 1 ml of 95% EtOH and the mixture was charged with 10 rng of palladium on carbon at 10 % and stirred under a hydrogen atmosphere for 12 hours, then the mixture was filtered through celite and concentrated to give 16.

EXAMPLE 17 Synthesis of (2R) -C (lS) -N-hydroxycarboxamido] -ethyldecanoic acid (lN) -carbomethoxy-methyl) -caprolactam- (3S) -amine (17) amide EXAMPLE 18 Synthesis of (2R) -C (lR) -N-hydroxycarboxylodo] -ethoxydocanic acid amide of lN- (carbomethoxy-methyl) -caprolactam- (3S) -amine (18) 18 A (i do (2R) - T (IR) -Carbooter Bu oxyT-etii decanoic (0) Fl acid from batch 62 (4.5 g, 15.73 mol) dissolved 5 ml of dry THF under an argon atmosphere and cooled to -78 ° C and then lithium hexarnetyl disilazane (39.3 ml, 1M in THF, 39.3 mmol) was added via syringe and the mixture was stirred for 20 minutes.The mixture was allowed to warm up to 0 ° C and then cooled down again. -78 ° C. Methyl iodide (1.08 ml, 17.3 mmol) was added slowly by syringe and the resulting mixture was stirred for 2 hours at -78 ° C and 30 minutes at 0 ° C, after which the The reaction was quenched with NHCl, saturated, partitioned between EtOAc and water, the layers were separated, the organic layer was washed with NH4CI, brine, over MgSO *, filtered and evaporated to give 5.81 g of crude oil. which was chromatographed on flash silica with hexane: EtOAc (2: 1) to give 90. Acid (2R) - [(IR) -carbo-tert-butox?] et? ldecano? co (91). The acid predominantly (IR) 90 (1R: 1S = 8: 1, 5 g, 1.7 rnrols) was dissolved in 5 ml of dry THF under an atmosphere of 70 argon and cooled to -78 ° C. Then it was added by syringe dusopropy lithium sheet (47 rnl, 2 M in THF, 47 immoles) and the mixture was stirred for 16 hours at -78 ° C at 22 ° C according to the dry ice-acetone bath. heated to room temperature. The mixture was then cooled again to -78 ° C, quenched with 15 rnl of methane (78 min) and poured into NI-UC1. After warming-to room temperature, the reaction mixture was partitioned between EtOAc and water and the layers were evaporated. The organic layer was washed with 1N HCl and brine, dried over gSO, filtered and evaporated to give 5.81 g of crude oil which was subjected to flash chromatography with hexane: EtOAc (2: 1) to give 91 (1S: 1R = 2: 3). Amide of (2R) -T (IR, S) -Carbo-tert-butoxy] -e i i decanoic acid of N- (carhorneto ?? me? I) -caprolactarna- (3S) -amine (92). A mixture of acids 91 (1R: 15-3: 2, 1.5 g, 5.00 min), amine 55 (1.5 g, 7.50 mmol) and HOBT (1.53 g, 10.00 rnrols) in 10 ml of DMF and 1.1 ml of NMM was charged with EDAC (1.15 rnG, 6.00 mrnol) and the reaction was stirred for 15 hours at room temperature. Then the reaction was partitioned between water and EtOAc. The organic layer was washed with 1N HClNaHCO3, and brine, dried over MgSO4, filtered and evaporated to a crude solid which was chromatographed on flash silica with hexane: Et? Ac (1: 1) to give 92 (1R: 1S - 3: 2). Amide acid (2R) - [(IR) -O-Benc? J-N-hydroxycarboxarnide] -ethyl decanoic of lN- (carbo etox? Met? L) -caprolacta a- (35) -amine (94). Amide of (2R) -C (SS) -O-Benzyl-N-hydroxycarboxyamine T-e 1-olcanoic acid (carbornetoxy etLi) -caprolactam- (35) -arnma (95). the esters 92 (IR: 15 = 3: 2, 1.40 g, 2.90 mmol) were dissolved in 7 ml of CH2Cl2 under argon and to this mixture was added 7 ml of t-fluoroacetic acid by means of a syringe. The mixture was stirred for 2 hours after which it was concentrated to give 93. A mixture of the resulting crude acid 93 (1.27 g, 2.86 mol), 0-bonz hydrochloride 1 hydroxylanine (456 g, 2.B6 rnrols) and HOBT (875 g, 572 immoles) on 5 ml or DMF and 941 μl of NMM was charged with EDAC (658 mg, 3.43 mmol) and the reaction was stirred for 15 hours at ten. At room temperature, the coaction was then divided between water and EtOAc. The organic layer was then washed with 1N HCl, NaHCO3, and brine, dried over MgSO3, filtered and evaporated. The crude solid was then chromatographed through silica gel with hexanes: EtOAc (1: 2), f >to give 94 and 95. (2R) ~ L ~ (15) -N-hydroxycarboxarmido-1-ethyl decanoic acid acid of N- (carbomethoxy? -met 11) ~ caprolactarine- (35) -arnine (1) ). The benzylhydroxamic acid 95 (260 mg, 0.489 mmol) was converted to 6 mg of EtOH and the mixture was charged with palladium on carbon 10% (50 mg) and stirred under a hydrogen atmosphere for 45 minutes. The mixture was then filtered through celite, concentrated, and then recrystallized from ethyl acetate to give the acid (2R) - [(IR) -N-hydroxycarboxamide] -eti l decanoic acid (ca bometox ime j 1) -caprolactam- (35) -amine (18). The benzylhydroxamic acid 94 (300 mg, 0.565 mmol) was converted to 6 mL of EtOH and the mixture was loaded with 10% palladium on carbon (60 g) and stirred under a hydrogen atmosphere for 45 minutes. The mixture was then filtered through celite, concentrated, and then recrystallized from EtOAc to give 18.

EXAMPLE 19 Synthesis of (2R) -C (lS) -N-hydroxycarboxamido] -ethyldecanoic acid amide of N-E (2-methoxy) ethyl-3-caprolactam- (3S) -amine (19) EXAMPLE 20 Synthesis of (2R) -C (lR) -N-hydroxycarboxamido] -ethyldecanoic acid amide of N- [(2-methoxy) ethyl] -caprolactam- (3S) -amine (20) 01 Amide of acid (2R) - [(IR ^ l-ter-hutilcarboxi et? L decanoic of N ~ L "(2-? Ne or?) Et ii] - caprol c ama- (35) -aini na (96) Mixed (35) -arní non-NT (2 -met ox i) et 111-capí olact to 72 (2. (3 g, 10.78 mol) with the decanoic acid 91 (1.5 g, 5.2 mol), HOBT (3.65 g, 27 rnrnoles), FDAC (2.07 g, 10.8 mrnols) in 15 m DMF and 3 i (27 min) of NMM at 0 ° C, and it was stirred for 17 hours at room temperature, then the mixture was divided between water The organic layer was washed with 1N HCl, H2O2, 1N NaOH, and brine, dried over MgSO4, filtered and evaporated to give an oil which was chromatographed on flash silica with hexane: EtOAc ( 1: 1) to give 96. Acidic acid (2R) -C (15) -Q-benzyl hydroxydro-carhoxamic T-ethyl decane NC (2-rnetox?) Et? L] - caprolactam- (35) -amine (98). (2R) -C (15) -te-buty1carbo-3-ethyl-ecanoic acid amide of NC (2-me oxy) et? L] -caprol actarna- (35) was dissolved. -amine 96 (1.95 g, 4.1 mmol) in 20 ml of full rnet chloride and cooled to 0 ° C, tp fluroacetic acid (20 ml) was slowly added. The mixture was stirred for 2 hours at room temperature and evaporated to give 97. A mixture of crude acid 97 (2.3 g, 4.1 mrnols), 0-benzylhydroxylanine hydrochloride (0.78 g, 4.92 rnmoles) and HOBT (1.66 g, 12.3 H2 rnmoles) in 15 i of DMF and 1.54 nmol of NMM was charged with FDAC (0"94g, 4.92 mmol) and the reaction was stirred for 15 hours at room temperature. The reaction was then divided between water and TtOAc. The organic layer was then washed with 1 N HCl, NaOH IN, and brine, dried over MgSO <; was filtered and evaporated to give an oil which was chromatographed on flash silica with E + OAC.CH2Cl2: CH3? H = 10: 10: 1) to give the desired product as a diastereomeric mixture (1R: IS = 3: 2). The separation of individual isomers is achieved by cri-stabilization of EtOAc-hexane (3: 2) to give 15-98. Acid (2R) -C (IR) -0-benzyl Ihydroxycarboxylate-11 decanter ico of N-1 ~ (2-methyl) et? L] -caprolactam- (3S) -amine (99). The mother liquor was concentrated to give- 1R-99. Amide of acid (2R) - T (1 S) -N- hi droxy carhoxarní dol -et 11 decanoic of Nf (2-meto? J) e? I "l- cap olactam • (35) -arní na (19) The benzo hydroxyl acid 98 (280 mg, 0.54 mmol) was rolled in 8 mL of EtOH and the mixture was loaded with 10% palladium on carbon (28 mg) and stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered through celite, concentrated to give a solid which was purified by crystallization from EtOAc: CH3 → H (10: 1) to give 19. Acid amide (2R) -l "(IR) -N-hydroxy carboxarnide] -e 11 decanoi co of NT (2 -met 0x1) et t 1] -caprolac ma- (5) -amine (20). The benzyl hydroxanic acid 99 (670 mg, 1.3 mmol) was rolled in 10 mL of EtOH and the mixture loaded with palladium on 03 % carbon (66 rng) and stirred under a hydrogen atmosphere for 3.5 hours. The mixture was filtered through celite and concentrated to give a solid which was purified by crystallization of FtOAc to give 20.

EXAMPLE 21 Synthesis of (2R) -isobutyl-3- (N-hydroxycarboxamidolpropanoic acid) N- (carbomethoxymethyl) -valerolactam- (3S) -amine acid amide 104 I (35) -Arnino-valerolactarna (101). To a 1 liter 3 neck round bottom flask equipped with a condenser, thermometer, magnetic stirrer and argon inlet, L-or tma 100 hydrochloride (15 g, 89 mmol) acetonitoplo (280 nl) and hexamethyldisilazane were added. (100 rnl, 620 rnmoles). The mixture was refluxed for 2 days, then cooled to room temperature and poured into 100 ml of methane. The solvents were removed by rotary evaporation. The residue is turned into 250 rnl of methylene chloride., then treated with activated charcoal, filtered and concentrated to a 10L solid. The compound was used without purification. (5) - ter -Buto i carbo l noval rolact ma (102). Mixed (35) -arninovalerolacna (crude, 101 g, 88.4 mol) with di-butyl dicarbonate 101 (19.9 g, 88.4 mmoles) on 50 in L of methyl sulfoxide. The mixture was stirred during L not.ho. The reaction was then partitioned between water and ethyl acetate, the organic layer was then washed with 0.1 N HCl, H 2 O, and L dye, dried over MgSO 4, filtered and evaporated to give an oil which was then evaporated. chromatographed on flash silica with hexanes: EtOAc (1: 1) to give '102. (35) -ter-But-oxycarbonyl-lane-N-carbornet or 1-rin-11 -valerolact-arna (103). The non-valerolactarine Jain (35) -ter-butoxycarboni 102 (1.85 g, 8.63 mmol) was dissolved in THF (5 mL) and cooled to -78 ° C. Bisit r-imet? Ls? L was added drop by drop? Lithium Darnide (11 nm, 10.4 nm, 1 M in THF). After 10 minutes, methyl bromide acetate (1.1 ml, 11.2 mmol) was added. The resulting mixture was stirred at -78 ° C for 2 hours, and at room temperature for 1 hour. The reaction was extracted with NH 4 Cl, extracted with ethyl acetate. The organic layer was then washed with 0.1N H2O HCl, and brine, dried over MgSO.v, filtered and evaporated to give an oil which was chromatographed on flash silica with hexanes: EtOAc (1: 1) to give 103. Amide of f (2R) -? - Butbutyl-3- carbo- t -butoxy-N-carbohydrate -no-methanoic acid - methyl-vaieroiactam - (35) -amine (105). (35) - tert.-butoxycarbolarylnino-N-carborne oxirnenyl-vletrol was dissolved at 103 (2.1 g, 7.3 mmol) in 20 ml of methylene chloride and t-1-uracetic acid was slowly added (20 g. rnl). The mixture was stirred for 2 hours and evaporated to give 104. The valerolactam 104 amine was mixed with (2R) -isobu 11 -3-carbo-tert-butoxy-propanoi acid or 23 (2.52 g, 11 mmol), HOBT (3.0 g, 21.9 rnmoles), EDAO (2.1 g, 11 immoles) in 10 rnl of DM6 and 4.2 ml (29.2 mrnol) of triethylannin at 0 ° C, and was stirred for 15 hours at room temperature. The reaction was then partitioned between water and ethyl acetate. The organic layer was then washed with 1 N HCl, NaHCO 3, and brine, dried over MgSO 4, filtered and evaporated to give an oil which was chromatographed on flash silica with ethyl acetate to give 105. acid L ~ (2R) -? sobutyl -3- (0-benzyl-1-N-hydro- or icarboxarnido) 3 -propanoyl co? N- (carbornetoxirnet i) -valerolactarna- (35) -amine (107). Amide (2R) -i-butyl-il-tert-butyl-carboxy] -propanoic acid amide of N-car- methoxyrnethyl-valerolac- tene- (3S) -amine 105 (2.2 g, 5.5 rnrnoles) was dissolved 10 rnl of full meth- and tpfluoroacetic acid (10 ml) was added slowly. The mixture was stirred for 2 hours and evaporated to give 106. A mixture of the crude acid 106 (2.8 g, 5.5 mmol), O-benzylhydroxylanine hydrochloride (L.96 g, 12.3 mmol) and HOBT (3.3 g, 24.0 mmol), on 10 mmol of DMF and 2 mmol of NMM (28.7 mmol) were charged with EDAC (2.0 g, 10.7 mrnols) and the reaction was stirred for 15 hours at ambient ur-a. The reaction was then partitioned between water and EtOAc. The organic layer was then washed with 1N HCl, NaHCO 3, and brine, dried over MgSO 4, filtered and evaporated to give an oil which was chromatographed on flash silica with hexane: EtOAc (1: 1). - > 1: 4) to give 107. Amide of aculo (2R) - i obut i l-3 - (N-hi dr-o i carboxa gone) 1 - propanoi co of N- (carbomot ox nnet 11) -va 1 e ro 1 act arna - (3 S) - arní na (21). The benzylhydroxarnide acid 107 (850 mg, 1.90 min) was added to 10 mL of E + OH and the mixture was charged with palladium on 10% carbon-bonded (85 mg) and stirred under a hydrogen atmosphere for 1 hour. hour. The mixture was then filtered through celite and concentrated to an oil. The crude product was purified on a column of silica gel using 2% formic acid in ethyl acetate as eluent to give 21.

EXAMPLE 22 Synthesis of (2R) -isobutyl-3- (N-hydroxycarboxamido) 3-propanoic acid amide of 2-oxo-3-amino-N- (carbomethoxymethyl) -pyridinone (22). 2-QXO-3 -nitro-N- (carbornetoxirnet ll) -pi ridmona (109).

Was 2-h mixed? droxi-3- i ropyridma 108 (10 g, 71.38 immoles) with powdered potassium carbonate (10.9 g, 78.5 min) and 30 i of DMF. After 10 minutes methyl brizoacetate (10.4 rnl, 107 rnmoles) was added. The resulting mixture was stirred at room temperature for 4.5 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was then washed with brine, dried over MgSO *, filtered and evaporated to give an oil which was subjected to flash chromatography with EtOAc to give 109. 2 -Qxo-3-n? Tro-N- (carbomethoxymethyl) -pin di none (110).

Pipdinone 109 (3.0 g, 14.1 mmol) was converted to 45 ml of ethane and the mixture was loaded with 10% palladium on carbon. (0.3 g) and stirred under a hydrogen atmosphere for 17 BR hours. The mixture was then filtered through t.eli ta and concentrated to an oil. The crude product was chromatographed on flash silica with hexane: ethyl acetate (1: 1 to 100% FtOAc) to yield 110. (2R) - Isobut 11-3-carbo- bu i -propanoic toxin of 2 -oxo-3-arn i not -N- (c rboinetoximet jl) - f > ? i di nona (111). The acid 23 (2.5 g, 11 mmol) is dissolved in 15 ml. of THF and cooled to ~) 5 ° C. NMM (1.3 i., 11 mol) or i sobuthochloroformate (11 rnmoles, 1.6 inL) are added. After equalizing for 30 minutes, NMM (1.3 rnL, Ll minolos) and 110 are added. (2.0 g, 11 mmol). The reaction mixture is stirred for 17 hours and then quenched with 1N HCl and extracted with EtOAc. The organic layer is washed with 1N HCl, NaHCO 3, and brine, dried over MgSO 4, filtered and evaporated to give an oil which is chromatographed on flash silica with l: t? c to give 111. Amide of C (2R) -Isobut i i -3-0-benzylhydroxycarboxarnido] -propanoic acid of l-oxo-3-arn? no-N- (arbome oxyethyl) - i ul'one (113). Ester 111 (0.8 g, 2 rnrnoles) is dissolved in 5 L of full rnet chloride and slowly added rifluoroacetic acid (5 mL) at 0 ° C. The mixture is stirred for 2 hours and evaporated to give 112. The crude acid 112 is mixed with 0-benzyl hydroxylanine hydrochloride (0.5 g, 3.0 rnmoles), HOBT (0.81 g, 6 mmoles), EDAC (0.58 g, 3). immoles) in 10 mL of DMF and 0.77 rnL (7 mmol) of NMM at 0 ° C, and stirred for 17 hours at room temperature. The reaction is then partitioned between water and EtOAc. The organic layer is then washed with 1 N HCl, NaHCO 3, and brine, dried over MgSO < u, filter and evaporate to give an oil which is chromatographed on flash silica with hexane: EtOAc (2: 3 to 1: 4) to give 113. Amide of aci do (2R) -Isobut jj - 3- (N-hydroxy-1-hydroxycarboxylic acid) 2-oxo-3-propane-2-non-N- (c rborne oxirnet 11) - ?? p di nona (22). Only the benzoyl hydroxyaic acid 113 (180 g, 0.4 mol) in 5 ml. of Ft OH and the mixture is loaded with 10% palladium on carbon (20 rng) and stirred under a hydrogen atmosphere for 6 hours. TLC (EtOAc) indicates the persistence of a small amount of starting material that remains. More palladium on car-bond (18 rn) is added, 113 is hydrogenated for another 20 minutes. The mixture is then filtered through celite and concentrated to give a sernisolide, which is purified by preparative TLC (silica, EtOAc) to give '22.

EXAMPLE A A tablet composition is made for oral administration, in accordance with the present invention, comprising: Component Can i dad - (2R) -C (lS) -N-hydrox? Carboxamido] - ethyl decanoic acid N-E (2-methoxy) et? caprolactene- (35) -aini na1 15. ing -la (< bear 1 0. ing -starch maize 70 ing • lay 4. ing-magnesium stearate 1. ing 1 a hydroxainic acid prepared in accordance with Example 19 Other compounds that have a structure conforming to the formula T are used with anneal final results in the same way. EXAMPLE B A capsule is made for oral administration, in accordance with the present invention, which comprises: Component Quantity -amide acid (2R) -L "(5) -N-hydroxycarboxarnitamide and 1.1 decanoic of iN- (carbometox i-met 11) -caprolactam- (35) -amina2 15% -Polyethylene glycol 85% 2 a hydroxarnic acid prepared according to example 17. Other compounds having a structure according to formula I are used with results substantially similar.? r EXAMPLE C 3e makes a composition based on saline for local admiistration, in accordance with the present invention, comprising: Component Quantity - acid amide (2R) -Isobut 11 - (35) -CN-hydroxycarboxyamido] -6- hydroxy (IN) carbomethoxet imet i-caprolact ama (35) - amine 3 10% -F ano L ()% -Saline solution 80% 3 a hydroxamic acid prepared in accordance with the example 16. Other compounds that have a structure according to the formula I are used with similar results if my i-os.

EXAMPLE D A human female subject weighing 60 kg (132 lbs), suffering from rheumatoid arthritis, is treated by a method of this invention. Specifically, for 2 years, a tablet containing 50 mg of (2R) ~ N-hydroxycarboxarnidamethyldecanoic acid amide of 1N- (car-bornetoxymethyl) -capr or lact arna- is administered orally to said subject. 35) -am na (prepared according to example 9). At the end of the treatment period, the patient is examined and discovered to have reduced inflammation, and improved movement without concomitant pain. Other compounds having a structure of < )2 conformity with the phyiinu (T) with similar subst an the 1st nni l r-es.

EXAMPLE E A human male subject weighing 90 l-g (198 Jbs), suffering from ost ooart p tis, is treated by a method of this invention. Specifically, for 5 years, said subject is administered daily a capsule containing 70 acid amide (2R) -isobutyl-3- (N-hydroxy carboxamido) -pr-o-anole of N- (carbo otoxirneti 1) -valerolacta a- (3S) -arní na (made according to example 2L). At the end of the treatment period, the patient is examined by orthoscopy, and it is found that there is no progress in erosion / fibplation of the articular cartilage. Other compounds having a structure according to formula (I) are used with similar substantially similar.

EXAMPLE F A human subject weighing 90 l-g (198 lbs), suffering from corneal ulcerations, is treated by a method of this invention. Specifically, for 2 months, a saline solution containing 10 mg of acid amide (2R) -N- 33 is administered to the affected eye of said subject twice a day. hydroxy carboxamidoinet 11-N- (carbomethoxy irnet L I) -caprolactane- (35) -ca in (made in accordance with example ü). Other compounds having a structure in accordance with formula (I) are used with substantially similar if my lores.

Claims (20)

1. NOVELTY OF THE INVENTION

   ] .- A compound that has a structure according to the formula T

   wherein (A) (1) (a) R1 is hydrogen; I rent; hete roa! quilo a heterocyclic ring; a carbocyclic ring; alkoxy; carbocycle-alkyl; heterocycline alkyl; carbocycle-het or-oalqu lo; or heterocycloheteroalkyl; and (b) R2 is hydrogen; hydroxy; I rent; alkenyl; alkynyl; I have eroalkyl; a heterocyclic ring; a carbocyclic ring; carbocycle-alkyl; heterozyme the o-alkyl; or -OR, wherein R 'is alkyl, alkenyl, or carbocycloalkyl; or (2) R1 and R2 together form a cycloalkyl ring of 3 to 8 ring atoms; (B) R3 is hydrogen; I rent; or carbocycle-alkyl; (C) R * is (1) alkyl; (2) carboci clo-al qui lo; (3) -X-C (= Y) -Z-RS or -X-CH2 -Z-R5, wherein (a) X is a covalent or alkyl bond; (b) And it is

   0, 5 or NH; (c) Z is 0, 5 or NH; and (d) RS is hydrogen; I rent;

   alkenyl; carbocycle-alkyl; or aplo; or (4) -SO 2 -R 6, wherein RS is alkyl, carbocyclyl-alkyl, heterocycle-alkyl, or aplo; and (D) 0 is C -C (R7) - - l-n / where (1) n is the integer 2, 3 or 4; and (2) each R7 is independently hydrogen or alkyl such that the heterocycle containing O is saturated; or the portion of R7 at two adjacent carbon atoms is a covalent bond so that the heterocycle containing O of the formula (I) is more saturated; or a pharmaceutically acceptable salt, or biohydroxylated alkoxy, acyloxyamide or attached thereto.
2. 2. The compound in accordance with the claim

   1, further characterized in that R3 is hydrogen or alkyl.
3. 3. The compound according to the claim

   2, further characterized in that R3 is hydrogen.
4. 4. The compound in accordance with the claim

   3, further characterized in that R1 is hydrogen; alkyl or heteroalkyl.
5. 5. The compound in accordance with the claim

   4, further characterized in that R1 is hydrogen; methyl; n-propyl or 3-hydroxypropyl.
6. 6. The compound according to claim 3, further characterized in that R2 is hydrogen; alkoxy; I rent; alkenyl; or -OR, wherein R is alkyl or alkenyl.
7. 7. The compound according to claim 6, further characterized in that R2 is Ci-Cß alkyl or C 2 -Ce alkenyl.
8. B "- The compound in accordance with the rei indication 7, characterized adornas because R2 is n-? En? Lo; n-oct? lo or 2-rnet i i propLlo.
9. 9. The compound according to claim 7, further characterized in that R4 is carbocyclic to the qui lo; -X-C - (Y) -7-R5; or -X-CH2-Z-RS.
10. 10. The compound according to claim 9, further characterized in that (a) when R1 is carbocycloalkyl, the alkyl is alkyl of Oj. -0.v and the earbocycle is aplo; (b) when R * os -X-C (= Y) -Z-RS, X is Ci; Y is 0, Z is 0; and RS is alkyl, carbocyclic-al qui lo or ap Jo; (c) when R * is -X-C (= Y) -Z- RS, X is C-j.; And it is 0; Z is NH; and RS is alkyl, carbocycle-alkyl or aryl; or (d) when R * is -X-CH2-Z-RS, X is Ci; Z is 0 or 5; and RS is Ci ~ C3 - 11.- A compound having a structure according to the formula (T)
11. wherein (A) (1) (1) R1 is hydrogen; alkyl or heteroalkyl; and di) R2 is alkyl; or (2) R1 and R2 together form a cycloalkyl ring having from 3 to 8 ring atoms; (B) R3 is hydrogen; (OR * is (l) alkyl, (2) carbocycloalkyl; (3) -XC (tY) ~ Z-RS or -X-CH2-Z-R5, wherein (a) X is an eovalent or alkyl, (b) Y is 0, (c) Z is 0 or NH, and (d) RS is alkyl, carbocycloalkyl or aryl, or (4) -SO2-R6, where RS is alkyl, carbo i-cloi-alkyl, heterocycle-alkyl or aryl, and (D) 0 is -CC (R7) 2 -] "n, where n is 4 and each R7 is either hydrogen or alkyl, so that the heterocycle contains 0 is saturated, on is 4 and the portion of R7 at two adjacent carbon atoms is a covalent umon, so that the heterocycle containing 0 in the formula (I) is unsaturated, or a pharmaceutically acceptable salt, biohydrolysable amide or biohydrolyzable ester thereof.
12. 12. The compound according to claim 11, further characterized in that R1 and R2 do not together form a cycloalkyl ring.
13. 13. The compound according to claim 12, further characterized in that each R7 is hydrogen or alkyl.
14. 14. The compound according to claim 13, further characterized in that R * is ~ X-C (= Y) ~ 7-RS.
15. 15. The compound according to claim 14, further characterized in that X is C1-C2 alkyl; And it is 0; Z is 0; and R5 is methyl, benzyl or t-butyl.
16. 16. - The compound according to claim 14, further characterized in that X is Ci-C2 alkyl; And it is 0; Z is NH; and R5 is methyl, benzyl or n-butyl.
17. 17. The compound according to claim 13, further characterized in that R * is -X-CH2 -Z-RS.
18. 18. The compound according to claim 17, further characterized in that X is a covalent bond or Ci-C2; Z is 0; and RS os Ci -O3.
19. 19. The compound according to claim 1, further characterized in that the compound is selected from: acid amide (R) -Isohutil -3- (N-hLdrocarboxamdo) -propane ico of lN- (carbornetox? - methanol) -caprolactarine- (35) -amine; acid (2R) -Isobut 11-3- (N-hydroxycarboxarido) -propionic acid of lN- (methyl carboxamidornet? l) -ca? rolactam- (35) -amine; acid amide (R) -Tsobutyl -3- (N-hydrox 1 carboxarnide) -propionic acid of 1N- (carbo-butoxy-rnetii) -caprolactam- (3S) -am? na acid amide (2R) -Isobutyl-3- (N-h 1 d or 1 carboxymer) -pronic acid of 1N-benzyl 1-ca p rol ctarna- (3 S) -amine; (2R) -Isobutyl-3- (N-hydroxycarboxaride) -amino-1-propionic acid amide (carbo-benzyloxymethyl) -caprolactam- (35) -amine; (2R) -Teobu il- (N-hydroxycarboxaride) -propionic acid amide of IN- (N-benzylcarboxamidomethyl) -caprolactane- (3S) -amine; (2R) -Isobutyl-3- (N-hydroxcarboxamide) -propionic acid amide of 1N- (n-butylcarboxarm domethyl) -caprolactane- (3?) -aima; (2R) -N-hydroxy carboxamidomethyl heptanoic acid amide of N ~ (carbomethoxymethyl) -caprolactane - (35) -amine; acid amide (2R) -N-h? drox? N- (carbornetoxymethyl) -caprolactam- (35) -amine carboxainido-methylene decanoic acid; acid amide (2R) ~ N-hydroxycarboxylennethexyl decanoic acid of N-toJ uensul fonyl-ca-rolactam- (35) -a i na; (2R) N-hydroxycarboxamidohexyl decanoic acid amide of N-C (2-me + ox?) ethyl] -caprolactane- (35) -amine; (2R) -N-hydroxycarboxamidomethyl decanoic acid amide of 1-N-n-butyl-ca-rolactam- (3S) -arnine; acid amide (2R) -Isobut? i- (35) - UNhydroxycarboxar- do] -butane? co (IN) -carbomethoxymethyl-ca? rolactam- (35) -amine; acid amide (2R) -Isobu? l- (R) -CN-hydroxycarboxylic acid] -butane? co (IN) -carbornetoxirnethyl-caprolactam- (5) -amine; amide of (2R) -Isobutyl- (35) -UN-hydroxcarboxamido] -hexaoic acid (lN) -carbo and oxirnenyl-caprolactam- (35) -nane; acid amide (2R) -Isobuti l- (3S) -L ~ N-hydroxcarboxamido] -6-hydroxyhexanoic acid (1N) -carbo-ethoxymetho-caprolactane- (35) -amine; (2R) ~ C (15) -N-hydroxycarboxamide] -etu decanoic acid amide of 1N- (carbomethoxy-methyl) -caprolactane- (35) -amine; (2R) -C (1R) -N-hydroxycarboxarnido] -ethydecanoic acid amide of lN- (carbomethoxy-yl) -caprolactam- (3S) -amine; (2R) -C (1S) -N-hydroxycarboxarnide] -etiidecanoic acid amide of N- [(2-rnetoxy?) et? l] -caprolactam- (35) -amine; (2R) - [(IR) -N-hydroxycarboxy] -ethyl ethanoic acid amide of N-C (2-methoxy i) et i 1] -caprolactam- (35) -amine; amide acid (2R) -Isobutyl-3- (N-hydroxycarboxamido) -? ropanoico N- (carboethoxymethyl) -valerolacta a- (35) -amina; and acid amide I "(2R) -Tsobutyl -3- (N-hydroxycarboxamide)] -propane? co of 2-oxo-3-a? n? no-N- (carbornetoxirnetii) -? pdmone.
20. 20. A pharmaceutical composition comprising: (a) an effective amount of a compound of claim 1, and (b) a pharmaceutically acceptable carrier 21. - A pharmaceutical composition comprising-, (a) an effective amount of a The compound of claim 11, and (b) a pharmaceutically acceptable carrier 22. A pharmaceutical composition comprising: (a) an effective amount of a compound of claim 19, and (b) a pharmaceutically acceptable carrier. - The use of an effective amount of a compound of claim 1, in the preparation of a pharmaceutical composition for preventing- or treating a disease associated with

    The unwanted matrix rnetaloprotease activity in a human or other animal subject. 24. The use of an effective amount of a compound of claim 11, in the preparation of a pharmaceutical composition for preventing or treating a disease associated with unwanted matrix metalloprotease activity in a human or other animal subject. 25. The use of an effective amount of a compound of claim 19, in the preparation of a pharmaceutical composition for preventing or treating a disease associated with unwanted matrix metalloprotease activity at a 10 '.

    human or another animal subject

    SUMMARY OF THE INVENTION

    The present invention relates to compounds that exhibit inhibitory activity cont rnetaloproteasas matrix ("MMPs"); since it is known that MMPs play a role in tissue degradation, the compounds of the present invention may be useful for preventing or treating diseases associated with excess MMP activity; in particular, the compounds have a structure according to formula (I), wherein (A) (1) (a) R 1 is hydrogen; I rent; heteroalk 1 o; a heterocyclic ring; a carbocyclic ring; alkoxy; carlociclo-al qui lo; heterocycloalkyl; earbocycloheteroalkyl; or heterocycloheteroyl; and (b) R2 is hydrogen; hydroxy; I rent; alkenyl; alkynyl; het eroalkyl; a hoterocic ring; a carbocyclic ring; carbocycloalkyl, heterocycloalkyl; or -OR, wherein R is alkyl, alke Jo, or carbocyclic-cycloalkyl; or (2) R1 and R2 together form a cycloalkyl ring of 3 to 8 ring atoms; (13) R3 is hydrogen; I rent; or carbocycle-alkyl lo; (OR] is (l) alkyl, (2) carbocycle-alkyl, (3) -XC (= Y) -Z-RS or -X-CH2-Z-RS, wherein (a) X is a covalent bond or alkyl, - (b) Y is 0, 5 or NH; (c) Z is 0.5 or NH; and (d) R5 is hydrogen, alkyl, alkenyl, carbocycloalkyl, or (4) - SO2-R6, where RS is alkyl, carbocycloalkyl, heterocyclic-to which Jo, or aplo; and (D) 0 is L ~ -C (R7) 2 -] ~ n> where (1) n is the integer 2, 3, or 4, and (2) each R7 is independently hydrogen or alkyl such that the heterocycle containing 0 is saturated, or the portion of R7 at two adjacent carbon atoms is a covalent bond of the other. heterocycle containing 0 of the formula (I) is unsaturated, or a pharmaceutically acceptable salt, or biohydrolyzable alkoxyamide, acyloxy amide or bound thereof, the invention also relates to pharmaceutical compositions comprising these compounds, and to the use of said compounds and compositions in the preparation of pharmaceutical compositions to prevent ot ratar diseases associated with the activity of unwanted MMP.

    BS / EA / fac * aprn * -l? M * P97 / 929F