MXPA97004968A - Inhibitors containing hydroxamic acid metaloprotease mat - Google Patents

Abstract

The invention provides hydroxamic acid containing compounds which are useful as matrix metalloprotease inhibitors and which are effective to treat conditions associated with the excess activity of these enzymes, in particular, the present invention relates to a compound having a structure in accordance with Formula I, wherein: (A) R1, R2, R3, R4 and R5 are independently selected from several substituents, and (B) wherein R3 and R4 or R4 and R5 together may comprise a cyclic portion; pharmaceutically acceptable salt, biohydrolyzable amide or biohydrolyzable amide thereof, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of formula (I), and to methods for treating diseases characterized by matrix metalloprotease activity using these compounds or pharmaceutical compositions containing them

Description

INHIBITORS CONTAINING HIDRQXRI ICQ OF ETRLOPROTEñSS OF IIRTRIZ TECHNICAL CRHPO This invention is di erently related to the fact that it is the harmonization of those associated with the activity of oppressive control over oxcoso and / or unwanted, <., ¿n? ular the activity of est romo isi na. fias espocí f? e-unont o, 10 the invention is d? rj < to compounds that contain hydroxamic acid.

BACKGROUND OF THE INVENTION )!? A number of checks are made on the division of "broken". aioprot oasas related ':, es4, ruct u ral ont e. These include eola < The skin of the human skin, the gel-like gel of the human skin with co-onasa and < "jp 1 a t i nasa do sμ? t u human, and osi i OIÍI" 1 i ", na ? { } human I + s are on / imas met a loprot easa < What do they contain? , as are the enzymes < \ e become an < j? ot ensí na and l.is anco (t 11 nasas., ls in / a do os-t romo 1 LS i na and 1 as the cionada are i iiiport.ai'd is to mediate the si nt omat or 1 or < j that of a number of. • n (-eye, including art ri t is reuma to id < - (Mul l ins, DI .., y '"> ot ro- ,, Ihochiin .Diophys lleta (l < -) m) FiFSr 117 -? W?); Ost ^ ai't? ») S (llondor'-on, Ti., and t r, nru s ol t future (l '? O) 1 S -'.?, 508); metastasis of tumor cells (ibid, Broadhurst, M "3., and others, 4B Cancer Res 3307-3312 (1988), and various ulcerated conditions.The ulcerative conditions may result in the cornea as the result of lcali burns or As a result of infection by Pseudomonas aeruginosa, Hoantharnoeba, Herpes sirnplex, and vaccine virus, other conditions characterized by unwanted matrix metalloprotease activity include popodontal disease, erythrolysis, and sclerosis. Since the matrix alloproteases 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 FUfi patent No. 4,771,038, issued on September 13, 1908 to Uolanin, and others, US Patent No. 4,743,587, issued May 10, 1988 to December, and others; European Patent Publication Number 575,844; published on December 29, 1993 by Broadhurst, and others; International Patent Publication No »UO 93/09090, published May 13, 1993 by Tsoinura, et al .; Publication of the European Patent Number 498,665, published on 1? August 1992 by Beckett, and others; and patent of E..U.R. No. 5,183,900, issued on February 2, 1993 to GaLardy. It is known in the art that matrix inhibitors are useful in the treatment of diseases caused, at least in part, by the division of structural proteins. Although many inhibitors have been prepared, there is a continuing need for compounds useful in the treatment of said diseases. The compounds of the present invention are added to the repertoire of agents available for the treatment of conditions and diseases that are characterized by undesired activity by the class of proteins that destroy structural proteins.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds which are useful as metal matrix oppressed inhibitors and which are effective in the treatment of conditions characterized by the excess activity of these enzymes. In addition, unlike the prior art compounds, these compounds have reduced peptide character, which may allow biocli sporubi 1 and improved stability. This improvement is important, since the peptide nature of known inhibitors results in typically b odisponi t »? 11 given due to the rot eo1 i. In particular, the present invention relates to a compound having a structure in accordance with formula I in the nucleus (R) (1) R1 is hydrogen; I rent; het eroal < | u i 1 o; alque what; Boncilo a ring I have erocí cli co; a carbolic ring; alkoxy; carbocycle-allo; heterocyclic to whom; carbocí cío-het e o i qu lo; het erocycloheteroalkyl; carbocycle-? o; or het erocí clo-? o; (2) P2 is hydrogen; I rent; alkenyl; a heterocyclic ring; a carbocyclic ring; earbocí clo-al c? u? lo, heterOcí clo-alquiJ o; or oarhocí cío-hete roalqui 1 o; (3) R3 is hyrogen; I rent; a carbocyclic ring; or a heterocyclic ring; (4) R * is alkyl; heteroalk to whom I call; aci lamino; carboxyalkyl; to i noalqui lo; a carbocyclic ring; a ring hetorocicl i co; heterozyme clonee roa 1 qu i lo; heterocycle-al ui lo; or a portion capable of supporting a load; and (5) RS «o. (a) -0-R6; wherein R6 is hydrogen, alkyl or benzyl; (b) -N (R9) CH (Rio) (Rii), wherein (i) R9 is hydrogen or alkyl; and (11) Ri ° and Rii are, independently, hydrogen, alkyl, aplakyl, coxy, or ammoacyl; or (111) R9 and Rio, together with the atoms of nitrogen and carbon to which they are attached, comprise a monocyclic heterocyclic ring of 4-9 atoms; (c) an acidic acid or a peptide having 2 or 3 arnino acids, where said acid or said peptide (Jo is attached to the formula (I) by means of its amino acid; (1) (1) (1) R3 and R * together can comprise a noncyclic carbocyclic ring of (b) carbocycloalkyl; or (g) carbocyclecycle; 3-9 atoms, a polycyclic carbocyclic ring of 7-17 atoms, a monocyclic heterocyclic ring of 4-9 atoms, or a polycyclic het erocyclic ring of 7-17 atoms, or (2) R * and R5 together may comprise a carbocyclic rnonoclic ring with 3-13 atoms, a polycyclic carbolic ring of 7-17 atoms, a 4-10-atom onerocyclic hoterocyclic ring, or a 7-6 atom polycyclic heterocyclic ring; a pharmaceutically acceptable salt, a biohylachlorizable amide, or a biorepellent ester thereof, these compounds have the ability to inhibit at least one amide-parent oprotease metal. Accordingly, 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 inetaloprotease using these compounds or the pharmaceutical compositions. that contain them Matrix metalloproteases in a particular undesired location can be idenified by conjugating the compounds of the invention to a specific target ligand for a marker at said location such as an antibody or fragment thereof or a ligand. receiver-. The invention is also directed to several other methods that take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of the formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired matrix metal.

In ot aspect, the invention is directed to the compounds of the formula (T) conjugated to a brand. As the compounds of the invention bind to at least one metal oprotease matrix, the label can be used for the presence of relatively high levels of matrix metalloprotease in cell culture. vo on v11 ro In addition, the compounds of the formula (I) can be conjugated to vehicles that allow the use of these compounds in the immunization of the protocols to prepare antibodies specifically to the compounds of the invention. These antibodies are then useful both in therapy and in the control of the dose of the inhibitors.

DETAILED DESCRIPTION 1 The compounds of the present invention are inhibitors of mammalian matrix eta-opiate. These compounds have an axis structure according to the formula T - •? (AHÍ) Rl is hydrogen; I rent; uilo heteroal; alkenyl; benzyl; a heterocyclic ring; a carbocyclic ring; alkoxy; car ocic I o-ali lo; het erociclo-alqui lo; carbocycle-heteroaryl what; heterocyclic-heteroalk; carbocyte clo-thio; or het? oci c Jo-t o; (preferably hydrogen, alkyl or carbocycloalkyl; most preferred hydrogen, methyl, or ilo, isopropyl or -eni lot i) o) (2) R2 is hydrogen; I rent; alcμjomlo; a heterocyclic ring; a carbocyclic ring; carbocycle-to whom, heterocycle-alkyl; or carbocycloheteroalkyl; (preferably C 1 -C 0 alkyl, O 4 -C 10 alkenyl, or carbocycloalkyl; highly preferred decyl, 2-nitropropyl, 2-phenote 1 lo, or '3-fen? Ipropyl) (3) R3 is hydrogen; I rent; a carbocyclic ring; or a heterocyclic ring; (preferably hydrogen or alkyl, more preferably hydrogen, methyl or ethyl; very preferred hydrogen) (4) R * is alkyl; heteroalk ali lamino; aci lamino; carboxial what; to inoalkyl; a carbocyclic ring; a heteric ocular ring; heterocycle-het eroalkyl; het erocí clo-al quilo; or a portion capable of supporting a load; (preferably 2-inet ilpropi lo, carbo imef i lo, 2 ~ car-box? et? lo, 4-even not?, 2-phenylein, 3-epropyl, benzyl, or 3-guani di noprop lo) and (5) R5 is (a) -0-R6, - wherein R6 is hydrogen, alkyl or benzene; (10 (preferably) -N (R9) CH (Rio) (RI I) wherein (i) R9 is hydrogen or alkyl, and (ii) R and RII <, independently, hydrogen, alkyl, ap-alkyl, alkoxycyl, or arninoacyl, (preferably one from Rio or RH ee hydrogen) or (ni) R9 and Rio, together with the nitrogen and carbon atoms to which they are attached, comprise a monocyte monocyte ring. " with 4 9 lathes; (c) an acidic acid or a peptide having 2 or 3 amino acids, wherein said non-acidic acid or peptide is linked to the formula (I) by means of its amino group; ci) lq? i lo; (e) alkyl, (f) carbocycle-alkyl or (g) carbocycle-alkenyl; (13) and wherein (1) R3 and R * together may comprise a carl-oleyol ring monocyclic of 3-9 atoms, a carbocylic elastic ring of 7-17 atoms, a heterocyclic chemical ion of 4-9 atoms, or a polycyclic heterocyclic ring of 7-17 atoms (preferably a carbocyclic monocyclic ring or saturated cyclic poly, most preferred a saturated rnonocicyclic ring) or (2) * and S together may comprise a monocyclic carbocyclic ring of 3-J3 atoms; a polycyclic carbocyclic ring of 7-17 atoms; a heterocyclic er-ocicylic ring of 4-9 atoms; or a polycyclic heterocyclic ring of 7-17 atoms; or a pharmaceutically acceptable salt, biohydrolyzable amide or biohydrolyzable ester thereof. Preferred compounds of formula (I) are those wherein none of R3, R4, and R5 combine to form a ring; and those where only R3 and * together form a ring. More preferred is where none of R3, R1 and R5 combine to form a ring. Examples of preferred R5 groups include, but are not limited to, 3 L DEFINITIONS AND USE OF TERMS: The following is a list of definitions for the terms used herein: "Acyl" or "carbonyl" is a radical formed by - the removal of hydroxy from a carboxylic acid (ie, RC (-O) -) . Preferred acyl groups include (for example) acetyl, forrnyl and proper i.o., "Aryloxy" is an oxygen radical having an acyl sub-solvent (ie, -0-acyl); for example, -0 -C (= 0) -alkyl. "Aci lamino" is an arnmo radical that has an acyl substituent (ie, N-acyl); for example, -NH-C (= 0) -alqu? lo. "Alkoxy" is an acyl radical (-C (-O) -) having an alkoxy substituent (i.e., -0-R), for example, -C (= 0) -0- to the quilo. "Alcyonon" is a substituted or unsubstituted hydrocarbon chain radical having from 2 to 15 carbon atoms; preferably axis 2 to 10 carbon atoms; preferably from 4-10; except where indicated. Preferred are the alkenyl surfactants having at least one double olefinic ion (including, for example, vmilo, ai lo and but in i lo) .. "Alkynyl" is a substituted or unsubstituted hydrocarbon chain radical having from 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more P? e fon bJe between '+ -10; except where indicated. The chain has at least one triple carbon-carbon bond. "Alkoxy" is a radical oxygen axis having a hydrocarbon chain substituent, wherein the hydrocarbon chain is an alkyl or alkenyl (i.e., -0-alkyl? ~ 0-to the quen lo). Preferred alkoxy groups include (for example) tnetoxy, ethoxy, propoxy and ali-oxy. "Alkyl" is a sub- or non-substi tuted hydrocarbon chain radical having from 1 to 15 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 4-10; except where indicated. Preferred alkyl groups include (for example) substituted and unsubstituted methyl, ethyl, propyl, sopropyl and butyl. "Al quilami no" is a mood radical having one or two alkyl substi tutes (i.e., N-alkyl). "Aní noacilo" is an acyl radical having a substitute of arnino (ie, -C (-O) -N); for example, - C (= 0) -NH2. The arnine group of the ammoacyl moiety may be unsubstituted (ie, primary amine) or may be substituted with one (secondary amine) or two phi say, tertiary amine) groups to which, "A ilo" is a radical of aromatic carbocyclic ring. Preferred acyl groups include (for example) phenyl, tolyl, xylyl, cu nyl and naphthyl. "Ar-i which is" is an alkyl radical substi tuted with an aplo group. Preferred aplakyl groups include bonillo, fen lethyl and phenyl propyl. "Ari Lamino" is an amine radical substituted with an aplo group (is elecir, -NH-aplo). "Ar-yloxy" is an oxygen radical having an aryl substi tute (i.e., -0-aplo). "Capable of supporting a load" refers to a portion that supports a charge (eg, quaternary ammonium group) or one that can withstand a charge at an appropriate pH (eg, carboxyl or amino). "Carbocyclic ring" is a substituted or unsubstituted, saturated, unsaturated or aromatic hydrocarbon ring radical. LCOS carbocyclic rings are monocyclic or are polycyclic ring systems, bridged or spiral. The carbocyclic ring rings generally contain from 3 to 9 atoms, preferably from 3 to 6 atoms, however, where R * and Rs together form a ring, said ring rings preferably contain 3-13 atoms. »Polycyclic carbocyclic rings contain 7 to 17 atoms, J pre fep Leinente from 7 to 13 nights. "Cai bocí clo-aJ quilo" is a substituted or non-substituted alkyl radical, substituted with a ring < arbocí cl ico. The carbocyclic ring is preferably an aplo or cycloalkyl; more preferably an aplo. Preferred carbocycloalkyl groups include benzyl, fexyethyl, and phenolyl. "Cac bociclo-heteroal qui lo" is a radical of heteroalkyl substituted not substi tuido, replaced with a ring bocí cl i co. The carbocyclic ring is preferably an aplo or cycloal ei, u? the; preferably one aplo. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-etho, 2-thia-propyl or 2-tα-aetho. "Car bocí clo-t o" is a sulfur atom substituted with a carbocyclic ring. The carbocyclic ring is preferably an aplo or cycloalkyl; more preferably an aplo, "Carboxyalkyl" is an unsubstituted or substi tuted alky radical substituted with a carboxy moiety (-C (= 0) 0H). "Oteroheteroalkyl" is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) inorpholine, piperadine, perazine and furanyl. "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 another ring.

"Hetero-cycloalkyl" is a substituted or unsubstituted alkyl radical, substi tuted with a het orocyclic ring. The heterocyclic ring is preferably a compound or alkyl radical; more preferably an aplo. "Meter ocíelo- hoteroal quilo" is a substituted or unsubstituted heteroalkyl radical, substituted with a heterocyclic ring. The heterocyclic ring is preferably a < ocle or cycloheteroal qu i lo; more preferably an aplo. "Het er ociclo-t 10" is a sulfide atom substituted with a heterocyclic ring. The heterocyclic ring is preferably an aplo or cycloheteroalkyl; more preferably an aplo. "Heter-oate or" is a nitrogen atom, sul uro or oxygen. The groups containing one or more heterogeneous lathes may contain different het eroatnes, "Hoteroalq ilo" is a radical of the saturated chain substi tuted or not denoted as having 3 to 0 member axes that comprise carbon atoms. -Bono 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. The heterocyclic rings are monocyclic or are polyocyclic ring systems, bridged or spiral. The heterocyclic ring rings contain from 3 to 9 atoms, preferably from 4 to 7 atoms. The cyclic pol rings contain from 7 to 17 atoms, preferably from 7 to 1 atoms. "Heteroaplo" is an aromatic heterocyclic ring radica. Preferred heteroaryl groups include (for example) thienyl, fupyl, pyrrolyl, pipdm lo, pyrazinyl, t-azolyl, pi-i-dimido, quinyl, and tetrazolyl. "Halo", "halogen" or "halide" is a radical of the chlorine, bromine, fluorine * or iodine atom. Preferred halides are chlorine and fluorine. Also, as referred to herein, a "lower" hydrocarbon portion (eg, "lower") is a hydrocarbon chain composed of 1 to 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 ino). Piggy banks of said salts are known in í < or technique, as described in the publication World Patent 37/05297, 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 alkaline and non-ferrous metal salts (such as magnesium and calcium). Preferred ammonium salts include halides (such as or chloride salts). A "biohazard ester" is an ester of a hydroxamic acid that does not interfere essentially with the inhibitory activity of the compound, or that is readily converted by a human or lower animal subject to an active hydroxamic acid. Said esters include those that do not interfere with the biological activity of the hydroxaric acid. Many such esters are known in the art, as described in World Patent Publication 87/05297, Johnston et al., Published September 11, 1987 (incorporated herein by reference). Such esters include esters of lower alkyl, esters of acyloxy-lower alkyl (such as esters of acetyl oxiranet, acetyl oxyethyl, ammocarbomloxy ethyl, pivaloylox irnet i, and pivaloi loxiet i lo), lactonyl esters (such as phthalidyl esters) and thiophthal dyl), esters of alkox lací loxia, lower alkyl (such as esters of rnetoxi carbonil ox met i lo, ethoxycarbomloxiet lo and isopropoxi carbo lox Let i lo), esters of alkoxyalkyl, esters of colma, and esters of alkyl aci lamino? Íjuju Jo (such acetarm et es et i lo esters). A "biohydrolyzable amide" is an amide of a compound of formula (I) which does not interfere with the metalloprotease inhibitory activity of these compounds, or which is readily converted by a human or lower animal subject to give an active compound of the formula (I). Said amides include those that do not interfere with the biological activity of the compounds of the formula (I). Many of said amides are known in the art and include: lower alkyl amides (e.g., acetone, propionide, etc.), IB .-I will give them acid (for example, glycine amides, amides to the animal, amides of proline, etc.), to polypeptides (for example, Lalanma wing amides, glycillin amides, etc.), alkoxycarbon amides (for example, ethoxycarbonyl amides, benzylcarboxamide amides, etc.), and alkylaminocarbonyl amides (for example, methylcarbonyl amides, ethylenecarbonyl amides, etc. ) . A "solvate" is a complex formed by the combination of a solute (for example, a hydroxyl acid) and a solvent (for example, water). See 3. Hong and others, The M Nostrand Chemist's ctionary, p. fi50 (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, ethanol, acetic acid, N, N-d? Methylene forrnarnide). As used before, and as it is used in the present, the substituent groups can be replaced by themselves. Such substitution can be one or more substituents. Said substituents include those listed in C. Hansch and A. Leo, ubsti tuent Constanfs for Correlat on Analysis in Chernistr-y and Biology, (1979), incorporated herein by reference. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ainino, arm, which (eg, amino, etc.), cyano, halo, carboxy, alkoxyaceil (eg, carboethoxy) , etc.), thiol, aplo, cycloalkyl, heteroaryl, heterocyclic alkyl example, pipen dini Lo, rnorfol nilo, ?? rrol? d? Nile, etc. ), unino, tiox, hydroxyl, aplox, ap lalquiJo and combinations thereof. As used herein, "protein logs of the matrix" means any enzyme found in inactive sources that is capable of catalyzing the cleavage of collagen, gelatin, or proteoglycan under suitable test conditions. Suitable test conditions can be found, for example, in the US. Ho. 4,743,587, with references to the procedure ele Cawst on and other - ,, Anal Biochem (1979) 99: 340-345, the use of a synthetic substrate is described by Uemgarten, H. et al., Biochem Biophy Res Cornin (1984) 139: 1184-1187. Of course, any normal method can be used to analyze the division of these structural proteins. The metalloprotease enzymes referred to herein are all zinc-containing proteases that are similar in structure to, for example, the human isomer or fibroblast collagenase of the β-1. , the ability of the candidate compounds to inhibit matrix metalloprotease activity can be tested in the tests described above.The isolated matrix metalloprotease enzymes can be used to confirm the inhibitory activity of the compounds of the invention, or raw extracts can be used They contain the axis scale enzymes capable of dividing the tissue.

COMPOUNDS: The following is a representative, non-exhaustive list of the preferred compounds within the scope of the invention. twenty In general, the hydroxamic compounds of the formula (I) can be prepared by the following procedure. A < Suitably protected (0-protected or N, 0-protected) hydroxyainic acid derivative of N-alkyl glycine or D-arnino acid of r, N-alkyl is coupled an appropriately substituted carboxylic acid. Vanishing reagents of car-bodumide f > They can be used, as well as mixed anhydride methods, or other coupling methods commonly used in peptide couplings. The desired compounds are obtained after the removal of the protective groups by appropriate chemistry.

COMPOSITIONS: The compositions of the invention comprise: S (a) a safe and effective amount of a compound of the formula (T); and (b) a pharmaceutically acceptable vehicle. As discussed above, numerous diseases are known to be regulated by the activity of mel loprotease that destroys mderate matrix or excess cié. These include tumor metastasis, osteoartpt? S, arthritis re? Rnatoi, inflammation of the p? El, ulcerations, particularly of the cornea, reaction to infection, pepodontiti s and the like. In this way, the compounds of the invention are useful in the therapy with respect to conditions that involve this unwanted activity. : > q Therefore, the compounds of the invention can be formulated in pharmaceutical compositions for use in the treatment or prophylaxis of these conditions. The normal pharmaceutical formulation techniques are used, such as those described in Phapnaceut i cal Sciences de Rern gton, Nací'- Publishing Company, aston, Pa., Last edition. A "safe and effective amount" of a compound of the formula (T) is an amount that is effective to inhibit matrix ine + proteases at the site (s) of activity in a human or animal subject within, without adverse side effects. undue (such as toxicity, irritation, or allergic response), which corrects with a reasonable benefit / risk ratio when used in this manner of this invention. The "safe and effective amount" specifies, obviously, with such factors as the condition treated, the physical condition of the patient, the duration of the treatment, the nature of the concurrent therapy (if any), the specific dosage form. which is to be used, the vehicle employed, the solubility of the compound of the formula (I) therein, and the desired dosage regime for the composition. The co-positions of this invention are preferably provided in a unit dosage form. As used herein, a "unit dose form" is a composition that contains an amount of a compound of formula (I) that is suitable for administration to a human or subject. lower animal, in a single dose, of 3 (3 compliance with good medical practice. These compositions preferably contain from about C g (milligrams) to about 1000 mg, more preferably from about LO up to about 500 ing, most preferably from about 10 rng to about 300 ing, of a compound of the formula (1) ). The compositions of this invention may be in any of a variety of suitable forms (for example) for oral, rectal, topical or parenteral administration. Depending on the particular-desired administration / administration, a variety of pharmaceutically acceptable carriers well known in the art could be used. These include solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating trust substances. Optional pharmaceutically active materials may be included, which do not substantially interfere with the inhibitory activity of the compound of the formula (T). The amount of the vehicle used together with the compound of the formula (1) is sufficient to provide a practical amount of material for the administration of unit dose of the compound of the formula (TJ) 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 retention: not from R n P ra ra c e 1 cs, Chapters 9 and 10 (Banl-er a Rhodes, editors, 1979); Lieberrnan et al., Pharmaceutical osage Forrns: Tablets (1981); and Rnsel, Int roduct ion to Pharmaceutical osage Forrns 23 edition (1 7R),.

In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and their derivatives, malt, gelatin, calcium, calcium sulfate, vegetable oils, synthetic oils, and the like. polyols, algic acid, phosphate buffer solutions, sulphonic acids, isophonic saline, and pyrogen book water. Preferred vehicles for parenteral administration include propi lengli col, Ethyl oleate, ?? rrolidone, ethanol and sesame oil. Preferably, the pharmaceutically acceptable carrier O, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition. Various oral dosage forms may be used, including solid forms such as tablets, capsules, granules and 5 bulky powders. These organic forms comprise a safe and effective amount, usually at least about%, and preferably from about 25% to about 50% of the compound of the formula (I). The tablets may be compressed, tablet crushed, or fully coated, sugar coated, film coated, or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, sabotagers, inducing agents, It's flow, and fusion agents. The forms of liquid oral doses include aqueous solutions, preparations, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, agents ernul sifi cers, suspending agents, diluents, sweeteners, fusing agents, coloring agents and sabopzant agents. Preferred vehicles for oral administration include gelatin, propylene glycol, cottonseed oil and sesame oil. The compositions of this invention can also be administered topically to a subject, i.e., by direct placement or spreading of the composition in the epithelial or epithelial tissue of the subject. Such compositions include, for example, lotions, creams, solutions, gels and sols. These topical compositions preferably comprise a safe and effective amount, usually at least 0.1% preferably, and preferably from about 1% to about 5% of the compound of formula (I). vehicles suitable for topical administration preferably remain in place in the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the vehicle is organic in nature and capable of having in the same way the compound of the formula (T) dispersed or dissolved. The vehicle may include pharmaceutically acceptable emollients, ernulsifiers, thickening agents and solvents.

METHODS OF ADMINISTRATION: The invention also provides methods for treating or preventing hyper-disturbances associated with excess or unwanted matrix metallopeptide activity in a human or other animal subject by administering a safe and effective amount of a compound of formula (I) to said subject. As used herein, a "disturbance associated with the richness of metalop rotates from excess or unwanted matrix" is any disturbance characterized by the degradation of matrix proteins. The methods of the invention are useful for treating such disturbances as (for example) osteoarthritis, penodontitis, ulceration of the cornea, tumor invasion, arthritis reurna toi, etc. The compounds of the formula (T) and the compositions of this invention can be administered topically or '-? cynically The systemic application includes any method for introducing the compound of the formula (I) into the tissues of the body, for example, tra-articular administration (especially in the treatment of rheumatoid arthritis), mthecal, epidural, intramuscular, transdermal , intravenous, mt raper-i toneal, subcutaneous, sublingual, rectal and oral. The compounds of formula (I) of the present invention are preferably orally administered, The specific dose of inhibitor to be administered, as well as the duration of the treatment, are mutually dependent. The eosis regime and treatment will also depend on such factors as the compound of the specific formula (T) used, the indication of the treatment, the ability of the compound of the formula (T) to reach the minimum inhibitory concentrations at the site. of the target matrix loprotease to be inhibited, the personal attributes of the subject (such as weight), adherence to the treatment regimen, and the presence and severity of any effect 1 at 1 treatment. Typically , for a human adult (weighing approximately 70 1-1 log grams), axis about 5 rng to about 3000 ng, more preferably about 5 to about 1000 mg, most preferred about 10 rng to about 100 mg, of the compound of the formula (T) are administered per day. It is understood that these cié dose scales are by way of example only, and that the daily administration can be adjusted depending on the factors listed above. A preferred method of administration for the treatment of reu atoide arthritis is orally or parenterally by int-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (taking into account an approximate weight of 70 liters) we prefer the individual doses around "Je JO mg to approximately 1000 rng.

A preferred method of < ? dmm? sisternica ration is oral. It f > refer to individual doses of from about 10 mg to about 1000 mg, preferably from about 10 mg to about 300 mg. Topical administration can be used to deliver the compound of formula (T) systemically, or to treat JocaJmente a subject. The amounts of the compound of the formula (1) to be administered topically depend on such factors as the skin sensitivity, type and location of the tissue to be treated, the composition and vehicle (if any) that it is going to be administered, the compound of the formula (T) in particular, to be administered, as well as the particular disturbance that is going to be treated and the degree to which sisternic effects are desired (as distinguished from the crazy ones). Them). For the indications that are going to be treated if it is feared, it is preferred that the compounds be administered or to the mind. These conditions include reurnatoid arthritis, osteoart pf is and tumor metastasis. The inhibitors of the invention can be identified at specific locations where the matrix metalloprotease is accumulated using target ligands. For example, to target matrix metalloprotease inhibitors contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof that is immunoreactive with a tumor marker as generally understood in the preparation of immunotoxins in general. The Jfi The target ligand can also be a suitable target for a receptor that is present in the tumor. Any ligand can be used to specifically target a marker for the desired target tissue. Methods for coupling the compound of the invention to the targeting ligand are well known and are similar to those described above for coupling to vehicle. The conjugates are formulated and administered as described above. For localized locations, topical administration is preferred. For example, to treat ulcerated cornea, direct application to the affected eye can employ a formulation with 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 protector of hieroglyphic polymer. The materials can also be inserted as a contact lens or as a sub-module. For the treatment of inflammation of the skin, the compound is applied locally or tactically, in a gel, paste, balm or ointment. In this way, the mode of treatment 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 further include additional or additional drugs. excipients as appropriate for the indication. Some of the compounds of the invention also inhibit bacterial metaloprotases although generally at a level lower than that exhibited with respect to the metal ophidose molasses. Some bacterial metaloprot eaeas appear to be less dependent on the inhibitor's stereochemistry, while substantial differences are found between diastereomers in their ability to activate mammalian protons. In this way, this pattern of activity can be used to distinguish between bacterial and bacterial enzymes.

PREPARATION AND USE OF ANTIBODIES: The compounds of the invention can also be used in immunization protocols to obtain antiserum for the compounds of the invention. Since the compounds of the invention are relatively small, they are advantageously coupled to anti-neutral vehicles such as vehicles of haemocyanic axle lapellae of the genus F ssurel la (KLH) or serum albumin. For those compounds of the invention having a carboxy functional value, it can be made to the vehicle coupling by methods generally known in the art. For example, the carboxy residue can be reduced in an aldehyde and coupled to a vehicle through the reaction with amino groups. of .lateral chain in protein-based vehicles, followed optionally by the reduction of the irnino bond formed. The carboxyl residue can also be reacted with side chain groups using condensing agents such as car bodiimide of dicylohexy Lo or other dehydration agents of the oarbodurnide axis. The linker compounds can also be used to perform the coupling; Both obfunctional linkers and functional hethobiols are available from P erce Chemical Company, Rocl'ford, TIT. The resulting rnunogene complex can then be injected into suitable mammalian subjects such as mice, rabbits and the like. Suitable protocols involve the repeated injection of the immunogene in the presence of adjuvants in accordance with a program that boosts the production of antibodies in the serum. The titres of the immune serum can be readily measured using immunity procedures, now standard on the technique, which employ the compounds of the invention as antigens. The anti-serum obtained can be used directly or monoclonal antibodies can be obtained by cultivating the peripheral blood foci or the spleen of the immunized animal and immortalizing the cells that produce antibodies., followed by the i inification of suitable antibody procedures using normal immunity techniques. Polyclonal or monoclonal preparations are then useful in the control of the therapy or pr-or fil-axis 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 ad mtered at different times during the treatment protocol using normal immunity techniques employing the antibody preparations of the invention. The compounds of the invention can also be coupled to such bases as igneous scintillant labels, for example, technet 99 or T-131, using standard coupling methods. The labeled compounds are administered to subjects determined to determine the locations of the amounts in excess of one or more active matrix I etaproteases. The ability of the inhibitors to selectively bind the metalloprotease in this way makes it advantageous to plot the distribution of these enzymes in situ. The techniques can also be employed in histological procedures and the compounds of the invention can be used in competitive immunity tests. The following non-limiting examples illustrate the compounds, compositions, methods and uses of the present invention.

EXAMPLE 1 Synthesis of 3-iN-C (N-Hydroxyaminocarbonyl) methyl] -N-isobutylaminocarbsnil amide} -2- (R) -isobutylpropanoyl-L-phenylalanine 8 7 4 i Dissolve 4-methylated valeric acid (150 g, 1.3 rnoles) in 150 rnl of benzene. Oxali chloride is added slowly (163 g, 1.3 rnoles), the mixture is heated to 50 ° C and stirred 1.5 hours. The? Ro? Jucto is distilled at 140-145 ° C fiara Dissolve (S) 4-benc? 1-oxazolidinone (100 g, 565 nmrnols) in tetrahydrofuran (T? F) (000 i.) Under argon and cooled to -78 ° C. It is added in the form of drops n-but? Ll? T? O (250 inL, 620 mmoles, 2.5 M in hexanes), and the mixture is stirred for 15 minutes. Then, valeroyl chloride is added slowly 4-? Net? Io, 1, (83.4 g, 85.7 L, 620 mmoles) and stirring continued for 2 hours; the IS reaction quenched with ammonium chloride and extracted with ethyl acetate. The product is purified using 4: 1 hexane: EtOflc on a silica gel column to give 2. A solution of 2 (50 g, 181.8 mmol) in THF (100 mL) is cooled (i 70 C under argon. Slowly add bs (t pmetiisi lithium LiDarnide (200 L, 200 rnmoles, 1 M in THF), and the mixture is stirred for 10 minutes.T-butylbronyl acetate (29.5 ml, 200 mmol) is slowly added. and after 3.5 hours the reaction is warmed to -10 ° C and stirred an additional 1.5 hours.The reaction is quenched with ammonium chloride and extracted with ethyl acetate.The product is purified using 7: 1 hexane.FtOñc in a column of silica gel to give 3. A solution of 3 (9.725 g, 25 mmol) in 4: 1 and THF- water (125 L) is cooled to 0 ° C under argon. aqueous hydrogen (30%, 10.2 mL, 100 min), then L? OH-H2? (1.64 g, 40 mmol) in 50 mL of H 2 O. After 1.5 h, sodium sulfite (12.6 g) is slowly added. , 1 00 rnrnoles) in water (75 L). This mixture is extracted 3 times with ethyl chloride. The aqueous layer is acidified (pH = 2) with HCl and extracted 4 times with ethyl acetate. The ethyl acetate layer is washed with brine and < - Cause of magnesium sulfate. After filtering, the ethyl acetate is removed m vacuo to give 4. A mixture of 0.230 g (1"00 mmoles) of 4, 0.135 g (1.00 mmoles) 1-h axis is stirred. droxibenzotpazola, 0.127 rnL (1.00 minol) of 4-et? lrnor folin and 0.164 g (1.00 mmol) ele fen lalanina in 2 rnL. of N, N-d? rnet? lformarn? (DMF) at room temperature under an inert atmosphere, 0.192 g (1.00 min.) of l- (3-ilunet 1 larninopr or? J) -3-et 1 J carliodi irn da hydrochloride is added. The mixture is stirred for 24 hours and is concentrated under reduced pressure. The residue is taken up in ethyl acetate plus dichloromethane and the organic solution is extracted twice with 1 M of hydrochloric acid solution, twice with 1 M of sodium hydroxide solution, once with water, and once with brine. . The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 5-t-butyl ester 5 (0.376 g, 1.00 mol) is dissolved in 3.5 ml of 1% gold and let stand for 1 hour at room temperature, the removal of the acid tr if Juoroacet or under reduced pressure provides the product 6. A mixture 20.0 g (0.125 rnoles) of 0-benz hydrochloride is cooled to -78 ° C. lh? drox? larnone and 35.0 ml (25.4 g, 5 0.251 mol) of triethyl ether in 300 inL of dichloromethane. Bromoacotyl bromide (11.0 rnL, 25.5 g, 0.126 mol) is slowly added to the mixture, and the solution is stirred for an additional 45 minutes at -8 ° P after completion of the addition. The solution is extracted twice with water, the organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is treated with 1: 1 mixture of hexane and ethyl acetate, and the resulting precipitate of 7 is isolated by filtration medium. A solution containing a cold bath is cooled 1.5 g of 7 (6.15 mmoles) in 20 int. of DMF as it is added 0. 84 rnL (0.61 g, 6.0 immoles) of rietilarní na. After addition of 0.92 ml (0.60 g, 9.2 mmol) of water and 1 to 1 to cooled solution, the mixture is stirred an additional 45 minutes before diluting with 100 L of water. The mixture is extracted with Acetate ethyl acetate, then the organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 8 .. A mixture of 0.320 g (1.00 mol) of 6, 0.135 g (1.00 mmol) of 1-H? Drox? Benzotriazole, 0.127 L of 4-o ,: ethylmorphol ina, and 0.236 g (1.00 mmoles) of 8 in 2 rnL of DMF at room temperature under an inert atmosphere as 0.192 j (1.00 mmol) is added. ) of l- (3-di ot i lammopr opi 1) -3-ethecarbodi hydrochloride. The mixture is stirred for 24 hours and concentrated under reduced pressure. The residue is taken up in ethyl acetate plus no organic solution and the organic solution is extracted twice with 1 M hydrochloric acid solution, twice with 1 M sodium hydroxide solution, once with water and once with water. brine. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 9%. A hydrogenated solution is added to a 0.553 g solution.

(L.OO immoles) from 9 to 20 nL «Methane J using 0.10 g of 10% palladium on carbon under a hydrogen atmosphere. The catalyst is removed by filtration and 10 is isolated after concentration under reduced pressure.

EXAMPLE 2 Synthesis of amide of 3-. { N- [(N-Hydroxy-aminocarbonyl-D-methyl-N-decylamino-carbon-1) -2- (R) -sobutyl-propanoyl-L-phenylalanine (5) Cool in an ice bath and stir a solution containing 2.36 g of "lecila ina (15.0 mmoles) and 0.84 L (0.61 g, 6.0 rnrnoles) in t riet j Jauu na in 15 inL of N, N-dimethylformamide (DrIF). ). The addition in the form of droplets of 1.22 g (5.0 mrnoles) of 1 (made in accordance with the method used to make compound 7 in example J) to the cooled solution is followed by an additional 45 minutes of stirring before removing the freezing bath. . After an additional 30 minutes of agitation, the mixture is diluted with 100 rnL water axis. The mixture is extracted with ethyl acetate, then the organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. FJ residue is purified by means of column chromatography (silica gel) eluting with dichloroethane / isopropanol mixtures to provide 2. A mixture of 0.320 g (1.00 mol) of 3 is stirred. (made in accordance with the method used to make the compound 6 in Example 1), 0.135 g (1.00 mg) of 1-hydroxybenzotpazole, 0.127 mL of 4-ethylene glycol, and 0.320 g (L.OO rnrols) 2 in 2 rnL of DMF at room temperature under an inert atmosphere as 0.192 g (1. (30 mol) of hydrochloride of l- (3-dirneti inopropyl) -3-ef il carbodiimide is added. it is stirred for 24 hours and concentrated under reduced pressure.The residue is taken up in ethyl acetate plus dichloroethane and the organic solution is extracted twice with 1 M hydrochloric acid solution, twice with 1 liter of solution. Sodium hydroxide, once with tagua, and once with brine, The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue that is purified by column chromatography (silica gel). silica) eluting with mixtures of ei? chloromethane /? sopropanol to give 4. It is subjected to hydrogenation nolysis a solution of 0.300 g (0.48 nm) of 4 in 20 mL of methanol using 0.10 g of 10% palladium on carbon under a hydrogen atmosphere. The catalyst is removed by filtration and is isolated after concentration under reduced pressure.

EXAMPLE 3 Synthesis of acid 3-. { N-C (N-Hydroxy-aminocarbonyl) methyl] -N-decylaminocarbonyl} -2- (R) -isobutylpropanoic acid 2-phenylethyl amide (6) A mixture of 0.230 g (1.00 rnrnol.es) of 1 (made according to the method used to make compound 4 in example 1), 0.135 g (1.00 mrnolee) of 1-hydroxybenzotriazole, 0.127 L of 4- ethylrnorpholine, and 0.121 g (1.00 rnrnolee) of phenylethylamine in 2 rnL of DMF at room temperature under an inert atmosphere as 0.1.92 40 is added. g (L.OO immoles) of the hydride of 1 - (3-d? rnet ílami nopr opil) -3-et i] car hodiirrp da. The mixture is stirred for 24 hours and concentrated under reduced pressure. The residue is absorbed in acetate, the most dichloromethane and the organic solution is excreted twice with 1 ml of hydrochloric acid solution, twice with 1 M of sodium hydroxide shaft solution, once with water, and once with brine The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue (eg, purified by silica gel column chromatography) eluting with cichloromethane / isopropanol mixtures. t-butyl 2 (0.315 g, 0.94 mmol) is dissolved in 3.5 mL of luo-acetic acid and allowed to stand for 12 hours at room temperature. Removal of the acid fluoroacetic acid under reduced pressure provides the product 3. A mixture of 0.250 g (0.90 mmol) of 3, (1135 g (L.OO mrnol) of 1- hydrox ibenzot p azole, 0.127 mL is stirred ( 1.00 immoles) of 4-et? L? Nor fol i na, and 0.320 g (1.00 immoles) of 4 (made in accordance with the method used to make compound 2 in example 2) in 2 mL of DNF at room temperature under an inert atmosphere as 0.192 g (1.00 mol) of 1- (3-drnet and larinopropyl) -3-ethycarbodrine hydrochloride is added.The mixture is stirred for 24 hours and concentrated The residue is taken up in ethyl acetate plus d-chloroethane and the organic solution is extracted twice with 1 M hydrochloric acid solution, twice with 1 M sodium hydroxide solution, once with water, and once with brine, the organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue of water. It is purified by column chromatography (silica gel 5) eluting with dichloroethane / isopropanol mixtures to give 5. A solution of 0.111 g is hydrogenated. (0.22 min.) Axis 5 in 5 rnL of methanol using 0.040 g of 10% palladium in carbonus under a hydrogen atmosphere. ? '. l The catalyst is removed by filtration and 6 is isolated after concentration under reduced pressure.

EXAMPLE 4 Synthesis of amide of 3-. { N-L "1- (R) - (N-Hydroxyaminocarbonyl) ethyl] -L N- (2-phenylethyl) aminocarbonyl} -2- (R) -isobutylpropanoyl-L-phenylalanine (6) A mixture of 3.70 g (0.90 rnmoles) axis Nt-J30C-D-aLanma, 1, L.35 g (10.0 mole) of L-h droxi bonzot r lazóla, 1.27 mL (10.0 mole) ele 4 -ef i is stirred. Imorfol ina, and 2.00 g (12.5 rnrnoles) of 0-benzylhydroxide hydrochloride in 1? L of DMF at room temperature under an inert atmosphere as 1.92 g (10.0 rnrnol.es) of hydrochloride of 1 - (3-drnet and mopropyl) -3-et? Icarbod ?? rn is added. gives. The mixture is cured for 24 hours and concentrated under reduced pressure. The residue is taken up in acetate of the other chloro-methane and the organic solution is extracted twice with 1 ml of hydrochloric acid solution, two voices with the M < eluci n < lr cold sodium hydroxide, once with water, and once with brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. This residue is dissolved in 30 L of 5 M HCl in ethyl acetate, stirred for 5 hours, then concentrated on reduced pressure to provide 2 with its hydrochloride salt. This material is dissolved in 15 ml. of methanol together with 2.40 g (20.0 rnrols) of femlacetaldehyde and cooled in an ice bath. Sodium eioborhydrate (2.00 g, 31.8 rnmoles) is added to the mixture and after 2 hours the ba or cold is removed. After stirring for an additional 20 hours, the mixture is concentrated under reduced pressure, and the residue is partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to provide an aqueous residue. is purified by column chromatography (ice gel) eluting with dichloromethane / isopropanol mixtures for <jar 3. A mixture of 0.250 g (0.838 mmol) of 3, 0. L35 g (1.00 ritmóles) of 1 -hi drox ibenzotp azol, 0.127 inL (1. (30 mol) of 4-y il orfol n, and 0.320 g (1.00 m oles) of 4 (made in accordance with the method used to make compound 2 in example 2) in 2 ml of DMF at room temperature under an inert atmosphere as 0.192 is added. g (1.00 nrnoles) of 1 - (3 - di metí larnmopropyl) -3-et? lcarbod? The mixture is stirred for 24 hours and concentrated under reduced pressure. The residue is taken up in ethyl acetate plus dichloromethane and the organic solution is extracted twice with J fl hydrochloric acid solution, twice with JN sodium hydroxide solution, once with water, and once with brine. The organic layer is dried over sodium sulfate, is filtered, and is concentrated under reduced pressure to provide a residue which is purified by column chromatography (silica gel) eluting with mixtures of dichloromethane / isopropanol to give 5. hydrogenolysis a solution of 0.120 g (0.276 mol) of 5 in 5 rnl of methane 1 using 0.040 g of 10% ele pal adio in carbonus under a hydrogen atmosphere. FL catalyst - is removed by filtration and 6 is isolated after the concentration under reduced pressure.

EXAMPLE 5 Synthesis of trans-l- (R) -. { N-Cl- (R) - (N-Hydroxyaminocarbonyl) ethyl] -N- (2-phenylethyl) aminocarbonyl} -2- (R) -. { N- (2-phenylethyl) aminocarbonyl} cyclohexane (5), and trans-l- (S) -. { N- [l- (R) - (N-hydroxyaminocarbonyl) ethyl] -N- (2-phenylethyl) aminocarbonyl-2- (S) -. { N- (2-phenylethyl) aminocarbonyl} cyclohexane (6) A mixture of 20.0 g (0.J30 oJes) of t rans-L, 2-c? Cl ohoxanodicarbox 111 co-anhydride, 1, is stirred at 120 rnl. The mixture is stirred for 24 hours and is concentrated under reduced pressure, while the residue is absorbed in ethyl acetate and the mixture is stirred under an inert atmosphere while 30.0 g (0.248 mol) of eni let i lamin is added. ethyl rnás dic Jo rom aoy The organic solution is extracted twice with LM of hydrochloric acid solution, twice with 1 M of hydroxide solution of '-odium, once with water, and once with salt. The organic layer is dried over sodium chloride, is fixed, and is concentrated under reduced pressure to give a mixture of diameters and a mixture of 1.25 g (4.54 mmol) of 2, 0.676 g. 5.00 rnmoles) 1-hydroxide benzot riazole, 0.635 L (5.0 mrnoles) of 4-ethyl orfolone, and 1.49 g (5.00 mol) of 3 (made in accordance with the method used to make compound 3 in the Example 4) in JO mL of DMF at room temperature under an inert atmosphere as 0.958 g (5.00 mmoles) of chlor'hi-cirate is added. of J - (3 -di met i lanmopropí L) - 3- etiicarbod irní a. The mixture is stirred for 24 hours and concentrated under reduced pressure. The residue is taken up in ethyl acetate acetate, and the organic solution is extracted twice with 1 fl of hydrochloric acid solution, then with 1 M sodium hydroxide solution, once with water, and once with water. once with sa die. The organic layer is dried over sodium hydroxide, filtered, and concentrated under reduced pressure to provide a residue which is purified by column chromatography (silica gel) eluting with dichloromethane / isopropanol mixtures to give 4. A solution of 0.120 g (0.216 mmoles) axis 4 in 5 mL methane is subjected to hi drogenol i SLS! using 0.040 g of 10% carbon dioxide in a hydrogen atmosphere. The catalyst is removed by filtration and 6 is concentrated under reduced pressure. Purification by liquid chromatography of the preparative inverted phase operation with mixtures of water, acetoniiplo and fluoroacetic acid provides 5 and 6.

EXAMPLE 6 Synthesis of 2- (R) -. { . { NL "l- (R) - (N-Hydroxyaminocarbonyl) -3- phenylpropyl] -N-decylaminocarbonyl} methyl] cyclohexanone (6) and 2- (S) - { - (R) - (N-hydroxyaminocarbonyl) -3-phenylpropyl] -N-decylaminocarbonyl} methyl] cyclohexanone (7) A mixture of 2.51 g (9.0 rmoles) axis N-t-ROC-D-hornofem lalamna, 1, 1.35 g (10.0 mmols) of 1-hydroxy enzot r lazóla, 1.27 rnl is stirred. (10.0 rnrnoles) of 4-et Umor-fol ma, and 2.00 g (12.5 immoles) of 0-benz hydrochloride? lhydroxylate in 2 (1 ml) DMF at room temperature under an inert atmosphere as 1.92 g (10.0 mmol) of 1 - (3-d? met i inopropyl) -3-et is added. The mixture is stirred for 24 hours and concentrated under reduced pressure, the residue is taken up in ethyl acetate acetate, dichloromethane, and the organic solution is extracted twice with 11% cold hydrochloric acid solution., twice with 1 M cold sodium hydroxide solution, once with water, and once with r'aJ dies, the organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. . The resulting residue is dissolved in 30 ml. of 5 M HCl in ethyl acetate, stirred for 5 hours, then reduced or reduced pressure to provide 2 as its hydrochloride salt. This material is dissolved in 15 rnL of methanol together with 3.12 g (20.0 mol) of decyl aldehyde and cooled in an ice bath. Sodium cyanoborhydrate (2.00 g, 31.8 mmol) is added to the mixture and after 2 hours the ba or cold is removed. After stirring an additional 20 hours, the mixture is concentrated under reduced pressure, and the residue is partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a residue which is purified by column chromatography (silica gel shaft) eluting with ßiic mixtures Lorornetane / isopropanol to give 3. A mixture of 0.400 g (0.942 rnrnoles) of 3, 0.135 g (1.00 rnmoles) axis l-hi droxibenzot pazola, 0.127 L (1.00 immoral) of 4-ti imor fol i na, and 0.156 g (1.00 rumo les) of 4 in? mL of DMF at room temperature or in an inert atmosphere as 0.192 g (1.00 mol) of 1- (3-dirnet i 1 to 1 mopropyl) -3-ethecarbod hydrochloride is added. gives. The mixture is stirred 24 hours and concentrated under reduced pressure. The residue is taken up in ethyl acetate plus dichloromethane and the organic solution is extracted twice with 1 M hydrochloric acid solution, twice with 1 h of sodium hydroxide solution, once with water, and once with water.;: with brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue which is purified by column chromatography (silica gel) eluting with dichloromethane / isopropanol mixtures to give 5. hydrogenolysis a solution of 0.125 g (0.222 rnmoles) of 5 in 5 mL of eta no 1 using 0.050 g of 10% palladium on carbon ba or a hydrogen atmosphere. The catalyst * is removed by filtration and the mixture is concentrated under reduced pressure. Purification by liquid chromatography high performance axis of preparative inverted phase with mixtures of water, acetom t rilo and acid fluoroacetic t r i provides 6 and 7.

EXAMPLE fl A tablet composition is made for oral administration, in accordance with the present invention, comprising-, Component Cant i d d • a? N? Da2 of 3-. { N-L ~ (N-Hydroxiam nocarbon 1) rnet i? L- -ßleci lamí noca rbom l} -2- (R) -isobut lp op noil- L- eni lalanin 15 .. rng -Lactose 120. rng -starch of aíz 70. ing -Talco 4"ing • Est carato de magnesio 1. rng 2 a hydroxarnic acid prepared In accordance with Example 2. Other compounds having a structure conforming to formula I are used with substantially similar results.

EXAMPLE B A capsule is made for oral administration, according to the present invention, comprising: Component Amount -arní da ele 3-. { N- [1- (P) - (N-Hydroxaminocarbonyl) et i11 -N- (2-fem let L!) Arn? Nocarbon? 13-2 (R) sobutiipropanoi 1-L-pheni lalanma 1% -Pol ethylene glycol 85% 3 a hydroxarnic acid prepared in accordance with the example 3. Other compounds, eg, have a structure according to formula T, are used with substantial results < , n? Lt

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS s 1.- A compound that has a structure according to the formula I 5 wherein (A) (1) R 1 is hydrogen; I rent; hetoroal ui 1 o; t \ lque? benciJo; a heterooiclic ring ?; a carbocyclic ring; alkoxy; car'bocí clo-al qui Jo; heterocyclic; rboc c lo -hete roa 1 kilo; hete hete hete heal heal; 0 carbocyc-f? O; or heterocyclothio; (2) is hydrogen; I rent; allo ilo; a he + erocyclic ring; a carbocyclic ring co; carbocycle-alkyl, heterocycle-alkyl; or < , arboc clo-hef eroalqui lo; (3) R3 is hydrogen; a carbocyclic ring; or a heterocyclic ring; (4) R * is H alkyl; het eroalqui lo; alkylam not; ac the mo; carbox i to whom; arninoalkyl; a carbocyclic ring; a heterocyclic ring; het n-ocicl or-hoteroal uilo; heterocyclic clo-al quilo; or a portion capable of supporting a load; and (5) R5 is (a) -0-R6; wherein R6 is hydrogen, alkyl or benzyl; (b) -N (R9) CH (Rio) (ii), wherein () R9 is hydrogen or alkyl; and (11) R or Rll are, independently, hydrogen, alkyl, ap 1 to 1 qui, alkoxyacyl, or to inoacil; or (in) R9 and Rio t together with the atoms and nitrogen atoms to which they are attached, comprise a heterocyclic heterocyclic ring of 4-9 a. (c) an acimole or a peptide having 2 or 3 non-acid arn, wherein said acid arnide or said peptide is linked to the formula (I) by means of its amino group; (d) alkyl; (e) alkenyl; (f) carboci clo-al qui 1 o; or (g) carbocycle -alkene; (B) and wherein (l) R3 and R1 together may comprise a mononuclear carbocyclic ring of 3-9 atoms; a polycyclic carbocyclic ring of 7-17 atoms; a heterocyclic and co-cyclic ring of 4-9 atoms; or a helicic cyclophilic ring of 7-17 atoms; or (2) R * and R5 together may comprise a monocyclic carbocyclic ring 3-13 atoms; a carbocyclic, cycloicyclic ring of 7-17 atoms; an heterocyclic heterocyclic ring of 4-9 atoms; or a polycyclic heterocyclic ring of 7-17 atoms; or a pharmaceutically acceptable salt, biohydrolysable amide or biohydrolyzable ester thereof.
2. 2. The compound according to claim 1, further characterized in that R is hydrogen, alkyl or alkali.
3. 3. The compound in accordance with the claim 2, further characterized in that Rl is hydrogen, methyl, ethyl, i sopropy 1 or 2-phenyl J et i 1. 4, - Fl composed in accordance with Claim 2, further characterized in that wherein R 3 is hydrogen or rt 1 c | u i J o. 5. Fl composed of confo mi ad with claim 4, caracterized also because R3 is hydrogen. 6. Fl composed in accordance with claim 4, further characterized in that R2 is alkyl, alkenyl, < ? um? lo, carbocí clo-alqui lo, heterocyclic-alkyl or ca I 'bocí cio-hete roa L quilo. 7. The compound according to claim h, further characterized in that R2 is C4-C10 alkyl, C-C10 alkenyl or carbocycloalkyl. 8. The compound according to claim, further characterized because R2 is n-decyl, 2-rnet? 1 propílo, 2 lemletilo or 3- fem Ipropil o. 9. The compound according to claim b, further characterized in that R4 is alkyl, heteroalkyl, or aryl, which is. 10. The compound according to claim 9, further characterized in that R is 2-rnet 1 lpropyl or -ammobut 1 l. 11. The compound according to claim 6, further characterized in that R5 is N (R9) CH (Rio) (Rii), wherein R9 is hydrogen; and Rio and RII are, h? independently, hydrogen, alkyl, aplaxyl, a1 cox i ac 11 or o arn i no i lo. 12. The compound according to claim 11, further characterized in that Rio is hydrogen or alkali. 13. The compound according to claim 12, further characterized in that R is hydrogen and H is benzyl or arninoacyl. 14. The compound according to the invention J2, further characterized in that Rio is aplaxyl and RH is aminoacyl. 15. The compound according to claim 1, further characterized in that R3 and R * together comprise a carbocyclic inonyocyclic ring of 3 to 9 carbon atoms; a cyclic polycarbonate ring of 7 to 17 carbon atoms; a helocyclic onocliclic ring of 4 to 9 carbon atoms; or a polyethylene oxide ring with 7 to 7 carbon atoms. 16. The compound according to claim 15, further characterized in that said ring is a saturated monocyclic carbocyclic ring. 17. The compound according to claim 1, further characterized in that R * and RS together comprise a mononuclear carbocyclic ring of 3 to 3 carbon atoms; a carbonic ring and a polycyclic ring of 7 to 1 7 carbon atoms; A monocyclic heterocyclic ring of 4 to 9 atoms b3 of carbon; or a polycyclic heterocyclic ring of 7 to 17 years of age. 10. A compound that has a structure according to formula 1 wherein (A) (1) R1 is hydrogen; I rent; benzyl; or carbocyl clo-al ui lo; (2) R2 is alkyl; alquemlo; carbocyl clo-ale | Uilo, hetcrocycloalkyl; or L-heteroalkyl car'boc; (3) R3 is hydrogen; I rent; (4) R¿ is alkaline; het eroalqu L 1 o; rent it not; or to inoalkyl; and (5) R5 is (a) N (F ^) CH (R o) (Rii), wherein (i) R9 is hydrogen; and (ii) Rio and Ri are, independently, hydrogen, alkyl, arylalkyl, alkoxyacyl, or amnoacyl; or (m) R9 and R o, together with the nitrogen and carbon atoms to which they are attached, comprise a heterocyclic and non-cyclic ring of 4-9 atoms; (b) an acid arnide or a peptide having 2 or 3 arnides, wherein said acid arc or said peptide is one of the formula (I) by means of its lower group; (B) and wherein (1) R3 and * together can comprise a monocyclic carbocyclic ring 3-9 atom atoms; or (2) R * and RS together can comprise a carbocyclic ring, rnonocic, of 3-13 atoms, a < -On? oarbociclico policicl co of 7-17 nights; a rhinocyclic heterocyclic ring of 4-9 atoms; or a polycyclic heterocyclic anion of 7-17 atoms; or a pharmaceutically acceptable salt, biohi-rollable amide or biohydrolyzable ester thereof. 19. A compound selected from the group consisting of; arnidd of 3-. { N-T (N-H droxiami nocarboml) rnet 111 -isobuylaminocarboni l} -2- (R) -isobutyl p r-or cloth ll -L- fenlalam na; 3 ~ amide. { N-T (N-H droxyarninocarbon 1) rnet l] -N- deci lamí noca rbom l} -2- (R) - isobuty ipropanoyl-L-phenylalamine; acid 3-. { N-r (N-Hydroxyarninoca boni 1) is useful] -N-dec larní nocarbo il) -2- (R) -isobu i lpropanoic, amide of 2-phen? J e < mess; amide of 3-. { N-fl - (R) - (N-Hydro-Ono-Boni-Jetill-N- (2-pheni Let? I) arnmo-e-ai bon? 3 - 2- (R) - i so but jl? R opa 1-L-pheni 1 to the aniña; t r-ans-1 - f R). { N- f 1- (R) - (N-Hi-d-aminocarboniDe ill -N- (2- fem 1 et 11) am? Nca rbonyl 3-2- (R) - { N- (2-fem lethyl) arnmocarboml.}. c? clohexane; trans-l- (S) - { M-CL- (R) - (N-hydroxyarninocarboni 1) et? 1] -N- (2-f in i le ti i) arní noca rbon i l-2- (S) - { N- (2- f eni let 11) arn i noca rboni 13 -cyclohexane; 2- (R) - {. {N- T 1 - (R) - (M-Hydrox 1) -3-fem 1 -propyl 11-N-dec? La? N? Nocarbon? L et l.}. C? Clohex none; and 2- (S) - C CN-1 - (R) - (N-hydroxy arn and 1-rbom 1) -3-phen 1 propy 1] -N-deci laminocarboni 1 met 113 cyclohexanone .. 20. - A pharmaceutical composition comprising: (a) a safe and effective amount of a compound of claim 1, and (b) a pharmaceutically acceptable vehicle, or a pharmaceutical composition comprising: (a) a safe and effective amount of a compound of claim 18 and (b) a pharmaceutically acceptable carrier 22.- FJ use of a compound of claim J in the prep. tion of compositions to treat or prevent a disturbance associated with rnetaioprotease activity of the excess or unwanted matrix in a human or other anim al subject "