MXPA99003734A - Substituted 4-biphenyl-4-hydroxybutyric acid derivatives as matrix metalloprotease inhibitors - Google Patents

Abstract

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have generalized formula (I) in which T is a pharmaceutically acceptable substituent group;A is CH 2, CH, or N;G is CH 2 or CH;and R 1 is any of a variety of disclosed substituent groups. The class of compounds of the invention includes ring-containing materials in which the units A and G are joined. The compounds of the invention are mixtures of diastereomers, or individual diastereomers making up these mixtures.

Description

TITLE: 'DERIVATIVES OF 4-BIFENIL-4-HYDROXTBUTYRIC ACIDS SUBSTITUTED AS MATRIX METALOPROTEASE INHIBITORS. FIELD: This invention relates to enzyme inhibitors and more particularly to novel 4-biphenyl-4-hydrobutyric acid derivatives which are useful for inhibiting matrix metaioproteases. BACKGROUND: Matrix metalloproteases (known as matrix metallo-endoproteinases or MMPs) are a family of zinc endoproteinases that do not include but are not limited to interstitial collagen (also known as MMP-1), stromelicin (also known as proteoglycanase, transin or MMP-3), gelatinase A (also known as, 72kDa-gelatinase or MMP-2) and gelatinase B (also known as, 95kDa-gelatinase or MMP-9). These MMPs are secreted by a variety of cells including fibroblasts and chondrocytes, along with natural proteinaceous inhibitors known as TIMPs (metalloproteinase tissue inhibitor). MMPs are capable of destroying a variety of connective tissue components of articular cartilage or basement membranes. Each MMP is secreted as an inactive proenzyme that must be dissociated at a subsequent stage before it is able to exert its own proteolytic activity. In addition to the matrix destroying effect, some of MMPs such as MMP-3 have been implicated as an in vivo activator for other MMPs such as MMP-1 and MMP-9 (mess, A. and Nagase, H., Harch. Biochem. Biophys. - .267, 211-6 (1988), Ogata, Y., Enghild, J. and Nagasse, H., J. Biol. Chem 26Z, 3581-4 (1992)). Therefore, a cascade of proteolytic activity can be initiated by an excess of MMP-3. It appears that specific MMP-3 inhibitors should limit the activity of other MMPs that are not directly inhibited by such inhibitors. It has also been reported that MMP-3 can dissociate and therefore inactivate the endogenous inhibitors of other proteinases such as elastase (Winyard, PG; Zhang, Z .; Chidwick, K .; Carrel, RW; Murphy, G., FEBS. 27g_, 91-4 (1991) .MMP-3 inhibitors could therefore influence the activity of other destructive proteinases by modifying the level of their endogenous inhibitors.A variety of diseases are considered to be mediated by an excess or by an undesirable matrix-destroying metalloprotease activity or an imbalance in the ratio of MMPs to TIMP, These include: a) osteoarthritis Woessner, JF, Jr .; Selzer, M.G., J. Biol. Chem. 2J5.9, 3633-8 (1984) and Phadke, K., J. Rhematol. 1_Q, 852-60 (1983)), b) rheumatoid arthritis (Mullins, DE, Rohrlich, ST, Biochim, Biophys, Acta 695, 117.214 (1983), Woolley, DE Crossley, M, J .; Evanson, M. ., Arthritis Rheum, 2O, 1231-9 (1977), and Gravalese EM, Darling, JM, Ladd, AL, Katz, JN, Glimcher, LH, Arthritis Rheum, 3.4, 1076-84 (1991)), c. septic arthritis (Williams, RJ, III, Smith, R. L, Schurman, D J., Arthritis Rheum, 3_3_, 533-41 (1990)), d) tumor metastasis (Reich, R. Thompson, EW, Iwamoto, And, Martin, GR, Deason, JR, Fuller, G. O, Miskin R., Cancer Res. 4S_, 3307-12 (1988) and Matrisian, L M .; Bowden, GT, Krieg, P. Fuerstenberger, G Briand, JP, Leroy, P., Breathanach, R., Proc. Nati, Acad Sci. USA, 3, 9413-7 (1986)), e) Periodontal diseases (Overall, O M. Wiebkin, OW; Thonard, JCJ Peridontal, Res 22, 81-8 (1997)), f) corneal ulceration (Burns, FR, FR, Stack, MS, Gray, RD, Paterson, CA, Invest. Ophthalmol, Vis. Sci. 3J), 1569-75 (1989)), g ) proteinuria (Baricos, W. H .; Murphy, G .; Zhou, Y .; Nguyen, H. H .; Shah, S. V. Biochem. J. 254, 609-12 (1988)), h) coronary thrombosis due to rupture of the atherosclerotic plaque, (Davies, MJ, Foster, K .; Hembry, R .; Murphy, G .; Humphries, S .; Proc. Nati, Acad. Sci. USA 88., 8154-8) (1991), i) Aneurysmal aortic disease (Vine, N .: Powell T., Clin, Sci. D., 233-9 (1991)), j) birth control (Woessner, JF, Jr., Morioka, N., Zhu, C, Mukaida, T .; Butler, T., LeMaire, WJ, Steroids 54, 491-9 (1989)), k) dystrophic epidermolosis hullosa (Kronberger, A.; Valle, K. J .; Eissen, A. Z .; Bauen, E. A .; J. Invest- Dermotol. 79_, 208-11 (1982)), and I) degenerative loss of cartilage after traumatic joint damage, all conditions that lead to inflammatory responses, osteopenias mediated by MMP activity, diseases of the temperomandibular joints, demyelinating diseases of the nervous system , etc. (Chantry, A., Earl, C; Groome, N .; Glunn, P., J. Neurochem, 50, 688-94 (1988)). The need to find new therapies is especially important in the case of arthritic diseases. The primary disabling effect of osteoarthritis (OA), rheumatoid arthritis (RA), and septic arthritis is the progressive loss of articular cartilage and therefore the normal function of the joints. No currently marketed pharmaceutical agent is able to prevent or slow down this loss of cartilage, although non-spheroidal anti-inflammatory drugs (NSAIDs) have been administered to control pain and swelling. The final result of these diseases is the total loss of joint function that can be treated only by joint replacement surgery. It is expected that MMP inhibitors stop or reverse the advance of cartilage loss and obviate or delay surgical intervention. Proteases are critical elements in several stages in the progression of metastatic cancer. In this process, proteolytic degradation of the structural protein in the basement membrane allows expansion of a tumor at the primary site, evasion of ester site as well as occupation and invention at distant distant sites. Likewise, tumor-induced angiogenesis is necessary for a tumor to develop and depends on the remodeling of the proteolytic tissue. Transfection experiments with several types of proteases have shown that matrix metalloproteases, in particular A and B (MM-2 and MM-9, respectively) play a dominant role in these processes. For a review of this field see (Mullins, DE, Rohrlich, ST, Biochim, Biophys, Acta 695, 117.214 (1983), Ray, JM, Stetler-Stevenson, WG, Eur. Respir J. 7, 2062-72 ( 1994) and Birkelad-Hansen, H., Moore, WG L, Bodden, MK, Windsor, LJ, Birkedal-Hansen, B., Decarlo, A., Englar, JA, Crit. Rev. Oral. Biol. Med. , 197-250 (1993) Furthermore, it could be shown that the inhibition of the extracellular matrix by the native matrix metalloprotease inhibitor TIMP-2 (a protein) stops the development of cancer (De clerk, YA; Pérez, N .; Shimada, H .; Boone, T. C; Langley, KE; Taylor, SM, Cancer Res. 52, 701-8 (1992) and that and that TIMP-2 inhibits tumor-induced angiogenesis in experimental systems (Moses, MA; Sudhalter, J .; Langer, R., Science 248_, 1408-10 (1990) For a review see De Clerk, Y., Shimada, H., Taylor, SM Langley, KE, Ann., NY Acad. Sci. 732, 222-32 (1994). It was also shown that the metalloprotease inhibitor of ma Synthetic batimastat when administered intraperitoneally inhibits the development and spread of human colon tumor in mice see (Wang, X .; Fu, X .; Brown, P. D., Crimmin, M. J .; Hoffman, R. M. Cancer Res. = 4, 4726-8 (1994) and prolong the survival of mice that are carriers of human ovarian carcinoma xenografts. (Davies, B .; Brown, PD; East, N .; Crimmin, MJ; Balkwill, FR 53-, 2087-91 (1993).) The use of this and other related compounds have been described in the WO-A- patent. 9321942. There are several patents and patent applications that describe the use of metalloproteinase inhibitors to delay mastastic cancer to promote tumor regression, to inhibit the proliferation of cancer cells, to slow down or to prevent the loss of cartilage that is associated with osteoarthritis or for the treatment of other diseases such as those indicated above (eg, WO-A-9519965, WO-A-9519956, WO-A-9519957; WO-A-9519961; WO-A-9321942; WO-A-9321942; WO-9421625; U.S. Patent No. 4,599,361; U.S. Patent No. 5,190,937; European Patent No. 0574 758 A1, published on December 22, 1993; European Patent 026 436 A1 published on August 3, 1988; and European Patent No. 0520 573 A1, published December 30, 1992). Preferred compounds of these patents have peptide backbones with a zinc complex forming group (hydroxamic acid, thiol, carboxylic acid or phosphinic acid) at one end of a variety of side chains, both being found in natural amino acids as well as in those who have more new functional groups. Such small peptides are often very poorly absorbed, and exhibit low oral availability. They are also subject to rapid proteolytic metabolism, thus having short short half-lives. As an example, batimastat, which is the compound described in WO-A-9321942, can only be administered intraperitoneally. In WO 9615096, published May 23, 1996, it describes substituted 4-diarylbutyric acid or 5-diaryl pentanoic acid and derivatives as inhibitors of matrix metalloproteases. This is a continuation in part of the US patent application Acta No. 08 / 339,846, filed on November 15, 1994, which is incorporated herein by reference. The application describes two substituted 4-biphenyl-4-hydroxybutyric acid derivatives (Examples 33 and 34, as shown below). These compounds are less potent as MMP-3 inhibitors than the corresponding 4-biphenyl-4-oxobutyric acid derivatives.

WO 9615096 Example 1 Isomer A WO 9615096 Example 33 Cl50 486 nM (vs. MMP-3) Cl 5o 2,600 nM (vs. MMP-3) Isomer B WO 9615096 Example 34 Cl s or 5,000 nM (vs. MMP-3) It is convenient have effective MMP inhibitors possessing improved bioavailability and biological stability relative to the peptide-based compounds of the prior art and which can be optimized for use against the particular MMPs which constitute the target. Said compounds are the object of the present invention. COMPENDIUM: In view of the fact that the substituted biaryl-4-hydroxybutyric acids described in WO 9615096 appear to be less active as MMP inhibitors than the identical 4-biaryl-4-oxobutyric acid analogs, it is surprising that it has been found that the active isomer of other 4-biaryl-4-hydroxybutyric acids may be significantly more potent as MMP inhibitors than the corresponding 4-oxo compounds. The present invention relates to compounds having matrix metalloprotease inhibitory activity and having the following general formula (I) ) where: T is a pharmaceutically acceptable substituent group; X is 0, 1 or 2; m is 0 or an integer of 1-4; n is 0 or 1; and either A and G are both CH2; or A is a chemical bond and G is CH2; A is CH or N; and G is CH; and A is connected to G by a ring-forming bond having the formula (CH 2) or 3 (Q) (CH 2) 0.3; where Q is a chemical bond, S, or O; and C, S, and O constitute linking atoms; the formation of a ring including A, said ring and G linker; with the conditions that the sum of n plus the total amount of linking atoms in said ring-forming bond is an integer from 1 to 4; and the number of heteroatoms in said ring is 0 or 1; R1 is: * aryl of 6-10 carbons, with the proviso that if this aryl group is phenyl, then X is one or two; heteroaryl comprising 4-9 carbon atoms and at least one heteroatom N, O, or S; * aryl-substituted alkenyl wherein the aryl portion contains 6-20 carbon atoms, and the alkenyl portion contains 2-5 carbon atoms; * heteroaryl-substituted alkenyl wherein the heteroaryl portion comprises 4-9 carbon atoms and at least one heteroatom N, O or S, and the alkenyl portion contains 2-5 carbon atoms; * aryl-substituted alkenyl wherein the aryl portion contains 6-10 carbon atoms and the alkenyl portion contains 2-5 carbon atoms; * substituted heteroaryl alkenyl wherein the heteroaryl portion comprises 4-9 carbon atoms and at least one N, O, or S heteroatom and the alkenyl portion contains 2-5 carbon atoms; * N-phthalimidoyl; * N- (1,2-naphthalenedicarboximidoyl); * N- (2,3-naphthalenedicarboxymidoyl); * N- (1 l8-naphthalenedicarboximidoyl); * N-indoloyl; * N- (2-pyrroldinonyl); * N-succinimidoyl; ^ N-maleimidoyl; * 3-hydantoinyl; * 1, 2,4-urazoyl * amido; * a urethane; * a urea; * a substituted or unsubstituted non-aromatic heterocycle which contains and which is connected through an N atom and which comprises an additional O or S; * an amino; and * ZRd in which Z represents ; and R8 is: * aryl of 6-10 carbon atoms; heteroaryl comprising 4-9 carbon atoms and at least one heteroatom N, O or S; * arylalkyl where the aryl portion contains 6-12 carbon atoms and the portion contains 1-4 carbon atoms; or * heteroaryl-alkyl wherein the aryl portion comprises 4-9 carbon atoms and at least one heteroatom N, O, or S and the alkyl portion contains 1-4 carbon atoms; and with the proviso that when Z is O, R8 may also be alkyleneoxy or polyalkyleneoxy terminated by H, alkyl or phenyl. Aryl or heteroaryl portions of any of the groups T or R 1 which may optionally be carriers of up to two substituents which are selected from the group consisting of - (CH 2) and S (O) R, 1"1, - (CH 2) y S (O ) R, 1? 1 ?, - (CH2) and SO2N (R11) 2, - (CH2) and N (R11) 2, - (CH2) and N (R11) COR12, -OC (R11) 2O- in which both atoms of oxygen are connected to the aryl ring, - (CH2) and COR11, - (CH2) and CON (R11) 2, - (CH2) and CO2R11, - (CH2) and OCOR11, -halogen, -CHO, -CF3, -NO2, -CN , and -R12, where y is 0-4, R11 represents H or lower alkyl of 1-4 carbon atoms, and R12 represents lower alkyl of 1-4 carbon atoms.

As prepared the compounds of the invention are mixtures of, diastereomers. For each compound, the materials of interest are mixtures of diaetereomers or the single diastereomer that has an MMP inhibitory activity of the diastereomers that constitute the mixture of diastereomers. Pharmaceutically acceptable salts are also within the scope of the invention. In addition to the compounds previously described, the invention also relates to pharmaceutical compositions comprising a compound of the invention as described above and in more detail in the detailed description below in addition to a pharmaceutically acceptable carrier. The invention further relates to a method for treating a condition mediated by a matrix metalloprotease in a mammal to achieve an effect comprising administering to the mammal an amount of a compound of the invention as described above and in more detail in the following detailed description that is effective in treating said condition.

DETAILED DESCRIPTION: This invention relates in general terms to inhibitory compounds of matrix metalloproteases having the general formula (I) as shown above. The symbol "T" in the formula (I) represents a pharmaceutically acceptable substituent group. Examples of the T groups are portions such as halogen; I rent; haloal alkenyl; alkynyl; - (CH2) PQ where p is 0 or an integer of 1-4; and -alkenyl-Q wherein the alkenyl portion comprises 2-4 carbon atoms. Q in these latter two groups can be aryl, heteroaryl, -CN, -CHO, -NO2, -CO2R4, -OCOR4, -SOR5, -SO2R5, -CON (R4) 2, -COR4, -N (R4) 2, - N (R4) COR4, N (R4) CO2R5, -N (R) CON (R) 2, -OR6, and -SR6. In these formulas R 4 represents H, al aryl, hateroaryl, arylal or heteroaryl-al R 5 represents al ary, heteroaryl, arylal or heteroaryl-al and R6 represents H, al aryl, hateroaryl, arylal heteroaryl-al alkenyl, alkynyl, haloal acyl or alneoxy or polyalneoxy terminated with H, alor phenyl. The unsaturation in a portion that is encompassed by Q or that is part of Q is separated from any of N, O, or S of Q, by at least one carbon atom. This phenyl ring terminator of (I) can be unsubstituted or can carry up to two substituents T. Therefore, the subscript x is 0, 1 or 2. In the immediately preceding text referring to "T", correspond the following further definitions: "al refers to straight and branched chain cyclic and polycyclic hydrocarbon groups containing 1-10 carbon atoms; "haloal refers to partially or fully halogenated algroups containing 1-10 carbon atoms; "alkenyl" refers to straight or branched polycyclic and cyclic unsaturated hydrocarbon groups containing 2-10 carbon atoms and at least one double bond; "alkynyl" refers to straight and branched chain cyclic and polycyclic hydrocarbon groups containing 2-10 carbon atoms and at least one triple bond; "aryl" refers to aromatic carbocycles of a carbocyclic group of 6-12 carbon atoms such as phenyl or biphenyl or naphthyl; "hateroaryl" refers to cyclic aromatic groups of 6-12 carbon atoms containing 1-4 heteroatoms selected from O, N and S; "arylal refers to an alchain of 1-4 carbon atoms terminated by an aryl group; "hateroaryl-al refers to an alchain of 1-4 carbon atoms terminated with a heteroaryl group; "acyl" means -Coal Coaryl, or Coheteroaryl; "alnoxy" refers to a 1-6 methylene diradical chain of an oxygen; and "polyalnoxy" refers to a diradical chain of 1-6 and 2-3 oxygens, with the proviso that each oxygen is separated from each other oxygen by at least one carbon. More particularly, the invention relates in a first aspect to compounds of formula (I) in which each of A and G is CH2 n is 0. Said compounds have the formula (II) shown below. (ll) In formula (II), m is preferably 0, 1 or 2, In addition when m is 0, R1 is preferably when m is 1, R1 is preferably ; and when m is 2, R1 is preferably In a more preferred aspect, in formula (II) T is halogen or OR6 where R6 is alkyl of 1-6 carbons or benzyl; x is 1; m is 0 or 2; and when m is 0, R1 is and when m is 2, R is - In addition to the compounds of formula (II), the invention relates in a second aspect to compounds having the formula (I), which n is 0 or 1; A is CH or N; G is CH; and A is connected to G by a ring-forming link having the formula (CH2) 0.3 (Q) (CH2) 0_3 wherein Q is a chemical bond, S, or Q; and C, S, or O constitute linking atoms. These parameter selections result in the formation of a ring including A, the ring-forming link previously described and G, This subset of compounds is based on formula (I) with the conditions that the sum of n plus the number total of linking atoms in the ring-forming bond is an integer from one to four; the number of heteroatoms in the ring is 0 or 1. T, x, m, and R1 are as defined, defined with reference to formula (I). These compounds therefore have a ring of 4 to 7 members which can include a heteroatom of N, O, or S, and are represented by the following formula (III).

(III) In a preferred subgroup of the ring-containing compounds previously described, n is 0; A is CH; Q is a chemical bond; and in ring-forming bond is - (CH2) 2-- The resulting compounds have the formula (Illa) shown below.

(Illa) More preferably the compounds of formula (Illa) are materials in which T is halogen or OR6 in which R6 is alkyl of 1-6 carbon atoms or benzyl; x is I and m is O or l. When m is 0, R1 is more preferably and when m is 1, R1 is more preferably Those skilled in the art will appreciate that each of the compounds of the invention exist in more than one diastereomeric form, and will understand that said stereoisomers generally exhibit different activities in the biological systems. This invention comprises all possible stereoisomers possessing inhibitory activity against an MMP, independently of its stereoisomeric designations, although only the most active of the stereoisomers in each mixture has been claimed here. It also encompasses mixtures of stereoisomers in which at least one member possesses an MMP inhibitory activity. The invention also encompasses the pharmaceutically acceptable "prodrugs" of the claimed compounds. These are typically acylated derivatives of the alcohol-containing compounds of the invention or of lower alkyl esters and lower alkyl amides of the carboxylic acid moiety as well as lactones formed by the reaction between the carboxylic acid function and the hydroxyl group. Other types of prodrugs are however known. Said prodrugs, which may be intrinsically physiologically inactive or active, are converted to the active compounds of the invention in the body of the treated subject. A note of the interconversion of the lactone and the straight chain shapes of a material is shown below.

The preparations of said derivatives are within the experience in the matter. The most preferred compounds of the present invention are as indicated and named in the following list, 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (phenylthiomethyl) butanoic acid; [2S, 4R] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2-phenylthiomethyl) -butanoic acid; 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2 - [(4-hydroxy-phenyl) -thiomethyl] -butanoic acid; the most active of the compounds, [2S, 4R] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2 - [(4-hydroxyphenyl) -thiomethyl] butanoic acid and [2S, 4S] - 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2 - [(4-hydroxyphenyl) -thiomethyl] butanoic; 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (3-phenylpropyl) butanoic acid; the most active of the compounds' [2S, 4R] -4- [4- [4-) 4-chlorophenyl) phenyl] -4-hydroxy-2- (3-phenylpropyl) -butanoic and [2S, 4S] -4 - [4- (4-chlorophenyl) phenyl] -4-hydroxy-xi-2- (3-phenylpropyl) butanoic; 4-t4- (4-chlorophenyl) phenyl] -4-hydroxy-2- [2-3-N, N-diethylcarbamoyl) -phenylethyljbutanoic acid; the most active of the compounds, [2S, 4R] -4- [4 (4-chlorophenyl) phenyl] -4-hydroxy-2- [2-) 3-N, N-diethylcarbamoyl) phenylethyl l] butanoic; and [2S, 4S] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- [2-) 3-N, N-dethecarbamoyl) phenylethyl] butanoic acid; 4- [4- (4-pentyloxyphenyl) fenii] -4-hydroxy-2- (3-phenylpropyl) butanoic acid; the most active of the compounds [2S, 4R] -4- [4- (4-pentyloxyphenyl) phenyl] -4-hydroxy-2- (3-phenylpropyl) -butane; and [2S, 4S] -4- [4- (4-pentyloxyphenyl) phenyl] -4-hydroxy-2- (3-phenylpropyl) -butanoic acid; 4- [4-) 4-benzyloxyphenyl] phenyl] -4-hydroxy-2- (3-phenylpropyl) butanoic acid; the most active of the compounds [2S, 4R] -4- [4- (4-benzyloxyphenyl) phenyl] -4-hydroxy-2- (3-phenylepropyl) butanoic; and [2S, 4S] -4- [4- (4-benzyloxyphenyl) phenyl] -4-hydroxy-2- (3-phenylpropyl) butanoic acid; 4- [4-) 4-chlorophenyl) phenyl] -4-hydroxy-2- (2-phthalimidoethyl) butanoic acid; the most active of the compounds [2S, 4R] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (3-phthalimidoethyl) -butanoic; and [2S, 4S] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (2-phthalimidoethyl) -butanoic acid; trans-5 - [(4- (4-chlorophenyl) phenyl) hydroxyethyl] -trans-2-phenylthiocyclopentanecarboxylic acid; the most active of the compounds (1 S, 2R, 5S) -trans-5 - [(4- (4-chlorophenyl) phenyl-S-hydroxymethyl] -trans-2-phenylthiocyclopentanecarboxylic acid and (1S, 2R, 5S) acid -trans-5- [(4- (4-chlorophenyl) phenyl) -Rh -hydroxymethyl] -trans-2-phenyltiocyclopentanecarboxylic acid trans-5 - [(4- (4-chlorophenyl) phenyl) hydroxymethyl] -cis-2- (2-methoxycarbonyl-phenylthio) -cyclopentanecarboxylic acid, the most active of the compuets (1S, 2S, 5S) -trans-5 - [(4- (4-chlorophenyl) phenyl) -S-hydroxymethyl-cis -2- (2-methoxycarbonylphthio) cyclopentanecarboxylic acid and (1S, 2S, 5S) -trans-5 - [(4-) 4-chlorophen I) phen il) -Rh id roxymethyl] - cis-2- (2-methoxycarbonylphenylthio) cyclopentanecarboxylic; trans-5 - [(4- (4-chlorophenyl) phenyl) hydroxymethyl-trans-2-phthalimido-methylcyclopentanecarboxylic acid; and the most active of the compounds (1 S, 2R, 5S) -trans-5 - [(4- (4-chlorophenyl) phenyl) -S-hydroxymethyl-trans-2-phthalimidomethylcyclopentanecarboxylic acid and (1S, 2R, 5S) -trans-5 - [(4- (4-chlorophenyl) phenyl) -R-hydroxymethyl] -trans-phthalimidomethylcyclopentanecarboxylic acid.

Method General Preparations: The compounds of the invention can be prepared easily by the use of known chemical procedures and reactions. However, the following general preparative methods are presented to assist the reader in the synthesis of the inhibitors, and more detailed examples are presented below in the experimental section. All the variable groups of these methods are as described in the generic description if they have not been specifically defined below.

General Method A The compounds of this invention are conveniently prepared by the reduction of 4-biphenyl-4-oxobutyric acid derivatives substituted with a selective hydride reducing agent such as sodium borohydride or sodium cyanoborohydride in a solvent such as ethanol or tetrahydrofuran at 0 ° C to room temperature. Alternatively, the reducing agent can be any number of other reagents used by those skilled in the art to reduce carbonyl to secondary alcohol with the proviso that said reducing agent does not effect undesirable changes in the T, carboxy, or R portions of said starting materials. The isomers of the product can be isolated in pure form by a combination of crystallization and chromatography. The starting 4-biphenyl-4-oxobutyric acid derivatives are prepared as described in the North American Patent Application No. 08 / 539,409 and WO 9615096.

General Method B - Materials isomerically. pure are conveniently prepared as in Method A but by the use of a chiral reducing agent such as the CBS system (Corey, EJ; Bakshi, Shibata, S., J. Am. Chem. Soc. 1987, 5551-5553, or Corey, EJ; Bakshi, RK Shibata; S; Chen, CP; Singh, VK, J. Am. Chem. Soc. 1987, 109, 7925-7926.) in place of sodium borohydride. Pharmaceutically appropriate salts of the compounds of the present invention include addition salts formed with organic or inorganic bases. The salt forming ion derived from said bases can be constituted by metal ions, for example aluminum ions, of alkali metals, such sodium, potassium, alkaline earth metal ions such as calcium or magnesium, or an ion of an amine salt , of which the number for that purpose is known. Examples include ammonium salts, arylalkylamines, such as dibenzylamine, and N, N-dibenzylenediamine, lower alkylamines such as methylamine, t-butylamine, procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine. , 1-adamantylamine, benzathine, or salts derived from amino acids such as arginine; power plant or similar. Physiologically acceptable salts such as the sodium or potassium salts and the amino acid salts can be used medicinally as described below and are the preferred salts. These and other salts that are not necessarily physiologically acceptable are useful in the isolation or purification of an acceptable product for the purposes described below. For example, the use of commercially available enantiomerically pure amines such as (+) cinchonin in appropriate solvents can provide crystals of salts of a single enantiomer of the compounds of the invention, leaving the opposite enantiomer in solution in a procedure often mentioned as "classic resolution". As an enantiomer of a particular compound of the invention is usually > substantially superior in its physiological effect than its antipode, this active isomer can therefore be found purified both in the crystals and in the liquid phase. The salts are produced by reacting the acid form of the compound with an equivalent of the base that provides the desired basic ion in a medium in which the salt precipitates or in an aqueous medium, which is then lyophilized. The free acid form can be obtained from the salt by conventional neutralization techniques, for example with potassium bisulfate, hydrochloric acid, etc. The appropriate amide and ester derivatives of the compounds of the invention are for example esters of carboxylic acids of alkyl and aryl of the 4-hydroxyl group or alkyl or aryl esters of the carboxylic acid, or the amides prepared from the carboxylic acid together with lower alkyl amines or natural amino acids. The compounds of the present invention were shown to inhibit the matrix metalloproteases MMP-3, MMP-9, and MMP-2, and are therefore useful for treating or avoiding the conditions mentioned above. As other MMPs not listed above share a high degree of homology with those listed above, especially at the catalytic site, it is estimated that the compounds of the invention should also inhibit said other MMPs to different degrees. The variation of the substituents in the aryl portions of the molecules, as well as those of the butanoic acid chain of the claimed compounds, have been shown to affect the relative inhibition of the MMPs listed. Therefore, compounds of this general class can be "refined" selected specific substituents such as the inhibition of specific MMP associated with specific pathological conditions that can improve leaving MMPs less involved less affected.

The inhibitors of the present invention have been contemplated for use in human and veterinary applications. Accordingly, this invention relates to a method for treating mammals (including humans and / or animals reared for dairy, meats or in the skin industries or as pets for example, mice, rats, horses, cattle, sheep, dogs, cats , etc.) suffering from conditions mediated by matrix metalloproteases such as those previously described, by administering an effective amount of a compound of the invention. In this method of treatment the mammal is preferably a human being. The effects that can be achieved are: relief of osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal diseases, corneal ulceration, proteinuria, aneurysmal aortic diseases, epidermolysis hullosa, dystrophobic, conditions that lead to inflammatory responses, intermediary osteopenias by MMP activity, diseases of the tempero-mandibular joints, or demyelinating diseases of the nervous system; delay of tumor metastasis or degenerative loss of cartilage following damage to the traumatic joints; reduction of coronary thrombosis of atherosclerotic plaque rupture; or improvements in birth control. In this method of treatment, the amount of inhibitor compound is effective to inhibit the activity of at least one matrix metalloproteotease which results in the achievement of the desired effect. The compounds of the invention are used in pharmaceutical compositions containing active ingredients in addition to one or more carriers, diluents, fillers, binders, pharmaceutically acceptable, and other excipients, depending on the mode of administration and the method of administration contemplated.

The administration of the inhibitors can be by any appropriate means known to those skilled in the art. Examples of suitable parenteral administration include intravenous, intraarticular, subcutaneous and intramuscular routes. Intravenous administration can be used to obtain an accurate regulation of the plasma peak concentrations of the drug. An improved half-life and the direction of the drug to the joint cavities can be aided by entrapping the drug in the liposomes. It may be possible to improve the selectivity of the liposomal target in the articular cavities by incorporating ligands on the outside of the liposomes that adhere to the specific synovial macromolecules. Alternatively, an injection of intramuscular, intra-articular or subcutaneous depot with or without encapsulation of the drug into degradable microspheres, for example comprising poly (DL-lactide-co-glycolide), can be used to obtain sustained and prolonged release of the drug. To improve the convenience of the dosage form it may be possible to use a reservoir implanted in i.p. form. and septum such as the Percuseal system obtainable in Pharmacia. It can also be achieved better compliance with the patient and with the conveniences through the use of either injector pens (for example Novo Pin or Q-pen or needle-free jet injectors (for example Bioject, Mediject or Dickinson becton). prolonged zero-order or precisely controlled such as pulsatile delivery, can also be obtained when necessary using implantable pumps with release of the drug through a cannula in the synovial spaces.Examples include osmotic pumps subcutaneously implanted that can be obtained in ALZA, such as the ALZET osmotic pump.

Nasal administration can be achieved by incorporating the drug into particulate bioadhesive carriers (<200 μm) such as those comprising cellulose, polyacrylate or polycarbophil, together with improved absorption improvers such as phospholipids or acylcamitins. The systems obtainable include those developed by DanBiosys and Scios Nova. Oral administration can be achieved by incorporating the drug in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. Oral administration can also be effected by incorporating the drug into enteric coated capsules designed to release the drug in the colon where the digestive activity of the protease is low. Examples include the OROS-CT / Osmet ™ and PULSINCAP ™ ALZA systems and the Scherer Drug Delivery System, respectively. Other systems use azo-crosslinked polymers that are degraded by colon specific bacterial azo reductases, or pH sensitive polyacrylate polymers that are activated by increasing the pH in the colon. The foregoing systems can be used in conjunction with a wide range of absorption enhancers available. Rectal administration can be achieved by incorporating the drug into suppositories. The compounds of the invention can be manufactured in the formulations listed above by the addition of various therapeutically inert inorganic or organic carriers that are well known to those skilled in the art. Examples thereof include but are not limited to lactose, corn starch, or derivatives thereof, talc, vegetable oils, waxes, fats, polyols such as polyethylene glycol, water, sucrose, alcohols, glycerin, and the like. Various presenters, emulsifiers, dispersants, flavorings, wetting agents, antioxidants, sweeteners, colorants, stabilizers, salts, buffers and the like may also be added as necessary to aid in the stabilization of the formulation or to help increase the bioavailability of the formulation. the active ingredients or to provide an acceptable flavor or odor formulation in the case of oral dosing. The amount of pharmaceutical composition to be used will depend on the person receiving it and the disease in question. The required amount can be determined without undue experimentation by protocols that are well known to those skilled in the art. Alternatively, the required amount can be calculated, based on a determination of the amount of enzyme which constitutes the target and which must be inhibited in order to treat the disease. Typically, dosage levels of from about 0.05 mg to approximately 150 mg per kilogram of body weight per day (approximately 4 mg to approximately 12 grams per adult human per day) are useful for the treatment of the conditions indicated above.

It should be understood, however, that the specific dosage level for any particular subject will depend on a variety of factors including the subject's age, body weight, overall health, sex and diet, activity and the level of side effects. expected of the specific compound used, the time and route of administration, the excretion regime as well as drug combinations and the severity of the particular conditions being treated. The matrix metalloprotease inhibitors of the invention are useful not only for the treatment of the physiological conditions discussed above, but are also useful in such activities as purification of metalloproteases, and for testing the activity of matrix metalloproteases. Such activity assays can be used both in vitro using natural or synthetic enzymatic preparations, or in vivo using for example animal models in which abnormal levels of destructive enzymes have been found spontaneously (use of genetically mutated or trapsgenic animals), or are induced by administration of exogenous agents or by surgery that breaks joint stability.

Experiments: General Procedures: All reactions were carried out in oven-dried or flame-dried dishes under a positive argon pressure and were stirred magnetically unless otherwise indicated. The solutions and sensitive liquids were transferred through the syringe or cannula and were introduced into the reaction vessels through rubber septa. The solutions of the reaction products were concentrated using a Buchi evaporator unless indicated otherwise.

Materials: Commercial quality solvents and reagents were used without further purification except that diethyl ether and tetrahydrofuran were usually distilled under argon from cetyl benzophenones, and methylene chloride which was distilled under argon from calcium hydride. Many of the special organic or organometallic starting materials and reagents were obtained from Aldrich, 1001 West St. Paul Avenue, Miiwaukee, Wl 53233. The solvents were often obtained in EM Science distributed by VWE Scientific.

Chromatography: Thin-layer analytical chromatography (TLC) was performed on 250 μm silica gel plates of 60 A F-254, glass-based and previously coated. The visualization of the spots was carried out by one of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating , and (d) immersion of the plate in a 3% solution of p-anisaldehyde in ethanol containing 0.5% concentrated sulfuric acid followed by heating. Column chromatography was carried out using 230-400 mesh EM Science® silica gel. Analytical high performance liquid chromatography (HPLC) was performed at 1 mL min "1 on a 4.6 x 250 mm Microsorb® column monitored at 288 nm, and the semi-preparative HPLC was performed at 24 mi min" 1 in a column of 21, 4 x 250 mm Microsorb® monitored at 288 nm. Instrumentation: The melting points (pf) were determined with an apparatus to measure the Thomas-Hoover melting point and are not corrected. The proton nuclear magnetic resonance (1H) (NMR) spectra (except for the NOESY experiments) were measured with a General Electric GN-OMEGA 300 spectrometer (300 Mhz), and the 13 C (13C) carbon NMR spectra were measured with a General Electric GN-OMEGA 300 spectrometer (75 MHz). Most of the compounds synthesized in the following experiments were analyzed by NMR, and the spectra coincided with the structures proposed in each case. The 1HRMN NOESY spectra (Nuclear Overhauser Effect Spectroscopy) were collected on a Bruker DMX-500 NMR spectrometer (TH = 500.15 MHz, 13 C = 125.78 MHz). The data was processed using the Bruker XWINNMR software on a Silicon Graphics Indy computer. The mass spectrum (MS) data were obtained in a Kratos Concept 1-H spectrometer by cesium-liquid secondary ion (LCIMS), an updated version of fast atom bombardment (FAB). Most of the compounds synthesized in the following experiments were analyzed by mass spectroscopy and the spectra coincided with the structures proposed for each case.

General Comments: For multistage procedures, sequential steps were indicated with numbers. The variations within the stages are indicated by letters. The dashed lines in the tabular data indicate adhesion point.

Experimental Procedures Examples 1 and 2 Preparation of acid [2S.4R1-4- [4- (4-chlorophenyl) phenyl] -4R-hydroxy-2- (phenylthiomethyl) butanoic acid and f2S.4S] -4- [4- ( 4-chlorophenyl) phenyl] -4-hydroxy-2- (phenylthiomethyl) butanoic [S] -4- [4- (4-chlorophenyl) phenyl] -4-oxo-2- (phenylthiomethyl) -butanoic acid (Reference Compound A) was prepared in the manner as described in WO - 09615096 (Example 197). A solution of this material (6.52 g, 15.9 mmol) in absolute ethanol (100 ml) was stirred under an argon atmosphere in an ice bath (0 ° C) while cooling as sodium borohydride was added portionwise. (4.12 g, 109 mmol). The reaction mixture was stirred as the ice bath melted and then at room temperature overnight. The resulting mixture containing a significant white solid was quenched by the addition of water (100 ml), and then evaporated in vacuo to almost one third of its volume. The condensed mixture was mixed with almost 100 ml of ethyl acetate and then mixed vigorously as it was cautiously quenched with 1N hydrochloric acid until the aqueous phase was strongly acidic (evolution of hydrogen gas from excess borohydride). The aqueous phase was extracted and then the organic phase was washed several times with water, then with brine and then dried over sodium sulfate and evaporated in vacuo. The residue was dissolved as much as possible in 100 ml of a mixture of methylene chloride / methanol (99: 1) and then filtered to remove the white solid which proved to be a pure isomer [2S, 4S] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (phenyltomethyl) -butane as shown by analytical HPLC (silica column, 1 ml / minute, 99: 1 methylene chloride / methanol in addition to 0.05% acetic acid, detection peak at 254 nM, this 4-S isomer is the second to be eluted). The filtrate was chromatographed on a preparative silica HPLC column (46 mm ID) using the same solvent at 80 ml / min to obtain 444 mg of the pure 4R isomer by condensing the best fractions in vacuo to low volume, cooling and collecting the crystals by filtration. Substantial material that eluted very early proved to be a mixture of the lactone isomers of the 4-hydroxy acids that were separated as shown in the procedures for Reference Compounds B and C. The NMR evaluation of lactones and the correlation of these isomers with those of Examples 1 and 2 led to the identification of the stereochemistry at carbon 4 of the hydroxy acids (see procedures for compounds B and C). Example 1 (2S, 4R): MP 122-122 ° C; HPLC (1 ml / min, 1% methanol in methylene chloride in addition to 0.05% acetic acid, Rainin silica column 4.6 mm x 25 cm) R = 10.02 min; [α] D + 64.4 ° (c 0.55, acetone); 1 H NMR (Acetone d6) d 7.12-12.77 (m, 13H), 4.82 (dd, J = 4.08, 8.45 Hz, 1 H), 3.2 (m, 2H), 2 , 98 (m, 1 H) others low peak of acetone. Example 2 (2S, 4S); MP 137-138 ° C; HPLC (preceding conditions) 'R = 13.11 min; [] D + 28.8 ° (c. 0.93, acetone); 1H NMR (acetone-d6) d 7.15-15-7.7 (m, 13H), 4.83 (dd, J = 5.88, 8.46 Hz, 1H), 3.25 (d, J = 6.61 Hz, 2H), 2.79 (m, 1 H), 1.95-2.25 (m, 2H).

Reference Compounds B and C Isolation of r2S.4R] -4-f4- (4-chlorophenyl) phenyl] -2- (phenylthiomethyl) -? - butyrolactone v 2S.4S] -4- [4-í4-chlorophenol ) phenyl] -2 - (, phenylthio-methyl) -y-butyrolactone: Preparative HPLC of the condensed early fractions of the purification of [2S, 4S and R] -4- [4- (4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (phenylthiomethyl) -butanoic acid in silica columns using either 5% ethyl acetate in hexane or a slow gradient of 0-1% methanol in methylene chloride led to the isolation of pure samples from each of the γ-butyrolactone isomers (Reference Compound B and C).

The determination of the relative stereochemistry around the chiral ring carbons can be achieved by identifying the relative position of the protons attached to these carbons, ie whether the pairs of protons are on the same side or on opposite sides of the ring plane. The NMR spectroscopy, in particular, a nuclear Overhauser spectroscopy of a bi- dimensional dimension (NOESY), is the ideal technique to solve this problem, taking advantage of Overhauser nuclear differential enhancements (NOEs) based on the relative spatial proximity of the protons. . See, Macura, S. and Ernst, R.R., J. Mol. Biol., 1980, 206, 397. This was done for the two isomers of the? -butylactone to demonstrate a higher NOE between H-1 and H-4 of the isomer with those cis protons (2S, 4S) than the isomers with the trans protons (2S.4R). All other NOEs observed among the other protons in the lactone ring and CH2 adhered to the two isomers were self-consistent with this interpretation. Although the purified crystalline hydroxy acids (Examples 1 and 2) are relatively stable as solids, the aged solutions of these compounds slowly showed one or other of the lactones as a result of spontaneous lactonization. This was evidenced by the chemical shift of H-4 in the lactone to 4S at d 540 ppm and that of 4R lactone in d to 5.65 ppm. The hydroxy acid that was converted to 2S, 4R lactone was thus identified as the 2S.4R hydroxy acid (Example 1) and that was the one that was converted to the 2S.4S lactone identified as 2S, 4S hydroxy acid (Example 2).

Compound B (2S.4R): MP 122-123 ° C; 1 H NMR (CDCl 3, 500 MHz) d 7.21-7.60 (m series, 13 H aromatic H), 5.65 (dd, J = 4.59, 7.98 Hz, 1 H, H-4), 3.55 (dd, J = 3.74, 13.29 Hz, 1 H, SCH), 3.04 (dd, J = 9.97, 13.28 Hz, 1 H, SCH), 2.94- 2.98 (m, 1 H, H-2), 2.64-2.70 (m, 1 H, H-3A), 2.46-2.51 (m, 1H, H-3B).

Compound C (2S, 4S): MP 142-143 ° C; 1 HNMR (CDCI ^, 500 MHz) d 7.21-7.60 (m series, 12H, aromatic H) 5.40 (dd, J = 5.79, 10.58 Hz, 1 H, H-4) , 3.65 (dd, J = 3.50, 13.40 Hz, 1 H, SCH), 2.96 (dd, J = 9.90, 13.37 Hz, 1 H, SCH), 3.02 - 3.07 (m, 1 H, H-2), 2.87-2.92 (m, 1H, H-3A), 2.07 (dd, J = 12.26, 23.08 Hz, 1H , H- 3B). Examples 3 and 4 Preparation of Acid [2S.4R] -4- [4- (4-chlorophenyl) phenyl] -4R-hydroxy-2- (3-phenylpropylbutanoic acid and [2S.4S] -4- [4- ( 4-chlorophenyl-phenyl] -4-hydroxy-2- (3-phenylpropyl) butanoic [S] -4- [4- (4-chlorophenyl) phenyl] -4-oxo-2- (phenylpropyl) butanoic acid (Reference Compound D) was prepared as described in WO-09615096 (Example 116). A solution of this material (1.00 g, 2.46 mmol) in absolute ethanol (30 mL) was stirred under argon atmosphere with an ice bath (0 ° C) as sodium borohydride (0.743 g) was added. , 19.6 mmol) in portions. The reaction mixture was stirred on melting the ice bath and then at room temperature for several days. The resulting mixture containing a significant white solid was quenched by the addition of water (150 ml) of ethyl acetate and the resulting mixture was stirred vigorously while adding concentrated sulfuric acid by dropping so that the aqueous phase was strongly acidic. The aqueous phase was extracted and the organic phase was washed several times with water, dried over sodium sulphate and evaporated in vacuo. The white residue was chromatographed on a preparative HPLC column (loaded with Prochrom with 13-23 μm angular silica) using 1% methanol in methylene chloride to provide 292 mg of pure isomer of first elution and 267 mg of pure second isomer. elution The α-lactones can be formed from the isomers of 4-hydroxycarboxylic acid by treatment of each of them separately with traces of toluene sulfonic acid in refluxing benzene using a Dean Stark trap to remove the water. Experiments with nuclear Overhauser spectroscopy (NOESY) in lactones can then be used to establish which of these lactone isomers has the 4S stereochemistry and which has the 4R stereochemistry and consequently which of the hydrocarboxylic acids each stereochemistry has since the conversion to lactone does not result in a change in stereochemistry. Example 3 (or 4) (First elution): PF 103-104 ° C; HPLC (2 ml / min 1% methanol in methylene chloride, Rainin silica column 4.6 mm x 15 cm) * R = 6.55 min; 1 HNMR (DMSO-d6) d 12.10 (s, 1H), 7.65 (d, J = 8.46 Hz, 2H), 7.59 (d, J = 84.6 Hz, 2H), 7, 48 (D, J = 8.46 Hz, 2H), 7.34 (d, J = 8.09 Hz, 2H), 7.24 (t, J = 7.36 Hz, 2H), 7.11- 7.15 (m, 3H), 5.28 (d, J = 4.78 Hz, 1 H, OH), 4.46-4.52 (m, 1 H), 2.46-2.61 (m, 3H), m, 3H partially under DMSO), 1, 76-1, 89 (m, 1 H) 1, 36-165 (m, 5H).

Example 4 (or 3) (Second elution): MP 155-157 ° C; HPLC (preceding conditions) LR = 9.75 min; 1 H NMR (DMSO-d6) d 12.04 (s, 1H), 7.66 (d, J = 8.82 Hz, 2H), 7.60 (d, J = 8.46 Hz, 2H), 7, 48 (d, J = 8.46 Hz, 2H), 7.36 (d, J = 8.09 Hz, 2H), 7.22 (t, J = 6.99 Hz, 2H), 7.10- 7.15 (m, 3H), 5.28 (bs, 1 H, OH), 4.49 (bm, 1H), 2.3-2.7 (m, 2H under DMSO), 2.21-2 , 28 (m, 1 H), 1, 88-1, 97 (m, 1 H), 1, 4-1, 65 (m, 5H).

Reference Compounds FYG Isolation of [2S] -4- [4- (4-chlorophenyl) phenyl] -4-oxo-2 - [(4-hydroxy-phenyl) thiomethyl] butanoic acid and [2R] -4- [ 4- (4-chlorophenyl) phenylj-4-oxo-2 - [(4-hydroxyphenyl) thiomethyl] butanoic Racemic 4- [4- (4-chlorophenyl) phenyl] -4-oxo-2 - [(4-hydroxyphenyl) -thiomethyl] butanoic acid (5.6 g) was prepared as described in WO-09615096 ( Example 204). Chromatography of this material in a chiral stationary phase recorded according to the general procedures of D. Arlt, B. Boemer, R. Grosser and W. Lange, Angew. Chem. Int. Ed. Engl. 30 (1991) No. 12, pages 1662-1664 was used to separate this racemate into the enantiomers. The first isomer to elute was the 2S isomer (1.60 g) with one more sign of rotation and the second to elute was the 2R isomer (1.43 g) with a negative sign of rotation. The compound F (2S): MP 130-132 ° C; HPLC (1 ml / min, 1% ethanol in hexane, Recorded, 4.6 mm x 25 cm chiral column) R = 7.72 min, 99.6% pure; [α] D + 102.6 ° fe 0.88, acetone); 1 H NMR (CD3OD) d 7.97 (d, J = 8.46 Hz, 2H), 7.69 (d, J = 8.46 Hz, 2H), 7.64 (d, J = 8.45 Hz, 2H); 7.44 (d, J = 8.82 Hz, 2H), 7.28 (d, J = 8.46 Hz, 2H), 6.70 (d, J = 8.82 Hz, 2H), 4, 86 (bs, 2H), 2.98-3.54 (series of m, 5H). Compound G (2R): HPLC (1 ml / min, 1% ethanol in hexane, Chiral 4.6 mm x 25 cm column) R = 10.80 min, 99.8% pure; [α] D -103.8 ° (c 10.0, acetone), 1 H NMR (CD3OD) same as Compound C.

Examples 5 and 6 Preparation of [2S, 4R] -4- [4- (4-chlorophenyl) phenyl] -4-h¡droxi-2 - [(4-hydroxyphenyl) tiometilJbutanoico and [2S, 4S] -4 - [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- [(4-hydroxyphenyl) chloromethyl] butanoic The general method of Examples 1 and 2 can be used to prepare these compounds except that Reference Compound F was used instead of [S] -4- [4- (4-chlorophenyl) phenyl] -4-oxo-2 acid. - (phenylthiomethyl) butanoic.

Examples 7 - 16: The names and structures are shown below. The general method of Examples 5 and 6 can be used to prepare the compounds of Examples 9-20 except that the appropriate 4-oxo compounds are prepared according to the procedures of WO-09615096 were employed instead of the acid [S] - 4- [4- (4-chlorophenyl) phenyl] -4-oxo-2- (2-phthaliminoethyl) butanoic.

Eiemplos 7-8 Preparation of [2S.4R] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- [2- (3-NN- dietilcarbamoiDfeniletiljbutanoico: [2S, 4S ') - 4-j4- (4-chlorophenyl) phenyl] -4-hydroxy-2- [2- (3-NN-diethylcarbamoyl) -phenethyl] butanoic Examples 9 to 10 Preparation of [2S.4R1-4- (4-pentyloxyphenyl) phenyl] -4-hydroxy-2- (3-feniipropinbutanoico: acid [2S.4S] -4-F4- (4-pentyloxyphenyl) phenyl ] -4-hydroxy-2- (3-phenylpropiPbutanoic) Examples 11-12 Preparation of [2S.4R] -4- [4-4 4-benzyloxyphenyl] -phenyl] -4-hydroxy-2- (3-phenylpropibutanoic acid and [2S.4S] -4- [4- (4-benzyloxy-phenyl) -phenyl-4-hydroxy-2- (3-phenylpropylbutanoic) Examples 13 - 14 Preparation of (1 S.2R.5S) -trans-5 - [(4- (4-chlorophenyl) -phenyl) -Sh¡droximetil] -trans-2- feniltiociclopentancarboxílico and acid (1 S.2R. 5S) -trans-5 - [(4- (4-chlorophenyl) phenyl) -R-hydroxymethyl] trans-2-phenylthiocyclopentanecarboxylic acid Examples 15 to 16 Preparation of (1S.2S.5S) -trans-5 - [(4- (4-chlorophenyl) -phenyl) -S-hydroxymethyl] -cis-2- (2-carbox lic-metoxicarbonilfeniltioVciclopentano and acid (1S.2S.5S) -trans-5- [(4- (4-chlorophenip-phenyl) -R-hydroxymethyl] -cis-2- (2-methoxycarbonylphenylthio) -cyclopentane-carboxylic acid Biological Protocols and In Vitro Assay Data Fluorescence Assay Off P218 for Inhibition with MMP The fluorescence assay off P218 (Microfluorometric Profiling Assay) is a modification of the one originally described by C.G. Knight et al, FEBS Letters, 296, 263-266 (1992) for a related substrate and for a variety of matrix metalloproteinases (MMP) in cuvettes. The test was carried out with each exemplary compound of the invention and with the three MMPs, MMP-3, MMP-9, and MMP-2, analyzed in parallel, adapted as follows for a 96-well microtiter plate and a Hamilton AT® workstation. Fluoroane substrate P218 P218 is a synthetic substrate containing a group of 4-acetyl-7-methoxycoumarin (MCA) in the N-terminal position and a 3- (2,4-dinitrophenyl) - (L) -2,3- group diaminopropionil (DPA) internally. This is a modification of a peptide reported by Knight (1992) that was used as a substrate for matrix metalloproteinases. Once the peptide P218 (putative clip site in the Ala-Leu link) is dissociated, the fluorescence of the MCA group can be detected in a fluorometer with excitation at 328 nm and emission at 393 nm. P218 is currently produced by BACHEM exclusively for Bayer Corp. P218 has the structure: H-MCA-Pro-Lys-Pro-Leu-Ala-Leu-DPA-Ala-Arg-NH2 (PM 1332.2) Recombinant human CHR Estromelicin ( MMP-3: Pro-MMP-3 Recombinant human CHO: Pro-stromelysin CHO 257 (pro-MMP-3) was expressed and purified as described by TJ Housely et al., J. Biol. Chem. 2 O8, 4481-4487 (1993) Activation of Pro-MMP-3: Pro-MMP-3 at 1.72 μM (100 μg / ml) in an MMP-3 activation buffer consisting of 5 mM Tris at pH 7 , 5, 5 mM CaCl2, 25 mM NaCl, and 0.005% Brij-35 was activated by incubation with TPCK (N-tosyl- (L) -phenylalanine chloromethyl ketone) trypsin (1: 100 p / pa pro-MMP-3) at 25 ° C for 30 minutes The reaction was stopped by the addition of a soybean trypsin inhibitor (SBTI); 5.1 p / p at trypsin concentration). This activation protocol results in the formation of 45-kDa active MMP-3, which still contains the C-terminal portion of the enzyme.

Preparation of human recombinant Pro-aelatinase A (MMP ^ -2): Human recombinant Pro-MMP-2: human pro-geiatinase A (pro-MMP-2) was prepared using a vaccine expression system according to the method of R. Fridman et al., J. Biol. Chem. 2 £ Z, 15398-405, (1992). Activation of Pro-MMP-2: Pro-MMP2 at 252 mg / ml was diluted 1: 5 to a final concentration of a 50 mg / ml solution in an activation buffer MMP-2 consisting of 25 nN Tris at pH 7.5, 5 mM CaCl2, 150 mM NaCI, and 0.005% of Brij-33. P-aminopheneimercacrylic acetate (APMA) was prepared 100 mM (3.5 mg / ml in 0.05 N NaOH.) The APMA solution was added to 1/20 of the reaction volume for a final APMA concentration of 0.5 mm and the enzyme was incubated at 37 ° C. for 30 minutes The activated MMP-2 (15 ml) was double-laced versus 2 liters of MMPA-2 activation buffer (the dialysis membranes were pretreated with a solution consisting of 0.1% BSA in buffer). MMP-2 activation for 1 minute, followed by extensive washing with H2O The enzyme was concentrated in Centricon concentrators (the concentrates were also pretreated with a solution consisting of 0.1% BSA solution in MMP-2 activation buffer during 1 minute followed by washing with H2O, and then with MMP-2 activation buffer), with redilution followed by repeated reconcentration twice.The enzyme was diluted to 7.5 ml (0.5 times the original volume) with activation buffer MMP-2 Preparation of Recombinant Human Pro-Gelatinase B (MMP-9): Recombinant Pro-MMP-9 Human Name: Human recombinant pro-gelatinase B (pro-MMP-9) derived from U397 cDNA as described by SM Wilhelm et al, Biol, Chem, 264, 17213-17221 (1989) was expressed as length form total using a baculovirus protein expression system. The proenzyme was purified using the methods previously described by M.S. Hibbs, et al., J. Biol. Chem., 260, 2493-500 (1984).

Activation of Pro-MMP-9: Pro-MMP-9 (20 μg / ml) in a. activation buffer, of MMP-9 consisting of 50 mM Tris at pH 7.4, 150 mM NaCl, 10 mM CaCI2 and 0.005%) Brij-35 was activated by incubation with a 0.5 mM p-aminophenylmercuric acetate (APMA ) for 3.5 hours at 37 ° C. The enzyme was dialyzed against the same buffer to eliminate APMA. Instrumentation: Hamilton Microlac AT Plus®: The MMP profiling assay was carried out in a robotic manner using a Hamilton MicroLab AT Plus®. The Hamilton was programmed to: (1) be serially diluted up to eleven inhibitory potentials automatically using a 2.5 mM loading solution of the inhibitor in 100% DMSO; (2) the substrate followed by inhibitor was distributed in a 96-well Cytofluor plate; and (3) a single enzyme was added to the plate by mixing to start the reaction. Subsequent plates for each additional enzyme were prepared automatically by starting the program at the substrate addition point, remixing the diluted inhibitors, and initiating the reaction by the addition of enzyme. In this way all MMP assays were performed using the same dilutions of inhibitor. Millipore Cytoflour II: After incubation, the plate was read on a fluorometric Cytofluor II plate reader with excitation at 340 nM and emission at 395 nM with the indicator set at 80. Buffers: Microfluorometric reaction buffer (MRB): dilutions of the test compounds, enzymes and P218 substrate for the microfluorometric assay were performed in the microfluorometric reaction buffer (MRB) consisting of 50 mM of 2- (N-morpholino) ethanesulfonic acid (MES) at pH 6, 5 with 10 mM CaCl2, 150 mM NaCl, 0.005% Brij-35 and 1% DMSO. Methods: Microfluorometric profiling assay MMP: This test was carried out with a final concentration of P218 of 6 μM, approximately 0.5 to 0.8 nM of activated MMP (one MMP for each 96-well plate), and with variable inhibitor concentrations . The Hamilton MicroLab AT Plus® was programmed to serially dilute up to eleven compounds of a 2-fold load., 5 mM (100% DMSO) up to ten times the concentration of final compound in the assay. Initially, the instrument provided several quantities of microfluorometric reaction buffer (MRB) in a 96-tube rack, in 1 ml Marsh dilution tubes. The instrument collected up to 20 μL of inhibitor (2.5 mM) and mixed with the buffer in row A of the Marsh shelf, resulting in a concentration of 50 μM of inhibitor. The inhibitors were then serially diluted to 10, 1, 0.2, 0.05 and 0.01 μM. Position 1 on the sample rack contained only DMSO for wells with "enzyme only" in the assay, which resulted in no inhibitor in column 1, rows A through H. The instrument then distributed 107 μL of P218 to a plate 96 well single Cytofluor microtitrator. The instrument was remixed and charged 14.5 μL of diluted compound from rows A to G in the Marsh row to the corresponding rows in the microtiter plate. Row A represents the "base" row. To this was added 39.5 μL of the microfluorometric reaction buffer in place of the drug or enzyme. The reaction was initiated by adding 25 μL of the appropriate enzyme (at 5.86 times the final enzyme concentration) from a BSA-treated reagent reservoir to each of the wells, excluding row H, which is the "base" row . (The enzyme deposit was pretreated with 1% BSA in 50 mM Tris at pH 7.5 containing 150 mM NaCl for 1 hour at room temperature followed by extensive washing with H2O and drying at room temperature). After the addition and mixing of the enzyme the plate was covered and incubated for 25 minutes at 37 ° C. The additional enzymes were tested in the same manner by initiating the Hamilton program with the distribution of the P218 substrate to the microtitre plate followed by remixing and distribution of the drug from the same Marsh row to the microtiter plate. The second MMP (or third, etc.) that was tested was then distributed from a row of reagents to the microtiter plate by mixing before covering and incubating. Determination of Cl50 in microfluorometric assay. The data generated in Cytofluor II was copied from an exported "CSV" file to an Excel spreadsheet master. Data from several different MMPs (one plate of 96 wells per MMP) were calculated simultaneously. Percent inhibition was determined for each drug concentration by comparing the amount of hydrolysis (units of fluorescence generated during 25 minutes of hydrolysis), from the wells containing the compound to the wells that "contained enzymes only" from column 1. After for subtraction of the base, the inhibition percentage was calculated as: ((Control Values - Treated Values) Control values) x 100 Percent inhibitions were determined for inhibitor concentrations of 5, 1, 0.5, 0 , 1, 0.02, 0.005 and 0.001 μM. The linear regression analysis of percent inhibition versus logarithmic inhibitory concentration was used to obtain Cl50 values.

Profiling Test Data for Certain Compounds of the Invention Table 5 Profiling data of the MMP. All Cl50 values are expressed as nM.

* The example numbers of diastereomers 3 and 4 can be reversed, because the stereochemistry at the carbon atom carrying the hydroxyl group has not been determined. Other embodiments of the invention will be apparent to those skilled in the art from a consideration of this specification or by the practice of the invention described herein. It is proposed that the memory and the examples are considered only examples, indicating the true scope and spirit of the invention by means of the following claims.

Claims (16)

1. A compound having metal inhibitory activity or matrix protease having the general formula wherein: T is a pharmaceutically acceptable substituent group; X is 0, 1 or 2; m is 0 or an integer of 1-4; n is 0 or 1; and either A and G are both CH2;

A is a chemical bond and G is CH2;

A is CH or N; and G is a "~ _ _ and A is connected to G by a ring-forming bond having the formula (CH2) 0.3 (Q) (CH2) 0-3, where Q is a chemical bond, S, or O; and C, S, and O constitute linking atoms, resulting in the formation of a ring including A, said ring-forming linker and G, with the conditions that the sum of n plus the amount of total atoms of bond in said ring-forming bond is an integer from 1 to 4, and the number of heteroatoms in said ring is 0 or 1; R1 is: * aryl of 6-10 carbons, with the proviso that if this aryl group is phenyl, then X is one or two; * heteroaryl comprising 4-9 carbon atoms and at least one hetero atom N, O, or S; * aryl-substituted alkenyl where the aryl portion contains 6-20 carbon atoms and the alkenyl portion contains 2-5 carbon atoms; * heteroaryl-substituted alkenyl where the heteroaryl portion comprises 4-9 carbon atoms and at least one teroatome N, O or S, and the alkenyl portion contains 2-5 carbon atoms; * aryl-substituted alkenyl wherein the aryl portion contains 6-10 carbon atoms and the alkenyl portion contains 2-5 carbon atoms; * substituted heteroaryl alkenyl wherein the heteroaryl portion comprises 4-9 carbon atoms and at least one N, O, or S heteroatom and the alkenyl portion contains 2-5 carbon atoms; * N-phthalimidoyl; * N- (1,2-naphthalenedicarboximidoyl); * N- (2,3-naphthalenedicarboximidoyl); * N- (1,8-naphthalenedicarboximido); * N-indoloyl; * N- (2-pyrroldinonyl); * N-succinimidoyl; * N-maleimidoyl; * 3-hydantoinyl; * 1, 2,4-urazoyl * amido; * a urethane; * a urea; * a substituted or unsubstituted non-aromatic heterocycle which contains and which is connected through an N atom and which comprises an additional O or S; * an amino; and * ZR8 in which Z represents // ; and R8 is: * aryl of 6-10 carbon atoms; heteroaryl comprising 4-9 carbon atoms and at least one heteroatom N, O or S; * arylalkyl where the aryl portion contains 6-12 carbon atoms and the portion contains 1-4 carbon atoms; or * heteroaryl-alkyl wherein the aryl portion comprises 4-9 carbon atoms and at least one heteroatom N, O, or S and the alkyl portion contains 1-4 carbon atoms; and with the proviso that when Z is O, R8 may also be alkyleneoxy or polyalkyleneoxy terminated by H, alkyl or phenyl. Aryl or heteroaryl portions of any of the groups T or R 1 which may optionally be carriers of up to two substituents which are selected from the group consisting of - (CH 2) and C (R 11) (R 12) OH, - (CH 2) yOR 11, - ( CH2) and SR11, - (CH2) and S (O) R11, - (CH2) and S (O) R11, 2z) / y and N (R 1) COR12, -OC (R11) 2O- wherein both oxygen atoms are nl na ol a onillllo a aririllno, 11, (CH2) and CON (R11) 2) - (CH2) and CO2R11, - (CH2) and OCOR11, -halogen, -CHO, -CF3, -NO2, -CN, and -R12, wherein y is 0-4; R11 represents H or lower alkyl of 1-4 carbon atoms; and R 12 represents lower alkyl of 1-4 carbon atoms. said compound being a mixture of diastereomers, or a single diastereomer having the higher MMP inhibitory activity than the diastereomers constituting said mixture of diastereomers; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein A is CH2; G is CH2 and n is 0; said compound having the formula where T, x, m, and R1 are as defined in claim 1. 3. The compound of claim 2 wherein m is O, 1, or 2; and when m is O, R1 is when m is 1, R1 is when m is 2, R is; Y

4. The compound of claim 3 wherein T is halogen or OR6 where R6 is alkyl of 1-6 carbon atoms or benzyl; x is 1; m is 0 or 2; when m is 0, R1 is ; and when m is 2, R1 is

5. A compound of claim 2 having the name 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (phenylthomethyl) butanoic acid; [2S, 4R] -4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (phenylthiomethyl) -butanoic acid; 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2 - [(4-hydroxyphenyl) -thiomethyl] -butanoic acid; 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- (3-phenylpropyl) butanoic acid; 4- [4- (4-chlorophenyl) phenyl] -4-hydroxy-2- [2- (3-N, N-diethylcarbamoyl) -phenylethyl] butanoic acid; 4- [4- (4-pentyloxy-phenyl) -phenyl] -4-hydroxy-2- (3-phenypropyl) -butanoic acid; 4- [4- (4-benzyloxyphenyl) phenyl] -4-hydroxy-2- (3-phenylpropyl) butanoic acid; 4- [4 (4-chlorophenyl) phenyl] -4-hydroxy-2- (2-phthalimidyl) butanoic acid;

6. The compound of claim 1 wherein n is 0 or 1; and A is CH or N; and G is CH; and A is connected to G by a ring-forming link having the formula: (CH2) 0-3 (Q) (CH2) 0.3; where Q is a chemical bond, S, or O; and C, S, and O constitute linking atoms; which results in the formation of a ring including A, said ring-forming bond is G; and said compound having the formula with the provisos that the sum of n plus the total amount of linking atoms in said ring-forming bond is an integer from 1 to 4; and the number of heteroatoms in said ring is 0 or 1; T, x, m, and R1 are as defined in claim 1.

7. The compound of claim 6 wherein n is 0; A is CH; Q is a chemical bond; and said ring-forming bond is - (CCH2) 2; and said compound has the formula

8. The compound of claim 7 wherein T is halogen or OR6 where R6 is alkyl of 1-6 carbon atoms or benzyl; x is 1; m is 0 or 1; and when m is 0, R1 is ; and when m is 1, R1 is

9. A compound of claim 6, which has the name trans-5 - [(4-4-chlorophenol) phenyl) hydroxymethyl] -trans-2-phenylthiocyclopentanecarboxylic acid; trans-5 - [(4- (4-chlorophenyl) phenyl) hydroxymethyl] -cis-2- (2-methoxycarbonyl-phenylthio) -cyclopentanecarboxylic acid; and trans-5 - [(4- (4-chlorophenyl) phenyl) hydroxymethyl] -trans-2-phthalimidomethylcyclopentanecarboxylic acid.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier.

13. A method for treating a condition mediated by a matrix metalloprotease in a mammal to achieve an effect, comprising administering to said mammal an amount of a compound of claim 1 which is effective to treat said condition. The method of claim 13 wherein said mammal is a human. 15. The method of claim 13 wherein said effect is: relief of osteoroarthritis, rheumatoid arthritis, septic arthritis, periodontal diseases, corneal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis huullosis, conditions that lead to inflammatory responses, intermediated osteopenias for activity MMP, temporomandibular joint diseases, or demyelinating disorders of the nervous system; delayed tumor metastasis or degenerative loss of cartilage after traumatic joint baths; reduction of coronary thrombosis due to the rupture of atherosclerotic plaques; or better birth control; and said amount of compound of claim 1 is effective to inhibit the activity of at least one metalloprotease matrix in said mammal, thereby obtaining said effect. 16. A method for preparing a compound having the formula comprising: reducing a hydroxyl group in the ketone carbonyl in a compound having the formula 1 where T, x, G, n, A, m and R1 are as defined in claim 1.