Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to therapeutically active pseudopeptide or peptidyl compounds, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine.
• the compounds are inhibitors of metalloproteinases involved in tissue degradation.
• MMPs matrix metalloproteinases
• the matrix metalloproteinases are a family of enzymes including interstitial collagenase, neutrophil collagenase, collagenase-3, 72kDa gelatinase, 92kDa gelatinase, stromelysin-1 , stromelysin-2, stromelysin-3, matrilysin, macrophage metalloelastase, membrane-type metalloproteinase-1 and membrane-type metalloproteinase-2. These enzymes share a common zinc-containing catalytic domain and a pro-sequence which maintains latency.
• MMPs can express MMPs in response to activation by inflammatory stimuli such as interleukin-1 or tumour necrosis factor- ⁇ (TNF- ⁇ ).
• inflammatory stimuli such as interleukin-1 or tumour necrosis factor- ⁇ (TNF- ⁇ ).
• TNF- ⁇ tumour necrosis factor- ⁇
• Different stimuli can induce overlapping yet distinct repertoires of MMPs and different cell types can respond to the same stimuli by expression of distinct combinations of MMPs.
• MMPs can attack the protein components of extracellular matrix such as collagens, vitronectin and elastin, and have recently been shown to process membrane proteins such as pro-TNF- ⁇ to release soluble TNF- ⁇ .
• MMPs are thought to play a central role in the pathology of inflammatory diseases such as rheumatoid arthritis as well as in the growth and metastasis of tumours.
• Compounds which have the property of inhibiting the action of MMPs are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth.
• MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas.
• MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage site in the collagen molecule. Chapman et al., (J. Med. Chem. 1993, 36, 4293-4301 ) report some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics.
• Such compounds usually have a functional group capable of binding to the active site zinc(ll) ion in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, mercapto, and oxygenated phosphorus (eg phosphinic acid and phosphonic acid) groups.
• the zinc binding group is a hydroxamic acid, carboxylic acid, mercapto, and oxygenated phosphorus (eg phosphinic acid and phosphonic acid) groups.
• the present invention makes available a new class of MMP inhibitors having as zinc binding groups ⁇ -mercaptoamide groups analogous to those of Gray et al., WO 95/13289 and WO 96/11209.
• the compounds of the invention are principally distinguished from the compounds disclosed in WO 95/13289 and WO 96/11209, by having on the carbon atom carrying the zinc binding mercaptoamide group a biarylalkyl group or biarylalkyl group in which the alkyl moeity is interrupted by an O or S heteroatom.
• the present invention provides compounds of general formula I
• R 2 is a group -(Alk) m -(Q) n -(Alk 1 ) p -Ar wherein m, n and p are independently 0 or 1 ,
• Alk and Alk 1 each independently represents a divalent (C CgJalkylene group
• Q represents -O-, -S-, -SO- or -SO 2 -
• Ar represents an optionally substituted phenyl or heteroaryl group
• R. is hydrogen or acyl; is a group -(CH 2 ) t -W wherein t represents 1 , 2, 3 or 4 and W represents a 5- or 6- membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO 2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by C r C 6 alkyl, or oxo and/or on any additional N atoms by C r C 6 alkyl, phenyl or heteroaryl;
• R 3 is the side chain of a natural or non-natural ⁇ -amino acid in which any functional groups may be protected; is
• R x and R y each independently represents an optionally substituted phenyl or heteroaryl ring which may be linked covalently to each other by a bond or by a C,-C 4 alkylene or C 2 -C 4 alkenylene bridge, or (ii) R represents a group D 1 -(C 1 -C 6 alkyl)- wherein D, is optionally substituted phenyl or heteroaryl, and R y represents an optionally substituted phenyl or heteroaryl ring, or
• R 3 and R 4 taken together represent a divalent chain of formula -C(R a )(R b )-A"-Alk- wherein R a and R b are independently hydrogen or C r C 6 alkyl, A" is a bond, -O-, -S-, -S-S-, -NH- or - NR a - wherein R a is alkyl, and Alk is C r C 6 alkylene; and
• R 5 is hydrogen or a (C C 6 )alkyl group
• (C r C 6 )alkyl or "lower alkyl” means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl.
• (C 2 -C 6 )alkenyl means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. This term would include, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
• cycloalkyl means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclohexyl, cyclooctyl, cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.
• cycloalkenyl means an unsaturated alicyclic moiety having from 4-8 carbon atoms and includes, for example, cyclohexenyl, cyclooctenyl, cycloheptenyl, cyclopentenyl, and cyclobutenyl. In the case of cycloalkenyl rings of from 5-8 carbon atoms, the ring may contain more than one double bond.
• heterocyclyl or “heterocyclic” as used herein means a 5-7 membered aromatic or non-aromatic heterocyclic ring containing one or more heteroatoms selected from S, N and O, and optionally fused to a carbocyclic or second heterocyclic ring.
• Specific examples of such groups include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, and benzimidazolyl.
• the term encompasses a 5- or 6- membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO 2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by C C 6 alkyl, or oxo and/or on any additional N atoms by C 1 -C 6 alkyl, phenyl or heteroaryl.
• Examples of the latter class of heterocyclic groups include maleimido, succinimido, phthalimido, 1 ,2-dimethyl-3,5-dioxo-1 ,2,4-triazolidin-4-yl, 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo-1 ,2,4-oxadiazol-4-yl, 3- methyl-2,4,5-trioxo-1 -imidazolidinyl, 2,5-dioxo-3-phenyl-1 -imidazolidinyl-2-oxo-1 - pyrrolidinyl, 2,5-dioxo-1-pyrrolidinyl, 2,6-dioxopiperidinylnaphththalimido (ie 1 ,3- dihydro-1 ,3-dioxo-2H-benz[f]isoindol-2-yl), 1 ,3-di
• heteroaryl as used herein means an aromatic 5 or 6 membered monocyclic aromatic heterocyclic group. Specific examples of the latter include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, trizolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
• An "optionally substituted phenyl or heteroaryl group” is a phenyl or heteroaryl group which is either unsubstituted or is substituted
• substituents each of which independently may be substituted by one or more substituents selected from C r C 6 alkyl, C 2 -C 6 alkenyl, halo, cyano ( -CN), -CO 2 H, -CO 2 R, -CONH 2 , -CONHR, -CON(R) 2 , - OH, -OR, oxo-, -SH, -SR, -NHCOR, and -NHCO 2 R wherein R is C r C 6 alkyl or benzyl; or
• substituted means substituted with up to four substituents, each of which independently may be (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C r C 6 )alkoxy, hydroxy, mercapto, (C r C 6 )alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, nitro, CN, -COOH, -CONH 2 , - COOR A , -NHCOR A , -NHCO 2 R A , -CONHR A , or -CONR A R B wherein R A and R B are each independently a (C r C 6 )alkyl, benzyl, or heterocyclyl(C.,-
• side chain of a natural or non-natural alpha-amino acid means the group R in a natural or non-natural amino acid of formula NH 2 -CH(R)-COOH.
• side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5- hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ⁇ -aminoadipic acid, ⁇ -amino-n-butyric acid, 3,4-dihydroxyphenylaianine, homoserine, ⁇ - methylserine, ornithine, pipecolic acid, and thyroxine.
• Natural alpha-amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups in their characteristic side chains include arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine, and cysteine.
• R 3 in the compounds of the invention is one of those side chains, the functional substituent may optionally be protected.
• side chains of non-natural alpha amino acids include those referred to below in the discussion of suitable R 3 groups for use in compounds of the present invention.
• the term "protected" when used in relation to an amino, hydroxy, mercapto, or carboxy group means a derivative of such a group which is substantially nonfunctional.
• Such groups are widely known, for example from the art of peptide synthesis, and are discussed in the widely used handbook by T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991.
• amides for example as a NHCOC r C 6 alkyl amide
• carbamates for
• Salts of the compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. Salts may also be formed with bases, for example sodium, potassium, magnesium, and calcium salts.
• R 2 is a group -(Alk) m -(Q) n -(Alk 1 ) p -Ar wherein m, n and p are independently 0 or 1 , Alk and Alk 1 each independently represents a divalent (C C 3 )alkylene group, Q represents -O-, -S-, -SO- or -SO 2 -, and Ar represents an optionally substituted phenyl or heteroaryl group.
• Ar represents an optionally substituted phenyl or heteroaryl group.
• Hetroaryl groups may be bonded to the rest of the molecule (I) via a ring carbon atom in Ar or via a ring nitrogen atom in Ar.
• Suitable heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, trizolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
• the group Ar is substituted in accordance with the definition of Ar in formula (I), preferably only one substituent in present.
• the substituent is preferably in the 4-position of the ring relative to the bond connecting Ar to the rest of molecule (I).
• the substituent is preferably in the 3- or 4-position of the ring relative to the bond connecting Ar to the rest of molecule (I).
• a sole substituent in Ar may be any of those defined above for "optionally substituted phenyl or heteroaryl".
• substituents include C ⁇ C ⁇ alkyl eg methyl, ethyl, n- propyl, n-butyl, n-pentyl and n-hexyl; trifluoromethyl; halo eg chloro; cyano ( -CN); - OH;and -OR, wherein R is C C 6 alkyl or benzyl.
• Another preferred such substituent is a phenyl or heteroaryl group which may be unsubstituted or substituted with, preferably, one substituent selected from those defined above for "optionally substituted phenyl or heteroaryl".
• a single substituent in a phenyl or heteroaryl-substituted Ar group is the 4-position of phenyl or 6 membered heteroaryl groups or the 3- or 4-position of 5 membered heteroaryl groups, relative to the bond connecting the phenyl or heteroaryl goup to Ar.
• Preferred such substituents include C ⁇ Ce alkyl eg methyl, ethyl, n- and iso-propyl, n- sec- and tert-butyl; trifluoromethyl; halo eg chloro; cyano ( -CN); -OH;and methoxy.
• Ar may be a phenyl group which is substituted in the 4-position by a phenyl or heteroaryl group which in turn is optionally substituted by C C 6 alkyl; trifluoromethyl; halo; cyano ( -CN); -OH;or -OR, wherein R is C r C 6 alkyl or benzyl, for example a biphenyl group optionally substituted in the 4' position by chloro or methoxy.
• n, n and p are each 1
• Alk and Alk 1 each independently represent -CH 2 - or -CH 2 CH 2 -
• m and n are both 0.
• the compounds of the present invention are principally distinguished from the compounds disclosed in the prior patent publications listed above by the identity of the group R 2 , discussed above. Accordingly the groups R 21 , Z, R.,, R 3 , R 4 , and R 5 may include those which have been disclosed in the corresponding positions of compounds disclosed in prior art patent publications mentioned above, or of other structurally related MMP inhibitors. Without limiting the generality of the foregoing, examples of substituents R 21 , Z, R ⁇ R 3 , R 4 ,and R 5 are given below.
• R 21 groups -(CH 2 ) t -W include those wherein t is 1 , 2, 3 or 4 and W is phthalimido, 1 ,2-dimethyl-3,5-dioxo-1 ,2,4-triazolidin-4-yl, 3,4,4-trimethyl- 2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo-1 ,2,4-oxadiazol-4-yl, 3-methyl-2,4,5- trioxo-1 -imidazolidinyl, 2,5-dioxo-3-phenyl-1 -imidazolidinyl-2-oxo-1 -pyrrolidinyl, 2,5- dioxo-1-pyrrolidinyl or 2,6-dioxopiperidinylnaphththalimido (ie 1 ,3-dihydro-1 ,3-dioxo- 2H-benz[f]isoindol-2
• R 21 is phthalimidopropyl, phthalimidobutyl, phthalimidoethyl, phthalimidomethyl, 3,4,4- trimethyl-2,5-dioxo-1 -imidazolidinylpropyl, 3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyethyl, and 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyimethyl.
• R 1 groups suitable for inclusion in the compounds of the invention include hydrogen, and groups R 20 C(O)- where R 20 is a (C r C 6 )alkyl group such as methyl or ethyl.
• Z in compounds of the invention is a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom
• suitable Z groups include substituted or unsubstituted 1-pyrrolidinyl, piperidino, 1 -piperazinyl, hexahydro-1-pyhdazinyl, morpholino, tetra hydro- 1 ,4- thiazin-4-yl, tetrahydro-1 ,4-thiazin-4-yl 1 -oxide, tetra hydro-1 , 4-th iazin-4-yl 1 ,1- dioxide, thiazolidin-3-yl, hexahydroazipino, or octahydroazocino.
• Such groups include piperidin-1-yl, 2-(methylcarbamoyl)-1-pyrrolidinyl, 2- (hydroxymethyl)-l-pyrrolidinyl, 4-hydroxypiperidino, 2-(methylcarbamoyl)piperidino, 4-hydroxyiminopiperidino, 4-methoxypiperidino, 4-methyl-1 -piperazinyl, 4-phenyl-1- piperazinyl, 1 ,4-dioxa-8-azaspiro[4,5]decan-8-yl, hexahydro-3-(methylcarbamoyl)-2- pyridazinyl, hexahydro-1-(benzyloxycarbonyl)-2-pyridazinyl, 5,5-dimethyl-4- methylcarbamoyl-thiazolidin-3-yl, or 5,5-dimethyl-4-propylcarbamoyl-thiazolidin-3-yl.
• Alk is a (C r C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more -O-, or -S- atoms or -N(R 23 )- groups [where R 23 is a hydrogen atom or a (C r C 6 )alkyl group], n is 0 or 1 , and R 22 is an optionally substituted cycloalkyl or cycloalkenyl group; and a benzyl group substituted in the phenyl ring by a group of formula -OCH 2 COR 24 where R 24 is hydroxyl, amino, (C r C 6 )alkoxy, phenyl(C r C 6 )alkoxy, (C r C 6 )alkylamino, di((C r C 6 )alkyi)amino, phenyl(C 1 -C 6 )alkyla
• heterocyclic((C C 6 )alkyl group either being unsubstituted or mono- or di- substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 )alkoxy, cyano, (C r C 6 )alkanoyl, trifluoromethyl (C 1 -C 6 )alkyl, hydroxy, formyl, amino, (C 1 -C 6 )alkylamino, di-(C r C 6 )alkylamino, mercapto, (C 1 -C 6 )alkylthio, hydroxy(C r C 6 )alkyl, mercapto(C r C 6 )alkyl or (C r C 6 )alkylphenylmethyl;
• each of R a , R b and R c is independently hydrogen, (C
• R c is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C r C 6 )alkyl, or (C 3 -C 8 )cycloalkyl, and R a and R b together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or
• R a , R b and R c together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or
• R a and R b are each independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, phenyl(C.,-C 6 )alkyl, or a group as defined for R c below other than hydrogen, or R a and R b together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 3- to 8- membered heterocyclic ring, and R c is hydrogen, -OH, -SH, halogen, - CN, -CO 2 H, (C r C 4 )perfluoroalkyl, -CH 2 OH, -CO 2 (C r C 6 )alkyl, -O(C r C 6 )alkyl, -O(C 2 -C 6 )alkenyl, -S(C r C 6 )alkyl, -SO(
• R 3 groups suitable for inclusion in the compounds of the invention include benzyl, 4-chlorophenylmethyl, 2-thienylmethyl, iso-butyl or t-butyl, 1-benzylthio-1-methylethyl, and 1-mercapto-1-methylethyl.
• R 3 is benzyl, t-butyl or 1-mercapto-1-methylethyl.
• R 2 groups include biphenyl-4-ylmethylthiomethyl, biphenyl-4-ylmethyloxomethyl, 4-chlorophenylmethylthiomethyl, 4- chlorophenylmethyloxomethyl, 4'-chlorobiphenyl-4-ylmethylthiomethyl, 4'- chlorobiphenyl-4-ylmethyloxomethyl, 4-methoxyphenylmethylthiomethyl, 4- methoxyphenylmethyloxomethyl, 4-methoxybiphenyl-4-ylmethylthiomethyl, 4-methoxybiphenyl-4-ylmethyloxomethyl, 3-(biphenyl-4-yl)propyl, and 3-(4'- chlorobiphenyl-4-yl)propyl; and
• R 4 groups examples include
• R x and R y independently represent phenyl or 4- chlorophenyl or R x and R y are linked covalently in a 9-H-fluoren-9-yl ring;
• a polyether chain possessing at least two non-adjacent oxygen atoms for example 2-(2-methoxyethoxy)ethyl; or
• R 5 groups include hydrogen, methyl and ethyl. Presently preferred are compounds in which R 5 is hydrogen.
• Examples of compounds of the invention include those specified in the Examples herein, and salts, hydrates and solvates thereof.
• R 10 is a thiol protecting group and Z, R 2 and R 21 are as defined in formula (I) except that any functional groups in Z, R 2 and R 21 may be protected, and after or together with deprotection of the protected thiol group, any protected functional groups in Z, R 2 and R 21 are also deprotected.
• Suitable thiol protecting groups for use in the above process include benzyl and tert-butyl, but others which are suitable are known from the art of peptide synthesis, see for example "Protective Groups in Organic Synthesis", by Greene and Wuts, and "The Practice of Peptide Synthesis" by Bodanszki et al.
• Protecting groups for other functional groups which may be present in R 2 , R 3 , R 4 , R 5 , and R 21 are also known from those publications and from the art of peptide synthesis generally.
• Amino groups are often protectable by benzyloxycarbonyl, t-butoxycarbonyl or acetyl groups, or in the form of a phthalimido group.
• Hydroxy groups are often protectable as readily cleavable ethers such as the t-butyl or benzyl ether, or as readily cleavable esters such as the acetate.
• Carboxy groups are often protectable as readily cleavable esters, such as the t-butyl or benzyl ester.
• This coupling reaction may be carried out by conversion of (V) to an activated derivative such as the pentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl ester by reaction with the appropriate alcohol in the presence of a dehydrating agent such as dicyclohexyl dicarbodiimide (DCC), N,N-dimethylaminopropyl-N'-ethyl carbodiimide (EDC), or 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ), followed by reaction of the actvated ester with (VI).
• DCC dicyclohexyl dicarbodiimide
• EDC N,N-dimethylaminopropyl-N'-ethyl carbodiimide
• EEDQ 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline
• R 10 in compound (V) is a group of formula R 20 CO as defined in relation to group R ⁇ of formula (I)
• the product to the above coupling reaction is of course a compound of the invention of formula (I) in which R 1 is other than hydrogen.
• Amine intermediates of formula (VI) are either known compounds or may be prepared from known amino acid starting materials using standard methods and by analogy with the specific preparative examples herein.
• Substituted 2-mercapto carboxylic acids (V) are known or are accessible by methods analagous to those used for such intermediates in the specific examples herein.
• compounds of formula (I) are useful in human or veterinary medicine since they are active as inhibitors of MMPs.
• this invention concerns:
• a method of management by which is meant treatment or prophylaxis of diseases or conditions mediated by MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound as defined with respect to formula (I) above, or a pharmaceutically acceptable salt thereof;
• Diseases or conditions mediated by MMPs include those involving tissue breakdown such as bone resorption, inflammatory diseases, dermatological conditions, tumour growth and vascularisation, and tumour invasion by secondary metastases, in particular rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration and tumour invasion by secondary metastases.
• a pharmaceutical or veterinary composition comprising a compound of formula (I) together with a pharmaceutically or veterinarily acceptable excipient or carrier.
• a further aspect of the invention comprises a pharmaceutical or veterinary composition comprising a compound of formula (I) together with a pharmaceutically or veterinarily acceptable excipient or carrier, characterised in that the composition is adapted for oral administration.
• One or more compounds of general formula (I) may be present in the composition together with one or more excipient or carrier.
• the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
• the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or acacia
• non-aqueous vehicles which may include edible oils
• almond oil fractionated coconut oil
• oily esters such as glycerine, propylene
• the dosage unit involved in oral administration may contain from about 1 to 250mg, preferably from about 25 to 250mg of a compound of the invention.
• a suitable daily dose for a mammal may vary widely depending on the condition of the patient. However, a dose of a compound of general formula I of about 0.1 to 300mg/kg body weight, particularly from about 1 to 100mg/kg body weight may be appropriate.
• the drug may be made up into a cream, lotion or ointment.
• Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
• the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
• Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
• the dosage for topical administration will of course depend on the size of the area being treated. For the eyes, each dose may typically be in the range from 10 to 100mg of the drug.
• the active ingredient may also be administered parenterally in a sterile medium.
• the drug can either be suspended or dissolved in the vehicle.
• adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the drug can be administered by the oral route or by injection intra-articularly into the affected joint.
• the daily dosage for a 70kg mammal may be in the range 10mgs to 1gram.
• amino acids used in the examples were commercially available or were prepared according to literature procedures.
• Boc-S-Biphenylmethylcysteine 600 mg, 1.63 mmol
• t-butylglycine methyl amide 220 mg, 1.53 mmol
• ⁇ /-hydroxybenzotriazole 240 mg
• dichloromethane 25 ml
• WSCDI 302 mg was added in one portion and the resulting solution stirred at room temperature for 3 days.
• the solution was diluted with dichloromethane (100 ml) and washed successively with 1M potassium hydrogen sulphate solution, 5% aqueous sodium hydrogen carbonate and brine. After drying, the solvent was removed to leave a white solid (590 mg) essentially pure by tic and nmr.
• This dipeptide was suspended in a solution of 4M hydrogen chloride in dry dioxan (50 ml) at 0°C for 1 hour when tic indicated the removal of the Boc group. The solution was evaporated to dryness and then resuspended in dichloromethane (80 ml). 2S-Mercaptoacety-5-phthalamidopentanoic acid (387 mg) and HOBt (184 mg) were added to the solution which was cooled to 0°C and WSCDI (231 mg) added. The resulting mixture was stirred for 1 h at 0°C and then 18h at room temperature before being worked up as above to give the desired product as a gummy foam. Flash chromatograpghy on silica (0-3% methanol in dichloromethane) gave the pure thioacetate as a crisp white solid.
• Example 1 The Boc dipeptide of Example 1 (650 mg) was dissolved in dichloromethane (30 ml) and cooled to 0°C. m-Chloroperoxybenzoic acid (538 mg, 2.4 equiv) was added portionwise and the solution was stirred for 2h when tic indicated all the stating material had been converted to a slightly more polar product. Aqueous sodium sulphite solution was added and the mixture was stirred for 30 minutes before it was diluted with dichloromethane, washed with sodium hydrogen carbonate solution and dried (MgSO 4 ). Evaporation gave the desired sulphone as a white foam (661 mg), essentially pure by nmr.
• Example 7 Using the method of Example 4 the thiol was obtained as a white solid from the thioacetate of Example 7.
• Example 9 Thioacetic 1 S-[1 -(biphenyl-4-ylmethylthiomethyl)-2-oxo-2R-piperidin-1 -yl- ethylcarbamoyl]-4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-butyl ester.
• Example 9 From Example 9 as a white foam.

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