WO1998023588A1

WO1998023588A1 - Metalloproteinase inhibitors

Info

Publication number: WO1998023588A1
Application number: PCT/GB1997/003258
Authority: WO
Inventors: Christopher David Floyd
Original assignee: British Biotech Pharmaceuticals Limited
Priority date: 1996-11-28
Filing date: 1997-11-27
Publication date: 1998-06-04
Also published as: JP2001509790A; AU5128298A; EP0944597A1; GB9624817D0

Abstract

Compounds of formula (I) wherein R2 is a group -(Alk)m-(Q)n-(Alk1)p-Ar wherein m, n and p are independently 0 or 1, Alk and Alk1 each independently represents a divalent (C¿1?-C3)alkylene group, Q represents -O-, -S-, -SO-, or -SO2-, and Ar represents an optionally substituted phenyl or heteroaryl group; R1 is hydrogen or acyl; R21 is a group -(CH2)t-W wherein t represents 1, 2, 3 or 4 and W represents a 5- or 6-membered N-heterocyclic ring as defined in the specification; Z is either (a) a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring as defined in the specification, or (b) a radical of formula (IB) wherein R3 is the side chain of a natural or non-natural α-amino acid in which any functional groups may be protected; R4 is one of a variety of groups defined in the specification; and R5 is hydrogen or a (C1-C6)alkyl group. The compounds are matrix metalloproteinase inhibitors.

Description

Metalloproteinase Inhibitors

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. In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation.

Background to the Invention

The matrix metalloproteinases (MMPs) 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. A wide range of cells and tissues can express MMPs in response to activation by inflammatory stimuli such as interleukin-1 or tumour necrosis factor-α (TNF-α). 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-α to release soluble TNF-α. 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.

Many known 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.

Gray et al., (Biochemical and Biophysical Research Communication, Vol. 101 , No. 4, 1981 ) discloses collagense inhibitors which are α-mercaptoamides of tetrapeptides, in which the mercapto group functions as the zinc binding group. The patent publications WO 95/13289 and WO 96/11209 disclose a class of MMP inhibitors in which the zinc binding group is again an α-mercaptoamide group.

Other known classes of collagenase inhibitors include those disclosed in EP-A- 0574758 (Roche), EP-A-0684240 (Roche), and WO 95/33731 (Roche). In general, the compounds disclosed in those publications may be represented by the structural formula (IA)

in which X, Y and the N-containing ring are variable in accordance with the specific disclosures of the publications.

Brief Description of the Invention

The present invention makes available a new class of MMP inhibitors having as zinc binding groups α-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. These structural features can confer benefits in terms of increased intrinsic activity or bioactivity as inhibitors of specific enzymes.

Detailed Description of the Invention

The present invention provides compounds of general formula I

wherein

R₂ is a group -(Alk)_m-(Q)_n-(Alk¹)_p-Ar wherein m, n and p are independently 0 or 1 ,

Alk and Alk¹ each independently represents a divalent (C CgJalkylene group,

Q represents -O-, -S-, -SO- or -SO₂-, and

Ar represents an optionally substituted phenyl or heteroaryl group;

R., is hydrogen or acyl; is a group -(CH₂)_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 SO₂ 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_rC₆alkyl, or oxo and/or on any additional N atoms by C_r C₆alkyl, phenyl or heteroaryl;

is either

(a) a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, (i) optionally contains as a ring member O, S, SO, SO₂, or NR₅ wherein R₅ is hydrogen, hydroxy, C_rC₆ alkyl, (C_rC₆ alkoxy)C_rC₆ alkyl, benzyl, acyl, an amino protecting group, or a group -SO₂R₆ wherein R₆ is

alkyl or a substituted or unsubstituted phenyl or heteroaryl group, and/or (ii) is optionally substituted on one or more C atoms by hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy, cyano, oxo, ketalised oxo, amino, mono(C_rC₆ alkyl)amino, di(C_rC₆ alkyl)amino, carboxy, C_rC₆ alkoxycarbonyl, hydroxymethyl, C_rC₆ alkoxymethyl, carbamoyl, mono(C_rC₆ alkyl)carbamoyl, di(C_rC₆ alkyl)carbamoyl, or hydroxyimino; or

(b) a radical of formula (IB)

wherein

R₃ is the side chain of a natural or non-natural α-amino acid in which any functional groups may be protected; is

(a) an optionally substituted phenyl, heteroaryl, cycloalkyl or cycloalkenyl ring, or

(b) a group -CHR R^y wherein (i) 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,-C₄ alkylene or C₂-C₄ alkenylene bridge, or (ii) R represents a group D¹-(C₁-C₆ alkyl)- wherein D, is optionally substituted phenyl or heteroaryl, and R^y represents an optionally substituted phenyl or heteroaryl ring, or

(c) a group of formula -(Z'-O)_w-Z' wherein Z' is straight or branched C_rC₆ alkyl optionally interrupted by one or more non- adjacent S and/or N atoms, w is an integer >1 , and no continuous linear sequence of atoms in the group R₄ is >12, or

(d) a straight or branched C_rC₆ alkyl group, optionally interrupted by one or more non-adjacent S and/or N atoms, which is substituted by at least two substituents of formula - (Z'")_x-(OZ^,,,)_q wherein Z" is straight or branched C_rC₆ alkyl optionally interrupted by one or more non-adjacent S and/or N atoms, x is 0 or 1 , q is 1 or 2, and no continuous linear sequence of atoms in the group R₄ is >12, or

(e) hydrogen, C_rC₆ alkyl, C_rC₄ perfluoroalkyl, or a group D-(C_r C₆ alkyl)- wherein D is hydroxy, C_rC₆ alkoxy, C C₆ alkylthio, acylamino. optionally substituted phenyl or heteroaryl, NH₂, or mono- or di-(C_rC₆ alkyl)amino;

or R₃ and R₄ 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_rC₆ alkyl, A" is a bond, -O-, -S-, -S-S-, -NH- or - NR^a- wherein R^a is

alkyl, and Alk is C_rC₆ alkylene; and

R₅ is hydrogen or a (C C₆)alkyl group;

or a salt, hydrate or solvate thereof.

As used herein the term "(C_rC₆)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.

The term "(C₂-C₆)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.

The term "cycloalkyl" means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclohexyl, cyclooctyl, cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term "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.

The unqualified term "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 SO₂ 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 C₆alkyl, or oxo and/or on any additional N atoms by C₁-C₆alkyl, 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-dihydro-1-oxo-2H-benz[f]isoindol-2-yl, 1 ,3-dihydro-1 ,3-dioxo-2H-pyrrolo[3,4-b]quinolin-2-yl, or 2,3-dihydro-1 ,3-dioxo-1 H- benz[d,e]isoquinolin-2-yl group.

The term "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

(i) with 1 , 2, 3 or 4 substituents, each of which independently may be substituted by one or more substituents selected from C_rC₆ alkyl, C₂-C₆ alkenyl, halo, cyano ( -CN), -CO₂H, -CO₂R, -CONH₂, -CONHR, -CON(R)₂, - OH, -OR, oxo-, -SH, -SR, -NHCOR, and -NHCO₂R wherein R is C_rC₆ alkyl or benzyl; or

(ii) with 0, 1 , or 2 substituents, each of which independently is selected from those listed under (i) above, and with a phenyl or heteroaryl group which may be unsubstituted or substituted with 1 , 2, 3 or 4 substituents, each of which independently is selected from those listed under (i) above.

In all contexts except in "optionally substituted phenyl or heteroaryl", the term "substituted" as applied to any moiety herein means substituted with up to four substituents, each of which independently may be (C_rC₆)alkyl, (C₂-C₆)alkenyl, (C₂- C₆)alkynyl, (C_rC₆)alkoxy, hydroxy, mercapto, (C_rC₆)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, nitro, CN, -COOH, -CONH₂, - COOR^A, -NHCOR^A, -NHCO₂R^A, -CONHR^A, or -CONR^AR^B wherein R^A and R^B are each independently a (C_rC₆)alkyl, benzyl, or heterocyclyl(C.,-C₆)alkyl- group.

The term "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 NH₂-CH(R)-COOH.

Examples of 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, α-aminoadipic acid, α-amino-n-butyric acid, 3,4-dihydroxyphenylaianine, homoserine, α- 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. When R₃ in the compounds of the invention is one of those side chains, the functional substituent may optionally be protected.

Examples of side chains of non-natural alpha amino acids include those referred to below in the discussion of suitable R₃ 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. For example, carboxyl groups may be esterified (for example as a C C₆ alkyl ester), amino groups may be converted to amides (for example as a NHCOC_rC₆ alkyl amide) or carbamates (for example as an NHC(=O)OC₁-C₆ alkyl or NHC(=O)OCH₂Ph carbamate), hydroxyl groups may be converted to ethers (for example an OC_rC₆ alkyl or a O(C C₆ alkyl)phenyl ether) or esters (for example a OC(=O)C₁-C₆ alkyl ester) and thiol groups may be converted to thioethers (for example a tert-butyl or benzyl thioether) or thioesters (for example a SC(=O)C_rC₆ alkyl thioester).

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.

There are several chiral centres in the compounds according to the invention because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereomers with R or S stereochemistry at each chiral centre. General formula (I), and (unless specified otherwise) all other formulae in this specification are to be understood to include all such stereoisomers and mixtures (for example racemic mixtures) thereof. Compounds of formula (I) in which the following stereochemistry predominates are presently preferred: carbon atom carrying the R₂₁ group - S. carbon atom carrying the R₂ group - R. In the compounds of the invention R₂ is a group -(Alk)_m-(Q)_n-(Alk¹)_p-Ar wherein m, n and p are independently 0 or 1 , Alk and Alk¹ each independently represents a divalent (C C₃)alkylene group, Q represents -O-, -S-, -SO- or -SO₂-, 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.

When the group Ar is substituted in accordance with the definition of Ar in formula (I), preferably only one substituent in present. In 6 membered Ar groups, such as phenyl and pyridyl, the substituent is preferably in the 4-position of the ring relative to the bond connecting Ar to the rest of molecule (I). In 5 membered Ar groups, such as thienyl and furanyl, 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". Preferred such substituents include C^C_β 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 C₆ 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". Again the preferred location of 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.

Thus 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 C₆ alkyl; trifluoromethyl; halo; cyano ( -CN); -OH;or -OR, wherein R is C_rC₆ alkyl or benzyl, for example a biphenyl group optionally substituted in the 4' position by chloro or methoxy.

In one class of compounds of the invention, m, n and p are each 1 , and Alk and Alk¹ each independently represent -CH₂- or -CH₂CH₂-, while in another class, m and n are both 0.

As previously stated, 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 R₂, discussed above. Accordingly the groups R₂₁, Z, R.,, R₃, R₄, and R₅ 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 R₂₁, Z, R^ R₃, R₄,and R₅ are given below.

Examples of particular R₂₁ groups -(CH₂)_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-yl), 1 ,3-dihydro-1-oxo-2H-benz[f]isoindol-2-yl, 1 ,3-dihydro-1 ,3- dioxo-2H-pyrrolo[3,4-b]quinolin-2-yl, or 2,3-dihydro-1 ,3-dioxo-1 H- benz[d,e]isoquinolin-2-yl. Presently preferred are compounds in which R₂₁ 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.

Examples of particular R₁ groups suitable for inclusion in the compounds of the invention include hydrogen, and groups R₂₀C(O)- where R₂₀ is a (C_rC₆)alkyl group such as methyl or ethyl.

When the group 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, examples of 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. Specific examples of 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. Presently preferred is piperidin-1-yl.

When the group Z in compounds of the invention is a radical of formula (IB), the following classes of substituent R₃, are suitable:

(C_rC₆)alkyl, benzyl, hydroxybenzyl, benzyloxybenzyl, (C C₆)alkoxybenzyl, or benzyloxy(C₁-C₆)alkyl group; and

the characterising group of a natural α-amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; and

a group -[Alk]_nR₂₂ where Alk is a (C_rC₆)alkyl or (C₂-C₆)alkenyl group optionally interrupted by one or more -O-, or -S- atoms or -N(R₂₃)- groups [where R₂₃ is a hydrogen atom or a (C_rC₆)alkyl group], n is 0 or 1 , and R₂₂ is an optionally substituted cycloalkyl or cycloalkenyl group; and a benzyl group substituted in the phenyl ring by a group of formula -OCH₂COR₂₄ where R₂₄ is hydroxyl, amino, (C_rC₆)alkoxy, phenyl(C_r C₆)alkoxy, (C_rC₆)alkylamino, di((C_rC₆)alkyi)amino, phenyl(C₁-C₆)alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid; and

a heterocyclic((C C₆)alkyl group, either being unsubstituted or mono- or di- substituted in the heterocyclic ring with halo, nitro, carboxy, (C₁-C₆)alkoxy, cyano, (C_rC₆)alkanoyl, trifluoromethyl (C₁-C₆)alkyl, hydroxy, formyl, amino, (C₁-C₆)alkylamino, di-(C_rC₆)alkylamino, mercapto, (C₁-C₆)alkylthio, hydroxy(C_rC₆)alkyl, mercapto(C_rC₆)alkyl or (C_rC₆)alkylphenylmethyl;

a group -CR_aR_bR_c in which:

each of R_a, R_b and R_c is independently hydrogen, (C|-C₆)alkyl, (C₂- C₆)alkenyl, (C₂-C₆)alkynyl, phenyl(C_rC₆)alkyl, (C₃-C₈)cycloalkyl, the foregoing being subject to the proviso that R_a, R_b and R_c are not all hydrogen; or

R_c is hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl(C_r C₆)alkyl, or (C₃-C₈)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 (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂- C₆)alkynyl, phenyl(C.,-C₆)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, -CO₂H, (C_rC₄)perfluoroalkyl, -CH₂OH, -CO₂(C_rC₆)alkyl, -O(C_r C₆)alkyl, -O(C₂-C₆)alkenyl, -S(C_rC₆)alkyl, -SO(C C₆)alkyl, -SO₂(C_rC₆) alkyl, -S(C₂-C₆)alkenyl, -SO(C₂-C₆)alkenyl, -SO₂(C₂-C₆)alkenyl or a group -Q-W wherein Q represents a bond or -O-, -S-, -SO- or -SO₂- and W represents a phenyl, phenylalkyl, (C₃-C₈)cycloalkyl, (C₃- C₈)cycloalkylalkyl, (C₄-C₈)cycloalkenyl, (C₄-C₈)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, -CN, -CO₂H, -CO₂(C_rC₆)alkyl, -CONH₂, -CONH(C_r C₆)alkyl, -CONH(C_rC₆alkyl)₂, -CHO, -CH₂OH, (C_rC₄)perfluoroalkyl, - O(C_rC₆)alkyl, -S(C_rC₆)alkyl, -SO(C_rC₆)alkyl, -SO₂(C_rC₆)alkyl, -NO₂, - NH₂, -NH(C_rC₆)alkyl, -N((C_rC₆)alkyl)₂, -NHCO(C_rC₆)alkyl, (C_r C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, (C₄- C₈)cycloalkenyl, phenyl or benzyl.

Examples of particular R₃ 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. Presently preferred are compounds in which R₃ is benzyl, t-butyl or 1-mercapto-1-methylethyl.

Also when the group Z in compounds of the invention is a radical of formula (IB):

examples of suitable R₂ 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

examples of suitable R₄ groups include

3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, thiazol-2-yl, 4-ethoxycarbonyl- methylthiazol-2-yl, 5-methyl-1 ,3,4-thiadiazol-2-yl, 4-terf-butylthiazol-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

a group -CHR^xR^y wherein 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

hydrogen or methyl; and

examples of suitable R₅ groups include hydrogen, methyl and ethyl. Presently preferred are compounds in which R₅ is hydrogen.

Examples of compounds of the invention include those specified in the Examples herein, and salts, hydrates and solvates thereof.

Compounds according to the present invention may be prepared by a process comprising deprotecting the protected thiol group in a compound of formula (IV)

wherein R₁₀ is a thiol protecting group and Z, R₂ and R₂₁ are as defined in formula (I) except that any functional groups in Z, R₂ and R₂₁ may be protected, and after or together with deprotection of the protected thiol group, any protected functional groups in Z, R₂ and R₂₁ 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 R₂, R₃, R₄, R₅, and R₂₁ 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.

Compounds of formula (IV) may be prepared by coupling a carboxylic acid of formula (V) with an amine of formula (VI)

(V) (VI)

wherein R₁₀, R₂, Z and R₂₁ are as described above in relation to formula (IV). 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). In the case where R₁₀ in compound (V) is a group of formula R₂₀CO 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 R₁ 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.

Further details of preparative methods suitable for the synthesis of compounds according to the invention are given in the preparative examples below.

As mentioned above, compounds of formula (I) are useful in human or veterinary medicine since they are active as inhibitors of MMPs.

Accordingly in another aspect, this invention concerns:

(i) 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; and

(ii) a compound as defined with respect to formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs; and

(iii) the use of a compound as defined with respect to formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs.

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.

In a further aspect of the invention there is provided a pharmaceutical or veterinary composition comprising a compound of formula (I) together with a pharmaceutically or veterinarily acceptable excipient or carrier. In view of the oral bioavailability advantages of compounds in accordance with the invention, 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.

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.

For topical application to the skin, 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.

For topical application to the eye, 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. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

For use in the treatment of rheumatoid arthritis, 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.

The following Examples illustrate embodiments of the invention:

The amino acids used in the examples were commercially available or were prepared according to literature procedures.

The following abbreviations have been used throughout:

Boc terf-Butyloxycarbonyl

HOBt 1-Hydroxybezotriaxole

WSCDI 1-(3-Diethylaminopropyl)-3-ethyl carbodiimide hydrochloride

¹H and ¹³C NMR spectra were recorded using a Bruker AC 250E spectrometer at 250.1 and 62.9 MHz, respectively. Example 1

Thioacetic acid 1 S-{2-(biphenyl-4-ylmethylthio)-1 R-[2,2-dimethyl-1 S- (methylcarbamoyl)-propylcarbamoyl]-ethylcarbamoyl}-4-(1 ,3-dioxo-1 ,3-dihydro- isoindol-2-yl}-butyl ester

Cysteine (1.5 g, 12.5 mmol) was added at 0°C under argon to a stirred solution of sodium ethoxide (from 0.58 g, 25 mmol of sodium) in ethanol (80 ml). After 15 minutes a solution of 4-phenylbenzyl bromide (3.08 g, 12.5 mmol) in ethanol (15 ml) was added dropwise and the mixture stirred for 30 minutes at 0°C and 3h at room temperature. The solution was then diluted with water, made pH 6 with 2M hydrochloric acid and filtered to give the benzylated cysteine as a creamy white solid (3.3 g). Following drying in vacuo this was then converted into the t-butoxycarbonyl derivative using the method of Bolin (IJPPR, 1989, 33, 353) to give the desired intermediate as white flakes.

Boc-S-Biphenylmethylcysteine (600 mg, 1.63 mmol), t-butylglycine methyl amide (220 mg, 1.53 mmol) and Λ/-hydroxybenzotriazole (240 mg) were stirred together in 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. ¹H nmr (CDCI₃); δ 1.00 (9H, s, tBu), 1.45 (9H, s, OtBu), 2.78 (3H, d, J = 4.8 Hz, NMe), 2.84 (1 H, dd, J = 6.4, 14.8 Hz, CH^S), 2.91 (1 H, dd, J = 6.2, 14.8 Hz, CH_aH_bS), 3.77 (2H, s, SCH₂Ar), 4.16 (1 H, d, J = 9.0 Hz, CHtBu), 4.25 (1 H, m, CHCH₂S), 5.31 (1 H, m, NH), 6.03 (1 H, brd, NH), 6.97 (1 H, d, J = 8.9 Hz, NHCHtBu) and 7.26-7.59 (9H, m, aromatic).

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.

¹H nmr (CDCI₃); δ 0.96 (9H, s, tBu), 1.74-2.05 (4H, m, -CH₂CH₂.), 2.33 (3H, s, MeCOS), 2.77 (3H, d, J = 4.8 Hz, NMe), 2.82 (1 H, dd, J = 6.8, CH_aH_bS), 2.87 (1 H, dd, J = 6.4 and 14.1 Hz, CH^S), 3.71 (2H, m, CH₂N), 3.77 (2H, s, SCH₂Ar), 4.16 (1 H, brd, CHtBu), 4.19 (1 H, brs, CHSCO), 4.52 (1 H, m, CHCH₂S), 6.02 (1 H, brm), 7.00 (1 H, m, NH), 7.32-7.48 (5H, m, Ar), 7.53-7.61 (4H, m, Ar), 7.68-7.74 (2H, m, phth) and 7.71-7.87 (2H, m, phth).

¹³C nmr (CDCI₃); δ 25.9, 26.0, 26.6, 27.5, 30.2, 33.2, 34.4, 36.1 , 37.0, 45.8, 52.8, 61.1 , 123.1 , 126.9, 127.2, 128.6, 129.3, 131.9, 133.8, 136.8, 139.7, 140.5, 168.2, 169.6, 170.2 and 170.8. Example2

Thioacetic acid 1 S-{2-(biphenyl-4-ylmethylthio)-1 R-[2-methyl-2-benzylthio-1 R- (methylcarbamoyl)-propylcarbamoyl]-ethylcarbamoyl}-4-(1 ,3-dioxo-1 ,3-dihydro- isoindol-2-yl}-butyl ester

In the same manner as described for Example 1 , S-benzyl-L-penicillamine N-methyl amide (300 mg) was stirred with Boc-S-biphenylmethylcysteine (460 mg), N- hydroxybenzotriazole (181 mg) and WSCDI (239 mg) in dichloromethane (50 ml) overnight. Workup gave the Boc-dipeptide as a white foam (721 mg); ESMS (M+H⁺ = 622).

550 mg of this compound was taken on as above to give the thioacetate as a white foam (740 mg).

¹H nmr (CDCI₃); δ 1.30 (3H, s, Me), 1.43 (3H, s, Me), 1.63-1.80 (3H, m), 1.96 (1 H, m), 2.30 (3H, s, MeCOS), 2.72 (3H, d, J = 4.8 Hz, NHMe), 2.85 (1 H, dd, J = 1.8, 9.3, Hz, CJiH_bS), 2.88 (1 H, dd, J = 1.5, 9.2 Hz, CH_aH_bS), 3.64 (2H, t, J = 6.3 Hz, CH₂N), 3.73 (2H, s. SCH₂Ar), 3.77 (2H, s, CH₂Ar), 4.14 (1 H, d, J = 6.2 Hz, CHS), 4.42-4.50 (3H, m, NH & alpha H), 6.46 (1 H, brs, NH), 7.11 (1 H , m , NHMe), 7.13-7.52 (9H, m, aromatic), 7.62-7.75 (2H, m, phth), 7.74-7.81 (1H, m, phth); (M+H⁺ = 825.4). ¹³C nmr (CDCI₃); δ , 25.8, 25.9, 26.0, 26.2, 26.3, 27.5, 30.3, 33.1 , 36.2, 36.9, 45.5, 48.8, 52.8, 59.5,.123.2, 127.0, 127.1 , 127.2, 127.3, 128.6, 128.7, 128.8, 129.1 129.5, 132.1 , 133.9, 134.9, 140.0, 150.5, 168.2, 169.1 , 170.3, 171.0.

Example 3

5-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-2S-mercaptopentanoic acid {2-(biphenyl-4- ylmethylsulfonyl)-1 R-[2,2-dimethyl-1S-(methylcarbamoyl)-propylcarbamoyl]-ethyl} amide

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 (MgSO₄). Evaporation gave the desired sulphone as a white foam (661 mg), essentially pure by nmr.

¹H nmr (CDCI₃); δ 1.02 (9H, s, tBu), 1.45 (9H, s, OtBu), 2.79 (3H, d, J = 4.8 Hz, NMe), 3.41 (1H, dd, J = 5.0, 14.9 Hz, CH_aH_bSO₂), 3.71 (1 H, dd, J = 5.8, 14.8 Hz, CH_aH_bSO₂), 4.15 (1 H, d, J = 9.0 Hz, CHtBu), 4.33 (1 H, d, J = 13. 9 Hz, SO₂CH_aH_bAr), 4.45 (1 H, d, J = 13. 9 Hz, SO₂CH_aH_bAr), 4.64 (1 H, m, CHCH₂S), 5.78 (1 H, d, J = 6.4 Hz, NH), 5.89 (1 H, brd, J = 4.7 Hz, NHMe), 7.17 (1 H, d, J = 8.9 Hz, NHCHtBu) and 7.26-7.62 (9H, m, aromatic); (M+H)⁺ = 546.2.

Following the method of Example 1 the title thioacetate was prepared as a white foam following chromatography (740 mg).

¹H nmr (CDCI₃); δ 0.98 (9H, s, tBu), 1.61-1.83 (3H, m), 1.96-2.08 (1 H, m), 2.36 (3H, s, CH₃COS), 2.76 (3H, d, J = 4.5 Hz, NMe), 3.43 (1 H, dd, J = 4.9, 11.8 Hz, CJiH_bSO₂), 3.69 (1 H, dd, J = 6.1 , 11.8 Hz, CH_aH_bSO₂), 3.68 (2H, m, CH₂N), 4.13 (1 H, d, J = 8.7 Hz, CHtBu), 4.18 (1 H, m, CHS), 4.36 (1 H, d, J = 13. 9 Hz, SO₂CH_aH_bAr), 4.39 (1 H, m, CHCH₂SO₂), 4.43 (1 H, d, J = 13. 9 Hz, SO₂CH_aH_bAr), 4.86 (1 H, m, NH), 5.95 (1 H, d, J = 4.8 Hz, NH), 7.12 (1 H, d, J = 8.9 Hz, NHCHtBu), 7.26-7.62 (9H, m, aromatic), 7.63-7.70 (2H, m, phth) and 7.77-7.85 (2H, m, phth); (M+H)⁺ = 749.4.

Example 4 5-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-2S-mercaptopentanoic acid {2-(biphenyl-4- ylmethylthio)-1 R-[2,2-dimethyl-1 S-(methylcarbamoyl)-propylcarbamoyl]-ethyl} amide

Sodium hydroxide (1.1 ml of a 0.46 M soln) was added under argon to a cooled solution in methanol (20 ml) of the thioacetate from Example 1 (360 mg) and mercaptoethanol (250 μL). After 20 minutes tic analysis indicated that the starting material had been consumed. Acetic acid (0.8 ml) was added and the solvent evaporated to leave a gum which was triturated with ether to give a white solid. Residual solvent and mercaptoethanol were removed by decantating and the pure thiol was obtained by flash chromatography on silica (2-5% methanol in dichloromethane) as a white solid. Reverse phase Hplc indicated the purity as > 97%.

¹H nmr (CDCI₃); δ 0.93 (9H, s, tBu), 1.63-2.04 (4H, m), 2.75 (3H, d, J - 4.7 Hz, NHMe), 2.79 (1 H, dd, J = 8.4 Hz, CH_aH_bS), 2.89 (1 H, dd, J = 6.0, 14.0 Hz, CH_aH_bS), 3.53 (1 H, brdd), 3.67 (2H, brt, J = 9.3 Hz, CH₂N), 3.77 ( 2H, s, SCH₂Ar), 4.35 (1 H, d, J = 9.3 Hz, CHtBu), 4.83 (1H, dd, CHCH₂), 6.74 (1H, brq, NHMe), 7.28 (5H, m, Ar and NH), 7.44-7.58 (6H, m Ar), 7.59-7.68 (3H, m, phth and Ar), and 7.73-7.81 (2H, m, phth).

¹³C nmr (CDCI₃); δ 25.8, 26.1 , 26.6, 32.7, 33.9, 34.1 , 34.6, 37.1 , 41.9, 53.0, 61.1 , 123.2, 127.0, 127.3, 126.7, 128.7, 129.4, 131.8, 133.9, 137.1 , 140.0, 140.5, 168.2, 170.1 , 170.6 and 172.3.

Example 5 5-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-2S-mercaptopentanoic acid {2-(biphenyl-4- ylmethylthio)-1 R-[2-benzylthio-2-methyl-1 R-(methylcarbamoyl)-propylcarbamoyl]- ethyl} amide

From Example 2 the thiol was prepared as a white solid.

¹H nmr (CDCI₃-MeOD); δ 1.28 (3H, s, Me), 1.44 (3H, s, Me), 1.63-2.04 (4H, m), 2.75 (3H, d, J = 4.8 Hz, NMe), 2.76 (1 H, m, CHS), 2.91 (1 H, dd, J = 3.3, 9.3 Hz, CHS), 3.66 (2H , t, J = 6.6 Hz, CH₂N), 3.70 (1H, m), 3.75 (2H, s, CH₂Ar), 3.78 (2H, s, CH₂Ar), 4.13 (1 H, m, NH), 4.37 (1 H, d, J = 9.0 Hz, CHtBu), 4.52 (1 H, d, J = 8.9 Hz, CH_pen), 6.31 (1 H, brd, NH), 7.04 (1 H, m, NH), 7.22-7.37 (5H, m, aromatic), 7.39 ( 4H, m) 7.54 (5H, m), 7.63-7.71 (2H, m. phth) and 7.76-7.83 92H, m. phth).; ESMS (M+H)⁺ = 783.2

Example 6 5-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-2S-mercaptopentanoic acid {2-(biphenyl-4- ylmethylsulfonyl)-1 R-[2,2-dimethyl-1S-(methylcarbamoyl)-propylcarbamoyl]-ethyl} amide

From Example 3 as a white solid.

¹H nmr (CDCI₃); δ 0.98 (9H, s, tBu), 1.72-2.08 (4H, m), 2.77 (3H, d, J = 4.6 Hz, NMe), 3.43 (3H, m, CH iSO;, &), 3.66 (3H, brt, CH₂N &), 4.13 (1 H, d, J = 8.7 Hz, CHtBu), 4.43 (1 H, d, J = 13. 6 Hz, SO₂CH_aH_bAr), 4.48 (1 H, d, J = 13. 6 Hz, SO.CϋH_bAr), 4.86 (1 H, m, NH), 5.93 (1 H, d, J = 4.8 Hz, NH), 7.22 (1 H, d, J = 8.9 Hz, NHCHtBu), 7.26-7.62 (9H, m, aromatic), 7.63-7.70 (2H, m, phth), 7.77-7.85 (2H, m, phth); ESMS (M+H)⁺ = 707.4.

Example 7 Thioacetic acid 1 S-{2-(biphenyl-4-ylmethylthio)-1 R-[2,2-dimethyl-1 S-(1 -pyridin-4- ylcarbamoyl)-propylcarbamoyl]-ethylcarbamoyl}-4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2- yl}-butyl ester

t-Butoxycarbonyl-L-S-biphenylcysteine (0.7 g), t-butylglycine 4-aminopyridinyl amide (0.45 g), HOAt (0.3g), WSCDI (0.42 g) and N-methylmorpholine (195 μL) were stirred together overnight to give after workup the desired protected cysteine aminopyridine amide. Following removal of the Boc group in the normal manner the desired thioacetate was prepared as a white solid using the manner described above.

¹H nmr (CDCI₃); δ 1.04 (9H, s, tBu), 1.71-2.04 (4H, m), 2.37 (3H, s, COMe), 2.90 (2H, m, CH₂S), 3.70 (2H, brt, J = 5.9 Hz, CH₂N), 3.78 (2H, s, SCH₂Ar), 4.17, (1 H, dd, J = 6.1 , 7.2 Hz), 4.37 (1 H, d, J = 8.3 Hz, CHtBu), 4.50 (1 H, dd, J = 6.3, 12.5 Hz), 7.07 (1 H, d, J = 8.3 Hz, NH), 7.22 (1 H, d, J =6.4 Hz, NH), 7.30-7.46 (5H, m, Ar & py), 7.51-7.57 ( 4H, m, Ar & py), 7.71 (4H, m phth & Ar), 7.82 (2H, m, phth), 8.46 (2H, brd, J =6.3 Hz, py), and 8.98 (1 H, brs, NH).

Example 8 5-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-2S-mercaptopentanoic acid {2-(biphenyl-4- ylmethylthio)-1 R-[2,2-dimethyl-1S-pyridinyl-4-ylcarbamoyl)-propylcarbamoyl]-ethyl} amide

Using the method of Example 4 the thiol was obtained as a white solid from the thioacetate of Example 7.

¹H nmr (MeOD); δ 0.97 (9H, s, tBu), 1.611.89 (4H, m), 1.97 (1 H, m), 2.78 (2H, m, CH₂S), 3.27 (2H, brt, J = 6.2 Hz, CH₂N), 3.35 (1 H, brt, CHS), 3.71 , (2H, s, SCH₂Ar), 4.33 (1H s, CHtBu), 4.46 (1 H, t, J = 6.5 Hz, CHCH₂S), 7.05-7.45 (13H, m, Ar & phth), 7.67 (2H, dd, J = 1.5, 6.5 Hz, py) and 8.25 (2H, brd, py).

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.

t-Butoxycarbonyl-L-S-biphenylcysteine piperidinyl amide (280 mg) was deprotected using the standard methods and then coupled with the thioacetyl- phthalamidopentanoic acid to give the thioacetate as a white solid (306 mg) following chromatographic purification.

¹H nmr (CDCI₃); δ 1.35-1.64 (4H, m), 1.65 (1 H, brs), 1.71-1.90 (3H, m), 2.34 (3H, s, MeCOS), 2.61 (1 H, dd, J = 7.0, 13.9 Hz, CH_aH_bS), 2.77 (1 H, dd, J = 5.9, 13.9 Hz, CH_aH_bS), 3.23 (2H, m), 3.53 (3H, m), 3.77 (2H, t, J = 6.6 Hz, CH₂N), 3.78 (2H, dd, J = 4.1 , 8.3 Hz, CH₂N), 5.03 (1 H, m), 7.04 (1 H, d, J, 8.8 Hz, NH), 7.22-7.48 (5H, m, Ar), 7.53 (2H, d, J = 7.4 Hz, ArCH₂S), 7.58 (2H, d, J = 7.3 Hz, ArCH₂S), 7.68-7.73 (2H, m, phth) and 7.81-7.88 (2H, m, phth).

¹³C nmr (CDCI₃) δ 24.2, 25.3, 26.1 , 27.8, 30.2, 33.7, 35.9, 32.1 , 43.2, 46.2, 46.5, 47.8, 123.1 , 126.8, 127.1 , 128.7, 129.3, 131.9, 133.7, 136.8, 139.9, 140.5, 168.0, 168.2 and 169.7. Example 10

-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-2S-mercaptopentanoic acid 1S-{1-(biphenyl- -ylmethylthiomethyl)-2-oxo-2-piperidin-1 -yl propylcarbamoylj-ethyl} amide

From Example 9 as a white foam.

¹H nmr (CDCI₃); δ 1.34-1.56 (4H, m), 1.66-1.98 (6H, m), 2.53-2.73 (2H, m), 3.11 (1 H, brdd), 3.34-3.51 (4H, m, CH₂N-pip), 3.63 (2H, t, J = 6.3 Hz, CH₂N), 3.66 (1 H, d, J = 7.3 Hz, CHAr), 3.76 (1 H, d, J = 7.3 Hz, CHAr), 4.49 (1 H, dd, J = 4.7, 5.8 Hz, CHCH₂S), 7.21-7.37 (6H, m, Ar &NH), 7.47 -7.72 (4H, m, Ar), 7.68-7.71 (2H, m, phth) and 7.72-7.78 (2H, m, phth).

¹³C nmr (CDCI₃) δ 24.7, 26.8, 30.0, 33.6, 34.2, 36.0, 37.4, 43.0, 43.9, 48.1 , 49.6, 49.7, 123.7, 127.4, 128.1 , 129.3, 131.1 , 134.4, 137.4, 140.5, 141.1 , 168.8, 171.7, 172.2.

Claims

Claims:

1. A compound of general formula I

wherein

Alk and Alk¹ each independently represents a divalent (C_rC₃)alkylene group,

Q represents -O-, -S-, -SO- or -SO₂-, and

Ar represents an optionally substituted phenyl or heteroaryl group;

R₁ is hydrogen or acyl;

R 21 is a group -(CH₂)_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 SO₂ 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 C₆alkyl, or oxo and/or on any additional N atoms by C_r C₆alkyl, phenyl or heteroaryl;

is either

(a) a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, (i) optionally contains as a ring member O, S, SO, SO₂, or NR₅ wherein R₅ is hydrogen, hydroxy, C C₆ alkyl, (C C₆ alkoxy)C C₆ alkyl, benzyl, acyl, an amino protecting group, or a group -SO₂R₆ wherein R₆ is C,-C₆ alkyl or a substituted or unsubstituted phenyl or heteroaryl group, and/or (ii) is optionally substituted on one or more C atoms by hydroxy, C_rC₆ alkyl, C_rC₆ alkoxy, cyano, oxo, ketalised oxo, amino, mono(C_rC₆ alkyl)amino, di(C,-C₆ alkyl)amino, carboxy, C^Ce alkoxycarbonyl, hydroxymethyl, C_rC₆ alkoxymethyl, carbamoyl, mono(C₁-C₆ alkyl)carbamoyl, di(C_rC₆ alkyl)carbamoyl, or hydroxyimino; or

(b) a radical of formula (IB)

wherein

R₃ is the side chain of a natural or non-natural α-amino acid in which any functional groups may be protected;

(b) a group -CHR^xR^y wherein (i) 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_rC₄ alkylene or C₂-C₄ alkenylene bridge, or (ii) R^x represents a group D¹-(C C₆ alkyl)- wherein D., is optionally substituted phenyl or heteroaryl, and R^y represents an optionally substituted phenyl or heteroaryl ring, or (c) a group of formula -(Z'-O)_w-Z' wherein Z' is straight or branched C_rC₆ alkyl optionally interrupted by one or more non- adjacent S and/or N atoms, w is an integer >1 , and no continuous linear sequence of atoms in the group R₄ is >12, or

(d) a straight or branched

alkyl group, optionally interrupted by one or more non-adjacent S and/or N atoms, which is substituted by at least two substituents of formula - (Z'ΗOZ'"^ wherein Z"' is straight or branched C_rC₆ alkyl optionally interrupted by one or more non-adjacent S and/or N atoms, x is 0 or 1 , q is 1 or 2, and no continuous linear sequence of atoms in the group R₄ is >12, or

(e) hydrogen, C_rC₆ alkyl, C_rC₄ perfluoroalkyl, or a group D-(C_r C₆ alkyl)- wherein D is hydroxy, C_rC₆ alkoxy, C_rC₆ alkylthio, acylamino. optionally substituted phenyl or heteroaryl, NH₂, or mono- or di-(C_rC₆ alkyl)amino;

or R₃ and R₄ 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_rC_β alkyl, A" is a bond, -O-, -S-, -S-S-, -NH- or - NR^a- wherein R^a is C_rC₆ alkyl, and Alk is C_rC₆ alkylene; and

R₅ is hydrogen or a (C_rC₆)alkyl group;

or a salt, hydrate or solvate thereof.

2. A compound as claimed in claim 1 wherein Z is a group of formula (IB) and R₄ is

(a) an optionally substituted cycloalkyl or cycloalkenyl ring or (b) a group -CHR^xR^y wherein (i) 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,, alkylene or C₂-C₄ alkenylene bridge, or (ii) R^x represents a group D¹-(C_rC₆ alkyl)- wherein D₁ is optionally substituted phenyl or heteroaryl, and R^y represents an optionally substituted phenyl or heteroaryl ring, or

(c) a group of formula -(Z'-O)_w-Z' wherein Z' is straight or branched C_rC₆ alkyl optionally interrupted by one or more non-adjacent S and/or N atoms, w is an integer >1 , and no continuous linear sequence of atoms in the group R₄ is >12, or

(d) a straight or branched C_rC₆ alkyl group, optionally interrupted by one or more non-adjacent S and/or N atoms, which is substituted by at least two substituents of formula -(Z^,,,)_x-(OZ^m)_q wherein Z"' is straight or branched C_rC₆ alkyl optionally interrupted by one or more non-adjacent S and/or N atoms, x is 0 or 1 , q is 1 or 2, and no continuous linear sequence of atoms in the group R₄ is >12, or

(e) hydrogen, C₁-C₆ alkyl, C_rC₄ perfluoroalkyl, or a group D-(C_rC₆ alkyl)- wherein D is hydroxy, C_rC₆ alkoxy,

alkylthio, acylamino. optionally substituted phenyl or heteroaryl, NH₂, or mono- or di-(C_rC₆ alkyl)amino;

or R₃ and R₄ 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_rC₆ alkyl, A" is a bond, -O-, -S-, -S-S-, -NH- or -NR^a- wherein R^a is C_rC₆ alkyl, and Alk is C_rC₆ alkylene

or a salt, hydrate or solvate thereof.

3. A compound as claimed in claim 1 or claim 2 wherein Ar is a phenyl group which is substituted in the 4-position by a phenyl or heteroaryl group which in turn is optionally substituted by C C₆ alkyl; trifluoromethyl; halo; cyano ( -CN); -OH;or - OR, wherein R is C_rC₆ alkyl or benzyl.

4. A compound as claimed in claim 1 or claim 2 wherein Ar is a biphenyl group optionally substituted in the 4' position by chloro or methoxy.

5. A compound as claimed in any of the preceding claims wherein Q represents -O- or -S-.

6. A compound as claimed in any of the preceding claims wherein m, n and p are each 1 , and Alk and Alk¹ each independently represent -CH₂- or -CH₂CH₂-.

7. A compound as claimed in any of claims 1 to 6 wherein m and n are both 0.

8. A compound as claimed in any of the preceding claims wherein R₂ is biphenyl-4-ylmethylthiomethyl, biphenyl-4-ylmethyloxomethyl, 4-chlorophenyl- methylthiomethyl, 4-chlorophenylmethyloxomethyl, 4'-chlorobiphenyl-4- ylmethylthiomethyl, 4'-chlorobiphenyl-4-ylmethyloxomethyI, 4-methoxy- phenylmethylthiomethyl, 4-methoxyphenylmethyloxomethyl, 4-methoxybiphenyl-4- ylmethylthiomethyl, 4-methoxybiphenyl-4-ylmethyloxomethyl, 3-(biphenyl-4-yl)propyl, or 3-(4'-chlorobiphenyl-4-yl)propyl.

9. A compound as claimed in any of the preceding βlaims wherein R₂₁ is a group -(CH₂)_t-W 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-yl),

1 ,3-dihydro-1-oxo-2H-benz[f]isoindol-2-yl, 1 ,3-dihydro-1 ,3-dioxo-2H-pyrrolo[3,4- b]quinolin-2-yl, or 2,3-dihydro-1 ,3-dioxo-1 H-benz[d,e]isoquinolin-2-yl.

10. A compound as claimed in any of claims 1 to 8 wherein R₂₁ is phthalimidopropyl, phthalimidobutyl, phthalimidoethyl, phthalimidomethyl, 3,4,4- trimethyl-2,5-dioxo-1 -imidazolidinylpropyl, 3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyethyl, or 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinylmethyl.

11. A compound as claimed in any of the preceding claims wherein R^ is hydrogen, or a group R₂₀C(O)- where R₂₀ is a (C C₆)alkyl group.

12. A compound as claimed in claim 11 wherein R^ is a group R₂₀C(O)- wherein R₂₀ is methyl or ethyl.

13. A compound as claimed in any of the preceding claims wherein Z is a group of formula (IB) and R₃ is benzyl, 4-chlorophenylmethyl, 2-thienylmethyl, iso-butyl or t- butyl, 1-benzylthio-1-methylethyl, or 1-mercapto-1-methylethyl.

14. A compound as claimed in any of the preceding claims wherein Z is a group of formula (IB) and R₄ is cyclopropyl, cyclobutyl, cyciopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-(2-methoxyethoxy)ethyl, hydrogen or methyl.

15. A compound as claimed in any of claims 1 or 3 to 14 wherein Z is a group of formula (IB) and R₄ is 3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, thiazol-2-yl, 4- ethoxycarbonyl-methylthiazol-2-yl, 5-methyl-1 ,3,4-thiadiazol-2-yl, or 4-tert- butylthiazol-2-yl.

16. A compound as claimed in any of the preceding claims wherein Z is a group of formula (IB) and R₅ is hydrogen.

17. A compound as claimed in any of claims 1 , or 3 to 12 wherein Z is substituted or unsubstituted 1-pyrrolidinyl 1 -piperazinyl, hexahydro-1-pyridazinyl, morpholino, tetrahydro-1 , 4-thiazin-4-yl, tetrahydro-1 ,4-thiazin-4-yl 1 -oxide, tetrahydro-1 ,4-thiazin- 4-yl 1 ,1-dioxide, thiazolidin-3-yl, hexahydroazipino, or octahydroazocino. Specific examples of such groups include piperidin-1 -yl, 2-(methylcarbamoyl)-1-pyrrolidinyl, 2-(hydroxymethyl)-1-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.

18. A compound as claimed in any of claims 1 , or 3 to 12 wherein Z is piperidin-1 - yi.

19. A compound as claimed in any of the preceding claims wherein the stereochemistry is as follows: carbon atom carrying the R₂₁ group - S. carbon atom carrying the R₂ group - R.

20. A pharmaceutical composition comprising a compound as claimed in any of the preceding claims, together with a pharmaceutically acceptable carrier.