ZA200101231B - Arylpiperazines and their use as metalloproteinase inhibiting agents (MMP). - Google Patents

Description

' .

ARYLPIPERAZINES AND THEIR USE AS METALLOPROTEINASE

INHIBITING AGENTS (MMP)

The present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising these, as well as their use.

The compounds of this invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N.M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMP) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP 10, MMP11), matrilysin (MMP7), metalloelastase (MMP 12), enamelysin (MMP 19), the MT-MMPs (MMP 14,

MMPI15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloprotenases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.

Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin.

Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M.

Hooper et al., (1997) Biochem J. 321:265-279).

Metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these disease conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro- intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis),

. RK 2 inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion, in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget’s disease)); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer’s disease; and extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis.

A number of metalloproteinase inhibitors are known; different classes of compounds may have different degrees of potency and selectivity for inhibiting various metalloproteinases. We have discovered a new class of compounds that are inhibitors of metalloproteinases and are of particular interest in inhibiting MMP-13, as well as MMP-9.

The compounds of this invention have beneficial potency and/or pharmacokinetic properties.

MMP13, or collagenase 3, was initially cloned from a cDNA library derived from a breast tumour [J. M. P. Freije et al. (1994) Journal of Biological Chemistry 269(24):16766- 16773]. PCR-RNA analysis of RNAs from a wide range of tissues indicated that MMP13 expression was limited to breast carcinomas as it was not found in breast fibroadenomas, normal or resting mammary gland, placenta, liver, ovary, uterus, prostate or parotid gland or in breast cancer cell lines (T47-D, MCF-7 and ZR75-1). Subsequent to this observation

MMP13 has been detected in transformed epidermal keratinocytes [N. Johansson ef al., (1997) Cell Growth Differ. 8(2):243-250], squamous cell carcinomas {N. Johansson et al., (1997) Am. J. Pathol. 151(2):499-508] and epidermal tumours [K. Airola ez al, (1997) J.

Invest. Dermatol. 709(2):225-231]. These results are suggestive that MMP13 is secreted by transformed epithelial cells and may be involved in the extracellular matrix degradation and cell-matrix interaction associated with metastasis especially as observed in invasive breast cancer lesions and in malignant epithelia growth in skin carcinogenesis.

Recent published data implies that MMP13 plays a role in the turnover of other connective tissues. For instance, consistent with MMP13’s substrate specificity and preference for degrading type II collagen [P. G. Mitchell er al., (1996) J. Clin. Invest. 97(3).761-768; V. Knauper et al. (1996) The Biochemical Journal 271:1 544-1550], MMP13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M.

: . ~3-

Stahle-Backdahl ef al., (1997) Lab. Invest. 76(5):717-728; N. Johansson ef al., (1997) Dev.

Dyn. 208(3):387-397], in destructive joint diseases such as rheumatoid and osteo-arthritis [D.

Wernicke et al , (1996) J. Rheumatol. 23:590-595; P. G. Mitchell et al., {1996) J. Clin.

Invest. 97(3):761-768; O. Lindy ef al., (1997) Arthritis Rheum 40(8):1391-1399]; and during the aseptic loosening of hip replacements [S. Imai ef al., (1998) J. Bone Joint Surg. Br. . 80(4):701-710]. MMP13 has also been implicated in chronic adult periodontitis as it has been localised to the epithelium of chronically inflamed mucosa human gingival tissue [V. I. Uitto etal. (1998) Am. J. Pathol 152(6):1489-1499] and in remodelling of the collagenous matrix in chronic wounds [M. Vaalamo ef al., (1997) J. Invest. Dermatol. 109(1):96-101].

MMP9 (Gelatinase B; 92kDa TypelV Collagenase; 92kDa Gelatinase) is a secreted protein which was first purifed, then cloned and sequenced, in 1989 (S.M. Wilhelm et al (1989) J. Biol Chem. 264 (29) : 17213-17221. Pubished erratum in J. Biol Chem. (1990) 265 (36): 22570.). A recent review of MMP9 provides an excellent source for detailed information and references on this protease : T.H. Vu & Z. Werb (1998) (In : Matrix Metalloproteinases. 1998. Edited by W.C. Parks & R.P. Mecham. ppl15 - 148. Academic

Press. ISBN 0-12-545090-7). The following points are drawn from that review by T.H. Vu & Z. Werb (1998).

The expression of MMP is restricted normally to a few cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, it's expression can be induced in these same cells and in other cell types by several mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators often implicated in initiating an inflammatory response. As with other secreted MMPs, MMP? is released as an inactive Pro-enzyme which is subsequently cleaved to form the enzymatically active enzyme.

The proteases required for this activation in vivo are not known. The balance of active MMP9 versus inactive enzyme is further regulated in vivo by interaction with TIMP-1 (Tissue

Inhibitor of Metalloproteinases -1), a naturally-occurring protein. TIMP-1 binds to the C- terminal region of MMP, leading to inhibition of the catalytic domain of MMPS. The balance of induced expression of ProMMP9, cleavage of Pro- to active MMP9 and the presence of

TIMP-1 combine to determine the amount of catalytically active MMPS which is present at a local site. Proteolytically active MMP attacks substrates which include gelatin, elastin, and native Type IV and Type V collagens; it has no activity against native Type I collagen, proteoglycans or laminins.

There has been a growing body of data implicating roles for MMP9 in various physiological and pathological processes. Physiological roles include the invasion of embryonic trophoblasts through the uterine epithelium in the early stages of embryonic implantation; some role in the growth and development of bones; and migration of inflammatory cells from the vasculature into tissues. Increased MMP9 expression has observed in certain pathological conditions, therebye implicating MMP in disease processed such as arthritis, tumour metastasis, Alzheimer's, Multiple Sclerosis, and plaque rupture in atherosclerosis leading to acute coronary conditions such as Myocardial Infarction.

In a first aspect of the invention we provide compounds of the formula I

SAN

TRUFTN, 7

R3, . —~X

R1 R2 wherein ring B is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring comprising up to 12 ring atoms and containing one or more heteroatoms independently chosen from N, O, and §; alternatively ring B may be biphenyl; ring B may optionally be linked to ring A by a C1-4 alkyl or a C1-4 alkoxy chain linking the 2-position of ring B with a carbon atom alpha to X2; each R3 is independently selected from hydrogen, halogen, NO2, COOR wherein R is hydrogen or C1-6alkyl, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -SO2-C1-6 alkyl ,C1-6 alkoxy and up to C10 aryloxy, nis 1,2 or 3;

P is -(CH)n- whereinn=0, 1, 2, or P is an alkene or alkyne chain of up to six carbon atoms; where X2 is C, P may be -Het-, -(CH[R6])n-Het-, -Het-(CH[R6]n-or -Het-(CH[R6])n-Het-, wherein Het is selected from - CO-, -S-, SO-, -SO2-, -NR6-, or -O- wherein n is 1 or 2, or P may be selected from -CO-N(R6)-, -N(R6)-CO-, -SO2-N(R6)- and - N(R6)-SO2-, and R6 is hydrogen, C1-6 alkyl, up to C10 aralkyl or up to C9 heteroalkyl;

Ring A is a 5-7 membered aliphatic ring and may optionally be mono- or di- substituted by optionally substituted C1-6 alkyl or C1-6 alkoxy, each substituent being independently selected from halogen, C1-6 alkyl or an oxo group;

, sy

X1 and X2 are independently selected from N and C, where a ring substituent on ring

A is an oxo group this is preferably adjacent a ring nitrogen atom;

Y is selected from -SO2- and -CO-;

Z is -CONHOH, Y is -CO- and Q is selected from -C(R6)(R7)-, -C(R6)(R7)-CH2-, -

N(R6)-, and -N(R6)-CH2- wherein R6 is as defined above, and solely in relation to Q as here defined, R6 may also represent up to C10 aryl and up to C9 heteroaryl, and R7 is H, C1-6 alkyl, or together with R6 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the latter containing at least one heteroatom selected from N, O, and S;

Z is -CONHOH, Y is -SO2- and Q is selected from -C(R6)(R7)-, and —C(R6)(R7)- CH2-; or Z is -N(OH)CHO and Q is selected from -CH(R6)-,-CH(R6)-CH2-, and -N(R6)-

CH2-;

R1is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10aryl, up to C10heteroaryl, up to Cl2aralkyl, or up to Cl2heteroarylalkyl, all optionally substituted by up to three groups independently selected from NO2, CF3, halogen, C1-4alkyl, carboxy(C1-4)alkyl, up to Cécycloalkyl,-OR4, -SR4, C1-4alkyl substituted with -OR4, SR4 (and its oxidised analogues), NR4, N-Y-R4, or

C1-4alkyl-Y-NR4, with the proviso that where R1 is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, or R1 is 2,3,4,5,6-pentafluorophenyl,

R4 is hydrogen, C1-6 alkyl, up to C10 aryl or up to C10 heteroaryl or up to C9 aralkyl, each independently optionally substituted by halogen, NO2, CN, CF3, C1-6 alkyl, -S-

C1-6 alkyl, -SO-C1-6 alkyl, -SO2-C1-6 alkyl or C1-6 alkoxy;

R2 is H, C1-6 alkyl, or together with R1 forms a carbocyclic or heterocyclic spiro 3, 6 or 7 membered ring, the latter containing at least one heteroatom selected from N, O, and S; also the group Q can be linked to either R1 or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S and N.

Any alkyl groups outlined above may be straight chain or branched.

Convenient values for the above groups include the following: ring A = a 5-6 membered aliphatic ring, such as a piperazine ring, and may optionally be mono- or di-substituted by optionally substituted C1-6 alkyl or C1-6 alkoxy, each substituent being independently selected from halogen, C1-6 alkyl or an oxo group;

R3 = hydrogen, halogen, NO2, CF3, C1-4 alkyl, and C1-4 alkoxy, nis 1 or 2, such as individually 4-fluoro, CF3, 4-chloro and 3,4-dichloro;.

ring B = monocyclic or bicyclic aryl, aralkyl or heteroaryl having up to 10 ring atoms, especially monocyclic aryl, aralkyl or heteroaryl having up to 7 ring atoms, more especially monocyclic aryl or heteroaryl having up to 6 ring atoms, such as a phenyl or pyridyl ring;

P = -(CH2)n- wherein nis 0 or 1, or -O-, or -CO-N(R6)-~; one or both of X2 and X1 =N, or X1 is N, or X2is C;

Y = -802-, Y=-CO-;

Q = -CH(R6)-, -CH(R6)-CH2-, and -N(R6)-CH2- wherein R6 is hydrogen or C1-6 alkyl; also where Q is linked to R1 or R2 to form a C5-7 alkyl or heteroalkyl ring such as a cyclohexyl ring;

R1 = hydrogen, Cl-6alkyl, C5-7 cycloalkyl, up to C12aralkyl, up to

C11heteroarylalkyl, up to C10 aryl or heteroaryl such as up to C6 aryl, all optionally substituted by up to three halogen atoms, or by CF3;

R2 = hydrogen, or together with R1 represent a carbocyclic or heterocyclic spiro 5-or 6 membered ring, such as a tetrahydropyran ring;

R4 = up to C10 aryl optionally substituted by halogen, NO2, CN, CF3, C1-6 alkyl, -S-

C1-6 alkyl, -SO-C1-6 alkyl, -SO2-C1-6 alkyl or C1-6 alkoxy;

Z = -CONHOH-, Z = -N(OH)CHO.

Preferred values for the above groups include the following:

R3 = hydrogen, halogen such as chlorine, bromine or fluorine, NO2, CF3, methyl, ethyl, methoxy, ethoxy, particularly methoxy or fluorine; ring B = a monocyclic aryl, aralkyl or heteroaryl ring having up to 7 ring atoms such as phenyl, biphenyl, napthyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, especially phenyl, pyridyl and pyrimidyl, more especially phenyl, 2-pyridyl and 2,4-pyrimidyl,

P = a direct bond, both X2 and X1 are N;

Y =-802-;

Q=-CH2-,

R1 is phenyl, 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, pyridyl, pyridylethyl, thiophenylpropyl, bromothiophenyl, pyrimidinylethyl, pyrimidinylpropyl, pyridylethyl, pyridylpropyl or together with R2 is spirocyclohexane or spiro-4-pyran; R2 is hydrogen

Z = -N(OH)CHO.

! + .

More preferred values include R3 being halogen, the substituent is preferably meta or para to the ring junction where ring B is an aryl or heteroaryl ring, where ring B is phenyl then especially 4-fluoro and where ring B is pyridyl! then 3-, or 4-chloro (as appropriate);

Q =-CH2-.

Preferred combinations of Rings B and A include phenyl and piperazinyl, . pyridyl and piperazinyl, and pyrimidine and piperazinyl respectively.

Particular alicyclic, fused and heterocyclic rings for ring B include any one of

N N N N N

AN ~~ ~N

N° A | 7) 1 \ /

ZZ = N ~~ \ / gS Vd Ny ~N ON ~ NC

N N

S S S S xX) sy Sr

N N N—N N

Particular rings for ring A include any one of _ —_ —_ __/

NN

-o- ~O- Om Or and its corresponding seven membered analogue(s).

It will be appreciated that the particular substitituents and number of substituents on rings A and B are selected so as to avoid sterically undesirable combinations. This also applies to rings as may be formed by R1 and Q, R2 and Q as well as R6 and R7.

Where optically active centres exist in the compounds of formula I, we disclose all individual optically active forms and combinations of these as individual specific embodiments of the invention, as well as their corresponding racemates.

Specific compounds include a 74 AN / \ 2

F N N—S: x UN __/ o

NJ

( 0 lo) }

M/Z M+1 (ESP+) 438 fo} [0] \ 4 eo © N

NN 0

NN

M/Z M+1 (ESP+) 455 cl

O04 cl N N—S ‘o _N fo h) o)

M/Z M+1 (ESP+) 487 o 0} / 0 JW

SHEARS or cl ZN

M/Z M+1 (ESP+) 454 0 0 \ 7

Ne N

INO

LN. ld

M/Z M+1 (ESP+) 420

NANA

Nee 1

M/Z M+1 (ESP+) 451 o) 0 N

OO

I] 0 lo}

S

\

M/Z M+1 (ESP+) 457

[0] ~~ \_/ \__/ J N

O—N ? 0

M/Z M+1 (ESP+) 438 cl 0 Cl 7 NJ \,

N N N—S’ [ lo)

S M/Z M+1 (ESP+) 496 o) o, yy 7 ] ge

AA rN

NN

M/Z M+1 (ESP+) 471

Claims (1)

1. CLAIMS: What we claim is:-

   1. A compound of the formula I

   5 . TO P— i _— AN v4 R3, a XK R1 R2 wherein ring B is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring comprising up to 12 ring atoms and containing one or more heteroatoms independently chosen from N, O, and S; alternatively ring B may be biphenyl; ring B may optionally be linked to ring A by a C1-4 alkyl or a C1-4 alkoxy chain linking the 2-position of ring B with a carbon atom alpha to X2; each R3 is independently selected from hydrogen, halogen, NO2, COOR wherein R is hydrogen or Cl-6alkyl, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -SO2-C1-6 alkyl ,C1-6 alkoxy and up to C10 aryloxy, nis 1,2 or 3; P is -(CH;)n- whereinn=0, 1, 2: or P is an alkene or alkyne chain of up to six carbon atoms; where X2 is C; P may be -Het-, -(CH[R6])n-Het-, -Het-(CH[R6]n-or -Het-(CH[R6])n-Het-, wherein Het is selected from - CO-, -S-, SO-, -SO2-, -NR6- , or -O- wherein nis 1 or 2; or P may be selected from -CO-N(R6)-, -N(R6)-CO-, -SO2-N(R6)- and - N(R6)-SO2-, and R6 1s hydrogen, C1-6 alkyl, up to C10 aralkyl or up to C9 heteroalkyl; Ring A is a 5-7 membered aliphatic ring and may optionally be mono- or di- substituted by optionally substituted C1-6 alkyl or C1-6 alkoxy, each substituent being independently selected from halogen, C1-6 alkyl or an oxo group. X1 and X2 are independently selected from N and C, where a ring substituent on ring A is an oxo group this is preferably adjacent a ring nitrogen atom; Y is selected from -SO2- and -CO-; Z is -CONHOH, Y is -CO- and Q is selected from -C(R6)(R7)-, -C(R6)(R7)-CH2-, - N(R6)-, and -N(R6)-CH2- wherein R6 is as defined above, and solely in relation to Q as here defined, R6 may also represent up to C10 aryl and up to C9 heteroaryl, and R7 is H, C1-6 alkyl, or together with R6 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the latter containing at least one heteroatom selected from N, O, and S; Z 1s -CONHOH, Y is -SO2- and Q is selected from -C(R6)(R7)-, and —C(R6)(R7)- CH2- . or Zis -N(OH)CHO and Q is selected from -CH(R6)-,-CH(R6)-CH2-, and -N(R6)- CH2-; R1is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10aryl, up to C10heteroaryl, up to C12aralkyl, or up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from NO2, CF3, halogen, C1-4alkyl, carboxy(C1-4)alkyl, up to Cécycloalkyl,-OR4, -SR4, C1-4alkyl substituted with -OR4, SR4 (and its oxidised analogues), NR4, N-Y-R4, or C1-4alkyl-Y-NR4, with the proviso that where R1 is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, or R1 is 2,3,4,5,6-pentafluorophenyl; R4 is hydrogen, C1-6 alkyl, up to C10 aryl or up to C10 heteroaryl or up to C9 aralkyl, each independently optionally substituted by halogen, NO2, CN, CF3, C1-6 alkyl, -S- C1-6 alkyl, -SO-C1-6 alkyl, -S02-C1-6 alkyl or C1-6 alkoxy; R2 is H, C1-6 alkyl, or together with R1 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the latter containing at least one heteroatom selected from N, O, and S; also the group Q can be linked to either R1 or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S and N; and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof.

   2. A compound as claimed in claim 1 and wherein: ring A is a 5-6 membered aliphatic ring, and may optionally be mono- or di- substituted by optionally substituted C1-6 alkyl or C1-6 alkoxy, each substituent being independently selected from halogen, C1-6 alkyl or an oxo group; R3 is hydrogen, halogen, NO2, CF3, C1-4 alkyl, and C1-4 alkoxy, nis 1 or 2; ning B is monocyclic or bicyclic aryl, aralkyl or heteroaryl having up to 10 ring atoms; P is -(CH2)n- wherein nis 0 or 1, or -O-, or -CO-N(R6)-; one or both of X2 and X1 =N, or X1is N, or X2 is C;

   ro . R1 is hydrogen, C1-6alkyl, C5-7 cycloalkyl, up to C12aralkyl, up to Cl1heteroarylalkyl, up to C10 aryl or C10 heteroaryl; all optionally substituted by up to three halogen atoms, or by CF3; R2 is hydrogen, or together with R1 represent a carbocyclic or heterocyclic spiro 5-or 6 membered ring; : R4 1s up to C10 aryl optionally substituted by halogen, NO2, CN, CF3, C1-6 alkyl, - S-C1-6 alkyl, -SO-C1-6 alkyl, -SO2-C1-6 alkyl or C1-6 alkoxy. or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof.

   3. A compound as claimed in claim 1 wherein: R3 is hydrogen, halogen, NO2, CF3, methyl, ethyl, methoxy or ethoxy; ring B is a monocyclic aryl, aralkyl or heteroaryl ring having up to 7 ring atoms; P is a direct bond; both X2 and X1 are N; Y is -SO2-; Qs -CH2-; R1 is phenyl, 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, 2-pyridyl, 3-pyridyl, 2-pyridylethyl, 3-pyridylethyl, thiophenylpropyl, bromothiopheneyl, 2-pyrimidinylethyl, 2-pyrimidinylpropyl,, pyridylpropyl or together with R2 is spirocyclohexane or spiro-4-pyran; R2 is hydrogen Z 1s -N(OH)CHO; or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof. 4 A compound as claimed in any one of the previous claims wherein ring A is a piperazinyl ring and ring B is selected from an optionally substituted phenyl, pyridyl or pyrimidine ring; or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof.

   S. A compound of the formula I as claimed in claim 1wherein ring B substituted by R3(n) is a phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, or 3,4- dichlorophenyl ring or is 5-chloro-2-pyridyl; P is a direct bond; ring A is piperidinyl or

   . -74 - PCT/GB99/02801 piperazinyl,Y is SO2, Q is -CH2-, and Z is -N(OH)CHO; or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof.

   6. A compound of the formula I as claimed in claim 1 wherein ring B is a phenyl, 3- methyiphenyl, 4-tfluorophenyl, 3-chlorophenyl, 4-chlorophenyl, or 3,4-dichlorophenyl ring or 5-chloro-2-pyridyl; P is a direct bond; ring A is piperidinyl or piperazinyl, Y is SO2, Q is -CH2-, Z is -N(OH)CHO and R1 is phenyl, phenbutylene, phenisopropylene, 2- pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene, or 4-chlorophenyloxydimethylmethylene; or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof.

   7. A compound of the formula I as claimed in claim 1 wherein ring B is phenyl monosubstituted by chlorine or fluorine, P is a direct bond, ring A is piperidinyl, Y is SO2, Q is -CH2-, Z is -CONHOH and R1 is hydrogen, i-butyl, or spiro-tetrahydropyranyl; or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof.

   8. A pharmaceutical composition which comprises a compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and a pharmaceutically acceptable carrier.

   9. A substance or composition for use in a method of therapeutic treatment of the human or animal body, said substance or composition comprising a compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and said method comprising administering said substance or composition.

   10. A substance or composition for use in a method of treating metalloproteinase mediated disease condition, said substance or composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and said method comprising administering to a warm-blooded animal a therapeutically effective amount of said substance or composition.

   11. A process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises a) reacting a compound of the formula (II) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof with a compound of the formula (III) AMENDED SHEET

   1 4 [a - R a BN x A R3, AN 7 a —~ on R1 R2 wherein X,' represents X or a precursor of X (whether by modification or displacement) or an S activated form of X suitable for reaction with Y;; Y represents Y, a precursor of Y, or an activated form of Y suitable for reaction with X,'; Z' represents a protected form of Z, a precursor of Z (whether by modification or displacement of Z") or an activated form of Z; and where Q is -(CH;)(R6)- then by reacting a compound of the formula IX with an appropriate compound of the formula R1-CO-R2 to yield an alkene of the formula X, which is then converted to a compound of the formula XI wherein Z* is a hydroxylamine precursor of the group Z, and then converting Z* to the group Z, all as set out below:

   . EY A s

   R6 / AYN | wr P— X X;— §0,— CH, tT =0 IX _ R2 R3, R6 B 7A BR P— X, —an Hi X NA or / A R R3, | 2 6 AN Bi . — X J x i NA 50; Xi R, R or b) reacting a compound of the formula (IV) ) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof with a compound of the formula (V).

   AYN PX, X,—Y Z NE Ng — wv R1 R2 (7 ’ R3, wherein B' represents a suitable ring function or substituent group for reaction with P'; Z! is as hereinbefore defined; and P' represents a suitably activated form of the linker P for reaction with B!

   . -77 - PCT/GB99/02801 or where X2 is N then P1 may be present on ring A rather than ring B or, as required, the linker P may be formed by appropriate reaction of precursor groups P’’ and P**’ provided on rings B* and A respectively, or vice versa.

   12. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in a disease condition mediated by one or more metalloproteinase enzymes.

   13. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of arthritis.

   14. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of atherosclerosis.

   15. A compound as claimed in claim 1, substantially as herein described and illustrated.

   16. A composition as claimed in claim 8, substantially as herein described and illustrated.

   17. A substance or composition for use in a method of treatment as claimed in claim 9 or claim 10, substantially as herein described and illustrated.

   18. A process as claimed in claim 11, substantially as herein described and illustrated.

   19. Use as claimed in claim 12, claim 13, or claim 14, substantially as herein described and illustrated.

   20. A new compound, a new composition, a substance or composition for a new use in a method of treatment, a new process for preparing a compound, or new use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof, substantially as herein described. AMENDED SHEET