Title of Invention	"A PIPERAZINE OF THE FORMULA I"
Abstract	The present invention relates to a piperazine of the formula I wherein ring B is phenyl, pyridyl or pyrimidyl; each R3 is independently selected from hydrogen, halogen, N02, COOR wherein R is hydrogen or C1-6alkyl, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -S02-C1-6 alkyl, C1-6 alkoxy and up to CIO aryloxy, n is 1, 2 or 3; P is a direct bond; Ring A is piperazinyl; Both X2 and X1 are N; Y is -SO2-; Z is -N(OH)CHO and Q is CH2; R1 is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10aryl, up to C10aryl, up to C10heteroaryl, up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from NO2, CF3, halogen, C1-4alkyl, carboxy (Cl-4) alkyl, up to C6 cycloalkyl, -OR4, -SR4, Cl-4 alkyl substituted with -OR4, SR4 (and its oxidized analogues), NR4, N-Y-R4, or Cl-4 alkyl-Y-NR4, with the proviso that where Rl is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, Rl 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; and R2 is H, C1-6 alkyl, or together with Rl 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 Rl or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S ad N; and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically acceptable salt thereof.

Title of Invention

"A PIPERAZINE OF THE FORMULA I"

Abstract

The present invention relates to a piperazine of the formula I wherein ring B is phenyl, pyridyl or pyrimidyl; each R3 is independently selected from hydrogen, halogen, N02, COOR wherein R is hydrogen or C1-6alkyl, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -S02-C1-6 alkyl, C1-6 alkoxy and up to CIO aryloxy, n is 1, 2 or 3; P is a direct bond; Ring A is piperazinyl; Both X2 and X1 are N; Y is -SO2-; Z is -N(OH)CHO and Q is CH2; R1 is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10aryl, up to C10aryl, up to C10heteroaryl, up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from NO2, CF3, halogen, C1-4alkyl, carboxy (Cl-4) alkyl, up to C6 cycloalkyl, -OR4, -SR4, Cl-4 alkyl substituted with -OR4, SR4 (and its oxidized analogues), NR4, N-Y-R4, or Cl-4 alkyl-Y-NR4, with the proviso that where Rl is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, Rl 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; and R2 is H, C1-6 alkyl, or together with Rl 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 Rl or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S ad N; and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically acceptable salt thereof.

Full Text	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, MMP 15, MMP 16, MMP 17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM 10 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 gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), 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 et al., (1997) Cell Growth Differ. 8(2):243-250], squamous cell carcinomas [N. Johansson etal., (1997) Am. J. Pathol. 151(2).499-508] and epidermal tumours [K. Airola etal., (1997) J. Invest. Dermatol. 109(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 et al., (1996) J. Clin. Invest. 97(3)J6l-768; V. Knauper et al., (1996) The Biochemical Journal 271:1544-1550], MMP13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M. Stahle-Backdahl etai, (1997) Lab. Invest. 76(5V717-728; N. Johansson eial, (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 etal., (1997) Arthritis Rheum 40(8): 1391-1399]: and during the aseptic loosening of hip replacements [S. Imai etai, (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. J. Uitto et al., (1998) Am. J. Pathol 152(6): 1489-1499] and in remodelling of the collagenous matrix in chronic wounds [M. Vaalamo et 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. ppl 15 - 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 MMP9 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, MMP9 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 fiirther 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 MMP9, leading to inhibition of the catalytic domain of MMP9. 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 MMP9 which is present at a local site. Proteolytically active MMP9 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 MMP9 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 (Formula Removed) 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, N02, COOR wherein R is hydrogen or C1-6alkyl, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -S02-C1-6 alkyl ,C1-6 alkoxy and up to C10 aryloxy, n is 1,2 or 3; P is -(CH2)n- wherein n = 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; XI 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 -S02- 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, CI-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 -S02- 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-; Rl is 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(C 1-4)alkyl, up to C6cycloalkyl,-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 Rl is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, or Rl 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 Rl 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. 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, n is 1 or 2, such as individually 4-fluoro, CF3, 4-chloro and 3,4-dichloro;. -Erring 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 n is 0 or 1, or -O-, or -CO-N(R6)-; one or both of X2 and X1 = N, or X1 is N, or X2 is C; Y = -SO2-, 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, C1-6alkyl, C5-7 cycloalkyl, up to C12aralkyl, up to C1 lheteroarylalkyl, 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 Rl 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, N02, 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, N02, 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 = -SO2-; Q = -CH2-; Rl 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-chIoro (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 (Formula Removed) Particular rings for ring A include any one of (Formula Removed) 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 (Formula Removed) wherein R = phenyl or phenethyl and (Formula Removed) wherein R = isobutyl or a spiro-4-pyran ring As previously outlined the compounds of the invention are metalloproteinase inhibitors, in particular they are inhibitors of MMP13. Each of the above indications for the compounds of the formula I represents an independent and particular embodiment of the invention. Whilst we do not wish to be bound by theoretical considerations, the compounds of the invention are believed to show selective inhibition for any one of the above indications relative to any MMP1 inhibitory activity, by way of non-limiting example they may show 100-1000 fold selectivity over any MMP1 inhibitory activity. In addition we have found that compounds of the formula 1 wherein ring B is phenyl, pyridyl (such as 2-pyridyl or 3-pyridyl, especially 2-pyridyl) ring optionally mono- or di-substituted, preferably mono-substituted, by halogen (for example chlorine ), P is a direct bond; ring A is a piperazinyl or piperidinyl ring, Y is -S02- and Q is Cl-4alkylene (for example -CH2-), especially -CH2-; Rl is as defined for Formula 1 and is especially 2-phenylpropyl, 2-(2-pyridyl)propyl, 2-(3-pyridyl)propyl, 2-(4-pyridyl)propyl, phenyl, benzyloxymethyl, 4-phenylbutyl, 2-phenylbutyl, or 2-(2-thienyl)propyl; and Z is -N(OH)CHO, are of particular use as aggrecanase inhibitors ie. inhibitors of aggrecan degradation. Of particular note are compounds of the formula I wherein ring B is a phenyl, 3-methylphenyl, 4-fluorophenyl, 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 especially piperazinyl, Y is SO2, Q is -CH2-, Z is -N(OH)CHO and Rl is phenyl, phenbutylene, phenisopropylene, 2-pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene, or 4-chlorophenyloxydimethylmethylene. Also of mention are compounds of the formula I wherein ring B is phenyl monosubstituted by chlorine or fluorine, especially 4-chlorophenyl and 4-fluorophenyl; P is a direct bond; ring A is piperidinyl, Y is SO2, Q is -CH2-, Z is -CONHOH and Rl is hydrogen, i-butyl, or spiro-tetrahydropyranyl. Particular compounds include (Formula Removed) (Table Removed) wherein PIP = piperazinyl RH = reverse hydroxamate group and R2 = hydrogen The compounds of the invention may be provided as pharmaceutically acceptable salts. These include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine. They may also be provided as in vivo hydrolysable esters. These are pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and pharmaceutically acceptable carrier. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal adminstration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove. The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.5 to 75 mg/kg body weight (and preferably of 0.5 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of the human or animal body. In yet a further aspect the present invention provides a method of treating a metalloproteinase mediated disease condition which comprises administering to a warmblooded animal a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. In another aspect the present invention provides 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) (Formula Removed) wherein X1 represents X or a precursor of X (whether by modification or displacement) or an activated form of X suitable for reaction with Y1; Y1 represents Y, a precursor of Y, or an activated form of Y suitable for reaction with X11; by way of non-limiting example, when X is C then X1 may be derivatised to include a precursor of Y for reaction with a compound of formula III wherein Y1 is a precursor of Y; Z1 represents a protected form of Z, a precursor of Z (whether by modification or displacement of Z1) or an activated form of Z; and where Q = -(CH2)(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: (Formula Removed) 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). (Formula Removed) wherein B1 represents a suitable ring function or substituent group for reaction with P1; Z1 is as hereinbefore defined, and P1 represents a suitably activated form of the linker P for reaction with B1 or where X2 = 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 B1 and A respectively, or vice versa. A compound of the formula (II) is conveniently prepared by reacting a compound of the formula (VI) with a compound of the formula (VII) (Formula Removed) wherein B1 represents a suitable ring function or substituent group, X2' represents X or a precursor of X (whether by modification or displacement) or an activated form of X suitable for reaction with B1 and wherein B1 and X2' when reacted together provide the linker P between ring A and ring B in the compound of formula (II). By way of non-limiting example, when X2is N then ring B is suitably derivatised to introduce the linker P via B1, and when X2 is C then both ring B and ring A are suitably derivatised to provide the linker P by the reaction of B1 and X2'. It will be appreciated that many of the relevant starting materials are commercially available. In addition the following table shows details of aldehyde intermediates and their corresponding registry numbers in Chemical Abstracts. (Table Removed) Aldehydes without Chemical Abstracts Registry Numbers 3-(2-pyrimidyl) propionaldehyde. To a solution of 2-Bromopyrimidine (7.95 g, 0.05 M) in acetonitrile (150 mL) was added propargylalcohol (4.2 g, 0.075 M ), bis-(triphenylphosphine)-palladium(ll)chloride (750 mg, 1 mM), copper iodide (100 mg, 0.5 mM) and triethylamine (25mL, 0.25 M) and the mixture was stirred and heated at 70°C for 2 hours. An additional amount of propargyl alcohol (2.1 g, 0.038 M), bis-(triphenylphosphine)- palladium(l l)chloride (375 mg, 0.5 mil), and copper iodide (50 mg, 0.25 mil) was then added to the reaction mixture which was stirred and heated at 70°C for an additional 1 hour. The reaction mixture was evaporated to dryness and the residue which was pre-adsorbed on to silica, chromatographed. Elution with ethyl acetate gave 3-(2-pyrimidyl) prop-2-yn-3-ol as a yellow solid 4.45 g (66 %). NMR (CDCfe) 2.9 (1H, t), 4.5 ( 2H, d), 7.3 ( 1H, d), 8.8 ( 2H, t), MS found NfflT 135 3-(2-pyrimidyl) prop-2-yn-l-ol (4.45 g, 0.033 M) was dissolved in ethyl acetate (140 mL), 10 % Pd/C (890 mg) was added and the mixture stirred under an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through Celite and the filtrate evaporated to give 3-(2-pyrimidyl) propan-1-ol as a yellow oil, 4.15 g (91 %).. NMR (CDC13) 2.1 ( 2H, m), 3.2 (2H, t), 3.8 ( 2H, t), 7.2 ( 1H, t), 8.7 ( 2H, d) MS found MhT 139. 3-(2-pyrimidyl) propan-1-ol was oxidized to give 3-(2-pyrimidyl) propionaldehyde as a yellow oil NMR (CDC13) 3.0 ( 2H, t), 3.4 ( 2H, t), 7.1 ( 1H, t), 8.7 (2H, d), 9.9 ( 1H, s) using the Swern oxidation described in this patent. Using the procedure described above the following aldehydes were prepared 4-(2-pyrimidyl) butyraldehyde by using 3-butyn-l-ol in place of propargylalcohol NMRCDCI3 9.8(1H, s), 8.6 (2H, m), 7.15 (1H, m), 3.0 (2H, m), 2.5 (2H, m), 2.2 (2H, m). 4-(5-pyrimidyi) butyraldehyde by using 3-butyn-l-ol in place of propargylalcohol and 5-bromopyrimidine in place of 2-bromopyrimidine NMR CDCI3 9.8 (1H, s), 9.1 (1H, s), 8.6 ( 2h, s), 2.7 (2H, t), 2.55 (2H, t), 2.0(2H, m). 4-(2-pyridyl) butyraldehyde by using 3-butyn-l-ol in place of propargylalcohol and 2-bromopyridine in place of 2-bromopyrimidine NMR CDCI3 9.8 (1H, s); 8.6 (1H, d), 7.6 ( 1H, m); 7.1( 2H m ); 2.8 (2H, t); 2.55 (2H, t), 2.0(2H, m). The compounds of the invention may be evaluated for example in the following assays: Isolated Enzyme Assays Matrix Metalloproteinase family including for example MMP13. Recombinant human proMMP 13 may be expressed and purified as described by Knauper et al. [V. Knauper et al., (1996) The Biochemical Journal 271; 1544-1550 (1996)]. The purified enzyme can be used to monitor inhibitors of activity as follows: purified proMMP13 is activated using ImM amino phenyl mercuric acid (APMA), 20 hours at 21°C; the activated MMP13 (11.25ng per assay) is incubated for 4-5 hours at 35°C in assay buffer (0.1M Tris-HCl, pH 7.5 containing 0.1M NaCl, 20mM CaCl2, 0.02 mM ZnCl and 0.05% (w/v) Brij 35 using the synthetic substrate 7-methoxycoumarin-4- yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg.NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at ex 328nm and A.em 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescenceplus inhibitor - Fluorescencebackground] divided by the [Fluorescenceminus inhibitor -Fluorescencebackground] . A similar protocol can be used for other expressed and purified pro MMPs using substrates and buffers conditions optimal for the particular MMP, for instance as described in C. Graham Knight etal., (1992) FEBS Lett. 2960)263-266. Adamalvsin family including for example TNF convertase The ability of the compounds to inhibit proTNFa convertase enzyme may be assessed using a partially purified, isolated enzyme assay, the enzyme being obtained from the membranes of THP-1 as described by K. M. Mohler et al, (1994) Nature 370:218-220. The purified enzyme activity and inhibition thereof is determined by incubating the partially purified enzyme in the presence or absence of test compounds using the substrate 4',5'-Dimethoxy-fluoresceinyl Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-succinimid-l-yl)-fluorescein)-NH2 in assay buffer (50mM Tris HC1, pH 7.4 containing 0.1% (w/v) Triton X-100 and 2mM CaCl2), at 26°C for 18 hours. The amount of inhibition is determined as for MMP 13 except ex 490nm and em 530nm were used. The substrate was synthesised as follows. The peptidic part of the substrate was assembled on Fmoc-NH-Rink-MBHA-polystyrene resin either manually or on an automated peptide synthesiser by standard methods involving the use of Fmoc-amino acids and 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) as coupling agent with at least a 4- or 5-fold excess of Fmoc-amino acid and FiBTU. Ser1 and Pro2 were double-coupled. The following side chain protection strategy was employed; Ser1Bu'), Gln5(Trityl), Arg8'12(Pmc or Pbf), Ser9'10'11(Trityl), Cys13(Trityl). Following assembly, the N-terminal Fmoc-protecting group was removed by treating the Fmoc-peptidyl-resin with in DMF. The amino-peptidyl-resin so obtained was acylated by treatment for 1.5-2hr at 70°C with 1.5-2 equivalents of 4',5'-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna & Ullman, (1980) Anal Biochem. 108:156-161) which had been preactivated with diisopropylcarbodiimide and 1 -hydroxybenzotriazole in DMF]. The dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane. The dimethoxyfluoresceinyl-peptide was isolated by evaporation, trituration with diethyl ether and filtration. The isolated peptide was reacted with 4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid. The product was characterised by MALDI-TOF MS and amino acid analysis. Natural Substrates The activity of the compounds of the invention as inhibitors of aggrecan degradation may be assayed using methods for example based on the disclosures of E. C. Arner et al., (1998) Osteoarthritis and Cartilage 6:214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601 and the antibodies described therein. The potency of compounds to act as inhibitors against collagenases can be determined as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345. Inhibition of metaHoproteinase activity in cell/tissue based activity Test as an agent to inhibit membrane sheddases such as TNF convertase The ability of the compounds of this invention to inhibit the cellular processing of TNFα production may be assessed in THP-1 cells using an ELISA to detect released TNF essentially as described K. M. Mohler et al., (1994) Nature 370:218-220. In a similar fashion the processing or shedding of other membrane molecules such as those described in N. M. Hooper et al, (1997) Biochem. J. 321:265-279 may be tested using appropriate cell lines and with suitable antibodies to detect the shed protein. Test as an agent to inhibit cell based invasion The ability of the compound of this invention to inhibit the migration of cells in an invasion assay may be determined as described in A. Albini et al., (1987) Cancer Research 47:3239-3245. Test as an agent to inhibit whole blood TNF sheddase activity The ability of the compounds of this invention to inhibit TNFa production is assessed in a human whole blood assay where LPS is used to stimulate the release of TNFa. Heparinized (10Units/ml) human blood obtained from volunteers is diluted 1:5 with medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160µl) with 20µl of test compound (triplicates), in DMSO or appropriate vehicle, for 30 min at 37°C in a humidified (5%C02/95%air) incubator, prior to addition of 20µl LPS (E. coli. 0111:B4; final concentration 10µg/ml). Each assay includes controls of diluted blood incubated with medium alone (6 wells/plate) or a known TNFa inhibitor as standard. The plates are then incubated for 6 hours at 37°C (humidified incubator), centrifuged (2000rpm for 10 min; 4° C), plasma harvested (50-100µJ) and stored in 96 well plates at -70°C before subsequent analysis for TNFa concentration by ELISA. Test as an agent to inhibit in vitro cartilage degradation The ability of the compounds of this invention to inhibit the degradation of the aggrecan or collagen components of cartilage can be assessed essentially as described by K. M. Bottomley et a!., (1997) Biochem J. 323:483-488. Pharmacodynamic test To evaluate the clearance properties and bioavailability of the compounds of this invention an ex vivo pharmacodynamic test is employed which utilises the synthetic substrate assays above or alternatively HPLC or Mass spectrometric analysis. This is a generic test which can be used to estimate the clearance rate of compounds across a range of species. Animals (e.g. rats, marmosets) are dosed iv or po with a soluble formulation of compound (such as 20%w/v DMSO, 60% w/v PEG400) and at subsequent time points (e.g. 5, 15, 30, 60, 120, 240, 480, 720, 1220 mins) the blood samples are taken from an appropriate vessel into 10U heparin. Plasma fractions are obtained following centrifligation and the plasma proteins precipitated with acetonitrile (80%w/v final concentration). After 30 mins at -20°C the plasma proteins are sedimented by centrifugation and the supernatant fraction is evaporated to dryness using a Savant speed vac. The sediment is reconstituted in assay buffer and subsequently analysed for compound content using the synthetic substrate assay. Briefly, a compound concentration-response curve is constructed for the compound undergoing evaluation. Serial dilutions of the reconstituted plasma extracts are assessed for activity and the amount of compound present in the original plasma sample is calculated using the concentration-response curve taking into account the total plasma dilution factor. In vivo assessment Test as an anti-TNF agent The ability of the compounds of this invention as ex vivo TNFa inhibitors is assessed in the rat. Briefly, groups of male Wistar Alderley Park (AP) rats (180-210g) are dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route e.g. peroral (p.o), intraperitoneal (i.p.), subcutaneous (s.c). Ninety minutes later rats are sacrificed using a rising concentration of CO2 and bled out via the posterior vena cavae into 5 Units of sodium heparin/ml blood. Blood samples are immediately placed on ice and centrifuged at 2000 rpm for 10 min at 4°C and the harvested plasmas frozen at -20°C for subsequent assay of their effect on TNFa production by LPS-stimulated human blood. The rat plasma samples are thawed and 175µl of each sample are added to a set format pattern in a 96U well plate. Fifty µl of heparinized human blood is then added to each well, mixed and the plate is incubated for 30 min at 37°C (humidified incubator). LPS (25µl; final concentration 10µg/ml) is added to the wells and incubation continued for a further 5.5 hours. Control wells are incubated with 25 µl of medium alone. Plates are then centrifuged for 10 min at 2000 rpm and 200µl of the supernatants are transferred to a 96 well plate and frozen at -20°C for subsequent analysis of TNF concentration by ELISA. Data analysis by dedicated software calculates for each compound/dose: Percent inhibition of TNFa= Mean TNFa (Controls) - Mean TNFa (Treated') X 100 Mean TNFa (Controls) Test as an anti-arthritic agent Activity of a compound as an anti-arthritic is tested in the collagen-induced arthritis (CIA) as defined by D. E. Trentham et al, (1977) J. Exp. Med. 146,:857. In this model acid soluble native type II collagen causes polyarthritis in rats when administered in Freunds incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates. Test as an anti-cancer agent Activity of a compound as an anti-cancer agent may be assessed essentially as described in I.J. Fidler (1978) Methods in Cancer Research 15:399-439, using for example the B16 cell line (described in B. Hibner et al., Abstract 283 p75 10th NCI-EORTC Symposium, Amsterdam June 16-19 1998). The invention will now be illustrated but not limited by the following Examples: Accordingly, there is provided a piperazine of the formula I (Formula Removed) wherein ring B is phenyl, pyridyl or pyrimidyl; each R3 is independently selected from hydrogen, halogen, N02, 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, n is 1, 2 or 3; P is a direct bond; Ring A is piperazinyl; Both X2 and XI areN; Y is -SO2-; Z is -N(OH)CHO and Q is CH2; Rl is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10aryl, up to C10aryl, up to C10heteroaryl, up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from N02, CF3, halogen, C1-4alkyl, carboxy (C1-4) alkyl, up to C6 cycloalkyl, -OR4, -SR4, C1-4 alkyl substituted with -OR4, SR4 (and its oxidized analogues), NR4, N-Y-R4, or C1-4 alkyl-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, 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; and R2 is H, C1-6 alkyl, or together with Rl 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 Rl or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S ad N; and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically acceptable salt thereof. EXAMPLES Example 1 1-[2-(N-formvl-N-hvdroxvamino)-2-phenylethanesulfonyl]-4-(4-fluorophenvl)piperazine (Formula Removed) To a solution of l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added a preformed mixture of formic acid (2 ml) and acetic anhydride (0.5 ml). The mixture was stirred at room temperature for one hour. The mixture was evaporated in vacuo and toluene (2 x 5 ml) was added and evaporated in vacuo. The residue was taken in CH2C12 -methanol (6 ml, 9 : 1) and silica (1 g) was added. The mixture was stirred for 18 hours. The silica was filtered off and rinsed with CH2C12 - methanol (9 .1). The residue was purified on silica gel (eluant: CH2Cl2 - MeOH 4 %) to give the title compound as a light orange solid (220mg, 61%). 1H NMR (CDC13) : 8.45 and 8.15 (s, 1H), 7.39 (m, 5H), 6.97 (m, 2H), 6.88 (m, 2H), 5.89 and 5.35 (m, 1H), 4.05 and 3.85 (m, 1H), 3.30-3.53 (m, 5H), 3.20-3.10 (m, 4H); MS (ESI): 408 (MET), 430 (MNa+); EA: calculated for C19H22FN3O4S: C 56.01, H 5.44, N 10.31, S 7.87, Found: C 56.01, H 5.52, N 10.04, S 7.39. The starting material was prepared as follows : i) To a solution of l-(4-fluorophenyl)piperazine (35 g, 194 mmol) and pyridine (17.5 ml) in dry dichloromethane (200 ml) at 0°C was added methanesulfonyl chloride (20 ml, 258 mmol) dropwise. The mixture was stirred for 3 hours at room temperature. The mixture was washed with water and extracted with dichloromethane (2 x 100 ml). The organic layers were dried with MgSO4 and evaporated in vacuo. The residue was triturated and washed with methanol to give l-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (39.35 g) as white crystals. 1H NMR (CDCl3): 7.00 (m, 2H), 6.90 (m, 2H), 3.40 (m, 4H), 3.20 (m, 4H), 2.83 (s, 3H). ii) To a solution of LDA [8.5 mmol; prepared by slow addition of n-butyl lithium (3.5 ml, 8.5 mmol, 2.5 M in hexane) to a solution of diisopropylamine (860 mg, 8.5 mmol) in dry THF (5 ml) at -78°C] at -78°C was added a solution of l-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (1 g , 3.87 mmol) in THF (25 ml) dropwise. The mixture was stirred at -78°C for 1 hour and a solution of diethylchlorophosphate (670 mg ; 3.87 mmol) in THF (3 ml) was added. The mixture was stirred at -78°C for 1 hour and benzaldehyde (450 mg; 4.24 mmol) in THF (3 ml) was added. The mixture was gently warmed to room temperature and stirred for 18 hours. The mixture was washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over MgSO4. Purification of the residue on silica (eluant : dichloromethane) afforded l-(4-fluorophenyl)-4(trans-P-styrenesulfonyl)piperazine as a white powder (621 mg, 46 %). 1H NMR (CDCl3): 7.50 (m, 3H), 7.43 (m, 3H), 6.97 (m, 2H), 6.89 (m, 2H), 6.71 (d, 1H, J= 15.4 Hz), 3.37 (m, 4H), 3.19 (m, 4H). iii) To a solution of l-(4-fluorophenyl)-4-(trans-P-styrenesulfonyl)piperazine (620 mg, 1.79 mmol) in THF (20 ml) was added hydroxylamine (3 ml, 50 % aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried on MgS04 to give l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine(730 mg). 1H NMR (CDCl3): 7.4-7.1 (m, 5H), 6.97 (m, 2H), 6.87 (m, 2H), 5.95 (s br, 1H), 4.74 (s, 1H), 4.60 (dd, 1H, J=4 Hz, T= 8.8 Hz), 3.56 (dd, 1H, J- 8.8 Hz, T= 14.3 Hz), 3.40 (m, 4H), 3.19 (dd, 1H, J= 4 Hz, J'= 14.3 Hz), 3.12 (m, 4H). Example 2 Similarly the following compounds were obtained: (Formula Removed) Example 3 N-hvdroxv-3-f4-(4-fluorophenvnpiperazine-l-suIfonyllpropionamide (Formula Removed) To a solution of N-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]propionamide (125 mg, 0.19 mmol) in dichloromethane (2 ml) was added triethylsilane (66 ul, 0.42 mmol) and trifluoroacetic acid (150 µl). The mixture was stirred at room temperature for 4 hours. The solvents were evaporated in vacuo. The residue was purified by chromatography on silica (eluant : dichloromethane, then ethyl acetate then dichloromethane -10 % MeOH) to give 35 mg of the title compound. 1H NMR (DMSO d-6 + CF3COOD): 7.16 (m, 4H), 3.36 (m, 6H), 3.25 (m, 4H), 2.45 (t, 2H, J = 7.4 Hz); MS (ESI): 332 (MN+), 354 (MNa+). The starting material was obtained as follows: i) A solution of 3-mercaptopropionic acid (20 g, 185 mmol) in acetic acid (150 ml) -water (30 ml) at 0° C was reacted with gaseous chlorine (preferably condensed at -78° C, 20 ml). After chlorine had distilled, the solvents were evaporated in vacuo; toluene was added and evaporated to give l,2-oxathiolane-5-one 2-dioxyde (36.12 g). 'H NMR (DMSO d-6): 2.70 (t, 2H, J= 7.2 Hz), 2.50 (t, 2H, J= 7.2 Hz). ii) A solution of l,2-oxathiolane-5-one 2-dioxide (3.8 g, 28 mmol) in thionyl chloride (20 ml) and DMF (5 drops) was stirred at room temperature for 18 hours. The mixture was heated at 40°C for 1 hour. The solvents were evaporated, toluene was added and evaporated in vacuo to give crude 3-chlorosulfonylpropionyl chloride (NMR purity : 70 %, 3.58 g). 1H NMR (CDC13): 4.02 (t, 2H, J= 7.2 Hz), 3.63 (t, 2H, J= 7.2 Hz) iii) To a solution of 3-chlorosulfonylpropionyl chloride (500 mg, 1.83 mmol, 70 % purity) and diisopropylethylamine (75 ul) in dichloromethane (5 ml) at -78°C was added a solution of 0-dimethoxybenzyl-N-trimethoxybenzylhydroxylamine[Rrf 1] (664 mg ,1.83 mmol) and diisopropylethylamine (320 ul, 1.83 mmol) in dichloromethane (5 ml) dropwise over 2 hours. After 30 minutes, a solution of l-(4-fluorophenyl)piperazine (330 mg, 1.83 mmol) and diisopropylethylamine (320 µl, 1.83 mmol) in dichloromethane (5 ml) was added to the reaction mixture. The solution was warmed to room temperature and stirred for 2 hours. The solution was partitioned between dichloromethane and IN hydrochloric acid. The organic layers were washed with brine and dried over MgSCv Chromatography of the residue on silica gel (eluant: ethyl acetate - petroleum ether: gradient from 50/50 to 80/20) gave N-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]propionamide (260 mg). MS (EI): 661 (M+) Example 4 N-hvdroxv-3-f4-benzvlpiperazine-l-sulfonvl]propionamide (Formula Removed) In a manner analogous to that described in Example 3, from 4-benzylpiperazine and 3-chlorosulfonylpropionyl chloride there was obtained the title compound. 1H NMR (DMSO d-6 + CF3COOD): 7.50 (m, 5H), 4.41 (s, 2H), 3.78 (m, 2H), 3.41 (m, 4H), 3.18 (m, 2H), 2.43 (t, 2H, J= 7.1 Hz); MS (ESI) : 328 (MH+). Example 5 N-hvdroxy-3-[4-(4-fluorophenvnptperazine-l-sulfonyl]-2-isobutylpropionamide. (Formula Removed) To a solution of N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionamide (220 mg) in dichloromethane (4 ml) was added trifluoroacetic acid (200 ui) and triethylsilane (145 ul). The mixture was stirred at room temperature for 15 minutes, evaporated in vacuo and the residue was purified on silica gel (eluant: dichloromethane-ether-methanol (80:20:0.5) to dichloromethane-methanol (80:20) to give the title compound (88 mg, 56 %). 1H NMR (DMSO d-6): 10.72 (s, 1H), 7.08 (m, 2H), 6.99 (m, 2H), 3.37 (dd, 1H, J= 8.4 Hz, J'= 14.3 Hz), 3.27 (m, 4H), 3.15 (m, 4H), 3.00 (dd, 1H, J= 4 Hz, J'= 14.3 Hz), 2.62 (m, 1H), 1.6-1.2 (m, 3H), 0.89 (d, 3H, J = 6.6 Hz), 0.85 (d, 3H, J- 6.6 Hz); MS (ESI): 388 (MH+), 410 (MNa+). The starting material was obtained as follows: i) A solution of 3-acetylthio-2-isobutylpropionic acid [obtained by Michael addition of thiolacetic acid onto 2-isobutylacrylic acid] (7 g, 34.3 mmol), benzyl bromide (4.29 ml, 36 mmol) and DBU (5.2 ml, 35 mmol) in toluene (55 ml) was stirred for 18 hours at room temperature. The solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was washed with brine and dried over MgSO-t. Purification of the residue by chromatography on silica gel (eluant: dichloromethane-ether (9:1)) gave benzyl 3-acetylthio-2-isobutylpropionate (8.4 g) MS(ESI):317(MNa+). ii) A solution of benzyl 3-acetyIthio-2-isobutylpropionate (588 mg, 2 mmol) in acetic acid (12 ml) - water (1.6 ml) at 0°C was reacted with gaseous chloride (prealably condensed at -78°C, 1.9 ml). After chlorine had distilled, the solvents are evaporated in vacuo to give crude benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg). MS (EI): 318 (M+). iii) A solution of benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg, 2 mmol), 1-(4-fluorobenzyl)piperazine (378 mg , 2.1 mmol) and triethylamine (340 ul, 2.4 mmol) in dichloromethane (15 ml) was stirred at 0° C for 18 hours. After evaporation of the solvents, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgSO4. After evaporation of the solvent in vacuo, the residue was purified by chromatography on silica gel (eluant: dichloromethane - ether (91) to give benzyl 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionate (640 mg) MS (EI) : 462 (M+). iv) A solution of benzyl 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionate (630 mg) in methanol (10 ml) was hydrogenated under 40 PSI pressure for 18 hours in the presence of palladium on charcoal (63 mg, 10 %). The catalyst was removed by filtration and the solvents were removed in vacuo to give 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionic acid (460 mg). MS (ESI): 373 (MH+), 395 (MNa4). v) To a solution of 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionic acid (230 mg, 0.62 mmol), 2,4-dimethoxybenzylhydroxylamine [Rcf 1] (124 mg, 0.68 mmol), DMAP (75 mg, 0.62 mmol) in DMF (1 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (152 mg , 0.8 mmol). The mixture was stirred at room temperature for 2 days. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, brine and dried over MgSO4. Purification of the residue on silica gel (eluant: dichloromethane - ether: gradient from 9/1 to 8/2) gave N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionamide (158 mg). lH NMR (CDC13) : 8.21 (s, 1H), 7.30 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 6.46 (m, 2H), 4.95 (m, 2H), 3.82 (s, 6H), 3.50 (dd, 1H, J= 9 Hz, J'= 14.2 Hz), 3.37 (m, 4H), 3.14 (m, 4H), 2.84 (dd, 1H, J= 14.2 Hz, J'= 2 Hz), 2.60 (m, 1H), 1.7-1.2 (m, 3H), 0.90 (m, 6H). Example 6 4-[4-(4-fluorophenvl)piperazine-l-sulfonvlmethvlltetrahvdropvran-4-(N-hvdroxv carboxamide) (Formula Removed) To a solution of 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid (470 mg, 1.21 mmol) in dichloromethane (8 ml) was added oxalyl chloride (700 mg, 5.6 mmol) and DMF (18 ul). The mixture was heated at 35° C for 1 hour. After evaporation of the solvents, the crude acid chloride dissolved in dichloromethane (4 ml) was added to a ice-cooled solution of hydroxylamine (440 ul, 50 % aqueous solution) in THF (8 ml). The mixture was stirred for 90 minutes at room temperature. After evaporation of the solvents, the residue was triturated in dichloromethane-ether-methanol (80 : 20 : 5). The resulting solid was washed with water and ethyl acetate and dried to give the title compound as white crystals (230 mg, 47 %). 1H NMR (DMSO d-6): 10.56 (s br, 1H), 8.74 (s br, 1H), 7.07 (m, 2H), 6.99 (m, 2H), 3.66 (m, 2H), 3.47 (m, 2H), 3.40 (s, 2H), 3.25 (m, 4H), 3.16 (m, 4H), 1.99 (m, 2H), 1.72 (m, 2H); MS (ESI): 402 (MH+), 424 (MNa+). The starting material was prepared as follows: (i) Thiolacetic acid (760 ul, 10 mml) and tributylphosphine (2.5 ml, 10 mmol) in DMF (5 ml) was added dropwise to a ice-cooled suspension of sodium hydride (530 mg, 60 % in oil, 13 mmol) in DMF (1.5 ml) under an argon atmosphere. The mixture was stirred at 0° C for 30 minutes. To the above solution was added 2,7-dioxaspiro[3,5]nonane-l-one[Rcf 2] (1.4 g, 10 mmol) in DMF (10 ml). The mixture was stirred at 0° C for 30 minutes and at room temperature for 18 hours. The reaction mixture was diluted with ether. The precipitate was filtered and dried to give 4-(acetylthiomethyl)tetrahydropyran-4-carboxylic acid sodium salt. 'H NMR (DMSO d-6): 3.65-3.40 (m, 4H), 2.99 (s, 2H), 2.27 (s, 3H), 1.86 (m, 2H), 1.23 (m, 2H). (ii) Using the same procedure described in Example 5 i), ii), iii), iv), v) except that no DBU was used in step 1, from 4-(acetylthiomethyl)tetrahydropyran-4-carboxylic acid sodium salt was obtained 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid (490 mg). 4-(acetylthiomethyl)tetrahydropyran-4-( carboxylic acid benzyl ester): MS (ESI): 331 (MNa+); 4-(chlorosulfonylmethyl)tetrahydropyran-4-( carboxylic acid benzyl ester): MS (ESI): 354 (MNa+); 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid benzyl ester: MS (ESI): 477 (MH+), 499 (MNa+); 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid: MS (ESI): 387 (MH+), 409 (MNa+). Ref 1: B.Barlaam, A.Hamon, M.Maudet; Tetrahedron Lett, 1998,39,7865 Ref 2: F. Hoffmann-La Roche, Agouron Pharm.; Eur. Patent Appl. EP 780386. Example 7 l-f2-(N-formvl-N-hvdroxvamino)-2-phenvlethanesu!fonvn-4-phenYlpiperazine (Formula Removed) To a solution of l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-phenylpiperazine (140 mg) in THF (0.75 ml) and formic acid (0.25 ml) was added a preformed mixture of formic acid (0.58 ml) and acetic anhydride (0.29 ml). The solution was stirred at ambient temperature for 18 hours. The mixture was evaporated in vacuo, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1 % methanol in dichloromethane to give l-phenyl-(4- trans-b-styrenesulfonyl)piperazine (420 mg) as a foam (105 mg). 1H NMR (d6-DMSO at 373K): 9.60 (s, 1H), 8.25 (s, 1H), 7.40 (m, 2H), 7.30 (m, 3H), 7.20 (m, 2H), 6.90 (d, 2H), 6.75 (m, 1H), 5.60 (m, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.30 (m, 4H);3.15(m, 4H) m/z: 390 (M+1). The starting material was prepared as follows. A solution of phenylpiperazine (487 mg) in dichloromethane (6 ml) containing triethylamine (0.63 ml) was added dropwise over 5 minutes to trans-b-styrenesulfonyl chloride (638 mg) in dichloromethane (4 ml). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1 % methanol in dichloromethane to give 1 -phenyl-(4- trans-b-styrenesulfonyl)piperazine (420 mg) as a solid. 1H NMR (d6-DMSO): 7.75 (m, 2H), 7.40 (m, 4H), 7.30 (d, 1H), 7.20 (dd, 2H), 6.90 (d, 2H), 6.80 (dd, 1H), 3.20 (s, 8H) m/z 329 (M+l). To a solution of l-phenyl-4-( trans-b-styrenesulfonyl)piperazine (108 mg) in THF (3 ml) was added hydroxylamine (0.45 ml, 50 % aqueous solution). The mixture was stirred at ambient temperature for 18 hours. Solvent was removed in vauo and the residue dissolved in dichloromethane, washed with water, dried (Na2SO4) and evaporated to give the product l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-phenylpiperazine as a foam (120 mg). lH NMR (d6-DMSO): 7.50 (m, 1H), 7.40 (m, 2H), 7.30 (m, 5H), 6.90 (d, 2H), 6.80 (dd, 1H), 5.90 (m, 1H), 4.20 (m, 1H), 3.60 (dd, 1H), 3.40 (dd, 1H), 3.20 (m, 4H); 3.10 (m, 4H) m/z 362 (M+l). Example 8 l-[2-(N-formyl-N-hvdroxvamino)-2-(quinoline-4-yl)ethane-l-sulfonyl]-4-(4- fluorophenyl)piperazinc (Formula Removed) To a suspension of l-[2-(N-hydroxyamino)-2-(quinoline-4-yl)ethane-l-sulfonyl]-4-(4-fluorophenyl)piperazine (148 mg, 0.34 mmol) in THF (2 ml) - CH2Cl2 (2 ml) was added 5-methyl-3-formyl-l,3,4-thiadiazole-2(3H)-thione(1) (140 mg, 0.87 mmol). The mixture was stirred for 3 h. After addition of methanol (2 ml) and silica (1 g), the mixture was stirred for 18 h. The solids were filtered. The filtrates were washed with sat. NaHCO3 and brine. Evaporation of the solvents followed by trituration in acetonitrile - CH2Cl2 gave the starting material (60 mg). Chromatography of the mother liquors with acetonitrile - CH2Cl2 (1:1) gave the title compound (20 mg, 13%). 1H-NMR (CDCl3): 8.97 (m, 1H), 8.21 (m, 2H), 8.01 (s, 1H), 7.8-7.65 (m, 3H), 6.97 (m, 2H), 6.86 (m, 2H), 5.66 (m, 1H), 3.55-3.1 (m, 10H), MS (ESI): 459 (MH+). The starting material was prepared from quinoline-4-carboxaldehyde and 1-(fluorophenyl)-4-(methanesulfonyl)piperazine in a similar manner to Example 1 ii-iii): 188 mg: MS (ESI): 431 (MET); HPLC tR (Column TSKgel super ODS 2mm 4.6mm x 5cm, gradient methanol/ water 20 to 100% in 5 min, flow rate: 1.4 ml/mn): 3.43 min (1) Yazawa, H.; Goto, S. Tetrahedron Lett., 1985, 26, 3703 Example 9 l-fl-(N-formvi-N-hvdroxyamino)-l-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4- fluorophenyl)piperazine. (Formula Removed) Similarly to Example 1, the syn and anti diastereoisomers of l-[l-(N-hydroxyamino)-l-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-fluorophenyl)piperazine were converted to the title compound (as 2 diastereoisomers): - diastereoisomer 1 from the less polar hydroxylamine: 36 mg, 70%; 'H-NMR (CDC13): 8.45 and 8.10 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.8 (m, 2H), 5.96 and 5.18 (m, 1H), 3.8-3.4 (m, 5H), 2.9-3.15 (m, 4H), 2.0-1.0 (m, 4H), 0.88 and 0.76 (t, 3H, J= 7 Hz); MS (ESI): 540 (M{35Cl,35Cl}Na+), 542 (M{37Cl,35Cl}Na+). - diastereoisomer 2 from the more polar hydroxylamine: 49 mg, 63%; 'H-NMR (CDCl3) : 8.28 and 8.13 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.85 (m, 2H), 5.54 and 5.02 (m, 1H), 3.45-3.9 (m, 5H), 3.15 (m, 4H), 1.7-1.2 (m, 4H), 0.76 (t, 3H, J= 7 Hz); MS (ESI): 540 (M{35Cl,35Cl}Na+), 542 (M{37Cl,35Cl}Na+). The starting material was prepared as follows: Similarly to Example 1 i), from l-(4-fluorophenyl)piperazine and 1-butanesulfonyl chloride was obtained l-(4-fluorophenyl)-4-(butane-l-sulfonyl)piperazine (1.84 g); similarly to Example 1 ii), this was reacted with 3,4-dichlorobenzaldehyde to give 4-(4-fluorophenyl)-l-[l-(3,4-dichlorophenyl)pent-l-ene-2-sulfonyl]piperazine as a mixture of Z/E isomers (330 mg, 22%): MS (ESI): 457 (M{35Cl,35Cl}H+), 459 (M{37C1,35C1}H+); similarly to Example 1 iii) except that the mixture was refluxed for 3 days, this was converted to 1-[1-(N-hydroxyamino)-l-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-fluorophenyl)piperazineas the syn and anti diastereoisomers. Less polar isomer (50 mg, 15%) (TLC: eluant EtOAc - CH2Cl2- petroleum ether (15-45-50); 1H-NMR (CDCl3): 7.53 (d, 1H, J= 2.2 Hz), 7.46 (d, 1H, J= 7.4 Hz), 7.27 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 4.63 (m, 1H), 3.55 (m, 4H), 3.16 (m, 5H), 1.75 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H), 0.77 (t, 3H, J= 7.4 Hz). More polar isomer (76 mg, 23 %); 'H-NMR (CDC13) : 7.52 (d, 1H, J= 2 Hz), 7.45 (d, 1H, J= 8 Hz), 7.27 (m, 1H), 6.99 (m, 2H), 6.89 (m, 2H), 4.42 (m, 1H), 3.55 (m, 4H), 3.41 (m, 1H), 3.14 (m, 4H), 1.6 (m, 2H), 1.25 (m, 2H), 0.76 (t, 3H, J= 7.3 Hz). Example 10 Trans l-[2-(N-formyl-N-hvdroxyamino)cyclohexane-l-sulfonvl]-4-(4-fluorophenyl)-piperazine. (Formula Removed) Similarly to Example 1, from trans l-[2-(N-hydroxyamino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyl)piperazine was obtained the title compound (68 mg, 23%). 1H-NMR (CDCl3) : 8.39 and 8.02 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.40 and 3.92 (m, 1H), 3.35-3.55 (m, 5H), 3.15 (m, 4H), 2.35 (m, 1H), 2.0-1.8 (m, 3H), 1.2-1.6 (m, 4H); MS (ESI): 408 (MNa+). The starting material was obtained as follows : i) To a solution of LDA (51 mmol, prepared by slow addition of n-butyl lithium (20.4 ml, 2.5M in hexane, 51 mmol) to a solution of diisopropylamine (5.16 g, 51 mmol) in THF (30 ml) at -78°C) at -78°C was added a solution of l-(4-fluorophenyl)-4-(methanesulfonyI)-piperazine (6 g, 23.2 mmol) in THF (150 ml). The mixture was stirred for 1 h at -78°C. A solution of 5-chlorovaleryl chloride (4 g, 25.8 mmol) in THF (20 ml) was added dropwise. The mixture was stirred at -78°C for 1 h and at room temperature for 18 h. The solution was diluted with EtOAc and washed with sat. NH4CI and brine and dried over MgSCv Chromatography of the residue on silica gel (eluant : EtOAc - CH2CI2 - petroleum ether (15:35.50)) afforded l-(6-chloro-2-hexanone-l-sulfonyl)-4-(4-fluorophenyl)piperazine (5.22 g, 60%) as white crystals: MS (ESI): 399 (MNa+). ii) A mixture of this compound (5.22 g, 13.9 mmol) and Nal (42 g) in acetone (90 ml) was refluxed for 5 h. After cooling and partitioning between EtOAc and water, the organic layer was washed with 10 % NaHSO3 and brine, and dried over MgSO4 to give l-(6-iodo-2-hexanone-l-sulfonyl)-4-(4-fluorophenyl)piperazine (6.13 g, quantitative) as yellowish crystals: 1H-NMR (CDC13): 6.98 (m, 2H), 6.88 (m, 2H), 4.00 (s, 2H), 3.46 (t, 4H, J= 4.8 Hz), 3.19 (t, 2H, J= 6.6 Hz), 3.16 (t, 4H, J= 4.8 Hz), 2.79 (t, 2H, J= 6.6 Hz), 1.85 (m, 2H), 1.74 (m,2H). iii) A mixture of this compound (1.27 g, 4.85 mmol) and cesium carbonate (8 g, 24.5 mmol) in CH2Cl2 (90 ml) was stirred at room temperature for 4 h. To the mixture was slowly added water and 2N HCl until pH ~ 7. The mixture was extracted with CH2C12. The organic layer was dried over MgSCv Chromatography on silica gel (eluant: EtOAc - petroleum ether (4:6)) afforded l-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (880 mg, 53%). !H-NMR(CDC13): 6.97 (m, 2H), 6.88 (m, 2H), 3.83 (m, 1H), 3.48 (m, 4H), 3.12 (m, 4H), 2.81 (m, 1H), 2.54 (m, 1H), 2.46 (m, 1H), 2.2-2.0 (m, 3H), 1.75 (m, 2H); MS (ESI): 363 (MNa+); IR: 1716. Further elution (EtOAc - petroleum ether (6:4)) afforded 1-[(tetrahydropyran-2-yl)methylidenesulfonyl]-4-(4-fluorophenyl)piperazine (630 mg, 38 %): 'H-NMR (CDC13) : 6.98 (m, 2H), 6.87 (m, 2H), 5.21 (s, 1H), 4.14 (t, 2H, J= 5.2 Hz), 3.32 (m, 4H), 3.15 (m, 4H), 2.35 (t, 2H, J- 6.6 Hz), 1.82 (m, 4H); MS (ESI): 363 (MNa+). iv) To a solution of l-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (284 mg, 0.83 mmol) in methanol-THF (16 ml, 3:1) at 0°C was added sodium borohydride (3.7 mg, 1 mmol). The mixture was stirred at 0°C for 30 min and at room temperature for 1 h 30. The solvents were evaporated. Saturated NH4CI and water were added. The precipitate was filtered, washed with water and dried to give l-(2-cyclohexanol-l-sulfonyI)-4-(4-fluorophenyl)piperazine (250 mg, 88%): MS (ESI) : 343 (MH+). v) To a solution of l-(2-cyclohexanol-l-sulfonyl)-4-(4-fluorophenyl)piperazine (310 mg, 0.9 mmol) in THF (15 ml) was added triphenylphosphine (1.18 g ; 4.5 mmol) and DEAD (712 p.1, 4.5 mmol) dropwise. The mixture was stirred at room temperature for 18 h. Evaporation of the solvents and purification on silica gel (eluant: EtOAc -petroleum ether, gradient from 2:8 to 3:7) gave l-[l-cyclohexene-l-sulfonyl]-4-(4-fluorophenyl)piperazine (285 mg, 98%): MS (ESI): 325 (MH+). vi) Similarly to Example 1 iii) except that the reaction was heated at 65°C for 30 h, from l-(l-cyclohexene-l-sulfonyl)-4-(4-fluorophenyl)piperazine (280 mg, 0.86 mg) was obtained trans 1 -[2-(N-hydroxyamino)cyclohexane-1 -sulfonyl]-4-(4-fluorophenyl)piperazine (270 mg, 88%): !H-NMR (CDC13): 6.98 (m, 2H), 6.88 (m, 2H), 3.54 (m, 4H), 3.34 (m, 2H), 3.14 (m,4H), 2.30 (m, 1H), 2.17 (m, 1H), 2.05 (m, 1H), 1.9-1.2 (m, 5H); MS (ESI): 358 (MH+). Example 11 Cis l-r2-(N-formvl-N-hvdroxvamino)cvclohcxaiie-l-sulfonvll-4-(4-fluoroDhenvl)- piperazinc. (Formula Removed) Similarly to Example 1, from cis l-[2-(N-hydroxyamino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyl)piperazine was obtained the title compound (18 mg, 18%): 'H-NMR (CDCI3): 8.39 and 8.07 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.77 and 4.25 (m, 1H), 3.48 (m, 5H), 3.13 (m, 4H), 2.25-1.3 (m, 8H); MS (ESI) : 408 (MNa+). The starting material was obtained as follows : i) A mixture of l-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (50 mg, 0.14 mmol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and potassium acetate (72 mg, 0.73 mmol) in methanol (5 ml) was heated at 70°C for 4 h. The solvents were evaporated. After partitioning between EtOAc and water, the organic layer was washed with brine and dried over MgSO4 to give l-[2-(N-hydroxyimino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyi)piperazine as a white solid (48 mg, 94%): MS (ESI): 356 (MET), ii) To this compound (210 mg, 0.6 mmol) in a mixture of THF - acetic acid (7 ml, 1:1) was added sodium cyanoborohydride (276 mg, 4.4 mmol). The mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 9. The mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgS04. Chromatography on silica (eluant: EtOAc - petroleum ether, gradient from 1:1 to 8:2) afforded cis l-[2-(N-hydroxyamino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyl)piperazine (97 mg, 45%). 'H-NMR (CDCI3): 6.98 (m, 2H), 6.89 (m, 2H), 3.63 (m, 1H), 3.52 (m, 4H), 3.24 (dt, 1H, Jd= 10.6 Hz, Jt= 3.5 Hz), 3.15 (m, 4H), 2.2-1.2 (m, 8H); MS (ESI) : 358 (MH"). Example 12 The following compounds were made using the method outlined in Example 1: (Formula Removed) * =M-H R2 = hydrogen PIP = piperazinyl RH = reverse hydroxamate A = carboxylic acid (Table Removed) MS for C17H24FN305S (M+H) calcd 402, found 402. (Formula Removed) The aryl/heteroarylpiperazines and piperidines used as starting materials were commercially available or were described in the literature, for example 4-(4-fluorophenyl)-piperidine, CAS number 37656-48-7 Piperazine, 1 -[ 1,1 '-biphenyl]-4-yl-( 180698-19-5) Piperazine, l-[l,l'-biphenyl]-3-yl- (115761-61-0) Piperazine, l-(2-naphthalenyl)- (57536-91-1) Piperazinone, 1 -phenyl-(90917-86-5) 1H-1,4-Diazepine, l-(4-chlorophenyl)hexahydro-(41885-98-7) Quinoline, 4-methyl-2-(l-piperazinyl)-( 50693-78-2) Piperazine, l-(4-phenoxyphenyl)- 62755-61-7 Piperazine, l-(3-chlorophenyl)- The 2-methyl-4-(4-fluorophenyl)-piperazine used as starting material was prepared as follows: Sodium-t-butoxide (4.1g) was added to a solution of tir-tolylphosphine (0.638g) and palladium acetate (0.319g ) in toluene (250 mL) under argon and the mixture was stirred for 20 minutes. 4-Fluoro-bromobenzene (5g) and 2-methylpiperazine (2.85g) were added and the mixture was heated at 110 °C for 7 hours, then allowed to cool to ambient temperature and keep at this temperature for 20 hours. The reaction mixture was filtered through Celite®, the filter cake was washed twice with dichloromethane (2X25 mL) and the filtrate was evaporated to dryness. The residue was chromatographed on silica eluting initially with dichloromethane and then with a mixture of dichloromethane, methanol and ammonium hydroxide (100:5:1) to give 2-methyl-4-(4-fluorophenyl)-piperazine, 2.5g. Using this same method and 2,6-dimethylpiperazine as starting material there was obtained 2,6-dimethyl-4-(4-fluorophenyl)-piperazine. Piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl hydrochloride tert-butoxycarbonyl piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl (0.712g) was stirred in a mixture of dichloromethane (10ml) and trifluoroacetic acid (1.0ml) for 18 hours at ambient temperature, evaporated in vacuo to a grey solid and used without further purification. The_tert-butoxycarbonyl piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl used as starting material was prepared as follows: Sodium-t-butoxide (1.35g) was added to a solution of S-(-)-2,2'-bis(diphenylphosphino)-l,l'-binapthyl (0.046g) and bis(dibenzylideneacetone)palladium (0.023g ) in toluene (25 ml) under argon and then added 4-bromo-4'-fluorobiphenyl (2.5 lg) and 1-tert-butoxycarbonylpiperazine (2.2g) and the mixture was heated at 80°C for 5 hours. The reaction mixture was filtered, filtrate evaporated in vacuo to a yellow solid which was triturated and then filtered from diethyl ether(20 ml) to give tert-butoxycarbonyl piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl, (2.67g), mp 165-166 °C. NMR(d6-DMSO) 1.42 (s, 9H), 3.15 (m, 4H), 3.48 (m, 4H), 7.02 (d, 2H), 7.22 (m, 2H), 7.51 (d, 2H), 7.63 (m, 2H), m/z 357(M+1). Example 13 (Formula Removed) Acetic anhydride (0.23mi) was added directly to formic acid (0.9ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(6-chloropyrimidin-4-yl)tetrahydropyrazin-1 -yl]sulfonyl} -1 -(3,4- dichlorophenyl)ethyl]hydroxylamine (0.227g) in tetrahydrofuran (5ml). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water-bath temperature 30 °C) and the residual gum was purified by chromatography using a lOg silica isolute eluting with CH2C12-3% Methanol/CH2C12 to give N-[2-{[4-(6-chloropyrimidin-4-yl)piperazino]sulfonyl}-l-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.178g), 98-101°C. NMR (d6-DMSO 373 °K): 3.31 (m, 4H), 3.70 (dd, 1H), 3.75 (m, 4H), 3.95 (dd, 1H), 5.61 (vbs, 1H), 6.89 (s, 1H), 7.43 (dd, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 8.29 (s, 1H), 8.36 (s, lH);m/z494(M+l). (Formula Removed) Acetic anhydride (0.63ml) was added directly to formic acid (2.48ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-l-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.6lg) in tetrahydrofuran (10ml). The solution was stirred at room temperature for 3 hours.and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2S04), and evaporated to dryness. The residue was purified by chromatography using a lOg silica isolute eluting with 10% ethyl acetate/heaxane-80% ethyl acetate/hexane and then evaporated to dryness. The resulting white solid was filtered from diethyl ether to give N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-l-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.43 lg), 211-212°C. NMR (d6-DMSO 373 °K): 3.30 (m, 4H), 3.80 (m, 4H), 3.85 (dd, 1H), 3.95 (dd, 1H), 5.58 (vbs, 1H), 6.85 (d, 1H), 7.43 (m, 1H), 7.58 (m, 2H), 7.85 (d, 1H), 8.10 (d, 1H), 8.13 (s, lH);m/z 493 (M+l) Acetic anhydride (0.48ml) was added directly to formic acid (1 9ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-(2-(benzyloxy)-l-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyI}ethyl)hydroxylamine (0.42g) in tetrahydrofuran (5ml). The solution was stirred at room temperature for 3 hours.and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2S04), and evaporated to dryness. The residue was purified by chromatography using a 10g silica isolute eluting with CH2C125% Methanol/CH2C12 to give N-(2-(benzyIoxy)-l-{[(4-pyridin-2-ylpiperazino)sulfonyI]methyl-ethyl)-N-hydroxyformamide (0.233g) , 70-75 °C. NMR(d6-DMSO 373 °K): 3.25 (dd, 1H), 3.31 (m, 4H), 3.48 (dd, 1H), 3.65 (m, 4H)„ 3.66 (dd, 1H), 3.70 (dd, 1H), 4.55 (vbs, 1H),4.55 (s, 2H), 6.70 (m, 1H), 6.85 (d, 1H), 7.28 (m, H), 7.32 (m, 4H), 7.58 (m, 1H), 8.17 (m, 2H), 9.45 (bs, lH);m/z435 (M+l). (Formula Removed) Acetic anhydride (0.48ml) was added directly to formic acid (1 9ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-(3-pyridin-2-yl-l-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyl-propyl)hydroxylamine (0.152g) in tetrahydrofuran (5ml). The solution was stirred at room temperature for 3 hours.and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2S04), and evaporated to dryness. The residue was purified by chromatography using a 10g silica isolute eluting with CH2C125% Methanol/CH2C12 to give N-hydroxy-N-(3-pyridin-2-yl-l-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyl}propyl)formamide (0.039g), 80-84 °C NMR(d6-DMSO 373 °K):2.10 (m, 2H), 2.80 (m, 2H), 3.25 (dd, 1H), 3.30 (m, 4H), 3.50 (dd, 1H), 3.60 (m, 4H), 4.42 (vbs, 1H), 6.70 (m, 1H), 6.85 (d, 1H), 7.19 (m, 1H), 7.22 (d, 1H), 7.54 (m, 1H), 7.65 (m, 1H), 8.10 (vbs, 1H), 8.15 (m, 1H), 8.45 (m, 1H), 9.50 (vbs, lH);m/z420(M+l). Example 14 N-{l-[((4-("(5-chloropyridin-2-vl)oxy]piperidino}sulfonyl)methyl]-3-pyridin-3-ylpropyl}-N-hydroxyformamide (Formula Removed) To a solution of l-N-[2-(hydroxyamino)-2-(3-pyridinyl)butanesulfonyl]-4-0-(5-chloro-2-pyridinyl)piperidine (2.1 g, 4.18 mmol) in THF (36 ml) added a preformed mixture of formic acid (9.0 ml) and acetic anhydride (2.25 ml). The mixture was stirred at room temperature for 18 hrs. The reaction was neutralised using saturated aqueous NaHCO3 before extracting the solution with EtOAc (x2). The combined organics were dried over Na2SO4 and evaporated in vacuo. The residue was stirred in MeOH at room temperature for 20 hrs to remove the bis-formyl. The residue was crystallised from EtOH to afford a white solid (0.898g). m.p. 130-140°C. 1H NMR(DMSO-100°C):9.50(brs, 1H), 8.43 (d, 1H), 8.39 (dd, 1H), 8.15(d, 1H), 8.13 (br s, 1H), 7.74 (dd, 1H), 7.60 (m, 1H), 7.27 (m, 1H), 6.83 (d, 1H), 5.12 (m, 1H), 4.32 (br s, 1H), 3.42 (m, 3H), 3.16 (m, 3H), 2.68-2.54 (m, 2H), 2.06-1.93 (m, 4H), 1.76 (m, 2H); MS (ES+): 469.2 (MH+), 491.1 (MNa+); EA: calculated for C20H25ClN4O5S: C 51.22, H 5.37.C1 7.56, N 11.95, S 6.84, Found: C 50.92, H 5.30, CI 7.55, N 11.90, S 6.75. The starting material was prepared as follows : i) NaH (2.88g, 66mmol, 55% dispersion in mineral oil) was stirred in dry DME (200ml), under Argon. A mixture of 2,5- dichloropyridine (8.87g, 60mmol) and 4-hydroxypiperidine (6.67g, 66mmol) dissolved in dry DME (200ml) was added to the NaH suspension dropwise, over a period of 30 minutes. After complete addition the reaction is heated to 82°C for 48 hrs, maintaining the Argon blanket. The reaction was slowly quenched with water before removing most of the THF. Extracted the aqueous with DCM (x3). The organic layers were dried with Na2SO4 and evaporated in vacuo to afford 2-(4-piperidinyloxy) -5-chloropyridine as a yellow oil (12.7g, quantitative). 'H NMR (DMSO): 8.17 (d, 1H), 7.76 (dd, 1H), 6.81 (d, 1H), 4.96 (m, 1H), 2.93 (m, 2H), 2.53 (m, 2H), 1.91 (m, 2H), 1.46 (m, 2H); MS (ES+): 213.3 (MET), 225.3 (MNa+) ii) To a solution 2-(4-piperidinyloxy) -5-chloropyridine(12.9 g, 0.06 mol) and Et3N (25.4 ml, 0.182 mol) in dry dichloromethane (400 ml) at 0°C and under Argon, was added methanesulfonyl chloride (5.3 ml, 0.067 mol) in dry dichloromethane (100 ml), dropwise. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with dichloromethane (250 ml), then washed with water (x3) then brine. The organic layers were dried with Na2SO4 and evaporated in vacuo. The residue was triturated and washed with diethylether to give 2-(N-methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (15.1 g) as a pale yellow solid. 1H NMR (DMSO): 8.20 (d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.90 (s, 3H), 2.02 (m, 2H), 1.75 (m, 2H); MS (ES+): 291.2 (MH+), 313.2 (MNa4). iii) 2-(N-methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (2.0g, 6.89 mmol) was taken into anhydrous THF (100 ml) under Argon then cooled to -78°C before the addition of Li(TMSA) (13.8 ml of a 1.0M solution in THF, 13.8 mmol), . The mixture was stirred at -78°C for 20 minutes and a solution of diethylchlorophosphate (1.05 ml, 7.23 mmol) was added. The mixture was stirred at -78°C for 1 hour before 3-pyridinylpropanaI (1.12g, 8.27 mmol) was added then stirred at -78 for a further lhr. The mixture was allowed to warmed to room temperature then was washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over Na2SO4. Purification of the residue on silica (eluant: gradient, DCM - 2% MeOH/DCM ) afforded 2-{N-[E/Z-4(3-pyridyl)-but-lenyl] sulfonyl}4-piperidinyloxy) -5-chloropyridine as a yellow oil (2.09g). 1HNMR (DMSO): 8.45 (m, 1H), 8.37 (m, 1H), 8.19 (m, 1H), 7.82 (m, 1H), 7.64 (m, 1H,), 7.30 (m, 1H), 6.85 (m, 1H), 6.88-6.27 (m, 2H, E/Z isomers), 5.00 (m, 1H), 3.15 (m, 2H), 2.83 (m, 5H), 2.61 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H); MS (ES+): 408.1 (MH+), 430.2 (MNa+). iv) To a solution of 2-{N-[E/Z-4(3-pyridyl)-but-lenyl] sulfonyl}4-piperidinyloxy) -5-chloropyridine(2.09 g, 5.1 mmol) in THF (20 ml) was added hydroxylamine (3.4 ml, 50 % aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in EtOAc and washed with water (x4). The organic layer was dried on Na2SO4 and evaporated in vacuo to give 2-(4-piperidinyloxy) -5-ch!oropyridine l-N-[2-(hydroxyamino)-2-(3-pyridinyl)butanesulfonyl]-4-0-(5-chloro-2-pyridinyl)piperidine (730 mg). 'HNMR (DMSO): 8.43 (d, 1H), 8.37 (dd, 1H), 8.18 (d, 1H), 7.78 (dd, 1H), 7.61 (m, 1H), 7.36 (s, 1H), 7.29 (m, 1H), 7.85 (d, 1H), 5.70 (s, 1H), 5.08 (m, 1H), 3.35 (m, 3H), 3.16-3.00 (br m, 4H), 2.80-2.60 (br m, 2H), 1.98 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H); MS (ES+); 441.2 (MH+), 463.2 (MNa+). Using an analogous procedure to that described in Example X, a aryl-4-O-piperidine was reacted with the appropriate aldehyde to give the compounds listed below. (Formula Removed) (Table Removed) The following aryl-4-O-piperidines have been described previously: Piperidine, 4-(3-chlorophenoxy)-(9Cl), CAS (97840-40-9) Piperidine, 4-(4-chlorophenoxy)-(9Cl), CAS (97839-99-1) Pyridine, 2-(4-piperidinyloxy)-(9Cl), CAS (127806-46-6) Piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) was synthesised in the following alternative route:- 1) To a stirred solution 4-hydroxypiperidine(3.5 g, 0.035 mol) in dry methanol (50 ml) at 0°C, was added di-butyl dicarbonate (9.2 ml, 0.042 mol) in dry methanol (50 ml), dropwise. The mixture was stirred for 20 hours at room temperature. The methanol was removedand the remaining solution was taken into Et2O, then washed with 1M citric acid (x3) and water (x3). The combined aqueous extracts were extracted with Et20 which was dried with Na2SO4 and evaporated in vacuo. Purification of the residue on silica (eluant: gradient, DCM - 30% MeOH/DCM ) afforded N-BOC-4-hydroxypiperidine as a yellow oil (6.4g). 'H NMR (DMSO). 4.05 (m, 2H), 3.70-3.52 (br m, 3H), 2.92 (m, 2H), 1.66 (m, 2H), 1.40 (s, 9H), 1.33-1.18 (br m, 2H); MS (ES+): 201.3 (MH+), 219.4 (MNH/). 2) To a stirred solution N-BOC-4-hydroxypiperidine(2.0 g, 0.01 mol), triphenylphosphine (3.68g, 0.014 mol) and 3,4-dichlorophenol (1.96g, 0.012 mol) in dry toluene (75 ml) [with molecular sieves, at 0°C and under Argon] was added diethyl azodicarboxylate (2.52 ml, 0.016 mol), dropwise. The mixture was stirred for 1.5hrs at 0°C. Filtered the solution and removed the toluene before vigorously stirringin isohexane (100ml) and filtered the resulting suspension. The filtrate was washed with 2M aqueous NaOH (x8), dried with Na2S04 and evaporated in vacuo. Purification of the residue on silica (eluant: 20% EtOAc/isohexane ) afforded N-Boc-Piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) as a yellow solid (1.96g). H NMR (DMSO): 7.52 (d, 1H), 7.31 (d, 1H), 7.01 (dd, 1H), 4.62 (m, 1H), 3.65 (m, 2H), 3.15 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H), 1.40 (s, 9H); MS (ES+): 346.3 (MH+), 368.4 (MNa+). 3) 50% aquous trifluoroacetic acid (18ml) was added to a stirred solution N-Boc- piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) (1.96 g, 5.66 mmol). After 3.5hrs toluene is added and evaporated in vacuo, this was repeated twice. The residue was then taken into EtOAc washed with saturated aqueous NaHCO3 (x3), dried with Na2SO4 and evaporated in vacuo to afforded piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) a white solid (1 3g). 'H NMR (DMSO): 7.54 (d, 1H), 7.35 (d, 1H), 7.04 (dd, 1H), 4.70 (m, 1H), 3.31 (m, 2H), 3.09 (m, 2H), 2.08 (m, 2H), 1.80 (m, 2H); MS (ES+): 2.26.3 (MH+). Piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) was then taken through steps ii-iv as described above. Example 15 l-Mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine 1-Mesylpiperazine hydrochloride (4.24g) was added to a solution of methyl 6-chloronicotinate (1.7g) and N,N-diisopropylethylamine (6.3ml) in dimethylacetamide (20ml) and the mixture was heated at 120°C for 2 hours. The mixture was allowed to cool to ambient temperature and poured onto crushed ice/water (50ml) to precipitate a tan solid. The solid was collected by filtration and dried at 80 °C for 18 hours in a vacuum oven, to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05g), mp 205-207°C. NMR (d6-DMSO): 2.90 (s, 3H), 3.20 (m, 4H), 3.78 (m, 3H), 3.80 (s, 3H), 6.92 (d, 1H), 8.00 (dd, 1H), 8.67 (d, 1H); m/z 300 (M+l). Using an analogous procedure 1-mesylpiperazine hydrochloride, CAS( 161357-89-7), was reacted with the appropriate chloropyridine to give the following compounds. (Table Removed) 1 -(6-chloropyrimidin-4-yl)-4- mesylpiperazine A mixture of 4,6-dichloropyrimidine (39.4g), 1-mesylpiperazine hydrochloride (55.7g) and triethylamine (116ml) in ethanol (500ml) was stirred at reflux temperature for 4 hours. The mixture was then stirred at room temperature for 12 hours. The solid, which had separated, was collected by filtration, slurry washed with ethanol (2x80ml, 160ml) then with diethyl ether (150ml), and dried to give l-(6-chloropyrimidin-4-yl)-4- mesylpiperazine as a cream solid (71.9g). mp 200-202°C NMR (d6-DMSO): 2.88 (s, 3H), 3.18 (m, 4H), 3.80 (m, 4H), 7.04 (s, 1H), 8.38 (m, 1H); m/z 277.3 (M+l). Using an analogous procedure 1-mesylpiperazine hydrochloride, CAS( 161357-89-7), was reacted with the appropriate chloropyrimidine or chloropyridazine to give the following compounds. (Table Removed) Example 16 (Formula Removed) Acetic anhydride (19ml) was added directly to formic acid (76ml). The solution was stirred at room temperature for 30 minutes. A solution of l-(6-chloropyrimidin-4-yl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine (17.2g) in tetrahydrofuran (85ml) was added in portions, to the above solution at 27 °C over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30°C) and the residual gum was dissolved in ethyl acetate (500ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (200ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in ethanol, a solid separated and the mixture was stirred for 2 days. The solid was collected by filtration, slurry washed with diethyl ether (100ml), and dried to give N-[l-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamide as a colourless solid (12.8g). mp 155-157°C. Found C, 50.29, H, 5.29, Cl, 7.82, N, 15.31, and S, 6.82 %. C19H24ClN5O4S requires C, 50.27, H, 5.33, Cl, 7.81, N, 15.43, and S, 7.06 %. NMR(d6-DMSO 373°K). 1.93 (m, 1H), 2.03 (m, 1H), 2.57 (m, 1H), 2 65 (m, 1H), 3.20 (dd, 1H), 3.26 (t, 4H), 3.48 (dd, 1H), 3.74 (t, 4H), 4.3 (v br, 1H), 6.90 (s, 1H), 7.19 (m, 3H), 7.27 (m, 2H), 8.1 (br, 1H), 8.38 (s, 1H), 9.5 (s, 1H); m/z 454.2 (M+l). (Formula Removed) Acetic anhydride (31.5ml) was added directly to formic acid (126ml). The solution was stirred at room temperature for 30 minutes. A solution of l-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine (29.5g) in tetrahydrofuran (150ml) and formic acid (25ml), was added in portions to the above solution at 25 °C over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30°C) and the residual gum was dissolved in ethyl acetate (500ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2x250ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in methanol (70ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water-bath temperature 30 °C). The residual foam was stirred in ethanol (250ml), solid separated and the mixture was stirred for 18 hours. The solid was collected by filtration, slurry washed with diethyl ether (100ml), and dried to give N-[2-(benzyloxy)-l-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide (25.5g). mp 118-120°C Found C, 48.35, H, 5.09, Cl, 7.26, N, 14.73, and S, 6.78 %. C19H24ClN5O5S requires C, 48.56, H, 5.15, Cl, 7.54, N, 14.90, and S, 6.82 %. NMR(d6-DMSO 373 °K): 3.23 (dd, 1H), 3.30 (t, 4H), 3.46 (dd, 1H), 3.57 (dd, 1H), 3.67 (dd, 1H), 3.72 (t, 4H), 4.50 (s, 2H), 4.50 (m, 1H), 7.35 (m, 5H), 8.15 (br, 1H), 8.38 (s, 1H), 9.48 (br, 1H), m/z 470.2 (M+1). (Formula Removed) Acetic anhydride (0.8ml) was added directly to formic acid (3.2ml). The solution was stirred at room temperature for 30 minutes. A solution of l-(5-chloro-2-pyridyl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine (0.72g) in tetrahydrofuran (5ml) was added to the above solution at room temperature. The solution was stirred at room temperature for 2 days. The solution was evaporated (water-bath temperature 40°C). The residue was dissolved in 5% methanol in dichloromethane. Silica (5g Merck 9385) was added to the solution, the mixture was stirred for 21 hours, and evaporated to dryness. The material (pre-adsorbed on the silica) was purified by chromatography on silica (Bond Elut 10g), using 0-3% methanol in dichloromethane as eluent, to give N-[ 1-({[4-(5-chloro-2-pyridyl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamide as an orange foam (0.17g). NMR (d6-DMSO 373°K): 1.92 (m, 1H), 2.04 (m, 1H), 2.55 (m, 1H), 2.64 (m, 1H), 3.20 (dd, 1H), 3.27 (m, 4H), 3.47 (dd, 1H), 3.58 (m, 4H), 4.35 (v br, 1H), 6.88 (dd, 1H), 7.17 (m, 3H), 7.27 (m, 2H), 7.57 (dd, 1H), 8.10 (s, 1H), 8.10 (br, 1H), 9.5 (s, 1H); m/z 453.3 (M+l). Example 17 (Formula Removed) To formic acid (31.5ml) at 0°C was added acetic anhydride (7.9ml). After 20 minutes this was added to the hydroxylamine (6. lOg) dissolved in THF (80ml) and formic acid (40ml) and the resulting solution stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue dissolved in DCM (500ml), washed with saturated sodium bicarbonate solution (2x500ml), dried and evaporated to dryness. To the residue dissolved in DCM (10ml) was added diethyl ether (100ml) to give the product as a white solid (5.60g) which was collected by filtration. Mpt 168-170°C. NMR DMSOd6 d 10.2 (br s, 1H); 9.8 (br s, 1H); 8.7 (br s, 1H); 8.6 (br s, 1H); 8.5 (d, 1H); 8.3 (m, 1H), 8.1 (d, 1H); 7.9-7.8 (m, 1H); 7.6 (dd, 1H); 7.4 (dd, 1H); 6.9 (d, 1H); 5.8 (m, 1H); 5.5 (m, 1H); 4.1-3.6 (m, 2H); 3.6 (m, 4H); 3.2 (m, 4H). Anal. Calcd for C17H20ClN5O4S: C, 48.0; H, 4.7; Cl, 8.3; N, 16.5; S, 7.5. Found: C, 47.9; H, 4.7; CI, 8.4, N, 16.3; S, 7.5. MS for C17H20CIN5O4S (M+H) calcd 426, found 426. rotameric signals Step A (Formula Removed) The oxime (31.05g) [Tetrahedron Letters 1994,_35, 1011 ] was dissolved in DCM (500ml) and 3-pyridinecarboxaldehyde (12.09g) was added followed by anhydrous magnesium sulfate (13.6g). After 2 days stirring at room temperature more magnesium sulfate (13.6g) was added and stirring was continued for a further 3 days. The mixture was then filtered, the solvent evaporated and the residue triturated with diethyl ether to give the product (36.34g) as a white solid. Mpt 174-175°C. NMR CDC13 d 9.0 (s, 1H); 8.9 (d, 1H); 8.7 (d, 1H), 7.7 (s, 1H); 7.4 (dd, 1H); 5.6 (s, 1H); 5.3 (d, 1H), 4.9 (dd, 1H); 4.6 (dd, 1H); 4.4 (ddd 1H); 4.2 (dd, 1H); 3.7 (dd, 1H); 1.5 (s, 3H); 1.4 (s, 3H); 1.4(s, 3H); 1.3 (s, 3H). StepB (Formula Removed) The methyl sulfonamide (14.30g) was dissolved in THF (500ml) and cooled to -10°C when lithium hexamethyldisylazide (78ml, 1.0M in THF) was added. After 30 minutes the solution was cooled to -78°C, and the nitrone (18.00g) dissolved in THF (350ml) was added, keeping the temperature below -65°C. The resulting solution was stirred for 3 hours at -78°C when it was quenched by the addition of brine (500ml) and the aqueous layer extracted with ethyl acetate (3x500ml). The combined organic layers were dried and evaporated to give a yellow solid which was triturated with ethyl acetate / isohexane (4:1) and then purified by flash column chromatography eluting with dichloromethane / methanol (97:3) to give 1 (16.40g) as a white solid. Mpt 209-211°C (dec). NMR CDC13 d 8.6 (s, lH);8.4(d, 1H);8.1 (d, 1H); 7.8 (d, 1H); 7.5 (br s, 1H); 7.4 (dd, 1H); 7.3 (dd, 1H); 6.6 (d, 1H), 4.9 (d, 1H); 4.8 (s, 1H); 4.7-4.6 (m, 2H); 4.2-4.1 (m, 3H); 3.8 (dd, 1H); 3.6 (dd, 1H); 3.5-3.4 (m, 5H); 3.3-3.2 (m, 4H); 1.4 (s, 3H); 1.3 (s, 3H); 1.3 (s, 3H); 1.3 (s, 3H). (Formula Removed) To a solution of hydroxylamine 2 (14.90g,) in ethanol (300ml) was added water (220ml) followed by O-benzylhydroxylamine hydrochloride (13.91g) and sodium bicarbonate (6.95g). Heating gave a solution which was stirred overnight at 80°C. The ethanol was removed under reduced pressure and the residue separated between water (500ml) and ethyl acetate (500ml). The aqueous layer was washed with ethyl acetate (2x500ml), and the combined organic layers were dried and evaporated to give a residue which was triturated with dichloromethane (100ml) to give 3 (6.10g) as a white solid. The mother liquor was purified by flash column chromatography eluting with ethyl acetate followed by dichloromethane/methanol (96:4) to give further 3 (0.85g). Mpt 170-173°C. NMR DMSOck d 8.6 (s, 1H); 8.5 (d, 1H), 8.1 (d, 1H); 7.8 (d, 1H); 7.6 (dd, 1H); 7.6 (s, 1H); 7.3 (dd, 1H); 6.9 (d, 1H); 6.1 (br s, 1H); 4.3 (br s, 1H); 3.7-3.4 (m, 6H); 3.2-3.1 (m, 4H). Example 18 The following compounds were made using the method outlined in Example 7 (Formula Removed) (Table Removed) * =M-H R2 = hydrogen PIP = piperazinyl RH = reverse hydroxamate The starting material was prepared as follows: The addition of hydroxylamine to l-trans-p-styrenesulphonyl-piperidine-4-(N-phenylcarboxamide) and the subsequent formylation of the product was carried out as described in Example 7. Dimethylformamide (2 drops) was added to a suspension of 1-trans-fi-styrenesulphonyl-piperidine-4-carboxylic acid (0.75g) and oxalyl chloride (0.23 mL) in dichloromethane (10 mL) and was stirred for 2 hours. The reaction mixture was evaporated to dryness, re-dissolved in dichloromethane (10 mL) and evaporated to dryness again. The residue obtained was dissolved in dichloromethane (4 mL) and a mixture of aniline (0.23 mL) and triethylamine (0.35 mL) was added dropwise. The mixture was stirred for 20 hours and was washed with dilute 2M hydrochloric acid, water, aqueous saturated sodium bicarbonate solution and water and dried. Removal of the solvent gave l-trans-{3-styrenesulphonyl-piperidine-4-(N-phenylcarboxamide), 0.89g Using the method described above there were prepared the following l-trans-P-styrenesulphonyl-piperidine-4-carboxamides (Table Removed) A solution of ethyl piperidine-4-carboxylate (3.99g) in a mixture of THF (30 mL) and methanol (6 mL) was treated with aqueous sodium hydroxide solution (20 mL of 2M NaOH) and the mixture stirred for 3 hours, evaporated to small volume and acidified to pH 5 with dilute 2M hydrochloric acid. The mixture obtained was extracted with ethyl acetate (2x25 mL), the ethyl acetate extracts were washed with water, dried and evaporated to dryness to give l-trans-P-styrenesulphonyl-piperidine-4-carboxylic acid, 2.64 g. A solution of ethyl piperidine-4-carboxylate (3.0 mL) and triethylamine (2.7 mL) in dichloromethane (10 mL) was added dropwise to a cooled (ice bath) solution of trans-P-styrenesulphonyl chloride (3.95g) in dichloromethane (10 mL). The reaction mixture was allowed to warm to ambient temperature and stirring was continued for 20 hours. The reaction mixture was evaporated to dryness , the residue was diluted with water and extracted with ethyl acetate (2x25 mL). The combined ethyl acetate extracts were washed with brine and dried (MgS04) to give ethyl -(l-trans-P-styrenesulphonyl)-piperidine-4-carboxv!ate 5.76g, M+H = 324. An alternative procedure for the preparation of 1 -trans-P-3,4dichlorostyrenesulphonyl-piperidine-4-carboxylic acid may be used: To a solution of l-trans-P-3,4dichlorostyrenesulphonylchloride (2.7g) and isonipecotic acid (1.41g) in acetonitrile (15ml) was added 2M sodium hydroxide (I I ml) and stirred at ambient temperature for 1 hour. The reaction mixture was acidified to pH 3 with 2M hydrochloric acid and extracted with ethyl acetate (2x15ml), the ethyl acetate extracts were dried (Na2SO4), fitered and evaporated to give l-trans-P-3,4dichlorostyrenesulphonyl-piperidine-4-carboxylate (2.67g), m/z 364 (M+l). Example 19 The following compounds were prepared PEP = piperazinyl Z = reverse hydroxamate group R2 = hydrogen (Table Removed) Example 20 We provide NMR data for the following compounds: (Formula Removed) (DMSO) 9.6 (1H, s), 8.5 (1H, m), 8.4 and 7.9 (1H, s), 7.7 (1H, m), 7.2 (2H, m), 7.1 (2H, m), 7.0 (2H, m), 4.7 and 4.2 (1H, broad m), 3.4 (1H, m), 3.3 (5H, m), 3.1 (4H, m), 2.7 (2H, m), 2.0 (2H, m). (Formula Removed) (DMSO) 9,8 and 9.5 (1H, broad s), 8.3 and 8.0 (1H, s), 8.1 (1H, d), 7.6 (1H, dd), 7.2 (5H, m), 6.9 (1H, d), 4.7 and 4.1 (1H broad m), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.6 (2H, m), 1.6(4H, m). (Formula Removed) (DMSO) 9.6 (1H, broad S), 8.4 (1H, m), 8.3 and 7.9 (1H, s), 8.1 (1H, d), 7.6 (2H, m), 7.2 (1H, d), 7.1 (1H, m), 6.9 (1H, d), 4.7 and 4.1 (1H, broad m), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.7 (2H, m), 2.0 (2H, m). (Formula Removed) (DMSO) 9.7 (1H, broad s), 8.5 (1H, m), 8.4 (1H, m), 8.1 and 7.9 (1H, s), 7.6 (1H, in), 7.2 (2H, m), 7.0 (1H, m), 4.6 and 4.1 (1H, broad m), 3.7 (4H, m), 3.4 (1H, m), 3.3 (5H. m), 2.7 (2H, m), 2.0 (2H, m). (Formula Removed) (DMSO) 9.9 (1H, s), 8.4 (2H, m), 8.2 (1H, d), 7.65 (2H, m), 7.3 (1H, m), 7.0 (1H, m), 4.0-4.2 (2H, m), 3.6 (4H, br m), 3.4-3.2 (6H, br m), 2.0 (2H, br m). (Formula Removed) (DMSO) 10.0 (1H, s), 8.5 (2H, d), 8.2 (1H, br s), 7.8 (1H, br), 7.6 (1H, m), 7.4 (II I, m), 6.9 (1H, m), 3.6 (4H, br m), 3.2 (6H, br m). (Formula Removed) 10.0 (1H, s), 8.5 (2H, m), 8.4 and 8.0 (1H, s), 7.9 (1H, m), 7.7 (1H, m), 7.3 (1H, m), 7.1 (1H, m), 3.7 (4H, br m), 3.45 (2H, m), 3.3 (4H, br m), 2.75 (3H, m), 2.1 (2H, m). (Formula Removed) (DMSO) 10.0 (1H, br s), 8.6 (2H, m), 8.2 (1H, d), 7.2 (1H, m), 6.9 (4H, m), 4.9 and 4.2 (1H, br), 3.4 (6H, m), 3.0 (6H, m), 1.9 (4H, m). (Formula Removed) (DMSO) 9.8 (1H, br), 8.7 (2H, m), 8.3 and 7.9 (1H, s), 8.1 (2H, s), 7.6 (1H, m), 7.3 (1H, m), 6.9 (1H, m), 4.1 (1H, br m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m). (Formula Removed) (CDC13) 8.5 (1H, m), 8.1 (2H, s), 8.5 and 8.0 (1H, s), 7.8 (1H, m), 7.4 (1H, m), 7.3 (2H, m), 6.6 (1H, m), 4.8 and 4.2 (1H, br m), 3.6 (4H, m) 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m). (Formula Removed) (DMSO) 8.5 (1H, d), 8.4 and 8.2 (1H, s), 7.7 (1H, m), 7.2 (6H, m), 4.8 and 4.2 (1H, br m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m). Example 21 The following compounds were prepared (Formula Removed) PIP = piperazinyl Z = reverse hydroxamate group R2 = hydrogen (Table Removed) All compounds were prepared as in Example 1 except those where ring A is 4-0-piperidinyl which were prepared as in Example 14. Example 22 We provide NMR data for the following compounds listed in Example 21: (Table Removed) Example 23 Preparation of: (Formula Removed) To formic acid (4.8ml) at 0°C was added acetic anhydride (1.2ml). After 20 minutes this was added to the hydroxylamine 2 (0.68g) dissolved in THF (11ml) and formic acid (5ml) and the resulting solution stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue dissolved in DCM (100ml), washed with saturated sodium bicarbonate solution (2x100ml), dried (MgS04) and evaporated to dryness. The residue was purified by flash column chromatography eluting with dichloromethane / methanol (96:4) to give the product (0.41g) as a gum. NMR CDC13 5 9.7 (br s, 1H); 9.2 (br s, 1H); 8.4 (s, 1H); 8.0 (s, 1H); 7.5-7.2 (m, 5H); 7.0-6.8 (m, 4H), 5.7 (m, 1H); 5.4 (m, 1H); 3.9-3.4 (m, 5H); 3.3 (m, 1H); 3.2-2.9 (m, 4H); 2.8 (m, 1H). MS for C20H22FN3O3 (M+H) calcd 372, found 372. * rotameric signals Step A (Formula Removed) To l-(4-fluorophenyl)piperazine (l.OOg) dissolved in DCM (10ml) was added cinnamoyl chloride (0.85g) in DCM (10ml) followed by triethylamine (1 55ml). The solution was stirred at room temperature overnight.. It was then separated between DCM (1 50ml) and water (100ml), the organic layer was then washed with water (100ml) dried (MgSO4) and evaporated to dryness to give a cream solid which was triturated with diethyl ether (10ml) to give 1 (1.20g) as a white solid. NMR CDC13 5 7.7 (d, 1H); 7.5 (m, 2H); 7 4 (m, 3H); 7.0-6.9 (m, 5H); 4.0-3.8 (m, 4H); 3.1 (m, 4H). MS for C19H19FN2O (M+H) calcd 311, found 311. StepB (Formula Removed) To the amide (2.00g) dissolved in THF (40ml) was added hydroxylamine (1ml, 50% aqueous solution). The solution was stirred at room temperature for 48 hours. The solvent was then evaporated under reduced pressure, toluene was added (50ml) and this was also evaporated under reduced pressure. The residue was triturated with dichloromethane / methanol (98:2) and the mother liquor purified by flash column chromatography eluting with dichloromethane / methanol (98:2) to give 2 (0.70g) as a gum. NMR CDC13 5 7.5-7.2 (m, 5H); 7.0-6.9 (m, 2H); 6.9-6.8 (m, 2H); 4.5 (dd, 1H); 3.8-3.7 (m, 2H), 3.6-3.5 (m, 2H); 3.1-2.8 (m, 5H); 2.7 (dd, 1H). MS for C19H22FN3O2 (M+H) calcd 344, found 344. WE CLAIM: 1. A piperazine of the formula I (Formula Removed) wherein ring B is phenyl, pyridyl or pyrimidyl; each R3 is independently selected from hydrogen, halogen, N02, 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 CIO aryloxy, n is 1, 2 or 3; P is a direct bond; Ring A is piperazinyl; Both X2 and XI are N; Y is -S02-; Z is -N(OH)CHO and Q is CH2; Rl is H, C1-6 alkyl, C5-7 cycloalkyl, up to ClOaryl, up to ClOaryl, up to C10heteroaryl, up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from N02, CF3, halogen, C1-4alkyl, carboxy (C1-4) alkyl, up to C6 cycloalkyl, -OR4, -SR4, CI-4 alkyl substituted with -OR4, SR4 (and its oxidized analogues), NR4, N-Y-R4, or Cl-4 alkyl-Y-NR4, with the proviso that where Rl is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, Rl 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, N02, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -S02-C1-6 alkyl or C1-6 alkoxy; and 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 Rl or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S ad N; and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically acceptable salt thereof. 2. A piperazine as claimed in claim 1 and wherein: R3 is hydrogen, halogen, N02, CF3, C1-4 alkyl, and C1-4 alkoxy, n is 1 or 2; Rl is hydrogen, C1-6alkyl, C5-7 cycloalkyl, up to C12 aralkyl, up to C11 heteroarylalkyl, up to C10 aryl or C10 heteoraryl; all optionally substituted by up to three halogen atoms, or by CF3; R2 is hydrogen, or together with Rl represent a carbocyclic or heterocyclic spiro 5-or 6-membered ring; and R4 is up to C10 aryl optionally substituted by halogen, NO2, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl or -SO2-C1-6 alkyl or C1-6 alkoxy; or a pharmaceutically acceptable salt thereof. 3. A piperazine as claimed in claim 1 wherein: R3 is hydrogen, halogen, N02, CF3, methyl, ethyl, methoxy or ethoxy; 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; and R2 is hydrogen; or a pharmaceutically acceptable salt thereof. 4. A piperazine of the formula I as claimed in claim 1 wherein 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; or a pharmaceutically acceptable salt thereof. 5. A piperazine of the formula I as claimed in claim 1 wherein ring B is a phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, or 3,4-dichlorophenyl ring or 5-chloro-2-pyridyl; and Rl is phenyl, phenbutylene, phenisopropylene, 2-pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene, or 4-chlorophenyloxydime thylmethylene; or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition which comprises a piperazine of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 7. A process for preparing a piperazine of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof which process comprises a) reacting a piperazine of the formula (II) or a pharmaceutically acceptable salt with a compound of the formula (III) (Formula Removed) wherein X11 represents X or a precursor of X (whether by modification or displacement) or an activated form of X suitable for reaction with Y1; Yi represents Y, a precursor of Y, or an activated form of Y suitable for reaction with X11; Z1 represents a protected form of Z, a precursor of Z (whether by modification or displacement of Z1) or an activated form of Z; and where Q is -(CH2)(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: (Formula Removed) or b) reacting a compound of the formula (IV) or a pharmaceutically acceptable salt thereof with a compound of the formula (V). (Formula Removed) wherein B1 represents a suitable ring function or substituent group for reaction with P1; Z1 is as hereinbefore defined; and P1 represents a suitably activated form of the linker P for reaction with B1 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 B1 and A respectively, or vice versa. 8. A compound of the formula I substantially as herein described with reference to the foregoing examples. 9. A process for preparing a compound substantially as herein described with reference to the foregoing examples.

Full Text

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, MMP 15, MMP 16, MMP 17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM 10 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 gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis),
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 et al., (1997) Cell Growth Differ. 8(2):243-250], squamous cell carcinomas [N. Johansson etal., (1997) Am. J. Pathol. 151(2).499-508] and epidermal tumours [K. Airola etal., (1997) J. Invest. Dermatol. 109(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 et al., (1996) J. Clin. Invest. 97(3)J6l-768; V. Knauper et al., (1996) The Biochemical Journal 271:1544-1550], MMP13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M.
Stahle-Backdahl etai, (1997) Lab. Invest. 76(5V717-728; N. Johansson eial, (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 etal., (1997) Arthritis Rheum 40(8): 1391-1399]: and during the aseptic loosening of hip replacements [S. Imai etai, (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. J. Uitto et al., (1998) Am. J. Pathol 152(6): 1489-1499] and in remodelling of the collagenous matrix in chronic wounds [M. Vaalamo et 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. ppl 15 - 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 MMP9 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, MMP9 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 fiirther 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 MMP9, leading to inhibition of the catalytic domain of MMP9. 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 MMP9 which is present at a local site. Proteolytically active MMP9 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 MMP9 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
(Formula Removed)
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, N02, COOR wherein R is hydrogen or C1-6alkyl, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -S02-C1-6 alkyl ,C1-6 alkoxy and up to C10 aryloxy, n is 1,2 or 3;
P is -(CH2)n- wherein n = 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;
XI 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 -S02- 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, CI-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 -S02- 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-;
Rl is 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(C 1-4)alkyl, up to C6cycloalkyl,-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 Rl is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, or Rl 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 Rl 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.
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, n is 1 or 2, such as individually 4-fluoro, CF3, 4-chloro and 3,4-dichloro;.
-Erring 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 n is 0 or 1, or -O-, or -CO-N(R6)-; one or both of X2 and X1 = N, or X1 is N, or X2 is C;
Y = -SO2-, 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, C1-6alkyl, C5-7 cycloalkyl, up to C12aralkyl, up to
C1 lheteroarylalkyl, 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 Rl 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, N02, 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, N02, 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 = -SO2-;
Q = -CH2-;
Rl 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-chIoro (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
(Formula Removed)

Particular rings for ring A include any one of
(Formula Removed)
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
(Formula Removed)
wherein R = phenyl or phenethyl and
(Formula Removed)
wherein R = isobutyl or a spiro-4-pyran ring
As previously outlined the compounds of the invention are metalloproteinase inhibitors, in particular they are inhibitors of MMP13. Each of the above indications for the compounds of the formula I represents an independent and particular embodiment of the invention. Whilst we do not wish to be bound by theoretical considerations, the compounds of the invention are believed to show selective inhibition for any one of the above indications relative to any MMP1 inhibitory activity, by way of non-limiting example they may show 100-1000 fold selectivity over any MMP1 inhibitory activity.
In addition we have found that compounds of the formula 1 wherein ring B is phenyl, pyridyl (such as 2-pyridyl or 3-pyridyl, especially 2-pyridyl) ring optionally mono- or di-substituted, preferably mono-substituted, by halogen (for example chlorine ), P is a direct bond; ring A is a piperazinyl or piperidinyl ring, Y is -S02- and Q is Cl-4alkylene (for example -CH2-), especially -CH2-; Rl is as defined for Formula 1 and is especially 2-phenylpropyl, 2-(2-pyridyl)propyl, 2-(3-pyridyl)propyl, 2-(4-pyridyl)propyl, phenyl, benzyloxymethyl, 4-phenylbutyl, 2-phenylbutyl, or 2-(2-thienyl)propyl; and Z is -N(OH)CHO, are of particular use as aggrecanase inhibitors ie. inhibitors of aggrecan degradation. Of particular note are compounds of the formula I wherein ring B is a phenyl, 3-methylphenyl, 4-fluorophenyl, 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 especially
piperazinyl, Y is SO2, Q is -CH2-, Z is -N(OH)CHO and Rl is phenyl, phenbutylene, phenisopropylene, 2-pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene, or 4-chlorophenyloxydimethylmethylene. Also of mention are compounds of the formula I wherein ring B is phenyl monosubstituted by chlorine or fluorine, especially 4-chlorophenyl and 4-fluorophenyl; P is a direct bond; ring A is piperidinyl, Y is SO2, Q is -CH2-, Z is -CONHOH and Rl is hydrogen, i-butyl, or spiro-tetrahydropyranyl. Particular compounds include
(Formula Removed)
(Table Removed)
wherein PIP = piperazinyl
RH = reverse hydroxamate group
and R2 = hydrogen
The compounds of the invention may be provided as pharmaceutically acceptable salts. These include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine.
They may also be provided as in vivo hydrolysable esters. These are pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal adminstration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.5 to 75 mg/kg body weight (and preferably of 0.5 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of the human or animal body.
In yet a further aspect the present invention provides a method of treating a metalloproteinase mediated disease condition which comprises administering to a warmblooded animal a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
In another aspect the present invention provides 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)
(Formula Removed)
wherein X1 represents X or a precursor of X (whether by modification or displacement) or an activated form of X suitable for reaction with Y1;
Y1 represents Y, a precursor of Y, or an activated form of Y suitable for reaction with X11; by way of non-limiting example, when X is C then X1 may be derivatised to include a precursor of Y for reaction with a compound of formula III wherein Y1 is a precursor of Y; Z1 represents a protected form of Z, a precursor of Z (whether by modification or displacement of Z1) or an activated form of Z;
and where Q = -(CH2)(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:
(Formula Removed)
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).
(Formula Removed)
wherein B1 represents a suitable ring function or substituent group for reaction with P1;
Z1 is as hereinbefore defined, and
P1 represents a suitably activated form of the linker P for reaction with B1
or where X2 = 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 B1 and A respectively, or vice versa.
A compound of the formula (II) is conveniently prepared by reacting a compound of the formula (VI) with a compound of the formula (VII)
(Formula Removed)
wherein B1 represents a suitable ring function or substituent group, X2' represents X or a precursor of X (whether by modification or displacement) or an activated form of X suitable for reaction with B1 and wherein B1 and X2' when reacted together provide the linker P between ring A and ring B in the compound of formula (II). By way of non-limiting example, when X2is N then ring B is suitably derivatised to introduce the linker P via B1, and when X2 is C then both ring B and ring A are suitably derivatised to provide the linker P by the reaction of B1 and X2'.
It will be appreciated that many of the relevant starting materials are commercially available. In addition the following table shows details of aldehyde intermediates and their corresponding registry numbers in Chemical Abstracts.
(Table Removed)
Aldehydes without Chemical Abstracts Registry Numbers
3-(2-pyrimidyl) propionaldehyde. To a solution of 2-Bromopyrimidine (7.95 g, 0.05 M) in acetonitrile (150 mL) was added propargylalcohol (4.2 g, 0.075 M ), bis-(triphenylphosphine)-palladium(ll)chloride (750 mg, 1 mM), copper iodide (100 mg, 0.5 mM) and triethylamine (25mL, 0.25 M) and the mixture was stirred and heated at 70°C for 2 hours. An additional amount of propargyl alcohol (2.1 g, 0.038 M), bis-(triphenylphosphine)-
palladium(l l)chloride (375 mg, 0.5 mil), and copper iodide (50 mg, 0.25 mil) was then added to the reaction mixture which was stirred and heated at 70°C for an additional 1 hour.
The reaction mixture was evaporated to dryness and the residue which was pre-adsorbed on to silica, chromatographed. Elution with ethyl acetate gave 3-(2-pyrimidyl) prop-2-yn-3-ol as a yellow solid 4.45 g (66 %). NMR (CDCfe) 2.9 (1H, t), 4.5 ( 2H, d), 7.3 ( 1H, d), 8.8 ( 2H, t), MS found NfflT 135
3-(2-pyrimidyl) prop-2-yn-l-ol (4.45 g, 0.033 M) was dissolved in ethyl acetate (140 mL), 10 % Pd/C (890 mg) was added and the mixture stirred under an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through Celite and the filtrate evaporated to give 3-(2-pyrimidyl) propan-1-ol as a yellow oil, 4.15 g (91 %).. NMR (CDC13) 2.1 ( 2H, m), 3.2 (2H, t), 3.8 ( 2H, t), 7.2 ( 1H, t), 8.7 ( 2H, d) MS found MhT 139.
3-(2-pyrimidyl) propan-1-ol was oxidized to give 3-(2-pyrimidyl) propionaldehyde as a yellow oil NMR (CDC13) 3.0 ( 2H, t), 3.4 ( 2H, t), 7.1 ( 1H, t), 8.7 (2H, d), 9.9 ( 1H, s) using the Swern oxidation described in this patent.
Using the procedure described above the following aldehydes were prepared 4-(2-pyrimidyl) butyraldehyde by using 3-butyn-l-ol in place of propargylalcohol NMRCDCI3 9.8(1H, s), 8.6 (2H, m), 7.15 (1H, m), 3.0 (2H, m), 2.5 (2H, m), 2.2 (2H, m).
4-(5-pyrimidyi) butyraldehyde by using 3-butyn-l-ol in place of propargylalcohol and 5-bromopyrimidine in place of 2-bromopyrimidine NMR CDCI3 9.8 (1H, s), 9.1 (1H, s), 8.6 ( 2h, s), 2.7 (2H, t), 2.55 (2H, t), 2.0(2H, m).
4-(2-pyridyl) butyraldehyde by using 3-butyn-l-ol in place of propargylalcohol and 2-bromopyridine in place of 2-bromopyrimidine
NMR CDCI3 9.8 (1H, s); 8.6 (1H, d), 7.6 ( 1H, m); 7.1( 2H m ); 2.8 (2H, t); 2.55 (2H, t), 2.0(2H, m).
The compounds of the invention may be evaluated for example in the following assays:
Isolated Enzyme Assays
Matrix Metalloproteinase family including for example MMP13. Recombinant human proMMP 13 may be expressed and purified as described by Knauper et al. [V. Knauper et al., (1996) The Biochemical Journal 271; 1544-1550 (1996)]. The purified enzyme can be used to monitor inhibitors of activity as follows: purified
proMMP13 is activated using ImM amino phenyl mercuric acid (APMA), 20 hours at 21°C; the activated MMP13 (11.25ng per assay) is incubated for 4-5 hours at 35°C in assay buffer (0.1M Tris-HCl, pH 7.5 containing 0.1M NaCl, 20mM CaCl2, 0.02 mM ZnCl and 0.05% (w/v) Brij 35 using the synthetic substrate 7-methoxycoumarin-4-
yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg.NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at ex 328nm and A.em 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescenceplus inhibitor - Fluorescencebackground] divided by the [Fluorescenceminus inhibitor -Fluorescencebackground] .
A similar protocol can be used for other expressed and purified pro MMPs using substrates and buffers conditions optimal for the particular MMP, for instance as described in C. Graham Knight etal., (1992) FEBS Lett. 2960)263-266.
Adamalvsin family including for example TNF convertase
The ability of the compounds to inhibit proTNFa convertase enzyme may be assessed using a partially purified, isolated enzyme assay, the enzyme being obtained from the membranes of THP-1 as described by K. M. Mohler et al, (1994) Nature 370:218-220. The purified enzyme activity and inhibition thereof is determined by incubating the partially purified enzyme in the presence or absence of test compounds using the substrate 4',5'-Dimethoxy-fluoresceinyl Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-succinimid-l-yl)-fluorescein)-NH2 in assay buffer (50mM Tris HC1, pH 7.4 containing 0.1% (w/v) Triton X-100 and 2mM CaCl2), at 26°C for 18 hours. The amount of inhibition is determined as for MMP 13 except ex 490nm and em 530nm were used. The substrate was synthesised as follows. The peptidic part of the substrate was assembled on Fmoc-NH-Rink-MBHA-polystyrene resin either manually or on an automated peptide synthesiser by standard methods involving the use of Fmoc-amino acids and 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) as coupling agent with at least a 4- or 5-fold excess of Fmoc-amino acid and FiBTU. Ser1 and Pro2 were double-coupled. The following side chain protection strategy was employed; Ser1Bu'), Gln5(Trityl), Arg8'12(Pmc or Pbf), Ser9'10'11(Trityl), Cys13(Trityl). Following assembly, the N-terminal Fmoc-protecting group was removed by treating the Fmoc-peptidyl-resin with in DMF. The amino-peptidyl-resin so obtained was acylated by treatment for 1.5-2hr at 70°C with 1.5-2 equivalents of
4',5'-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna & Ullman, (1980) Anal Biochem. 108:156-161) which had been preactivated with diisopropylcarbodiimide and 1 -hydroxybenzotriazole in DMF]. The dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane. The dimethoxyfluoresceinyl-peptide was isolated by evaporation, trituration with diethyl ether and filtration. The isolated peptide was reacted with 4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid. The product was characterised by MALDI-TOF MS and amino acid analysis.
Natural Substrates
The activity of the compounds of the invention as inhibitors of aggrecan degradation may be assayed using methods for example based on the disclosures of E. C. Arner et al., (1998) Osteoarthritis and Cartilage 6:214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601 and the antibodies described therein. The potency of compounds to act as inhibitors against collagenases can be determined as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345.
Inhibition of metaHoproteinase activity in cell/tissue based activity Test as an agent to inhibit membrane sheddases such as TNF convertase
The ability of the compounds of this invention to inhibit the cellular processing of
TNFα production may be assessed in THP-1 cells using an ELISA to detect released TNF
essentially as described K. M. Mohler et al., (1994) Nature 370:218-220. In a similar fashion
the processing or shedding of other membrane molecules such as those described in N. M.
Hooper et al, (1997) Biochem. J. 321:265-279 may be tested using appropriate cell lines and
with suitable antibodies to detect the shed protein.
Test as an agent to inhibit cell based invasion
The ability of the compound of this invention to inhibit the migration of cells in an invasion assay may be determined as described in A. Albini et al., (1987) Cancer Research 47:3239-3245.
Test as an agent to inhibit whole blood TNF sheddase activity
The ability of the compounds of this invention to inhibit TNFa production is assessed in a human whole blood assay where LPS is used to stimulate the release of TNFa. Heparinized (10Units/ml) human blood obtained from volunteers is diluted 1:5 with medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160µl) with 20µl of test compound (triplicates), in DMSO or appropriate vehicle, for 30 min at 37°C in a humidified (5%C02/95%air) incubator, prior to addition of 20µl LPS (E. coli. 0111:B4;
final concentration 10µg/ml). Each assay includes controls of diluted blood incubated with medium alone (6 wells/plate) or a known TNFa inhibitor as standard. The plates are then incubated for 6 hours at 37°C (humidified incubator), centrifuged (2000rpm for 10 min; 4° C), plasma harvested (50-100µJ) and stored in 96 well plates at -70°C before subsequent analysis for TNFa concentration by ELISA.
Test as an agent to inhibit in vitro cartilage degradation
The ability of the compounds of this invention to inhibit the degradation of the aggrecan or collagen components of cartilage can be assessed essentially as described by K. M. Bottomley et a!., (1997) Biochem J. 323:483-488.
Pharmacodynamic test
To evaluate the clearance properties and bioavailability of the compounds of this invention an ex vivo pharmacodynamic test is employed which utilises the synthetic substrate assays above or alternatively HPLC or Mass spectrometric analysis. This is a generic test which can be used to estimate the clearance rate of compounds across a range of species. Animals (e.g. rats, marmosets) are dosed iv or po with a soluble formulation of compound (such as 20%w/v DMSO, 60% w/v PEG400) and at subsequent time points (e.g. 5, 15, 30, 60, 120, 240, 480, 720, 1220 mins) the blood samples are taken from an appropriate vessel into 10U heparin. Plasma fractions are obtained following centrifligation and the plasma proteins precipitated with acetonitrile (80%w/v final concentration). After 30 mins at -20°C the plasma proteins are sedimented by centrifugation and the supernatant fraction is evaporated to dryness using a Savant speed vac. The sediment is reconstituted in assay buffer and subsequently analysed for compound content using the synthetic substrate assay. Briefly, a compound concentration-response curve is constructed for the compound undergoing
evaluation. Serial dilutions of the reconstituted plasma extracts are assessed for activity and the amount of compound present in the original plasma sample is calculated using the concentration-response curve taking into account the total plasma dilution factor.
In vivo assessment
Test as an anti-TNF agent
The ability of the compounds of this invention as ex vivo TNFa inhibitors is assessed in the rat. Briefly, groups of male Wistar Alderley Park (AP) rats (180-210g) are dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route e.g. peroral (p.o), intraperitoneal (i.p.), subcutaneous (s.c). Ninety minutes later rats are sacrificed using a rising concentration of CO2 and bled out via the posterior vena cavae into 5 Units of sodium heparin/ml blood. Blood samples are immediately placed on ice and centrifuged at 2000 rpm for 10 min at 4°C and the harvested plasmas frozen at -20°C for subsequent assay of their effect on TNFa production by LPS-stimulated human blood. The rat plasma samples are thawed and 175µl of each sample are added to a set format pattern in a 96U well plate. Fifty µl of heparinized human blood is then added to each well, mixed and the plate is incubated for 30 min at 37°C (humidified incubator). LPS (25µl; final concentration 10µg/ml) is added to the wells and incubation continued for a further 5.5 hours. Control wells are incubated with 25 µl of medium alone. Plates are then centrifuged for 10 min at 2000 rpm and 200µl of the supernatants are transferred to a 96 well plate and frozen at -20°C for subsequent analysis of TNF concentration by ELISA.
Data analysis by dedicated software calculates for each compound/dose: Percent inhibition of TNFa= Mean TNFa (Controls) - Mean TNFa (Treated') X 100
Mean TNFa (Controls) Test as an anti-arthritic agent
Activity of a compound as an anti-arthritic is tested in the collagen-induced arthritis (CIA) as defined by D. E. Trentham et al, (1977) J. Exp. Med. 146,:857. In this model acid soluble native type II collagen causes polyarthritis in rats when administered in Freunds incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates.

Test as an anti-cancer agent
Activity of a compound as an anti-cancer agent may be assessed essentially as described in I.J. Fidler (1978) Methods in Cancer Research 15:399-439, using for example the B16 cell line (described in B. Hibner et al., Abstract 283 p75 10th NCI-EORTC Symposium, Amsterdam June 16-19 1998).
The invention will now be illustrated but not limited by the following Examples:
Accordingly, there is provided a piperazine of the formula I
(Formula Removed)
wherein ring B is phenyl, pyridyl or pyrimidyl;
each R3 is independently selected from hydrogen, halogen, N02, 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, n is 1, 2 or 3;
P is a direct bond;
Ring A is piperazinyl;
Both X2 and XI areN;
Y is -SO2-;
Z is -N(OH)CHO and Q is CH2;
Rl is H, C1-6 alkyl, C5-7 cycloalkyl, up to C10aryl, up to C10aryl, up to C10heteroaryl, up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from N02, CF3, halogen, C1-4alkyl, carboxy (C1-4) alkyl, up to C6 cycloalkyl, -OR4, -SR4, C1-4 alkyl substituted with -OR4, SR4 (and its oxidized analogues), NR4, N-Y-R4, or C1-4 alkyl-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, 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; and
R2 is H, C1-6 alkyl, or together with Rl 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 Rl or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S ad N; and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically acceptable salt thereof.
EXAMPLES Example 1
1-[2-(N-formvl-N-hvdroxvamino)-2-phenylethanesulfonyl]-4-(4-fluorophenvl)piperazine
(Formula Removed)
To a solution of l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added a preformed mixture of formic acid (2 ml) and acetic anhydride (0.5 ml). The mixture was stirred at room temperature for one hour. The mixture was evaporated in vacuo and toluene (2 x 5 ml) was added and evaporated in vacuo. The residue was taken in CH2C12 -methanol (6 ml, 9 : 1) and silica (1 g) was added. The mixture was stirred for 18 hours. The silica was filtered off and rinsed with CH2C12 - methanol (9 .1). The residue was purified on silica gel (eluant: CH2Cl2 - MeOH 4 %) to give the title compound as a light orange solid (220mg, 61%).
1H NMR (CDC13) : 8.45 and 8.15 (s, 1H), 7.39 (m, 5H), 6.97 (m, 2H), 6.88 (m, 2H), 5.89 and 5.35 (m, 1H), 4.05 and 3.85 (m, 1H), 3.30-3.53 (m, 5H), 3.20-3.10 (m, 4H); MS (ESI): 408 (MET), 430 (MNa+); EA: calculated for C19H22FN3O4S: C 56.01, H 5.44, N 10.31, S 7.87, Found: C 56.01, H 5.52, N 10.04, S 7.39.
The starting material was prepared as follows :
i) To a solution of l-(4-fluorophenyl)piperazine (35 g, 194 mmol) and pyridine (17.5 ml) in dry dichloromethane (200 ml) at 0°C was added methanesulfonyl chloride (20 ml, 258 mmol) dropwise. The mixture was stirred for 3 hours at room temperature. The mixture was
washed with water and extracted with dichloromethane (2 x 100 ml). The organic layers were dried with MgSO4 and evaporated in vacuo. The residue was triturated and washed with methanol to give l-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (39.35 g) as white crystals. 1H NMR (CDCl3): 7.00 (m, 2H), 6.90 (m, 2H), 3.40 (m, 4H), 3.20 (m, 4H), 2.83 (s, 3H).
ii) To a solution of LDA [8.5 mmol; prepared by slow addition of n-butyl lithium (3.5 ml, 8.5 mmol, 2.5 M in hexane) to a solution of diisopropylamine (860 mg, 8.5 mmol) in dry THF (5 ml) at -78°C] at -78°C was added a solution of l-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (1 g , 3.87 mmol) in THF (25 ml) dropwise. The mixture was stirred at -78°C for 1 hour and a solution of diethylchlorophosphate (670 mg ; 3.87 mmol) in THF (3 ml) was added. The mixture was stirred at -78°C for 1 hour and benzaldehyde (450 mg; 4.24 mmol) in THF (3 ml) was added. The mixture was gently warmed to room temperature and stirred for 18 hours. The mixture was washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over MgSO4. Purification of the residue on silica (eluant : dichloromethane) afforded l-(4-fluorophenyl)-4(trans-P-styrenesulfonyl)piperazine as a white powder (621 mg, 46 %). 1H NMR (CDCl3): 7.50 (m, 3H), 7.43 (m, 3H), 6.97 (m, 2H), 6.89 (m, 2H), 6.71 (d, 1H, J= 15.4 Hz), 3.37 (m, 4H), 3.19 (m, 4H).
iii) To a solution of l-(4-fluorophenyl)-4-(trans-P-styrenesulfonyl)piperazine (620 mg, 1.79 mmol) in THF (20 ml) was added hydroxylamine (3 ml, 50 % aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried on MgS04 to give l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine(730 mg). 1H NMR (CDCl3): 7.4-7.1 (m, 5H), 6.97 (m, 2H), 6.87 (m, 2H), 5.95 (s br, 1H), 4.74 (s, 1H), 4.60 (dd, 1H, J=4 Hz, T= 8.8 Hz), 3.56 (dd, 1H, J- 8.8 Hz, T= 14.3 Hz), 3.40 (m, 4H), 3.19 (dd, 1H, J= 4 Hz, J'= 14.3 Hz), 3.12 (m, 4H).
Example 2
Similarly the following compounds were obtained:
(Formula Removed)
Example 3 N-hvdroxv-3-f4-(4-fluorophenvnpiperazine-l-suIfonyllpropionamide
(Formula Removed)
To a solution of N-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]propionamide (125 mg, 0.19 mmol) in dichloromethane (2 ml) was added triethylsilane (66 ul, 0.42 mmol) and trifluoroacetic acid (150 µl). The mixture was stirred at room temperature for 4 hours. The solvents were evaporated in vacuo. The
residue was purified by chromatography on silica (eluant : dichloromethane, then ethyl acetate then dichloromethane -10 % MeOH) to give 35 mg of the title compound. 1H NMR (DMSO d-6 + CF3COOD): 7.16 (m, 4H), 3.36 (m, 6H), 3.25 (m, 4H), 2.45 (t, 2H, J = 7.4 Hz); MS (ESI): 332 (MN+), 354 (MNa+).
The starting material was obtained as follows:
i) A solution of 3-mercaptopropionic acid (20 g, 185 mmol) in acetic acid (150 ml) -water (30 ml) at 0° C was reacted with gaseous chlorine (preferably condensed at -78° C, 20 ml). After chlorine had distilled, the solvents were evaporated in vacuo; toluene was added and evaporated to give l,2-oxathiolane-5-one 2-dioxyde (36.12 g). 'H NMR (DMSO d-6): 2.70 (t, 2H, J= 7.2 Hz), 2.50 (t, 2H, J= 7.2 Hz).
ii) A solution of l,2-oxathiolane-5-one 2-dioxide (3.8 g, 28 mmol) in thionyl chloride (20 ml) and DMF (5 drops) was stirred at room temperature for 18 hours. The mixture was heated at 40°C for 1 hour. The solvents were evaporated, toluene was added and evaporated in vacuo to give crude 3-chlorosulfonylpropionyl chloride (NMR purity : 70 %, 3.58 g). 1H NMR (CDC13): 4.02 (t, 2H, J= 7.2 Hz), 3.63 (t, 2H, J= 7.2 Hz)
iii) To a solution of 3-chlorosulfonylpropionyl chloride (500 mg, 1.83 mmol, 70 % purity) and diisopropylethylamine (75 ul) in dichloromethane (5 ml) at -78°C was added a solution of 0-dimethoxybenzyl-N-trimethoxybenzylhydroxylamine[Rrf 1] (664 mg ,1.83 mmol) and diisopropylethylamine (320 ul, 1.83 mmol) in dichloromethane (5 ml) dropwise over 2 hours. After 30 minutes, a solution of l-(4-fluorophenyl)piperazine (330 mg, 1.83 mmol) and diisopropylethylamine (320 µl, 1.83 mmol) in dichloromethane (5 ml) was added to the reaction mixture. The solution was warmed to room temperature and stirred for 2 hours. The solution was partitioned between dichloromethane and IN hydrochloric acid. The organic layers were washed with brine and dried over MgSCv Chromatography of the residue on silica gel (eluant: ethyl acetate - petroleum ether: gradient from 50/50 to 80/20) gave N-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]propionamide (260 mg). MS (EI): 661 (M+)
Example 4 N-hvdroxv-3-f4-benzvlpiperazine-l-sulfonvl]propionamide
(Formula Removed)
In a manner analogous to that described in Example 3, from 4-benzylpiperazine and 3-chlorosulfonylpropionyl chloride there was obtained the title compound. 1H NMR (DMSO d-6 + CF3COOD): 7.50 (m, 5H), 4.41 (s, 2H), 3.78 (m, 2H), 3.41 (m, 4H), 3.18 (m, 2H), 2.43 (t, 2H, J= 7.1 Hz); MS (ESI) : 328 (MH+).
Example 5 N-hvdroxy-3-[4-(4-fluorophenvnptperazine-l-sulfonyl]-2-isobutylpropionamide.
(Formula Removed)
To a solution of N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionamide (220 mg) in dichloromethane (4 ml) was added trifluoroacetic acid (200 ui) and triethylsilane (145 ul). The mixture was stirred at room temperature for 15 minutes, evaporated in vacuo and the residue was purified on silica gel (eluant: dichloromethane-ether-methanol (80:20:0.5) to dichloromethane-methanol (80:20) to give the title compound (88 mg, 56 %).
1H NMR (DMSO d-6): 10.72 (s, 1H), 7.08 (m, 2H), 6.99 (m, 2H), 3.37 (dd, 1H, J= 8.4 Hz, J'= 14.3 Hz), 3.27 (m, 4H), 3.15 (m, 4H), 3.00 (dd, 1H, J= 4 Hz, J'= 14.3 Hz), 2.62 (m, 1H), 1.6-1.2 (m, 3H), 0.89 (d, 3H, J = 6.6 Hz), 0.85 (d, 3H, J- 6.6 Hz); MS (ESI): 388 (MH+), 410 (MNa+).
The starting material was obtained as follows:
i) A solution of 3-acetylthio-2-isobutylpropionic acid [obtained by Michael addition of thiolacetic acid onto 2-isobutylacrylic acid] (7 g, 34.3 mmol), benzyl bromide (4.29 ml, 36 mmol) and DBU (5.2 ml, 35 mmol) in toluene (55 ml) was stirred for 18 hours at room temperature. The solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was washed with brine and dried over MgSO-t. Purification of the residue by chromatography on silica gel (eluant: dichloromethane-ether (9:1)) gave benzyl 3-acetylthio-2-isobutylpropionate (8.4 g) MS(ESI):317(MNa+).
ii) A solution of benzyl 3-acetyIthio-2-isobutylpropionate (588 mg, 2 mmol) in acetic acid (12 ml) - water (1.6 ml) at 0°C was reacted with gaseous chloride (prealably condensed at -78°C, 1.9 ml). After chlorine had distilled, the solvents are evaporated in vacuo to give crude benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg). MS (EI): 318 (M+).
iii) A solution of benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg, 2 mmol), 1-(4-fluorobenzyl)piperazine (378 mg , 2.1 mmol) and triethylamine (340 ul, 2.4 mmol) in dichloromethane (15 ml) was stirred at 0° C for 18 hours. After evaporation of the solvents, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgSO4. After evaporation of the solvent in vacuo, the residue was purified by chromatography on silica gel (eluant: dichloromethane - ether (91) to give benzyl 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionate (640 mg) MS (EI) : 462 (M+).
iv) A solution of benzyl 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionate (630 mg) in methanol (10 ml) was hydrogenated under 40 PSI pressure for 18 hours in the presence of palladium on charcoal (63 mg, 10 %). The catalyst was removed by filtration and the solvents were removed in vacuo to give 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionic acid (460 mg). MS (ESI): 373 (MH+), 395 (MNa4).
v) To a solution of 3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionic acid (230 mg, 0.62 mmol), 2,4-dimethoxybenzylhydroxylamine [Rcf 1] (124 mg, 0.68 mmol), DMAP (75 mg, 0.62 mmol) in DMF (1 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (152 mg , 0.8 mmol). The mixture was stirred at room temperature for 2 days. The reaction mixture was poured in water and extracted with ethyl
acetate. The organic layer was washed with 5% sodium bicarbonate, brine and dried over MgSO4. Purification of the residue on silica gel (eluant: dichloromethane - ether: gradient from 9/1 to 8/2) gave N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-l-sulfonyl]-2-isobutylpropionamide (158 mg).
lH NMR (CDC13) : 8.21 (s, 1H), 7.30 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 6.46 (m, 2H), 4.95 (m, 2H), 3.82 (s, 6H), 3.50 (dd, 1H, J= 9 Hz, J'= 14.2 Hz), 3.37 (m, 4H), 3.14 (m, 4H), 2.84 (dd, 1H, J= 14.2 Hz, J'= 2 Hz), 2.60 (m, 1H), 1.7-1.2 (m, 3H), 0.90 (m, 6H).
Example 6
4-[4-(4-fluorophenvl)piperazine-l-sulfonvlmethvlltetrahvdropvran-4-(N-hvdroxv
carboxamide)
(Formula Removed)
To a solution of 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid (470 mg, 1.21 mmol) in dichloromethane (8 ml) was added oxalyl chloride (700 mg, 5.6 mmol) and DMF (18 ul). The mixture was heated at 35° C for 1 hour. After evaporation of the solvents, the crude acid chloride dissolved in dichloromethane (4 ml) was added to a ice-cooled solution of hydroxylamine (440 ul, 50 % aqueous solution) in THF (8 ml). The mixture was stirred for 90 minutes at room temperature. After evaporation of the solvents, the residue was triturated in dichloromethane-ether-methanol (80 : 20 : 5). The resulting solid was washed with water and ethyl acetate and dried to give the title compound as white crystals (230 mg, 47 %).
1H NMR (DMSO d-6): 10.56 (s br, 1H), 8.74 (s br, 1H), 7.07 (m, 2H), 6.99 (m, 2H), 3.66 (m, 2H), 3.47 (m, 2H), 3.40 (s, 2H), 3.25 (m, 4H), 3.16 (m, 4H), 1.99 (m, 2H), 1.72 (m, 2H); MS (ESI): 402 (MH+), 424 (MNa+).
The starting material was prepared as follows:
(i) Thiolacetic acid (760 ul, 10 mml) and tributylphosphine (2.5 ml, 10 mmol) in DMF (5 ml) was added dropwise to a ice-cooled suspension of sodium hydride (530 mg, 60 % in oil, 13 mmol) in DMF (1.5 ml) under an argon atmosphere. The mixture was stirred at 0° C
for 30 minutes. To the above solution was added 2,7-dioxaspiro[3,5]nonane-l-one[Rcf 2] (1.4 g, 10 mmol) in DMF (10 ml). The mixture was stirred at 0° C for 30 minutes and at room temperature for 18 hours. The reaction mixture was diluted with ether. The precipitate was filtered and dried to give 4-(acetylthiomethyl)tetrahydropyran-4-carboxylic acid sodium salt. 'H NMR (DMSO d-6): 3.65-3.40 (m, 4H), 2.99 (s, 2H), 2.27 (s, 3H), 1.86 (m, 2H), 1.23 (m, 2H).
(ii) Using the same procedure described in Example 5 i), ii), iii), iv), v) except that no DBU was used in step 1, from 4-(acetylthiomethyl)tetrahydropyran-4-carboxylic acid sodium salt was obtained 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid (490 mg).
4-(acetylthiomethyl)tetrahydropyran-4-( carboxylic acid benzyl ester): MS (ESI): 331 (MNa+); 4-(chlorosulfonylmethyl)tetrahydropyran-4-( carboxylic acid benzyl ester): MS (ESI): 354 (MNa+); 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid benzyl ester: MS (ESI): 477 (MH+), 499 (MNa+); 4-[4-(4-fluorophenyl)piperazine-l-sulfonylmethyl]tetrahydropyran-4-carboxylic acid: MS (ESI): 387 (MH+), 409 (MNa+).
Ref 1: B.Barlaam, A.Hamon, M.Maudet; Tetrahedron Lett, 1998,39,7865
Ref 2: F. Hoffmann-La Roche, Agouron Pharm.; Eur. Patent Appl. EP 780386.
Example 7 l-f2-(N-formvl-N-hvdroxvamino)-2-phenvlethanesu!fonvn-4-phenYlpiperazine
(Formula Removed)
To a solution of l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-phenylpiperazine (140 mg) in THF (0.75 ml) and formic acid (0.25 ml) was added a preformed mixture of formic acid (0.58 ml) and acetic anhydride (0.29 ml). The solution was stirred at ambient
temperature for 18 hours. The mixture was evaporated in vacuo, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1 % methanol in dichloromethane to give l-phenyl-(4- trans-b-styrenesulfonyl)piperazine (420 mg) as a foam (105 mg).
1H NMR (d6-DMSO at 373K): 9.60 (s, 1H), 8.25 (s, 1H), 7.40 (m, 2H), 7.30 (m, 3H), 7.20 (m, 2H), 6.90 (d, 2H), 6.75 (m, 1H), 5.60 (m, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.30 (m, 4H);3.15(m, 4H) m/z: 390 (M+1).
The starting material was prepared as follows.
A solution of phenylpiperazine (487 mg) in dichloromethane (6 ml) containing triethylamine (0.63 ml) was added dropwise over 5 minutes to trans-b-styrenesulfonyl chloride (638 mg) in dichloromethane (4 ml). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1 % methanol in dichloromethane to give 1 -phenyl-(4- trans-b-styrenesulfonyl)piperazine (420 mg) as a solid.
1H NMR (d6-DMSO): 7.75 (m, 2H), 7.40 (m, 4H), 7.30 (d, 1H), 7.20 (dd, 2H), 6.90 (d, 2H), 6.80 (dd, 1H), 3.20 (s, 8H) m/z 329 (M+l).
To a solution of l-phenyl-4-( trans-b-styrenesulfonyl)piperazine (108 mg) in THF (3 ml) was added hydroxylamine (0.45 ml, 50 % aqueous solution). The mixture was stirred at ambient temperature for 18 hours. Solvent was removed in vauo and the residue dissolved in dichloromethane, washed with water, dried (Na2SO4) and evaporated to give the product l-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-phenylpiperazine as a foam (120 mg).
lH NMR (d6-DMSO): 7.50 (m, 1H), 7.40 (m, 2H), 7.30 (m, 5H), 6.90 (d, 2H), 6.80 (dd, 1H), 5.90 (m, 1H), 4.20 (m, 1H), 3.60 (dd, 1H), 3.40 (dd, 1H), 3.20 (m, 4H); 3.10 (m, 4H) m/z 362 (M+l).
Example 8
l-[2-(N-formyl-N-hvdroxvamino)-2-(quinoline-4-yl)ethane-l-sulfonyl]-4-(4-
fluorophenyl)piperazinc
(Formula Removed)
To a suspension of l-[2-(N-hydroxyamino)-2-(quinoline-4-yl)ethane-l-sulfonyl]-4-(4-fluorophenyl)piperazine (148 mg, 0.34 mmol) in THF (2 ml) - CH2Cl2 (2 ml) was added 5-methyl-3-formyl-l,3,4-thiadiazole-2(3H)-thione(1) (140 mg, 0.87 mmol). The mixture was stirred for 3 h. After addition of methanol (2 ml) and silica (1 g), the mixture was stirred for 18 h. The solids were filtered. The filtrates were washed with sat. NaHCO3 and brine. Evaporation of the solvents followed by trituration in acetonitrile - CH2Cl2 gave the starting material (60 mg). Chromatography of the mother liquors with acetonitrile - CH2Cl2 (1:1) gave the title compound (20 mg, 13%).
1H-NMR (CDCl3): 8.97 (m, 1H), 8.21 (m, 2H), 8.01 (s, 1H), 7.8-7.65 (m, 3H), 6.97 (m, 2H), 6.86 (m, 2H), 5.66 (m, 1H), 3.55-3.1 (m, 10H), MS (ESI): 459 (MH+).
The starting material was prepared from quinoline-4-carboxaldehyde and 1-(fluorophenyl)-4-(methanesulfonyl)piperazine in a similar manner to Example 1 ii-iii): 188 mg: MS (ESI): 431 (MET); HPLC tR (Column TSKgel super ODS 2mm 4.6mm x 5cm, gradient methanol/ water 20 to 100% in 5 min, flow rate: 1.4 ml/mn): 3.43 min
(1) Yazawa, H.; Goto, S. Tetrahedron Lett., 1985, 26, 3703
Example 9
l-fl-(N-formvi-N-hvdroxyamino)-l-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-
fluorophenyl)piperazine.
(Formula Removed)
Similarly to Example 1, the syn and anti diastereoisomers of l-[l-(N-hydroxyamino)-l-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-fluorophenyl)piperazine were converted to the title compound (as 2 diastereoisomers):
- diastereoisomer 1 from the less polar hydroxylamine: 36 mg, 70%; 'H-NMR (CDC13): 8.45 and 8.10 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.8 (m, 2H), 5.96 and 5.18 (m, 1H), 3.8-3.4 (m, 5H), 2.9-3.15 (m, 4H), 2.0-1.0 (m, 4H), 0.88 and 0.76 (t, 3H, J= 7 Hz); MS (ESI): 540 (M{35Cl,35Cl}Na+), 542 (M{37Cl,35Cl}Na+).
- diastereoisomer 2 from the more polar hydroxylamine: 49 mg, 63%; 'H-NMR (CDCl3) : 8.28 and 8.13 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.85 (m, 2H), 5.54 and 5.02 (m, 1H), 3.45-3.9 (m, 5H), 3.15 (m, 4H), 1.7-1.2 (m, 4H), 0.76 (t, 3H, J= 7 Hz); MS (ESI): 540 (M{35Cl,35Cl}Na+), 542 (M{37Cl,35Cl}Na+).
The starting material was prepared as follows:
Similarly to Example 1 i), from l-(4-fluorophenyl)piperazine and 1-butanesulfonyl chloride was obtained l-(4-fluorophenyl)-4-(butane-l-sulfonyl)piperazine (1.84 g); similarly to Example 1 ii), this was reacted with 3,4-dichlorobenzaldehyde to give 4-(4-fluorophenyl)-l-[l-(3,4-dichlorophenyl)pent-l-ene-2-sulfonyl]piperazine as a mixture of Z/E isomers (330 mg, 22%): MS (ESI): 457 (M{35Cl,35Cl}H+), 459 (M{37C1,35C1}H+); similarly to Example 1 iii) except that the mixture was refluxed for 3 days, this was converted to 1-[1-(N-hydroxyamino)-l-(3,4-dichlorophenyl)pentane-2-sulfonyl]-4-(4-fluorophenyl)piperazineas the syn and anti diastereoisomers.
Less polar isomer (50 mg, 15%) (TLC: eluant EtOAc - CH2Cl2- petroleum ether (15-45-50); 1H-NMR (CDCl3): 7.53 (d, 1H, J= 2.2 Hz), 7.46 (d, 1H, J= 7.4 Hz), 7.27 (m, 1H),
6.97 (m, 2H), 6.88 (m, 2H), 4.63 (m, 1H), 3.55 (m, 4H), 3.16 (m, 5H), 1.75 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H), 0.77 (t, 3H, J= 7.4 Hz).
More polar isomer (76 mg, 23 %); 'H-NMR (CDC13) : 7.52 (d, 1H, J= 2 Hz), 7.45 (d, 1H, J= 8 Hz), 7.27 (m, 1H), 6.99 (m, 2H), 6.89 (m, 2H), 4.42 (m, 1H), 3.55 (m, 4H), 3.41 (m, 1H), 3.14 (m, 4H), 1.6 (m, 2H), 1.25 (m, 2H), 0.76 (t, 3H, J= 7.3 Hz).
Example 10
Trans l-[2-(N-formyl-N-hvdroxyamino)cyclohexane-l-sulfonvl]-4-(4-fluorophenyl)-piperazine.
(Formula Removed)
Similarly to Example 1, from trans l-[2-(N-hydroxyamino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyl)piperazine was obtained the title compound (68 mg, 23%).
1H-NMR (CDCl3) : 8.39 and 8.02 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.40 and 3.92 (m, 1H), 3.35-3.55 (m, 5H), 3.15 (m, 4H), 2.35 (m, 1H), 2.0-1.8 (m, 3H), 1.2-1.6 (m, 4H); MS (ESI): 408 (MNa+).
The starting material was obtained as follows :
i) To a solution of LDA (51 mmol, prepared by slow addition of n-butyl lithium (20.4 ml, 2.5M in hexane, 51 mmol) to a solution of diisopropylamine (5.16 g, 51 mmol) in THF (30 ml) at -78°C) at -78°C was added a solution of l-(4-fluorophenyl)-4-(methanesulfonyI)-piperazine (6 g, 23.2 mmol) in THF (150 ml). The mixture was stirred for 1 h at -78°C. A solution of 5-chlorovaleryl chloride (4 g, 25.8 mmol) in THF (20 ml) was added dropwise. The mixture was stirred at -78°C for 1 h and at room temperature for 18 h. The solution was diluted with EtOAc and washed with sat. NH4CI and brine and dried over MgSCv Chromatography of the residue on silica gel (eluant : EtOAc - CH2CI2 - petroleum ether (15:35.50)) afforded l-(6-chloro-2-hexanone-l-sulfonyl)-4-(4-fluorophenyl)piperazine (5.22 g, 60%) as white crystals: MS (ESI): 399 (MNa+).
ii) A mixture of this compound (5.22 g, 13.9 mmol) and Nal (42 g) in acetone (90 ml) was refluxed for 5 h. After cooling and partitioning between EtOAc and water, the organic
layer was washed with 10 % NaHSO3 and brine, and dried over MgSO4 to give l-(6-iodo-2-hexanone-l-sulfonyl)-4-(4-fluorophenyl)piperazine (6.13 g, quantitative) as yellowish crystals: 1H-NMR (CDC13): 6.98 (m, 2H), 6.88 (m, 2H), 4.00 (s, 2H), 3.46 (t, 4H, J= 4.8 Hz), 3.19 (t, 2H, J= 6.6 Hz), 3.16 (t, 4H, J= 4.8 Hz), 2.79 (t, 2H, J= 6.6 Hz), 1.85 (m, 2H), 1.74 (m,2H).
iii) A mixture of this compound (1.27 g, 4.85 mmol) and cesium carbonate (8 g, 24.5 mmol) in CH2Cl2 (90 ml) was stirred at room temperature for 4 h. To the mixture was slowly added water and 2N HCl until pH ~ 7. The mixture was extracted with CH2C12. The organic layer was dried over MgSCv Chromatography on silica gel (eluant: EtOAc - petroleum ether (4:6)) afforded l-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (880 mg, 53%). !H-NMR(CDC13): 6.97 (m, 2H), 6.88 (m, 2H), 3.83 (m, 1H), 3.48 (m, 4H), 3.12 (m, 4H), 2.81 (m, 1H), 2.54 (m, 1H), 2.46 (m, 1H), 2.2-2.0 (m, 3H), 1.75 (m, 2H); MS (ESI): 363 (MNa+); IR: 1716.
Further elution (EtOAc - petroleum ether (6:4)) afforded 1-[(tetrahydropyran-2-yl)methylidenesulfonyl]-4-(4-fluorophenyl)piperazine (630 mg, 38 %): 'H-NMR (CDC13) : 6.98 (m, 2H), 6.87 (m, 2H), 5.21 (s, 1H), 4.14 (t, 2H, J= 5.2 Hz), 3.32 (m, 4H), 3.15 (m, 4H), 2.35 (t, 2H, J- 6.6 Hz), 1.82 (m, 4H); MS (ESI): 363 (MNa+).
iv) To a solution of l-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (284 mg, 0.83 mmol) in methanol-THF (16 ml, 3:1) at 0°C was added sodium borohydride (3.7 mg, 1 mmol). The mixture was stirred at 0°C for 30 min and at room temperature for 1 h 30. The solvents were evaporated. Saturated NH4CI and water were added. The precipitate was filtered, washed with water and dried to give l-(2-cyclohexanol-l-sulfonyI)-4-(4-fluorophenyl)piperazine (250 mg, 88%): MS (ESI) : 343 (MH+).
v) To a solution of l-(2-cyclohexanol-l-sulfonyl)-4-(4-fluorophenyl)piperazine (310 mg, 0.9 mmol) in THF (15 ml) was added triphenylphosphine (1.18 g ; 4.5 mmol) and DEAD (712 p.1, 4.5 mmol) dropwise. The mixture was stirred at room temperature for 18 h. Evaporation of the solvents and purification on silica gel (eluant: EtOAc -petroleum ether, gradient from 2:8 to 3:7) gave l-[l-cyclohexene-l-sulfonyl]-4-(4-fluorophenyl)piperazine (285 mg, 98%): MS (ESI): 325 (MH+).
vi) Similarly to Example 1 iii) except that the reaction was heated at 65°C for 30 h, from l-(l-cyclohexene-l-sulfonyl)-4-(4-fluorophenyl)piperazine (280 mg, 0.86 mg) was obtained trans 1 -[2-(N-hydroxyamino)cyclohexane-1 -sulfonyl]-4-(4-fluorophenyl)piperazine

(270 mg, 88%): !H-NMR (CDC13): 6.98 (m, 2H), 6.88 (m, 2H), 3.54 (m, 4H), 3.34 (m, 2H), 3.14 (m,4H), 2.30 (m, 1H), 2.17 (m, 1H), 2.05 (m, 1H), 1.9-1.2 (m, 5H); MS (ESI): 358 (MH+).
Example 11
Cis l-r2-(N-formvl-N-hvdroxvamino)cvclohcxaiie-l-sulfonvll-4-(4-fluoroDhenvl)-
piperazinc.
(Formula Removed)
Similarly to Example 1, from cis l-[2-(N-hydroxyamino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyl)piperazine was obtained the title compound (18 mg, 18%): 'H-NMR (CDCI3): 8.39 and 8.07 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.77 and 4.25 (m, 1H), 3.48 (m, 5H), 3.13 (m, 4H), 2.25-1.3 (m, 8H); MS (ESI) : 408 (MNa+).
The starting material was obtained as follows :
i) A mixture of l-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (50 mg, 0.14 mmol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and potassium acetate (72 mg, 0.73 mmol) in methanol (5 ml) was heated at 70°C for 4 h. The solvents were evaporated. After partitioning between EtOAc and water, the organic layer was washed with brine and dried over MgSO4 to give l-[2-(N-hydroxyimino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyi)piperazine as a white solid (48 mg, 94%): MS (ESI): 356 (MET), ii) To this compound (210 mg, 0.6 mmol) in a mixture of THF - acetic acid (7 ml, 1:1) was added sodium cyanoborohydride (276 mg, 4.4 mmol). The mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 9. The mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgS04. Chromatography on silica (eluant: EtOAc - petroleum ether, gradient from 1:1 to 8:2) afforded cis l-[2-(N-hydroxyamino)cyclohexane-l-sulfonyl]-4-(4-fluorophenyl)piperazine (97
mg, 45%). 'H-NMR (CDCI3): 6.98 (m, 2H), 6.89 (m, 2H), 3.63 (m, 1H), 3.52 (m, 4H), 3.24 (dt, 1H, Jd= 10.6 Hz, Jt= 3.5 Hz), 3.15 (m, 4H), 2.2-1.2 (m, 8H); MS (ESI) : 358 (MH").
Example 12
The following compounds were made using the method outlined in Example 1:
(Formula Removed)
* =M-H
R2 = hydrogen
PIP = piperazinyl
RH = reverse hydroxamate
A = carboxylic acid
(Table Removed)
MS for C17H24FN305S (M+H) calcd 402, found 402.
(Formula Removed)
The aryl/heteroarylpiperazines and piperidines used as starting materials were commercially available or were described in the literature, for example 4-(4-fluorophenyl)-piperidine, CAS number 37656-48-7 Piperazine, 1 -[ 1,1 '-biphenyl]-4-yl-( 180698-19-5) Piperazine, l-[l,l'-biphenyl]-3-yl- (115761-61-0) Piperazine, l-(2-naphthalenyl)- (57536-91-1) Piperazinone, 1 -phenyl-(90917-86-5)
1H-1,4-Diazepine, l-(4-chlorophenyl)hexahydro-(41885-98-7) Quinoline, 4-methyl-2-(l-piperazinyl)-( 50693-78-2) Piperazine, l-(4-phenoxyphenyl)- 62755-61-7 Piperazine, l-(3-chlorophenyl)-
The 2-methyl-4-(4-fluorophenyl)-piperazine used as starting material was prepared as follows:
Sodium-t-butoxide (4.1g) was added to a solution of tir-tolylphosphine (0.638g) and palladium acetate (0.319g ) in toluene (250 mL) under argon and the mixture was stirred for 20 minutes. 4-Fluoro-bromobenzene (5g) and 2-methylpiperazine (2.85g) were added and the mixture was heated at 110 °C for 7 hours, then allowed to cool to ambient temperature and keep at this temperature for 20 hours. The reaction mixture was filtered through Celite®, the filter cake was washed twice with dichloromethane (2X25 mL) and the filtrate was evaporated to dryness. The residue was chromatographed on silica eluting initially with dichloromethane and then with a mixture of dichloromethane, methanol and ammonium hydroxide (100:5:1) to give 2-methyl-4-(4-fluorophenyl)-piperazine, 2.5g.
Using this same method and 2,6-dimethylpiperazine as starting material there was obtained 2,6-dimethyl-4-(4-fluorophenyl)-piperazine. Piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl hydrochloride
tert-butoxycarbonyl piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl (0.712g) was stirred in a mixture of dichloromethane (10ml) and trifluoroacetic acid (1.0ml) for 18 hours at ambient temperature, evaporated in vacuo to a grey solid and used without further purification. The_tert-butoxycarbonyl piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl used as starting material was prepared as follows:
Sodium-t-butoxide (1.35g) was added to a solution of S-(-)-2,2'-bis(diphenylphosphino)-l,l'-binapthyl (0.046g) and bis(dibenzylideneacetone)palladium
(0.023g ) in toluene (25 ml) under argon and then added 4-bromo-4'-fluorobiphenyl (2.5 lg) and 1-tert-butoxycarbonylpiperazine (2.2g) and the mixture was heated at 80°C for 5 hours. The reaction mixture was filtered, filtrate evaporated in vacuo to a yellow solid which was triturated and then filtered from diethyl ether(20 ml) to give tert-butoxycarbonyl piperazine, l-[l,l'-biphenyl-4'-fluoro]-4-yl, (2.67g), mp 165-166 °C.
NMR(d6-DMSO) 1.42 (s, 9H), 3.15 (m, 4H), 3.48 (m, 4H), 7.02 (d, 2H), 7.22 (m, 2H), 7.51 (d, 2H), 7.63 (m, 2H), m/z 357(M+1).
Example 13
(Formula Removed)
Acetic anhydride (0.23mi) was added directly to formic acid (0.9ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(6-chloropyrimidin-4-yl)tetrahydropyrazin-1 -yl]sulfonyl} -1 -(3,4-
dichlorophenyl)ethyl]hydroxylamine (0.227g) in tetrahydrofuran (5ml). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water-bath temperature 30 °C) and the residual gum was purified by chromatography using a lOg silica isolute eluting with CH2C12-3% Methanol/CH2C12 to give N-[2-{[4-(6-chloropyrimidin-4-yl)piperazino]sulfonyl}-l-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.178g), 98-101°C.
NMR (d6-DMSO 373 °K): 3.31 (m, 4H), 3.70 (dd, 1H), 3.75 (m, 4H), 3.95 (dd, 1H), 5.61 (vbs, 1H), 6.89 (s, 1H), 7.43 (dd, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 8.29 (s, 1H), 8.36 (s, lH);m/z494(M+l).
(Formula Removed)
Acetic anhydride (0.63ml) was added directly to formic acid (2.48ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-l-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.6lg) in tetrahydrofuran (10ml). The solution was stirred at room temperature for 3 hours.and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2S04), and evaporated to dryness. The residue was purified by chromatography using a lOg silica isolute eluting with 10% ethyl acetate/heaxane-80% ethyl acetate/hexane and then evaporated to dryness. The resulting white solid was filtered from diethyl ether to give N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-l-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.43 lg), 211-212°C.
NMR (d6-DMSO 373 °K): 3.30 (m, 4H), 3.80 (m, 4H), 3.85 (dd, 1H), 3.95 (dd, 1H), 5.58 (vbs, 1H), 6.85 (d, 1H), 7.43 (m, 1H), 7.58 (m, 2H), 7.85 (d, 1H), 8.10 (d, 1H), 8.13 (s, lH);m/z 493 (M+l)
Acetic anhydride (0.48ml) was added directly to formic acid (1 9ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-(2-(benzyloxy)-l-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyI}ethyl)hydroxylamine (0.42g) in tetrahydrofuran (5ml). The solution was stirred at room temperature for 3 hours.and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2S04), and evaporated to dryness. The residue was purified by chromatography using a 10g silica isolute eluting with CH2C125% Methanol/CH2C12 to give N-(2-(benzyIoxy)-l-{[(4-pyridin-2-ylpiperazino)sulfonyI]methyl-ethyl)-N-hydroxyformamide (0.233g) , 70-75 °C.
NMR(d6-DMSO 373 °K): 3.25 (dd, 1H), 3.31 (m, 4H), 3.48 (dd, 1H), 3.65 (m, 4H)„ 3.66 (dd, 1H), 3.70 (dd, 1H), 4.55 (vbs, 1H),4.55 (s, 2H), 6.70 (m, 1H), 6.85 (d, 1H), 7.28 (m, H), 7.32 (m, 4H), 7.58 (m, 1H), 8.17 (m, 2H), 9.45 (bs, lH);m/z435 (M+l).
(Formula Removed)
Acetic anhydride (0.48ml) was added directly to formic acid (1 9ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-(3-pyridin-2-yl-l-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyl-propyl)hydroxylamine (0.152g) in tetrahydrofuran (5ml). The solution was stirred at room temperature for 3 hours.and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2S04), and evaporated to dryness. The residue was purified by chromatography using a 10g silica isolute eluting with CH2C125% Methanol/CH2C12 to give N-hydroxy-N-(3-pyridin-2-yl-l-{[(4-pyridin-2-ylpiperazino)sulfonyl]methyl}propyl)formamide (0.039g), 80-84 °C NMR(d6-DMSO 373 °K):2.10 (m, 2H), 2.80 (m, 2H), 3.25 (dd, 1H), 3.30 (m, 4H), 3.50 (dd, 1H), 3.60 (m, 4H), 4.42 (vbs, 1H), 6.70 (m, 1H), 6.85 (d, 1H), 7.19 (m, 1H), 7.22 (d, 1H), 7.54 (m, 1H), 7.65 (m, 1H), 8.10 (vbs, 1H), 8.15 (m, 1H), 8.45 (m, 1H), 9.50 (vbs, lH);m/z420(M+l).
Example 14
N-{l-[((4-("(5-chloropyridin-2-vl)oxy]piperidino}sulfonyl)methyl]-3-pyridin-3-ylpropyl}-N-hydroxyformamide
(Formula Removed)
To a solution of l-N-[2-(hydroxyamino)-2-(3-pyridinyl)butanesulfonyl]-4-0-(5-chloro-2-pyridinyl)piperidine (2.1 g, 4.18 mmol) in THF (36 ml) added a preformed mixture of formic acid (9.0 ml) and acetic anhydride (2.25 ml). The mixture was stirred at room temperature for 18 hrs. The reaction was neutralised using saturated aqueous NaHCO3 before extracting the solution with EtOAc (x2). The combined organics were dried over Na2SO4 and evaporated in vacuo. The residue was stirred in MeOH at room temperature for
20 hrs to remove the bis-formyl. The residue was crystallised from EtOH to afford a white solid (0.898g). m.p. 130-140°C.
1H NMR(DMSO-100°C):9.50(brs, 1H), 8.43 (d, 1H), 8.39 (dd, 1H), 8.15(d, 1H), 8.13 (br s, 1H), 7.74 (dd, 1H), 7.60 (m, 1H), 7.27 (m, 1H), 6.83 (d, 1H), 5.12 (m, 1H), 4.32 (br s, 1H), 3.42 (m, 3H), 3.16 (m, 3H), 2.68-2.54 (m, 2H), 2.06-1.93 (m, 4H), 1.76 (m, 2H); MS (ES+): 469.2 (MH+), 491.1 (MNa+); EA: calculated for C20H25ClN4O5S: C 51.22, H 5.37.C1 7.56, N 11.95, S 6.84, Found: C 50.92, H 5.30, CI 7.55, N 11.90, S 6.75.
The starting material was prepared as follows :
i) NaH (2.88g, 66mmol, 55% dispersion in mineral oil) was stirred in dry DME (200ml), under Argon. A mixture of 2,5- dichloropyridine (8.87g, 60mmol) and 4-hydroxypiperidine (6.67g, 66mmol) dissolved in dry DME (200ml) was added to the NaH suspension dropwise, over a period of 30 minutes. After complete addition the reaction is heated to 82°C for 48 hrs, maintaining the Argon blanket. The reaction was slowly quenched with water before removing most of the THF. Extracted the aqueous with DCM (x3). The organic layers were dried with Na2SO4 and evaporated in vacuo to afford 2-(4-piperidinyloxy) -5-chloropyridine as a yellow oil (12.7g, quantitative). 'H NMR (DMSO): 8.17 (d, 1H), 7.76 (dd, 1H), 6.81 (d, 1H), 4.96 (m, 1H), 2.93 (m, 2H), 2.53 (m, 2H), 1.91 (m, 2H), 1.46 (m, 2H); MS (ES+): 213.3 (MET), 225.3 (MNa+)
ii) To a solution 2-(4-piperidinyloxy) -5-chloropyridine(12.9 g, 0.06 mol) and Et3N (25.4 ml, 0.182 mol) in dry dichloromethane (400 ml) at 0°C and under Argon, was added methanesulfonyl chloride (5.3 ml, 0.067 mol) in dry dichloromethane (100 ml), dropwise. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with dichloromethane (250 ml), then washed with water (x3) then brine. The organic layers were dried with Na2SO4 and evaporated in vacuo. The residue was triturated and washed with diethylether to give 2-(N-methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (15.1 g) as a pale yellow solid.
1H NMR (DMSO): 8.20 (d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.90 (s, 3H), 2.02 (m, 2H), 1.75 (m, 2H); MS (ES+): 291.2 (MH+), 313.2 (MNa4).
iii) 2-(N-methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (2.0g, 6.89 mmol) was taken into anhydrous THF (100 ml) under Argon then cooled to -78°C before the addition of Li(TMSA) (13.8 ml of a 1.0M solution in THF, 13.8 mmol), . The mixture was stirred at -78°C for 20 minutes and a solution of diethylchlorophosphate (1.05 ml, 7.23 mmol) was added. The
mixture was stirred at -78°C for 1 hour before 3-pyridinylpropanaI (1.12g, 8.27 mmol) was added then stirred at -78 for a further lhr. The mixture was allowed to warmed to room temperature then was washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over Na2SO4. Purification of the residue on silica (eluant: gradient, DCM - 2% MeOH/DCM ) afforded 2-{N-[E/Z-4(3-pyridyl)-but-lenyl] sulfonyl}4-piperidinyloxy) -5-chloropyridine as a yellow oil (2.09g). 1HNMR (DMSO): 8.45 (m, 1H), 8.37 (m, 1H), 8.19 (m, 1H), 7.82 (m, 1H), 7.64 (m, 1H,), 7.30 (m, 1H), 6.85 (m, 1H), 6.88-6.27 (m, 2H, E/Z isomers), 5.00 (m, 1H), 3.15 (m, 2H), 2.83 (m, 5H), 2.61 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H); MS (ES+): 408.1 (MH+), 430.2 (MNa+).
iv) To a solution of 2-{N-[E/Z-4(3-pyridyl)-but-lenyl] sulfonyl}4-piperidinyloxy) -5-chloropyridine(2.09 g, 5.1 mmol) in THF (20 ml) was added hydroxylamine (3.4 ml, 50 % aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in EtOAc and washed with water (x4). The organic layer was dried on Na2SO4 and evaporated in vacuo to give 2-(4-piperidinyloxy) -5-ch!oropyridine l-N-[2-(hydroxyamino)-2-(3-pyridinyl)butanesulfonyl]-4-0-(5-chloro-2-pyridinyl)piperidine (730 mg). 'HNMR (DMSO): 8.43 (d, 1H), 8.37 (dd, 1H), 8.18 (d, 1H), 7.78 (dd, 1H), 7.61 (m, 1H), 7.36 (s, 1H), 7.29 (m, 1H), 7.85 (d, 1H), 5.70 (s, 1H), 5.08 (m, 1H), 3.35 (m, 3H), 3.16-3.00 (br m, 4H), 2.80-2.60 (br m, 2H), 1.98 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H); MS (ES+); 441.2 (MH+), 463.2 (MNa+).
Using an analogous procedure to that described in Example X, a aryl-4-O-piperidine was reacted with the appropriate aldehyde to give the compounds listed below.

(Formula Removed)
(Table Removed)
The following aryl-4-O-piperidines have been described previously: Piperidine, 4-(3-chlorophenoxy)-(9Cl), CAS (97840-40-9) Piperidine, 4-(4-chlorophenoxy)-(9Cl), CAS (97839-99-1) Pyridine, 2-(4-piperidinyloxy)-(9Cl), CAS (127806-46-6) Piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) was synthesised in the following alternative route:-
1) To a stirred solution 4-hydroxypiperidine(3.5 g, 0.035 mol) in dry methanol (50 ml) at 0°C, was added di-butyl dicarbonate (9.2 ml, 0.042 mol) in dry methanol (50 ml), dropwise. The mixture was stirred for 20 hours at room temperature. The methanol was removedand the remaining solution was taken into Et2O, then washed with 1M citric acid (x3) and water (x3). The combined aqueous extracts were extracted with Et20 which was dried with Na2SO4 and evaporated in vacuo. Purification of the residue on silica (eluant: gradient, DCM - 30% MeOH/DCM ) afforded N-BOC-4-hydroxypiperidine as a yellow oil (6.4g). 'H NMR (DMSO). 4.05 (m, 2H), 3.70-3.52 (br m, 3H), 2.92 (m, 2H), 1.66 (m, 2H), 1.40 (s, 9H), 1.33-1.18 (br m, 2H); MS (ES+): 201.3 (MH+), 219.4 (MNH/).
2) To a stirred solution N-BOC-4-hydroxypiperidine(2.0 g, 0.01 mol), triphenylphosphine (3.68g, 0.014 mol) and 3,4-dichlorophenol (1.96g, 0.012 mol) in dry toluene (75 ml) [with molecular sieves, at 0°C and under Argon] was added diethyl azodicarboxylate (2.52 ml, 0.016 mol), dropwise. The mixture was stirred for 1.5hrs at 0°C. Filtered the solution and removed the toluene before vigorously stirringin isohexane (100ml) and filtered the resulting suspension. The filtrate was washed with 2M aqueous NaOH (x8), dried with Na2S04 and evaporated in vacuo. Purification of the residue on silica (eluant: 20% EtOAc/isohexane ) afforded N-Boc-Piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) as a yellow solid (1.96g). *H NMR (DMSO): 7.52 (d, 1H), 7.31 (d, 1H), 7.01 (dd, 1H), 4.62 (m, 1H), 3.65 (m, 2H), 3.15 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H), 1.40 (s, 9H); MS (ES+): 346.3 (MH+), 368.4 (MNa+).
3) 50% aquous trifluoroacetic acid (18ml) was added to a stirred solution N-Boc-
piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) (1.96 g, 5.66 mmol). After 3.5hrs toluene is added
and evaporated in vacuo, this was repeated twice. The residue was then taken into EtOAc
washed with saturated aqueous NaHCO3 (x3), dried with Na2SO4 and evaporated in vacuo to afforded piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) a white solid (1 3g). 'H NMR (DMSO): 7.54 (d, 1H), 7.35 (d, 1H), 7.04 (dd, 1H), 4.70 (m, 1H), 3.31 (m, 2H), 3.09 (m, 2H), 2.08 (m, 2H), 1.80 (m, 2H); MS (ES+): 2.26.3 (MH+).
Piperidine, 4-(3,4-dichlorophenoxy)-(9Cl) was then taken through steps ii-iv as described above.
Example 15
l-Mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine
1-Mesylpiperazine hydrochloride (4.24g) was added to a solution of methyl 6-chloronicotinate (1.7g) and N,N-diisopropylethylamine (6.3ml) in dimethylacetamide (20ml) and the mixture was heated at 120°C for 2 hours. The mixture was allowed to cool to ambient temperature and poured onto crushed ice/water (50ml) to precipitate a tan solid. The solid was collected by filtration and dried at 80 °C for 18 hours in a vacuum oven, to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05g), mp 205-207°C.
NMR (d6-DMSO): 2.90 (s, 3H), 3.20 (m, 4H), 3.78 (m, 3H), 3.80 (s, 3H), 6.92 (d, 1H), 8.00 (dd, 1H), 8.67 (d, 1H); m/z 300 (M+l).
Using an analogous procedure 1-mesylpiperazine hydrochloride, CAS( 161357-89-7), was reacted with the appropriate chloropyridine to give the following compounds.

(Table Removed)
1 -(6-chloropyrimidin-4-yl)-4- mesylpiperazine
A mixture of 4,6-dichloropyrimidine (39.4g), 1-mesylpiperazine hydrochloride (55.7g) and triethylamine (116ml) in ethanol (500ml) was stirred at reflux temperature for 4 hours. The mixture was then stirred at room temperature for 12 hours. The solid, which had separated, was collected by filtration, slurry washed with ethanol (2x80ml, 160ml) then with diethyl ether (150ml), and dried to give l-(6-chloropyrimidin-4-yl)-4- mesylpiperazine as a cream solid (71.9g). mp 200-202°C
NMR (d6-DMSO): 2.88 (s, 3H), 3.18 (m, 4H), 3.80 (m, 4H), 7.04 (s, 1H), 8.38 (m, 1H); m/z 277.3 (M+l).
Using an analogous procedure 1-mesylpiperazine hydrochloride, CAS( 161357-89-7), was reacted with the appropriate chloropyrimidine or chloropyridazine to give the following compounds.
(Table Removed)
Example 16
(Formula Removed)
Acetic anhydride (19ml) was added directly to formic acid (76ml). The solution was stirred at room temperature for 30 minutes. A solution of l-(6-chloropyrimidin-4-yl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine (17.2g) in tetrahydrofuran (85ml) was
added in portions, to the above solution at 27 °C over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30°C) and the residual gum was dissolved in ethyl acetate (500ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (200ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in ethanol, a solid separated and the mixture was stirred for 2 days. The solid was collected by filtration, slurry washed with diethyl ether (100ml), and dried to give N-[l-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamide as a colourless solid (12.8g). mp 155-157°C.
Found C, 50.29, H, 5.29, Cl, 7.82, N, 15.31, and S, 6.82 %. C19H24ClN5O4S requires C, 50.27, H, 5.33, Cl, 7.81, N, 15.43, and S, 7.06 %.
NMR(d6-DMSO 373°K). 1.93 (m, 1H), 2.03 (m, 1H), 2.57 (m, 1H), 2 65 (m, 1H), 3.20 (dd, 1H), 3.26 (t, 4H), 3.48 (dd, 1H), 3.74 (t, 4H), 4.3 (v br, 1H), 6.90 (s, 1H), 7.19 (m, 3H), 7.27 (m, 2H), 8.1 (br, 1H), 8.38 (s, 1H), 9.5 (s, 1H); m/z 454.2 (M+l).
(Formula Removed)
Acetic anhydride (31.5ml) was added directly to formic acid (126ml). The solution was stirred at room temperature for 30 minutes.
A solution of l-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine (29.5g) in tetrahydrofuran (150ml) and formic acid (25ml), was added in portions to the above solution at 25 °C over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30°C) and the residual gum was dissolved in ethyl acetate (500ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2x250ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in methanol (70ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water-bath temperature 30 °C). The residual foam was stirred in ethanol (250ml),
solid separated and the mixture was stirred for 18 hours. The solid was collected by filtration, slurry washed with diethyl ether (100ml), and dried to give N-[2-(benzyloxy)-l-({[4-(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide (25.5g). mp 118-120°C
Found C, 48.35, H, 5.09, Cl, 7.26, N, 14.73, and S, 6.78 %. C19H24ClN5O5S requires C, 48.56, H, 5.15, Cl, 7.54, N, 14.90, and S, 6.82 %.
NMR(d6-DMSO 373 °K): 3.23 (dd, 1H), 3.30 (t, 4H), 3.46 (dd, 1H), 3.57 (dd, 1H), 3.67 (dd, 1H), 3.72 (t, 4H), 4.50 (s, 2H), 4.50 (m, 1H), 7.35 (m, 5H), 8.15 (br, 1H), 8.38 (s, 1H), 9.48 (br, 1H), m/z 470.2 (M+1).
(Formula Removed)
Acetic anhydride (0.8ml) was added directly to formic acid (3.2ml). The solution was stirred at room temperature for 30 minutes.
A solution of l-(5-chloro-2-pyridyl)-4-{[2-(hydroxyamino)-4-phenylbutyl]sulphonyl}piperazine (0.72g) in tetrahydrofuran (5ml) was added to the above solution at room temperature. The solution was stirred at room temperature for 2 days. The solution was evaporated (water-bath temperature 40°C).
The residue was dissolved in 5% methanol in dichloromethane. Silica (5g Merck 9385) was added to the solution, the mixture was stirred for 21 hours, and evaporated to dryness. The material (pre-adsorbed on the silica) was purified by chromatography on silica (Bond Elut 10g), using 0-3% methanol in dichloromethane as eluent, to give N-[ 1-({[4-(5-chloro-2-pyridyl)piperazino]sulphonyl}methyl)-3-phenylpropyl]-N-hydroxyformamide as an orange foam (0.17g).
NMR (d6-DMSO 373°K): 1.92 (m, 1H), 2.04 (m, 1H), 2.55 (m, 1H), 2.64 (m, 1H), 3.20 (dd, 1H), 3.27 (m, 4H), 3.47 (dd, 1H), 3.58 (m, 4H), 4.35 (v br, 1H), 6.88 (dd, 1H), 7.17 (m, 3H), 7.27 (m, 2H), 7.57 (dd, 1H), 8.10 (s, 1H), 8.10 (br, 1H), 9.5 (s, 1H); m/z 453.3 (M+l).
Example 17
(Formula Removed)
To formic acid (31.5ml) at 0°C was added acetic anhydride (7.9ml). After 20 minutes this was added to the hydroxylamine (6. lOg) dissolved in THF (80ml) and formic acid (40ml) and the resulting solution stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue dissolved in DCM (500ml), washed with saturated sodium bicarbonate solution (2x500ml), dried and evaporated to dryness. To the residue dissolved in DCM (10ml) was added diethyl ether (100ml) to give the product as a white solid (5.60g) which was collected by filtration. Mpt 168-170°C. NMR DMSOd6 d 10.2 (br s, 1H)*; 9.8 (br s, 1H)*; 8.7 (br s, 1H)*; 8.6 (br s, 1H)*; 8.5 (d, 1H); 8.3 (m, 1H), 8.1 (d, 1H); 7.9-7.8 (m, 1H); 7.6 (dd, 1H); 7.4 (dd, 1H); 6.9 (d, 1H); 5.8 (m, 1H)*; 5.5 (m, 1H)*; 4.1-3.6 (m, 2H); 3.6 (m, 4H); 3.2 (m, 4H). Anal. Calcd for C17H20ClN5O4S: C, 48.0; H, 4.7; Cl, 8.3; N, 16.5; S, 7.5. Found: C, 47.9; H, 4.7; CI, 8.4, N, 16.3; S, 7.5. MS for C17H20CIN5O4S (M+H) calcd 426, found 426.
* rotameric signals Step A
(Formula Removed)
The oxime (31.05g) [Tetrahedron Letters 1994,_35, 1011 ] was dissolved in DCM (500ml) and 3-pyridinecarboxaldehyde (12.09g) was added followed by anhydrous
magnesium sulfate (13.6g). After 2 days stirring at room temperature more magnesium sulfate (13.6g) was added and stirring was continued for a further 3 days. The mixture was then filtered, the solvent evaporated and the residue triturated with diethyl ether to give the product (36.34g) as a white solid. Mpt 174-175°C. NMR CDC13 d 9.0 (s, 1H); 8.9 (d, 1H); 8.7 (d, 1H), 7.7 (s, 1H); 7.4 (dd, 1H); 5.6 (s, 1H); 5.3 (d, 1H), 4.9 (dd, 1H); 4.6 (dd, 1H); 4.4 (ddd 1H); 4.2 (dd, 1H); 3.7 (dd, 1H); 1.5 (s, 3H); 1.4 (s, 3H); 1.4(s, 3H); 1.3 (s, 3H).
StepB
(Formula Removed)
The methyl sulfonamide (14.30g) was dissolved in THF (500ml) and cooled to -10°C when lithium hexamethyldisylazide (78ml, 1.0M in THF) was added. After 30 minutes the solution was cooled to -78°C, and the nitrone (18.00g) dissolved in THF (350ml) was added, keeping the temperature below -65°C. The resulting solution was stirred for 3 hours at -78°C when it was quenched by the addition of brine (500ml) and the aqueous layer extracted with ethyl acetate (3x500ml). The combined organic layers were dried and evaporated to give a yellow solid which was triturated with ethyl acetate / isohexane (4:1) and then purified by flash column chromatography eluting with dichloromethane / methanol (97:3) to give 1 (16.40g) as a white solid. Mpt 209-211°C (dec). NMR CDC13 d 8.6 (s, lH);8.4(d, 1H);8.1 (d, 1H); 7.8 (d, 1H); 7.5 (br s, 1H); 7.4 (dd, 1H); 7.3 (dd, 1H); 6.6 (d, 1H), 4.9 (d, 1H); 4.8 (s, 1H); 4.7-4.6 (m, 2H); 4.2-4.1 (m, 3H); 3.8 (dd, 1H); 3.6 (dd, 1H); 3.5-3.4 (m, 5H); 3.3-3.2 (m, 4H); 1.4 (s, 3H); 1.3 (s, 3H); 1.3 (s, 3H); 1.3 (s, 3H).
(Formula Removed)
To a solution of hydroxylamine 2 (14.90g,) in ethanol (300ml) was added water (220ml) followed by O-benzylhydroxylamine hydrochloride (13.91g) and sodium bicarbonate (6.95g). Heating gave a solution which was stirred overnight at 80°C. The ethanol was removed under reduced pressure and the residue separated between water (500ml) and ethyl acetate (500ml). The aqueous layer was washed with ethyl acetate (2x500ml), and the combined organic layers were dried and evaporated to give a residue which was triturated with dichloromethane (100ml) to give 3 (6.10g) as a white solid. The mother liquor was purified by flash column chromatography eluting with ethyl acetate followed by dichloromethane/methanol (96:4) to give further 3 (0.85g). Mpt 170-173°C. NMR DMSOck d 8.6 (s, 1H); 8.5 (d, 1H), 8.1 (d, 1H); 7.8 (d, 1H); 7.6 (dd, 1H); 7.6 (s, 1H); 7.3 (dd, 1H); 6.9 (d, 1H); 6.1 (br s, 1H); 4.3 (br s, 1H); 3.7-3.4 (m, 6H); 3.2-3.1 (m, 4H).
Example 18
The following compounds were made using the method outlined in Example 7
(Formula Removed)
(Table Removed)
* =M-H
R2 = hydrogen
PIP = piperazinyl
RH = reverse hydroxamate
The starting material was prepared as follows: The addition of hydroxylamine to l-trans-p-styrenesulphonyl-piperidine-4-(N-phenylcarboxamide) and the subsequent formylation of the product was carried out as described in Example 7.
Dimethylformamide (2 drops) was added to a suspension of 1-trans-fi-styrenesulphonyl-piperidine-4-carboxylic acid (0.75g) and oxalyl chloride (0.23 mL) in dichloromethane (10 mL) and was stirred for 2 hours. The reaction mixture was evaporated to dryness, re-dissolved in dichloromethane (10 mL) and evaporated to dryness again. The residue obtained was dissolved in dichloromethane (4 mL) and a mixture of aniline (0.23 mL) and triethylamine (0.35 mL) was added dropwise. The mixture was stirred for 20 hours and was washed with dilute 2M hydrochloric acid, water, aqueous saturated sodium bicarbonate solution and water and dried. Removal of the solvent gave l-trans-{3-styrenesulphonyl-piperidine-4-(N-phenylcarboxamide), 0.89g
Using the method described above there were prepared the following l-trans-P-styrenesulphonyl-piperidine-4-carboxamides

(Table Removed)
A solution of ethyl piperidine-4-carboxylate (3.99g) in a mixture of THF (30 mL) and methanol (6 mL) was treated with aqueous sodium hydroxide solution (20 mL of 2M NaOH) and the mixture stirred for 3 hours, evaporated to small volume and acidified to pH 5 with dilute 2M hydrochloric acid. The mixture obtained was extracted with ethyl acetate (2x25 mL), the ethyl acetate extracts were washed with water, dried and evaporated to dryness to give l-trans-P-styrenesulphonyl-piperidine-4-carboxylic acid, 2.64 g.
A solution of ethyl piperidine-4-carboxylate (3.0 mL) and triethylamine (2.7 mL) in dichloromethane (10 mL) was added dropwise to a cooled (ice bath) solution of trans-P-styrenesulphonyl chloride (3.95g) in dichloromethane (10 mL). The reaction mixture was allowed to warm to ambient temperature and stirring was continued for 20 hours. The reaction mixture was evaporated to dryness , the residue was diluted with water and extracted with ethyl acetate (2x25 mL). The combined ethyl acetate extracts were washed with brine and dried (MgS04) to give ethyl -(l-trans-P-styrenesulphonyl)-piperidine-4-carboxv!ate 5.76g, M+H = 324.
An alternative procedure for the preparation of 1 -trans-P-3,4dichlorostyrenesulphonyl-piperidine-4-carboxylic acid may be used:
To a solution of l-trans-P-3,4dichlorostyrenesulphonylchloride (2.7g) and isonipecotic acid (1.41g) in acetonitrile (15ml) was added 2M sodium hydroxide (I I ml) and stirred at ambient temperature for 1 hour. The reaction mixture was acidified to pH 3 with 2M hydrochloric acid and extracted with ethyl acetate (2x15ml), the ethyl acetate extracts were dried (Na2SO4), fitered and evaporated to give l-trans-P-3,4dichlorostyrenesulphonyl-piperidine-4-carboxylate (2.67g), m/z 364 (M+l).
Example 19
The following compounds were prepared
PEP = piperazinyl
Z = reverse hydroxamate group
R2 = hydrogen

(Table Removed)
Example 20
We provide NMR data for the following compounds:
(Formula Removed)
(DMSO) 9.6 (1H, s), 8.5 (1H, m), 8.4 and 7.9 (1H, s), 7.7 (1H, m), 7.2 (2H, m), 7.1 (2H, m),
7.0 (2H, m), 4.7 and 4.2 (1H, broad m), 3.4 (1H, m), 3.3 (5H, m), 3.1 (4H, m), 2.7 (2H, m),
2.0 (2H, m).
(Formula Removed)
(DMSO) 9,8 and 9.5 (1H, broad s), 8.3 and 8.0 (1H, s), 8.1 (1H, d), 7.6 (1H, dd), 7.2 (5H, m), 6.9 (1H, d), 4.7 and 4.1 (1H broad m), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.6 (2H, m), 1.6(4H, m).
(Formula Removed)
(DMSO) 9.6 (1H, broad S), 8.4 (1H, m), 8.3 and 7.9 (1H, s), 8.1 (1H, d), 7.6 (2H, m), 7.2 (1H, d), 7.1 (1H, m), 6.9 (1H, d), 4.7 and 4.1 (1H, broad m), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.7 (2H, m), 2.0 (2H, m).
(Formula Removed)
(DMSO) 9.7 (1H, broad s), 8.5 (1H, m), 8.4 (1H, m), 8.1 and 7.9 (1H, s), 7.6 (1H, in), 7.2 (2H, m), 7.0 (1H, m), 4.6 and 4.1 (1H, broad m), 3.7 (4H, m), 3.4 (1H, m), 3.3 (5H. m), 2.7 (2H, m), 2.0 (2H, m).
(Formula Removed)
(DMSO) 9.9 (1H, s), 8.4 (2H, m), 8.2 (1H, d), 7.65 (2H, m), 7.3 (1H, m), 7.0 (1H, m), 4.0-4.2 (2H, m), 3.6 (4H, br m), 3.4-3.2 (6H, br m), 2.0 (2H, br m).
(Formula Removed)
(DMSO) 10.0 (1H, s), 8.5 (2H, d), 8.2 (1H, br s), 7.8 (1H, br), 7.6 (1H, m), 7.4 (II I, m), 6.9 (1H, m), 3.6 (4H, br m), 3.2 (6H, br m).
(Formula Removed)
10.0 (1H, s), 8.5 (2H, m), 8.4 and 8.0 (1H, s), 7.9 (1H, m), 7.7 (1H, m), 7.3 (1H, m), 7.1 (1H, m), 3.7 (4H, br m), 3.45 (2H, m), 3.3 (4H, br m), 2.75 (3H, m), 2.1 (2H, m).
(Formula Removed)
(DMSO) 10.0 (1H, br s), 8.6 (2H, m), 8.2 (1H, d), 7.2 (1H, m), 6.9 (4H, m), 4.9 and 4.2 (1H, br), 3.4 (6H, m), 3.0 (6H, m), 1.9 (4H, m).
(Formula Removed)
(DMSO) 9.8 (1H, br), 8.7 (2H, m), 8.3 and 7.9 (1H, s), 8.1 (2H, s), 7.6 (1H, m), 7.3 (1H, m), 6.9 (1H, m), 4.1 (1H, br m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).
(Formula Removed)
(CDC13) 8.5 (1H, m), 8.1 (2H, s), 8.5 and 8.0 (1H, s), 7.8 (1H, m), 7.4 (1H, m), 7.3 (2H, m), 6.6 (1H, m), 4.8 and 4.2 (1H, br m), 3.6 (4H, m) 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).
(Formula Removed)
(DMSO) 8.5 (1H, d), 8.4 and 8.2 (1H, s), 7.7 (1H, m), 7.2 (6H, m), 4.8 and 4.2 (1H, br m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).
Example 21
The following compounds were prepared
(Formula Removed)
PIP = piperazinyl
Z = reverse hydroxamate group
R2 = hydrogen
(Table Removed)
All compounds were prepared as in Example 1 except those where ring A is 4-0-piperidinyl which were prepared as in Example 14.
Example 22
We provide NMR data for the following compounds listed in Example 21:
(Table Removed)
Example 23 Preparation of:
(Formula Removed)
To formic acid (4.8ml) at 0°C was added acetic anhydride (1.2ml). After 20 minutes this was added to the hydroxylamine 2 (0.68g) dissolved in THF (11ml) and formic acid (5ml) and the resulting solution stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue dissolved in DCM (100ml), washed with saturated sodium bicarbonate solution (2x100ml), dried (MgS04) and evaporated to dryness. The residue was purified by flash column chromatography eluting with dichloromethane / methanol (96:4) to give the product (0.41g) as a gum. NMR CDC13 5 9.7 (br s, 1H)*; 9.2 (br s, 1H)*; 8.4 (s, 1H)*; 8.0 (s, 1H)*; 7.5-7.2 (m, 5H); 7.0-6.8 (m, 4H), 5.7 (m, 1H)*; 5.4 (m, 1H)*; 3.9-3.4 (m, 5H); 3.3 (m, 1H)*; 3.2-2.9 (m, 4H); 2.8 (m, 1H)*. MS for C20H22FN3O3 (M+H) calcd 372, found 372.
* rotameric signals Step A
(Formula Removed)
To l-(4-fluorophenyl)piperazine (l.OOg) dissolved in DCM (10ml) was added cinnamoyl chloride (0.85g) in DCM (10ml) followed by triethylamine (1 55ml). The solution was stirred at room temperature overnight.. It was then separated between DCM (1 50ml) and water (100ml), the organic layer was then washed with water (100ml) dried (MgSO4) and evaporated to dryness to give a cream solid which was triturated with diethyl ether (10ml) to give 1 (1.20g) as a white solid. NMR CDC13 5 7.7 (d, 1H); 7.5 (m, 2H); 7 4 (m, 3H); 7.0-6.9 (m, 5H); 4.0-3.8 (m, 4H); 3.1 (m, 4H). MS for C19H19FN2O (M+H) calcd 311, found 311.
StepB
(Formula Removed)
To the amide (2.00g) dissolved in THF (40ml) was added hydroxylamine (1ml, 50% aqueous solution). The solution was stirred at room temperature for 48 hours. The solvent was then evaporated under reduced pressure, toluene was added (50ml) and this was also evaporated under reduced pressure. The residue was triturated with dichloromethane / methanol (98:2) and the mother liquor purified by flash column chromatography eluting with dichloromethane / methanol (98:2) to give 2 (0.70g) as a gum. NMR CDC13 5 7.5-7.2 (m, 5H); 7.0-6.9 (m, 2H); 6.9-6.8 (m, 2H); 4.5 (dd, 1H); 3.8-3.7 (m, 2H), 3.6-3.5 (m, 2H); 3.1-2.8 (m, 5H); 2.7 (dd, 1H). MS for C19H22FN3O2 (M+H) calcd 344, found 344.

WE CLAIM:
1. A piperazine of the formula I
(Formula Removed)
wherein ring B is phenyl, pyridyl or pyrimidyl;
each R3 is independently selected from hydrogen, halogen, N02, 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 CIO aryloxy, n is 1, 2 or 3;
P is a direct bond;
Ring A is piperazinyl;
Both X2 and XI are N;
Y is -S02-;
Z is -N(OH)CHO and Q is CH2;
Rl is H, C1-6 alkyl, C5-7 cycloalkyl, up to ClOaryl, up to ClOaryl, up to C10heteroaryl, up to C12heteroarylalkyl, all optionally substituted by up to three groups independently selected from N02, CF3, halogen, C1-4alkyl, carboxy (C1-4) alkyl, up to C6 cycloalkyl, -OR4, -SR4, CI-4 alkyl substituted with -OR4, SR4 (and its oxidized analogues), NR4, N-Y-R4, or Cl-4 alkyl-Y-NR4, with the proviso that where Rl is -OH, -OR4, -SR4, or NR4, or N-Y-R4 then Z is not -N(OH)CHO, Rl 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, N02, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl, -S02-C1-6 alkyl or C1-6 alkoxy; and
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 Rl or R2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring comprising one or more of O, S ad N; and wherein any alkyl groups outlined above may be straight chain or branched, or a pharmaceutically acceptable salt thereof.
2. A piperazine as claimed in claim 1 and wherein:
R3 is hydrogen, halogen, N02, CF3, C1-4 alkyl, and C1-4 alkoxy, n is 1 or 2;
Rl is hydrogen, C1-6alkyl, C5-7 cycloalkyl, up to C12 aralkyl, up to
C11 heteroarylalkyl, up to C10 aryl or C10 heteoraryl; all optionally substituted by up to three halogen atoms, or by CF3;
R2 is hydrogen, or together with Rl represent a carbocyclic or heterocyclic spiro 5-or 6-membered ring; and
R4 is up to C10 aryl optionally substituted by halogen, NO2, CN, CF3, C1-6 alkyl, -S-C1-6 alkyl, -SO-C1-6 alkyl or -SO2-C1-6 alkyl or C1-6 alkoxy;
or a pharmaceutically acceptable salt thereof.
3. A piperazine as claimed in claim 1 wherein:
R3 is hydrogen, halogen, N02, CF3, methyl, ethyl, methoxy or ethoxy;
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; and
R2 is hydrogen; or a pharmaceutically acceptable salt thereof.
4. A piperazine of the formula I as claimed in claim 1 wherein 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; or a pharmaceutically acceptable salt thereof.
5. A piperazine of the formula I as claimed in claim 1 wherein ring B is a phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, or 3,4-dichlorophenyl ring or 5-chloro-2-pyridyl; and Rl is phenyl, phenbutylene, phenisopropylene, 2-pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene, or 4-chlorophenyloxydime thylmethylene; or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition which comprises a piperazine of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

7. A process for preparing a piperazine of the formula (I) as claimed in
claim 1 or a pharmaceutically acceptable salt thereof which process
comprises
a) reacting a piperazine of the formula (II) or a pharmaceutically
acceptable salt with a compound of the formula (III)
(Formula Removed)
wherein X11 represents X or a precursor of X (whether by modification or displacement) or an activated form of X suitable for reaction with Y1;
Yi represents Y, a precursor of Y, or an activated form of Y suitable for reaction with X11; Z1 represents a protected form of Z, a precursor of Z (whether by modification or displacement of Z1) or an activated form of Z;
and where Q is -(CH2)(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:
(Formula Removed)
or
b) reacting a compound of the formula (IV) or a pharmaceutically
acceptable salt thereof with a compound of the formula (V).
(Formula Removed)
wherein B1 represents a suitable ring function or substituent group for reaction with P1;
Z1 is as hereinbefore defined; and
P1 represents a suitably activated form of the linker P for reaction with B1 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 B1 and A respectively, or vice versa.
8. A compound of the formula I substantially as herein described with
reference to the foregoing examples.
9. A process for preparing a compound substantially as herein
described with reference to the foregoing examples.

Documents:

1162-del-1999-abstract.pdf

1162-del-1999-assignment.pdf

1162-del-1999-claims.pdf

1162-del-1999-correspondence-others.pdf

1162-del-1999-correspondence-po.pdf

1162-del-1999-description (complete).pdf

1162-del-1999-form-1.pdf

1162-del-1999-form-13 (06-02-2006).pdf

1162-del-1999-form-13 (17-09-2007).pdf

1162-del-1999-form-19.pdf

1162-del-1999-form-2.pdf

1162-del-1999-form-3.pdf

1162-del-1999-form-6.pdf

1162-del-1999-gpa.pdf

1162-del-1999-petition-137.pdf

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Patent Number

254130

Indian Patent Application Number

1162/DEL/1999

PG Journal Number

39/2012

Publication Date

28-Sep-2012

Grant Date

21-Sep-2012

Date of Filing

30-Aug-1999

Name of Patentee

ASTRAZENECA UK LTD.,

Applicant Address

15 STANHOPE GATE, LONDON W1K 1LN, UNITED KINGDOM

Inventors:

#	Inventor's Name	Inventor's Address
1	BERNARD CHRISTOPHE BARLAAM	1800 CONCORD PIKE, P.O. BOX 15437, WILMINGTON, DELAWARE 19850-5437, USA;
2	NICHOLAS JOHN NEWCOMBE	MERESIDE, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG, ENGLAND
3	HOWARD TUCKER	MERESIDE, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG, ENGLAND
4	DAVID WATERSON	MERESIDE, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG, ENGLAND

PCT International Classification Number

C07D 213/64

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA