CA2440473C - Metalloproteinase inhibitors - Google Patents

Metalloproteinase inhibitors Download PDF

Info

Publication number
CA2440473C
CA2440473C CA2440473A CA2440473A CA2440473C CA 2440473 C CA2440473 C CA 2440473C CA 2440473 A CA2440473 A CA 2440473A CA 2440473 A CA2440473 A CA 2440473A CA 2440473 C CA2440473 C CA 2440473C
Authority
CA
Canada
Prior art keywords
disease
compound
alkyl
apci
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA2440473A
Other languages
French (fr)
Other versions
CA2440473A1 (en
Inventor
Anders Eriksson
Matti Lepistoe
Michael Lundkvist
Magnus Munck Af Rosenschoeld
Pavol Zlatoidsky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of CA2440473A1 publication Critical patent/CA2440473A1/en
Application granted granted Critical
Publication of CA2440473C publication Critical patent/CA2440473C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

Compounds of the formula (II) are useful as metalloproteinase inhibitors, especially as inhibitors of MMP12:

(see formula ll)

Description

Metalloproteinase inhibitors The present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising these, as s 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 (MMPs) such as the collagenases (MMP1, MMP8, MMP 13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP 10, MMP
11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), the MT-MMPs (MMP 14, MMP 15, MMP 16, MMP 17); the reprolysin or adamalysin or MDC family which is includes the secretases and sheddases such as TNF converting enzymes (ADAM10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases 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 diseases or conditions.
Inhibition of the activity of one or more metalloproteinases may well be of benefit in these diseases or conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), 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 io 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; extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis; asthma; rhinitis; and chronic obstructive pulmonary diseases (COPD).

MMP 12, also known as macrophage elastase or metalloelastase, was initially cloned in the mouse by Shapiro et al [1992, Journal of Biological Chemistry 267: 4664]
and in man by the same group in 1995. MMP-12 is preferentially expressed in activated macrophages, and has been shown to be secreted from alveolar macrophages from smokers [Shapiro et al, 1993, Journal of Biological Chemistry, 268: 23824] as well as in foam cells in atherosclerotic lesions [Matsumoto et al, 1998, Am J Pathol 153: 109]. A mouse model of COPD is based on challenge of mice with cigarette smoke for six months, two cigarettes a day six days a week. Wildtype mice developed pulmonary emphysema after this treatment. When MMP12 knock-out mice were tested in this model they developed no significant emphysema, strongly indicating that MMP-12 is a key enzyme in the COPD

pathogenesis. The role of MMPs such as MMP12 in COPD (emphysema and bronchitis) is discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1 1 : 29-38. It was recently discovered that smoking increases macrophage infiltration and macrophage-derived MMP-12 expression ,in human carotid artery plaques Kangavari [Matetzky S, Fishbein MC et al., Circulation 102:(18), 36-39 Suppl. S, Oct 31, 2000].

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 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 MMP 13 has been detected in transformed epidermal keratinocytes [N. Johansson et al., (1997) Cell Growth Differ. 8(2):243-250], squamous cell carcinomas [N.
Johansson et al., (1997) Am. J. Pathol. 151(2):499-508] and epidermal tumours [K. Airola et al., (1997) J.
Invest. Dermatol. 109(2):225-23 1 ]. These results are suggestive that MMP 13 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 MMP 13 plays a role in the turnover of other connective tissues. For instance, consistent with MMP 13's substrate specificity and preference for degrading type II collagen [P. G. Mitchell et al., (1996) J.
Clin. Invest.
97(3):761-768; V. Knauper et al., (1996) The Biochemical Journal 271:1544-1550], MMP 13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M. Stahle-Backdahl et al., (1997) Lab. Invest. 76(5):717-728; N.
Johansson et al., (1997) Dev. Dyn. 208(3):387-397], in destructive joint diseases such as rheumatoid and osteo-arthritis [D. Wernicke et al., (1996) J. Rheumatol. 23:590-595; P.
G. Mitchell et al., (1996) J. Clin. Invest. 97(3):761-768; O. Lindy et al., (1997) Arthritis Rheum 40(8):1391-1399]; and during the aseptic loosening of hip replacements [S.
Imai et al., (1998) J. Bone Joint Surg. Br. 80:701-710]. 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 TypeIV Collagenase; 92kDa Gelatinase) is a secreted protein which was first purified, then cloned and sequenced, in 1989 [S.M.
Wilhelm et al (1989) J. Biol Chem. 264 (29): 17213-17221; published 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. pp115 - 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 further regulated in vivo by interaction with TIMP-1 (Tissue Inhibitor of Metalloproteinases -1), a naturally-occurring protein. TIMP-1 binds to the C-terminal region of 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.
MMP-9 release, measured using enzyme' immunoassay, was significantly enhanced in fluids and in AM supernantants from untreated asthmatics compared with those from other s populations [Am. J. Resp. Cell & Mol. Biol.,.Nov 1997, 17 (5):583-59 1 ].
Also, increased MMP9 expression has been observed in certain other pathological conditions, thereby implicating MMP9 in disease processes such as COPD, arthritis, tumour metastasis, Alzheimer's, Multiple Sclerosis, and plaque rupture in atherosclerosis leading to acute coronary conditions such as Myocardial Infarction.

to MMP-8. (collagenase-2, neutrophil collagenase) is a 53 kD enzyme of the matrix metalloproteinase family that is preferentially expressed in neutrophils.
Later studies indicate MMP-8 is expressed also in other cells, such as osteoarthritic chondrocytes [Shlopov et al, 1997, Arthritis Rheum, 40:2065]. MMPs produced by neutrophils can cause tissue remodelling, and hence blocking MMP-8 should have a positive effect in fibrotic diseases of for instance the lung, and in degradative diseases like pulmonary emphysema. MMP-8 was also found to be up-regulated in osteoarthritis, indicating that blocking MMP-8 many also be beneficial in this disease.

MMP-3 (stromelysin-1) is a 53 kD enzyme of the matrix metalloproteinase enzyme family. MMP-3 activity has been demonstrated in fibroblasts isolated from inflamed gingiva [Ditto V. J. et al, 1981, J. Periodontal Res., 16:417-424], and enzyme levels have been correlated to the severity of gum disease [Overall C. M. et al, 1987, J.
Periodontal Res., 22:81-88]. MMP-3 is also produced by basal keratinocytes in a variety of chronic ulcers [Saarialho-Kere U. K. et al, 1994, J. Clin. Invest., 94:79-88]. MMP-3 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may thus prevent the epidermis from healing. Several investigators have demonstrated consistent elevation of MMP-3 in synovial fluids from rheumatoid and osteoarthritis patients as compared to controls [Walakovits L. A. et al, 1992, Arthritis Rheum., 35:35-42; Zafarullah M. et al, 1993, J. Rheumatol., 20:693-697]. These studies provided the basis for the belief that an inhibitor of MMP-3 will treat diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, or loss of structural integrity necessary for organ function.

A number of metalloproteinase inhibitors are known (see for example the review of s MMP inhibitors by Beckett R.P. and Whittaker M., 1998, Exp. Opin. Ther.
Patents, 8(3):259-282]. Different classes of compounds may have different degrees of potency and selectivity for inhibiting various metalloproteinases.

Whittaker M. et al (1999, Chemical Reviews 99(9):2735-2776] review a wide range of known MMP inhibitor compounds. They state that an effective MMP inhibitor requires a zinc binding group or ZBG (functional group capable of chelating the active site zinc(II) ion), at least one functional group which provides a hydrogen bond interaction with the enzyme backbone, and one or more side chains which undergo effective van der Waals interactions with the enzyme subsites. Zinc binding groups in known MMP
inhibitors include carboxylic acid groups, hydroxamic acid groups, sulfhydryl or mercapto, etc. For example, Whittaker M. et al discuss the following MMP inhibitors:
O O

HS N N `'- _NHMe H
O
ON O

N
The above compound entered clinical development. It has a mercaptoacyl zinc binding group, a trimethylhydantoinylethyl group at the P 1 position and a leucinyl-tert-butyllglycinyl backbone.

S
O O
H`
'~'A H O
HS N N v 'NHMe f--r ON O

The above compound has a mercaptoacyl zinc binding group and an imide group at the P1 position.

O
HORN N
'K.
H
O
O N~O

N
The above compound was developed for the treatment of arthritis. It has a non-peptidic succinyl hydroxamate zinc binding group and a trimethylhydantoinylethyl group at the P1 position.

O ro HORN NJ
H
O
O N O

The above compound is a phthalimido derivative that inhibits collagenases. It has a non-peptidic succinyl hydroxamate zinc binding group and a cyclic imide group at P1.
Whittaker M. et al also discuss other MMP inhibitors having a P1 cyclic imido group and various zinc binding groups (succinyl hydroxamate, carboxylic acid, thiol group, phosphorous-based group).

HN)~ NH

N

IN

O
N O

The above compounds appear to be good inhibitors of MMP8 and MMP9 (PCT patent applications W09858925, W09858915). They have a pyrimidin-2,3,4-trione zinc binding group.

The following compounds are not known as MMP inhibitors:-Lora-Tamayo, M et al (1968, An. Quim 64(6): 591-606) describe synthesis of the following compounds as a potential anti-cancer agent: H

0 N i ZC-S-NH C-S-NH

C-S-NH O- /N ZC-S-NH
~N HZ O
H
O H O OEt Me Czech patent numbers 151744 (19731119) and 152617 (1974022) describe the synthesis and the anticonvulsive activity of the following compounds:

O N H

R O
CI
CI
R= 4-N02, 4-OMe, 2-NO2, US patent number 3529019 (19700915) describes the following compounds used as intermediates:

H
O 0 OMe 0N OMe 0 H O 0Me O
H 0 I H O I j H I
NHZ
D F

PCT patent application number WO 00/09103 describes compounds useful for treating a vision disorder, including the following (compounds 81 and 83, Table A, page 47):

~NH ~NH
s-~ I . N-o=S=o 0 O=S=O H O

We have now discovered a new class of compounds that are inhibitors of metalloproteinases and are of particular interest in inhibiting MMPs such as MMP-12. The compounds are metalloproteinase inhibitors having a metal binding group that is not found in known metalloproteinase inhibitors. In particular, we have discovered compounds that are potent MMP12 inhibitors and have desirable activity profiles. The compounds of this invention have beneficial potency, selectivity and/or pharmacokinetic properties.

The metalloproteinase inhibitor compounds of the invention comprise a metal binding 5 group and one or more other functional groups or side chains characterised in that the metal binding group has the formula (k) Yl NH
X

YZ (k) wherein X is selected from NR1, 0, S;

Y1 and Y2 are independently selected from 0, S;
10 R1 is selected from H, alkyl, haloalkyl;

Any alkyl groups outlined above may be straight chain or branched; any alkyl group outlined above is preferably (C 1-7)alkyl and most preferably (C 1-6)alkyl.

A metalloproteinase inhibitor compound is a compound that inhibits the activity of a is metalloproteinase enzyme (for example, an MMP). By way of non-limiting example the inhibitor compound may show IC50s in vitro in the range of 0.1-10000 nanomolar, preferably 0.1-1000 nanomolar.

A metal binding group is a functional group capable of binding the metal ion within the active site of the enzyme. For example, the metal binding group will be a zinc binding group in MMP inhibitors, binding the active site zinc(II) ion. The metal binding group of formula (k) is based on a five-membered ring structure and is preferably a hydantoin group, most preferably a -5 substituted 1-H,3-H-imidazolidine-2,4-dione.

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

R5 A z m NH

X

wherein Xis selected from NRI, O, S;

Y1 and Y2 are independently selected from 0, S;
Z is selected from SO2N(R6), N(R7)SO2, N(R7)SO2N(R6);
m is 1 or 2;

A is selected from a direct bond, (C 1-6)alkyl, (C 1-6)haloalkyl, or (C 1-6)heteroalkyl io containing a hetero group selected from N, 0, S, SO, S02 or containing two hetero groups selected from N, 0, S, SO, S02 and separated by at least two carbon atoms;
R1 is selected from H, (C1-3)alkyl, haloalkyl;

Each R2 and R3 is independently selected from H, halogen (preferably fluorine), alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-is heteroaryl, heteroalkyl-aryl, heteroalkyl-heteroaryl, aryl-alkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl;

Each R4 is independently selected from H, halogen (preferably fluorine), (C1-3)alkyl or haloalkyl;

20 R6 is selected from H, alkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl, heteroalkyl-heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl;

Each of the R2, R3 and R6 radicals may be independently optionally substituted with one or more (preferably one) groups selected from alkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, arylthiol, alkylsulfon, haloalkylsulfon, arylsulfon, aminosulfon, N-alkylaminosulfon, N,N-dialkylaminosulfon, s arylaminosulfon, amino, N-alkylamino, N,N-dialkylamino, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkylsulfonamino, arylsulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitro-ethene-1,1-diamin, carboxy, alkyl-carboxy, nitro;

Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or and R4 may join to form a ring comprising up to 7 ring atoms, or R2 and R6 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R6 may join to form a ring comprising up to 7 ring atoms, or R4 and R6 may join to form a ring comprising up to 7 ring atoms;

R5 is a monocyclic, bicyclic or tricyclic group comprising one, two or three ring structures each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate, alkylcarboxylate, aminocarboxy, N-alkylamino-carboxy, N,N-dialkylamino-carboxy, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, N-alkylaminosulfonyl, carboxylate, alkylcarboxy, aminocarboxy, N-alkylaminocarboxy, N,N-dialkylaminocarboxy;

when R5 is a bicyclic or tricyclic group, each ring structure is joined to the next ring structure by a direct bond, by -0-, by (C 1-6)alkyl, by (C 1-6)haloalkyl, by (C 1-6)heteroalkyl, by (C 1-6)alkenyl, by (C 1-6)alkynyl, by sulfone, or is fused to the next ring structure;

R7 is selected from (C1-6) alkyl, (C3-7)cycloalkyl, (C2-6)heteroalkyl, (C2-6)cycloheteroalkyl;

s Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, 0, S, SO, S02, (a hetero group being a hetero atom or group of atoms);

Any heterocycloalkyl or heteroaryl group outlined above contains one or more hetero groups independently selected from N, 0, S, SO, S02;

io Any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (C 1-7)alkyl and most preferably (C 1-6)alkyl;

Provided that:

when XisNR1,R1 is H, Yl isO,Y2is0,ZisSO2N(R6),R6isH,R2isH,mis 15 1, R3 is H, R4 is H, and A is a direct bond, then R5 is not phenyl, p-nitro-phenyl, p-ethoxyphenyl or m-methylphenyl;

when X is S or NR1 and R1 is H, Yl is 0, Y2 is 0, Z is S02N(R6), R6 is alkyl, R2 is H, m is 1, one of R3 and R4 is H and the other is alkyl, R3 and R6 or R4 and R6 join to form a 5-membered ring, and A is a direct bond, then R5 is not phenyl.

Preferred compounds of the formula I are those wherein any one or more of the following apply:

X is NRI;

Z is S02N(R6), especially wherein the S atom of group Z is attached to group A
in the compound of formula I;

At least one of Y1 and Y2 is 0; especially both Y1 and Y2 are 0;
mist;
R1 is H, (C1-3) alkyl, (C1-3) haloalkyl; especially R1 is H;

R2 is H, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; especially R2 is alkyl, aminoalkyl or heteroaryl-alkyl.

R3 and/or R4 is H;

R3 and/or R4 is methyl;

R3 and R4 form a 5- or 6-membered ring (preferably a 5-membered ring) or R3 and R6 form a 5- or 6-membered ring (preferably a 5-membered ring) or R4 and R6 form a 5-or 6-membered ring (preferably a 5-membered ring); especially R3 and R6 form a 5- or 6-membered ring, most preferably a 5-membered ring;

R2 and R3 form a 5-membered ring or R2 and R6 form a 5-membered ring;

R5 comprises one, two or three optionally substituted aryl or heteroaryl 5- or membered rings;

R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures;

R3 and R6 form a 5- or 6-membered ring (preferably a 5-membered ring) or R4 and R6 form a 5- or 6-membered ring (preferably a 5-membered ring) and R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures.

Particularly preferred compounds of formula I are those wherein R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures.

For example, particular compounds of formula I are those wherein Y1 is 0, Y2 is 0, X
is NR1, Rl is H, R2 is H, m is 1, R3 is H, R4 is H, Z is SO2N(R6), R6 is H, (C1-4)alkyl, methylbenzyl, or methylpyridyl, A is a direct bond, and R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures. Some such compounds are described in Examples 1 and 2.

Other particular compounds of formula I are those wherein Y1 is 0, Y2 is 0, X
is NR1, R1 is H, R2 is H, methyl, or benzyl, m is 1, R3 is H or methyl, R4 is H, Z is SO2N(R6), R6 is H, A is a direct bond, and R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures. Some such compounds are described in Example 3.

5 The invention further provides compounds of the formula II

G1 G2 z NH
H 4~ II
O
wherein io each of GI and G2 is a monocyclic ring structure comprising each of up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate, 15 alkylamide, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy;
Z is SO2N(R6);

B is selected from a direct bond, 0, (C 1-6)alkyl, (C 1-6)heteroalkyl;
R2 is selected from H, (C l -6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of formula III

p G3 Formula III

C and D are independently selected from a direct bond, H, (C 1-C6)alkyl, (C 1-C6)haloalkyl, or (C 1-C6)heteroalkyl containing one or two hetero atoms selected from N, O or S such that when two hetero atoms are present they are separated by at least two s carbon atoms;

G3 is a monocyclic ring structure comprising up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, optionally substituted by one or two substituents independently selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, or alkyl substituted with one or more groups selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy;

Optionally R2 is substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, nitroguanidino, 2-nitro-ethene-1,1-diamino, carboxy, alkylcarboxy;

R3 and R4 are independentyl selected from H or (C 1-3)alkyl;

R6 is selected from H, (C 1 -3)alkylamino, or R6 is (C1-3)alkyl optionally substituted by aryl, heteroaryl, heterocycloalkyl;

Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or and R4 may join to form a ring comprising up to 7 ring atoms, or R2 and R6 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms, or R3 and R6 may join to form a ring comprising up to 7 ring atoms, or R4 and R6 may join to form a ring comprising up to 7 ring atoms;

Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, 0, S, SO, S02, (a hetero group being a hetero atom or group of atoms);

Any heterocycloalkyl or heteroaryl group outlined above contains one or more hetero groups independently selected from N, 0, S, SO, S02;

Any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (C 1-7)alkyl and most preferably (C 1-6)alkyl.

Preferred compounds of the formula II are those wherein one or more of the following apply:

Z is SO2N(R6) and the S atom of group Z is attached to the G2 ring;
B is a direct bond or 0;

R2 is not optionally substituted, or R2 is selected from H, (C 1-6)alkyl, aryl-(C 1-6)alkyl or heteroaryl-(C 1-6)alkyl optionally substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitroguanidino, 2-nitro-ethene-1,1-diamino, caboxy, alkylcarboxy;
Each of R3 and R4 is H;

R6 is H, benzyl or methylenepyridine;

G1 and G2 are each selected from an aryl or a heteroaryl;

R3 and R4 form a 5- or 6-membered ring (preferably a 5-membered ring) or R3 and R6 form a 5- or 6-membered ring (preferably a 5-membered ring) or R4 and R6 form a 5-or 6-membered ring (preferably a 5-membered ring); especially R3 and R6 form a 5- or 6-membered ring, most preferably a 5-membered ring;

R2 and R3 form a 5-membered ring or R2 and R6 form a 5-membered ring.

Particularly preferred compounds of the formula II are those wherein Z is SO2N(R6) and the S atom of group Z is attached to the G2 ring.

For example, particular compounds of the invention include compounds of formula II
wherein:

(a) B is a direct bond or 0; and Z is SO2N(R6); and R2 is selected from H, (Cl-.
6)alkyl, aryl-(C 1-6)alkyl or heteroaryl-(C 1-6)alkyl optionally substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfonyl, aminosulfonyl, N-alkylamino-sulfonyl, N,N-dialkylamino-sulfonyl, amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitroguanidino, 2-nitro-ethene-1,1-diamino, caboxy, alkylcarboxy; and each of and R4 is H; and R6 is H, benzyl or methylenepyridine; or (b) Z is SO2N(R6), and R3 is H, and R4 is H (compounds of the formula II') wherein R2 is not optionally substituted; preferably G1 and G2 are each selected from an aryl or a heteroaryl:
H H O

it _ N

H II' Suitable values for R2 include the following:

OH N N~

/\/ \ l N\ I C
N
~ I N~ I N~

F
NI N NON
CI F

CI F

Suitable values for R5 include the following:

/ HZ
_ H CFZ \ Q-1L-c/
\ 0 R
N" R / N X 0 R / \ X \ / R / \ X' / N ~ ~/

R /_\ X - O\ R /-\ X __ N N
X = a bond, 0, CH2,, CHF, CF2 R= F, CI, Br, CF3, CF3O, CH3O, OH, CF3CH2 (J-[JN Q-.NCN &O-CN
&ON QON s It will be appreciated that the particular substituents and number of substituents in compounds of the invention are selected so as to avoid sterically undesirable combinations.
io Each exemplified compound represents a particular and independent aspect of the invention.
Where optically active centres exist in the compounds of the invention, we disclose all individual optically active forms and combinations of these as individual specific embodiments of the invention, as well as their corresponding racemates.
Racemates may 15 be separated into individual optically active forms using known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, p104-107) including for example the formation of diastereomeric derivatives having convenient optically active auxiliary species followed by separation and then cleavage of the auxiliary species.
It will be appreciated that the compounds according to the invention may contain one or, more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres (chiral centres) in a compound of formula I can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
io Where tautomers exist in the compounds of the invention, we disclose all individual tautomeric forms and combinations of these as individual specific embodiments of the invention.
As previously outlined the compounds of the invention are metalloproteinase inhibitors, in particular they are inhibitors of MMP 12. Each of the above indications for is the compounds of the formula I represents an independent and particular embodiment of the invention.
Certain compounds of the invention are of particular use as inhibitors of and/or MMP9 and/or MMP8 and/or MMP3.
Compounds of the invention show a favourable selectivity profile. Whilst we do not 20 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.
The compounds of the invention may be provided as pharmaceutically acceptable 25 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.
30 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 metalloproteinase inhibitor compound of the invention (a compound of the formula I or II) 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 invention (a compound of the formula I
or II) 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 or 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 diseases or 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 or 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, we provide 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 or for use as a therapeutic agent. We disclose use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes. In particular we disclose use in the treatment of a disease or condition mediated by MMP12 and/or MMP13 and/or MMP9 and/or MMP8 and/or MMP3; especially use in the treatment of a disease or condition mediated by MMP12 or MMP9; most especially use in the treatment of a disease or condition mediated by MMP 12.
In particular we provide a compound of the formula II 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 or for use as a therapeutic agent (such as use in the treatment of a disease or condition mediated by MMP 12 and/or MMP 13 and/or and/or MMP8 and/or MMP3; especially MMP12 or MMP9; most especially MMP12).

In yet a further aspect we provide a method of treating a metalloproteinase mediated disease or condition which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. We also disclose the use of a compound of the formula I or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
For example we provide a method of treating a metalloproteinase mediated disease or condition which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula II (or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof). We also provide the use of a compound of the formula II (or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof) in the preparation of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.

Metalloproteinase mediated diseases or conditions include asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related diseases such as Alzheimer's disease and Multiple Sclerosis (MS), hematological disorders.
In a use aspect, the invention provides use of a compound, salt or composition of the invention for: (i) preparing a medicament for the treatment of a disease or condition mediated by one or more metalloproteinase enzymes, or (ii) for the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.

In a commercial package aspect, the invention provides a compound, salt or composition of the invention and associated therewith instructions for the use thereof in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.

Preparation of the compounds of the invention In another aspect the present invention provides a process for preparing a compound of the formula I or II or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as described in (a) to (c) below. It will be appreciated that many of the relevant starting materials are commercially or otherwise available or may be synthesised by known methods or may be found in the scientific literature.

24a (a) Compounds of formula I in which Y1 and Y2 are each 0, Z is SO2N(R6), A is a direct bond, Xis NR1, RI is H, R2 is H,in is 1, R3 is H, R4 is H, and R5 and R6 are defined as in formula I may be prepared according to Scheme 1.

When R6 is H, an N'-BOC-D-diaminopropionic acid derivative of formula IV is reacted with suitable sulfonyl chloride of formula V in basic medium to form sulfonamides of formula VI. Deprotection in acid medium, reaction with potassium cyanate to the corresponding urea and finally cyclization in acid medium yields compounds of formula I.
When R6 is alkyl such as methyl, ethyl, propyl, isopropyl and n-butyl, the N2 -alkyl-N'-BOC-D-diaminopropionic acid of formula IV is prepared according to Andruszkiewics, io R.: PoLJ.Chem, 62,257, (1988).

When R6 is an optionally substituted benzyl, methylbenzyl, methylpyridyl, methyl heteroaryl, the N2-substituted amino acid of formula IV is prepared according to Helv.Chim.Acta, 46,327, (1963).

5 Scheme 1:
R6 R5. :O RS,S
N s 1.strong acid I O
I 2.KCNO IN
O R5-SO,CI V R6IN 3.strong acid RE
O_JL 1'r N O
base O~N,, O N )-r- O
o /lam -Ir N
O O
IV O
The reaction IV-VI is preferably performed in suitable solvent optionally in the presence of base for 1 to 24h at ambient to reflux temperature. Preferably, solvents such as 10 pyridine, dimethylformamide, tetrahydrofurane, acetonitrile or dichlorometane are used with bases like triethylamine, N-methylmorpholine, pyridine or alkali metal carbonates at ambient temperature for 2-16 h reaction time, or until end of reaction is achieved as detected by chromatographic or spectroscopic methods. Reactions of sulfonyl chlorides of formula V with various secondary amines are previously described in the literature, and the is variations of the conditions will be evident for those skilled in the art.
A variety of compounds of formula V are commercially available or their synthesis is described in the literature. Specific derivatives of formula VI may be made according to known processes by those skilled in the art.

20 (b) Compounds of formula I in which Yl and Y2 are each 0, Z is S02N(R6), R6 is H, A
is a direct bond, X is NR1, R1 is H, in is 1, and R2, R3, R4 and R5 are defined as in formula I may be prepared according to Scheme 1.

Compounds in which R2 is H, R3 is H and R4 is alkyl or aryl, may be prepared starting from the corresponding BOC N-protected a-amino aldehydes of formula VII, 25 prepared according to Fehrentz,JA,Castro,B.; Synthesis, 676, (1983).

Compounds in which R2 is alkyl or aryl, R3 is H and R4 is alkyl or aryl, may be prepared starting from the corresponding BOC N-protected a-amino ketone of formula VII
as depicted in Scheme 2., The BOC N-protected a-amino ketones are prepared according to Nahm,S, Weinreb,SM: Tetrahedron Lett. 22,3815,(1981), optionally when R6 is not H, according to Shuman, Robert T. US 4448717 A 19840515 Some compounds prepared by the process shown in Scheme 2 are described in Example 3.

to Scheme 2:

1.separation of KCN0 0 R4 R3 diastereoisomeres R4 R3 0 R4 R3 ammonium R2 2. deprotection O R2 O
X 'R2 carbonate O N O 3. R5-SOKI/Base OAS= \
0. N R6 N R5 N N

VII Vila 0 The compounds of formula VII are reacted with alkali cyanide and ammonium carbonate (Strecker reaction) to yield the corresponding hydantoins of formula VIIa. The diastereoisomeres can optionally be separated after any of the three remaining synthetic steps: carbamates of formula Vila and sulfonamide compounds of formula I on silicagel chromatography, after deprotection amino intermediate by chrystallisation. The amine intermediates are optionally used to directly couple with sulfonyl chlorides of formula V as described in the sulfonylation in (a) above, in basic medium to form compounds of formula I.
The reaction VII to Vila is preferably run in a closed steel vessel in an aqueous alcohol solvent at 90-130 C for 3-16 hours or until end of reaction is achieved as detected by chromatographic or spectroscopic methods. Treatment with 1-4 fold excess cyanide salts, preferrably 1-2 equivalents, and 2-6 fold excess of ammonium carbonate, preferrably 4-6 equivalents yields hydantoins of formula VIIa. Deprotection and sulfonylation as in Scheme 1 then yields compounds of formula I.

Amino aldehydes or ketones of formula VII and their protected derivatives are commercially available and other methods to a-amino aldehydes and ketones of formula VII. Specific derivatives of formula Vila may be made according to known processes by those skilled in the art.

(c) Compounds of formula I in which Yl and Y2 are each 0, X is NR1 (R1=H), Z=N(R7)SO2, m=1, R4=H and R2, R3, R5 and R7 are as described in formula I may be prepared by reacting a compound of formula VIII in which R2, R3, R5,R7 and A
are as described in formula I, with sulfonyl chlorides of formula IX in polar aprotic solvents such io as THE or DMF in the presence of bases such as alkali carbonates or tertiary alkyl amines or polymeric amines.

-A-N CIS NH

R7 S1 \\O H
O
VIII IX

Amines of formula VIII are well known in the literature and are available from numerous commercial sources. Specific new variations of compounds of formula VIII may be made according to known processes by those skilled in the art. The sulfonyl chlorides of formula IX may be prepared by chlorine oxidation of sulfides or disulfides of formula X, where R8 is a group such as hydrogen, isopropyl, benzyl or a sulfide such that formula X comprises of a symmetrical disulfide.

R3 11> R2 R2 R 8 - S ; N4 0 X XI
Sulfides of formula X may be made from cysteine or cystine (R2, R3=H) and their esters by sequential treatment with alkali cyanate and strong acids like potassium cyanate and hydrochloric acid. Alternatively, sulfides of formula X may be prepared by subjecting ketones of formula XI to conditions as described in the transformation of VII
to VIla above in (a).

The compounds of the invention may be evaluated for example in the following assays:

Isolated Enzyme Assays Matrix Metalloproteinase family including for example MMP12, MMP13.
Recombinant human MMP 12 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20:152. The purified enzyme can be used to monitor inhibitors of activity as follows:
MMP12 (50 ng/ml final concentration) is incubated for 30 minutes at RT in assay buffer (0.1M Tris-HCI, pH 7.3 containing 0.1 M NaCl, 20mM CaCl2, 0.040 mM ZnCI and 0.05% (w/v) Brij 35) using the synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at ?,ex 328nm and Xem 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescenceplus inhibitor - Fluorescencebackground] divided by the [Fluorescenceminus inhibitor - Fluorescencebackgr und]=
Recombinant human proMMP 13 may be expressed and purified as described by Knauper et al. [V. Knauper et al., (1996) The Biochemical Journal 271:1544-15 5 0 (1996)].
The purified enzyme can be used to monitor inhibitors of activity as follows:
purified proMMPl.3 is activated using 1mM 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-HCI, pH 7.5 containing 0.1M NaCl, 20mM CaC12, 0.02 mM
ZnCI
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 Xex 328nm and Xem 393mn. Percent inhibition is calculated as follows: %

Inhibition is equal to the [Fluorescenceplõ s inhibitor - Fluorescenceba kgoõnd] 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 et al., (1992) FEBS Lett. 296(3):263-266.

Adamalysin 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- 1 -yl)-fluorescein)-NH2 in assay buffer (50mM Tris HCI, pH 7.4 containing 0.1 % (w/v) Triton X- 100 and 2mM CaC12), at 26 C for 18 hours. The amount of inhibition is determined as for MMP13 except Xex 490nm and k 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 O-benzotriazol-1-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 HBTU. Ser' and Pro 2 were double-coupled. The following side chain protection strategy was employed; Ser'(But), Gln5(Trityl), Arg"12(Pmc or Pbf), Ser9'10,"(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 s MALDI-TOF MS and amino acid analysis.
Natural Substrates The activity of the compounds of the invention as inhibitors of aggrecan degradation to may be assayed using methods for example based on the disclosures of E. C.
Amer 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 metalloproteinase 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 TNFa 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 (RPMI 1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160gl) with 20 l of test compound (triplicates), in DMSO or appropriate vehicle, for 30 min at 37 C in a humidified (5%CO2/95%air) incubator, prior to addition of 20 l LPS (E.
coli. 0111:134; final concentration 10.ig/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 (50-100 l) 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 al., (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 IOU heparin. Plasma fractions are obtained following centrifugation s 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 io 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.
is 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 20 (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 25 samples are thawed and 175 l of each sample are added to a set format pattern in a 96U
well plate. Fifty l 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 (25 l; final concentration 10.Lg/ml) is added to the wells and incubation continued for a further 5.5 hours. Control wells are incubated with 25 l of medium alone. Plates are then centrifuged for 10 min at 2000 rpm and 200 1 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 B 16 cell line (described in B. Hibner et al., Abstract 283 p75 10th NCI-EORTC Symposium, Amsterdam June 16 - 19 1998).
Test as an anti-emphysema agent .25 Activity of a compound as an anti-emphysema agent may be assessed essentially as described in Hautamaki et al (1997) Science, 277: 2002.

The invention will now be illustrated but not limited by the following Examples:

General analytical methods: 1H-NMR spectra were recorded on either a Varian U"Ylnova 400MHz or Varian Mercury- VX 300MHz instrument. The central solvent peak of chloroform-d (SH 7.27 ppm), dimethylsulfoxide-d6 (5H 2.50 ppm) or methanol-d4 (SH 3.31 ppm) were used as internal references. Low resolution mass spectra were obtained on a Agilent 1100 LC-MS system equipped with an APCI ionization chamber.

N-{[(4S)-2,5-dioxoimidazolidinyl]methyl}-4-(4- fluorophenoxy) benzenesulfonamide and N-{ [(4S)-2,5-dioxoimidazolidinyl] methyl} [1,1'-biphenyl]-4-sulfonamide R
0 N O%S / O, ,O O
O ~= O N SAN
0 N O li,lll.ly N
O O N O R \ INS
O O
i C6H4SO2C1 ii HCI/dioxane . iii KCNO iv wt. HCI, 100 C

R = 4-fluorophenoxy or R = phenyl To the stirred solution of N-alfa-BOC-(S)-diaminopropionic acid (100 mg,0.5 mmol) in 2.5 ml water containing 0.04g (0.55 mmol) of sodium carbonate was added the soln.of the sulfonyl chloride (0.5 mmol) in 2.5 ml of dioxane.The solution was stirred overnight at room temperature, distributed between ethyl acetate (10 ml) and ca 20% citric acid (10 ml),the water phase was three times reextracted with ethyl acetate,organic extract was washed with brine,dried,evaporated and the residue was treated with 4N HCl in dioxane.The mixture was stirred for 20 min,evaporated and dried in vacuo for 4 hrs at 40 C.Then,the residue was quenched with 3m1 of water solution of sodium carbonate (0.08g, 0.85 mmol) and 0.9 g (1.1 mmol) of potassium cyanate was added and the mixture was stirred for 4 hrs at 100 C.After this period,! ml of conc.HC1 as added,stirred for 1 hr at the same temperature and then allowed to stand at room temperature overnight.The crystalls were filtered,washed with dist.water and dried in vacuo (recrystallised from wt.ethanol if 5 necessary) N-{[(4S)-2,5-dioxoimidazolidinyl]methyl}-4-(4- fluorophenoxy) benzenesulfonamide MS:m/z=380.1 N-{ [(4S)-2,5-dioxoimidazolidinyl] methyl} [ 1,1'-biphenyl]-4-sulfonamide 10 MS:m/z=346.1 1H NMR:(DMSO):3.00 m (1.5H),3.10m(0.6H),(CH2), 4.10 m (1H,CH),7.5 m (3H),7.70d (2H),7.4 s (4H).

is Compounds of formula I were prepared wherein Yl is 0, Y2 is 0, X is NR1, R1 is H, R2 is H, m is 1, R3 is H, R4 is H, Z is SO2N(R6), R6 is H, (Cl-4)alkyl, methylbenzyl, or methylpyridyl, A is a direct bond, and R5 varies.

The syntheses were performed in parallel on 20-well plate manually operated.
The amino acid (20 um) was dissolved in 5 ml water containing 6.36 mg (60 um) of 20 sodium carbonate. 0.5 ml of the solution was pipetted to each well, followed by 0.5 ml of dioxane solution containing 20 um of corresponding sulfonyl chloride. The reaction mixture was shaken for 18 hrs at room temperature, diluted with 2 ml of methanol and treated with 20 mg of Lewatite S100 in each well (acid form) for 5 min. Then all reaction mixtures was filtered, evaporated in vacuo and the evaporate was treated with 1 ml of 4 N

25 HCl in dioxane for 30 min, evaporated in vacuo and 0.5 ml of 0.5 M wt.
solution of potassium cyanate was added and heated to 100 C for 3 hrs. Then 10 mg of Lewatite S 100 (acid form) was added to each well after being cooled to room temperature, followed by 2 ml of methanol, evaporated in vacuo and threated with trifluoroacetic acid at 80 C for 2 hrs. After being evaporated, the residue was purified by flash chromatography on silica using ethyl acetate-methanol gradient (up to 10% MeOH). The purity and mol.weight was monitored by HPLC-MS. Yields : 0.5-1 mg per each well.
5-(2-Methyl-thiazol-5-yl)-thiophene-2-sulfonic acid (2,5-dioxo-imidazolidin-4-ylmethyl)-amide N' S

Vx O"S_O
N
O
A -N

LC-MS (APCI) M++ H+ 373.4 (m/z) 3-(4-Chloro-phenoxy)N-(2,5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide CI _&O
/ \O-S_O
ON~

N-i LC-MS (APCI) M++ H+= 396.8(m/z) 4-(4-Chloro-phenoxy)N-(2,5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide Y~o Sso N
Cl 0~,, N
N_~

LC-MS (APCI) M++ H+ = 396.8(m/z) N-(2,5-.Dioxo-imidazolidin-4-ylmethyl)-4-(4-methoxy-phenoxy)-benzenesulfonamide S=o N
o 0 J -i N
0.
LC-MS (APCI) M++ H+ = 392.6(m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-3-(4-methoxy-phenoxy)-benzenesulfonamide 1\0=0 oN
\ N-~
0 o LC-MS (APCI) M++ H+ = 392.6(m/z) 5-(5-TrifluoromethyH-pyrazol-3-yl)-thiophene-2-sulfonic acid (2,5-dioxo-imidazolidin-4-ylmethyl )-amide F F
F

N
N S o S_o O N
N-LC-MS (APCI) M++ H+ = 410.4(m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyp -4--tolyloxy-benzenesulfonamide S.O
N
N-~
O
LC-MS (APCI) M++ H+ = 376.4(m/z) 3-(3,4-Dichloro-phenoxy)- N -(dioxo-imidazo Iidin-4-ylmethyl)-benzenesulfonamide CI

j3Oo CI
S~O
N
N-~
O
LC-MS (APCI) M++ H+= 430.6(m/z) 4-(3,4-Dichloro-phenoxy)- N-(2,5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide g:O
/ \ N
O
N

CI

LC-MS (APCI) M++ H+ 430.6(m/z) 4'-Fluoro-biphenyl-4-sulfonic acid (2,5-dioxo-imidazolidin-4-ylmethyl)-amide S,O
N

F
N-~
O
LC-MS (APCI) M++ H+= 364.4(m/z) 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2,5-dioxo-imidazolidin-4-ylmethyl)-amide l rs N ("
~ :O

NI
N-~
O
LC-MS (APCI) M++ H+ = 353.4(m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-4-(2-methoxy-phenoxy)-benzenesulfonamide S=0 O O N

\ N-N

LC-MS (APCI) M++ H+= 392.5(m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-3-(2-trifluoromethyl-phenoxy)-benzenesulfonamide F F
F
62N~so O, N
N-~
O
LC-MS (APCI) M++.H+= 430.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-3-(4-trifluoromethyl-phenoxy)-benzenesulfonamide F O
F 9.O
F N

Nom( LC-MS (APCI) M++ H+ 430.4 (m/z) N-(2,5-Dioxo-im idazo I idin-4-y Imethy l)-4-(4-trifluoromethy I-phenoxy)-benzenesulfonamide O / o O
F / N~
N
F F N

LC-MS (APCI) M++ H+ = 430.4 (m/z) 4'-Trifluoromethyl-biphenyl-4-sulfonic acid (2,5-dioxo-imidazolidin-4-ylmethyl)-amide F Q
F =0 F N

N -( LC-MS (APCI) M++ H+= 414.4 (m/z) N -(2, 5-Dioxo-imidazo lidin-4-ylmethyl)-4- o -tolyloxy-benzenesulfonamide 0 / S:O
J
ON
N

LC-MS (APCI) M++ H+= 376.4 (m/z) 4-(3,5-Dichloro-phenoxy)- N -(2,5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide Cl Cl O
O 0-~ S.o N
O
N
N-i LC-MS (APCI) M++ H+ =431.3 (m/z) 4-(2-Chloro-phenoxy)- N-(2,5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide O
CI O / S=O
N
N
N-LC-MS (APCI). M++ H+ =396.8 (m/z) N-(2,5-Dioxo-im.idazolidin-4-ylmethyl)-3-p-tolyloxy-benzenesulfonamide O

' so ONI
N N
N -\

LC-MS (APCI) M++ H+=376.4 (m/z) 4-(4-Cyano-phenoxy)-N-(2, 5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide N

O
O a N O
N
N -i LC-MS (APCI) M++ H+=387.4 (m/z) 4-(4-Cyano-phenoxy)- N -(2, 5-dioxo-imidazolidin-4-ylmethyl)- N -methyl-benzenesulfonamide N\

O
O
0-~a, N1' N
N -~
O
LC-MS (APCI) M++ H+=401.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-methyl-4-(4-trifluoromethyl-phenoxy)-benzenesulfonamide F F
F

O
O \ S

N --O
LC-MS (APCI) M++ H+ =444.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-ethyl-4-(4-trifluoromethyl-phenoxy)-benzenesulfonamide F F
F
O
g_O
O \ ~ N' O ',,.='~
N
-i LC-MS (APCI) M++ H+=458.4 (m/z) N-(2, 5-Dioxo-imidazolidin-4-ylmethyl)-N-isopropyl-4-(4-tritluoromethyl-phenoxy)-benzenesulfonami de F F
F

O \ / S^
N
0 '~"" N
N-i LC-MS (APCI) M++ H+ =472.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-isobutyl-4-(4-trifluoromethyl-phenoxy)-benzenesulfonamid F F
F
O
O \ /
N
N
-LC-MS (APCI), M++ H+ =486.5 (m/z) N-Benzyl-N-(2,5-dioxo-imidazol idin-4-ylmethyl)-4-(4-trifluoromethyl-phenoxy)-benzenesulfonami de F F
F

g.0 O \ /

ON

LC-MS (APCI) M++ H+ =520.5 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-pyridin-3-ylmethyl-4-(4-trifl uorotnethyl-phenoxy)-benzene F F
F
O
O \ ~ ~O
N

N, , N-~

LC-MS (APCI) M++ H+ =521.5 (m/z) 5 N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-4-(4-fluoro-phenoxy)-N-methyl-benzenesulfonamide F
O
S~O
aN
O
N-.LC-MS (APCI) M++ H+=394.4 (m/z) N-(2, 5-Dioxo-imidazol idin-4-ylmethyl)-N-ethyl-4-(4-fluoro-phenoxy)-benzenesulfonamide F

O
O \ S

ON
N
N-i LC-MS (APCI) M++ H+=408.4 (m/z) N-Benzyl-N-(2, 5-dioxo- imidazol idin-4-ylmethyl)-4-(4-fluoro-phenoxy)-benzen.esulfonam ide F

O a-N

O

LC-MS (APCI) M++ H+ =470.5 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-4-(4-fluoro-phenoxy)-N-pyridin-3-ylmethyl-benzenesul.fonami F
O
O
- N~
NN-N
O
LC-MS (APCI) M++ H+ =471.5 (m/z) 4-(4-Chloro-phenoxy)-N-(2,5-dioxo-imidazolidin-4-ylmethyl)-N-methyl-benze.nesulfonamide CI
O
O

N
O
J N
N -~

LC-MS (APCI) M++ H+=410.5 (m/z) 4-(4-Chloro-phenoxy)-N-(2, 5-d ioxo-im idazol idin-4-ylmethyl)-N-ethyl-benzenesulfonam i de CI

S_O
N

N-~
O
LC-MS (APCI) M++ H+=424.88 (m/z) 4-(4-Chloro-phenoxy)-N-(2,5-dioxo-imidazolidin-4-ylmethyl)-N-isopropyl-benzenesulfonamide CI
O
S_O
ON

Nj O
LC-MS (APCI) M++ H+=424.88 (m/z) N-.Benzyl-4-(4-chloro-phenoxy)-.N-(2,5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide CI
O
O
N-O
O
LC-MS (APCI) M++ H+ =486.9 (m/z) i5 4-(4-Chloro-phenoxy)-N-(2,5-dioxo-imidazolidin-4-ylmethyl)-N-pyrid in-3-ylmethyl-benzenesulfonami de Cl O
N

N N
O

LC-MS (APCI) M++ H+ =487.9 (m/z) s N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-methyl-4-p-tolyloxy-benzenesulfonamide O
.
O
O
O
aN
N--O

LC-MS (APCI) M++ H+=390.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-ethyl-4-p -tolyloxy-benzenesulfonamide O
O ^
S
N
l /0-""l, N
N-~

LC-MS (APCI) M++ H+ =404.5 (m/z) is N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-isopropyl-4-p -tolyloxy-benzenesulfonamide O

N-~
O
LC-MS (APCI) M++ H+=418.5 (m/z) N-Benzyl- N-(2,5-dioxo-imidazolidin-4-ylmethyl)-4-p -tolyloxy-benzenesulfonamide Q
S=O
O N

/ N-~
O

LC-MS (APCI) M++ H+=466.5 (m/z) N -(2,5-Dioxo-imidazolidin-4-ylmethyl)-N-pyridin-3-ylnethyl-4-p -tolyloxy-benzenesulfonamide S^O
O \ ~ N

/N-~
O
LC-MS (APCI) M++ H+ =467.5 (m/z) N -(2,5 -Dioxo-imidazo lid in-4-yl methyl)-4-(4-methoxy-phenoxy)- N -methyl-benzenesulfonamide -O
O
O \ / I N
,.=
O
N
N-~
O
LC-MS (APCI) M++ H+ =406.5 (m/z) .N -(2, 5-Dioxo-imidazolidin-4-ylmethyl)- N -ethy I-4-(4-methoxy-phenoxy)-benzenesulfonami de -O
/ O
/N
O~ N
N--~
O
LC-MS (APCI) M++ H+=420.5 (m/z) 10 N-(2,5-.Dioxo-imidazolidin-4-ylmethyl)-N-isopropyl-4-(4-methoxy-phenoxy)-benzenesulfonamide -O

Q

N
~='`
N
N-i LC-MS (APCI) M++ H+=433.5 (m/z) N -Benzyl- N -(2,5-dioxo-imidazolidin-4-ylmethyl)-4-(4-methoxy-phenoxy)-benzenesulfonamide -O
\ O
O
N
'.1 N
- ~

O
LC-MS (APCI) M++ H+ =482.5 (m/z) N -(2,5-Dioxo-imidazolidin-4-ylmethyl)-4-(4-methoxy-phenoxy)- N -pyridin-3-ylmethyl-benzenesulfonam -O
O
O
N
N - O~ :I, /N-~
O

LC-MS (APCI) M++ H+=483.5 (m/z) N -(2,5-Dioxo-imidazolidin-4-ylmethyl)-4-(pyridin-4-yloxy)-benzenesulfonamide .N .\ O
SsO
O N
'A
N

LC-MS (APCI) M++ H+ =363.5 (m/z) N -(2,5-Dioxo-imidazolidin-4-ylmethyl)- N-methyl-4-(pyridin-4-yloxy)-benzenesulfonamide N \ O
O
I
O aN

N
O
LC-MS (APCI) M++ H+=377.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylnethyl)-N-ethyl-4-(pyridin-4-yloxy)-benzenesulfonamide O
O
S~
O \ ~- N
N-i LC-MS (APCI) M++ H+ =363.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-4-(pyridin-4-yloxy)-benzenesulfonamide O
"SO
O \ N

0 ",.t LC-MS (APCI) M++ H+ =363.5 (m/z) i5 N -(2, 5-Dioxo-imidazolidin-4-ylmethy l)-4-(pyridin-2-yloxy)-benzenesulfonamide O Ooo N
O
N
N-O
LC-MS (APCI) M++ H+=376.4 (m/z) N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-.N-ethyl-4-(pyridin-2-yloxy)-benzenesulfonamide CO
N ISO
S=O
\'IN

N-~

LC-MS (APCI) M++ H+=391.4 (m/z) 4-(5-Chloro-pyridin-2-yloxy)- N -(2,5-dioxo-imidazolidin-4-ylmethyl)-benzenesulfonamide O

I O.CI S-O
N
N-LC-MS (APCI) M++ H+=397.8 (m/z) i5 4-(5-Chloro-pyridin-2-yloxy)- N-(2,5-dioxo-imidazolidin-4-ylmethyl)- N-methyl-benzenesulfonamide O
O
~L,~ I CI as~o Nom( LC-MS (APCI) M++ H+=410.8 (m/z) 4-(5-Chloro-pyridin-2-yloxy)-N-(2,5-dioxo-imidazolidin-4-yhnethyl)-N-ethyl-benzenesulfonamide O
CE! O
CI S
N-LC-MS (APCI) M++ H+=425.8 (m/z) N -(2,5-Dioxo-imidazolidin-4-ylmethyl)- N -ethyl-4-(5-fluoro-pyrimidin-2-yloxy)-benzenesulfonamide NYO I ~ 0 r N
F S=0 ON
AN
N-~\

LC-MS (APCI) M++ H+ =409.8 (m/z) N -(2,5-Dioxo-imidazolid in-4-ylmethyl)-4-(5-fluoro-pyrimidin-2-yloxy)- N -methyl-benzenesulfonamide F
N p O
N O / SN' O~
~, l N-~
O
LC-MS (APCI) M++ H+=396.4 (m/z) 5 N-(2,5-Dioxo-imidazolidin-4-ylmethyl)-4-(5-fluoro-pyrimidin-2-yloxy)-benzenesulfonamide F
`N _ O
O
N ~ ~ / S-0N' N
N-~

LC-MS (APCI) M++ H+ =382.4 (m/z) Compounds were prepared according to Scheme 2 as shown in the description above.
(a) Preparation of starting materials (aldehydes or ketones) Aldehydes were prepared according to the procedure described by Fehrentz JA
and Castro B, Synthesis, 676, (1983). Ketones were prepared according to the procedure described by Nahm S and Weinreb SM:Tetrahedron Lett.22, 3815, (1981).

(b) Preparation of intermediate hydantoins The aldehyde or ketone (5 mmol) was dissolved in 50% water ethanol (10 ml) and 0.55 g (10 mmol) of sodium cyanide and 2.7 g (25 mmol) of ammonium carbonate was added and the mixture was heated in the sealed tube to 80 C for 6 hrs. Then it was cooled, pH was adjusted to 4 and it was evaporated in vacuo. The residue was distributed between water (10 ml) and ethyl acetate and water phase was 3-times re-extracted with ethyl acetate, then evaporated and diastereoisomeres were separated by silica chromatography (grad.TBME-methanol 0-10% MeOH). The following hydantoins were prepared.

R-1-(2,5-d.ioxoil:n.idazol:idi.1n-4-S-yl)-ethyl. carbamic acid tent.
butylester O
7~ N1-/O
N
N
O
LC-MS(APCI): ) M++ H+=244.4, ) M+-56 (isobutylene) 188.6, M+-BOC=144.4 (main peak) H-NMR (CDC13.ppm):1.23d (3H),1.45s (9.lH),4.36m(1.1H),5.30bs(1.1H),10.lbs (1.3H) 1sR.-1-(4-Methyl-2.5di.oxo.i.rri.idazolin-4-S-yl)ethyl. carbain.oic acid O

O
N

/~_ N
O

LC-MS(APCI): ) M++ H+=258.3 , ) M+-56 (-isobutylene) 202.3, ) M+-BOC=158.3 (main peak) H-NMR (CDC13.ppm):1.22d (3H), 1.44s (9.2H),1.58s(3.1 H), 3.95m(0.9H),5.5bs (1.5H),7.9bs(0.8H) R-1.-(4-.Methyl-2,Sdioxoi.rnidazolin-4-R-y.1)ethyl carhamoic acid tert-butylester O

N...
O
N

/~- N
O

LC-MS(APCI): M++ H+=258.3 , M+-56 (-isobutylene) 202.3, M+-BOC=158.3 (main peak) H-NMR (CDC13.ppm):1.29d (3H),1.54s (9.1H),1.50s(2.95H),4.25m(1.1H),5.5bs (1.8H),7.9bs(0.6H) R-1.-(2,5-dioxo-4-phen.ylixn.idazolidin.-4-S-yl)-ethyl earbarrmoi.c acid tert-butyl ester, O

O
N Q
N
O
LC-MS(APCI): ) M++ H+=320.3 ) M+-56 (-isobutylene) 264.3, M+-BOC=230.3 (main peak) H-NMR (CDC13 .ppm):1.31d(3H),1.35s (9.2H),4.65m(0.9H),6.10 d (0.94H), 7.25m(3.2H),7.60d (2.05H) tert-butyl (2S)-2-[(4R)-2,5-dioxoimidazolidin-4-yl]pyrrolidine-1-carboxylate LC-MS: M++ H+=170.0 (M+-BOC) NMR: (CDC13.ppm):1.26 s (9H),1.7-1.9m (3.37H),2.1-2.2m (0.84H),3.35-3,44m (1.82H), 4.1 bs (1.1 H), tert-butyl (2S)-2-[(4S)-2,5-dioxoimidazolidin-4-yi]pyrrolidine-1-carboxylate LC-MS: M++ H+=170.0 (M+-BOC) H-NMR: (CDC13.ppm):1.27 s (9H),1.65-2.0 in (broad),(4.47H),3.55m(1.15H,), 3.62m (0.55H),4.4 m (0.87H), tert-butyl (2R)-2-[(4S)-2,5-d ioxoimidazolidin-4-yl]pyrrolidine-1-carboxylate LC-MS: M++ H+=170.0 (M+-BOC) H-NMR: (CDC13.ppm):1.47 s (9H), 1.7-2.2m (broad) 4.30H,3.6 m (1.12H),3.8m (078H,3.6m(1.1 H), tert-butyl (2R)-2-[(4R)-2,5-dioxoimidazolidin-4-yl]pyrrolidine-1-carboxylate LC-MS: M++ H+=170.0 (M+-BOC) H-NMR: (CDC13.ppm):1.47 s (9H), 1.7-2.2m (broad) 4.30H,3.6 in (1.12H),3.8m (078H,3.6m(1.1H), tert-butyl (2R)-2-[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yI]pyrrolidine-1-carboxylate LC-MS: M++ H+=183.1 (M+-BOC) H-NMR: (CDC13 .ppm):1.4 s (9H) 1.50s(3.2H), 1.65-2.1m (broad) 4.20H,3.4 in (1.1 H),3.5bs (0,78H,4.4m (0.94H), Deprotection of BOC protected hydantoins was performed via 40% trifluoroacetic acid in DCM and the final compound 5-(1-aminoethyl) 5-alkyl imidazoline-2,4 dione trifluoracetate was precipitated by ether after evaporated to dryness.

R-5-(S-1-a.minoethyl)-imidazoline-2,4-dione trif uoroacetate LC-MS(APCI): M++ H+= 144.2 (m/z) R-5-(1-aminoethyl.)-5-S-methyl i:m:idazolidine-2,4-dione trifluoroacetate LC-MS(APCI): M++ H+= 158.2 (m/z) R-5-(.l-arn:inoetllyl.)-5-.R-methyl imi.dazolidi_n.e-2,4-dione trifluoroacetate LC-MS(APCI): M++ H+= 158.2 (m/z) R-5-(1-am:inoethyl)-5-S-p.henylim:idazolidine-2,4-dione trifluoroacetate LC-MS(APCI): M++ H+ =220.3 (m/z) (5R)-5-[(2S)-pyrrolidin-2-yl]imidazolidine-2,4-dione trifluoroacetate LC-MS(APCI): M++ H+ = 169.1 (m/z) (5R)-5-[(2R)-pyrrolidin-2-yl]imidazolidine-2,4-dione LC-MS(APCI): M++ H+= 169.1 (m/z) (5R)-5-[(2S)-pyrrolidin-2-yl]imidazolidine-2,4-dione LC-MS(APCI): M++ H+= 169.1 (m/z) (5S)-5-[(2S)-pyrrolidin-2-yl]imidazolidine-2,4-dione LC-MS(APCI): M++ H+ = 169.1 (m/z) (5S)-5-methyl-5-[(2R)-pyrrolidin-2-yl]imidazolidine-2,4-dione LC-MS(APCI): M++ H+ = 183.21(m/z) (c) Preparation of hydantoins of formula I

Synthesis was performed in parallel, on 20 well plates, manually operated.

Each well was charged by ca 7.5 umol of the corresponding sulfonyl chloride in 0.5 ml of DCM, followed by ca 15-20 umol of the 5-(1-aminoethyl) 5-alkyl imidazoline-2,4-dione trifluoroacetate in 0.5 ml DCM (small amount of DMF added if necessary for complete dissolution) and 10 mg of the diethylaminomethyl polystyrene resin was added.
The mixture was shaked overnight, filtered through 200 mg of silica gel (washed with 3-5 ml of ethyl acetate and the purity was monitored by LC-MS. The solutions were evaporated to dryness to afford all expected compounds in sufficient purity.

4-R-(4-clilorophenoxy-N-(1-(2,5dioxoiinidazolin-4-S-yl)-ethyl) benzenesulfonainide -S=O
O \
O
N
N

CI
LC-MS(APCI): M++ H+= 411.1 (m/z) 4-R-(5-chi oropyr:idin-2-oxy)-N-(1-(2,5-d:ioxoinm.idazol.ine-4-S-y.l)-ethyl.) benzenes ulfonainide O
N
N
O

LC-MS(APCI): M++ H+= 412.1 (m/z) R-N-(1-(2,5-dioxo-imidazolidin-S-4-yl) ethyl)-4-(pyridin-2-yloxy)-benzenesulfo.nalnide \ S=O
O N....
O
N
\ ~N ~_N
O

15 LC-MS(APCI): M++2 H+ =378.9 (m/z) R-N-(1-(2,5-dioxo-imidazolidin-S-4-vl) ethyl)-4-(pyridin-4-yloxy)-benzenesulfonamide \ s O
O N....
O
' N
N O
LC-MS(APCI): M++2 H+ =378.9 (m/z) 4-R-(4-cyanophenoxy-N'-(1-(2,5dioxoimidazol.in-4-S-yl)-ethyl) benzenesul.fon.am.ide O
S=O
O N--' N
\x )-N

N

LC-MS(APCI): M++H+=401.5 (m/z) 4-R-(4-'fluorophenoxy-:N-(1-(2.5dioxoimid.azolin-4-S-vl)-ethyl) benzenesull:onainide -S=O

O
N
N
O
F
LC-MS(APCI): M++ H+=394.3 (m/z) 4-R-(4-triluoromethylphenoxy-N-(I -(2,Sdioxoirnidazolin-4-S-yl)-ethyl) be:nze nesul.to.n.amide S=O
O~ N....
O
N
~-N
O
F
F F

LC-MS(APCI): M++ H+=444.4 (m/z) 4-.R-(4-.inethvl.p:h.enox) -N-(.l -(2,5dioxoi.mi.dazolin.-4-S-v1)-ethyi) benzenesu:ltonamicle O
s o 0 \ N--O
~ N
\ ~N
O
LC-MS(APCI): M++ H+=389.43 (m/z) 4-R-(4-methoxyphenox.y-N-(.l-(2,5dioxoiinidazol.in-4-S-vl.)-eth.yl) ben.zenesultonamide \ S=O
O NJ,,, O
NN

LC-MS(APCI): M++H+=406.4 (m/z) 4-R-(4-phenoxy-N-(1-(2,5dioxoimidazolin-4-S-yl)-ethyl) benzenesulfonamide O
\ s O
O N....
O
~ N
\ N
O
LC-MS(APCI): M++2H+=376.2 (m/z) R-.N-(1-(4-rnethy 2.5-diox.o-im.i.dazolidi.:n-4-S-y.l)-ethyl-4-phenoxyben.zenesulfonamide O
\ S=O
O , N.....
O
N
6 ~-N
O
LC-MS(APCI): M++ H+=390.4 (m/z) 4-(4-Ch.lorohenoxy-N-(l -(4-S-meth.y.l-2.5-di.oxoirnidazoli.din-4-R-yl)-ethyl.
be:nzenesul.f.'on:ain.ide S=O
N....
O
N
~-N
O
CI
LC-MS(APCI): M++ H+=423.4 (m/z) i5 4-(5-chloropyridyl-2-oxy)-N-(1-(4-S-methyl-2,5-dioxoimiclazolidin-4-R-yl)-eth;yI
be.nze ne su l.:to n alai de O
\ s O
O N....
O
N N
N
O
CI
LC-MS(APCI): M++ H+=424.4 (m/z) N-(1-(4-S-methyl-2,5-dioxoirnidazolidin-4-R-5- l)-ethyl)-4-(pyridin-2-yloxy) benzenesulfonamide S=O
N..., O
N
\ IN N
O
LC-MS(APCI): M++ 2H+ =392.4 (m/z) N-(l. -(4-S-methyl.-2,5-di.oxoimidazolidin-4-R-yl)-ethyl)-4-(p),rid:in-2-yloxy) benze:nesul onamide O
/ \ S O
O , N-, O
~ N
-N
N

LC-MS(APCI): M++ 2H+=392.4 (m/z) 4-(4-cyanophenoxy-N-(1-(4-S-methyl-2,5-dioxoimidazolid.in-4-R-vl)-ethyl be:n z e ne su l fo:n axn..i de O
\ s O
O N--~ N
\ ~-N

N

LC-MS(APCI): M++ 2H+=415.4 (m/z) R-N-(1-(4-methy 2,5-dioxo-irn.idazoli.din-4-R-yl)-ethy.l-4-phen.oxybenzenesulfonam.ide O
S=O
N....
O
N '' 'r \ / ~
N
O
LC-MS(APCI): M++ H+=390.4 (m/z) 4-(4-C.hloroh.e:noxy-N -(1-(4-.R-methyl-2, 5-di.oxoi:mida.zol i.di n-4-R-yl)-ethyl benzenesulfonain i.de S=O
N

ci LC-MS(APCI): M++ H+=423.4 (m/z) 4-(5-chlorop),,r.idyl-2-oxy)-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-yl)-ethyl benzenesu l.fon:an.ide \ s O
O N,...

O
N N

/- N
O
CI
LC-MS(APCI): M++ H+=424.4 (m/z) N-(1-(4-R-methyl-2.5-d.ioxoimidazolidin-4-R-yl)-ethyl)-4-(pyri.din-2-yloxy) benzenesulfonarnide O
\ s O
O , N,....
O
~ N N
\ / N
O
LC-MS(APCI): M++ 2H+ =392.4 (m/z) N-(] -(4-R-methyl-2.5-dioxoimidazolidin-4-R-yl)-ethyl)-4-(pyridin-2-yloxy) benze.nesulfonamide ~ \ s o Or N,,..

O
N
-N

O
LC-MS(APCI): M++ 2H+=392.4 (m/z) 4-(4-cya.nophenoxy-N-(l -(4-R-methyl-?..5-dioxoimidazolidin-4-R-yl)-ethyl bean zenesu l.fiinam.i de \ s o O N....
N ''r0 ~j-N

N
LC-MS(APCI).: M++ H+=415.4 (m/z) 4-(4-fluorophen.oxy-N-(l.-(4-. -meth.yl-2.5-di.oxoi:m:idazoli.din-4-S-yl)-ethyl benzenesulforian:tide S=0 0 i N---N

O~-N
F

LC-MS(APCI): M++ H+=407.4 (m/z) 4-(4-trill.uorom:nethy.lpllenoxy-N-(I-(4-R-meth.y1-2.5-di.oxoimidazol.idin-4-S-yl)-ethyl be:nzenesul.fonamide S=O
Nl-O
N

F
F F

LC-MS(APCI): M++ H+=458.4 (m/z) 4-(4-Methylphenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-S-yl)-ethyl benzenesul_fo.nam.ide S=O
O N

/ N
i ~
O

LC-MS(APCI): M++ H+=404.5 (m/z) 4-(4-Methoxyphenoxy-N -(I -(4-R-methyl-2.5 -clioxo imidazolidin-4-S-yl)-ethyl benzenes ul.:lan:a aide s=o O NI-N
O
__O

LC-MS(APCI): M++ H+=420.5 (m/z) 4-(4-Phenoxy-N-(l -(4-R-inethyl.-2.5-dioxoi.mid.azolidin-4-S-yl)-ethyl benzenesulfonamide O
S=O
O N....
i O
N
\ )_ N

LC-MS(APCI): M++ H+=390.5 (m/z) 4-(4-fluorophenoxy-N-(1-(4-R-methyl-2.5-dioxoimidazolidin-4-R-yl)-ethyl be.nzenesullanalnide O
S=O
O \N..õ
O
N fl~ N

O
F

LC-MS(APCI): M++ H+=407.4 (m/z) 4-(4-trill uoromethylphenoxy-N-(1-(4-R-met:hyl-2,5-dioxoim.idazol id:in-4-R-yl)-ethyl benzenesulfonamide /O
-S=O
N
>/- N

F F

LC-MS(APCI): M++ H+=458.4 (m/z) 4-(4-MethyIphenoxy-N-(1-(4-R-methyl-2,5-di.oxoim:idazolidin-4-R-y1)-ethyl benzenesulfonamide O
S=O
\N

N
N
O

LC-MS(APCI): M++ H+=404.5 (m/z) 4-(4-Meth.oxyphenoxy-N-(l. -(4-R.-mneth.y.l-2,5-dioxoi.n...midazoli.di.n-4-R-yl)-ethyl.
benzenesul.aon.axnide P, S=O
0 \N l l-O
N
)- N
O
-O
5 LC-MS(APCI): M++ H+=420.5 (m/z) 4-(4-Phenoxy-N-(1-(4-R-nlethy.1-2, 5-dioxoimidazolidin-4-R-yl)-ethyl benzenesullonamide O
S=O
0 i No----N
O
\t/ )- N
O
LC-MS(APCI): M++ H+=390.5 (m/z) 4-(4-Ch.lorophenoxy)-N-(1-((2.5-d.ioxo-4-S-plien.yl-imid.azolidin-4-R-yl)-ethyl) be nzenesuldonamide O
rs\ O
0 Noll..

~N
O
CI

LC-MS(APCI): M++ H+=486.8 (m/z) 4-(5-ch.loropyr..idi.n-2-yloxy)-N-(l. -((2.5-dioxo-4-S-ph.e.nvl.-im.i.dazol..idi:n-4-R.-yl)-ethyl) be.n.zenesuldo namn.ide SaN?"
O O

N N
/

CI
I
LC-MS(APCI): M++ H+=487.8 (m/z) N-(1-S-(2.5-dioxo-4-ph.envliin:idazol.idin-4-R-yl:)-ethyl-4-(pyri.d.in-2-yloxy)-benzenesulfonamide O
S O
N N

tN
io LC-MS(APCI): M++ 2H+=454.6 (m/z) N-(1-S-(2,5-d.ioxo-4-phenylimidazol.idin-4-R-yl.)-ethyl-4-(p),rid.in-4-yloxy)-benzenesulfonainide O
S=O 00 N
' /~- N
\N O
LC-MS(APCI): M++ 2H+=454.6 (m/z) 4-(4-Cyanophenoxy)-N-(1-((2,5-dioxo-4-S-phenyl-imidazolidin-4-R-yl)-ethyl) be:nze nesu l.to.naln:ide s=o N
O

N
LC-MS(APCI): M++ H+=477.6 (m/z) 4-(4-Fluorop.henoxy)-N-(l.-((2,5-dioxo-4-S-phenyl-imnidazolidin-4-R-yl)-ethyl.) benzenes ullonamide so N

, P'e~o "Ir N
N
F

LC-MS(APCI): M++ H+=470.5 (m/z) 4-(4-T:ri.Eluororneth),lphenoxy)-N-(I -((2,5-d:ioxo-4-S-phenyl.-.imi.dazol.:idi:n-4-R-yl)-ethyl) benzenesLdlonamide S
O N

O
N
N

F p, F
is LC-MS(APCI): M++ H+=519.1 (m/z) 4-(4-1Vleth.ylphen.oxy)-N-(1. -((2.5-d:ioxo-4-S-plh.enyl.-iri.dazol..idi:n-4-.R.-vl.)-ethyl) be.n.zenesuifon.amide O
SO P,:,"
NN

s LC-MS(APCI): M++ H+=466.4 (m/z) 4-(4- Methoxvphenoxy)-N-(1-((2.5-dio:xo-4-S-phenyl-imidazolidin-4-R-vl)-ethvl) benzenesulfonamide S=o Nõõ
P""
N
>-N

o io LC-MS(APCI): M++ H+=482.4 (m/z) 4-(4-Phenoxy)-N-(1-((2,5-(I.ioxo-4-S-phenyl-imidazolidin-4-R-yl)-ethyl) 15 benzenesulfonamide O
S\ O

/\r N
LC-MS(APCI): M++ H+=452.5 (m/z) 5-(1-{[4-(4-chlorophenoxy)phenyl] sulfonyl}pyrrolidin-2-yl)-5-methyl imidazolidine-2,4-dione O -N N
O O

CI
LC-MS(APCI): M++ H+=450.5 (m/z) 5-(1-{[4-(4-methoxyphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione ONO
N N

O O
LC-MS(APCI): M++ H+=446.2 (m/z) 5-(1-{[4-(4-methyl phenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methyl imidazolidine-2,4-dione O ~~
N
yN
O O

LC-MS(APCI): M++ H+=430.1 (m/z) 5-(1-{[4-(4-fluorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methyl imidazolidine-2,4-dione O qN\%
O
N
\ / ~N
O
F

s LC-MS(APCI): M++ H+=434.1 (m/z) (1-{[4-(4-cyanophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione O N
O
N
1 / ~N
O O
N

LC-MS(APCI): M++ H+=441.1 (m/z) 5-(1-{[4-(4-chlorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione ON /O
-O
N N
O O

CI
LC-MS(APCI): M++ H+=436.1 (m/z) 5-(1-{[4-(4-fluorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione O
N
yN
O O

F
LC-MS(APCI): M++ H+=420.1 (m/z) 5-(1-{[4-(4-methylphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione O gN
/O
N
N
O O

s LC-MS(APCI): M++ H+=416.1 (m/z) 5-(1-{[4-(4-methoxyphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione gN
O
SN N

O O
O -LC-MS(APCI): M++ H+=432.1 (m/z) 5-(1-{[4-(4-cyanophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione O~~

~ N N
/
O O
N

LC-MS(APCI): M++ H+=427.1 (m/z) [(4R)-2,5-dioxoimidazolidinyl]methanesulfonyl chloride, [(4S)-2,5-dioxoimidazolidinyl]methanesulfonyl chloride or [(R)-2,5-Dioxoimidazolidinyl]-methanesulfonyl chloride was reacted with the appropriate primary or secondary amine to give the compounds listed below. All the amines employed are commercially available.
Sulfonyl chloride (0.060 mmoles), amine (0.060 mmoles), triethylamine (0.0084 mL, 0.060 mmoles) in dry tetrahydrofuran (0.70 mL) were stirred at room temperature over night.

Polystyrene methylisocyanate (0.025 g, 0.030 mmoles) was added and the mixture was shaken over night. The white suspension was filtered and the solids were rinsed with tetrahydrofuran (2x1 mL). The filtrates were evaporated, the white solid was suspended in water (5 mL), collected on a filter, washed with water (2x1 mL), sucked free of water and dried in vacuo at 45 C over night to afford the title compounds.

The starting materials were prepared as follows:

5-methyl-5-{ [(phenylmethyl)thio]methyl}imidazolidine-2,4-dione A steel vessel was charged with ethanol and water (315mL/135mL).

31.7g (0.175 mol) of benzylthioacetone, 22.9g (0.351 mol) of potassium cyanide and 84.5g (0.879 mol) of ammonium carbonate was added. The closed reaction vessel was kept in an oil bath (bath temperature 90 C) under vigorous stirring for 3h.

The reaction vessel was cooled with ice-water (0.5 h), the yellowish slurry was evaporated to dryness and the solid residue partitioned between 400 mL water and 700 mL

ethylacetate and separated. The water-phase was extracted with ethylacetate (300 mL). The combined organic phases were washed with saturated brine (150 mL), dried (Na2SO4), filtered and evaporated to dryness. If the product did not crystallize, 300 mL
of dichloromethane was added to the oil. Evaporation gave the product as a slightly yellowish powder,43.8 g (90%).

LC-MS (APCI) m/z 251.1 (MH+).

'H NMR (DMSO-d6) S: 10.74 (1H,s); 8.00 (IH, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq, J=14.0 Hz); 1.29 (3H, s).

13C NMR (DMSO-d6) 8: 177.30, 156.38, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96, 5 36.39, 23.15.

(5S)-5-methyl-5-{ [(phenylmethyl)thio] methyl}imidazolidine-2,4-dione The title compound was prepared by chiral separation of the racemic material using a 250mm x 50mm column on a Dynamic Axial Compression Preparative HPLC system.
The 10 stationary phase used was CHIRALPAK AD, eluent=Methanol, flow=89mL/min, temp=ambient, UV=220nm, sample conc=150mg/mL, injection volume=20mL.
Retention time for title compound = 6 min.

Analysis of chiral purity was made using a 250mm x 4.6mm CHIRALPAK-AD column from Daicel, flow=0.5mL/min, eluent=Ethanol, UV=220nm, temp=ambient.

15 Retention time for title compound = 9.27min.
Purity estimated to >99% ee.

LC-MS (APCI) m/z 251.1 (MH+).
[a]D=-30.3 (c=0.01g/mL, MeOH, T=20 C).

1H NMR (DMSO-d6) S: 10.74 (1H,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 20 2.62 (1H each, ABq, J=14.0 Hz); 1.29 (3H, s).

13C NMR (DMSO-d6) 8: 177.30, 156.28, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96, 36.39, 23.15.

(5R)-5-methyl-5-{ [(phenylmethyl)thio]methyl}imidazolidine-2,4-dione 25 The title compound was prepared by chiral separation of the racemic material using a 250mm x 50mm column on a Dynamic Axial Compression Preparative HPLC system.
The stationary phase used was CHIRALPAK AD, eluent=Methanol, flow=89mL/min, temp=ambient, UV=220nm, sample conc=150mg/mL, injection volume=20mL.

Retention time for title compound = 10 min.

Analysis of chiral purity was made using a 250mm x 4.6mm CHIRALPAK-AD column from Daicel, flow=0.5mL/min, eluent=Ethanol, UV=220nm, temp=ambient.

Retention time for title compound = 17.81 min.
Chiral purity estimated to >99% ee.

LC-MS (APCI) m/z 251.0 (MH+).
[a]D=+30.3 (c=0.01g/mL, MeOH, T=20 C).

'H NMR (DMSO-d6) b: 10.74 (1H,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq, J=14.0 Hz); 1.29 (3H, s).

13C NMR (DMSO-d6) 8: 177.31, 156.30, 138.11, 128.74, 128.25, 126.77, 62.94, 37.97, 36.40, 23.16.

[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (5S)-5-methyl-5-{ [(phenylmethyl)thio]methyl}imidazolidine-2,4-dione (42.6g;
0.17mol) was dissolved in a mixture of AcOH (450 mL) and H2O (50 mL). The mixture was immersed in an ice/water bath, C12 (g) was bubbled through the solution, the flow of gas was adjusted so that the temperature was kept below +15 C. After 25 min the solution became yellow-green in colour and a sample was withdrawn for LC/MS and HPLC
analysis. It showed that starting material was consumed. The yellow clear solution was stirred for 30 min and an opaque solution /slurry was formed.

The solvent was removed on a rotary evaporator using waterbath with temperature held at +37 C. The yellowish solid was suspended in Toluene (400mL) and solvent removed on the same rotary evaporator. This was repeated once more.

The crude product was then suspended in iso-Hexane (400mL) and warmed to +40 C
while stirring, the slurry was allowed to cool to room temperature before the insoluble product was removed by filtration, washed with iso-Hexane (6x 100mL), and dried under reduced preassure at +50 C over night. This gave the product as a slightly yellow powder.
Obtained 36.9 g (95%) of the title compound.
Purity by HPLC = 99%, NMR supported that purity.
[a]D=-12.4 (c=0.01g/mL, THF, T=20 C).

1H NMR (THF-d8): S 9.91 (1H, bs); 7.57 (1H, s); 4.53, 4.44 (1H each, ABq, J=14.6Hz);
1.52 (s, 3H, CH3).

13C NMR (THF-dg): S 174.96; 155.86; 70.96; 61.04; 23.66.

[(4R)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride Following the procedure described for [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride.

Starting from (5R)-5-methyl-5-{ [(phenylmethyl)thio]methyl}imidazolidine-2,4-dione (10.0g, 40nunol).
to Obtained 8.78g (96% yield) of the title compound.
Purity by NMR > 98%.

[a]D=+12.8 (c=0.01g/mL, THF, T=20 C).

'H NMR (THF-d8): S 9.91 (1H, brs); 7.57 (1H, s); 4.53, 4.44 (1H each, ABq, J=14.6Hz);
1.52 (s, 3H, CH3).
13C NMR (THF-d8): b 174.96; 155.84; 70.97; 61.04; 23.66.
O
HNANH
O (R)-Amine-S' 0 O
The Table below gives the Amine group for each compound of the above structure.

H
N }-H/
~/ MW. 373.43 MW. 366 m/z374(M+1) m/z 367 M+1 CN-/--\H--- H

MW.320 ci m/z 321 (M+1) MW. 331.78 m/z 332 M+1 N
MeO H

MeO MW. 331.44 MW. 357.39 m/z 332 (M+l) m/z 358 M+1 I~ H
/ 7N~
H

MW. 336.37 m/z 337 (M+l) O
HN'J~ NH
(S)-O
Amine-S' 0 O

The Table below gives the Amine group for each compound of the above structure.

H
N }-H
~/ MW. 373.43 MW. 366 m/z 374 (M+1) m/z 367 M+1 0/---'N -H-- - H

MW.320 ci m/z 321 (M+1) MW. 331.78 m/z 332 M+1) N N
MeO H

MeO MW. 331.44 MW. 357.39 m/z 332 (M+1) m/z 358 M+1 O
H QN-07N~ INI

336.37 MW. 403.46 m/z 337 (M+1) m/z 404 (M+1) \ ~ \
O N
MW. 389.43 m/z 390 M+1) HN'J~ NH _ (S) I I
"'~4 Amine-S' O
The Table below gives the Amine group for each compound of the above structure.
Hydantoin Analysis("

MW. 375.41 CI N~
m/z 410 (MH+) m/z 374 (MH+) N"
MW. 373.43 0 N-~ m/z 388 (MH+) II N
,so MW. 387.42 s N-I4-(4-Chloro-phenoxy)-phenyll-C-((4S)-4-methyl-2,5-dioxo-imidazolidin-4-yl)-methanesulfonamide LC-MS (APCI) m/z 410 (MH+).

'H NMR (DMSO- d6): S 10.75 (1 H, s); 9.89 (1 H, s); 8.04 (1 H, s); 7.45-7.39 (2 H, m);
7.25-7.19 (2 H, m); 7.06-6.97 (4 H, m); 3.54 (1 H from ABq, J=14.1 Hz); 1.31 (3 H, s).

N-(4-Benzyl-p henyl)-C-((4S)-4-methyl-2,5-dioxo-imidazolidin-4-yl)-methanesulfonamide LC-MS (APCI) m/z 374 (MH+).

'H NMR (DMSO- d6): 8 10.74 (1 H, s); 9.82 (1 H, s); 8.01 (1 H, s); 7.33-7.05 (9 H, m);
3.49, 3.36 (1 H each, ABq, J16.2 Hz); 1.28 (3 H, s).

N-(4-Benzoyl-phenyl)-C-((4S)-4-methyl-2,5-dioxo-imidazolidin-4-yl)-methanesulfonamide LC-MS (APCI) m/z 388 (MH+).

'H NMR (DMSO- d6): 8 10.81 (1 H, s); 10.58 (1 H, s); 8.08 (1 H, s); 7.76-7.62 (5 H, m);
7.60-7.52 (2 H, m); 7.33-7.27 (2 H, m); 3.68, 3.52 (1 H each, ABq, J=14.7 Hz);
1.33 (3 H, s).

io Prepared from commercially available N-Boc-4-piperidone by methods described in Example 3.

0=g \N N' ,,~O

O
O

CI
m/z 437 (MH+) MW. 435.89 O

O=SAN O
0N~
N
O
O m/z 432 (MH+) MW. 431.47 i5 O=S,- N N O
N
OC
O
I \ O

m/z 416 (MH+) MW. 415.47 O/
N O
- Nei C N
O
I \ O

F m/z 420 (MH+) MW. 419.43 O
O,glN O C
NfN
O
O
N
m/z 427 (MH+) MW. 426.45

Claims (24)

CLAIMS:
1. A compound of the general formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

each of G1 and G2 is a monocyclic ring structure comprising each of up to 7 ring atoms which are independently cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents which are a halogen atom, hydroxy, haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate or alkylamide, wherein any alkyl radical within any substituent is optionally substituted with one or more groups which are a halogen atom, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy or haloalkoxy;

B is a direct bond, O, (C1-6)alkyl or (C1-6)heteroalkyl;

R2 is H, (C1-6)alkyl, aryl-(C1-6)alkyl or heteroaryl-(C1-6)alkyl;
R3 and R4 are independentyl H or (C1-3)alkyl; and R6 is: (i) H or (C1-3)alkylamino, or (ii) (C1-3)alkyl optionally substituted by aryl, heteroaryl or heterocycloalkyl; or R3 and R4 form a 5- or 6-membered ring; or R3 and R6 form a 5- or 6-membered ring; or R4 and R6 form a 5- or 6-membered ring; or R2 and R3 form a 5-membered ring; or R2 and R6 form a 5-membered ring.
2. A compound of the general formula (II) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein B is a direct bond or O.
3. A compound of the general formula (II) as claimed in claim 1 to 2, or a pharmaceutically acceptable salt thereof, wherein each of R3 and R4 is H.
4. A compound of the general formula (II) as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R6 is H, benzyl or methylenepyridine.
5. A compound of the general formula (II) as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein G1 and are each an aryl or a heteroaryl.
6. A compound of the general formula (II) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 and R6 form a 5-membered ring and wherein the compound is:

5-(1-{[4-(4-chlorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl )-5-methylimidazolidine-2,4-dione;

5-(1-{[4-(4-methoxyphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione;

5-(1-{[4-(4-methylphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl )-5-methylimidazolidine-2,4-dione;

5-(1-{[4-(4-fluorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione;

5-(1-{[4-(4-cyanophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione;

5-(1-{[4-(4-chlorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione;
5-(1-{[4-(4-fluorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione;

5-(1-{[4-(4-methylphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidine-2,4-dione;
5-(1-{[4-(4-methoxyphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl )imidazolidine-2,4-dione; or 5-(1-{[4-(4-cyanophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl )imidazolidine-2,4-dione.
7. The compound of the general formula (II) as claimed in the claim 1, or a pharmaceutically acceptable salt thereof, which is 5-(1-{[4-(4-cyanophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione.
8. A pharmaceutical composition which comprises a compound of the formula (II) as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound of the general formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the preparation of a medicament for the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
10. Use of a compound of the general formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
11. Use of a composition as claim in claim 8, in the preparation of a medicament for the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
12. Use of a composition as claim in claim 8, in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
13. The use according to any one of claims 9 to 12, wherein the disease or condition is asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis and restenosis, cancer, invasion and metastasis, a disease involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, a disease related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, a CNS related disease or a haematological disorder.
14. The use according to claim 13, wherein the arthritis is rheumatoid arthritis or osteoarthritis, and the CNS related disease is Alzheimer's disease or Multiple Sclerosis (MS).
15. A compound of the general formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the preparation of a medicament for the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
16. A compound of the general formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
17. A composition as claimed in claim 8, for use in the preparation of a medicament for the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
18. A composition as claimed in claim 8, for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
19. The compound, salt or composition as claimed in any one of claims 15 to 18, wherein the disease or condition is asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis and restenosis, cancer, invasion and metastasis, a disease involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, a disease related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, a CNS
related disease or a haematological disorder.
20. The compound, salt or composition as claimed in claim 19, wherein the arthritis is rheumatoid arthritis or osteoarthritis, and the CNS related disease is Alzheimer's disease or Multiple Sclerosis (MS).
21. A commercial package comprising a compound of the general formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and associated therewith instructions for the use thereof in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
22. A commercial package comprising a composition as claimed in claim 8, and associated therewith instructions for the use thereof in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes.
23. The commercial package as claimed in claim 21 or 22, wherein the disease or condition is asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis, atherosclerosis and restenosis, cancer, invasion and metastasis, a disease involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, a disease related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, a CNS related disease or a haematological disorder.
24. The commercial package as claimed in claim 23, wherein the arthritis is rheumatoid arthritis or osteoarthritis, and the CNS related disease is Alzheimer's disease or Multiple Sclerosis (MS).
CA2440473A 2001-03-15 2002-03-13 Metalloproteinase inhibitors Expired - Fee Related CA2440473C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE0100902A SE0100902D0 (en) 2001-03-15 2001-03-15 Compounds
SE0100902-6 2001-03-15
PCT/SE2002/000478 WO2002074751A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors

Publications (2)

Publication Number Publication Date
CA2440473A1 CA2440473A1 (en) 2002-09-26
CA2440473C true CA2440473C (en) 2011-08-30

Family

ID=20283374

Family Applications (3)

Application Number Title Priority Date Filing Date
CA2440630A Expired - Fee Related CA2440630C (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
CA2440473A Expired - Fee Related CA2440473C (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
CA002440631A Abandoned CA2440631A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA2440630A Expired - Fee Related CA2440630C (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors

Family Applications After (1)

Application Number Title Priority Date Filing Date
CA002440631A Abandoned CA2440631A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors

Country Status (33)

Country Link
US (8) US20040106659A1 (en)
EP (4) EP1676846B1 (en)
JP (4) JP2004527515A (en)
KR (4) KR100879905B1 (en)
CN (5) CN100526307C (en)
AR (2) AR035443A1 (en)
AT (3) ATE333454T1 (en)
AU (2) AU2002237626B2 (en)
BR (3) BR0207984A (en)
CA (3) CA2440630C (en)
CY (1) CY1107525T1 (en)
CZ (3) CZ20032499A3 (en)
DE (3) DE60237965D1 (en)
DK (1) DK1370556T3 (en)
EE (3) EE05364B1 (en)
ES (3) ES2357138T3 (en)
HK (3) HK1091492A1 (en)
HU (3) HUP0400194A3 (en)
IL (5) IL157657A0 (en)
IS (3) IS6942A (en)
MX (3) MXPA03008177A (en)
MY (2) MY136141A (en)
NO (3) NO20034044L (en)
NZ (3) NZ528140A (en)
PL (3) PL365099A1 (en)
PT (1) PT1370556E (en)
RU (3) RU2293729C2 (en)
SE (1) SE0100902D0 (en)
SI (1) SI1370556T1 (en)
SK (3) SK287766B6 (en)
UA (3) UA77408C2 (en)
WO (3) WO2002074751A1 (en)
ZA (4) ZA200306732B (en)

Families Citing this family (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0100902D0 (en) * 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
SE0100903D0 (en) * 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
US6890915B2 (en) 2001-05-25 2005-05-10 Bristol-Myers Squibb Pharma Company Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
SE0103710D0 (en) * 2001-11-07 2001-11-07 Astrazeneca Ab Compounds
DE10221018A1 (en) * 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Use of inhibitors of EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH) / prostatic hypertrophy
SE0202539D0 (en) 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
SE0202693D0 (en) * 2002-09-11 2002-09-11 Astrazeneca Ab Compounds
GB0221246D0 (en) * 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
EP1546109A4 (en) * 2002-10-04 2005-11-09 Bristol Myers Squibb Co Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme (tace)
US7632950B2 (en) 2003-08-18 2009-12-15 Fujifilm Finechemicals Co., Ltd Pyridyltetrahydropyridines and pyridylpiperidines and method of manufacturing them
US20050203156A1 (en) * 2004-03-12 2005-09-15 Wyeth Hydantoins having RNase modulatory activity
SE0401762D0 (en) * 2004-07-05 2004-07-05 Astrazeneca Ab Novel compounds
SE0401763D0 (en) * 2004-07-05 2004-07-05 Astrazeneca Ab Compounds
US7648992B2 (en) 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
EP1802331A2 (en) * 2004-09-08 2007-07-04 Boys Town National Research Hospital Treatment of glomerular basement membrane disease involving matrix metalloproteinase-12
AR051093A1 (en) 2004-09-20 2006-12-20 Xenon Pharmaceuticals Inc HETEROCICLIC DERIVATIVES AND THEIR USE AS INHIBITORS OF ESTEAROIL-COA DESATURASA
JP5094398B2 (en) 2004-09-20 2012-12-12 ゼノン・ファーマシューティカルズ・インコーポレイテッド Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturases
US7919496B2 (en) * 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
EP2266569A3 (en) 2004-09-20 2011-03-09 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
BRPI0515489A (en) 2004-09-20 2008-07-29 Xenon Pharmaceuticals Inc heterocyclic derivatives and their use as stearoyl coat desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
GB0427403D0 (en) * 2004-12-15 2005-01-19 Astrazeneca Ab Novel compounds I
SE0403085D0 (en) * 2004-12-17 2004-12-17 Astrazeneca Ab Novel componds
SE0403086D0 (en) * 2004-12-17 2004-12-17 Astrazeneca Ab Compounds
WO2006099598A2 (en) * 2005-03-16 2006-09-21 Sensus Metering Systems Inc. Determining a physical location of a sensor
AU2006343359A1 (en) 2005-06-03 2007-11-15 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors
WO2007078335A2 (en) * 2005-12-21 2007-07-12 Decode Genetics, Ehf. Biaryl nitrogen heterocycle inhibitors of lta4h for treating inflammation
PE20071240A1 (en) * 2006-01-17 2008-01-14 Schering Corp HYDANTOIN-DERIVED COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS
TW200740769A (en) * 2006-03-16 2007-11-01 Astrazeneca Ab Novel process
TW200800954A (en) * 2006-03-16 2008-01-01 Astrazeneca Ab Novel crystal modifications
WO2007133127A1 (en) * 2006-05-12 2007-11-22 Sca Hygiene Products Ab A pant-type absorbent article and a method for producing pant-type absorbent articles.
WO2007133128A1 (en) * 2006-05-12 2007-11-22 Sca Hygiene Products Ab Elastic laminate and a method for producing an elastic laminate
WO2008053199A1 (en) * 2006-10-30 2008-05-08 Astrazeneca Ab Combination therapy for the treatment of respiratory diseases
TW200831488A (en) 2006-11-29 2008-08-01 Astrazeneca Ab Novel compounds
GB0702456D0 (en) 2007-02-08 2007-03-21 Astrazeneca Ab New combination
WO2009007747A2 (en) * 2007-07-11 2009-01-15 Astrazeneca Ab Hydantoin derivatives used as mmp12 inhibitors
US8303561B2 (en) 2007-11-14 2012-11-06 Sca Hygiene Products Ab Method of producing an absorbent garment, and an absorbent garment produced according to the method
CN101854897B (en) 2007-11-14 2013-04-24 Sca卫生用品公司 Method of producing an absorbent garment, and an absorbent garment produced according to the method
FR2927330B1 (en) * 2008-02-07 2010-02-19 Sanofi Aventis 5,6-BISARYL-2-PYRIDINE CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE AS ANTAGONISTS OF UROTENSIN II RECEPTORS
MX337862B (en) 2008-04-28 2016-03-16 Revalesio Corp Compositions and methods for treating multiple sclerosis.
FR2944524B1 (en) 2009-04-17 2012-11-30 Ipsen Pharma Sas IMIDAZOLIDINE-2,4-DIONE DERIVATIVES AND THEIR USE AS A MEDICINAL PRODUCT
PL2433940T3 (en) * 2009-04-28 2015-03-31 Chugai Pharmaceutical Co Ltd Spiroimidazolone derivative
GB0913345D0 (en) 2009-07-31 2009-09-16 Astrazeneca Ab New combination 802
CN102711991B (en) * 2009-11-06 2015-01-21 巴斯夫欧洲公司 Heterogeneous catalyst containing iron and manganese and method for producing olefins by converting carbon monoxide with hydrogen
WO2011061527A1 (en) 2009-11-17 2011-05-26 Astrazeneca Ab Combinations comprising a glucocorticoid receptor modulator for the treatment of respiratory diseases
WO2011073662A1 (en) 2009-12-17 2011-06-23 Astrazeneca Ab Combination of a benzoxazinone and a further agent for treating respiratory diseases
US20110202284A1 (en) * 2010-02-10 2011-08-18 Mcreynolds Cristopher Novel groups of biomarkers for diagnosing alzheimer's disease
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
GB201021979D0 (en) 2010-12-23 2011-02-02 Astrazeneca Ab New compound
GB201021992D0 (en) 2010-12-23 2011-02-02 Astrazeneca Ab Compound
KR102189940B1 (en) * 2012-09-04 2020-12-14 샹하이 헨그루이 파마수티컬 컴퍼니 리미티드 Imidazoline Derivatives, Preparation Methods Thereof, and Their Applications in Medicine
MX2015007309A (en) 2012-12-10 2015-09-10 Chugai Pharmaceutical Co Ltd Hydantoin derivative.
PL3124021T3 (en) * 2013-11-13 2020-11-30 Hankkija Oy Feed supplement comprising resin acids
JP6227149B2 (en) * 2013-12-31 2017-11-08 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエＩｐｓｅｎ Ｐｈａｒｍａ Ｓ．Ａ．Ｓ． Novel imidazolidine-2,4-dione derivatives
EP2907512A1 (en) 2014-02-14 2015-08-19 Commissariat A L'energie Atomique Et Aux Energies Alternatives Inhibitors of MMP-12 as antiviral Agents
MX371090B (en) 2014-06-09 2020-01-16 Chugai Pharmaceutical Co Ltd Hydantoin derivative-containing pharmaceutical composition.
RU2688677C2 (en) 2014-10-24 2019-05-22 Лэндос Байофарма, Инк. Drug preparations based on lanthionine synthetase of c-like protein
JO3501B1 (en) 2014-12-22 2020-07-05 Servier Lab 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as adamts inhibitors for the treatment of osteoarthritis
WO2018056373A1 (en) * 2016-09-23 2018-03-29 科研製薬株式会社 Method for producing (r)-5-(3,4-difluorophenyl)-5-[(3-methyl-2-oxopyridin-1(2h)-yl)methyl]imidazolidine-2,4-dione and intermediate for producing same
WO2021011723A1 (en) * 2019-07-18 2021-01-21 Avidence Therapeutics, Inc. Anti-osteoarthritis hydantoin compounds and related compositions and methods
CA3158234A1 (en) * 2019-11-14 2021-05-20 Foresee Pharmaceuticals Co., Ltd. Matrix metalloproteinase (mmp) inhibitors and methods of use thereof
AU2020407645B2 (en) 2019-12-20 2022-10-06 Nimmune Biopharma, Inc. Lanthionine C-like protein 2 ligands, cells prepared therewith, and therapies using same
JP2023533462A (en) 2020-06-26 2023-08-03 ザ ユニバーシティ オブ バーミンガム Inhibition of MMP-9 and MMP-12 to treat spinal cord injury or related nerve tissue damage
WO2022007866A1 (en) * 2020-07-09 2022-01-13 深圳信立泰药业股份有限公司 Fused tricyclic derivative, preparation method therefor, and pharmaceutical application thereof
CN112574193B (en) * 2020-12-31 2022-05-17 南京医科大学 Oral GSNOR inhibitor and pharmaceutical application thereof

Family Cites Families (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2327890A (en) * 1940-04-17 1943-08-24 Parke Davis & Co Substituted phenoxyalkyl ethers
US2745875A (en) * 1953-06-30 1956-05-15 Hoechst Ag Preparation of nu-acylamino-phenylpropane diols
US3452040A (en) * 1966-01-05 1969-06-24 American Home Prod 5,5-disubstituted hydantoins
US3529019A (en) * 1968-04-23 1970-09-15 Colgate Palmolive Co Alkylaryloxy alanines
CS152617B1 (en) 1970-12-29 1974-02-22
CS151744B1 (en) 1971-01-19 1973-11-19
US3849574A (en) * 1971-05-24 1974-11-19 Colgate Palmolive Co Alpha-substituted-beta-arylthioalkyl amino-acids,for increasing heart rate
US4315031A (en) * 1977-09-01 1982-02-09 Science Union Et Cie Thiosubstituted amino acids
GB1601310A (en) * 1978-05-23 1981-10-28 Lilly Industries Ltd Aryl hydantoins
JPS6172762A (en) 1984-09-17 1986-04-14 Kanegafuchi Chem Ind Co Ltd Preparation of optically active hydantoin
JPS61212292A (en) * 1985-03-19 1986-09-20 Mitsui Toatsu Chem Inc Production of d-alpha-amino acid
CA1325222C (en) 1985-08-23 1993-12-14 Lederle (Japan), Ltd. Process for producing 4-biphenylylacetic acid
GB8618559D0 (en) 1986-07-30 1986-09-10 Genetics Int Inc Rhodococcus bacterium
JPH0279879A (en) 1988-09-17 1990-03-20 Canon Inc Image forming device
US4983771A (en) 1989-09-18 1991-01-08 Hexcel Corporation Method for resolution of D,L-alpha-phenethylamine with D(-)mandelic acid
NL9000386A (en) 1990-02-16 1991-09-16 Stamicarbon PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE AMINO ACID AMIDE
DK161690D0 (en) 1990-07-05 1990-07-05 Novo Nordisk As PROCEDURE FOR PREPARING ENANTIOMERIC COMPOUNDS
IL99957A0 (en) 1990-11-13 1992-08-18 Merck & Co Inc Piperidinylcamphorsulfonyl oxytocin antagonists and pharmaceutical compositions containing them
PH31245A (en) * 1991-10-30 1998-06-18 Janssen Pharmaceutica Nv 1,3-Dihydro-2H-imidazoÄ4,5-BÜ-quinolin-2-one derivatives.
US5308853A (en) * 1991-12-20 1994-05-03 Warner-Lambert Company Substituted-5-methylidene hydantoins with AT1 receptor antagonist properties
US5246943A (en) * 1992-05-19 1993-09-21 Warner-Lambert Company Substituted 1,2,3,4-tetahydroisoquinolines with angiotensin II receptor antagonist properties
NL9201230A (en) 1992-07-09 1994-02-01 Dsm Nv PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE METHIONIN AMIDE
EP0640594A1 (en) 1993-08-23 1995-03-01 Fujirebio Inc. Hydantoin derivative as metalloprotease inhibitor
JPH07105549A (en) 1993-09-30 1995-04-21 Canon Inc Optical information recording and reproducing method and optical information recording and reproducing device
WO1995014025A1 (en) 1993-11-16 1995-05-26 Merck & Co., Inc. Piperidinylcamphorsulfonyl oxytocin antagonists
RU2126404C1 (en) 1994-01-31 1999-02-20 Пфайзер Инк. 3r*,4s* 3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1- yl)chrohan-4,7-diol, optical isomers thereof and pharmaceutical composition based thereon, and method of medical treatment
DE69534213T2 (en) 1994-10-25 2006-01-12 Astrazeneca Ab Therapeutically effective heterocycles
ZA96211B (en) 1995-01-12 1996-07-26 Teva Pharma Compositions containing and methods of using 1- aminoindan and derivatives thereof and process for preparing optically active 1-aminoindan derivatives
US5863949A (en) 1995-03-08 1999-01-26 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
US6166041A (en) * 1995-10-11 2000-12-26 Euro-Celtique, S.A. 2-heteroaryl and 2-heterocyclic benzoxazoles as PDE IV inhibitors for the treatment of asthma
ES2172690T3 (en) * 1995-11-22 2002-10-01 Darwin Discovery Ltd MERCAPTOALQUILPEPTIDIL COMPOUNDS WITH AN IMIDAZOL SUBSTITUTE AND ITS USE AS INHIBITORS OF MATRIX METALOPROTEINASES (MMP) AND / OR TUMOR NECROSIS FACTOR (TNF).
GB9616643D0 (en) * 1996-08-08 1996-09-25 Chiroscience Ltd Compounds
US5919790A (en) * 1996-10-11 1999-07-06 Warner-Lambert Company Hydroxamate inhibitors of interleukin-1β converting enzyme
JP2001503400A (en) * 1996-10-22 2001-03-13 ファルマシア・アンド・アップジョン・カンパニー Α-Aminosulfonylhydroxamic acids as matrix metalloproteinase inhibitors
IL132170A0 (en) * 1997-05-06 2001-03-19 Novo Nordisk As Novel heterocyclic compounds
DK0877019T3 (en) * 1997-05-09 2002-04-08 Hoechst Ag Substituted diaminocarboxylic acids
CA2294259A1 (en) 1997-06-21 1998-12-30 Roche Diagnostics Gmbh Barbituric acid derivatives with antimetastatic and antitumor activity
DE19726427A1 (en) 1997-06-23 1998-12-24 Boehringer Mannheim Gmbh Pyrimidine-2,4,6-trione derivatives, processes for their preparation and medicaments containing these compounds
NZ501166A (en) * 1997-07-31 2001-12-21 Abbott Lab Reverse hydroxamate-containing compounds and their use as inhibitors of matrix metalloproteinases
TW514634B (en) 1997-10-14 2002-12-21 Lilly Co Eli Process to make chiral compounds
BR9814147A (en) 1997-11-12 2000-10-03 Darwin Discovery Ltd "derivatives of carboxylic and hydroxamic acid having inhibitory activity of mmp and tnf"
CA2318145C (en) 1998-02-04 2009-10-27 Novartis Ag Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
US6329418B1 (en) * 1998-04-14 2001-12-11 The Procter & Gamble Company Substituted pyrrolidine hydroxamate metalloprotease inhibitors
AU4074799A (en) * 1998-05-14 1999-11-29 Du Pont Pharmaceuticals Company Substituted aryl hydroxamic acids as metalloproteinase inhibitors
CN1295561A (en) 1998-06-03 2001-05-16 Gpinil控股公司 N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
WO1999065867A1 (en) * 1998-06-17 1999-12-23 Du Pont Pharmaceuticals Company Cyclic hydroxamic acids as metalloproteinase inhibitors
FR2782082B3 (en) 1998-08-05 2000-09-22 Sanofi Sa CRYSTALLINE FORMS OF (R) - (+) - N - [[3- [1-BENZOYL-3- (3,4- DICHLOROPHENYL) PIPERIDIN-3-YL] PROP-1-YL] -4-PHENYLPIPERIDIN-4 - YL] -N-METHYLACETAMIDE (OSANETANT) AND PROCESS FOR THE PREPARATION OF SAID COMPOUND
US6339101B1 (en) * 1998-08-14 2002-01-15 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or isosteres for vision and memory disorders
JP2000127349A (en) * 1998-08-21 2000-05-09 Komori Corp Intaglio printer
US6479502B1 (en) 1998-08-29 2002-11-12 British Biotech Pharmaceuticals Hydroxamic acid derivatives as proteinase inhibitors
GB9919776D0 (en) 1998-08-31 1999-10-27 Zeneca Ltd Compoujnds
ATE238236T1 (en) 1998-10-07 2003-05-15 Yazaki Corp SOL-GEL PROCESS USING POROUS MOLDS
US6114361A (en) * 1998-11-05 2000-09-05 Pfizer Inc. 5-oxo-pyrrolidine-2-carboxylic acid hydroxamide derivatives
AU779117B2 (en) 1998-12-18 2005-01-06 Axys Pharmaceuticals, Inc. Protease inhibitors
CA2356689A1 (en) * 1998-12-31 2000-07-13 Michael J. Janusz 1-carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of mmp-12
US6340691B1 (en) * 1999-01-27 2002-01-22 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors
US7553969B1 (en) 1999-01-28 2009-06-30 Chugai Seiyaku Kabushiki Kaisha Substituted phenethylamine derivatives
US6294694B1 (en) 1999-06-04 2001-09-25 Wisconsin Alumni Research Foundation Matrix metalloproteinase inhibitors and method of using same
GB9916562D0 (en) * 1999-07-14 1999-09-15 Pharmacia & Upjohn Spa 3-Arylsulfonyl-2-(substituted-methyl) propanoic acid derivatives as matrix metalloproteinase inhibitora
US20020006920A1 (en) * 1999-07-22 2002-01-17 Robinson Ralph Pelton Arylsulfonylamino hydroxamic acid derivatives
US6266453B1 (en) 1999-07-26 2001-07-24 Computerized Medical Systems, Inc. Automated image fusion/alignment system and method
DK1078923T3 (en) * 1999-08-02 2006-07-10 Hoffmann La Roche Process for the preparation of benzothiophene derivatives
EP1202733B1 (en) * 1999-08-12 2005-10-05 Pharmacia Italia S.p.A. 3(5)-amino-pyrazole derivatives, process for their preparation and their use as antitumor agents
JP3710964B2 (en) 1999-08-26 2005-10-26 富士通株式会社 Display device layout design method
SE9904044D0 (en) 1999-11-09 1999-11-09 Astra Ab Compounds
US6525202B2 (en) 2000-07-17 2003-02-25 Wyeth Cyclic amine phenyl beta-3 adrenergic receptor agonists
WO2002014262A1 (en) 2000-08-11 2002-02-21 Kaken Pharmaceutical Co.,Ltd. 2,3-diphenylpropionic acid derivatives or their salts, medicines or cell adhesion inhibitors containing the same, and their usage
US20020065219A1 (en) * 2000-08-15 2002-05-30 Naidu B. Narasimhulu Water soluble thiazolyl peptide derivatives
US20020091107A1 (en) * 2000-09-08 2002-07-11 Madar David J. Oxazolidinone antibacterial agents
WO2002020515A1 (en) 2000-09-08 2002-03-14 Abbott Laboratories Oxazolidinone antibacterial agents
EP1191024A1 (en) 2000-09-22 2002-03-27 Harald Tschesche Thiadiazines and their use as inhibitors of metalloproteinases
SE0100903D0 (en) * 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
KR20030082990A (en) * 2001-03-15 2003-10-23 아스트라제네카 아베 Metalloproteinase Inhibitors
SE0100902D0 (en) * 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
US6890915B2 (en) * 2001-05-25 2005-05-10 Bristol-Myers Squibb Pharma Company Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
GB0114004D0 (en) 2001-06-08 2001-08-01 Glaxo Group Ltd Chemical compounds
SE0103710D0 (en) 2001-11-07 2001-11-07 Astrazeneca Ab Compounds
CA2486350A1 (en) 2002-06-05 2003-12-24 Kaneka Corporation Process for producing optically active .alpha.-methylcysteine derivative
SE0202539D0 (en) * 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
SE0202692D0 (en) 2002-09-11 2002-09-11 Astrazeneca Ab Compounds
SE0202693D0 (en) 2002-09-11 2002-09-11 Astrazeneca Ab Compounds
GB0221246D0 (en) * 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
GB0221250D0 (en) 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
US6890913B2 (en) * 2003-02-26 2005-05-10 Food Industry Research And Development Institute Chitosans
US20040266832A1 (en) 2003-06-26 2004-12-30 Li Zheng J. Crystal forms of 2-(3-difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl pyridine
TWI220073B (en) * 2003-07-24 2004-08-01 Au Optronics Corp Method for manufacturing polysilicon film
SE0401762D0 (en) 2004-07-05 2004-07-05 Astrazeneca Ab Novel compounds
SE0401763D0 (en) * 2004-07-05 2004-07-05 Astrazeneca Ab Compounds
US7648992B2 (en) * 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
SE0403086D0 (en) * 2004-12-17 2004-12-17 Astrazeneca Ab Compounds
SE0403085D0 (en) * 2004-12-17 2004-12-17 Astrazeneca Ab Novel componds
TW200800954A (en) 2006-03-16 2008-01-01 Astrazeneca Ab Novel crystal modifications
TW200740769A (en) 2006-03-16 2007-11-01 Astrazeneca Ab Novel process
TW200831488A (en) * 2006-11-29 2008-08-01 Astrazeneca Ab Novel compounds

Also Published As

Publication number Publication date
HUP0400202A2 (en) 2004-08-30
EE200300445A (en) 2003-12-15
EP1370556B1 (en) 2006-07-19
CN1962641B (en) 2012-07-04
CZ20032500A3 (en) 2004-02-18
RU2285695C2 (en) 2006-10-20
SK287766B6 (en) 2011-09-05
NZ528106A (en) 2005-03-24
HK1059932A1 (en) 2004-07-23
HUP0400327A3 (en) 2005-06-28
RU2003127733A (en) 2005-03-20
MXPA03008181A (en) 2003-12-12
NO20034045L (en) 2003-11-10
ES2357138T3 (en) 2011-04-19
SI1370556T1 (en) 2006-10-31
HUP0400202A3 (en) 2004-10-28
US20040127528A1 (en) 2004-07-01
CY1107525T1 (en) 2013-03-13
ES2352246T3 (en) 2011-02-16
CA2440630C (en) 2011-09-27
NO20034045D0 (en) 2003-09-12
ES2267986T3 (en) 2007-03-16
IL157657A0 (en) 2004-03-28
DE60238794D1 (en) 2011-02-10
CN1509286A (en) 2004-06-30
DE60213216D1 (en) 2006-08-31
HK1091492A1 (en) 2007-01-19
AU2002237626B2 (en) 2007-05-17
JP2004523583A (en) 2004-08-05
CN1304377C (en) 2007-03-14
CN1509272A (en) 2004-06-30
WO2002074751A1 (en) 2002-09-26
HUP0400327A2 (en) 2005-01-28
US20080171882A1 (en) 2008-07-17
KR20030082989A (en) 2003-10-23
ATE493406T1 (en) 2011-01-15
NO20034044D0 (en) 2003-09-12
CZ20032497A3 (en) 2004-02-18
SK10962003A3 (en) 2004-03-02
DE60213216T2 (en) 2007-07-12
UA78502C2 (en) 2007-04-10
IS6946A (en) 2003-09-10
ZA200306737B (en) 2004-11-29
KR20080071210A (en) 2008-08-01
PT1370556E (en) 2006-11-30
AR035443A1 (en) 2004-05-26
EP1676846A3 (en) 2006-07-26
RU2293729C2 (en) 2007-02-20
WO2002074748A8 (en) 2004-04-22
ATE484496T1 (en) 2010-10-15
WO2002074748A1 (en) 2002-09-26
MXPA03008177A (en) 2003-12-12
WO2002074767A1 (en) 2002-09-26
US7427631B2 (en) 2008-09-23
DK1370556T3 (en) 2006-10-30
SE0100902D0 (en) 2001-03-15
EP1370537A1 (en) 2003-12-17
EP1370556A1 (en) 2003-12-17
BR0207983A (en) 2004-06-15
US7754750B2 (en) 2010-07-13
AR035695A1 (en) 2004-06-23
JP5140058B2 (en) 2013-02-06
ZA200306734B (en) 2004-11-29
SK10952003A3 (en) 2004-05-04
US20110003853A1 (en) 2011-01-06
EE05431B1 (en) 2011-06-15
PL364706A1 (en) 2004-12-13
EP1676846B1 (en) 2010-12-29
NO20034044L (en) 2003-11-10
MY136789A (en) 2008-11-28
JP2010077137A (en) 2010-04-08
BR0207984A (en) 2004-06-15
PL205315B1 (en) 2010-04-30
US7368465B2 (en) 2008-05-06
SK287834B6 (en) 2011-12-05
CA2440631A1 (en) 2002-09-26
HUP0400194A3 (en) 2004-10-28
US20080306065A1 (en) 2008-12-11
PL365099A1 (en) 2004-12-27
NO20034042D0 (en) 2003-09-12
EP1676846A2 (en) 2006-07-05
US8153673B2 (en) 2012-04-10
CA2440473A1 (en) 2002-09-26
ZA200306732B (en) 2004-11-29
NO326087B1 (en) 2008-09-15
CA2440630A1 (en) 2002-09-26
IS6943A (en) 2003-09-09
NZ528107A (en) 2005-06-24
ATE333454T1 (en) 2006-08-15
US20040106659A1 (en) 2004-06-03
KR20030082986A (en) 2003-10-23
EE200300451A (en) 2003-12-15
RU2003127734A (en) 2005-03-20
NZ528140A (en) 2005-02-25
US7666892B2 (en) 2010-02-23
CZ20032499A3 (en) 2004-03-17
AU2002237632B2 (en) 2007-05-10
RU2003127735A (en) 2005-03-20
RU2288228C2 (en) 2006-11-27
KR20030082987A (en) 2003-10-23
CN101602731A (en) 2009-12-16
UA77408C2 (en) 2006-12-15
BR0208104A (en) 2004-03-02
NO327114B1 (en) 2009-04-27
JP2004527515A (en) 2004-09-09
EP1370534A1 (en) 2003-12-17
CN100526307C (en) 2009-08-12
SK10922003A3 (en) 2004-05-04
EE200300449A (en) 2003-12-15
MXPA03008191A (en) 2004-01-29
IL157656A0 (en) 2004-03-28
CN1962641A (en) 2007-05-16
KR100886315B1 (en) 2009-03-04
DE60237965D1 (en) 2010-11-25
EP1370537B1 (en) 2010-10-13
UA77667C2 (en) 2007-01-15
US7625934B2 (en) 2009-12-01
IL157652A (en) 2010-11-30
IL157652A0 (en) 2004-03-28
HK1060121A1 (en) 2004-07-30
US20100273849A1 (en) 2010-10-28
KR100879905B1 (en) 2009-01-21
HUP0400194A2 (en) 2004-07-28
IS6942A (en) 2003-09-09
CN1269804C (en) 2006-08-16
JP2004523581A (en) 2004-08-05
US20080262045A1 (en) 2008-10-23
WO2002074767A8 (en) 2004-04-22
ZA200306731B (en) 2004-11-29
MY136141A (en) 2008-08-29
CN1509276A (en) 2004-06-30
PL364707A1 (en) 2004-12-13
EE05364B1 (en) 2010-12-15
NO20034042L (en) 2003-11-10
IL157656A (en) 2010-11-30
JP4390457B2 (en) 2009-12-24
US20040138276A1 (en) 2004-07-15

Similar Documents

Publication Publication Date Title
CA2440473C (en) Metalloproteinase inhibitors
AU2002237632A1 (en) Metalloproteinase inhibitors
RU2293730C2 (en) Inhibitors of metalloproteinases, their using and pharmaceutical compositions based on thereof
WO2002074750A1 (en) Metalloproteinase inhibitors
AU2002237626A1 (en) Metalloproteinase inhibitors
AU2002237629A1 (en) Metalloproteinase inhibitors
AU2002237627A1 (en) Metalloproteinase inhibitors
AU2002237628A1 (en) Metalloproteinase inhibitors

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20140313