WO2002074767A1 - Metalloproteinase inhibitors - Google Patents

Metalloproteinase inhibitors Download PDF

Info

Publication number
WO2002074767A1
WO2002074767A1 PCT/SE2002/000472 SE0200472W WO02074767A1 WO 2002074767 A1 WO2002074767 A1 WO 2002074767A1 SE 0200472 W SE0200472 W SE 0200472W WO 02074767 A1 WO02074767 A1 WO 02074767A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
apci
dialkylamino
alkylamino
heteroaryl
Prior art date
Application number
PCT/SE2002/000472
Other languages
French (fr)
Other versions
WO2002074767A8 (en
Inventor
Anders Eriksson
Matti Lepistö
Michael Lundkvist
Magnus Munck af Rosenschöld
Pavol Zlatoidsky
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
Priority to BR0208104-0A priority Critical patent/BR0208104A/en
Priority to HU0400327A priority patent/HUP0400327A3/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to SK1096-2003A priority patent/SK287766B6/en
Priority to AU2002237626A priority patent/AU2002237626B2/en
Priority to NZ528106A priority patent/NZ528106A/en
Priority to MXPA03008191A priority patent/MXPA03008191A/en
Priority to JP2002573776A priority patent/JP2004527515A/en
Priority to KR1020037011987A priority patent/KR100886315B1/en
Priority to SI200230386T priority patent/SI1370556T1/en
Priority to UA2003098171A priority patent/UA78502C2/en
Priority to US10/471,900 priority patent/US7427631B2/en
Priority to EP02704031A priority patent/EP1370556B1/en
Priority to EEP200300445A priority patent/EE05431B1/en
Priority to CA2440630A priority patent/CA2440630C/en
Priority to IL15765202A priority patent/IL157652A0/en
Priority to DE60213216T priority patent/DE60213216T2/en
Priority to PL02365099A priority patent/PL365099A1/en
Publication of WO2002074767A1 publication Critical patent/WO2002074767A1/en
Priority to IL157652A priority patent/IL157652A/en
Priority to IS6943A priority patent/IS6943A/en
Priority to NO20034045A priority patent/NO327114B1/en
Priority to HK04102796A priority patent/HK1059932A1/en
Publication of WO2002074767A8 publication Critical patent/WO2002074767A8/en
Priority to US11/928,040 priority patent/US7625934B2/en
Priority to US12/115,785 priority patent/US7754750B2/en
Priority to US12/830,763 priority patent/US20110003853A1/en

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

Definitions

  • the present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising these, as well as their use.
  • the compounds of this invention are inhibitors of one or more metalloproteinase enzymes.
  • Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N.M. Hooper (1994) FEBS Letters 354:1-6.
  • metalloproteinases examples include the matrix metalloproteinases (MMPs) such as the coUagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP 12), enamelysin (MMP 19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM 10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.
  • MMPs matrix metalloproteinases
  • MMP1
  • 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).
  • TNF tumour necrosis factor
  • 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 conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of
  • 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 MMP 12 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.
  • MMPs such as MMP 12 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.
  • MMP 13, 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 MMP 13 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.,
  • 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.
  • MMP 13 plays a role in the turnover of other connective tissues.
  • MMP13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M. Stahle-Backdahl et al, (1997) Lab. Invest. 76(51:717-728: N. Johansson et al, (1997) Dev. Dyn.
  • 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):96-1011.
  • MMP9 (Gelatinase B; 92kDa TypelV 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. ppl l5 - 148. Academic Press. ISBN 0-12-545090-7). The following points are drawn from that review by T.H. Vu & Z. Werb (1998).
  • MMP9 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.
  • TIMP-1 tissue Inhibitor of Metalloproteinases -1
  • 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.
  • MMP-9 release measured using enzyme immunoassay, was significantly enhanced in fluids and in AM supemantants from untreated asthmatics compared with those from other populations [Am. J. Resp. Cell & Mol. Biol., Nov 1997, 17 (5):583-5911. 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.
  • MMP-8 collagenase-2, neutrophil collagenase
  • 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 [Uitto 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.
  • Zinc binding groups in known MMP inhibitors include carboxylic acid groups, hydroxamic acid groups, sulfhydryl or mercapto, etc.
  • Whittaker M. et al discuss the following MMP inhibitors:
  • the above compound entered clinical development. It has a mercaptoacyl zinc binding group, a trimethylhydantoinylethyl group at the PI position and a leucinyl-tert- butyllglycinyl backbone.
  • the above compound has a mercaptoacyl zinc binding group and an imide group at the PI position.
  • 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 PI position.
  • the above compound is a phthalimido derivative that inhibits coUagenases. It has a non- peptidic succinyl hydroxamate zinc binding group and a cyclic imide group at PI .
  • Whittaker M. et al also discuss other MMP inhibitors having a PI cyclic imido group and various zinc binding groups (succinyl hydroxamate, carboxylic acid, thiol group, phosphorous-based group).
  • R 4-N02, 4-OMe, 2-N02,
  • 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):
  • the compounds are metalloproteinase inhibitors having a metal binding group that is not found in known metalloproteinase inhibitors.
  • the compounds of this invention have beneficial potency, selectivity and/or pharmacokinetic properties.
  • the metalloproteinase inhibitor compounds of the invention comprise a metal binding group and one or more other functional groups or side chains characterised in that the metal binding group has the formula (k)
  • X is selected from NRl, O, S;
  • Yl and Y2 are independently selected from O, S; Rl is selected from H, alkyl, haloalkyl;
  • Any alkyl groups outlined above may be straight chain or branched; any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl.
  • a metalloproteinase inhibitor compound is a compound that inhibits the activity of a metalloproteinase enzyme (for example, an MMP).
  • a metalloproteinase enzyme for example, an MMP
  • 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.
  • 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 l-H,3-H-imidazolidine-2,4-dione.
  • X is selected from NRl , O, S;
  • Yl and Y2 are independently selected from O, S;
  • Z is selected from SO, SO 2 ; m is 1 or 2;
  • A is selected from a direct bond, (Cl-6)alkyl, (Cl-6)haloalkyl, or (Cl-6)heteroalkyl containing a hetero group selected from N, O, S, SO, SO2 or containing two hetero groups selected from N, O, S, SO, SO2 and separated by at least two carbon atoms;
  • Rl is selected from H, (Cl-3)alkyl, haloalkyl
  • Each R2 and R3 is independently selected from H, halogen (preferably fluorine), alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl- 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, alkyl-cycloalkyl, alkyl- heterocycloalkyl, alkyl- heterocycloalkyl;
  • Each R4 is independently selected from H, halogen (preferably fluorine), (Cl-3)alkyl or haloalkyl;
  • R2 and R3 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, arylaminosulfon, amino, N-alkylamino, N,N-dialkylamino, amido, N-alkylamido, N,N- dialkylamido, cyano, sulfonamino, alkylsulfonamino, arylsulfonamino, amidino, N- aminosulfon-amidino, guanidino, N-
  • 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, alkylcarboxy amino, 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
  • Any heterocycloalkyl or heteroaryl group outlined above contains one or more hetero groups independently selected from N, O, S, SO, SO2; 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 (Cl-6)alkyl.
  • Preferred compounds of the formula I are those wherein any one or more of the following apply: X is NRl;
  • Z is SO or SO; especially Z is SO ;
  • At least one of Yl and Y2 is O; especially both Yl and Y2 are O; m is 1;
  • Rl is H, (Cl-3) alkyl, (Cl-3) haloalkyl; especially Rl is H, (Cl-3)alkyl; most especially Rl is H;
  • R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; especially R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl.
  • R3 and/or R4 is H; R3 and/or R4 is methyl;
  • R5 comprises one, two or three optionally substituted aryl or heteroaryl 5 or 6 membered rings
  • 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.
  • the invention further provides compounds of the formula II
  • each of Gl, G2 and G4 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, alylamide, 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, aryloxy, heteroaryloxy, carbamate;
  • Z is SO 2;
  • B and F is independently selected from a direct bond, O, (Cl-6)alkyl, (Cl-
  • R2 is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl;
  • R3 and R4 are independently selected from H or (Cl-3)alkyl
  • R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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;
  • Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (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, O, S, SO, SO2;
  • any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl.
  • Preferred compounds of the formula II include those wherein R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl.
  • the invention further provides compounds of the formula Ila
  • each of Gl 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, 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, aryloxy, heteroaryloxy, carbamate;
  • B is selected from a direct bond, O, (Cl- ⁇ )alkyl, (Cl-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl;
  • R2 is selected from H, (Cl-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of formula III
  • C and D are independently selected from a direct bond, H, (Cl-C ⁇ )alkyl, (Cl-
  • 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;
  • R2 is substituted with halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N
  • R3 and R4 are independently selected from H or (Cl-3)alkyl;
  • R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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;
  • Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (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, O, S, SO, SO2;
  • any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl.
  • Preferred compounds of the formula Ila are those wherein one or more of the following apply: B is selected from a direct bond, O, CO, S, alkynyl; especially B is a direct bond, O, S, or alkynyl;
  • R2 is selected from H, (Cl-6)alkyl, aryl-(Cl-6)alkyl or heteroaryl-(Cl-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, carbamate, cyano, sulfonamino, alkylsulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidin
  • G2 is a nitrogen containing six-membered ring; Gl is para substituted.
  • Particularly preferred compounds of formula Ila are those wherein each of R3 and R4 is H.
  • particular compounds of the invention include compounds of formula Ila wherein B is a direct bond, O, S or alkynyl; and R2 is selected from H, (Cl-6)alkyl, aryl- (Cl-6)alkyl or heteroaryl-(Cl-6)alkyl optionally substituted with cyckloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, alkoxy, aryloxy, 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,
  • Particularly preferred compounds of the invention are those of Formula lib:
  • G2 is optionally substituted piperidine or piperazine, and Gl, B, and R2 are as described for Formula Ila.
  • G2 is unsubstituted and Gl is optionally substituted, preferably Gl is para substituted.
  • Suitable values for R2 include the following:
  • Suitable values for R5 include the following:
  • X' bond, O, CH2, CHF, CF2, S, S02, CO
  • R F, CI, Br, CF3, CF30, CH30, OH, CF3CH2
  • 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 be separated into individual optically active forms using known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pi 04- 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 compounds of the invention are metalloproteinase inhibitors, in particular they are inhibitors of MMP 12.
  • metalloproteinase inhibitors in particular they are inhibitors of MMP 12.
  • Certain compounds of the invention are of particular use as inhibitors of MMP 13 and/or MMP9 and/or MMP8 and/or MMP3.
  • Compounds of the invention show a favourable selectivity profile. Whilst we do not wish to be bound by theoretical considerations, the compounds of the invention are believed to show selective inhibition for any one of the above indications relative to any MMP1 inhibitory activity, by way of non-limiting example they may show 100-1000 fold selectivity over any MMP1 inhibitory activity.
  • the compounds of the invention may be provided as pharmaceutically acceptable salts. These include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid.
  • 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.
  • bases 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.
  • esters may also be provided as in vivo hydrolysable esters.
  • esters are pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound.
  • 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.
  • a metalloproteinase inhibitor compound of the invention (a compound of the formula I or II, Ila or lib) 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.
  • the present invention provides a pharmaceutical composition which comprises a compound of the invention (a compound of the formula I or II, Ila or lib) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and pharmaceutically acceptable carrier.
  • a pharmaceutical composition 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.
  • 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.
  • 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.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • 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.
  • MMP3 especially use in the treatment of a disease or condition mediated by MMP 12 or MMP9; most especially use in the treatment of a disease or condition mediated by MMP 12.
  • a compound of the formula II, Ila or lib 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 MMP9 and/or MMP8 and/or MMP3; especially MMP 12 or MMP9; most especially MMP 12).
  • 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.
  • 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.
  • 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, Ila or lib (or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof).
  • a compound of the formula II, Ila or lib 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.
  • COPD chronic obstructive pulmonary diseases
  • 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
  • the present invention provides a process for preparing a compound of the formula I or II, Ila, lib or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as described in (a) to (d) 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.
  • the reaction is preferably performed in suitable solvent optionally in the presence of base for 1 to 24h at ambient to reflux temperature.
  • solvents such as 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 primary and secondary amines are previously described in the literature, and the variations of the conditions will be evident for those skilled in the art.
  • reaction is preferably performed in the presence of base such as diethyl isopropyl amine or cesium carbonate and in the presence of a suitable solvent e.g DMF.
  • base such as diethyl isopropyl amine or cesium carbonate
  • a suitable solvent e.g DMF.
  • the compounds under process (b) may be prepared in the same manner as in process (b), by reacting the compounds of formula VI and VII, but in which K in compound VI is the sulfhydryl (SH) or a hydroxyl group and G in formula VII represents a leaving group.
  • ammonium and cyanide salts in protic solvents, preferably in the presence of excess ammonium carbonat and potassium cyanide in ethanol in a sealed vessel at 40-80 C for 4- 24 hours.
  • ketones of formula XI are conveniently prepared by treating sulfonamides of formula XII in which R3 is H and R5 is as described in formula I, with excess strong base and then treatment with esters of formula XIII , in which R is an alkyl or aryl residue and R2 are as described for formula I, in non-protic solvents.
  • Preferrable conditions are 2-3 equivalents of lithium bases like lithium dusopropylamide or lithium hexamethyldisilazane or butyl lithium in dried etheral solvents like tetrahydrofurane.
  • ketones of formula XI in which R3 and R4 are each alkyl or form a ring, R5 is aryl or heteroaryl and R2 is alkyl or aryl, can also be prepared by treating sulfinates of formula XIV in which R5 is aryl or heteroaryl as described in formula I, with a base such as tetrabutylammonium bromide and a ketone of formula XV in which R2 is alkyl or aryl (Crandall et al J. Org. Chem. 1985, (8) 50, 1327-1329).
  • R3 and R4 are then introduced by reaction with alkyl halides or alkyl dihalides.
  • the reaction is preferably performed in the presence of base such as potassium carbonate or caesium carbonate and in the presence of a suitable solvent e.g. DMF or DMSO at 50-100°C.
  • the compounds of the invention may be evaluated for example in the following 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: MMP 12 (50 ng/ml final concentration) is incubated for 30 minutes at RT in assay buffer (0.1M Tris- HC1, pH 7.3 containing 0.1M NaCl, 20mM CaCl 2 , 0.040 mM ZnCl 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.
  • assay buffer 0.1M Tris- HC1, pH 7.3 containing 0.1M NaCl, 20mM CaCl 2 , 0.040 mM ZnCl and 0.05% (w/v) Brij 35
  • % Inhibition is equal to the [Fluorescence p
  • Recombinant human proMMP13 may be expressed and purified as described by Knauper et al. [V. Knauper et al, (1996) The Biochemical Journal 271:1544-1550 (1996)].
  • the purified enzyme can be used to monitor inhibitors of activity as follows: purified proMMP13 is activated using ImM amino phenyl mercuric acid (APMA), 20 hours at 21°C; the activated MMP13 (11.25ng per assay) is incubated for 4-5 hours at 35°C in assay buffer (0.1M Tris-HCl, pH 7.5 containing 0.1M NaCl, 20mM CaC12, 0.02 mM ZnCl and 0.05% (w/v) Brij 35) using the synthetic substrate 7-methoxycoumarin-4- yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg.
  • % Inhibition is equal to the [Fluorescence p ⁇ us inhibitor - Fluorescencebackground] divided by the [Fluorescenceminus inhibitor - Fluorescencebackground]-
  • the ability of the compounds to inhibit proTNF ⁇ convertase enzyme may be assessed using a partially purified, isolated enzyme assay, the enzyme being obtained from the membranes of THP-1 as described by K. M. Mohler et al, (1994) Nature 370:218-220.
  • the purified enzyme activity and inhibition thereof is determined by incubating the partially purified enzyme in the presence or absence of test compounds using the substrate 4',5'-Dimethoxy-fluoresceinyl Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3- succinimid-l-yl)-fluorescein)-NH 2 in assay buffer (50mM Tris HCl, pH 7.4 containing 0.1 % (w/v) Triton X- 100 and 2mM CaCl 2 ), at 26°C for 18 hours. The amount of inhibition is determined as for MMP 13 except ⁇ ex 490nm and ⁇ em 530nm were used.
  • the substrate was synthesised as follows.
  • the peptidic part of the substrate was assembled on Fmoc- NH-Rink-MBHA-polystyrene resin either manually or on an automated peptide synthesiser by standard methods involving the use of Fmoc-amino acids and 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 1 and Pro 2 were double- coupled.
  • the dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane.
  • the dimethoxyfluoresceinyl-peptide was isolated by evaporation, trituration with diethyl ether and filtration.
  • the isolated peptide was reacted with 4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid.
  • the product was characterised by MALDI-TOF MS and amino acid analysis.
  • the activity of the compounds of the invention as inhibitors of aggrecan degradation may be assayed using methods for example based on the disclosures of E. C. Arner et al, (1998) Osteoarthritis and Cartilage 6:214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601 and the antibodies described therein.
  • the potency of compounds to act as inhibitors against coUagenases can be determined as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345.
  • the ability of the compounds of this invention to inhibit the cellular processing of TNF ⁇ 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 compounds of this invention to inhibit TNF ⁇ production is assessed in a human whole blood assay where LPS is used to stimulate the release of TNF ⁇ .
  • Heparinized (lOUnits/ml) human blood obtained from volunteers is diluted 1 :5 with medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160 ⁇ l) with 20 ⁇ l of test compound (triplicates), in DMSO or appropriate vehicle, for 30 min at 37°C in a humidified (5%CO 2 /95%air) incubator, prior to addition of 20 ⁇ l LPS (E. coli. 0111 :B4; final concentration lO ⁇ g/ml).
  • Each assay includes controls of diluted blood incubated with medium alone (6 wells/plate) or a known TNF ⁇ inhibitor as standard. The plates are then incubated for 6 hours at 37°C (humidified incubator), centrifuged
  • 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 10U heparin.
  • a soluble formulation of compound such as 20% w/v DMSO, 60% w/v PEG400
  • Plasma fractions are obtained following centrifugation and the plasma proteins precipitated with acetonitrile (80% w/v final concentration). After 30 mins at -20°C the plasma proteins are sedimented by centrifugation and the supernatant fraction is evaporated to dryness using a Savant speed vac. The sediment is reconstituted in assay buffer and subsequently analysed for compound content using the synthetic substrate assay. Briefly, a compound concentration-response curve is constructed for the compound undergoing evaluation. Serial dilutions of the reconstituted plasma extracts are assessed for activity and the amount of compound present in the original plasma sample is calculated using the concentration-response curve taking into account the total plasma dilution factor.
  • 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 TNF ⁇ production by LPS-stimulated human blood.
  • the rat plasma 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 lO ⁇ g/ml
  • Control wells are incubated with 25 ⁇ l of medium alone. Plates are then centrifuged for 10 min at 2000 rpm and 200 ⁇ l of the supematants are transferred to a 96 well plate and frozen at -20°C for subsequent analysis of TNF concentration by ELISA.
  • Activity of a compound as an anti-cancer agent may be assessed essentially as described in I. J. Fidler (1978) Methods in Cancer Research 15:399-439, using for example the B16 cell line (described in B. Hibner et al, Abstract 283 p75 10th NCI-EORTC Symposium, Amsterdam June 16 - 19 1998).
  • Activity of a compound as an anti-emphysema agent may be assessed essentially as described in Hautamaki et al (1997) Science, 277: 2002.
  • the starting materials were prepared as follows:
  • the starting materials were prepared as follows:
  • the starting materials were prepared as follows:
  • the starting materials were prepared as follows:
  • the salt was treated with aqueous sodium hydroxide solution and the base was taken up in dichloro-methane. Drying with Na 2 SO 4 , filtering and concentrating the organic phase gave the title compound as an offwhite solid.
  • the starting materials were prepared as follows:
  • Hydantoins with the following general structure were synthesised (where E is carbon or a heteroatom):
  • the title compound was prepared as described in the synthesis of 4-(4-Fluoro-phenyl)-l- methanesulfonyl-piperidine.
  • the title compound was prepared as described in the synthesis of 4-(4-Fluoro-phenyl)-l- methanesulfonyl-piperidine.
  • the ketone l-[4-4(Fluorophenyl)-piperidine-l-sulfonyl]-propan-2-one (68mg; 0.23mmol), KCN (30mg; 0.46mmol) and (NH 4 ) 2 CO 3 (11 lmg; l .l ⁇ mmol) was suspended in 50% EtOH/H 2 ⁇ (8mL) in a 22 mL sealed tube and heated to 70° C, a solution was formed. The mixture was stirred at 70° C for 17 h.
  • the starting materials were prepared as follows:
  • Piperazine (4 eq) is charged in the reaction vessel as a solid. At room temperature pyridine (1.43 vols) is added to the vessel followed by toluene (2.14 vols). The final slurry is stirred and heated to reflux at 120°C to obtain a complete solution. To a separate vessel charge
  • DCP 2,5-dichloropyridine
  • Toluene (1.43 vols) to dissolve the solid.
  • the dissolution is endothermic, and it is necessary to warm up the solution to ⁇ 30°C to get complete solution.
  • the solution containing DCP is then slowly discharged into the reaction vessel over 5hours. At this point the remaining amount of DCP should be about 20%.
  • the reaction is left refluxing overnight to reach completion.
  • the reaction mixture is allowed to cool to room temperature, then water is added (6 vols).
  • the enantiomers were collected and analysed on a CHIRALCEL OD-H, 0.46x25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambient temperature, 220nm.
  • the title compound was prepared as described in the synthesis of l-(l,l'-biphenyl-4- ylsulfonyl)propan-2-one.
  • Reagents and conditions a) KCN, NH 4 CO 3 , EtOH/H 2 0, +90°C, 3h. b) Chiral separation, CHIRALPAK AD, Methanol as eluent. c) Cl 2 (g), AcOH/H 2 0, ⁇ +15°C, 25min. d) Diisopropylethylamine, THF. -20°C, 30 min.
  • the starting materials were prepared as follows:
  • 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 (Na 2 SO 4 ), 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%).
  • the title compound was prepared by chiral separation of the racemic material using a
  • 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.
  • Pd(PPh 3 ) 4 (87 mg, 0.0075mmol), LiCl (190 mg, 4.5 mmol), tert-butyl 4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -3,6-dihydropyridine-l(2H)-carboxylate (0.50 g 1.5 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.43 g, 2.1 mmol) and aq Na 2 CO 3 (2 mL, 2N solution) were mixed in 5.2 mL DME and heated at 85 °C for 3h followed by-cooling to room temperature and concentrated under reduced pressure.
  • the starting material was prepared as follows:
  • the starting material was prepared as follows:
  • 4-(4-Iodophenyl)piperazine-l -carboxylic acid tert-butyl ester (0.272 g, 0.70 mmoles), 3- pyridylboronic acid (0.078 g, 0.64 mmoles), tetrakis(triphenylphosphine)palladium (0.024 g, 0.02 mmoles), 1 M sodium hydrogencarbonate (1.0 mL) and 1 ,2-dimethoxyethane (1.5 mL) were stirred under nitrogen at 84° C for 3 hours, taken up in ethyl acetate and washed with water and brine.
  • the polymer was filtered off, using a short plug of silica with Toluene/EtOAc (5:1) as eluent.
  • the volume of the combined fractions was reduced by rotary evaporation and the solution was washed with 5% aqueous KOH and water, dried over ⁇ a 2 SO 4 and the solvent removed in vacuo.
  • the resulting white powder was dissolved in THF (10 ml) and cone. HCl (10 ml) and stirred at ambient temperature for 1 hr. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene, affording 230 mg (57%) of the title compound as a white powder.
  • LC-MS (APCI) m/z 235.1 (MH+).
  • the starting material was prepared as follows:
  • the amine was prepared in the same way as described in the synthesis of 2-Chloro-5- methoxy-pyridine 1 -oxide.
  • the starting material was prepared as follows:
  • the startingmaterial was prepared as follows:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Otolaryngology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Emergency Medicine (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Psychiatry (AREA)
  • Vascular Medicine (AREA)
  • Obesity (AREA)

Abstract

Compounds of the formula (I) wherein z is SO2 or SO, useful as metalloproteinase inhibitors, especially as inhibitors of MMP12.

Description

Metalloproteinase inhibitors
The present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising these, as well as their use.
The compounds of this invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N.M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMPs) such as the coUagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP 12), enamelysin (MMP 19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM 10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other 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 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 MMP 12 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 MMP 12 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 102:081 36-39 Suppl. S, Oct 31, 2000].
MMP 13, 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 MMP 13 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):499-5081 and epidermal tumours [K. Airola et al, (1997) J. Invest. Dermatol. 109(2):225-231]. 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 MMP13'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(51:717-728: 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(31:761-768: 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(4): 701-710]. MMP13 has also been implicated in chronic adult periodontitis as it has been localised to the epithelium of chronically inflamed mucosa human gingival tissue [V. J. Uitto et al, (1998) Am. J. Pathol 152(6}: 1489- 1499] and in remodelling of the collagenous matrix in chronic wounds [M. Vaalamo et al, (1997) J. Invest. Dermatol. 109(1):96-1011.
MMP9 (Gelatinase B; 92kDa TypelV 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. ppl l5 - 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 supemantants from untreated asthmatics compared with those from other populations [Am. J. Resp. Cell & Mol. Biol., Nov 1997, 17 (5):583-5911. 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. 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 [Uitto 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 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:
Figure imgf000007_0001
The above compound entered clinical development. It has a mercaptoacyl zinc binding group, a trimethylhydantoinylethyl group at the PI position and a leucinyl-tert- butyllglycinyl backbone.
Figure imgf000008_0001
The above compound has a mercaptoacyl zinc binding group and an imide group at the PI position.
Figure imgf000008_0002
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 PI position.
Figure imgf000008_0003
The above compound is a phthalimido derivative that inhibits coUagenases. It has a non- peptidic succinyl hydroxamate zinc binding group and a cyclic imide group at PI .
Whittaker M. et al also discuss other MMP inhibitors having a PI cyclic imido group and various zinc binding groups (succinyl hydroxamate, carboxylic acid, thiol group, phosphorous-based group).
Figure imgf000009_0001
The above compounds appear to be good inhibitors of MMP8 and MMP9 (PCT patent applications WO9858925, WO9858915). 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:
Figure imgf000009_0002
Czech patent numbers 151744 (19731119) and 152617 (1974022) describe the synthesis and the anticonvulsive activity of the following compounds:
Figure imgf000010_0001
R= 4-N02, 4-OMe, 2-N02,
US patent number 3529019 (19700915) describes the following compounds used as intermediates:
Figure imgf000010_0002
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):
Figure imgf000010_0003
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 MMP 12 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 group and one or more other functional groups or side chains characterised in that the metal binding group has the formula (k)
Figure imgf000011_0001
wherein X is selected from NRl, O, S;
Yl and Y2 are independently selected from O, S; Rl is selected from H, alkyl, haloalkyl;
Any alkyl groups outlined above may be straight chain or branched; any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl.
A metalloproteinase inhibitor compound is a compound that inhibits the activity of a 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 l-H,3-H-imidazolidine-2,4-dione. In a first aspect of the invention we now provide compounds of the formula I
Figure imgf000012_0001
wherein X is selected from NRl , O, S;
Yl and Y2 are independently selected from O, S;
Z is selected from SO, SO2; m is 1 or 2;
A is selected from a direct bond, (Cl-6)alkyl, (Cl-6)haloalkyl, or (Cl-6)heteroalkyl containing a hetero group selected from N, O, S, SO, SO2 or containing two hetero groups selected from N, O, S, SO, SO2 and separated by at least two carbon atoms;
Rl is selected from H, (Cl-3)alkyl, haloalkyl;
Each R2 and R3 is independently selected from H, halogen (preferably fluorine), alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl- 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, alkyl-cycloalkyl, alkyl- heterocycloalkyl;
Each R4 is independently selected from H, halogen (preferably fluorine), (Cl-3)alkyl or haloalkyl;
Each of the R2 and R3 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, 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-l,l- diamin, carboxy, alkyl-carboxy, nitro, carbamate; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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;
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, alkylcarboxy amino, 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, carbamate; when R5 is a bicyclic or tricyclic group, each ring structure is joined to the next ring structure by a direct bond, by -O-, by (Cl-ό)alkyl, by (Cl-6)haloalkyl, by (Cl-6)heteroalkyl, by (Cl-6)alkenyl, by (Cl-6)alkynyl, by sulfone, by CO, by NCO, by CON, by NH, by S, by C(OH) or is fused to the next ring structure; Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (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, O, S, SO, SO2; 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 (Cl-6)alkyl.
Preferred compounds of the formula I are those wherein any one or more of the following apply: X is NRl;
Z is SO or SO; especially Z is SO ;
At least one of Yl and Y2 is O; especially both Yl and Y2 are O; m is 1;
Rl is H, (Cl-3) alkyl, (Cl-3) haloalkyl; especially Rl is H, (Cl-3)alkyl; most especially Rl is H;
R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl; especially R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl. R3 and/or R4 is H; R3 and/or R4 is methyl;
R5 comprises one, two or three optionally substituted aryl or heteroaryl 5 or 6 membered rings;
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. The invention further provides compounds of the formula II
Figure imgf000015_0001
wherein each of Gl, G2 and G4 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, alylamide, 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, aryloxy, heteroaryloxy, carbamate;
Z is SO2; Each of B and F is independently selected from a direct bond, O, (Cl-6)alkyl, (Cl-
6)heteroalkyl, alkynyl, CO, NCO, CON, NH, S;
R2 is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl;
R3 and R4 are independently selected from H or (Cl-3)alkyl;
Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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; Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (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, O, S, SO, SO2;
Any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl.
Preferred compounds of the formula II include those wherein R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl.
The invention further provides compounds of the formula Ila
Figure imgf000016_0001
wherein each of Gl 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, 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, aryloxy, heteroaryloxy, carbamate;
Z is SO2;
B is selected from a direct bond, O, (Cl-ό)alkyl, (Cl-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl;
R2 is selected from H, (Cl-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of formula III
Figure imgf000017_0001
C and D are independently selected from a direct bond, H, (Cl-Cό)alkyl, (Cl-
C6)haloalkyl, or (Cl-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 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, 2- nitroguanidino, carboxy, alkylcarboxy, carbamate;
R3 and R4 are independently selected from H or (Cl-3)alkyl; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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;
Any heteroalkyl group outlined above is a hetero atom-substituted alkyl containing one or more hetero groups independently selected from N, O, S, SO, SO2, (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, O, S, SO, SO2;
Any alkyl, alkenyl or alkynyl groups outlined above may be straight chain or branched; unless otherwise stated, any alkyl group outlined above is preferably (Cl-7)alkyl and most preferably (Cl-6)alkyl.
Preferred compounds of the formula Ila are those wherein one or more of the following apply: B is selected from a direct bond, O, CO, S, alkynyl; especially B is a direct bond, O, S, or alkynyl;
R2 is selected from H, (Cl-6)alkyl, aryl-(Cl-6)alkyl or heteroaryl-(Cl-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, carbamate, cyano, sulfonamino, alkylsulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2-nitroguanidino, 2-nitro-ethene-l,l-diamino, carboxy, alkylcarboxy, carbamate; Each of R3 and R4 is H;
G2 is a nitrogen containing six-membered ring; Gl is para substituted. Particularly preferred compounds of formula Ila are those wherein each of R3 and R4 is H.
For example, particular compounds of the invention include compounds of formula Ila wherein B is a direct bond, O, S or alkynyl; and R2 is selected from H, (Cl-6)alkyl, aryl- (Cl-6)alkyl or heteroaryl-(Cl-6)alkyl optionally substituted with cyckloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, alkoxy, aryloxy, 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, carbamate, carboxy, alkylcarboxy; and each of R3 and R4 is H.
Particularly preferred compounds of the invention are those of Formula lib:
Figure imgf000019_0001
wherein G2 is optionally substituted piperidine or piperazine, and Gl, B, and R2 are as described for Formula Ila.
In a compound of Formula lib, preferably G2 is unsubstituted and Gl is optionally substituted, preferably Gl is para substituted. Suitable values for R2 include the following:
Figure imgf000020_0001
Suitable values for R5 include the following:
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
X' = bond, O, CH2, CHF, CF2, S, S02, CO
X"= bond, CH2; CHF, CF2; S02, CO
R= F, CI, Br, CF3, CF30, CH30, OH, CF3CH2
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. 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 be separated into individual optically active forms using known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pi 04- 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 the invention 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.
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 the compounds of the the invention represents an independent and particular embodiment of the invention.
Certain compounds of the invention are of particular use as inhibitors of MMP 13 and/or MMP9 and/or MMP8 and/or MMP3. Compounds of the invention show a favourable selectivity profile. Whilst we do not wish to be bound by theoretical considerations, the compounds of the invention are believed to show selective inhibition for any one of the above indications relative to any MMP1 inhibitory activity, by way of non-limiting example they may show 100-1000 fold selectivity over any MMP1 inhibitory activity. The compounds of the invention may be provided as pharmaceutically acceptable salts. These include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine. They may also be provided as in vivo hydrolysable esters. These are pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl.
In order to use a metalloproteinase inhibitor compound of the invention (a compound of the formula I or II, Ila or lib) 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, Ila or lib) 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 MMP 12 and/or MMP13 and/or MMP9 and/or MMP8 and/or
MMP3; especially use in the treatment of a disease or condition mediated by MMP 12 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, Ila or lib 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 MMP9 and/or MMP8 and/or MMP3; especially MMP 12 or MMP9; most especially MMP 12).
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, Ila or lib (or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof). We also provide the use of a compound of the formula II, Ila or lib (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.
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, Ila, lib or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as described in (a) to (d) 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.
(a) Compounds of formula I in which Yl and Y 2 are each O, Z is SO2, R2 is as defined in formula I, A is a direct bond and R5 comprises a nitrogen directly attached to Z, or A is (Cl-6) N-alkyl, may be prepared by reacting a compound of the formula IV in which R5 is defined as in formula I with the known compounds of the formula V in which X and m are as defined in formula I:
Figure imgf000026_0001
iv v
The reaction 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 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 primary and secondary amines are previously described in the literature, and the variations of the conditions will be evident for those skilled in the art.
Synthesis of compounds of formula V is described in the literature and can be prepared from e.g. cystein or homocystein (Mosher,J.:J.Org.Chem.23,1257 (1958). Sulfonylchlorides of formula V, in which m=l, X=NR1(R1=H) and R2 is as described in formula I, are conveniently prepared by oxidative chlorination of compounds of formula Va, in which R2 is as described in formula I (Griffith, O.: J. Biol. Chem., 1983, 258, 3, 1591).
Figure imgf000026_0002
Va (b) Compounds of formula I in which Yl and Y2 are each O, Z is S, and X and R5 are as described in formula I may be prepared by reacting a compound of formula VI in which K is a leaving group (e.g chloride, or sulfonate ester) and R5 as described in formula I,
Figure imgf000027_0001
VI VII
with a compound of formula VII, in which G is a sulfhydryl (SH), X and m as described in formula I. The reaction is preferably performed in the presence of base such as diethyl isopropyl amine or cesium carbonate and in the presence of a suitable solvent e.g DMF.
Alternatively, the compounds under process (b) may be prepared in the same manner as in process (b), by reacting the compounds of formula VI and VII, but in which K in compound VI is the sulfhydryl (SH) or a hydroxyl group and G in formula VII represents a leaving group.
(c) Compounds of the formula I in which Yl and Y2 are each O, Z is SO2 or S(O), and X, A , and R5 are as described in formula I, may be prepared by oxidizing the final products described under process (b) and in which Z is S, with oxidizing agents like peroxide reagents, preferably m-chloroperbenzoic acid or oxone.
(d) Compounds of the formula I in which Yl and Y2 are each O, X is NR1(R1=H), m is 1, and R2, R3, R4, R5 are as described in formula I may be prepared by reacting a compound of formula XI in which R2, R3, R4, R5 and A are as described in formula I,
Figure imgf000028_0001
XI
with ammonium and cyanide salts in protic solvents, preferably in the presence of excess ammonium carbonat and potassium cyanide in ethanol in a sealed vessel at 40-80 C for 4- 24 hours.
The ketones of formula XI are conveniently prepared by treating sulfonamides of formula XII in which R3 is H and R5 is as described in formula I, with excess strong base and then treatment with esters of formula XIII , in which R is an alkyl or aryl residue and R2 are as described for formula I, in non-protic solvents. Preferrable conditions are 2-3 equivalents of lithium bases like lithium dusopropylamide or lithium hexamethyldisilazane or butyl lithium in dried etheral solvents like tetrahydrofurane.
Figure imgf000028_0002
The ketones of formula XI, in which R3 and R4 are each alkyl or form a ring, R5 is aryl or heteroaryl and R2 is alkyl or aryl, can also be prepared by treating sulfinates of formula XIV in which R5 is aryl or heteroaryl as described in formula I, with a base such as tetrabutylammonium bromide and a ketone of formula XV in which R2 is alkyl or aryl (Crandall et al J. Org. Chem. 1985, (8) 50, 1327-1329). R3 and R4 are then introduced by reaction with alkyl halides or alkyl dihalides. The reaction is preferably performed in the presence of base such as potassium carbonate or caesium carbonate and in the presence of a suitable solvent e.g. DMF or DMSO at 50-100°C.
Figure imgf000029_0001
XIV XV
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: MMP 12 (50 ng/ml final concentration) is incubated for 30 minutes at RT in assay buffer (0.1M Tris- HC1, pH 7.3 containing 0.1M NaCl, 20mM CaCl2, 0.040 mM ZnCl 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 λex 328nm and λem 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescencep|US inhibitor - Fluorescencebackground] divided by the [Fluorescencemimis inhibitor - Fluorescencebackground]-
Recombinant human proMMP13 may be expressed and purified as described by Knauper et al. [V. Knauper et al, (1996) The Biochemical Journal 271:1544-1550 (1996)]. The purified enzyme can be used to monitor inhibitors of activity as follows: purified proMMP13 is activated using ImM amino phenyl mercuric acid (APMA), 20 hours at 21°C; the activated MMP13 (11.25ng per assay) is incubated for 4-5 hours at 35°C in assay buffer (0.1M Tris-HCl, pH 7.5 containing 0.1M NaCl, 20mM CaC12, 0.02 mM ZnCl and 0.05% (w/v) Brij 35) using the synthetic substrate 7-methoxycoumarin-4- yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg.NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 328nm and λem 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescencepιus inhibitor - Fluorescencebackground] divided by the [Fluorescenceminus inhibitor - Fluorescencebackground]-
A similar protocol can be used for other expressed and purified pro MMPs using substrates and buffers conditions optimal for the particular MMP, for instance as described in C. Graham Knight et al, (1992) FEBS Lett. 296(3):263-266.
Adamalysin family including for example TNF convertase
The ability of the compounds to inhibit proTNFα convertase enzyme may be assessed using a partially purified, isolated enzyme assay, the enzyme being obtained from the membranes of THP-1 as described by K. M. Mohler et al, (1994) Nature 370:218-220. The purified enzyme activity and inhibition thereof is determined by incubating the partially purified enzyme in the presence or absence of test compounds using the substrate 4',5'-Dimethoxy-fluoresceinyl Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3- succinimid-l-yl)-fluorescein)-NH2 in assay buffer (50mM Tris HCl, pH 7.4 containing 0.1 % (w/v) Triton X- 100 and 2mM CaCl2), at 26°C for 18 hours. The amount of inhibition is determined as for MMP 13 except λex 490nm and λem 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. Ser1 and Pro2 were double- coupled. The following side chain protection strategy was employed; Ser1 (But), Gln5(Trityl), Arg8,12(Pmc or Pbf), Ser9'10,11(Trityl), Cys13(Trityl). Following assembly, the N-terminal Fmoc-protecting group was removed by treating the Fmoc-peptidyl-resin with in DMF. The amino-peptidyl-resin so obtained was acylated by treatment for 1.5-2hr at 70°C with 1.5-2 equivalents of 4',5'-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna & Ullman, (1980) Anal Biochem. 108:156-161) which had been preactivated with diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF]. The dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane. The dimethoxyfluoresceinyl-peptide was isolated by evaporation, trituration with diethyl ether and filtration. The isolated peptide was reacted with 4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid. The product was characterised by MALDI-TOF MS and amino acid analysis.
Natural Substrates
The activity of the compounds of the invention as inhibitors of aggrecan degradation may be assayed using methods for example based on the disclosures of E. C. Arner et al, (1998) Osteoarthritis and Cartilage 6:214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601 and the antibodies described therein. The potency of compounds to act as inhibitors against coUagenases 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 TNFα production may be assessed in THP-1 cells using an ELISA to detect released TNF essentially as described K. M. Mohler et al, (1994) Nature 370:218-220. In a similar fashion the processing or shedding of other membrane molecules such as those described in N. M. Hooper et al, (1997) Biochem. J. 321:265-279 may be tested using appropriate cell lines and with suitable antibodies to detect the shed protein. Test as an agent to inhibit cell based invasion
The ability of the compound of this invention to inhibit the migration of cells in an invasion assay may be determined as described in A. Albini et al, (1987) Cancer Research 47:3239-3245.
Test as an agent to inhibit whole blood TNF sheddase activity
The ability of the compounds of this invention to inhibit TNFα production is assessed in a human whole blood assay where LPS is used to stimulate the release of TNFα. Heparinized (lOUnits/ml) human blood obtained from volunteers is diluted 1 :5 with medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160μl) with 20μl of test compound (triplicates), in DMSO or appropriate vehicle, for 30 min at 37°C in a humidified (5%CO2/95%air) incubator, prior to addition of 20μl LPS (E. coli. 0111 :B4; final concentration lOμg/ml). Each assay includes controls of diluted blood incubated with medium alone (6 wells/plate) or a known TNFα 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 (50-1 OOμl) and stored in 96 well plates at -70°C before subsequent analysis for TNFα 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 10U heparin. Plasma fractions are obtained following centrifugation and the plasma proteins precipitated with acetonitrile (80% w/v final concentration). After 30 mins at -20°C the plasma proteins are sedimented by centrifugation and the supernatant fraction is evaporated to dryness using a Savant speed vac. The sediment is reconstituted in assay buffer and subsequently analysed for compound content using the synthetic substrate assay. Briefly, a compound concentration-response curve is constructed for the compound undergoing evaluation. Serial dilutions of the reconstituted plasma extracts are assessed for activity and the amount of compound present in the original plasma sample is calculated using the concentration-response curve taking into account the total plasma dilution factor.
In vivo assessment
Test as an anti-TNF agent
The ability of the compounds of this invention as ex vivo TNFα inhibitors is assessed in the rat. Briefly, groups of male Wistar Alderley Park (AP) rats (180-210g) are dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route e.g. peroral (p.o.), intraperitoneal (i.p.), subcutaneous (s.c). Ninety minutes later rats are sacrificed using a rising concentration of CO2 and bled out via the posterior vena cavae into 5 Units of sodium heparin/ml blood. Blood samples are immediately placed on ice and centrifuged at 2000 rpm for 10 min at 4°C and the harvested plasmas frozen at -20° C for subsequent assay of their effect on TNFα production by LPS-stimulated human blood. The rat plasma samples are thawed and 175μl of each sample are added to a set format pattern in a 96U well plate. Fifty μl of heparinized human blood is then added to each well, mixed and the plate is incubated for 30 min at 37°C (humidified incubator). LPS (25μl; final concentration lOμg/ml) is added to the wells and incubation continued for a further 5.5 hours. Control wells are incubated with 25μl of medium alone. Plates are then centrifuged for 10 min at 2000 rpm and 200μl of the supematants 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 TNFα- Mean TNFα (Controls) - Mean TNFα (Treated X 100
Mean TNFα (Controls)
Test as an anti-arthritic agent
Activity of a compound as an anti-arthritic is tested in the collagen-induced arthritis (CIA) as defined by D. E. Trentham et al, (1977) J. Exp. Med. 146,:857. In this model acid soluble native type II collagen causes polyarthritis in rats when administered in Freunds incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates.
Test as an anti-cancer agent
Activity of a compound as an anti-cancer agent may be assessed essentially as described in I. J. Fidler (1978) Methods in Cancer Research 15:399-439, using for example the B16 cell line (described in B. Hibner et al, Abstract 283 p75 10th NCI-EORTC Symposium, Amsterdam June 16 - 19 1998).
Test as an anti-emphysema agent
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: ' H-NMR spectra were recorded on either a Varian VmtyInova 400MHz or Varian Mercury-VX 300MHz instrument. The central solvent peak of chloroform-^ (5H 7.27 ppm), dimethylsulfoxide-ύftf (5H 2.50 ppm) or methanol-^ (6H 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. EXAMPLE 1
5-(2-{[4-(4'-fluoro[l,r-biphenyll-4-yl)-l-piperazinyllsulfonyl)ethyl)-2,4- imidazolidinedione
Figure imgf000035_0001
To the solution of l-(4-fluorophenyl)-phenylpiperazin ( 0.125 mg ,0.48 mmol) in 5 ml of dichloromethane was added triethylamin (0.06 ml, 0.5 mmol ) and 2-(2,5-dioxo-4- imidazolidinyl)-l-ethanesulfonyl chloride (0.113 ml 0.48 mol). The mixture was stirred for 18 hrs,diluted with DCM to 25 ml,extracted with IN HCl (5 ml) sat.NaHCO3 (5 ml) and dried,evaporated,crystallised (EtOH-dioxan). LC-MS (APCI) m/z 446.9 (MH+).
IH NMR δ 1.95m (IH); 2.1m (1.15H),3.2 m(13.3H),4.1m (lH)J.05d (2H),7.25d(2.1H)J.65d (2.2H),7.80d(1.8H),8.0 bs (NH).
The starting materials were prepared as follows:
2-(2,5-dioxo-4-imidazolidinyl)-l-ethanesulfonyl chloride
To the suspension of 5-(2-{[2-(2,5-dioxo-4-imidazolidinyl)ethyl]disulfanyl}ethyl)-2,4- imidazolidinedione (6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violently in three necked flask with gas-inlet tube,thermometer and short reflux condenser ,placed in the ice bath,was bubbled chlorine gas for 15 min (until all precipitate dissolved) at max.temp.+5°C.Then,it was stirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C),dissolved in 50 ml of dichloromethane,shaken carefully with sat.NaHCO3 (ca 25 ml),then with 10% sodium thiosulfate, dried, evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64(6):591-606); 'H NMR : δ 2.55m (l.lH),2.65m (1.8H),2J0m (lH),4.55m (IH).
5-(2-{[2-(2,5-dioxo-4-imidazolidinyl)ethyI]disuIfanyl}ethyl)-2,4-imidazolidinedione
Commercially available RS homocystine (0.18 mol) was suspended in 25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and the mixture was stirred at 100°C for 45 min.Then it was allowed to cool partially and 10 ml of 10% HCl were added at once and the mixture was stirred at 100°C again for 50 min.lt was placed in the fridge overnight,crystals were filtered and washed successively with water and dried in vacuo. LC-MS (APCI) m/z 319.1 (MH+).
The overall generalised reaction scheme is shown below:
Figure imgf000036_0001
EXAMPLE 2 (5R)-5- (4-phenyl-l-piperazinvOsulfonyl1methv -2,4-imidazolidinedione
The title compound was prepared according to the scheme shown in Example 1.
To the solution of R-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride (100 mg,0.47 mmol) in 2.5 ml THF was added the solution of 1 -phenylpiperazine (85 mg,0.52 mmol) and 65 ul of triethylamine (0.52 mmol) in 2.5 ml THF via syringe at once. The mixture was stirred for 3 hrs, precipitated triethylammonium chloride was filtered, washed with two small portions of THF, evaporated and recrystallised from EtOH and a small amount of
AcOH. LC-MS (APCI) m/z 339.1 (MH+).
'H NMR δ 2.5 m (2H),3.1bs(6.5H),3.3m(2.5H),4.55m (1H),6.8 t(lH),6.9d(1.88H)J.2 t(2.05H),9.1 bs (1.7H).
The starting materials were prepared as follows:
R-(2,5-dioxo-4-imidazolidinyl)methanesulfonyI chloride
To the suspension of R-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4- imidazolidinedione ( 6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violently in three necked flask with gas-inlet tube,thermometer and short reflux condenser,placed in the ice bath,was bubbled chlorine gas for 15 min (until all precipitate dissolved) at max.temp.+5°C.Then,it was stirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C),dissolved in 50 ml of dichloromethane,shaken carefully with sat.NaHCO3 (ca 25 ml),then with 10% sodium thiosulfate, dried, evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64(6}: 591-606); 1H NMR (DMSO-d6): δ 3.21m (l.lH),3.3m (0JH).4,65m (IH).
R-5-({ [(2,5-dioxo-4-imidazolidinyl)methyl] disulf anyl}methyl)-2,4-imid azolidinedione
Commercially available R cystine (0.18 mol) was suspended in 25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and the mixture was stirred at 100°C for 45 min.Then it was allowed to cool partially and 10 ml of 10% HCl were added at once and the mixture was stirred at 100°C again for 50 min.lt was placed in the fridge overnight,crystals were filtered and washed successively with water and dried in vacuo. LC-MS (APCI) m/z 291 (MH+).
EXAMPLE 3
(5S)-5- (4-phenyl-l-piperazinyl)sulfonyllmethyl}-2,4-imidazolidinedione
The title compound was prepared according to the scheme shown in Example 1.
To the solution of S-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride (100 mg,0.47 mmol) in 2.5 ml THF was added the solution of 1 -phenylpiperazine (85 mg,0.52 mmol) and 65 ul of triethylamine (0.52 mmol) in 2.5 ml THF via syringe at once.The mixture was stirred for 3 hrs, precipitated triethylammonium chloride was filtered, washed with two small portions of THF, evaporated and recrystallised from EtOH and a small amount of AcOH. LC-MS (APCI) m/z 339.1 (MH+).
'H NMR: δ 2.5 m (2H),3.1bs(6.5H),3.3m(2.5H),4.55m (1H),6.8 t(lH),6.9d(1.88H)J.2 t(2.05H),9.1 bs (1.7H)
The starting materials were prepared as follows:
S-(2,5-dioxo-4-imidazolidinyl)methanesuIfonyl chloride
To the suspension of S-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4- imidazolidinedione ( 6.9 mol) in the mixture of 25 ml AcOH and 2 ml water stirred violently in three necked flask with gas-inlet tube,thermometer and short reflux condenser ,placed in the ice bath, was bubbled chlorine gas for 15 min (until all precipitate dissolved) at max.temp. +5°C.Then,it was stirred 15 min more,evaporated to a small volume in vacuo (max.temp 30°C),dissolved in 50 ml of dichloromethane,shaken carefully with sat.NaHCO3 (ca 25 ml),then with 10% sodium thiosulfate, dried, evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64(6):591-606); Η NMR (DMSO-d6): δ 3.2m (0.9H,3.35m (0.9H),4.50m (IH).
S-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazolidinedione
Commercially available S cystine (0.18 mol) was suspended in 25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and the mixture was stirred at 100°C for 45 min.Then it was allowed to cool partially and 10 ml of 10% HCl were added at once and the mixture was stirred at 100°C again for 50 min.lt was placed in the fridge overnight,crystals were filtered and washed successively with water and dried in vacuo. LC-MS (APCI) m/z 291.1 (MH+).
EXAMPLE 4
(R)-5-(([4-(4,-fluoro[l,l -biphenvn-4-yl)-l-piperazinyllsuIfonvπmethyl)-2,4- imidazolidinedione
Figure imgf000039_0001
[(R)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride (0.0127 g, 0.060 mmol), l-(4'- fluoro[l,l '-biphenyl]-4-yl)piperazine (0.0154 g, 0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and dry tetrahydrofuran (0J0 mL) were stirred at room temperature over night. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and the mixture was shaken over night. The white suspension was carefully transferred to a round-bottomed flask, the resin was rinsed with tetrahydrofuran (2x1 mL) and washings were transferred to the bulk of suspension. The solvent was 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 approx. 0.010 g of the title compound. LC-MS (APCI) m/z 434 (MH+).
Η NMR (DMSO-d6) δ 10.8 (IH, bs), 7.98 (IH, d, J=2Hz), 7.63 (2H, dd, J,=5Hz, J2=9Ez), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, y=9Hz), 4.45 (IH, ddd, J,=2Hz, J2=4Hz, J3=6Hz), 3.51 (IH, dd, J,=15Hz, J2=7Hz), 3.44 (IH, dd, ,Λ=15Hz, J2=4Hz), 3.35- 3.25 (8H, m's; obscured by water signal) ppm.
13C NMR (DMSO-d6) δ 173.7, 161.3 (d, J=243Hz), 157.3, 149.8, 136.4 (d, =3Hz), 130.1, 127J (d, J=8Hz), 127.2, 116.2, 115.5 (d, 7=21Hz), 53.4, 49.4, 48.0, 44.9.
The starting materials were prepared as follows:
[(R)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride was prepared according to Mosher et al, 1958, J. Org. Chem 23: 1257.
l-(4'-Fluoro[l,l '-biphenyl]-4-yI)piperazine
4-Bromo-4'-fluorobiphenyl (4.46 g, 17.8 mmol), N-tert-butoxycarbonyl piperazine (3.97 g, 21.3 mmol), sodium tert-butoxide (2.39 g, 24.9mmol), racemic 2,2'- bis(diphenylphosphino)-l,l '-binaphthyl (rαc-BINAP) (0.082 g, 0.131 mmol), bis- (dibenzylideneacetone)palladium (0) (0.041 g, 0.045 mmol) and dry toluene (45 mL) were stirred at 80°C under nitrogen atmosphere for six hours. The warm mixture was filtered, the solids were washed twice with warm toluene and the filtrate was concentrated in vacuo giving an orange-red crude, which was stirred with ether (50mL) for two hours. The solid was filtered off, washed with small volumes of ether and dried in vacuo at 45°C over night to give 5.57 g (88% yield) of tert-butyl 4-(4'-fluoro[l,l '-biphenyl]-4-yl)-l- piperazinecarboxylate. This product (5.52 g, 15.5 mmol) was dissolved in dioxane (150 mL) and stirred with 4M hydrochloric acid (8.1 mL) at RT over night. Concentrated hydrochloric acid (3.0 mL) was added and stirring was continued at 45°C for 1.5 hours and at 60°C for 1 hour. The solution was concentrated to dryness and the solid was triturated with ether (100 mL), filtered, washed with small volumes of ether and dried in vacuo at 45°C for two hours to give 5.26 g (103% yield) of l-(4'-fluoro[l,l '-biphenyl]-4- yl)piperazine dihydrochloride as a light-yellow salt.
LC-MS (APCI) m z 257 (MH+).
Η NMR (DMSO-d6) δ 9.40 (2H, bs), 7.64 (2H, dd, =6Hz, J2=9Hz), 7.55 (2H, d, J=9Hz), 7.24 (2H, t, J=9Hz), 7.07 (2H, d, J=9Hz), 3.46-3.41 (4H, m), 3.25-3.17 (4H, m).
The salt was treated with aqueous sodium hydroxide solution and the base was taken up in dichloro-methane. Drying with Na2SO4, filtering and concentrating the organic phase gave the title compound as an offwhite solid.
1H NMR (DMSO-d6) δ 7.61 (2H, dd, J^όHz, J2=9Hz), 7.49 (2H, d, J=9Hz), 7.22 (2H, t, 7=9Hz), 6.98 (2H, d, J=9Hz), 3.10-3.06 (4H, m), 2.86-2.81 (4H, m).
EXAMPLE 5
Using an analogous procedure to that described in Example 4, [(4R)-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.
Figure imgf000042_0001
The Table below gives the Amine group for each compound of the above structure.
Figure imgf000042_0002
EXAMPLE 6
(S)-5-((f4-(4 -nuororia -biphenyll-4-vn-l-piperazinyllsulfonvnmethvn-2.4-
Figure imgf000043_0001
[(S)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride (0.0127 g, 0.060 mmol), l-(4'- fluoro[l,r-biphenyl]-4-yl)piperazine (0.0154 g, 0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and dry tetrahydrofuran (0J0 mL) were stirred at room temperature over night. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and the mixture was shaken over night. The white suspension was carefully transferred to a round-bottomed flask, the resin was rinsed with tetrahydrofuran (2x1 mL) and washings were transferred to the bulk of suspension. The solvent was 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 approx. 0.010 g of the title compound. LC-MS (APCI) m/z 433 (MH+). Η NMR (DMSO-d6) δ 10.8 (IH, br s), 7.98 (IH, d, =2Hz), 7.63 (2H, dd, J,=5Hz, y2=9Hz), 7.53 (2H, d, J=9Hz), 7.23 (2H, t, J=9Hz), 7.05 (2H, d, /=9Hz), 4.45 (IH, ddd, 7,=2Hz, J2=4Hz, J3=6Hz), 3.51 (IH, dd, /..-15Hz, J2=7Hz), 3.44 (IH, dd, J,=15Hz, /2 = Hz), 3.35-3.25 (8H, m's; obscured by water signal). 13C NMR (DMSO-d6) δ 173J, 161.3 (d, J=243Hz), 157.3, 149.8, 136.4 (d, =3Hz), 130.1, 127.7 (d, J=8Hz), 127.2, 116.2, 115.5 (d, J=21Hz), 53.4, 49.4, 48.0, 44.9.
The starting materials were prepared as follows:
[(S)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride was prepared according to Mosher et al, 1958, J. Org. Chem 23:1257. l-(4'-FIuoro[l,l '-biphenyl]-4-yl)piperazine was prepared according to Example 4. EXAMPLE 7
Using an analogous procedure to that described in Example 6, [(4S)-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
Figure imgf000044_0001
The Table below gives the Amine group for each compound of the above structure.
Figure imgf000044_0002
EXAMPLE 8
Hydantoins with the following general structure were synthesised (where E is carbon or a heteroatom):
Figure imgf000045_0001
Representative synthetic route:
(5R,S)-5 4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethyl1-5-methyl-imidazolidine-
2,4-dione.
Figure imgf000045_0002
Figure imgf000045_0003
Reagents: a) MeS02Cl, DCM, 0°C, 2.5h. b) i. LHMDS, THF, 45min. ii. MeOAc, THF, 40 in. c) KCN, (NH„)2C03, 50%EtOH/H2O, 70°C, 17h. SULFONYL-AMIDE INTERMEDIATES
Figure imgf000046_0001
(i). For NMR-data see experimental part.
4-(4-Fluoro-phenyl)-l-methanesulfonyl-piperidine
4-(4-Fluoro-phenyl)piperidine hydrochloride (2.16g; lOmmol) and diisopropylethylamine (4.35ml; 25mmol) was dissolved in DCM (60ml) and cooled under nitrogen on a ice/water bath. Methanesulfonyl chloride (1.56ml; lO.lmmol) was dissolved in DCM (5ml) and added droppwise during' 2 min. The reaction mixture was stirred for 2.5 h on the ice/water bath. The reaction mixture was washed with dilute HCl (aq), pH=2, H2O, and IM Na2CO3. The organic phase was dried (Na2SO4), filtered and evaporated to give a crude product that was recrystallised from THF/n-Heptane. The colourless crystalls was removed by filtration and dried under vaccum at 45°C. Obtained 1.96g (76% yield) of the title compound. LC-MS (APCI) m/z 258 (MH+). 1H NMR(DMSO-d6): δ 7.31 (m, 2H), 7.12 (m, 2H), 3.67 (m, 2H), 2.80 (dt, 2H), 2.64 (m, IH), 1.85 (m, 2H), 1.65 (m, 2H).
5-Chloro-2-(l-methanesulfonyl-piperidine-4-yloxy)-pyridine
The title compound was prepared as described in the synthesis of 4-(4-Fluoro-phenyl)-l- methanesulfonyl-piperidine.
5-Chloro-2-(piperidine-4-yloxy)-pyridine (2.13g; lOmmol) (preparation of this compound was made as described in WO 99-GB2801), diisopropylethylamine (2.20ml; 12.5mmol) and Methanesulfonyl chloride (1.56ml; 10.1 mmol) gave 2.14g (74%) of the title compound. LC-MS (APCI) m/z 291 (MH+).
1H NMR (DMSO-d6): δ 8.20 (d, IH), 7.81 (dd, IH), 6.87 (d, IH), 5.09 (m, IH), 3.41-3.30 (m, 2H), 3.15-3.06 (m, 2H), 2.90 (s, 3H), 2.04 (m, 2H), 1.75 (m, 2H).
l-(methylsulfonyl)-4-[5-(trifluoromethyl)pyridin-2-yI]piperazine l-[5-(Trifluoromethyl)-Pyridin-2-yl]-piperazine (l.Og; 4.3mmol) and
Diisopropylethylamine (0.9ml; 5.4mmol) was dissolved in DCM (10ml). Molecular sieves (4A) was added and the solution was cooled on a ice/water bath. Methanesulfonylchloride (0.9ml; 12mmol) was added and a slurry formed that was stirred for 15 min, the reaction mixture was allowed to reach room temperature and after 1 h. the reaction was quenched by adding 5% KHCO3. Evaporation of solvents and the residue was dissolved between DCM and 5% KHCO3. Separation and extraction of the waterphase with DCM (lx). The combined organic phases was dried (MgSO4), filtered and evaporated to give a crude product as a slightly yellow solid. Recrystallised (3x) from EtOAc/Heptan gave the title compound as colourless crystalls. Obtained 1.06g (79% yield) of the title compound. Purity >95% (HPLC, 254nm) LC-MS (APCI) m/z 310 (MH+).
Η-NMR(DMSO-d6): δ 8.44 (IH, bs), 7.85 (IH, dd), 7.02 (IH, d), 3.77 (4H, bt), 3.20 (4H, bt), 2.90 (3H, s).
The following compounds were prepared as described in the synthesis of 1- (methylsulfonyl)-4- [5-(trifluoromethyl)pyridin-2-yl] piperazine
6-[4-(methylsulfonyl)piperazine-l-yl]pyridine-3-carbonitrile
6-(l-Piperazino)-pyridine-3-carbonitrile (2.07g; 1 lmmol), Diisopropylethylamine (2.4ml;
13.8mmol) and Methanesulfonylchloride (0.86ml; 1 lmmol) in DCM (20ml) gave 2.53g
(86%) of the title compound.
Purity >95% (NMR). LC-MS (APCI) m/z 267 (MH+).
Η-NMR(DMSO-d6): δ 8.52 (lH,dd), 7.90 (IH, dd), 7.00 (IH, d), 3.79 (4H, brt), 3.19 (4H, bt), 2.90 (3H, s).
l-(4-fluorophenyl)-4-(methylsulfonyI)piperazine l-(4-Fluorophenyl)-piperazine (1.98g; 1 lmmol), Diisopropylethylamine (2.4ml;
13.8mmol) and Methanesulfonylchloride (0.86ml; 1 lmmol) in DCM (20ml) gave 2.46g
(86%) of the title compound.
Purity >95% (NMR).
LC-MS (APCI) m/z 259 (MH+). Η-NMR(DMSO-d6): δ 7.11-6.96 (4H, m), 3.28-3.20 (4H, m), 3.20-3.14 (4H, m), 2.92
(3H, s). l-[(4-fluorophenyl)methyl]-4-(methylsulfonyl)piperazine l-(4-Fluor-benzyl)-piperazine (2.14g; 1 lmmol), Diisopropylethylamine (2.4ml; 13.8mmol) and Methanesulfonylchloride (0.86ml; 1 lmmol) in DCM (20ml) gave 1.97g (65%) of the title compound. Purity >95% (NMR)
LC-MS (APCI) m/z 273 (MH+).
1H-NMR(DMSO-d6): δ 7.40-7.28 (2H, m), 7.21-7.10 (2H, m), 3.50 (2H, bs), 3.10 (4H, m),
2.87 (3H, bs), 2.44 (4H, m).
2-[4-(methylsulfonyI)piperazin-l-yl)pyrimidine
1 -(2-Pyrimidyl)-piperazine dihydrochloride (2.61g; 1 lmmol) and Diisopropylethylamine
(7.2ml; 41.3mmol) was stirred in DCM (20ml) for 30 min. The precipitated salts was removed by filtration and solvents evaporated, residue was redissolved in DCM (20ml).
Diisopropylethylamine (2.4ml; 1 lmmol) and 4A mol. sieves was added, the yellow solution was cooled on ice/water bath and Methanesulfonylchloride (0.86ml; 1 lmmol) was added. The resulting red solution was stirred for 15 min, the reaction mixture was allowed to reach room temperature and after 1 h. the reaction was quenched by adding 5% KHCO3.
Evaporation of solvents and the residue was dissolved between DCM and 5%KHCO3.
Separation difficult due to foam formation. Waterphase was saturated with NaCl and pH adjusted to 10-11. Extraction with EtOAc (3x). The combined organic phases was dried
(K2CO3), filtered and evaporated to give a crude product as a red solid.
Recrystallised (3x) from EtOAc/Heptan gave the title compound as a red powder.
Obtained 0.6g (22%) of the title compound.
Purity >95% (NMR). LC-MS (APCI) m/z 243 (MH+).
Η-NMR(DMSO-d6): δ 8.39 (2H, d), 6.68 (IH, t), 3.85 (4H, bt), 3.17 (4H, bt), 2.88 (3H, s). 4-(4-chlorophenyl)-l-(methylsulfonyl)piperidine
The title compound was prepared as described in the synthesis of 4-(4-Fluoro-phenyl)-l- methanesulfonyl-piperidine.
4-(4-Chlorophenyl)piperidine hydrochloride (0.9g, 3.9 mmol), diisopropylethylamine (1.7 ml, 9.7 mmol) and methanesulfonylchloride (0.33ml, 4.3 mmol) in DCM (30ml) and gave
0.82g (78%) of the title compound after recrystallisation from EtOAc/ Heptane.
Purity > 95%.
LC-MS(APCI) m/z 274 (MH+).
Η NMR CDC13: δ 1.83 (2H, dd); 1.92-2.01 (2H, m); 2.55-2.68 (IH, m); 2.79 (2H, dt);
2.85 (3H, s); 3.97 (2H, d); 7.16 (2H, d); 7.32 (2H, d).
ESTER INTERMEDIATES
Figure imgf000050_0001
All other esters used are commercially available or earlier described.
4-Pyrimidin-2-yl-butyric acid ethyl ester
2-Bromopyrimidine (l .Og, 6.3mmol) was slurried in dry THF (8mL). N2 (g) was bubbled through the slurry for 5 min. Pd(CH3CN)2Cl2 (8mg, 0.03mmol) and PPh3 (23.6mg, 0.09mmol) was added. Under N2-atmosphere 4-Ethoxy-4-oxo-butylzincbromide
(0.5M/THF) (15mL, 7.5mL) was added in one portion. The resulting brown solution was stirred at room temperature for 2h. H2O (5mL) was added and the mixture stirred for 60 min. before evaporation of solvents. The residue was redissolved in DCM (150mL) and washed with 0.5M trisodiumcitrate (lOOmL), H2O (lOOmL) and brine (lOOmL), dried (MgSO ), filtered and evaporated to give 1.3 g of an orange oil. The crude product was purified on 70g of Si-60 gel using a gradient of 100%Heptane to 100% EtOAc as eluent. The fractions containing the product was collected and solvent evaporated to give a yellow oil. Purity by NMR>95% was considered enough for our need. Obtained 1.12g (92% yield) of the title compound. LC-MS (APCI) m/z 195 (MH+). 1H-NMR(CDC13): δ 8.67 (d, 2H), 7.14 (t, IH), 4.12 (q, 2H), 3.02 (t, 2H), 2.41 (t, 2H), 2.18 (q, 2H), 1.25 (t, 3H).
3-Pyrimidin-2-yl-propionic acid ethyl ester
2-Bromopyrimidine (l.Og, 6.3mmol) was dissolved in THF (8 mL) and bubbled through with nitrogen. Pd(MeCN)2Cl2 (8mg, 0.03mmol) and PPh3 (23.6mg, 0.09mmol) was added followed by addition of 3-ethoxy-3-oxopropylzinkbromid (15mL, 7.5mmol). The reaction was stirred at rt for several days. The crude product was purified on silica with Heptane - EtOAc 3 :1 as eluent giving 0.60g (52%) of the title compound. LC-MS (APCI) m/z 181 (MH+).
tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-l-carboxylate tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-l -carboxylate (3.6 g,14 mmol) and 10% Pd/C moistered with water (0.8 g) was mixed in MeOH (75 mL) and stirred under H2 (1 aim) for 4 h. The mixture was filtered through Celite and concentrated to give the title compound (3.6 g, 99%). LC-MS (APCI) m/z 158 (MH+-boc).
Η NMR (CDC13): δ 4.07 (2 H, bs); 3.68 (3 H, s); 2J2 (2 H, t); 2.25 (2 H, d, J=7.l Hz); 2.01-1.86 (1 H, m); 1.68 (2 H, d); 1.46 (9 H, s); 1.23-1.08 (2 H, m). KETONE INTERMEDIATES
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000054_0001
(1) : crude products, no NMR available, mtrl. used directly in next synthetic step.
l-[4-4(Fluoro-phenyl)-piperidine-l-sulfonyl]-propan-2-one.
4-(4-Fluoro-phenyl)-l-methanesulfonyl-piperidine (lOOmg; 0.39mmol) was dissolved in dry THF (3mL) under a protective nitrogen atmosphere. Lithium bis(trimethylsilyl)amide as a 1.0 M solution in THF (1.OmL; 1.Ommol) was added in one portion at room temperature, the resulting yellow solution was stirred for 45 min. Methylacetate (50mg; 0.68mmol) dissolved in dry THF (0.5mL) was added, the mixture was stirred at room temperature for 40 min. The reaction was quenched by adding NFLCl (sat.) (2mL). The mixture was evaporated and the resulting solid was dissolved in a mixture of DCM and H2O. The organic phase was separated and washed with brine, dried (MgSO ), filtrated and evaporated. The crude product was purified on 20g of Si-60 gel using a gradient of 100%Heptane to 50%EtOAc, a flow of 20mL/min was used and UV=254nm was used for detection. The fractions containing the product was evaporated and this gave the title compound as a colourless solid. Obtained 70mg (59% yield). TLC(Si-60; EtOAc:Heptane (2:1)): Rf=0.65 LC-MS (APCI) m/z 300.1 (MH+). 1H-NMR(CDC13): δ 7.17 (m, 2H), 7.01 (m, 2H), 4.02 (s, 2H), 3.93 (m, 2H), 2.94 (dt, 2H), 2.63 (m, IH), 2.46 (s, 3H), 1.91 (m, 2H), 1.77 (m, 2H). The following compounds were prepared as described in the synthesis of l-[4-4(Fluoro- phenyl) -piperidine- 1 -sulfonyl] -propan-2-one.
l-[4-4(Fluoro-phenyl)-piperidine-l-sulfonyl]-4-phenyl-butan-2-one 4-(4-Fluoro-phenyl)- 1 -methanesulfonyl -piperidine (lOOmg; 0.39mmol), Methyl-3- phenylpropionate (1 12mg; 0.68mmol) and Lithium bis(trimethylsilyl)arnide 1.0 M/THF (l.OmL; l.Ommol) gave 93 mg (61%) of the title compound. TLC(Si-60; EtOAc:Heptane (2:1)): Rf=0.68
Η-NMR(CDC13): δ 7.30-7.10 (m, 7H), 6.99 (m, 2H), 3.97 (s, 2H), 3.79 (m, 2H), 3.11 (t, 2H), 2.94 (t, 2H), 2.83 (dt, 2H) 2.57 (m, IH), 1.83 (m, 2H), 1.70 (m, 2H).
l-[4-4(Fluoro-phenyl)-piperidine-l-sulfonyl]-5-imidazol-pentan-2-one
4-(4-Fluoro-phenyl)-l-methanesulfonyl-piperidine (lOOmg; 0.39mmol), 4-imidazol-lyl- butyric acid ethyl ester (127mg; OJOmmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.OmL; 1.Ommol) gave 75 mg (48%) of the title compound. LC-MS (APCI) m/z 394 (MH+).
1H-NMR(CDC13): δ 7.48 (s, IH), 7.16 (m, 2H), 7.08 (s, IH), 7.02 (m, 2H), 6.93 (s, 2H), 4.00 (t, 2H), 3.97 (s, 2H), 3.90 (m, 2H), 2.92 (dt, 2H), 2.77 (t, 2H), 2.63 (m, IH), 2.12 (q, 2H), 1.92 (m, 2H), 1.77 (m, 2H).
l-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonyI]-5-pyrimidin-2-yl-pentan-2-one
4-(4-Fluoro-phenyl)-l -methanesulfonyl -piperidine (150mg; 0.39mmol) was dissolved in dry THF (3mL) and cooled on an ice/brine mixture. Lithium bis(trimethylsilyl)amide as a 1.0 M solution in THF (1.5mL; 1.5mmol) was added and the mixture was stirred for 40 min. 4-Pyrimidin-2-yl-butyric acid ethyl ester (169mg; 0.87mmol) in THF (0.5mL) was added, the reaction was stirred for 30 min and then allowed to reach room temperature. After 2 h. LC/MS analysis of the reaction mixture showed >98% conversion of the starting material and the reaction was quenched by adding saturated NF J,C1 (aq) (2mL). The mixture was evaporated and the resulting solid was dissolved in a mixture of DCM and 5%KHCO3. The organic phase was separated and the water phase was extracted once with DCM. The combined organic phases was washed with brine, dried (MgSO4), filtered, and evaporated to give a yellow oil. The oil was dissolved in EtOAc and isoHexane was added until a solid formed. Evaporation of solvent gave a yellow solid crude product. This material was analysed using LC/MS only and used without further purification in the next step.
Obtained 234 mg of the crude title compound. LC-MS (APCI) m/z 406.1 (MH+).
The following compounds were prepared as described in the synthesis of l-[4-(4-Fluoro- phenyl)-piperidine-l-sulfonyl]-5-pyrimidin-2-yl-pentan-2-one. They were obtained as crude products and used without further purification.
l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-propan-2-one Starting from 5-Chloro-2-(l-methanesulfonyl-piperidine-4-yloxy)-pyridine (150mg; 0.5 lmmol), Methylacetate (61mg; 0.82mmol) and Lithium bis(trimethylsilyl)amide 1.0M/THF (1.3ml; 1.3mmol).
Obtained 161mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 333.1 (MH+).
l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-4-phenyI-butan-2-one
Starting from 5-Chloro-2-(l-methanesulfonyl-piperidine-4-yloxy)-pyridine (150mg; 0.5 lmmol), Methyl-3-phenylpropionate (126mg; 0J7mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3ml; 1.3mmol). Obtained 258mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 423.2 (MH+). l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-suIfonyl]-5-imidazol-l-yl-pentan-2-one
Starting from 5-Chloro-2-(l -methanesulfonyl -piperidine-4-yloxy)-pyridine (150mg; 0.5 lmmol), 4-imidazol-lyl-butyric acid ethyl ester (140mg; 0J7mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3ml; 1.3mmol). Obtained 268mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 427.2 (MH+).
l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyI]-5-pyrimidin-2-yl-pentan-2-one
Starting from 5-Chloro-2-(l -methanesulfonyl -piperidine-4-yloxy)-pyridine (150mg; 0.5 lmmol), 4-Pyrimidin-2-yl-butyric acid ethyl ester (147mg; 0J6mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3ml; 1.3mmol).
Obtained 244mg of the crude title compound. Used without further purification. LC-MS (APCI) m/z 439.2 (MH+).
l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-butan-2-one LC-MS (APCI) m/z 347 (MH+)
l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-pentan-2-one
LC-MS (APCI) m/z 361 (MH+)
l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-4-methyl-pentan-2-one
LC-MS (APCI) m/z 375 (MH+)
l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyI]-4-pyrimidin-2-yl-butan-2-one LC-MS (APCI) m/z 425 (MH+)
l-({4-[(5-ChIoropyridin-2-yl)oxy]piperidin-l-yl}suIfonyl)-3-(3-methylphenyl)propan- 2-one
LC-MS (APCI) m/z 423 (MH+) l-({4-[(5-Chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-3-tetrahydro-2H-pyran-4- ylpropan-2-one
LC-MS (APCI) m/z 417 (MH+)
l-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-5-morpholin-4-ylpentan-2- one
LC-MS (APCI) m/z 446 (MH+)
5-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-4-oxopentanenitriIe LC-MS (APCI) m/z 372 (MH+)
1,1-dimethylethyl 5-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-4- oxopentylcarbamate LC-MS (APCI) m/z 476 (MH+)
l-({4-[(5-chIoropyridin-2-yI)oxy]piperidin-l-yl}suIfonyl)-4-morphoIin-4-ylbutan-2- one
LC-MS (APCI) m/z 432 (MH+)
2-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-l-phenylethanone
LC-MS (APCI) m/z 395 (MH+)
2-({4-[(5-chIoropyridin-2-yl)oxy]piperidin-l-yl}suIfonyl)-l-(4-fluorophenyl)ethanone LC-MS (APCI) m/z 413 (MH+)
2-({4-[(5-chloropyridin-2-yI)oxy]piperidin-l-yl}sulfonyl)-l-(lH-imidazol-4- yl)ethanone
LC-MS (APCI) m/z 385 (MH+) 4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyI)acetyl]benzamide n.d.
l-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yI}sulfonyI)-4-(lH-l,2,4-triazoI-l- yl)butan-2-one
LC-MS (APCI) m/z 414 (MH+)
l-{[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}-4-pyrimidin-2-ylbutan-2-one LC-MS (APCI) m/z 392 (MH+)
l-{[4-(4-fluorophenyl)piperidin-l-yl]su!fonyl}-3-tetrahydro-2H-pyran-4-ylpropan-2- one
LC-MS (APCI) m/z 384 (MH+)
4-({[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}acetyl)benzamide
LC-MS (APCI) m/z 405 (MH+)
2-{[4-(4-fluorophenyl)piperidin-l-yl]sulfonyl}-l-(lH-imidazol-4-yl)ethanone LC-MS (APCI) m/z 352 (MH+)
l-{[4-(4-chlorophenyl)piperidin-l-yl]sulfonyl}-3-tetrahydro-2H-pyran-4-yIpropan-2- one
LC-MS (APCI) m/z 400 (MH+)
l-{[4-(4-chlorophenyl)piperidin-l-yI]sulfonyl}-5-morpholin-4-ylpentan-2-one
LC-MS (APCI) m/z 429 (MH+) l-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-l-yl}sulfonyI)propan-2-one
LC-MS (APCI) m/z 352.1 (MH+)
6-{4-[(2-oxopropyl)sulfonyl]piperazin-l-yl}pyridine-3-carbonitrile LC-MS (APCI) m/z 309.1 (MH+)
l-{[4-(4-fluorophenyI)piperazine-l-yl]sulfonyI}propan-2-one
LC-MS (APCI) m/z 301.1 (MH+)
l-({4-[(4-fluorophenyl)methyl]piperazine-l-yl}sulfonyl)propan-2-one LC-MS (APCI) m/z 315.1 (MH+)
l-[(4-pyrimidin-2-ylpiperazine-l-yl)sulfonyl]propan-2-one
LC-MS (APCI) m/z 285.1 (MH+)
l,l-dimethylethyl 4-[3-({4-[(5-chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)-2- oxopropyl]piperidine-l-carboxylate
LC-MS (APCI) m/z 517 (MH+).
HYDANTOINS OF FORMULA I
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
(1) : NMR available, see experimental part. (2) : Not purified.
(5R,S)-5-f4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethvn-5-methyl-imidazolidine- 2,4-dione
The ketone l-[4-4(Fluorophenyl)-piperidine-l-sulfonyl]-propan-2-one (68mg; 0.23mmol), KCN (30mg; 0.46mmol) and (NH4)2CO3 (11 lmg; l .lόmmol) was suspended in 50% EtOH/H2θ (8mL) in a 22 mL sealed tube and heated to 70° C, a solution was formed. The mixture was stirred at 70° C for 17 h. a solid formed in the tube, the mixture was cooled to room temperature and solvent evaporated, the residue was suspended in water and pH adjusted to pH=6 using 1.0M HCl and preciptated product removed by filtration and washed with water. The water phase was saturated with NaCl and extracted with MeCN. The solid material and MeCN solutions was combined and evaporated. The crude product was purified using a semipreparative HPLC system and a C-18 column with MeCN/H2O+0.1%TFA as eluent. Fractions containing the product was combined and solvent removed by evaporation to give the title compound as a colourless solid. Obtained 53 mg (62% yield). Purity by NMR >98% LC-MS (APCI) m z 370.0 (MH+). 1H-NMR (DMSO-d6): δ 10.74 (s, IH), 8.02 (s, IH), 7.31 (m, 2H), 7.12 (m, 2H), 3.61 (m, 2H), 3.51 (d, IH), 3.34 (d, IH), 2.86 (m, 2H), 2.63 (m, IH), 1.82 (m, 2H), 1.63 (m, 2H), 1.34 (s, 3H).
(5R,S)-5-f4-(4-Fluoro-phenvD-piperidine-l-sulfonylmethvI1-5-phenethyl- imidazolidine-2,4-dione
The title compound was prepared as described in the synthesis of (5R,S)-5-[4-(4-Fluoro- phenyl)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione.
1 -[4-4(Fluorophenyl)-piperidine- 1 -sulfonyl] -4-phenyl-butan-2-one (93mg; 0.24mmol), KCN (40mg; 0.6 lmmol) and (NH4)2CO3 (117mg; 1.22mmol) gave 37mg (33%) of the title compound.
LC-MS (APCI) m/z 460.1 (MH+).
1H-NMR (DMSO-d6): δ 10.87 (s, IH), 8.13 (s, IH), 7.30 (m, 4H), 7.15 (m, 5H), 3.63 (m,
2H), 3.56 (d, IH), 3.41 (d, IH), 2.87 (m, 2H), 2.61 (m, 2H), 2.39 (m, IH), 1.92 (bt, 2H), 1.83 (m, 2H), 1.63 (m, 2H).
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethvn-5-(3-imidazol-l-yl- propyl)-imidazolidine-2,4-dione l-[4-4(Fluorophenyl)-piperidine-l-sulfonyl]-5-imidazol-butan-2-one (75mg; 0.19mmol), KCN (30mg; 0.46mmol) and (NH4)2CO3 (91mg; 0.95mmol) was dissolved in EtOH/H2O (1/1) (lOmL) in a sealed 22 mL tube and stirred for 17.5 h at 70 °C. Another portion of KCN (40mg; O.όlmmol) and (NH4)CO3 (250mg; 2.60 mmol) was added and the mixture was stirred at 70 °C for another 16 h. Evaporation of solvent and the residual material was suspended in H2O, precipitating crude product was removed by filtration and purified using a semipreparative HPLC system and a C- 18 column with MeCN/H2θ+0.1 %TFA as eluent. Fractions containing the product was combined and MeCN was removed by evaporation, the acidic waterphase was made basic, pH 8-9, using 5% KHCO3 and the precipitating product was extracted using EtOAc. Organic phase dried (Na2SO4), filtered and evaporated to give the title compound as a colourless solid. Obtained 60mg (68% yield) LC-MS (APCI) m/z 464.2 (MH+).
1H-NMR (DMSO-d6): δ 10.75 (bs, IH), 8.06 (s, IH), 7.59 (s, IH), 7.30 (m, 2H), 7.16-7.08 (m, 3H), 6.88 (s, IH), 3.95 (m, 2H), 3.60 (m, 2H), 3.47 (d, IH), 3.35 (d, IH), 2.86 (m, 2H), s 2.62 (m, IH), 1.86-1.50 (m, 8H).
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-l-sulfonylmethvn-5-t3-pyrimidin-2-yl- propyl)-imidazolidine-2,4-dione
Crude 1 -[4-(4-Fluoro-phenyl)-piperidine- 1 -sulfonyl]-5-pyrimidin-2-yl-pentan-2-one o (234mg; max 0.58mmol), KCN (151mg; 2.3mmol) and
Figure imgf000065_0001
(557mg; 5.8mmol) was suspended in EtOH/H2θ (1/1) (26mL) in a 40mL sealed tube. The mixture was heated
70° C and the resulting yellow solution was stirred for 16h.
LC/MS analysis showed that 15% unreacted ketone remained and another portion of KCN
(65mg; lmmol) and (NH4)2CO3 (245mg; 2.55mmol) was added and the mixture was heated to 70° C for another 16h. Solvent was removed by evaporation and the residue was treated with H2O (25mL). The precipitating crude product was removed by filtration and purified using semipreparative HPLC system and a C-18 column with
MeCN/H2O+0.1%TFA as eluent. Fractions containing the product was combined and
MeCN was removed by evaporation, the acidic waterphase was made basic, pH=8-9, using 5% KHCO3 and the precipitating product was filtered off, washed with water and dried in a desiccator under reduced pressure at 40° C over night. This gave the title compound as a colourless solid. Purity >98% by NMR.
Obtained 120mg (43% yield, 2 steps).
LC-MS (APCI) m/z 476.2 (MH+). 'H-NMR (DMSO-d6): δ 10.77 (s, IH), 8.72 (d, 2H), 8.03 (s, IH), 7.36-7.27 (m, 3H), 7.15-
7.09 (m, 2H), 3.60 (m, 2H), 3.50 (d, IH), 3.34 (d, IH), 2.92-2.80 (m, 4H), 2.62 (m, IH),
1.86-1.54 (m, 8H). The following compounds were prepared as described in the synthesis of(5R,S)-5-[4-(4- Fluoro-phenyl)-piperidine-l-sulfonylmethyl]-5-(3-pyrimidin-2-yl-propyl)-imidazolidine- 2, 4-dione.
(5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethylI-5-methyl- imidazolidine-2.4-dione
Purification not needed, after evaporation of reaction mixture and addition of water the precipitating product was pure enough >98% by HPLC (220nm, 254nm) and NMR. Obtained 147mg (71% yield, 2steps) of the title compound as a colorless solid. LC-MS (APCI) m/z 403.1 (MH+).
'H-NMR (DMSO-de): δ 10.73 (bs, IH), 8.20 (d, IH), 8.01 (s, IH), 7.81 (dd, IH), 6.87 (d, IH), 5.09 (m, IH), 3.52 (d, IH), 3.35 (d, IH), 3.42-3.26 (m, 2H + H2O), 3.18-3.06 (m, 2H), 2.08-1.96 (m, 2H), 1.79-1.65 (m, 2H), 1.33 (s, 3H).
(5S)-5-f4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methvI- imidazolidine-2,4-dione and (5R)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l- sulfonylmethyll-5-methyl-imidazolidine-2,4-dione
The coresponding racemic material (74mg), was dissolved in 36mL of isoHexane/EtOH
(25/75) and separated into the pure enantiomers by using the following Gilson HPLC system:
Column: CHIRALCEL OD, 2.0x25 cm, flow = 6.0 mL/min, eluent = isoHexane/EtOH
(25/75), temp = ambient, detector UV = 220nm.
The enantiomers were collected and analysed on a CHIRALCEL OD-H, 0.46x25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambient temperature, 220nm. Rt = 9.88 min. ee>99% for the faster eluting enantiomer, 29mg (39%).
Rt = 11.45 min. ee=98J% for the slower eluting enatiomer, 27mg (36%).
LC-MS (APCI) m/z 403.1 (MH+). (5R,S)-5-f4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-phenethyl- imidazolidine-2,4-dione.
Starting from crude l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-4-phenyl- butan-2-one (258mg; max 0.5 lmmol). Purification of crude product was made on 70g Si-60 gel using DCM+5%MeOH as eluent. Purity >96% by NMR and HPLC (220nm, 254nm).
Obtained 201mg (80% yield, 2 steps) of the title compound as a colourless solid. LC-MS (APCI) m/z 493.0 (MH+).
'H-NMR (DMSO-d6): δ 10.86 (bs, IH), 8.21 (bd, IH), 8.13 (s, IH), 7.81 (dd, IH), 7.33- 7.24 (m, 2H), 7.22-7.14 (m, 3H), 6.87 (d, IH), 5.10 (m, IH), 3.56 (d, IH), 3.42 (d, IH), 3.43-3.28 (m, 2H + H2O), 3.20-3.08 (m, 2H), 2.66-2.52 (m, IH), 2.45-2.31 (m, IH), 2.08- 1.96 (m, 2H), 1.96-1.83 (m, 2H), 1.81-1.65 (m, 2H.
(5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-(3-imidazol- lyl-propyl)-imidazoIidine-2,4-dione
Starting from crude l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-5-imidazol-l- yl-pentan-2-one (268mg; max 0.5 lmmol).
Obtained 151mg (59% yield, 2 steps) of the title compound as a colourless solid.
Purity >98% by NMR. LC-MS (APCI) m/z 497.2 (MH+).
'H-NMR (DMSO-d6): δ 10.81 (bs, IH), 8.20 (d, IH), 8.05 (s, IH), 7.81 (dd, IH), 7.59 (bs,
IH), 7.13 (bs, IH), 6.88 (bs, IH), 6.87 (d, IH), 5.08 (m, IH), 3.47 (d, IH), 3.40-3.28 (m,
3H + H2O), 3.17-3.06 (m, 2H), 2.07-1.95 (m, 2H), 1.79-1.64 (m, 3H), 1.61-1.48 (m, 3H).
(5R.S)-5-[4-(5-Chloro-pyridin-2-vIoxy)-piperidine-l-sulfonylmethyll-5-(3-pyrimidin- 2-yl-propyD-imidazolidine-2.4-dione
Starting from crude l-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-5-pyrimidin-2- yl-pentan-2-one (244mg; max 0.5 lmmol).
Obtained 105mg (49% yield, 2 steps) of the title compound as a colourless solid. Purity >98% by NMR.
'H-NMR (DMSO-d6): δ 10.77 (bs, IH), 8.72 (d, 2H), 8.20 (d, IH), 8.03 (s, IH), 7.81 (dd, IH), 7.34 (t, IH), 6.87 (d, IH), 5.08 (m, IH), 3.50 (d, IH), 3.41-3.29 (m, 3H + H2O), 3.16- 3.07 (m, 2H), 2.83 (t, 2H), 2.06-1.96 (m, 2H), 1.81-1.66 (m, 5H), 1.63-1.51 (m, IH).
(5S)-5-f4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-(3-pyrimidin-2- yl-propyl)-imidazolidine-2,4-dione and (5R)-5-f4-(5-Chloro-pyridin-2-yloxy)- piperidine-l-sulfonylmethyll-5-(3-pyrimidin-2-yl-propyl)-imidazolidine-2,4-dione
The coresponding racemic material (40mg), was dissolved in 26mL of isoHexane/EtOH (25/75) and separated into the pure enantiomers by using the same conditions as described for separation of (5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l -sulfonylmethyl]-5- methyl-imidazolidine-2,4-dione.
Rt = 17.6 min. ee>99% for the faster eluting enantiomer, 17mg (42%).
Rt = 21.0 min. ee=98.9% for the slower eluting enatiomer, 15mg (37%). LC-MS (APCI) m/z 509 (MH+).
5-f({4-[(5-chloropyridin-2-vI)oxylpiperidin-l-yl}suIfonyl)methyll-5- ethylimidazolidine-2,4-dione
LC-MS (APCI) m/z 417 (MH+). Η NMR (DMSO-d6): δ 0.76 (3H, t); 1.63 (2H, q); 1.66-1.76 (2H, m); 1.96-2.06 (2H, m); 3.12 (2H, bt); 3.48, 3.35 (IH each, ABq, /=14.9); 3.32-3.41 (2H, m); 5.04-5.12 (IH, m); 6.86 (IH, d); 7.80 (IH, dd); 7.96 (IH, s); 8.19 (IH, d); 10.73 (IH, s). LC-MS (APCI) m/z 417 (MH+).
5-f({4-[(5-chloropyridin-2-vDoxylpiperidin-l-yl}sulfonvDmethyll-5- propylimidazolidine-2,4-dione
LC-MS (APCI) m/z 431 (MH+).
'H NMR (DMSO-d6): δ 0.84 (3H, t); 1.03-1.16 (IH, m); 1.20-1.35 (IH, m); 1.58 (2H, t);
1.65-1.77 (2H, m); 1.96-2.06 (2H, m); 3.11 (2H, t); 3.21-3.42 (3H, D2O); 3.48 (IH, half ABq, /=14.9); 5.04-5.12 (IH, m); 6.86 (IH, d); 7.80 (IH, dd); 7.99 (IH, s); 8.19 (IH, d); 10.74 (IH, s).
5-[({4-f(5-chloropyridin-2-yI)oxylpiperidin-l-vπsulfonyl)methyll-5-(2- methylpropyπimidazolidine-2,4-dione
LC-MS (APCI) m/z 445 (MH+).
1H NMR (DMSO-d6): δ 0.81 (3H, d); 0.88 (3H, d); 1.50-1.59 (3H, m); 1,64-1.78 (2H, m); 1.95-2.05 (2H, m); 3.06-3.16 (2H, m); 3.22-3.41 (3H, D2O); 3.46 (lH half Abq, /=15.1); 5.03-5.12 (IH, m); 6.86 (IH, d); 7.80 (IH, dd); 7.99 (IH, bs); 8.19 (IH, d); 10.71 (IH, bs).
5-K(4-[(5-chloropyridin-2-yl)oxylpiperidin-l-v sulfonyl)methvn-5-(2-pyrimidin-2- ylethyl)imidazolidine-2,4-dione
LC-MS (APCI) m/z 495 (MH+).
1H NMR (DMSO-d6): δ 1.66-1.78 (2H, m); 1.96-2.16 (4H, m); 2.64-2.76 (IH, m); 2.84- 2.95 (IH, m); 3.08-3.18 (2H, m); 3.33-3.41 (2H, m); 3.43, 3.57 (IH each, ABq, H 4.9); 5.04-5.12 (IH, m); 6.86 (IH, d); 7.34 (1 H, t); 7.80 (IH, dd); 8.12 (IH, d); 8.19 (IH, d); 8.70 (lH, d); 10.84 (lH, s).
5-f({4-r(5-chloropyridin-2-vDoxy1piperidin-l-yl}suIfonyl)methyl1-5-f(3- methylphenyl)methyl1imidazolidine-2,4-dione
LC-MS (APCI) m/z 493 (MH+).
Η NMR (DMSO-d6): δ 1.66-1.78 (2H, m); 1.96-2.07 (2H, m); 2.23 (3H, s); 2.84 (2H, s);
3.09-3.20 (2H, m); 3.34-3.43 (2H, m); 3.45, 3.69 (IH each, ABq, 7=14.7 Hz); 5.06-5.13
(IH, m); 6.87 (IH, d); 6.93-6.98 (2H, m); 7.01-7,06 (IH, m); 7.10-7.17 (IH, m); 7.81 (IH, dd); 8.08 (IH, s); 8.20 (IH, d); 10.35 (IH, s). 5-f((4-f(5-chloropyridin-2-vπoxylpiperidin-l-yl}sulfonyl)methyll-5-(tetrahvdro-2H- pyran-4-ylmethyl)imidazolidine-2.4-dione
LC-MS (APCI) m/z 487 (MH+).
'H NMR (DMSO-dβ): δ 1.06-1.26 (2H, m); 1.39-1.77 (7H, m); 1.95-2.05 (2H, m); 3.06- 3.27 (4H, m); 3.27-3.41 (3H, D2O); 3.48 (IH half ABq, .7=15.0 Hz); 3.69-3.79 (2H, m); 5.03-5.12 (IH, m); 6.85 (IH, d); 7.80 (IH, dd); 8.03 (IH, bs); 8.19 (IH, d); 10.79 (IH, s).
5-f({4-[(5-chloropyridin-2-yl)oxylpiperidin-l-yl}sulfonyl)methyll-5-(3-morpholin-4- ylpropyl)imidazolidine-2,4-dione trifluoroacetic acid LC-MS (APCI) m/z 517 (MH+).
'H NMR (DMSO-d6): δ 1.40-1.78 (6H, m); 1.96-2.06 (2H, m); 2.94-3.18 (6H, m); 3.31- 3.44 (5H, m); 3.54 (IH half Abq, J=14.9 Hz); 3.60 (2H, t); 3.90-4.01 (2H, m); 4.25-6.27 (1H);6.85 (IH, d); 7.80 (IH, dd); 8.05 (IH, bs); 8.19 (IH, d); 9.52 (IH, bs); 10.88 (IH, s).
3-{4-f(H-f(5-chloropyridin-2-yl)oxy]piperidin-l-vI}sulfonyl)methyll-2,5- dioxoimidazolidin-4-vUpropanenitrile
LC-MS (APCI) m/z 442 (MH+).
'H NMR (DMSO-d6): δ 1.66-1.78 (2H, m); 1.95-2.05 (4H, m); 2.37-2.57 (2H, DMSO-d6); 3.07-3.17 (2H, m); 3.25-3.40 (2H, D2O); 3.42, 3.52 (IH each, Abq, J=14J); 5.04-5.12 (IH, m); 6.86 (IH, d); 7.80 (IH, dd); 7.99 (IH, bs); 8.20 (IH, d); 10.91 (IH, s).
l.l-dimethylethyl 3-{4-[({4-f(5-chloropyridin-2-yl)oxylpiperidin-l- v sulfonyl)methyll-2,5-dioxoimidazolidin-4-v propylcarbamate
LC-MS (APCI) m/z 547, 490 (MH+); (MH+)-tBu. 'H NMR (DMSO-de): δ 1.10-1.27 (lH, m); 1.27-1.43 (9H, s); 1.52-1.77 (4H, m); 1.94-2.06 (2H, m); 2.80-2.90 (2H, m); 3.06-3.16 (2H, m); 3.22-3.40 (4H, D2O); 3.47 (IH half ABq, j=15.1 Hz); 5.03-5.12 (IH, m); 6.76-6.88 (2H, m); 7.80 (IH, dd); 7.95 (IH, bs); 8.19 (IH, d); 10.73 (lH, bs). 5-[({4-f(5-chloropyridin-2-yl)oxylpiperidin-l-vUsulfonyl)methvn-5-tf2-morpholin-4- ylethyl)imidazolidine-2,4-dione
Not purified.
LC-MS (APCI) m/z 502 (MH+).
5-K{4-[(5-chloropyridin-2-yl)oxylpiperidin-l-yl}sulfonyl)methyll-5- phenylimidazolidine-2,4-dione
Not purified.
LC-MS (APCI) m/z 465 (MH+).
5-f({4-[(5-chIoropyridin-2-vI)oxylpiperidin-l-vI}suIfonyl)methyl1-5-(4- fluorophenyl)imidazolidine-2,4-dione
Not purified.
LC-MS (APCI) m/z 483 (MH+).
5-[({4-f(5-chIoropyridin-2-yl)oxylpiperidin-l-yl}sulfonyl)methyll-5-(lH-imidazol-4- yl)imidazolidine-2,4-dione
Not purified.
LC-MS (APCI) m/z 455 (MH+).
4-{4-K{4-K5-chloropyridin-2-yl)oxy1piperidin-l-yl}sulfonyl)methyll-2,5- dioxoimidazolidin-4-vUbenzamide
Not purified.
LC-MS (APCI) m/z 508 (MH+).
5-r((4-r(5-chloropyridin-2-vnoxylpiperidin-l-yl}sulfonvnmethyll-5-r2-(lH-l,2.4- triazol-l-vDethvI]imidazoIidine-2,4-dione
Not purified.
LC-MS (APCI) m/z 484 (MH+). 5-({[4-(4-fluorophenyl)piperidin-l-yllsulfonv methvI)-5-(2-pyrimidin-2- ylethyl)imidazolidine-2,4-dione
LC-MS (APCI) m/z 462 (MH+). s Η NMR (DMSO-d6): δ 1.62 (2H, dq); 1.77- 1.86 (2H, m); 2.07-2.19 (2H, m); 2.57-2.76 (2H, m); 2.81-2.96 (3H, m); 3.42, 3.56 (IH each, ABq, 7=14.6 Hz); 3.59-3.68 (2H, m); 7.11 (2H, t); 7.27-7.36 (3H, m); 8.08 (IH, bs); 8.71 (IH, d); 10.84 (IH, bs).
5-( 4-(4-fluorophenyl)piperidin-l-yllsulfonvUmethyl)-5-(tetrahvdro-2H-pyran-4- 0 ylmethyl)imidazoIidine-2,4-dione LC-MS (APCI) m/z 454 (MH+).
Η NMR (DMSO-d6): δ 1.07-1.28 (2H, m); 1.40-1.68 (7H, m); 1.77-1.85 (2H, m); 2.56- 2.67 (IH, m); 2.85 (2H, dq); 3.22 (2H, dq); 3.39-3.45 (IH, m); 3.48 (IH half ABq, 7=14.5 Hz); 3.53-3.66 (2H, m); 3.75 (2H, dt); 7.11 (2H, t); 7.26-7.33 (2H, m); 8.00 (IH, bs); 10.68 (lH, bs).
4-[4-({f4-(4-fluorophenyl)piperidin-l-yllsulfonyl|methyl)-2,5-dioxoimidazolidin-4- yllbenzamide
LC-MS (APCI) m/z 475 (MH+). Η NMR (DMSO-de): δ 1.61 (2H, dq); 1.77-1.88 (2H, m); 2.58-2.69 (IH, m); 2.85-3.01 (2H, m); 3.60 (IH half ABq, 7=14.6 Hz); 3.60-3.69 (2H, m); 7.12 (2H, t); 7.26-7.34 (2H, m); 7.42 (IH, bs); 7.65 (2H, d); 7.91 (2H, d); 8.01 (IH, bs); 8.85 (IH, s); 10.95 (IH, bs).
5-({[4-(4-fluorophenyl)piperidin-l-yllsulfonvI}methyl)-5-(lH-imidazol-4- vDimidazoIidine-2,4-dione Not purified. LC-MS (APCI) m/z 422 (MH+). 5-({[4-(4-chlorophenvπpiperidin-l-yllsulfonyl}methyl)-5-(tetrahvdro-2H-pyran-4- yImethyπimidazolidine-2,4-dione
LC-MS (APCI) m/z 470 (MH+).
'H NMR (DMSO-de): δ 1.07-1.28 (2H, m); 1.40-1.68 (7H, m); 1.76-1.85 (2H, m); 2.56- 2.68 (IH, m); 2.85 (2H, q); 3.22 (2H, q); 3.48 (IH half ABq, 7=14.5 Hz); 3.53-3.67 (2H, m); 3.75 (2H, t); 7.26-7.37 (4H, m); 8.02 (IH, bs); 10.79 (IH, bs).
5-({f4-(4-chlorophenyl)piperidin-l-yl]sulfonyl)methyl)-5-(3-morpholin-4- ylpropyl)imidazolidine-2,4-dione trifluoroacetic acid
LC-MS (APCI) m/z 499 (MH+).
Η NMR (DMSO-de): δ 1.41-1.87 (8H, m); 2.56-2.69 (IH, m); 2.86 (2H, q); 2.95-3.14 (4H, m); 3.33-3.44 (3H, m); 3.52 (IH half ABq, 7=14.6 Hz); 3.55-3.69 (4H, m); 3.90-4.00 (2H, m); 7.25-7.37 (4H, m); 8.07 (IH, s); 9.89 (IH, bs); 10.87 (IH, s).
(5R,S)-5-Methyl-5-f({4-r5-(trifluoromethyl)pyridin-2-yllpiperazine-l- yl}sulfonyl)methyllimidazolidine-2,4-dione
LC-MS (APCI) m/z 422.1 (MH+). Purity >95% by NMR. 1H-NMR (DMSO-de): δ 10.75 (IH, s); 8.44 (IH, d); 8.02 (IH, s); 7.85 (IH, dd); 7.03 (IH, d); 3.75 (4H, m); 3.55 (IH, d); 3.35 (IH, d); 3.21 (4H, m); 1.31 (3H, s).
6-(4-{[({4R,S}-4-methyl-2<5-dioxoimidazolidin-4-yl)methyllsulfonyl)piperazin-l- yl)pyridine-3-carbonitril LC-MS (APCI) m/z 379.1 (MH+). Purity >99% by NMR.
'H-NMR (DMSO-de): δ 10.74 (IH, s); 8.52 (IH, d); 8.00 (IH, s); 7.90 (IH, dd); 7.00 (IH, d); 3.78 (4H, m); 3.55 (IH, d); 3.36 (IH, d); 3.20 (4H, m); 1.31 (3H, s). (5R,S)-5-({[4-(4-fluorophenyl)piperazine-l-yllsulfonyl}methyl)-5- methylimidazolidine-2,4-dione
LC-MS (APCI) m/z 371.1 (MH+). Purity >98% by NMR. 1H-NMR (DMSO-de): δ 10.75 (IH, s); 8.03 (IH, s); 7.11-6.95 (4H, m); 3.56 (IH, d); 3.36 (IH, d); 3.25 (4H, m); 3.15 (4H, m); 1.33 (3H, s).
(5R,S)-5-f({4-f(4-fluorophenyl)methyllpiperazine-l-vI}sulfonvI)methyll-5- methylimidazolidine-2,4-dione LC-MS (APCI) m/z 385.1 (MH+). Purity >95% by NMR.
'H-NMR (DMSO-de): δ 10.72 (IH, s); 7.99 (IH, s); 7.33 (2H, m); 7.15 (2H, m); 3.50 (2H, s); 3.49 (IH, d); 3.30 (IH, d); 3.12 (4H, m); 2.42 (4H, m); 1.32 (3H, s).
(5R,S)-5-methyl-5-{[(4-pyrimidin-2-ylpiperazine-l-yl)sulfonyllmethyl}imidazolidine- 2,4-dione.
LC-MS (APCI) m/z 355.1 (MH+). Purity >99% by NMR.
'H-NMR (DMSO-de): δ 10.74 (IH, s); 8.40 (2H, d); 8.01 (IH, s); 6.68 (IH, t); 3.83 (4H, m); 3.53 (IH, d); 3.33 (IH, d); 3.18 (4H, m); 1.31 (3H, s).
5-(3-aminopropyι)-5-r({4-[(5-chloropyridin-2-v0oxylpiperidin-l- vUsulfonvDmethyllimidazolidine-2,4-dione trifluoroacetic acid
1 , 1 -dimethy lethy 1 3-{4-[({4-[(5 -chloropyridin-2-yl)oxy]piperidin- 1 -y 1 } sulfony l)methy 1] - 2,5-dioxoimidazolidin-4-yl}propylcarbamate (426mg, 0J8mmol) was dissolved in 10 mL CH2Cl2 and 4 mL of TFA was added. The reaction was stirred at rt for 1 hour. The solvent was removed to give 408mg (93%) of the title compound as a white solid. LC-MS (APCI) m/z 446 (MH+). Η NMR (CD3OD): δ 1.48-1.63 (IH, m); 1.69-1.96 (5H, m); 2.01-2.12 (2H, m); 2.93 (2H, t); 3.20-3.29 (2H, m); 3.40, 3.60 (IH each ABq, 7=14.6 Hz); 3.44-3.54 (2H, m); 4.85 (4H, D2O); 5.14-5.22 (IH, m); 6.78 (IH, d); 7.67 (IH, dd); 8.08 (IH, d).
5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethvπ-5-piperidin-4-yl- imidazolidine-2,4-dion hydro chloride
4-{4-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-2,5-dioxo-imidazolidin- 4-yl} -piperidine- 1 -carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) was solved in 2 M hydrogen chloride (ethyl acetate, 30 ml) and methanol (5 ml). The solution was stirred at 50 °C for 1 hour. Evaporation afforded 90.5 mg (0.16 mmol) of the title compound 5-[4- (5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-piperidin-4-yl-imidazolidine- 2,4-dion hydro chloride in quantitative yield. LC-MS (APCI) m/z 472.3 (MH+).
Η NMR (DMSO-de): δlθ.88 (IH, s); 9.05 (IH, d); 8.48 (lH,m); 8.21 (IH, d); 7.82 (IH, dd); 6.87 IH, d); 5.10 IH, m); 3.47 (2H, s); 3.43-3.13 (7H, m); 2J8 (2H, m); 2.02-1.39 (9H, m).
4-{4-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyI]-2,5-dioxo- imidazolidin-4-yl}-piperidine-l-carboxylic acid tert-butyl ester For preparation of the reacting ester, piperidine- 1 ,4-dicarboxylic acid 1 -tert-butyl ester 4- methyl ester, se for example Albert A Carr et al, Journal of Organic Chemistry (1990), 55(4), 1399-401.
LC-MS (APCI) m/z 472.3 (MH+-Boc).
5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-suIfonylmethyll-5-(tetrahvdo-pyran-4-
Figure imgf000075_0001
LC-MS (APCI) m/z 403.2 (MH+).
Η NMR (DMSO-de): δ 10.77 (lH,s); 8.20 (IH, d); 8.19 (lH,s); 7.81 (IH, dd); 6.87 (IH, d); 5.09 (IH, m); 3.88 (2H, t); 3.45 (2H, s); 3.38 (2H, m); 3.21 (2H, t); 3.13 (2H, m); 2.02 (2H, m); 1.84 (IH, t); 1.72 (2H, m); 1.60 (IH, d); 1.32 (4H, m). 5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-pyridin-4-yl- imidazolidine-2,4-dion trifluoroacetic acid
LC-MS (APCI) m/z 466.2 (MH+).
Η NMR (DMSO-d6): δ 11.15 (IH, s); 8.97 (IH, s); 8.76 (2H, d); 8.20 (IH, d); 7.82 (2H, dd); 7.80 (IH, d); 6.86 (IH, d); 5.10 (IH, m); 4.17 (IH, m); 3.73 (IH, d); 3.41 (2H, m); 3.17 (2H, m); 2.08 (2H, m); 1.72 (2H, m).
l -dimethylethyl 4-({4-f({4-[(5-chloropyridin-2-yl)oxylpiperidin-l- yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}methyl)piperidine-l-carboxylate The title compound was prepared essentially as described in the synthesis of (5R,S)-5-[4- (4-Fluoro-phenyl)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine- 2,4-dione LC-MS (APCI) m/z 530 (MH+ -boc).
Η NMR (DMSO-de): δ 0.88-1.10 (2H, m); 1.30-1.77 (16H, m); 1.94-2.06 (2H, m); 2.53- 2.77 (2H, m); 3.05-3.17 (2H, m); 3.21-3.41 (4H, D2O); 3.48 (IH half ABq, 7=14.7 Hz); 3.73-3.88 (2H, m); 5.03-5.12 (IH, m); 6.86 (IH, d); 7.80 (IH, dd); 8.04 (IH, bs); 8.19 (IH, d); 10.55 (lH, bs).
5-[({4-f(5-chloropyridin-2-yl)oxylpiperidin-l-yl}suIfonyl)methyl1-5-(piperidin-4- ylmethvQimidazolidine-2,4-dione trifluoroacetate The title compound was prepared as described in the synthesis of
5-(3-aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-l- yl}sulfonyl)methyl]imidazolidine-2,4-dione trifluoroacetic acid.
LC-MS (APCI) m/z 486 (MH+).
'H NMR (DMSO-de): δ 1.17-1.40 (2H, m); 1.47-1.81 (7H, m); 1.94-2.07 (2H, m); 2.75- 2.93 (2H, m); 3.06-3.42 (7H, m); 3.50 (IH half ABq, 7=15.6 Hz); 5.04-5.12 (IH, m); 6.85
(IH, d); 7.80 (IH, dd); 8.06 (IH, s); 8.08-8.22 (2H, m); 8.45 (IH, bd); 10.85 (IH, s). N-(3-{4-[({4-[(5-chloropyridin-2-yl)oxylpiperidin-l-yl)sulfonyl)methyll-2.5- dioxoimidazolidin-4-yl)propyDmethanesulfonamide
5 -(3 - Aminopropyl)-5 - [( {4- [(5-chloropyridin-2-yl)oxy]piperidin- 1 - yl}sulfonyl)methyl]imidazolidine-2,4-dione trifluoroacetic acid (lOOmg, 0.18mmol) was slurried in 2 mL DCM. DIPEA (62μL, 0.36mmol) was added and the slurry was stirred for some minutes. Sulfonylchloride (16μL, O.lδmmol) was added and the reaction was stirred at rt over night. The crude product was purified by preparative HPLC.
LC-MS (APCI) m/z 524 (MH+).
Η NMR (DMSO-de): δ 1.19-1.52 (2H, m); 1.58-1.77 (4H, m); 1.95-2.06 (2H, m); 2.85 (3H, s); 2.83-2.93 (2H, m); 3.12 (2H, t); 3.19-3.46 (3H, D2O); 3.50 (IH half ABq, 7=15.7
Hz); 5.04-5.12 (IH, m); 6.86 (IH, d); 6.97 (IH, t); 7.80 (IH, dd); 8.01 (IH, s); 8.19 (IH, d); 10.79 (IH, s).
EXAMPLE 9
(5R,S)-5-[4-(5-Chloro-pyridin-2-yl)-piperazine-l-sulfonylmethyll-5-(3-pyrimidin-2-yl- propyl)-imidazolidinc-2.4-dione
Figure imgf000077_0001
l-([4-(5-Chloro-2-pyridinyl)-l-piperazinyl]sulfonyl)-5-(2-pyrimidinyl)-2-pentanone (0.397 g, 0.936 mmol), potassium cyanide (0.122 g, 1.87 mmol), ammonium carbonate (0.500 g, 4.68 mmol) and 50% ethanol (4 mL) were stirred in a sealed vial at 75°C (oil temp) for 17 hours. The ethanol was removed by rotary evaporation, pH was adjusted to 6 with IM HCl, the suspension was filtered, the solid was washed with a little water, collected and dried in vacuo at 45°C. Some more product was recovered from the aqueous filtrate by adding solid sodium chloride to saturation and extracting the mixture with acetonitrile (2x10 mL). Drying with Na2SO4, filtering and concentrating the organic phase gave a second crop. The combined crops were dissolved in tetrahydrofuran (5-10 mL), adsorbed on silica (3 g) and applied on a short silica column. Elution with EtOAc followed by EtOAc-MeCN (1 : 1) gave 0.30 g (65% yield) of the title compound as a white crystalline solid. LC-MS (APCI) m/z 494 (MH+).
Η NMR (DMSO-de) δ 10.78 (IH, bs); 8.70 (2H, d, 7= 5Hz); 8.13 (IH, d, 7= 3Hz); 8.02 (IH, s); 7.63 (IH, dd, 7,= 3Hz, 72= 9Hz); 7.33 (IH, t, 7= 5Hz); 6.93 (IH, d, 7= 10Hz); 3.63-3.56 (4H, m); 3.52 (IH, d, 7= 14Hz); 3.34 (IH, d, 7= 14Hz; obscured by water signal), 3.24-3.14 (4H, m); 2.82 (2H, t, 7= 7Hz) and 1.79-1.50 (4H,m's). 13C NMR (DMSO-de) δ 175.6, 169.5, 157.2, 157.0, 156.5, 145.6, 137.3, 119.2, 119.1, 108.8, 62.4, 52.7, 44.5, 38.2, 36.4 and 21.2.
The starting materials were prepared as follows:
l-([4-(5-Chloro-2-pyridinyI)-l-piperazinyl]sulfonyl)-5-(2-pyrimidinyl)-2-pentanone
LHMDS
Figure imgf000078_0001
ZM503902 Sulfonamide
Figure imgf000078_0002
M=275.76 ZM503902 Ester M=194.23
Figure imgf000078_0003
ZM503902 Ketone M=423.93 A stirred solution of l-(5-Chloro-2-pyridinyl)-l-methylsulfonyl piperazine (0.64g, 2.32mmol) in dry THF (25 mL, 40 rel vol), under nitrogen, was cooled to -10°C causing the sulfonamide to precipitate out of solution. LHMDS IM in THF (4.64mL, 4.64mmol) was added dropwise, over 4 min, to the suspension of sulfonamide, the mixture was then stirred for 40 min. 4-(2-Pyrimidinyl)-butyric acid ethyl ester (0.68g, 3.48mmol) (example 8) in dry THF (6.4 mL, 10 rel vol) was added dropwise, over 4 min, and the mixture stirred for 30 min. The mixture was quenched with saturated NH4C1 (0.64 mL, 1 rel vol) and evaporated to a semi-solid residue. The residue was taken up in DCM (20 rel vol) and the organic layer was washed with water (15 mL, 24 rel vol), brine (15mL, 24 rel vol), and dried with MgSO4. Removal of the solvent by rotary evaporation gave the crude product as an off white solid (0.84g, 85%). The crude product was purified by Biotage FLASH chromatography, using ethyl acetate/isohexane (90:10) as eluant, to give pure ketone as a white amorphous solid.
l-(5-Chloro-2-pyridinyl)-l-methylsulfonyl piperazine
To a solution containing l-(5-Chloro-2-pyridinyl)-piperazine (1 eq.) in toluene (25 volumes) is added triethylamine (l.leq), and the mixture is cooled down to 5°C in an ice bath. Methanesulfonyl chloride diluted with toluene (0.5vols) is slowly added to the cooled solution, keeping the temperature below 10°C. Once the addition is finished, the reaction is allowed to warm-up to room temperature. Water (6.6vols) is added and the mixture is filtered and cake slurried in Toluene (2 vols). The cake is then washed with Toluene (2 vols) and dried in a vacuum oven at 40°C overnight. l-(5-Chloro-2-pyridinyl)-piperazine
Figure imgf000080_0001
DCP Piperazine ZM503902 Pyridine
M.W. 148 M.W. 86 M.W. 197.5
Piperazine (4 eq) is charged in the reaction vessel as a solid. At room temperature pyridine (1.43 vols) is added to the vessel followed by toluene (2.14 vols). The final slurry is stirred and heated to reflux at 120°C to obtain a complete solution. To a separate vessel charge
2,5-dichloropyridine (DCP) followed by Toluene (1.43 vols) to dissolve the solid. The dissolution is endothermic, and it is necessary to warm up the solution to ~ 30°C to get complete solution. The solution containing DCP is then slowly discharged into the reaction vessel over 5hours. At this point the remaining amount of DCP should be about 20%. The reaction is left refluxing overnight to reach completion.
The reaction mixture is allowed to cool to room temperature, then water is added (6 vols).
The two layers are separated, and the aqueous phase is re-extracted with Toluene (5 vols).
The two organic layers are combined and re-washed with H2O (6 vols). Finally, the organic layer is washed with brine (6 vols).
(5S)-5-f4-(5-Chloro-pyridin-2-yl)-piperazine-l-sulfonvImethyll-5-(3-pyrimidin-2-yl- propyO-imidazolidine-2,4-dione and (5R)-5-[4-(5-Chloro-pyridin-2-vι -piperazine-l- sulfonylmethyll-5-(3-pyrimidin-2-yl-propylHmidazolidine-2,4-dione
The coresponding racemic material (23mg) was dissolved in 8 mL of isoHexane/EtOH (25/75) and separated into the pure enantiomers by using the following Gilson HPLC system:
Column: CHIRALCEL OD, 2.0x25 cm, flow = 6.0 mL/min, eluent = isoHexane/EtOH
(25/75), temp = ambient, detector UN = 230nm.
The enantiomers were collected and analysed on a CHIRALCEL OD-H, 0.46x25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambient temperature, 220nm.
Rt = 11.5 min. ee>99% for the faster eluting enantiomer, 8Jmg (37%).
LC-MS (APCI) m/z 494.1 (MH+).
[<x]D = -26.4° (c=0.0022 g/mL, EtOH, t=20°C)
Rt = 14.5 min. ee=98 % for the slower eluting enatiomer, 9mg (39%). LC-MS (APCI) m/z 494.1 (MH+).
[α]D = +24.5° (c=0.0026 g/mL, EtOH, t=20°C)
EXAMPLE 10
The following compounds were prepared using a method analogous to that described in Example 8 or 9.
5-[4-(4-Chloro-phenyl)-piperazine-l- sulfonylmethyll-5-(3-pyrimidin-2-yl-propyll- α→G SA,
imidazolidine-2,4-dione m/z 493 (MH+)
5-[4-(4-Fluoro-phenyl)-piperazine-l- sulfonylmethyl]-5-[2-(5-fluoro-pyrimidin-2-yl)- ethyll -imidazolidine-2,4-dione
Figure imgf000082_0001
m/z 481 (MH+)
5-f4-(5-Chloro-pyridin-2-vO-piperazine-l- sulfonylmethyll-5-f2-(5-fluoro-pyrimidin-2-yl- ethyll-imidazolidine-2,4-dione
Figure imgf000082_0002
m/z 498 (MH+)
5-[4-(3,4-Dichloro-phenvπ-piperazine-l- suIfonylmethyll-5-(3-pyrimidin-2-yl-propyll- imidazolidine-2,4-dione
Figure imgf000082_0003
m/z 527 (MH+) EXAMPLE 11
Compounds with the general formula
Figure imgf000083_0001
were synthesised according to the method described in Example 8
KETONE INTERMEDIATES
Figure imgf000083_0002
(1): For NMR-data see experimental part.
l-(l,l'-biphenyl-4-ylthio)propan-2-one l-[(4-bromophenyl)thio]propan-2-one (357 mg, 1.46 mmol) was treated with phenyl boronic acid (231 mg, 1.89 mmol), [l,l '-bis(diphenylphosphino)ferrocene]dichloro palladium (II) complex with dichloromethane (1 :1) (36 mg), toluene (20 ml), methanol (7.5 ml), saturated sodium carbonate solution (3.5 ml) and were stirred together at 80 °C for 18 hours. After cooling the reaction mixture was treated with dilute hydrochloric acid and extracted into ethyl acetate. The product was purified by flash chromatography on silica, eluting with 25 % ethyl acetate : iso-hexane to give 277 mg product. GC/MS m/z: 242 [M+].
Η NMR (CDC13): δ 2.33 (3H, s); 3.73 (2H, s); 7.37 (IH, s); 7.42-7.48 (4H, m); 7.54-7.59 (4H, m).
The following compounds were prepared as described in the synthesis of 1-(1, 1 '-biphenyl- 4-ylthio)propan-2-one
4'-[(2-oxopropyI)thio]-l,l'-biphenyl-4-carbonitrile
GC/MS m/z: 267 [M +].
Η NMR (CDCI3): δ 2.34 (3H, s); 3.75 (2H, s); 7.44, 7.54 (4H, abq, 7=8.5 Hz); 7.67, 7.74 (4H, abq, 7=8.5 Hz).
l-({4'-[(trifluoromethyl)oxy]-l,l'-biphenyl-4-yl}thio)propan-2-one
GC/MS m/z: 326 [M +].
Η NMR (CDCI3): δ 2.34 (3H, s); 3.73 (2H, s); 7.30 (2H, d); 7.43 (2H, d); 7.51 (2H, d); 7.58 (2H, d).
l-(l,l'-biphenyl-4-ylsuIfonyl)propan-2-one l-(l,l'-biphenyl-4-ylthio)propan-2-one (69 mg, 0.28mmol) was stirred at room temperature with sodium bicarbonate (72 mg, 0.85 mmol), oxone ((525 mg, 0.85 mmol), water (5 ml) and methanol (10ml) for 3 hours. Water (50 ml) was added and the product extracted into ethyl, acetate (3 x 25 ml). The extracts were brine washed, sodium sulphate dried and evaporated to give 78 mg (99%) product that was of sufficient purity to use with out further purification. LC-MS (APCI) m/z 275 (MH+).
Η NMR (CDC13): δ 2.47 (3H, s); 4.22 (2H, s); 7.44-7.54 (3H, m); 7.64 (2H, d); 7.80, 7.97
(4H, abq, 7=8.6 Hz).
4'-[(2-oxopropyl)sulfonyl]-l,l'-biphenyl-4-carbonitrile
The title compound was prepared as described in the synthesis of l-(l,l'-biphenyl-4- ylsulfonyl)propan-2-one.
Η NMR (DMSO-d6): δ 2.48 (3H, s); 4.23 (2H, s); 7.74 (2H, d); 7.81 (4H, t); 8.02 (2H, d).
HYDANTOINS OF FORMULA I
The following compounds were prepared as described in the synthesis of(5R,S)-5-[4-(4- Fluoro-phenyl)-piperidine- 1 -sulfonylmethyl] -5-methyl-imidazolidine-2, 4-dione (Example 8).
Figure imgf000085_0001
(1) . For NMR-data see experimental part.
(5R,SH4-(5-Chloro-pyridin-2-yloxy)-benzenesulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 396 (MH+).
Η NMR (DMSO-d6): δ 1.27 (3H, s); 3.71, 3.78 (IH each, ABq, J=15.0); 7.23 (IH, d);
7.36-7.41 (2H, m); 7.82-7.87 (3H, m); 8.04 (IH, dd); 8.27 (IH, d); 10.79 (IH, s). 5-chloro-2-{[4-(methyIsulfonyI)phenyl]oxy}pyridine
2,5-dichloropyridine (1.48g; lOmmol), 4-methylsulfonylphenol (1.89g; 1 lmmol) and Cs2CO3 (4.24g; 13mmol) was slurried in 75mL of NMP. The slurry was heated to approx 170°C over night. After cooling the Cs CO3 was filtered off and the solvent was extracted between H O and EtOAc. The organic phase was dried over Na2SO and evaporated. Heptane :EtO Ac 2:1 was added to the residue and the crystalls was filtered off.1.42 g (50%).
LC-MS(APCI) m/z 284 (MH+). Η NMR CDC13: δ 3.09 (3H, s); 7.02 (IH, d); 7.33 (2H, d); 7.76 (IH, dd); 8.00 (2H, d); 8.17 (lH, s).
5-methyl-5-[({4'-f(trifluoromethyl)oxyl-l,l'-biphenyl-4- yl}sulfinyl)methyl1imidazolidine-2,4-dione 5-methyl-5-[({4'-[(trifluoromethyl)oxy]-l,r-biphenyl-4-yl}thio)methyl]imidazolidine-2,4- dione (48 mg, 0.112 mmol) was stirred at room temperature with oxone (50 mg), sodium bicarbonate (50 mg), water (5 ml)' and Methanol (10 ml) for 18 hours. The solid was filtered off and crystalissed from ethanol to give 20 mg of the title compound. LC-MS(APCI) m/z very weak 413 (MH+). Η NMR (DMSO-d6): δ 1.41 (3H, s); 3.04-3.27 (2H, m); 7.47 (2H, d); 7.61-7.12, (2H, m); 7.78-7.90 (5H, m); 8.21 and 8.37 (IH, 2 s); 10.79 and 10.91 (IH, 2 s) 5-methyl-5-[({4'-[(trifluoromethyl)oxy]-l, -biphenyl-4-yI}thio)methyl]imidazolidine- 2,4-dione LC-MS(APCI) m/z very weak 397 (MH+). Η NMR (DMSO-de): δ 1.33 (3H, s); 3.29 (2H, s); 7.42-7.45 (4H, m); 7.61 (2H, d); 7J7 (2H, d); 7.99 (IH, s); 10.75 (IH, s). 5-[(l '-biphenvI-4-ylsulfonyl)methyll-5-methylimidazolidine-2,4-dione
LC-MS(APCl) m/z 345 (MH+).
'H NMR (DMSO-de): δ 1.27 (3H, s); 3.72, 3.81 (2H, abq, 7=15.3 Hz); 7.45 (IH, t); 7.52
(2H, t); 7.76 (2H, d); 7.82 (IH, s); 7.88, 7.94 (4H, abq, 7=8.9 Hz); 10.80 (IH, bs).
4'- (4-methyl-2,5-dioxoimidazoIidin-4-vπmethylIsulfonyl)-l,l'-biphenyl-4- carbonitrile
LC-MS(APCI) m/z very weak 370 (MH+).
Η NMR (DMSO-de): δ 1.26 (3H, s); 3.74, 3.84 (2H, abq, 7=16.0 Hz); 7.81 (IH, s); 7.91-
8.03 (8H, m); 10.81 (lH, s).
EXAMPLE 12 Synthesis of enantiomeric pure hydantoins
Figure imgf000087_0001
Representative synthetic route is shown overleaf.
Figure imgf000088_0001
Figure imgf000088_0002
A B
Figure imgf000088_0003
Reagents and conditions: a) KCN, NH4CO3, EtOH/H20, +90°C, 3h. b) Chiral separation, CHIRALPAK AD, Methanol as eluent. c) Cl2 (g), AcOH/H20, <+15°C, 25min. d) Diisopropylethylamine, THF. -20°C, 30 min.
Experimental procedures
(5S)-5-({[4-(4-fluorophenvOpiperidin-l-yllsuIfonvUmethyl)-5-methylimidazolidine-
2,4-dione
4-(4-Fluorophenyl)piperidine hydrochloride (63 mg, 0.29 mmol) was taken up in 3 mL of dry THF , neutralized with diisopropylethylamine (50 μL, 0.29 mmol) and cooled on an ice-water bath. [(4S)-4-metyl-2,5-dioxo-imidazolodin-4-yl]methanesulfonyl chloride (80 mg, 0.35 mmol) was added and after stirring for 10 min, diisopropylethylamine (50 μL, 0.29 mmol) was added and the reaction mixture was stirred at ambient temperature until LC-MS (APCI) indicated consumption of the amine. The reaction mixture was evaporated and the residue taken up in EtOH and heated to 50 °C and allowed to cool before water was added. The precipitated product was collected and washed with EtOH/water and dried in vacuum to yield 87 mg.
LC-MS (APCI) m/z 370 (MH+).
'H NMR (DMSO-de): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.29 (2 H, dd); 7.11 (2 H, dd); 3.61 (2
H, dd); 3.50, 3.33 (1 H each, ABq, 7=14.7 Hz); 2.91-2.80 (2 H, m); 2.67-2.57 (1 H, m);
1.82 (2 H, d); 1.62 (2 H, ddd); 1.33 (3 H, s).
The starting materials were prepared as follows:
5-methyl-5-{[(phenylmethyI)thio]methyl}imidazolidine-2,4-dione
A steel vessel was charged with ethanol and water (315mL/135mL).
31Jg (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) δ: 10.74 (lH,s); 8.00 (IH, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (IH each, ABq, 7=14.0 Hz); 1.29 (3H, s).
13C NMR (DMSO-d6) δ: 177.30, 156.38, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96,
36.39, 23.15. (5S)-5-methyI-5-{[(phenylmethyl)thio]methyI}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 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.
Retention time for title compound = 9.27min. Purity estimated to >99% ee.
LC-MS (APCI) m/z 251.1 (MH+).
[α]D=-30.3° (c=0.01g/mL, MeOH, T=20°C).
Η NMR (DMSO-d6) δ: 10.74 (lH,s); 8.00 (IH, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72,
2.62 (IH each, ABq, 7=14.0 Hz); 1.29 (3H, s). 13C NMR (DMSO-d6) δ: 177.30, 156.28, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96,
36.39, 23.15.
(5R)-5-methyl-5-{[(phenyImethyl)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 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+).
[α]D=+30.3° (c=0.01g/mL, MeOH, T=20°C). Η NMR (DMSO-d6) δ: 10.74 (lH,s); 8.00 (IH, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2J2,
2.62 (IH each, ABq, 7=14.0 Hz); 1.29 (3H, s).
13C NMR (DMSO-d6) δ: 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-yI]methanesulfonyl chloride f5Sj-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, Cl2 (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 (6xl00mL), 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.
[α]D=-12.4° (c=0.01g/mL, THF, T=20°C).
Η NMR (THF-d8): δ 9.91 (IH, bs); 7.57 (IH, s); 4.53, 4.44 (IH each, ABq, 7=14.6Hz); 1.52 (s, 3H, CH3).
13C NMR (THF-d8): δ 174.96; 155.86; 70.96; 61.04; 23.66. [(4R)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyI 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
(lO.Og, 40mmol).
Obtained 8J8g (96%> yield) of the title compound.
Purity by NMR > 98%.
[α]D=+12.8° (c=0.01g/mL, THF, T=20°C). -
Η NMR (THF-d8): δ 9.91 (IH, brs); 7.57 (IH, s); 4.53, 4.44 (IH each, ABq, 7=14.6Hz);
1.52 (s, 3H, CH3).
13 C NMR (THF-d8): δ 174.96; 155.84; 70.97; 61.04; 23.66.
EXAMPLE 13
Compounds with the general formula
Figure imgf000092_0001
were synthesised according to the method described in Example 12.
AMINE INTERMEDIATES
Figure imgf000092_0002
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
All other amines used are commercially available or earlier described.
4-{4-[(trifluoromethyl)oxy]phenyl}piperidine trifluoroacetic acid
Pd(PPh3)4 (87 mg, 0.0075mmol), LiCl (190 mg, 4.5 mmol), tert-butyl 4- {[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-l(2H)-carboxylate (0.50 g 1.5 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.43 g, 2.1 mmol) and aq Na2CO3 (2 mL, 2N solution) were mixed in 5.2 mL DME and heated at 85 °C for 3h followed by-cooling to room temperature and concentrated under reduced pressure. The residure was partitioned between DCM (10 mL), aq Na2CO3 (10 mL, 2N solution) and cone NFLOΗ (0.6 mL). The layers were separated and the aqueous layer extracted with DCM (3 x 10 mL). The combined organic layers were dried (Na2SO4) and concentrated. Purification by column chromatography (Si
O2, Ηeptane/Ethylacetate/DCM 5:1 :1) gave tert-butyl 4-[4-(trifluoromethoxy)phenyl]-3,6- dihydropyridine-l(2H)-carboxylate (0.27g, 52%). The product and 5% Pd/C (30 mg) was mixed in MeOΗ (3 mL) and stirred under Η2 (1 atm) for 24 h. The mixture was filtered through Celite and concentrated to give tert-butyl 4-[4-
(trifluoromethoxy)phenyl]piperidine-l -carboxylate (0.23g, 86%). The crude product was dissolved in a mixture of TFA (2 mL) and DCM (4 mL) and stirred at RT for 2 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound (0.14 g, 58%, three steps 26%). LC-MS (APCI) m/z 246 (MH+).
'H NMR (CDCI3): δ 9.38 (1 H, bs); 8.97 (1 H, bs); 7.26 (2 H, d); 7.20 (2 H, d); 3.60 (2 H, bd); 3.07 (2 H, q); 2.88-2.72 (1 H, m); 2.18-2.01 (4 H, m). 19F NMR (CDCI3): δ -58.35 (3F), -76.19 (3F). 4-[(4-chlorophenyI)ethynyl]-l,2,3,6-tetrahydropyridine hydrochloride
PdCl2(PPh3)2 (47 mg, 0.07 mmol) and Cul (13 mg, 0.07 mmol) were dissolved in Et3N (2.7 mL) and THF (8.4 mL) under a stream of argon and stirred for 10 min. A solution of tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-l(2H)-carboxylate (0.46 g 1.4 mmol) and 2-ethynylpyridine (152 μL, 1.5 mmol) in 3.5 mL TΗF was added. The reaction mixture was stirred at RT for 2h, diethyl ether was added and the precipitate was filtered off. The clear solution was washed with saturated aqueous NΗ4C1, water, Brine and dried (Na2SO4). Concentration and purification by column chromatography (SiO2, Heptane/Diethyl ether 1 :2) gave tert-butyl 4-[(4-chlorophenyl)ethynyl]-3,6- dihydropyridine-l(2H)-carboxylate (0.26 g, 58%). The product was dissolved in TΗF (3 mL) and cone ΗC1 (3 mL) and stirred at RT for 30 min. Concentration several times with toluene and EtOΗ gave the title compound (0.20 g, 98%, two steps 57%). LC-MS (APCI) m/z 218/220 3:1 (MΗ+). Η NMR (DMSO-de): δ 9.25 (2 H, bs); 7.49-7.44 (4 H, m); 6.24-6.11 (1 H, m); 3.75-3.63 (2 H, m); 3.25-3.15 (2 H, m); 2.48-2.42 (2 H, m).
The following amines were prepared in a similar way as descibed for 4-[(4- chlorophenyljethynylj -1 , 2, 3, 6-tetrahydropyridine hydrochloride.
2-(l,2,3,6-tetrahydropyridine-4-ylethynyl)pyridine LC-MS (APCI) m/z 185 (MH+).
'H NMR (CDC13): δ 8.59-8.55 (1 H, m); 7.64 (1 H, dt); 7.43-7.39 (1 H, m); 7.20 (1 H, ddd); 6.30 (1 H, bs); 3.51 (2 H, q); 3.04 (2 H, t); 2.37-2.31 (2 H, m).
4-[(4-methylphenyl)ethynyl]- 1,2,3,6-tetrahydropyridine
LC-MS (APCI) m/z 198 (MH+).
Η NMR (CDCI3): δ 8.91 (1 H, bs); 7.33 (2 H, d); 7.15 (2 H, d); 6.06 (1 H, bs); 3.93-3.80
(2 H, m); 3.49-3.335 (2 H, m); 2.73-2.60 (2 H, m); 2.37 (3 H, s). 2-(Piperidin-4-yloxy)-5-trifluoromethyl-pyridine
Sodium hydride (0.52g, 12 mmol, 55% in oil) was washed twice in hexane, and suspended in dry dimethoxyethane (30 ml). 4-hydroxypiperidine (1.21g, 12 mmol) and 2-chloro-5- trifluoromethylpyridine was dissolved in dry dimethoxyethane (30 ml). The solution was added dropwise to the sodium hydride-suspension. The reaction was stirred at 80 °C under nitrogen over night. After cooling. Water was carefully added to the mixture and the solvents were removed by rotary evaporation. The residue was dissolved in water and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel eluting with 80:20:2 EtOAc/MeOH/Et3N affording 1 Jg (63%) of the title compound as a yellow oil, which crystallised after a few hours.
LC-MS (APCI) m/z 247.1 (MH+).
Η NMR (CDC13): δ 8.40 (1 H, s); 7.74 (1 H, dd, 7=2.52, 8.70 Hz); 6.78 (1 H, d, 7=8.74 Hz); 5.25-5.17 (1 H, m); 3.19-3.08 (2 H, m); 2.83-2.73 (2 H, m); 2.10-2.00 (2 H, m); 1.83 (l H, s); 1.73-1.62 (2 H, m).
The following amines were prepared in a similar way as descibed described in the synthesis of 2- (Piperidin-4-yloxy)-5-trifluoromethyl-pyridine.
6-(Piperidin-4-yloxy)-nicotinonitriIe LC-MS (APCI) m/z 204.2 (MH+).
Η NMR (CDCI3): δ 8.45 (1 H, s); 7.76 (1 H, dd, 7=2.40, 8.77 Hz); 6.78 (1 H, d, 7=8.77 Hz); 5.28-5.17 (1 H, m); 3.19-3.09 (2 H, m); 2.83-2.74 (2 H,.m); 2.10-2.01 (2 H, m); 1.74-1.63 (2 H, m).
5-MethyI-2-(piperidin-4-yloxy)-pyridine
Η NMR (Methanol-cU): δ 7.90 (1 H, s); 7.46 (1 H, dd, 7=2.47, 8.46 Hz); 6.68 (1 H, d, 7=8.50 Hz); 5.07-4.98 (1 H, m); 3.15-3.07 (2 H, m); 2.82-2.73 (2 H, m); 2.23 (3 H, s); 2.07-1.97 (2 H, m); 1.84-1.74 (2 H, m). 2-Methoxy-6-(piperidin-4-yloxy)-pyridine
Η NMR (CDCI3): δ 7.44 (1 H, t, 7=7.90 Hz); 7.25 (2 H, dd, 7=1.83, 7.90 Hz); 5.19-5.11 (1 H, m); 3.82 (3 H, s); 3.23-3.16 (2 H, m); 2.96-2.88 (2 H, m); 2.13-2.05 (2 H, m); 1.89-1.79 (2 H, m).
2-chloro-6-(piperidine-4-yIoxy)-pyridine
Η NMR (Methanol-cL : δ 7.64 (1 H, dd, 7=7.60, 8.22 Hz); 6.96 (1 H, dd, 7=0.66, 7.60 Hz); 6.73 (1 H, dd, 7=0.60, 8.19 Hz); 5.25-5.14 (1 H, m); 3.28-3.18 (2 H, m); 3.05-2.94 (2 H, m); 2.19-2.07 (2 H, m); 1.93-1.80 (2 H, m).
5-Fluoro-2-(piperidin-4-yloxy)-pyrimidine
'H NMR (CDCI3): δ 8.36 (2 H, s); 5.16-5.06 (1 H, m); 3.29-3.18 (2 H, m); 2.98-2.87 (2 H, m); 2.21-2.08 (2 H, m); 1.97-1.81 (2 H, m).
2-(Piperidin-4-yloxy)-4-trifluoromethyl-pyrimidine
Η NMR (CDCI3): δ 8.75 (1 H, d, 7=4.93 Hz); 7.27 (1 H, d, 7=5.07 Hz); 5.39-5.30 (1 H, m); 3.44-3.33 (2 H, m); 3.28-3.17 (2 H, m); 2.35-2.10 (4 H, m).
5-Ethyl-2-(piperidin-4-yIoxy)-pyrimidine
Η NMR (Methanol-cU): δ 8.40 (2 H, s); 5.16-5.08 (1 H, m); 3.16-3.06 (2 H, m); 2.11-2.10 (2 H, m); 2.60 (2 H, q, 7=7.66, 15.28 Hz); 2.10-2.00 (2 H, m); 1.76-1.66 (2 H, m); 1.23 (3 H, t, 7=7.63 Hz).
5-Methoxy-2-(piperidin-4-yloxy)-pyridine; hydrochloride
4-(5-Methoxy-pyridin-2-yloxy)-piperidine-l -carboxylic acid tert-butyl ester (45 mg, 0.14 mmol) was dissolved in THF (3 ml) and cone. HCl (2 ml) was added. The reaction was stirred at room temprature for 2 hrs after which the solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene affording 35 mg (97%) of the title compound as oily crystals. LC-MS (APCI) m/z 225.1 (MH+).
The starting material was prepared as follows:
2-Chloro-5-methoxy-pyridine 1 -oxide
2-chloro-5-methoxy-pyridine (200 mg, 1.39 mmol) and mCPBA (360 mg, 2.09 mmol) was dissolved in CH2CI2 (10 ml). The mixture was stirred at room temperature for 2 days. The mixture was then diluted with CH2CI2 and washed with 10% aqueous K2CO3 and brine and dried over Na2SO4. The solvent were removed in vacuo affording 140 mg (63%) of the title compound as white crystals.
1H NMR (DMSO-d6): δ 8.30 (1 H, d, 7=2.72 Hz); 7.68 (1 H, d, 7=9.23 Hz); 7.08 (1 H, dd, 7=2.70, 9.23 Hz); 3.31 (3 H, s).
4-(5-Methoxy-l-oxy-pyridin-2-yloxy)-piperidine-l -carboxylic acid tert-butyl ester Potassium tert-butoxide (128 mg, 1.14 mmol) was dissolved in dry THF (10 ml) and 4- Hydroxy-piperidine- 1 -carboxylic acid tert-butyl ester (177 mg, 0.88 mmol) dissolved in dry THF (5 ml) was added under nitrogen. The mixture was stirred at room temperature for 10 minutes after which 2-Chloro-5-methoxy-pyridine 1 -oxide (140 mg, 0.88 mmol) dissolved in dry THF (5 ml) was added. The reaction was stirred for 3 days at room temperature. The solvent were removed and the residue was partitioned between H2O and CHC1 . The organic phase was washed with brine and dried over Na2SO4. The solvent were removed in vacuo affording 245 mg (86%) of the title compound as a brown oil. Η NMR (CDC13): δ 7.95-7.93 (1 H, m); 6.86-6.84 (2 H, m); 4.95-4.85 (1 H, m); 3.79 (3 H, s); 3.25-3.14 (2 H, m); 3.07-2.96 (2 H, m); 1.98-1.79 (4 H, m); 1.46 (9 H, s). 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-l -carboxylic acid tert-butyl ester 4-(5-Methoxy-l-oxy-pyridin-2-yloxy)-piperidine-l -carboxylic acid tert-butyl ester (200 mg, 0.62 mmol) was dissolved in EtOH (5 ml). Indium (498 mg, 4.34 mmol) and saturated aqueous NH4C1 (4ml) was added to the solution and the reaction was refluxed for 4 days. The mixture was filtered through celite after cooling and the solvents were removed in vacuo. The residue was chromatographed on silica gel eluting with 5:1 Heptane/EtOAc affording 50 mg (26%) of the title compound as a yellowish oil.
Η NMR (CDC13): δ 7.77 (1 H, d, 7=3.06 Hz); 7.20 (1 H, dd, 7=3.07, 8.89 Hz); 6.66 (1 H, d, 7=8.99 Hz); 5.14-5.07 (1 H, m); 3.80 (3 H, s); 3.79-3.72 (2 H, m); 3.31-3.23 (2 H, m); 2.00-1.91 (2 H, m); 1.75-1.64 (2 H, m); 1.47 (9 H, s).
4-(4-Pyridin-3-yl-phenyl)piperazine; hydrochloride
4-(4-Pyridin-3-yl-phenyl)piperazine-l -carboxylic acid tert-butyl ester (60 mg, 0.18 mmol) in THF (3 ml) and cone. HCl (3 ml) was stirred for 1 hr. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using
EtOH/Toulene, affording 50 mg (100%) of the title compound as a yellow powder. LC-MS (APCI) m z 240.2 (MH+).
The starting material was prepared as follows:
4-(4-Iodophenyl)piperazine-l -carboxylic acid tert-butyl ester was prepared according to La Clair in Angew. Chem. Int. Ed.1998, 37(3), 325-329 in 55% overall yield starting from N-phenylpiperazine (19 mmol).
4-(4-Pyridin-3-yl-phenyl')piperazine-l -carboxylic acid tert-butyl ester (Ref. Wellmar et aL ./. Heterocycl. Chem. 32(4), 1995, 1159-1 164.)
4-(4-Iodophenyl)piperazine-l -carboxylic acid tert-butyl ester (0.272 g, 0.70 mmoles), 3- pyridylboronic acid (0.078 g, 0.64 mmoles), tetrakis(triphenylphosphine)palladium (0.024 g, 0.02 mmoles), 1 M sodium hydrogencarbonate (1.0 mL) and 1 ,2-dimethoxyethane (1.5 mL) were stirred under nitrogen at 84° C for 3 hours, taken up in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated with silica (1 g) by rotary evaporation to give a solid which was applied on a short silica column. Elution with dichloromethane, dichloromethane/ethyl acetate (4:1) and neat ethyl acetate gave 0.060 g (32% yield) of the title compound as a white solid and 0.060 g of starting material (the iodide), respectively. Yield was calculated from amount of converted iodide. LC-MS (APCI) m/z 340.3 (MH+).
Η NMR (Methanol-cL : δ 8.75 (IH, d, 7=2.0 Hz); 8.43 (IH, m); 8.04 (IH, m); 7.58 (2H, d, 7=8.0 Hz); 7.47 (IH, m); 7.10 (2H, d, 7=8.0 Hz); 3.59 (4H, m); 3.22 (4H, m); 1.50 (9H, s).
N-[3-(Piperidin-4-yloxy)-phenyl]-acetamide; hydrochloride
4-Hydroxy-piperidine-l -carboxylic acid tert-butyl ester (300 mg, 1.5 mmol) was dissolved in dry CH2CI2 and cooled to -10°C. Polymer bound triphenylphosphine (750 mg, 2.25 mmol) was added and allowed to swell. N-(3-Hydroxy-phenyl)-acetamide (340 mg, 2.25 mmol) dissolved in dry THF was added and the reaction was stirred at -10° C for 10 minutes after which DEAD (0.35 ml, 2.25 mmol) was added dropwise to the mixture. The reaction was stirred over night allowing the temperature rise to room temperature. The polymer was filtered off, using a short plug of silica with Toluene/EtOAc (5:1) as eluent. The volume of the combined fractions was reduced by rotary evaporation and the solution was washed with 5% aqueous KOH and water, dried over Νa2SO4 and the solvent removed in vacuo. The resulting white powder was dissolved in THF (10 ml) and cone. HCl (10 ml) and stirred at ambient temperature for 1 hr. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene, affording 230 mg (57%) of the title compound as a white powder. LC-MS (APCI) m/z 235.1 (MH+).
The following amines were prepared in a similar way as descibed described in the synthesis N-[ 3- (Piperidin-4-yloxy)-phenyl]-acetamide. 3-(Piperidin-4-yloxy)-benzonitrile
LC-MS (APCI) m/z 203.2 (MH+).
4-(3-Methoxy-phenoxy)-piperidine
5 LC-MS (APCI) m/z 208.2 (MH+).
4-(3-Trifluoromethoxy-phenoxy)-piperidine
LC-MS (APCI) m/z 262.1 (MH+).
l o 4-(2,4-Difluoro-phenoxy)-piperidine LC-MS (APCI) m/z 214.2 (MH+).
4-(4-Chloro-phenoxy)-piperidine
LC-MS (APCI) m/z 212.2 (MH+).
15
4-(Piperidin-4-yloxy)-benzonitrile
LC-MS (APCI) m/z 203.2 (MH+).
4-(4-Methoxy-phenoxy)-piperidine 0 LC-MS (APCI) m/z 208.2 (MH+).
4-(3,4-Dichloro-phenoxy)-piperidine
LC-MS (APCI) m/z 246.1 (MH+).
5 4-(3,4-Difluoro-phenoxy)-piperidine LC-MS (APCI) m/z 214.2 (MH+).
N-[4-(Piperidin-4-yloxy)-phenyl]-acetamide
LC-MS (APCI) m/z 235.1 (MH+). 4-{ [(3,4-dimethylphenyl)methyl] oxyjpiperidine hydrochloride
LC-MS (APCI) m/z 220 (MH+).
4-{[(2,5-dimethylphenyl)methyl]oxy}piperidine hydrochloride
LC-MS (APCI) m/z 220 (MH+).
5-chloro-2-piperidin-4-ylpyridine hydrochloride
Zn dust (225 mg, 3.5 mmol) was stirred in THF (1 mL) under Ar and 1 ,2-dibromoethane (50 μL) was added at room temperature. The mixture was heated to 65 °C for 3 min and allowed to cool to room temperature before trimethylsilyl chloride (70 μL) was added and the mixture was stirred at room temperature for 30 min. A solution of 4-iodo-N-Boc- piperideine (840 mg, 2.7 mmol) in THF (1.5 mL) was slowly added and the reaction mixture was stirred at 40 °C for 2h. Pd2(dba)3 (22 mg, 0.024 mmol) and P(2-furyl)3 (23 mg, 0.10 mmol) were mixed in THF (0.5 mL), the mixture stirred at room temperature for 10 min and then added to the organozink reagent solution, followed by 2-bromo-5-chloro- pyridine (624 mg, 3.24 mmol) in THF (1 mL) and DMA (4 mL).The reaction mixture was heated at 80 °C for 3 h, allowed to cool to room temperature and then filtered through Celite and diluted with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried Na2SO and concentrated. Purification on Siθ2 eluting with heptane/EtOAc 95:5 to 2:1 gave tert-butyl 4-(5-chloropyridin-2-yl)piperidine-l- carboxylate as an yellow oil (128 mg, 16%). The oil was dissolved in THF (1.5 mL) and cone HCl (1.5 mL) and stirred at RT for 30 min. Concentration several times with toluene and EtOH gave the title compound (89 mg, 89%) LC-MS (APCI) m/z 197 (MH+).
Η NMR (MeOD-d4): δ 8.54 (1 H, d); 7.86 (1 H, dd); 7.38 (1 H, d); 3.55-3-45 (2 H, m); 3.22-3.06 (3 H, m); 2.19-2.09 (2 H, m); 2.08-1.98 (2 H, m). 5-Benzyloxy-2-(piperidin-4-yloxy)-pyridine; hydrochloride
The amine was prepared in the same way as described in the synthesis of 5-Methoxy-2-
(piperidin-4-yloxy)-pyridine.
LC-MS (APCI) m/z 285 (MH+).
The starting material was prepared as follows:
2-Chloro-5-benzyloxypyridine
Sodium hydride (55% in oil, 236 mg, 5.40 mmol) washed in Hexane and 2-Chloro-5- hydroxypyridine (350 mg, 2.70 mmol) was suspended in dry DMF (20 ml). After 10 minutes at room temperature Benzylbromide (0.32 ml, 2.70 mmol) was added and the mixture was stirred for an additional 2 hrs. The reaction was diluted with water and extracted with EtOAc (3*50 ml). The combined organic layers were washed with water and brine, and dried over Na2SO4. The solvent was removed by rotary evaporation, affording 520 mg (88%) of the title compound as a yellow oil. LC-MS (APCI) m/z 220 (MH+).
Η NMR (CDC13): δ 8.19 (IH, d, 7=3.00 Hz); 7.55 (IH, dd, 7=3.15, 8.81 Hz); 7.48-7.31 (6H, m); 5.19 (2H, s).
2-Chloro-5-benzyloxy-pyridine 1 -oxide
The amine was prepared in the same way as described in the synthesis of 2-Chloro-5- methoxy-pyridine 1 -oxide.
LC-MS (APCI) m/z 236 (MH+).
Η NMR (DMSO-d6): δ 8.38 (IH, d, 7=2.61 Hz); 7.69 (IH, d, 7=9.28 Hz); 7.47-7.33 (5H, m); 7.15 (IH, dd, 7=2.69, 9.15 Hz); 5.19 (2H, s).
4-(5-Benzyloxy-l-oxy-pyridin-2-yloxy)-piperidine-l-carboxylic acid tert-butyl ester
The compound was prepared as described in the synthesis of 4-(5-Methoxy-l-oxy-pyridin-
2-yloxy)-piperidine-l -carboxylic acid tert-butyl ester. LC-MS (APCI) m/z 401 (MH+).
Η NMR (DMSO-d6): δ 8.12 (IH, d, 7=2.79 Hz); 7.48-7.32 (5H, m); 7.19 (IH, d, 7=9.16 Hz); 7.07 (IH, dd, 7=2.88, 9.18 Hz); 5.13 (2H, s); 4.84-4.76 (IH, m); 3.20-3.11 (2H, m); 3.00-2.87 (2H, m); 1.86-1.78 (2H, m); 1.59-1.49 (2H, m); 1.40 (9H, s).
4-(5-Benzyloxy-pyridin-2-yloxy)-piperidine-l -carboxylic acid tert-butyl ester The compound was prepared as described in the synthesis of 4-(5-Methoxy-pyridin-2- yloxy)-piperidine-l -carboxylic acid tert-butyl ester. LC-MS (APCI) m/z 385 (MH+). Η NMR (CDC13): δ 7.86 (IH, d, 7=3.10 Hz); 7.46-7.32 (5H, m); 7.28 (IH, dd, 7=3.16, 9.04 Hz); 6.67 (IH, d, 7=9.04 Hz); 5.16-5.08 (IH, m); 5.05 (2H, s); 3.84-3.72 (2H, m); 3.33-3.25 (2H, m); 2.02-1.93 (2H, m); 1.76-1.66 (2H, m); 1.49 (9H, s).
5-Hydroxy-2-(piperidin-4-yloxy)-pyridine trifluoroacetic acid 4-(5-Benzyloxy- 1 -oxy-pyridin-2-yloxy)-piperidine- 1 -carboxylic acid tert-butyl ester (476 mg, 1.19 mmol) was dissolved in Methanol (20 ml) and Pd(OH)2 (30 mg) was added. The mixture was hydrogenated at 1 atm and room temperature for 24 hrs. The catalyst was filtered off, and the mixture was purified using preparative HPLC affording, after freeze drying, 110 mg (30%) of the title compound as a TFA-salt and 34 mg (10%) of the neutral Boc-protected intermediate.
LC-MS (APCI) m/z 195 (MH+).
Η NMR (DMSO-de): δ 7.66 (IH, d, 7=2.94 Hz); 7.20 (IH, dd, 7=3.07, 8.82 Hz); 6.68 (IH, d, 7=8.93 Hz); 5.12-5.00 (IH, m); 3.29-3.00 (4H, m); 2.16-2.02 (2H, m); 1.93-1.75 (2H, m).
5-Bromo-2-(piperidin-4-yIoxy)-pyridine hydrochloride
The amine was prepared in the same way as described in the synthesis of 5-Methoxy-2-
(piperidin-4-yloxy)-pyridine.
LC-MS (APCI) m/z 257 + 259 (MH+) The starting material was prepared as described in the synthesis of 4-(5-Methoxy-pyridin- 2-yloxy)-piperidine-l -carboxylic acid tert-butyl ester:
4-(5-Bromo-pyridin-2-yloxy)-piperidine-l -carboxylic acid tgrt-butyl ester
LC-MS (APCI) m/z 357 + 359 (MH+).
Η NMR (DMSO-de): δ 8.26 (IH, dd, 7=0.53, 2.67 Hz); 7.88 (IH, dd, 7=2.66, 8.81 Hz);
6.80 (IH, dd, 7=0.53, 8.79 Hz); 5.15-5.07 (IH, m); 3.72-3.64 (2H, m); 3.20-3.09 (2H, m);
1.97-1.88 (2H, m); 1.58-1.48 (2H, m); 1.40 (9H, s).
4-(5-(4-FIuoro-phenyl)-pyridine-2-yl)-piperazine hydrochloride
4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-l-carbaldehyde (98 mg, 0.34 mmol) was dissolved in MeOH (5 ml) and cone. HCl (12M, 5 ml) was added. The mixture was stirred at room temperature over night. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene affording 102 mg (100%) of the title compound as a yellow powder. LC-MS (APCI) m/z 258 (MH+).
The starting material was prepared as follows:
4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-l-carbaldehvde 4-(5-Bromo-pyridine-2-yl)-piperazine-l-carbaldehyde (100 mg, 0.37 mmol), 4- Fluorobenzeneboronic acid (55 mg, 0.39 mmol), (l, -bis(diphenylphosphino)ferrocene)- dichloropalladium(II) (10 mg, 0.01 mmol), Toluene (2 ml), EtOH (0.5 ml) and 2M Na2CO3 solution (0.5 ml, 1 mmol) were heated at 80°C under N2 overnight. After cooling the mixture was diluted with toluene and separated. The organic phase was washed with water and brine, filtered through a pad of celite and dried over Na2SO4. The solvent were removed in vacuo affording 100 mg (94%) of the title product as a beige powder. LC-MS (APCI) m/z 286 (MH+). Η NMR (DMSO-de): δ 8.44 (IH, d, 7=2.66 Hz); 8.10 (IH, s); 7.97 (IH, dd, 7=2.52, 8.82 Hz); 7.70-7.31 (2H, m); 7.31-7.21 (2H, m); 6.97 (IH, d, 7=8.97 Hz); 3.65-3.43 (8H, m).
The following compounds were synthesised as described in the synthesis of 4-(5-(4-Fluoro- 5 phenyl)-pyridine-2-yl)-piperazine hydrochloride:
4-(5-(4-Methoxy-phenyl)-pyridine-2-yl)-piperazine hydrochloride
LC-MS (APCI) m/z 270 (MH+).
l o 4-(5-(4-Chloro-phenyl)-py ridine-2-yI)-piper azine hydrochloride
LC-MS (APCI) m/z 274, 276 (MH+).
4-(5-(4-Trifluoromethoxy-phenyl)-pyridine-2-yl)-piperazine hydrochloride
LC-MS (APCI) m/z 324 (MH+).
15
4-(5-Furan-2-yl-pyridine-2-yl)-piperazine hydrochloride
LC-MS (APCI) m/z 230 (MH+).
4-(5-(lH-PyrroI-2-yl)-pyridine-2-yl)-piperazine dihydrochloride 0 The title compound was prepared from 2-(6-(4-Formyl-piperazine-l-yl)-pyridine-3-yl)- pyrrole-1 -carboxylic acid tert-butyl ester. LC-MS (APCI) m/z 229 (MH+).
4-[3,3']-Bipyridinyl-6-yl-piperazine hydrochloride 5 LC-MS (APCI) m/z 241 (MH+).
4-(6-Piperazine-l-yl-pyridine-3-yl)-benzonitrile hydrochloride
LC-MS (APCI) m/z 265 (MH+). HYDANTOINS OF FORMULA I
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
(1): For NMR-data see experimental part.
The following compounds were prepared in the same way as (5S)-5-({[4-(4- fluorophenyl)piperidin-l-yl]sulfonyl}methyl)-5-methylimidazolidine-2, 4-dione (Example 12) and purified either by precipitation and washing with EtOH/water or by preparative HPLC.
(5S)-5-methyl-5-(U4-f4-(methyloxy)phenyll-3<6-dihvdropyridin-l(2H)- yllsulfonyl}methvOimidazolidine-2,4-dione
LC-MS (APCI) m/z 380 (MH+).
1H NMR (Methanol-d4): δ 7.35 (2 H, d, 7=8.9 Hz); 6.87 (2 H, d, 7=8.9 Hz); 6.01 (1 H, dd); 3.92 (2 H, dd); 3.78 (3 H, s); 3.56, 3.41 (1 H each, ABq, 7=14.6 Hz); 3.51-3.46 (2 H, m); 2.62-2.57 (2 H, m); 1.47 (3 H, s). (5S)-5-methyl-5-f({4-[4-(methyloxy)phenyllpiperidin-l- yl}sulfonyl)methyllimidazolidine-2,4-dione
LC-MS (APCI) m/z 382 (MH+).
Η NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.17 (2 H, d); 6.85 (2 H, d); 3.71 (3 H, s); 3.60 (2 H, dd); 3.50 (1 H, part of ABq, 7=14.8 Hz); 2.85 (2 H, q); 2.54 (1 H, t); 1.79 (2 H, d); 1.64-1.53 (2 H, m); 1.33 (3 H, s).
(5S -5-({f4-(4-chlorophenyl)-4-hvdroxypiperidin-l-yllsulfonyl}methyl)-5- methylimidazolidine-2,4-dione LC-MS (APCI) m/z 402/404 3 : 1 (MH+).
Η NMR (DMSO-d6): δ 10.72 (1 H, s); 8.01 (1 H, s); 7.51 (2 H, d); 7.37 (2 H, d); 5.22 (1 H, s); 3.49, 3.34 (1 H each, ABq, 7=14.9 Hz); 3.47-3.35 (2 H, m); 3.15 (2 H, q); 1.93 (2 H, t); 1.64 (2 H, d); 1.33 (3 H, s).
(5S)-5-methyI-5-[({4-f2-(methyloxy)phenyllpiperidin-l- yl}sulfonyl)methyl]imidazolidine-2,4-dione
LC-MS (APCI) m/z 382 (MH+).
Η NMR (DMSO-de): δ 10.72 (1 H, s); 8.01 (1 H, s); 7.24-7.14 (2 H, m); 6.96 (1 H, d); 6.90 (1 H, t); 3.78 (3 H, s); 3.60 (2 H, dd); 3.51, 3.33 (1 H each, ABq, 7=14.7 Hz); 3.02- 2.94 (1 H, m); 2.88 (2 H, q); 1.77 (2 H, d); 1.66-1.56 (2 H, m); 1.33 (3 H, s).
(5SV5-methyl-5-f({4-[4-(trifluoromethvDphenyllpiperidin-l- yl)sulfonyl)methyllimidazolidine-2,4-dione
LC-MS (APCI) m/z 420 (MH+). Η NMR (DMSO-de): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.66 (2 H, d); 7.50 (2 H, d); 3.63 (2 H, dd); 3.52, 3.34 (1 H each, ABq, 7=14.9 Hz); 2.88 (2 H, ddd); 2.79-2.68 (1 H, m); 1.86 (2 H, d); 1.67 (2 H, ddd); 1.33 (3 H, s). (55)-5-methyl-5-[({4-[3-(trifluoromethyl)phenyllp.peridin-l- v sulfonyl)methyllimidazolidine-2,4-dione
LC-MS (APCI) m/z 420 (MH+).
Η NMR (DMSO-de): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.63-7.52 (4 H, m); 3.63 (2 H, dd); 3.52 (1 H, part of ABq, 7=14.9 Hz); 2.87 (2 H, ddd); 2.79-2.70 (1 H, m); 1.87 (2 H, d); 1.75-1.63 (2 H, m); 1.33 (3 H, s).
(5S)-5-[({4-f3,5-bis(trifluoromethyl)phenyllpiperidin-l-yl}sulfonyl)methyll-5- methylimidazolidine-2,4-dione LC-MS (APCI) m/z 488 (MH+).
Η NMR (DMSO-de): δ 10.74 (1 H, s); 8.02 (1 H, s); 8.00 (2 H, s); 7.93 (1 H, s); 3.64 (2 H, dd); 3.52 (1 H, part of ABq, 7=14.9 Hz); 2.95-2.81 (3 H, m); 1.89 (2 H, d); 1.83-1.69 (2 H, m); 1.34 (3 H, s).
(5S)-5-({[4-(4-chlorophenvn-3,6-dihvdropyridin-l(2H)-yllsulfonyl}methvn-5- methylimidazolidine-2,4-dione
LC-MS (APCI) m/z 384/386 3:1 (MH+).
Η NMR (DMSO-de): δ 10.74 (1 H, s); 8.03 (1 H, s); 7.47 (2 H, d); 7.40 (2 H, d); 6.23 (1 H, app s); 3.85 (2 H, app s); 3.52, 3.39 (1 H each, ABq, 7=14.7 Hz); 3.39-3.32 (2 H, m); 2.55 (2 H, br s); 1.32 (3 H, s).
(5S)-5-({f4-(3-fluorophenyl)piperidin-l-yllsulfonyl)methvO-5-methylimidazolidine- 2,4-dione
LC-MS (APCI) m/z 370 (MH+). 'H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.38-7.31 (1 H, m); 7.15-7.08 (2 H, m); 7.05-6.98 (1 H, m); 3.62 (2 H, dd); 3.51, 3.33 (1 H each, ABq, 7=14.7 Hz); 2.95-2.80 (2 H, m); 2.68-2.60 (1 H, m); 1.82 (2 H, br d); 1.69-1.58 (2 H, m); 1.33 (3 H, s). (5S)-5-((f4-(2-fluorophenyl)piperidin-l-yllsulfonyl}methyl)-5-methylimidazolidine- 2,4-dione
LC-MS (APCI) m/z 370 (MH+).
'H NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.36 (1 H, t); 7.30-7.20 (1 H, m); 7.18-7.12 (2 H, m); 3.63 (2 H, dd); 3.52, 3.33 (1 H each, ABq); 2.96-2.85 (3 H, m); 1.80 (2 H, brd); 1.69 (2 H, ddd); 1.33 (3 H, s).
(5S)-5-methyl-5-( 4-(4-methylphenyl)piperidin-l-yl]sulfonyl}methyl)imidazolidine- 2,4-dione LC-MS (APCI) m/z 366 (MH+).
'H NMR (DMSO-de): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.15-7.07 (4 H, m); 3.60 (2 H, dd); 3.50, 3.32 (1 H each, ABq); 2.85 (2 H, q); 2.59-2.51 (1 H, m); 2.25 (3 H, s); 1.79 (2 H, br d); 1.60 (2 H, ddd).
(5S)-5-methyl-5-({[4-(phenylmethyl)piperidin-l-yllsulfonyl}methvπimidazolidine-2,4- dione
LC-MS (APCI) m/z 366 (MH+).
Η NMR (DMSO-de): δ 10.70 (1 H, s); 7.96 (1 H, s); 7.29-7.15 (5 H, m); 3.46 (2 H, t); 3.41, 3.24 (1 H each, ABq, 7=14.9 Hz); 2.68 (2 H, dt); 2.52 (2 H, d); 1.54-1.51 (3 H, m); 1.30 (3 H, s).
(5S)-5-f(l,4'-bipiperidin-l'-vIsulfonvπmethyll-5-methylimidazolidine-2,4-dione trifluoroacetic acid
LC-MS (APCI) m/z 359 (MH+). Η NMR (DMSO-de): δ 10.74 (1 H, s); 9.25 (1 H, br s); 8.02 (1 H, s); 3.63 (2 H, t); 3.51, 3.34 (1 H each, ABq, 7=14.8 Hz); 3.39 (2 H, d); 3.24 (1 H, t); 2.92 (2 H, q); 2.81 (2 H, t); 2.07 (2 H, d); 1.82 (2 H, d); 1.74-1.58 (5 H, m); 1.45-1.34 (1 H, m); 1.31 (3 H, s). 19F NMR (DMSO-d6): δ -74.48. (5S)-5-(([4-(3-furan-2-yl-lH-Pyrazol-5-vI)piperidin-l-yllsulfonyl}methvn-5- methylimidazolidine-2,4-dione
LC-MS (APCI) m/z 408 (MH+).
'H NMR (DMSO-de): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.66 (1 H, s); 6.64 (1 H, s); 6.53 (1 H, s s); 6.34 (1 H, s); 3.61-3.49 (2 H, m); 3.49 (1 H, half ABq, 7=14.9 Hz); 2.94-2.84 (2 H, m); 2.81-2.72 (1 H, m); 1.98 (2 H, br d); 1 JO- 1.58 (2 H, m); 1.32 (3 H, s).
(5S)-5-methyl-5- (4-{4-[(trifluoromethyl)oxylphenyl}piperidin-l- yl)sulfonyllmethyl}imidazolidine-2,4-dione 0 LC-MS (APCI) m/z 436 (MH+).
Η NMR (DMSO-d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.40 (2 H, d); 7.28 (2 H, d); 3.70-3.55 (2 H, m); 3.51, 3.33 (1 H each, ABq, 7=14.7 Hz); 2.94-2.80 (2 H, m); 2.73-2.61 (2 H, m); 1.86 (2 H, d); 1.71-1.57 (2 H, m); 1.33 (3 H, s).
s (5iSV5-({f4-(4-chlorophenyl)piperidin-l-yllsulfonyl}methyl)-5-methylimidazolidine- 2,4-dione
LC-MS (APCI) m/z 386/388 3:1 (MH+).
Η NMR (DMSO-de): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.36-7.28 (4 H, m); 3.66-3.54 (2 H, m); 3.51, 3.33 (1 H each, ABq, 7=14.9 Hz); 2.92-2.80 (2 H, m); 2.67-2.58 (1 H, m); 1.81 (2 H, br d); 1.68- 1.56 (2 H, m); 1.33 (3 H, s).
(5S -5-methyl-5- (4-pyrrolidin-l-ylpiperidin-l-yl)sulfonyllmethyl}imidazolidine-2.4- dione trifluoroacetic acid
LC-MS (APCI) m/z 345 (MH+). Η NMR (DMSO-de): δ 10.74 (1 H, s); 9.61 (1 H, br s); 8.01 (1 H, s); 3.60 (2 H, t); 3.51, 3.36 (1 H each, ABq, 7=14.8 Hz); 3.55-3.47 (2 H, m); 3.27-3.15 (1 H, m); 3.13-3.02 (2 H, m); 2.80 (2 H, t); 2.12 (2 H, br d); 2.07-1.94 (2 H, m); 1.86-1.77 (2 H, m); 1.62-1.49 (2 H, m); 1.32 (3 H, s). 19F NMR (DMSO-de): δ -74.02 (5S)-5-methyl-5-({[4-(tetrahvdrofuran-2-ylcarbonyl)piperazin-l- yllsulfonyl}methvDimidazoIidine-2,4-dione
LC-MS (APCI) m/z 375 (MH+). Η NMR (DMSO-de): δ 10.73 (1 H, s); 8.01 (1 H, s); 4.65 (1 H, dd); 3.80-3.68 (2 H, m); 3.60-3.42 (3 H and water, m); 3.33 (1 H, half ABq, 7=14.9 Hz); 3.19-3.00 (4 H, m); 2.09- 1.92 (2 H, m); 1.87-1.75 (2 H, m); 1.30 (3 H, s).
N-[l-({f(4S)-4-methyl-2,5-dioxoimidazolidin-4-vnmethv sulfonyl)piperidin-4- vUbenzamide
LC-MS (APCI) m/z 395 (MH+).
'H NMR (DMSO-d6): δ 10.72 (1 H, s); 8.30 (1 H, d); 8.01 (1 H, s); 7.82 (2 H, d); 7.51 (1 H, t); 7.45 (2 H, t); 3.96-3.85 (1 H, m); 3.52 (2 H, t); 3.50, 3.32 (1 H each, ABq, 7=14.7 Hz); 2.92 (2 H, t); 1.88 (2 H, d); 1.55 (2 H, q); 1.33 (3 H, s).
(5S)-5-{[(4-{r2-(l.l-dimethylethyl)-lH-indol-5-yllamino)piperidin-l- vDsulfonyllmethvU-5-methylimidazolidine-2,4-dione
LC-MS (APCI) m/z 462 (MH+).
Η NMR (DMSO-d6): δ 10.72 (1 H, s); 10.37 (1 H, s); 8.00 (1 H, s); 7.02 (1 H, d, 7=8.4 Hz); 6.58 (1 H, s); 6.45 (1 H, d, 7=8.4 Hz); 5.86 (1 H, s); 4.65 (1 H, Br s); 3.48, 3.29 (1 H each, ABq, 7=14.7 Hz); 3.46 (2 H, t); 2.93 (2 H, t); 1.95 (2 H, t); 1.45-1.35 (2 H, m); 1.33 (3 H, s); 1.29 (9 H, s).
(5S)-5-methyl-5-[(piperidin-l-ylsulfonyl)methyllimidazolidine-2,4-dione LC-MS (APCI) m/z 276 (MH+).
Η NMR (DMSO-de): δ 10.70 (1 H, s); 7.97 (1 H, s); 3.44, 3.23 (1 H each, ABq, 7=14.8 Hz); 3.13-3.01 (4 H, m); 1.58-1.42 (6 H, m); 1.30 (3 H, s). (5S)-5-K3,6-dihvdropyridin-l(2H)-ylsulfonyl)methyll-5-methylimidazolidine-2,4- dione
LC-MS (APCI) m/z 274 (MΗ+).
Η NMR (DMSO-d6): δ 10.72 (1 H, s); 8.00 (1 H, s); 5.85-5.78 (1 H, m); 5.74-5.68 (1 H, m); 3.67-3.62 (2 H, m); 3.47, 3.33 (1 H each, ABq, 7=14.7 Hz); 3.22 (2 H, dd); 2.14-2.10 (2 H, m); 1.31 (3 H, s).
(5S)-5-methyl-5-(([4-(2-oxo-2,3-dihydro-lH-benzimidazol-l-yl)piperidin-l- yl]sulfonyl}methyl)imidazolidine-2,4-dione LC-MS (APCI) m/z 408 (MH+).
Η NMR (DMSO-de): δ 10.86 (1 H, s); 10.75 (1 H, s); 8.02 (1 H, s); 7.27-7.17 (1 H, m); 7.05-6.91 (3 H, m); 4.38-4.20 (1 H, m); 3.65 (2 H, t); 3.56, 3.38 (1 H each, ABq, 7=14.8 Hz); 3.03-2.90 (2 H, m); 2.41-2.24 (2 H, m); 1.76 (2 H, d); 1.34 (3 H, s).
(5S)-5-({[4-(lH-l,2<3-benzotriazoI-l-yl)piperidin-l-vnsulfonyl}methyl)-5- methylimidazolidine-2,4-dione
LC-MS (APCI) m/z 393 (MH+).
Η NMR (DMSO-de): δ 10.77 (1 H, s); 8.05 (1 H, s); 8.05 (1 H, d); 7.93 (1 H, d); 7.56 (1 H, t); 7.41 (1 H, t); 5.12-4.97 (1 H, m); 3.71 (2 H, t); 3.58, 3.43 (1 H each, ABq, 7=14.7 Hz); 3.19-3.03 (2 H, m); 2.29-2.16 (4 H, m); 1.35 (3 H, s).
(5S)-5-methvI-5-((r4-(pyridin-2-ylethvnvn-3.6-dihvdropyridin-l(2H)- yl]sulfonyI}methvDimidazolidine-2,4-dione trifluoroacetic acid
LC-MS (APCI) m/z 375 (MH+). Η NMR (DMSO-d6): δ 10.57 (1 H, s); 8.56 (1 H, d); 8.03 (1 H, s); 7.82 (1 H, t); 7.53 (1 H, d); 7.38 (1 H, dd); 6.31 (1 H, br s); 3.83 (2 H, d); 3.54, 3.41 (1 H each, ABq, 7=14.8 Hz); 3.36-3.25 (2 H, m); 2.42-2.34 (2 H, m); 1.32 (3 H, s). 19F NMR (DMSO-de): δ -75.10 (5S)-5-methyl-5-((r4- 4-methylphenvnethvnyll-3,6-dihydropyridin-l(2H)- yllsulfonyl}methyPimidazolidine-2,4-dione
LC-MS (APCI) m/z 388 (MH+).
Η NMR (DMSO-de): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.32 (2 H, d); 7.19 (2 H, d); 6.17 (1 H, br s); 3.80 (2 H, d); 3.52, 3.39 (1 H each, ABq, 7=14.8 Hz); 3.29 (2 H, t); 2.39-2.32 (2 H, m); 2.30 (3 H, s); 1.32 (3 H, s).
(5S -5-({[4-[(4-chlorophenyl)ethvnyl]-3,6-dihvdropyridin-l(2H)-yllsulfonyl}methvπ- 5-methylimidazolidine-2,4-dione LC-MS (APCI) m/z 408 (MH+).
Η NMR (DMSO-de): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.54-7.38 (4 H, m); 6.23 (1 H, br s); 3.87-3.76 (2 H, m); 3.53, 3.41 (1 H each, ABq, 7=14.9 Hz); 3.34-2.25 (2 H, m); 2.42-2.29 (2 H, m); 1.32 (3 H, s).
(5S -5-[4-(3,4-Dichloro-phenoxy)-piperidine-l-sulfonylmethvIl-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z (APCI) m/z 436.1 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.53 (1 H, d, 7=9.2 Hz); 7.31 (1 H, d, 7=2.9 Hz); 7.02 (1 H, dd, 7=9.2, 2.9 Hz); 4.65-4.57 (1 H, m); 3.51, 3.34 (1 H each, ABq, 7=15.2 Hz); 3.39-3.27 (2 H, m); 3.17-3.08 (2 H, m); 2.00-1.90 (2 H, m); 1.75-1.65 (2 H, m); 1.33 (3 H, s).
(5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione LC-MS (APCI) m/z 403.3 (MH+).
Η NMR (DMSO-de): δ 10.74 (1 H, s); 8.20 (1 H, d, 7=2.7 Hz); 7.81 (1 H, dd, 7=8.7, 2.7 Hz); 6.87 (1 H, d, 7=2.7 Hz); 5.16-5.03 (1 H, m); 3.52, 3.35 (1 H each, ABq, 7=15.0 Hz); 3.43-3.28 (2 H, m); 3.19-3.07 (2 H, m); 2.08-1.95 (2 H, m); 1.80-1.65 (2 H, m); 1.33 (3 H, s). (5S)-5-Methyl-5-[4-(5-trifluoromethyl-pyridin-2-yIoxy)-piperidine-l-sulfonylmethyll- imidazolidine-2,4-dione
LC-MS (APCI) m/z 437 (MH+). Η NMR (CDC13): δ 8.95 (1 H, s); 8.42-8.38 (1 H, m); 7J9 (1 H, dd, 7=8.8, 2.5 Hz); 6.81 (1 H, d, 7=8.8 Hz); 6.71 (1 H, s); 5.40-5.28 (1 H, m); 3.52-3.39 (2 H, m); 3.40-3.28 (2 H, m); 3.32 (2 H, ABq, 7=24.6, 14.0 Hz); 2.16-2.02 (2 H, m); 2.02-1.84 (2 H, m); 1.67 (3 H, s).
6-fl-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-yloxy1- nicotinonitrile
LC-MS (APCI) m/z 394.3 (MH+).
'H NMR (DMSO- d6): δ 10.72 (1 H, s); 8.68 (1 H, d, 7=2.3 Hz); 8.14 (1 H, dd, 7=8.7, 2.3 Hz); 8.00 (1 H, s); 6.98 (1 H, d, 7=8.7 Hz); 5.27-5.14 (1 H, m); 3.56-3.28 (4 H, m); 3.18- 3.06 (2 H, m); 2.08-1.96 (2 H, m); 1.81-1.66 (2 H, m); 1.31 (3 H, s).
(5S)-5-Methyl-5-(4-p-tolyloxy-piperidine-l-sulfonylmethvO-imidazolidine-2,4-dione
LC-MS (APCI) m/z 382.5 (MH+).
Η NMR (DMSO- d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 7.09 (2 H, d, 7=8.4 Hz); 6.87 (2 H, d, 7=8.4 Hz); 4.50-4.42 (1 H, m); 3.50, 3.34 (1 H each, ABq, 7=14.8 Hz); 3.38-3.29 (2 H, m); 3.17-3.09 (2 H, m); 2.23 (3 H, s); 1.99-1.89 (2 H, m); 1.73-1.63 (2 H, m); 1.33 (3 H, s).
(5S)-5-Methyl-5-14-(4-trifluoromethyl-phenoxy)-piperidine-l-sulfonylmethyll- imidazolidine-2.4-dione LC-MS (APCI) m/z 436.3 (MH+).
'H NMR (DMSO- d6): δ 10.71 (1 H, brs); 8.02 (1 H, s); 7.65 (2 H, d, 7=8.8 Hz); 7.17 (2 H, d, 7=8.8 Hz); 4.72-4.64 (1 H, m); 3.52, 3.35 (1 H each, ABq, 7=14.7 Hz); 3.40-3.28 (2 H, m); 3.19-3.10 (2 H, m); 2.05-1.95 (2 H, m); 1.78-1.68 (2 H, m); 1.33 (3 H, s). 4-[l-(4S)-4-Methyl-2,5-dioxo-imidazolidin-4-yImethanesulfonyl)-piperidin-4-yloxyl- benzonitrile
LC-MS (APCI) M/Z 393.2 (MH+).
Η NMR (DMSO- d6): δ 10.73 (1 H, s); 8.00 (1 H, s); 7.76 (2 H, d, 7=8.8 Hz); 7.15 (2 H, d, 7=8.8 Hz); 4.74-4.65 (1 H, m); 3.51, 3.34 (1 H each, ABq, 7=14.9 Hz); 3.40-3.27 (2 H, m); 3.17-3.07 (2 H, m); 2.03-1.94 (2 H, m); 1.77- 1.66 (2 H, m); 1.32 (3 H, s).
(5S -5-f4-(4-Methoxy-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl-imidazolidine- 2,4-dione LC-MS (APCI) m/z 398.2 (MH+).
Η NMR (DMSO- d6): δ 10.73 (1 H, s); 8.01 (1 H, s); 6.89 (4 H, ABq, 7=29.1, 9.1 Hz); 4.43-4.34 (1 H, m); 3.70 (3 H, m); 3.51, 3.33 (1 H, ABq, 7=15.0 Hz); 3.38-3.28 (2 H, m); 3.16-3.05 (2 H, m); 1.97-1.87 (2 H, m); 1.73-1.62 (2 H, m); 1.33 (3 H, s).
(5S)-5-[4-(3,4-Difluoro-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 404.2 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.35 (1 H, q, 7=19.6, 9.2 Hz); 7.19- 7.11 (1 H, m); 6.86-6.80 (1 H, m); 4.57-4.48 (1 H, m); 3.51, 3.34 (1 H each, ABq, 7=14.9 Hz); 3.38-3.28 (2 H, m); 2.16-2.06 (2 H, m); 2.00-1.90 (2 H, m); 1.74-1.64 (2 H, m); 1.33 (3 H, s).
(5S)-5-f4-(4-Chloro-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl-imidazolidine- 2.4-dione LC-MS (APCI) m/z 402 (MH+).
Η NMR (DMSO- d6): δ 10.73 (1 H, s); 8.00 (1 H, s); 7.32 (2 H, d, 7=8.8 Hz); 7.00 (2 H, d, 7=8.8 Hz); 4.56-4.48 (1 H, m); 3.50, 3.33 (1 H each, ABq, 7=14.8 Hz); 3.37-3.28 (2 H, m); 3.16-3.06 (2 H, m); 2.00-1.90 (2 H, m); 1.73-1.63 (2 H, m); 1.32 (3 H, s). (5S)-5-[4-(5-Ethyl-pyrimidin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 398 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.47 (2 H, s); 8.02 (1 H, s); 5.11-5.03 (1 H, m); 3.52, 3.35 (1 H each, ABq, 7=14.8 Hz); 3.42-3.28 (2 H, m); 3.19-3.10 (2 H, m); 2.54 (2 H, q, 7=15.2, 7.6 Hz); 2.06-1.98 (2 H, m); 1.81-1.71 (2 H, m); 1.33 (3 H, s); 1.17 (3 H, t, 7=7.2 Hz).
(5S)-5-Methyl-5-[4-(4-trifluoromethyl-pyrimidin-2-vIoxy)-piperidine-l- sulfonylmethyll-imidazolidine^^-dione LC-MS (APCI) m/z 438 (MH+).
'H NMR (CDC13): δ 8.84-8.76 (1 H, m); 8.02 (1 H, s); 7.31 (1 H, d, 7=4.8 Hz); 6.33 (1 H, s); 5.41-5.34 (1 H, m); 4.54-4.42 (4 H, m); 3.35, 3.24 (1 H each, ABq, 7=12.9 Hz); 2.17- 2.07 (4 H, m); 2.02 (3 H, s).
(5S -5-Methyl-5-f4-(5-methyl-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll- imidazolidine-2,4-dione
LC-MS (APCI) m/z 383 (MH+).
1H NMR (CDCI3): δ 8.14 (1 H, s); 8.06-7.99 (2 H, m); 7.19 (1 H, s); 7.09 (1 H, d, 7=11.6 Hz); 5.28-5.21 (1 H, m); 3.70-3.41 (6 H, m); 2.44 (3 H, s); 2.13-1.96 (4 H, m); 1.62 (3 H, s).
(5S)-5-[4-(4-Fluoro-benzoyl)-piperidine-l-sulfonylmethyl1-5-methyl-imidazolidine- 2.4-dione LC-MS (APCI) m/z 398 (MH+).
Η NMR (DMSO- d6): δ 8.06 (2 H, q, 7=9.2, 6.0 Hz); 7.40 (2 H, t, 7=8.8 Hz); 3.61-3.41 (4 H, m); 3.00-2.91 (2 H, m); 1.90-1.81 (2 H, m); 1.62-1.50 (2 H, m); 1.33 (3 H, s). (5S)-5-f4-(5-Fluoro-pyrimidin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 388 (MH+).
'H NMR (CDC13): δ 8.42 (2 H, s); 8.30 (1 H, s); 6.40 (1 H, s); 5.30-5.23 (1 H, m); 3.53- 3.35 (4 H, m); 3.36, 3.21 (1 H each, ABq, 7=14.4 Hz); 2.10-2.02 (4 H, m); 1.70 (3 H, s).
(5S -5-[4-(6-Methoxy-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 399 (MH+). Η NMR (MeOD): δ 7.54 (1 H, t, 7=8.4 Hz); 6.33-6.28 (2 H, m); 5.24-5.14 (1 H, m); 3.86 (3 H, s); 3.53-3.42 (2 H, m); 3.58, 3.39 (1 H each, ABq, 7=14.4 Hz); 3.30-3.22 (2 H, m); 2.13-2.02 (2 H, m); 1.96-1.82 (2 H, m); 1.47 (3 H, s).
(5S)-5-f4-(6-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 403 (MH+).
Η NMR (MeOD): δ 7.65 (1 H, t, 7=7.8 Hz); 6.97 (1 H, d, 7=7.2 Hz); 6J3 (1 H, d, 7=7.2
Hz); 5.25-5.14 (1 H, m); 3.55-3.44 (2 H, m); 3.58, 3.39 (1 H each, ABq, 7=14.4 Hz); 3.28-
3.19 (2 H, m); 2.14-2.02 (2 H, m); 1.92-1.79 (2 H, m); 1.47 (3 H, s).
3-[l-((4S)-4-Methyl-2.5-dioxo-imidazolidin-4-ylmethanesulfonvO-piperidin-4-yloxyl- benzonitrile
LC-MS (APCI) m/z 393 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.52-7.47 (2 H, m); 7.42-7.38 (1 H, m); 7.36-7.31 (1 H, m); 4.69-4.61 (1 H, m); 3.52, 3.35 (1 H each, ABq, 7=17.2 Hz); 3.18-
3.07 (2 H, m); 2.02-1.95 (2 H, m); 1.79- 1.65 (2 H, m); 1.33 (3 H, s). (5S)-5-f4-(3-Methoxy-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl-imidazoIidine- 2,4-dione
LC-MS (APCI) m/z 398 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.21-7.15 (1 H, m); 6.58-6.50 (3 H, m); 4.57-4.49 (1 H, m); 3.73 (3 H, s); 3.51, 3.34 (1 H each, ABq, 7=14.4 Hz); 3.17-3.08 (2 H, m); 2.01-1.91 (2 H, m); 1.74-1.64 (2 H, m); 1.33 (3 H, s).
N-{4-fl-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonvπ-piperidin-4- yloxyl-phenv -acetamide LC-MS (APCI) m/z 425 (MH+).
Η ΝMR (DMSO- d6): δ 10.69 (1 H, brs); 9.78 (1 H, s); 8.00 (1 H, s); 7.47 (2 H, d, 7=9.2 Hz); 6.91 (2 H, d, 7=9.2 Hz); 4.48-4.41 (1 H, m); 3.51 (1 H from ABq, 7=14.4 Hz); 3.16- 3.06 (2 H, m); 2.00 (3 H, s); 1.98-1.90 (2 H, m); 1.73-1.63 (2 H, m); 1.33 (3 H, s).
(5S -5-[4-(3-Chloro-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl-imidazolidine- 2,4-dione
LC-MS (APCI) m/z 402 (MH+).
Η ΝMR (DMSO- d6): δ 10.76 (1 H, brs); 7.99 (1 H, s); 7.31 (1 H, t, 7=8.4 Hz); 7.08 (1 H, t, 7=2.2 Hz); 7.02-6.95 (2 H, m); 4.64-4.56 (1 H, m); 3.51 (1 H from ABq, 7=14.4 Hz); 3.17-3.09 (2 H, m); 2.00-1.91 (2 H, m); 1.75-1.65 (2 H, m); 1.33 (3 H, s).
(5S)-5-Methyl-5-f4-(4-trifluoromethoxy-phenoxy)-piperidine-l-sulfonylmethyll- imidazolidine-2,4-dione
LC-MS (APCI) m/z 452 (MH+). Η ΝMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.29 (2 H, d, 7=8.8 Hz); 7.08 (2 H, d, 7=9.2 Hz); 4.60-4.52 (1 H, m); 3.51 (1 H from ABq, 7=14.8 Hz); 3.17-3.08 (2 H, m); 2.02- 1.93 (2 H, m); 1.75- 1.65 (2 H, m); 1.33 (3 H, s). (5S)-5-Methyl-5-[4-(3-trifluoromethoxy-phenoxy)-piperidine-l-sulfonylmethyll- imidazolidine-2.4-dione
LC-MS (APCI) m/z 452 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.41 (1 H, t, 7=8.4 Hz); 7.06-6.91 (3 H, m); 4.65-4.58 (1 H, m); 3.51 (1 H from ABq, 7=14.8 Hz); 3.18-3.08 (2 H, m); 2.02-1.93 (2 H, m); 1J6-L65 (2 H, m); 1.33 (3 H, s).
(5S)-5-f4-(2,4-Difluoro-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2 ,4-dione LC-MS (APCI) m/z 404 (MH+).
'H NMR (DMSO- d6): δ 10.74 (1 H, s); 8.02 (1 H, s); 7.34-7.23 (2 H, m); 7.06-6.97 (1 H, m); 4.50-4.41 (1 H, m); 3.50 (1 H from ABq); 3.17-3.06 (2 H, m); 2.02-1.90 (2 H, m); 1.78-1.65 (2 H, m); 1.33 (3 H, s).
(5S)-5-14-(4-Fluoro-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl-imidazolidine- 2,4-dione
LC-MS (APCI) m/z 386 (MH+).
Η NMR (DMSO- d6): δ 10.75 (1 H, s); 8.02 (1 H, s); 7.17-6.97 (2 H, m); 4.52-4.43 (1 H, m); 3.17-3.06 (2 H, m); 2.00-1.89 (2 H, m); 1J5-1.62 (2 H, m); 1.33 (3 H, s).
(5S)-5-[4-(3-Fluoro-phenoxy)-piperidine-l-sulfonylmethyll-5-methyl-imidazolidine- 2,4-dione
LC-MS (APCI) m/z 386 (MH+).
'H NMR (DMSO- d6): δ 10.72 (1 H, s); 8.02 (1 H, s); 7.36-7.26 (1 H, m); 6.91-6J1 (3 H, m); 4.62-4.52 (1 H, m); 3.18-3.06 (2 H, m); 2.02-1.91 (2 H, m); 1.78-1.63 (2 H, m); 1.33 (3 H, s). (5S)-5-f4-(2-Fluoro-phenoxy)-piperidine-l-sulfonylmethyll-5-methyI-imidazolidine- 2,4-dione
LC-MS (APCI) m/z 386 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.28-J17 (2 H, m); 7.17-J08 (1 H, m); 7.02-6.97 (1 H, m); 4.59-4.47 (1 H, m); 2.04-1.92 (2 H, m); 1.80-1.67 (2 H, m); 1.33 (3
H, s).
(5Sr)-5-[4-(5-Methoxy-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl1-5-methyl- imidazolidi ne-2 ,4-dione LC-MS (APCI) m/z 399 (MH+).
Η NMR (DMSO- d6): δ 10.74 (1 H, s); 8.01 (1 H, s); 7.89 (1 H, d, 7=3.16 Hz); 7.39 (1 H, dd, 7=3.18, 9.07 Hz); 6.77 (1 H, d, 7=8.95 Hz); 5.08-4.96 (1 H, m); 3.76 (3 H, s); 3.51, 3.34 (1 H each, ABq, 7=14.7 Hz); 3.43-3.29 (2 H, m); 3.18-3.05 (2 H, m); 2.05-1.94 (2 H, m); 1.77-1.61 (2 H, m); 1.33 (3 H, s).
(5S)-5-Methyl-5-[4-(4-pyridin-3-yl-phenyl)-piperazine-l-sulfonylmethyll- imidazolidine-2,4-dione
LC-MS (APCI) m/z 430 (MH+).
Η NMR (DMSO- d6): δ 10.76 (1 H, s); 8.99 (1 H, s); 8.60 (1 H, d, 7=4.91 Hz); 8.35 (1 H, d, 7=7.81 Hz); 8.04 (1 H, s); 7J0 (2 H, d, 7=8.87 Hz); 7.12 (2 H, d, 7=8.91 Hz); 3.57 (1 H from ABq); 3.35 (4 H, m); 3.27 (4 H, m); 1.33 (3 H, s).
(5SV5-methyl-5-( 4-(pyridin-2-yloxy)piperidin-l-vIlsulfonvI}methvI midazolidine- 2.4-dione LC-MS (APCI) m/z 369 (MH+).
Η NMR (CDC13): δ 1.73 (3H, s); 1.96-2.04 (2H, m); 2.04-2.13 (2H, m); 3.21 (IH, d); 3.36-3.42 (3H, m); 3.45-3.50 (2H, m); 5.29-5.33 (IH, m); 6.30 (IH, bs); 6J8 (IH, d); 6.93 (IH, t); 7.65 (IH, t); 7.70 (IH, bs); 8.16 (IH, d). (5S)-5-f({4-f(3,4-dimethylbenzvDoxylpiperidin-l-yl)sulfonyl)methvH-5- methylimidazolidine-2,4-dione
(NB. contains 30%) of the 2,3-dimethyl isomer which was in the starting material) LC-MS (APCI) m/z 410 (MH+). 'H NMR (DMSO-d6): δ 1.3 (3 H, s); 1.53-1.64 (2H, m); 1.83-1.89 (2H, m); 2.18 (3 H, s); 2.20 (3H, s); 2.95-3.33 (2H, m); 3.25-3.31 (3H, m); 3.45 (IH, d); 3.45-3.53 (IH, m); 4.42 (2H, s); 7.01-7.15 (3H, m); 7.97 (IH, s); 10.70 (IH, s).
(5S -5-methyl-5-{r(4-phenoxypiperidin-l-yl)sulfonyllmethv imidazolidine-2,4-dione LC-MS (APCI) m/z 368 (MH+).
Η NMR (DMSO-de): δ 1.30 (3H, s); 1.64-1.73 (2H, m); 1.92-2.00 (2H, m); 3.08-3.15 (2H, m); 3.28-3.44 (4H, m); 4.49-4.54 (IH, m); 6.92 (IH, t); 6.96 (2H, d); 7.28 (2H, t); 7.69 (IH, bs); 10.7 (1 H, bs).
4-Fluoro-N-[l-((4S)-4-methyI-2,5-dioxo-imidazolidin-4-vImethanesulfonyl)-piperidin- 4-yll-benzamide
LC-MS (APCI) m/z 413 (MH+).
Η ΝMR (DMSO- d6): δ 10.73 (1 H, s); 8.34 (1 H, d, 7=7.50 Hz); 8.02 (1 H, s); 7.94-7.88 (2 H, m); 7.33-7.26 (2 H, m); 3.96-3.86 (1 H, m); 3.58-3.47 (2 H, m); 3.51, 3.32 (1 H each, ABq, 7=14.81 Hz); 2.97-2.88 (2 H, m); 1.92-1.84 (2 H, m); 1.62-1.48 (2 H, m); 1.33 (3 H, s).
(5S)-5-[({4-r(2,5-dimethylbenzyl)oxylpiperidin-l-vπsulfonvDmethvπ-5- methylimidazolidine-2,4-dione LC-MS (APCI) m/z 410 (MH+).
Η ΝMR (DMSO-de): δ 1.30 (3H, s); 1.54-1.62 (2H, m); 1.85-1.91 (2H, m); 2.21 (3H, s); 2.24 (3H, s); 2.97-3.03 (2H, m); 3.27-3.34 (3H, m); 3.45 (IH, d); 3.49-3.55 (IH, m); 6.97- 7.04 (2H, m); 7.11 (IH, s); 7.98 (IH, s); 10.70 (IH, s). (5S)- 5-{f4-(5-chloropyridin-2-yl)piperidin-l-yllsulfonyl}-5-methylimidazolidine-2.4- dione
LC-MS (APCI) m z 387 (MH+).
Η NMR (DMSO-de): δ 10.72 (1 H, s); 8.54 (1 H, d); 8.01 (1 H, s); 7.86 (1 H, dd); 7.38 (1 H, d); 3.61 (2 H, bt); 3.50, 3.32 (1 H each, ABq, 7=14.9 Hz); 2.96-2.76 (3 H, m); 1.92 (2 H, brd); 1.77-1.62 (2 H, m); 1.33 (3 H, s).
(5S)-5-f4-(5-Benzyloxy-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione LC-MS (APCI) m/z 475 (MH+).
1H NMR (DMSO-de): δ 10.73 (IH, s); 8.01 (IH, s); 7.90 (IH, d, 7=3.13 Hz); 7.48-7.30 (6H, m); 6.76 (IH, d, 7=8.97 Hz); 5.10 (2H, s); 5.05-4.98 (IH, m); 3.51 (IH (from ABq), 7=14.84 Hz); 3.40-3.30 (3H, m); 3.15-3.07 (2H, m); 2.07-1.95 (2H, m); 1.74-1.64 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(6-Chloro-pyridine-3-yloxy)-piperidine-l-sulfonylmethyl1 -5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 403 (MH+). Η NMR (DMSO-d6): δ 10.74 (IH, s); 8.17 (IH, d, 7=3.10 Hz); 8.01 (IH, s); 7.56 (IH, dd, 7=3.18, 8.80 Hz); 7.44 (IH, d, 7=8.77 Hz); 4.67-4.59 (IH, m); 3.52, 3.35 (2H, ABq, 7=15.22 Hz); 3.39-3.28 (2H, m); 3.17-3.08 (2H, m); 2.03-1.93 (2H, m); 1.77-1.67 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-Hvdroxy-pyridin-2-yloxy)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2.4-dione
LC-MS (APCI) m/z 385 (MH+).
Η NMR (Methanol-cU): δ 7.73 (IH, d, 7=3.01 Hz); 7.53 (IH, dd, 7=3.11, 9.03 Hz); 7.04 (IH, d, 7=9.04 Hz); 3.80-3.67 (IH, m); 3.58, 3.41 (2H, ABq, 7=15.04 Hz); 3.53-3.42 (2H, m); 3.36-3.18 (2H, m); 2.17-2.02 (2H, m); 1.96-1.81 (2H, m); 1.48 (3H, s).
(5S)-5-f4-(4-Chloro-phenylsulfanyl)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 418 (MH+).
Η NMR (DMSO-de): δ 10.74 (IH, s); 8.00 (IH, s); 7.45-7.39 (4H, m); 2.97-2.89 (2H, m);
2.00-1.91 (2H, m); 1.56-1.45 (2H, m); 1.31 (3H, s).
(5S)-5-[4-(4-Chloro-benzenesulfonyl)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 450 (MH+). Η NMR (DMSO-d6): δ 10.73 (IH, s); 7.99 (IH, s); 7.86 (2H, d, 7=8.77 Hz); 7.77 (2H, d, 7=8.75 Hz); 3.66-3.54 (2H, m); 3.50-3.41 (IH, m); 3.44, 3.32 (IH each, ABq, 7=14.63 Hz); 2.82-2.73 (2H, m); 1.97-1.88 (2H, m); 1.57-1.42 (2H, m); 1.30 (3H, s).
(5S)-5-[4-(4-Fluoro-phenylamino)-piperidine-l-sulfonylmethyll-5-methyl- imidazolidine-2.4-dione
LC-MS (APCI) m/z 385 (MH+).
Η NMR (Methanol-d4): δ 7.20-7.1 1 (4H, m); 3.84-3.71 (2H, m); 3.60-3.48 (IH, m); 3.56, 3.39 (IH each, ABq, 7=14.96 Hz); 2.97-2.84 (2H, m); 2.10-2.00 (2H, m); 1.69-1.53 (2H, m); 1.46 (3H, s). N-{3-[l-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4- yloxyl-phenyll-acetamide
LC-MS (APCI) m/z 425 (MH+).
Η ΝMR (DMSO-de): δ 10.74 (IH, s); 9.89 (IH, s); 8.01 (IH, s); 7.37-7.33 (IH, m); 7.21- 7.14 (IH, m); 7.08-7.03 (IH, m); 6.65 (IH, dd, 7=1.89, 8.04 Hz); 4.49-4.42 (IH, m); 3.51, 3.34 (IH each, ABq, 7=14.73 Hz); 3.39-3.28 (2H, m); 3.18-3.08 (2H, m); 2.02 (3H, s); 2.00-1.92 (2H, m); 1.76- 1.65 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(4-Chloro-benzoyl)-piperazine-l-sulfonylmethyll-5-methyl-imidazolidine- 2,4-dione
LC-MS (APCI) m/z 415 (MH+).
Η ΝMR (DMSO-d6): δ 10.75 (IH, s); 8.04 (IH, s); 7.54 (2H, d, 7=8.38 Hz); 7.45 (2H, d, 7=8.38 Hz); 3.79-3.55 (2H, bs); 3.56, 3.35 (IH each, ABq, 7=14.84 Hz); 3.51-3.31 (2H, bs); 3.27-3.06 (4H, bs); 1.33 (3H, s).
l-((4S)-4-Methyl-2,5-dioxo-imidazolidine-4-ylmethanesulfonyl')-piperidine-4- carboxylic acid (4-fluoro-phenyl)-amide LC-MS (APCI) m/z 413 (MH+).
Η ΝMR (DMSO-de): δ 10.74 (IH, s); 9.97 (IH, s); 8.02 (IH, s); 7.65-7.58 (2H, m); 7.16- 7.09 (2H, m); 3.62-3.52 (2H, m); 3.49, 3.33 (IH each, ABq, 7=14.94 Hz); 2.87-2.77 (2H, m); 2.48-2.39 (IH, m); 1.91-1.84 (2H, m); 1.70-1.57 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-Bromo-pyridin-2-yloxy)-piperidine-l-suIfonyImethyll-5-methvI- imidazolidine-2.4-dione
LC-MS (APCI) m/z 447, 449 (MH+).
Η ΝMR (DMSO-de): δ 10.73 (IH, s); 8.28 (IH, d, 7=2.64 Hz); 8.01 (IH, s); 7.91 (IH, dd,
7=2.60, 8.84 Hz); 6.83 (IH, d, 7=8.79 Hz); 5.12-5.05 (IH, m); 3.52, 3.35 (IH each, ABq, 7=14.85 Hz); 3.41-3.34 (2H, m); 3.17-3.08 (2H, m); 2.06-1.97 (2H, m); 1.78-1.67 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-(4-Fluoro-phenyl)-pyridin-2-yl)-piperazine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 448 (MH+).
'H NMR (DMSO-de): δ 10.75 (IH, s); 8.45 (IH, d, 7=2.51 Hz); 8.02 (IH, s); 7.88 (IH, dd, 7=2.57, 8.86 Hz); 7.70-7.62 (2H, m); 7.30-7.22 (2H, m); 6.98 (IH, d, 7=8.94 Hz); 3.70- 3.62 (4H, m); 3.55, 3.36 (1 H each, ABq, 7=14.73 Hz); 3.26-3.19 (4H, m); 1.32 (3H, s)
(5S)-5-[4-(5-(4-Methoxy-phenvI)-pyridin-2-yl)-piperazine-l-sulfonvImethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 460 (MH+).
(5S)-5-[4-(5-(4-Chloro-phenyl)-pyridin-2-vπ-piperazine-l-sulfonylmethyll-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 464, 466 (MH+).
(5S)-5-[4-(5-(4-Trifluoromethoxy-phenyl)-pyridin-2-yl)-piperazine-l-sulfonylmethyll- 5-methyl-imidazolidine-2,4-dione LC-MS (APCI) m/z 514 (MH+).
(5S)-5-[4-(5-Furan-2-yl-pyridin-2-yl)-piperazine-l-sulfonylmethvI]-5-methyl- imidazolidine-2,4-dione LC-MS (APCI) m/z 420 (MH+).
(5S)-5-Methyl-5-(4-f5-(lH-pyrrol-2-vn-pyridine-2-yll-piperazine-l-sulfonylmethvn- imidazolidine-2,4-dione
LC-MS (APCI) m/z 419 (MH+). (5S)-5-(4-[3,3,l-Bipyridinyl-6-yl-piperazine-l-sulfonylmethyl)-5-methyl- imidazolidine-2,4-dione
LC-MS (APCI) m/z 431 (MH+).
(4S)-4-(6-f4-(4-Methyl-2,5-dioxo-imidazoIidin-4-ylmethanesulfonyl)-piperazine-l-yll- pyridine-3-vD-benzonitrile
LC-MS (APCI) m/z 455 (MH+).
EXAMPLE 14
Compounds with the general formula
Figure imgf000134_0001
were synthesised according to the method described in Example 12.
Figure imgf000134_0002
Figure imgf000135_0001
(1) : NMR available, see experimental part.
5-K{4-f(5-chloropyridin-2-yl)oxylpiperidin-l-yl}sulfonvπmethyll-5-[(3<4,4-trimethyl- 2,5-dioxoimidazolidin-l-vI)methyl1imidazolidine-2,4-dione
The title compound was prepared as described in Examplel2 from racemic {2,5-dioxo-4-
[(3,4,4-trimethyl-2,5-dioxoimidazolidin-l-yl)methyl]imidazolidin-4-yl}methanesulfonyl chloride and 5-chloro-2-(piperidin-4-yloxy)-pyridine.
LC-MS (APCI) m/z 543 (MH+).
Η NMR (DMSO-d6): δ 1.28 (6H, s); 1.63-1.74 (2H, m); 1.95-2.05 (2H, m); 2J7 (3H, s);
3.14 (4H, d); 3.53-3.73 (3H, m); 4.14 (IH, q); 5.04-5.11 (IH, m); 6.85 (IH, d); 7.80 (IH, dd); 7.94 (IH, s); 8.19 (IH, d); 10.83 (IH, s).
The startingmaterial was prepared as follows:
3 - [3 -(benzylthio')-2-oxopropyl1 - 1.5 ,5-trimethylimidazolidine-2.4-dione
Benzyl mercaptan (256 μl, 2.2 mmol) was stirred with cesium carbonate (712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at room temperature for 1 hour. 3-(3-bromo-2- oxopropyl)-l,5,5-trimethylimidazolidine-2,4-dione (552 mg, 1.99 mmol) prepared as in W099/06361 was added and the mixture stirred 18 hours at room temperature. The reaction mixture was treated with water, extracted into ethyl acetate (3 x 25 ml), the organic phases combined, brine washed and dried. The product was purified by silica chromatography, eluting with 50% ethyl acetate / iso-hexane to give 300 mg product. LC-MS (APCI) m/z 321 (MH+). Η NMR (CDC13): δ 1.45 (6H, s); 2.91 (3H, s); 3.16 (2H, s); 3.70 (2H, s); 4.53 (2H, s); 7.22-7.33 (5H, m). 5-r(benzylthio)methyn-5-r(3,4.4-trimethyl-2,5-dioxoimidazolidin-l- yl)methyl]imidazolidine-2,4-dione
The title compound was prepared as described in the synthesis of 5-methyl-5-
{[(phenylmethyl)thio]methyl} imidazolidine-2,4-dione in Example 12.
LC-MS (APCI) m/z 391 (MH+).
Η NMR (DMSO-d6): δ 1.28 (6H, s); 2.64 and 2.76 (2H, abq, 7=14.2 Hz); 2.78 (3H, s);
3.54 & 3.64 (2H, abq, 7=14.2 Hz); 3.73 (2H, s); 7.20-7.32 (5H, m); 7.98 (IH, s); 10.83
(IH, s).
{2.5-dioxo-4-r(3.4.4-trimethyl-2.5-dioxoimidazolidin-l-yl)methvnimidazolidin-4- yll methanesulfonyl chloride
The title compound was prepared as described in the synthesis of [(4S) and (4R)-4-methyl- 2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride in Example 12. Η NMR (CD3OD): δ 1.38 (6H, s); 2.89 (3H, s); 3.81 and 3.92 (2H, abq, 7=14.3 Hz); 4.61 (2H, s).
The following compounds were prepared as described in the synthesis of 5- [({4- [(5- chloropyridin-2-yl)oxy]piperidin-l-yl}sulfonyl)methyl]-5-[(3, 4, 4-trimethyl-2, 5- dioxoimidazolidin-l-yl)methyl]imidazolidine-2, 4-dione.
5-F({4-[5-(trifluoromethyl)pyridin-2-yllpiperazin-l-yl)sulfonyl)methvIl-5-[(3,4,4- trimethyl-2,5-dioxoimidazoIidin-l-yl)methyllimidazolidine-2,4-dione
LC-MS (APCI) m/z 562 (MH+). Η NMR (DMSO-de): o 1.26 (6H, s); 2.76 (3H, s); 3.16-3.22 (4H, m); 3.48-3.76 (8H, m); 7.02 (IH, d); 7.81-7.76 (2H, m); 8.43 (IH, s); 10.83 (IH, s). 5-[4-(4-Fluoro-phenyl-piperazine-l-sulfonylmethyll-5-f(3,4,4-trimethyl-2,5- dioxoimidazolidin-l-yl)methyIlimidazolidine-2,4-dione
LC-MS (APCI) m/z 511 (MH+).
'H NMR (DMSO-d6): δ 1.28 (6H, s); 2.77 (3H, s); 3.10-3.16 (4H, m); 3.21-3.26 (4H, m); 5 3.48-3.71 (4H, m); 6.95-7.09 (4H, m); 7.88 (IH, s); 10.84 (IH, bs).
5-[({4-f(5-chloropyridin-2-yl)oxyIpiperidin-l-yl}sulfonvDmethyll-5-{2- [(phenylmethyl)oxy]ethyl}imidazolidine-2,4-dione
The title compound was prepared as described in the synthesis of 5-[({4-[(5-chloropyridin- l o 2-yl)oxy]piperidin- 1 -yl } sulfonyl)methyl] -5- [(3 ,4,4-trimethyl-2,5 -dioxoimidazolidin- 1 - yl)methyl]imidazolidine-2,4-dione starting from 5-Chloro-2-(piperidine-4-yloxy)-pyridine hydrochloride and (2,5-dioxo-4-{2-[(phenylmethyl)oxy]ethyl}imidazolidin-4- yl)methanesulfonyl chloride.
LC-MS (APCI) m/z 523 (MH+). is 'H NMR (DMSO-de): δ 1.37-1.79 (3H, m); 1.83-2.08 (4H, m); 3.00-3.56 (7H, m partially obscured by D2O); 4.33-4.44 (2H, m); 5.01-5.12 (IH, m); 6.85 (IH, d); 7.21-7.36 (5H, m);
7.80 (IH, dd); 8.02 (IH, s); 8.19 (IH, d); 10.70 (IH, bs).
6-({4-f(5-chloropyridin-2-vDoxylpiperidin-l-yl)sulfonyl ,3-diazaspiro[4.51decane- 0 2,4-dione
LC-MS (APCI) m/z 443 (MH+).
The startingmaterial was prepared as follows:
5 6- (phenylmethyl)thio]- 1.3-diazaspiror4.5]decane-2.4-dione
Benzylmercaptan (937mg, 7.5mmol) was dissolved in 70 mL of THF. NaH (362mg 60%), 9.0mmol) was added and the slurry was stirred for some minutes. 2-chlorocyclohexanone (l.Og, 7.5mmol) was added and the reaction was stirred at rt over night. The solid was filtered of and the solvent was removed by rotary evaporation. Potassium cyanid (4 eq), (NH4)2CO3 (8eq) and 25mL of ethanol was added. The reaction was stirred in a sealed vial at 80°C over night. The suspension was filtered and the solid was recrystallised from
DMSO and water to give the title compound as a white solid
LC-MS (APCI) m/z 291 (MH+).
Η NMR (DMSO-de): δ 1.21-1.81 (8H, m); 2.79 (IH, dd); 3.67-3.76 (2H, m); 7.18-7.32
(5H, m); 8.43 (IH, s); 10.68 (IH, s).
EXAMPLE 15
Figure imgf000138_0001
5-Methyl-5-(l-(toluene-4-sulfonyl)-cvclopentylHmidazolidine-2,4-dione l-(l-(Toluene-4-sulfonyl)-cyclopentyl))-ethanone (0.10 g, 0.38 mmol), potassium cyanide (0.049 g, 0J5 mmol), ammonium carbonate (0.18 g, 1.9 mmol), 50%) ethanol in water (1.6 mL) were stirred in a sealed tube (2 mL volume) at 90° C for 70 hours. The solution was acidified with 10% acetic acid to pH 6 and concentrated by rotary evaporation to half of its original volume upon which part of the product fell out. The solution and its solid contents were taken up in ethyl acetate, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give 0J4 g of a white solid. The crude product was dissolved in methanol (5 mL), concentrated with silica (1 g) by rotary evaporation and applied on a short silica column. Elution with ethyl acetate/ n-heptane (1 :2 and 2:1) gave 0.060 g (48%) of the title product as colourless needles. LC-MS (APCI) m/z 337 (MH+).
Η NMR (DMSO-ύfe): δ 0.96-1.10 (IH, m); 1.32-1.44 (IH, m); 1.36 (3H, s); 1.47-1.58 (2H, m); 2.10-2.30 (4H, m); 2.40 (3H, s); 7.41 (2H, d, 7= 8 Hz); 7.72 (2H, d, 7= 8 Hz); 7.80 (IH, bs) and 10.7 (lH, bs). 13C NMR (DMSO-έ β): δ 21.0, 22.60, 22.64, 26.1, 26.3, 30.8, 31.5, 64.1, 78.9, 129.2, 130.3, 135.3, 144.2, 156.0 and 176.2.
The starting material was prepared as follows: l-(Toluene-4-sulfonyl)-propan-2-one was prepared according to Crandall et al. J. Org. Chem. 1985, (8) 50, 1327-1329 from sodium ?-toluensulfinate dihydrate (4.2 g, 18 mmol), chloroacetone (1.0 mL, 12 mmol), n- tetrabutylammonium bromide (0.30 g) and water-benzene-acetone 4:3:3 (10 mL). Work-up and chromatography on silica of the crude using ethyl acetate/ n-heptane (1 :3 through 1 :2) as eluent gave 2.4 g (95%) of the title product as an oil which crystallised on standing in the fridge.
LC-MS (APCI) m/z 213 (MH+).
Η NMR (CDC13): δ 2.38 (3H, s); 2.42 (3H, s); 4.10 (2H, s); 7.35 (d2H, d, 7= 8 Hz); 7.74 (d, 2 H, d, 7= 8 Hz). 13C NMR (CDCI3): δ 21.7, 31.4, 67.7, 128.0, 129.8, 135.5, 145.3 and 195.9.
1 -( 1 -(Toluene-4-sulfonyl)-cvclopentyl))-ethanone l-(Toluene-4-sulfonyl)-propan-2-one (0.10 g, 0.47 mmol), 1 ,4-diiodobutane (0.068 mL, 0.52 mmol), finely ground potassium carbonate (0.14 g, 1.0 mmol) and dry dimethylsulfoxide (0.80 mL) were stirred at 50°C (oil bath temperature) for 22 hours. The heating was shut off and stirring was continued at 22° C for 22 hours. The crude product was taken up in ethyl acetate, washed with water (5x 50 mL) and brine (lx 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The oily residue was chromatographed on silica using ethyl acetate/ n-heptane (1 :4 through 1 :3) to give 0.10 g (80%) of the title product as a colourless oil.
LC-MS (APCI) m/z 267 (MH+).
Η NMR (CDCI3): δ 1.52 (2H, m); 1.77 (2H, m); 2.26 (2H, m); 2.37 (2H, m); 2.42 (3H, s);
2.48 (3H, s); 7.30 (2H, d, 7= 8 Hz) and 7.60 (2H, d, 7= 8 Hz).
13C NMR (CDCI3): δ 21.7, 25.4, 28.0, 31.3, 83.9, 129.4, 129.5, 133.2, 145.0 and 202.5.

Claims

CLAIMS:What we claim is:
1. A compound of the formula I or a pharmaceutically acceptable salt or an in vivo s hydrolysable ester thereof
Figure imgf000140_0001
wherein X is selected from NRl, O, S;
Yl and Y2 are independently selected from O, S;
Z is selected from SO, SO2; m is 1 or 2;
A is selected from a direct bond, (Cl-6)alkyl, (Cl-6)haloalkyl, or (Cl-6)heteroalkyl containing a hetero group selected from N, O, S, SO, SO2 or containing two hetero groups selected from N, O, S, SO, SO2 and separated by at least two carbon atoms;
Rl is selected from H, (Cl-3)alkyl, haloalkyl;
Each R2 and R3 is independently selected from H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-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, alkyl-cycloalkyl, alkyl-heterocycloalkyl;
Each R4 is independently selected from H, halogen, (Cl-3)alkyl or haloalkyl; Each of the R2 and R3 radicals may be independently optionally substituted with one or more groups selected from alkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, arylthiol, alkylsulfon, haloalkylsulfon, arylsulfon, aminosulfon, N-alkylaminosulfon, N,N-dialkylaminosulfon, 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-l,l-diamin, carboxy, alkylcarboxy, nitro, carbamate;
Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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;
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, carbamate; when R5 is a bicyclic or tricyclic group, each ring structure is joined to the next ring structure by a direct bond, by -O-, by (Cl-6)alkyl, by (Cl-6)haloalkyl, by (Cl-6)heteroalkyl, by (Cl-6)alkenyl, by (Cl-6)alkynyl, by sulfone, by CO, by NCO, by CON, by NH, by S, by C(OH) or is fused to the next ring structure
2. A compound of the formula I as claimed in claim 1 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein X is NRl, Z is SO2 or SO, at least one of Yl and Y2 is O, m is 1, and Rl is H, (Cl-3) alkyl, or (Cl-3) haloalkyl.
3. A compound of the formula I as claimed in either claim 1 or claim 2 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, cycloalkyl-alkyl, alkyl- cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl- heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl.
4. A compound of the formula I as claimed in any of the preceding claims or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein each of R3 and R4 is independently selected from H, methyl.
5. A compound of the formula I as claimed in any of the preceding claims or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein R5 comprises one, two or three optionally substituted aryl or heteroaryl 5 or 6 membered rings.
6. A compound of the formula I as claimed in any of the preceding claims or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein R5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures.
7. A compound of the formula II or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof
Figure imgf000143_0001
wherein each of Gl, G2 and G4 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, 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, aryloxy, heteroaryloxy, carbamate; Z is SO2, each of B and F is independently selected from a direct bond, O, (Cl-6)alkyl, (Cl- 6)heteroalkyl, alkynyl, CO, NCO, CON, NH, S;
R2 is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl;
R3 and R4 are independently selected from H or (Cl-3)alkyl; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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.
8. A compound of the formula II as claimed in claim 7 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein R2 is alkyl, aminoalkyl, alkyl- heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl.
9. A compound of the formula Ila or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof
Figure imgf000144_0001
wherein each of Gl 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, 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, aryloxy, heteroaryloxy, carbamate;
Z is SO2;
B is selected from a direct bond, O, (Cl-6)alkyl, (Cl-6)heteroalkyl, CO, NCO,CON, NH, S, akynyl; R2 is selected from H, (Cl-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of formula III
Figure imgf000145_0001
C and D are independently selected from a direct bond, H, (Cl-Cό)alkyl, (Cl-
C6)haloalkyl, or (Cl-Cό)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 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, 2- nitroguanidino, carboxy, alkylcarboxy, carbamate;
R3 and R4 are independently selected from H or (Cl-3)alkyl; Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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.
10. A compound of the formula Ila as claimed in claim 9 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein B is selected from a direct bond, O, CO, S, alkynyl.
11. A compound of the formula Ila as claimed in either claim 9 or claim 10 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein R2 is selected from H, (Cl-6)alkyl, aryl-(Cl-6)alkyl or heteroaryl-(Cl-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, carbamate, cyano, sulfonamino, alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguanidino, 2- nitroguanidino, 2-nitro-ethene-l,l-diamino, carboxy, alkylcarboxy, carbamate.
12. A compound of the formula Ila as claimed in any of claims 9 to 11 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, wherein each of R3 and R4 is H.
13. A compound of the formula lib or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof
Figure imgf000146_0001
wherein Gl 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, 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, aryloxy, heteroaryloxy, carbamate;
G2 is optionally substituted piperidine or piperazine; B is selected from a direct bond, O, (C 1 -6)alkyl, (C 1 -6)heteroalkyl, CO, NCO,CON,
NH, S, akynyl;
R2 is selected from H, (Cl-6)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of formula III
Figure imgf000147_0001
C and D are independently selected from a direct bond, H, (Cl-C6)alkyl, (Cl- C6)haloalkyl, or (Cl-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 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, 2- nitroguanidino, carboxy, alkylcarboxy, carbamate;
R3 and R4 are independently selected from H or (Cl-3)alkyl;
Optionally R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R2 and R4 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.
14. A pharmaceutical composition which comprises a compound of the formula I as claimed in claim 1 or a compound of the formula II as claimed in claim 7 or a compound of the formula Ila as claimed in claim 9 or a compound of the formula lib as claimed in claim 13 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier.
15. 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 formulae I or II or Ila or lib or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
16. Use of a compound of the formulae I or II or Ila or lib 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.
PCT/SE2002/000472 2001-03-15 2002-03-13 Metalloproteinase inhibitors WO2002074767A1 (en)

Priority Applications (24)

Application Number Priority Date Filing Date Title
CA2440630A CA2440630C (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
EP02704031A EP1370556B1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
SK1096-2003A SK287766B6 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
AU2002237626A AU2002237626B2 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
NZ528106A NZ528106A (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
MXPA03008191A MXPA03008191A (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors.
JP2002573776A JP2004527515A (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
KR1020037011987A KR100886315B1 (en) 2001-03-15 2002-03-13 Metalloproteinase Inhibitors
HU0400327A HUP0400327A3 (en) 2001-03-15 2002-03-13 Azole derivatives having metalloproteinase inhibitor effect pharmaceutical compositions containing them and their use
UA2003098171A UA78502C2 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors, use thereof, and pharmaceutical composition based thereon
US10/471,900 US7427631B2 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
BR0208104-0A BR0208104A (en) 2001-03-15 2002-03-13 Metalloproteinase Inhibitors
EEP200300445A EE05431B1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
SI200230386T SI1370556T1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
IL15765202A IL157652A0 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
DE60213216T DE60213216T2 (en) 2001-03-15 2002-03-13 metalloproteinase
PL02365099A PL365099A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
IL157652A IL157652A (en) 2001-03-15 2003-08-28 Metalloproteinase inhibitors, compositions comprising them and uses thereof for the preparation of medicaments for treating diseases or conditions mediated by metalloproteinase enzymes
IS6943A IS6943A (en) 2001-03-15 2003-09-09 metalloproteinase
NO20034045A NO327114B1 (en) 2001-03-15 2003-09-12 Metal proteinase inhibitors, pharmaceutical compositions comprising them, and uses thereof.
HK04102796A HK1059932A1 (en) 2001-03-15 2004-04-21 Metalloproteinase inhibitors
US11/928,040 US7625934B2 (en) 2001-03-15 2007-10-30 Metalloproteinase inhibitors
US12/115,785 US7754750B2 (en) 2001-03-15 2008-05-06 Metalloproteinase inhibitors
US12/830,763 US20110003853A1 (en) 2001-03-15 2010-07-06 Metalloproteinase Inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0100902-6 2001-03-15
SE0100902A SE0100902D0 (en) 2001-03-15 2001-03-15 Compounds

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US10471900 A-371-Of-International 2002-03-13
US11/928,040 Continuation US7625934B2 (en) 2001-03-15 2007-10-30 Metalloproteinase inhibitors
US12/115,785 Division US7754750B2 (en) 2001-03-15 2008-05-06 Metalloproteinase inhibitors

Publications (2)

Publication Number Publication Date
WO2002074767A1 true WO2002074767A1 (en) 2002-09-26
WO2002074767A8 WO2002074767A8 (en) 2004-04-22

Family

ID=20283374

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/SE2002/000478 WO2002074751A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
PCT/SE2002/000472 WO2002074767A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors
PCT/SE2002/000473 WO2002074748A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors

Family Applications Before (1)

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

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/SE2002/000473 WO2002074748A1 (en) 2001-03-15 2002-03-13 Metalloproteinase inhibitors

Country Status (33)

Country Link
US (8) US7368465B2 (en)
EP (4) EP1370534A1 (en)
JP (4) JP2004527515A (en)
KR (4) KR100879905B1 (en)
CN (5) CN1962641B (en)
AR (2) AR035695A1 (en)
AT (3) ATE333454T1 (en)
AU (2) AU2002237626B2 (en)
BR (3) BR0207983A (en)
CA (3) CA2440473C (en)
CY (1) CY1107525T1 (en)
CZ (3) CZ20032497A3 (en)
DE (3) DE60238794D1 (en)
DK (1) DK1370556T3 (en)
EE (3) EE05431B1 (en)
ES (3) ES2357138T3 (en)
HK (3) HK1059932A1 (en)
HU (3) HUP0400327A3 (en)
IL (5) IL157652A0 (en)
IS (3) IS6943A (en)
MX (3) MXPA03008191A (en)
MY (2) MY136141A (en)
NO (3) NO326087B1 (en)
NZ (3) NZ528107A (en)
PL (3) PL364707A1 (en)
PT (1) PT1370556E (en)
RU (3) RU2293729C2 (en)
SE (1) SE0100902D0 (en)
SI (1) SI1370556T1 (en)
SK (3) SK287834B6 (en)
UA (3) UA78502C2 (en)
WO (3) WO2002074751A1 (en)
ZA (4) ZA200306731B (en)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1397137A1 (en) * 2001-05-25 2004-03-17 Bristol-Myers Squibb Company Hydantion derivatives as inhibitors of matrix metalloproteinases
WO2004024718A1 (en) * 2002-09-11 2004-03-25 Astrazeneca Ab Imidazolidinedione-derivatives and their use as metalloproteinase inhibitors
WO2006004532A1 (en) * 2004-07-05 2006-01-12 Astrazeneca Ab Novel hydantoin derivatives for the treatment of obstructive airway diseases
WO2006004533A1 (en) * 2004-07-05 2006-01-12 Astrazeneca Ab Compounds
WO2006065215A1 (en) * 2004-12-17 2006-06-22 Astrazeneca Ab Novel compounds
WO2006065216A1 (en) * 2004-12-17 2006-06-22 Astrazeneca Ab Novel hydantoin derivatives as metalloproteinase inhibitors
WO2006064218A1 (en) * 2004-12-15 2006-06-22 Astrazeneca Ab Hydantoin derivatives useful as metalloproteinase inhibitors
WO2006034315A3 (en) * 2004-09-20 2006-07-27 Xenon Pharmaceuticals Inc Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-coa desaturase enzymes
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
WO2007078335A2 (en) * 2005-12-21 2007-07-12 Decode Genetics, Ehf. Biaryl nitrogen heterocycle inhibitors of lta4h for treating inflammation
WO2007106022A3 (en) * 2006-03-16 2007-11-01 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] - 5 -methyl -imidazolidine - 2,4-dione (i) and intermediates thereof.
US7354940B2 (en) 2002-08-27 2008-04-08 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
WO2008053199A1 (en) * 2006-10-30 2008-05-08 Astrazeneca Ab Combination therapy for the treatment of respiratory diseases
WO2009007747A2 (en) * 2007-07-11 2009-01-15 Astrazeneca Ab Hydantoin derivatives used as mmp12 inhibitors
JP2009530273A (en) * 2006-03-16 2009-08-27 アストラゼネカ・アクチエボラーグ Method for producing sulfonyl chloride derivative
WO2009134728A2 (en) 2008-04-28 2009-11-05 Revalesio Corporation Compositions and methods for treating multiple sclerosis
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
WO2011012897A1 (en) 2009-07-31 2011-02-03 Astrazeneca Ab New combinations for the treatment of asthma
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
EP2364704A1 (en) 2007-02-08 2011-09-14 AstraZeneca AB Combination of beta-adrenoceptor agonist and corticosteroid
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
EP2426120A1 (en) 2003-08-18 2012-03-07 Fujifilm Finechemicals Co., Ltd. Pyridyltetrahydropyridines and pyridylpiperidines, and method of manufacturing them
WO2012085582A1 (en) 2010-12-23 2012-06-28 Astrazeneca Ab Compound
WO2012085583A1 (en) 2010-12-23 2012-06-28 Astrazeneca Ab New compound
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
EP2907512A1 (en) 2014-02-14 2015-08-19 Commissariat A L'energie Atomique Et Aux Energies Alternatives Inhibitors of MMP-12 as antiviral Agents
WO2021260387A1 (en) 2020-06-26 2021-12-30 The University Of Birmingham Mmp-9 and mmp-12 inhibition for treating spinal cord injury or related injury to neurological tissue
US11718588B2 (en) 2014-12-22 2023-08-08 Galapagos Nv 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0100903D0 (en) * 2001-03-15 2001-03-15 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
GB0221246D0 (en) * 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
WO2004033632A2 (en) * 2002-10-04 2004-04-22 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme (tace)
WO2005090316A1 (en) * 2004-03-12 2005-09-29 Wyeth HYDANTOINS HAVING RNase MODULATORY ACTIVITY
US7648992B2 (en) * 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US20080187508A1 (en) * 2004-09-08 2008-08-07 Boys Town National Research Hospital Treatment of Golmerular Basement Membrane Disease Involving Matrix Metalloproteinase-12
MX2007011378A (en) * 2005-03-16 2008-03-18 Sensus Metering Systems Inc Method, system, apparatus, and computer program product for determining a physical location of a sensor.
PE20071240A1 (en) 2006-01-17 2008-01-14 Schering Corp HYDANTOIN-DERIVED COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS
CA2649926C (en) * 2006-05-12 2013-07-23 Sca Hygiene Products Ab Elastic laminate and a method for producing an elastic laminate
MX2008014154A (en) * 2006-05-12 2008-11-18 Sca Hygiene Prod Ab A pant-type absorbent article and a method for producing pant-type absorbent articles.
TW200831488A (en) * 2006-11-29 2008-08-01 Astrazeneca Ab Novel compounds
BRPI0722259A2 (en) 2007-11-14 2014-04-08 Sca Hygiene Prod Ab METHOD FOR PRODUCING AN ABSORBENT CLOTHING, AND ABSORBING CLOTHING PRODUCED IN ACCORDANCE WITH THE METHOD
BRPI0722260A2 (en) 2007-11-14 2014-04-01 Sca Hygiene Prod Ab METHOD OF PRODUCING AN ABSORBENT CLOTHING, AND AN ABSORBENT CLOTHING PRODUCED IN ACCORDANCE WITH 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
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
WO2011054734A1 (en) * 2009-11-06 2011-05-12 Basf Se 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
AU2011261375B2 (en) 2010-06-04 2016-09-22 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
CN103958480B (en) * 2012-09-04 2016-04-06 上海恒瑞医药有限公司 Imidazolines derivative, its preparation method and in application pharmaceutically
CN104854106B (en) 2012-12-10 2017-07-04 中外制药株式会社 Hydantoin derivatives
HUE050907T2 (en) * 2013-11-13 2021-01-28 Hankkija Oy Feed supplement comprising resin acids
ES2686353T3 (en) * 2013-12-31 2018-10-17 Ipsen Pharma S.A.S. New derivatives of imidazolidino-2,4-dione
CN106572994B (en) 2014-06-09 2020-09-18 中外制药株式会社 Pharmaceutical composition containing hydantoin derivatives
PL3209655T3 (en) 2014-10-24 2020-12-28 Landos Biopharma, Inc. Lanthionine synthetase c-like 2-based therapeutics
JP6934012B2 (en) * 2016-09-23 2021-09-08 科研製薬株式会社 Method for Producing (R) -5- (3,4-Difluorophenyl) -5-[(3-Methyl-2-oxopyridine-1 (2H) -yl) Methyl] Imidazolidine-2,4-dione and its Intermediate for manufacturing
WO2021011720A2 (en) * 2019-07-18 2021-01-21 Avidence Therapeutics, Inc. Anti-osteoarthritis compounds and related compositions and methods
US11673884B2 (en) 2019-11-14 2023-06-13 Foresee Pharmaceuticals Co., Inc. Matrix metalloproteinase (MMP) inhibitors and methods of use thereof
CA3135502C (en) 2019-12-20 2024-01-09 Josep Bassaganya-Riera Lanthionine c-like protein 2 ligands, cells prepared therewith, and therapies using same
CN115720578A (en) * 2020-07-09 2023-02-28 深圳信立泰药业股份有限公司 Tricyclic derivative, preparation method and medical application thereof
CN112574193B (en) * 2020-12-31 2022-05-17 南京医科大学 Oral GSNOR inhibitor and pharmaceutical application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999006361A2 (en) * 1997-07-31 1999-02-11 Abbott Laboratories N-hydroxyformamide derivatives as inhibitors of matrix metalloproteinases
WO1999024399A1 (en) * 1997-11-12 1999-05-20 Darwin Discovery Limited Hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity
WO2000040577A1 (en) * 1998-12-31 2000-07-13 Aventis Pharmaceuticals Inc. 1-carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of mmp-12
WO2001005756A1 (en) * 1999-07-14 2001-01-25 Pharmacia & Upjohn Spa 3-arylsulfonyl-2-(substituted methyl)propanoic acid derivates as matrix metalloproteinase inhibitors

Family Cites Families (90)

* 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
ATE183184T1 (en) 1994-01-31 1999-08-15 Pfizer NEUROPROTECTIVE CHROME COMPOUNDS
EP0709375B1 (en) 1994-10-25 2005-05-18 AstraZeneca AB Therapeutic 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
AU4812697A (en) * 1996-10-22 1998-05-15 Pharmacia & Upjohn Company Alpha-amino sulfonyl hydroxamic acids as matrix metalloproteinase inhibitors
HUP0003362A3 (en) 1997-05-06 2001-04-28 Novo Nordisk As Piperidine derivatives and pharmaceutical compositions containing them
DK0877019T3 (en) 1997-05-09 2002-04-08 Hoechst Ag Substituted diaminocarboxylic acids
KR20010014020A (en) 1997-06-21 2001-02-26 로셰 디아그노스틱스 게엠베하 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
TW514634B (en) 1997-10-14 2002-12-21 Lilly Co Eli Process to make chiral compounds
RU2208609C2 (en) 1998-02-04 2003-07-20 Новартис Аг Sulfonylamino-derivatives that inhibit activity of metalloproteinase decomposing matrix
US6329418B1 (en) 1998-04-14 2001-12-11 The Procter & Gamble Company Substituted pyrrolidine hydroxamate metalloprotease inhibitors
CA2330095A1 (en) 1998-05-14 1999-11-18 Dupont Pharmaceuticals Company Substituted aryl hydroxamic acids as metalloproteinase inhibitors
JP2002516904A (en) 1998-06-03 2002-06-11 ジーピーアイ ニル ホールディングス インコーポレイテッド N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
EP1087937A1 (en) 1998-06-17 2001-04-04 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
EP1107953A1 (en) 1998-08-29 2001-06-20 British Biotech Pharmaceuticals Limited 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
EA200100675A1 (en) 1998-12-18 2001-12-24 Аксис Фармасьютикалз, Инк. PROTEASE INHIBITORS
US6340691B1 (en) * 1999-01-27 2002-01-22 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors
KR100440643B1 (en) 1999-01-28 2004-07-21 쥬가이 세이야쿠 가부시키가이샤 Substituted phenethylamine derivatives
US6294694B1 (en) 1999-06-04 2001-09-25 Wisconsin Alumni Research Foundation Matrix metalloproteinase inhibitors and method of using same
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
ES2249270T3 (en) 1999-08-12 2006-04-01 Pharmacia Italia S.P.A. DERIVATIVES OF 3 (5) -AMINOPIRAZOL, PROCEDURE FOR ITS PREPARATION AND ITS 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
US7335673B2 (en) 2000-08-11 2008-02-26 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
BR0208105A (en) 2001-03-15 2004-03-09 Astrazeneca Ab Metalloproteinase Inhibitors
SE0100902D0 (en) * 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
DE60234028D1 (en) 2001-05-25 2009-11-26 Bristol Myers Squibb Co HYDANTION DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES
GB0114004D0 (en) 2001-06-08 2001-08-01 Glaxo Group Ltd Chemical compounds
SE0103710D0 (en) * 2001-11-07 2001-11-07 Astrazeneca Ab Compounds
EP1550725A4 (en) 2002-06-05 2010-08-25 Kaneka Corp PROCESS FOR PRODUCING OPTICALLY ACTIVE alpha-METHYLCYSTEINE DERIVATIVE
SE0202539D0 (en) 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
SE0202693D0 (en) 2002-09-11 2002-09-11 Astrazeneca Ab Compounds
SE0202692D0 (en) 2002-09-11 2002-09-11 Astrazeneca Ab Compounds
GB0221250D0 (en) 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
GB0221246D0 (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
US7648992B2 (en) 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
SE0401763D0 (en) 2004-07-05 2004-07-05 Astrazeneca Ab Compounds
SE0403086D0 (en) 2004-12-17 2004-12-17 Astrazeneca Ab Compounds
SE0403085D0 (en) 2004-12-17 2004-12-17 Astrazeneca Ab Novel componds
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
TW200831488A (en) 2006-11-29 2008-08-01 Astrazeneca Ab Novel compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999006361A2 (en) * 1997-07-31 1999-02-11 Abbott Laboratories N-hydroxyformamide derivatives as inhibitors of matrix metalloproteinases
WO1999024399A1 (en) * 1997-11-12 1999-05-20 Darwin Discovery Limited Hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity
WO2000040577A1 (en) * 1998-12-31 2000-07-13 Aventis Pharmaceuticals Inc. 1-carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of mmp-12
WO2001005756A1 (en) * 1999-07-14 2001-01-25 Pharmacia & Upjohn Spa 3-arylsulfonyl-2-(substituted methyl)propanoic acid derivates as matrix metalloproteinase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANALES REAL SOC. ESPAN. DIS. QUIM., SER. B, vol. 62, no. 2, MADRID, pages 173 - 186 *
CHEMICAL ABSTRACTS, vol. 65, 1966, Columbus, Ohio, US; abstract no. 13684H, LORA-TAMAYO M. ET AL.: "Potential anticancer agents. I. Glutamine sulfonate analogs" XP002969764 *

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7625934B2 (en) 2001-03-15 2009-12-01 Astrazeneca Ab Metalloproteinase inhibitors
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
US6906053B2 (en) 2001-05-25 2005-06-14 Bristol-Myers Squibb Pharma Company Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
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)
US7482372B2 (en) 2001-05-25 2009-01-27 Bristol-Myers Squibb Company Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
EP1397137A4 (en) * 2001-05-25 2004-10-13 Bristol Myers Squibb Co Hydantion derivatives as inhibitors of matrix metalloproteinases
EP1397137A1 (en) * 2001-05-25 2004-03-17 Bristol-Myers Squibb Company Hydantion derivatives as inhibitors of matrix metalloproteinases
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
US7354940B2 (en) 2002-08-27 2008-04-08 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12
WO2004024718A1 (en) * 2002-09-11 2004-03-25 Astrazeneca Ab Imidazolidinedione-derivatives and their use as metalloproteinase inhibitors
EP2426120A1 (en) 2003-08-18 2012-03-07 Fujifilm Finechemicals Co., Ltd. Pyridyltetrahydropyridines and pyridylpiperidines, and method of manufacturing them
WO2006004533A1 (en) * 2004-07-05 2006-01-12 Astrazeneca Ab Compounds
US7989620B2 (en) * 2004-07-05 2011-08-02 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
KR101222736B1 (en) 2004-07-05 2013-01-15 아스트라제네카 아베 Novel Hydantoin Derivatives for the Treatment of Obstructive Airway Diseases
WO2006004532A1 (en) * 2004-07-05 2006-01-12 Astrazeneca Ab Novel hydantoin derivatives for the treatment of obstructive airway diseases
JP2008505172A (en) * 2004-07-05 2008-02-21 アストラゼネカ・アクチエボラーグ Compound
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
EP2289510A1 (en) * 2004-09-20 2011-03-02 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-coa desaturase enzymes
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
WO2006034315A3 (en) * 2004-09-20 2006-07-27 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
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
WO2006064218A1 (en) * 2004-12-15 2006-06-22 Astrazeneca Ab Hydantoin derivatives useful as metalloproteinase inhibitors
US8129412B2 (en) 2004-12-15 2012-03-06 Astrazeneca Ab Hydantoin derivatives useful as metalloproteinase inhibitors
AU2005315459B2 (en) * 2004-12-15 2009-01-08 Astrazeneca Ab Hydantoin derivatives useful as metalloproteinase inhibitors
WO2006065215A1 (en) * 2004-12-17 2006-06-22 Astrazeneca Ab Novel compounds
WO2006065216A1 (en) * 2004-12-17 2006-06-22 Astrazeneca Ab Novel hydantoin derivatives as metalloproteinase inhibitors
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
WO2007078335A3 (en) * 2005-12-21 2007-11-29 Decode Genetics Inc Biaryl nitrogen heterocycle inhibitors of lta4h for treating inflammation
US7750012B2 (en) 2005-12-21 2010-07-06 Decode Genetics Ehf Biaryl nitrogen-heterocycle inhibitors of LTA4H for treating inflammation
WO2007078335A2 (en) * 2005-12-21 2007-07-12 Decode Genetics, Ehf. Biaryl nitrogen heterocycle inhibitors of lta4h for treating inflammation
US7772403B2 (en) * 2006-03-16 2010-08-10 Astrazeneca Ab Process to prepare sulfonyl chloride derivatives
WO2007106022A3 (en) * 2006-03-16 2007-11-01 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] - 5 -methyl -imidazolidine - 2,4-dione (i) and intermediates thereof.
JP2009530273A (en) * 2006-03-16 2009-08-27 アストラゼネカ・アクチエボラーグ Method for producing sulfonyl chloride derivative
WO2008053199A1 (en) * 2006-10-30 2008-05-08 Astrazeneca Ab Combination therapy for the treatment of respiratory diseases
EP2364704A1 (en) 2007-02-08 2011-09-14 AstraZeneca AB Combination of beta-adrenoceptor agonist and corticosteroid
WO2009007747A3 (en) * 2007-07-11 2009-03-05 Astrazeneca Ab Hydantoin derivatives used as mmp12 inhibitors
WO2009007747A2 (en) * 2007-07-11 2009-01-15 Astrazeneca Ab Hydantoin derivatives used as mmp12 inhibitors
WO2009134728A2 (en) 2008-04-28 2009-11-05 Revalesio Corporation Compositions and methods for treating multiple sclerosis
WO2011012897A1 (en) 2009-07-31 2011-02-03 Astrazeneca Ab New combinations for the treatment of asthma
WO2012085583A1 (en) 2010-12-23 2012-06-28 Astrazeneca Ab New compound
WO2012085582A1 (en) 2010-12-23 2012-06-28 Astrazeneca Ab Compound
EP2907512A1 (en) 2014-02-14 2015-08-19 Commissariat A L'energie Atomique Et Aux Energies Alternatives Inhibitors of MMP-12 as antiviral Agents
US11718588B2 (en) 2014-12-22 2023-08-08 Galapagos Nv 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis
WO2021260387A1 (en) 2020-06-26 2021-12-30 The University Of Birmingham Mmp-9 and mmp-12 inhibition for treating spinal cord injury or related injury to neurological tissue

Also Published As

Publication number Publication date
HK1060121A1 (en) 2004-07-30
ATE493406T1 (en) 2011-01-15
RU2293729C2 (en) 2007-02-20
NZ528106A (en) 2005-03-24
NO20034045D0 (en) 2003-09-12
US20080262045A1 (en) 2008-10-23
WO2002074767A8 (en) 2004-04-22
BR0207984A (en) 2004-06-15
IL157652A0 (en) 2004-03-28
CN100526307C (en) 2009-08-12
US7368465B2 (en) 2008-05-06
KR20030082987A (en) 2003-10-23
SI1370556T1 (en) 2006-10-31
US20040106659A1 (en) 2004-06-03
ATE333454T1 (en) 2006-08-15
HUP0400202A3 (en) 2004-10-28
NO20034042L (en) 2003-11-10
EP1676846A2 (en) 2006-07-05
PL364706A1 (en) 2004-12-13
US20080171882A1 (en) 2008-07-17
NO20034042D0 (en) 2003-09-12
IL157657A0 (en) 2004-03-28
PL364707A1 (en) 2004-12-13
JP2004523583A (en) 2004-08-05
US20110003853A1 (en) 2011-01-06
CN1509286A (en) 2004-06-30
ES2357138T3 (en) 2011-04-19
EE05431B1 (en) 2011-06-15
SK10952003A3 (en) 2004-05-04
UA77408C2 (en) 2006-12-15
ZA200306737B (en) 2004-11-29
RU2285695C2 (en) 2006-10-20
NO327114B1 (en) 2009-04-27
SK10922003A3 (en) 2004-05-04
NO20034044L (en) 2003-11-10
RU2003127735A (en) 2005-03-20
EE200300445A (en) 2003-12-15
SK287834B6 (en) 2011-12-05
IS6943A (en) 2003-09-09
RU2003127734A (en) 2005-03-20
US20080306065A1 (en) 2008-12-11
SE0100902D0 (en) 2001-03-15
JP4390457B2 (en) 2009-12-24
US20040138276A1 (en) 2004-07-15
MXPA03008191A (en) 2004-01-29
DK1370556T3 (en) 2006-10-30
RU2288228C2 (en) 2006-11-27
ZA200306732B (en) 2004-11-29
MXPA03008177A (en) 2003-12-12
EP1676846B1 (en) 2010-12-29
CN1962641B (en) 2012-07-04
MXPA03008181A (en) 2003-12-12
US7666892B2 (en) 2010-02-23
ES2267986T3 (en) 2007-03-16
HK1059932A1 (en) 2004-07-23
PL365099A1 (en) 2004-12-27
DE60213216D1 (en) 2006-08-31
JP5140058B2 (en) 2013-02-06
NZ528107A (en) 2005-06-24
JP2010077137A (en) 2010-04-08
CA2440473C (en) 2011-08-30
ATE484496T1 (en) 2010-10-15
US20040127528A1 (en) 2004-07-01
JP2004523581A (en) 2004-08-05
IL157656A (en) 2010-11-30
KR20030082986A (en) 2003-10-23
EE05364B1 (en) 2010-12-15
MY136789A (en) 2008-11-28
CN1509272A (en) 2004-06-30
NO326087B1 (en) 2008-09-15
HUP0400194A2 (en) 2004-07-28
EP1370537B1 (en) 2010-10-13
ZA200306731B (en) 2004-11-29
PT1370556E (en) 2006-11-30
UA78502C2 (en) 2007-04-10
CY1107525T1 (en) 2013-03-13
HUP0400202A2 (en) 2004-08-30
CA2440473A1 (en) 2002-09-26
AR035443A1 (en) 2004-05-26
AR035695A1 (en) 2004-06-23
HUP0400194A3 (en) 2004-10-28
EE200300449A (en) 2003-12-15
HUP0400327A3 (en) 2005-06-28
IL157652A (en) 2010-11-30
CN101602731A (en) 2009-12-16
WO2002074748A1 (en) 2002-09-26
DE60213216T2 (en) 2007-07-12
US20100273849A1 (en) 2010-10-28
NO20034044D0 (en) 2003-09-12
DE60237965D1 (en) 2010-11-25
ES2352246T3 (en) 2011-02-16
CN1509276A (en) 2004-06-30
US8153673B2 (en) 2012-04-10
AU2002237626B2 (en) 2007-05-17
IL157656A0 (en) 2004-03-28
IS6942A (en) 2003-09-09
KR100886315B1 (en) 2009-03-04
NO20034045L (en) 2003-11-10
EP1370537A1 (en) 2003-12-17
KR100879905B1 (en) 2009-01-21
US7625934B2 (en) 2009-12-01
PL205315B1 (en) 2010-04-30
RU2003127733A (en) 2005-03-20
MY136141A (en) 2008-08-29
CN1269804C (en) 2006-08-16
ZA200306734B (en) 2004-11-29
HUP0400327A2 (en) 2005-01-28
KR20080071210A (en) 2008-08-01
BR0207983A (en) 2004-06-15
CN1962641A (en) 2007-05-16
EE200300451A (en) 2003-12-15
WO2002074751A1 (en) 2002-09-26
US7427631B2 (en) 2008-09-23
EP1370534A1 (en) 2003-12-17
EP1676846A3 (en) 2006-07-26
KR20030082989A (en) 2003-10-23
EP1370556B1 (en) 2006-07-19
NZ528140A (en) 2005-02-25
WO2002074748A8 (en) 2004-04-22
HK1091492A1 (en) 2007-01-19
US7754750B2 (en) 2010-07-13
DE60238794D1 (en) 2011-02-10
IS6946A (en) 2003-09-10
SK287766B6 (en) 2011-09-05
UA77667C2 (en) 2007-01-15
SK10962003A3 (en) 2004-03-02
CZ20032499A3 (en) 2004-03-17
CA2440630A1 (en) 2002-09-26
CN1304377C (en) 2007-03-14
CZ20032497A3 (en) 2004-02-18
JP2004527515A (en) 2004-09-09
AU2002237632B2 (en) 2007-05-10
BR0208104A (en) 2004-03-02
CA2440630C (en) 2011-09-27
CZ20032500A3 (en) 2004-02-18
CA2440631A1 (en) 2002-09-26
EP1370556A1 (en) 2003-12-17

Similar Documents

Publication Publication Date Title
EP1370556B1 (en) Metalloproteinase inhibitors
AU2002237626A1 (en) Metalloproteinase inhibitors
EP1370536A1 (en) Metalloproteinase inhibitors
AU2002237632A1 (en) Metalloproteinase inhibitors
KR20020073594A (en) Piperidine- and piperazine substituted n-hydroxyformamides as inhibitors of metalloproteinases
AU2002237629A1 (en) Metalloproteinase inhibitors
AU2002237627A1 (en) Metalloproteinase inhibitors
AU2002237628A1 (en) Metalloproteinase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2002237626

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 805/MUMNP/2003

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2003/06734

Country of ref document: ZA

Ref document number: 157652

Country of ref document: IL

Ref document number: 10962003

Country of ref document: SK

Ref document number: 200306734

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 528106

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: PA/A/2003/008191

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2440630

Country of ref document: CA

Ref document number: 2002704031

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1-2003-500884

Country of ref document: PH

Ref document number: PV2003-2499

Country of ref document: CZ

Ref document number: 1020037011987

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2002573776

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 02809915X

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2002704031

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10471900

Country of ref document: US

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2003-2499

Country of ref document: CZ

WR Later publication of a revised version of an international search report
WWP Wipo information: published in national office

Ref document number: 528106

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 528106

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2002704031

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 2002237626

Country of ref document: AU