WO2005085232A1 - Hydantoin derivatives for use as tace and aggrecanase inhibitors - Google Patents

Hydantoin derivatives for use as tace and aggrecanase inhibitors Download PDF

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WO2005085232A1
WO2005085232A1 PCT/GB2005/000759 GB2005000759W WO2005085232A1 WO 2005085232 A1 WO2005085232 A1 WO 2005085232A1 GB 2005000759 W GB2005000759 W GB 2005000759W WO 2005085232 A1 WO2005085232 A1 WO 2005085232A1
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alkyl
methyl
optionally substituted
halo
hydrogen
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PCT/GB2005/000759
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French (fr)
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Jeremy Nicholas Burrows
Andrew David Morley
Howard Tucker
Jeffrey Philip Poyser
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • 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
    • 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
    • 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

Definitions

  • the present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising them, as well as their use.
  • the compounds of this invention are inhibitors of one or more metalloproteinase enzymes. They are particularly effective as inhibitors of TNF- ⁇ (Tumour Necrosis Factor- ⁇ ) production, as inhibitors of aggrecan breakdown or the combination thereof.
  • 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 inN.M. Hooper (1994) FEBS Letters 354:1-6.
  • metalloproteinases examples include the matrix metalloproteinases (MMP) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP 10, MMP 11), matrilysin (MMP7), metalloelastase (MMP 12), enamelysin (MMP19), 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 (AD AMI 0 and TACE); aggrecanases such as the ADAM-TS family (for example ADAM-TS 1 and ADAM-TS4); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as the endothelin converting enzyme family and the angiotensin converting
  • 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 ofthe 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 biologically 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.
  • Metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these disease conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation ofthe gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation ofthe skin (especially psoriasis, eczema and dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation ofthe 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 ofthe skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating
  • TACE also known as ADAM 17
  • ADAM 17 ADAM 17
  • TACE admalysin family of metalloproteins.
  • TACE has been shown to be responsible for the cleavage of pro-TNF- ⁇ , a 26kDa membrane bound protein to release 17kDa biologically active soluble TNF- ⁇ . [Schlondorff et al. (2000) Biochem. J. 347: 131-138].
  • TACE mRNA is found in most tissues, however TNF- ⁇ is produced primarily by activated monocytes, macrophages and T lymphocytes.
  • TNF- ⁇ has been implicated in a wide range of pro- inflammatory biological processes including induction of adhesion molecules and chemokines to promote cell trafficking, induction of matrix destroying enzymes, activation of fibroblasts to produce prostaglandins and activation ofthe immune system [Aggarwal et al (1996) Eur. Cytokine Netw. 7: 93-124].
  • Clinical use ofthe anti-TNF- ⁇ biologicals has shown TNF- ⁇ to play an important role in a range of inflammatory diseases including rheumatoid arthritis, Crohn's disease and psoriasis [Onrust et al (1998) Biodrugs 10: 397-422, Jarvis et al (1999) Drugs 57:945-964].
  • TACE activity has also been implicated in the shedding of other membrane bound proteins including TGF ⁇ , p75 and p55 TNF receptors, L-selectin and amyloid precursor protein [Black (2002) Int. J. Biochem. Cell Biol. 34: 1-5].
  • the biology of TACE inhibition has recently been reviewed and shows TACE to have a central role in TNF- ⁇ production and selective TACE inhibitors to have equal, and possibly greater, efficacy in the collagen induced arthritis model of rheumatoid arthritis than strategies that directly neutralise TNF- ⁇ [Newton et al (2001) Ann. Rheum. Dis. 60: iii25-iii32].
  • a TACE inhibitor might therefore be expected to show efficacy in all disease where TNF- ⁇ has been implicated including, but not limited to, inflammatory diseases including rheumatoid arthritis and psoriasis, autoimmune diseases, allergic/atopic diseases, transplant rejection and graft versus host disease, cardiovascular disease, reperfusion injury, malignancy and other proliferative diseases.
  • a TACE inhibitor might also be useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary diseases (referred to herein as COPD).
  • COPD chronic obstructive pulmonary diseases
  • Aggrecanase is a proteinase which is responsible for the cleavage ofthe large, hydrophilic aggregating proteoglycan, aggrecan.
  • a network of collagen fibres and aggrecan are the principal components of articulate cartilage, which allows for the almost frictionless articulation of joints and acts as a shock absorber by recovering from deformation after loading.
  • Aggrecan is composed of a central protein core to which glycosaminoglycan (GAG) chains are attached. At the amino terminal there are two globular domains, known as Gl and G2 that are separated by a short interglobular domain. At the carboxy terminus is another globular domain G3.
  • GAG glycosaminoglycan
  • Aggrecan can be cleaved at multiple sites along the aggrecan molecule but in human aggrecan the critical cleavage site is between the Gl and G2 globular domains at the Glu - Ala bond resulting in fragments with neo-epitopes of GI-NITEGE-CO2H and
  • NH2ARGSN-G2 Several members ofthe ADAM-TS family can cleave aggrecan generating these neo-epitopes.
  • Synovial fluid from patients with joint injury, inflammatory arthritis and osteoarthritis contains both fragments indicating aggrecan cleavage at the Glu - Ala peptide bond.
  • Excessive aggrecanase activity can destroy the cartilage matrix since most GAG bearing aggrecan fragments are released from the tissue into the synovial fluid following cleavage of the Glu 373 -Ala 374 peptide bond.
  • WO 02/096426 describes hydantoin derivatives which are useful as inhibitors of matrix metalloproteinases, TACE, aggrecanase, or a combination thereof.
  • TACE matrix metalloproteinases
  • AD AMI 7 inhibitors of TACE
  • the present invention provides a compound of formula (I):
  • A is arylene, heteroarylene or heterocyclylene
  • X is absent, -O-, -S-, -SO-, -SO 2 -, -NR 14 -, -C(O)NR 14 -, -NR 14 C(O)-, SO 2 NR 14 , -NR 14 SO 2 -,
  • B is a group selected from aryl, heteroaryl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, cyano, C 1 . 4 alkyl (optionally substituted by R 9 or C ⁇ .
  • R 1 , R la , R lb and R lc are independently selected from hydrogen, C ⁇ . 6 alkyl and C 3 . 6 cycloalkyl;
  • R 2 is selected from hydrogen, halo, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -NR 12 R 13 , -
  • C 1 . 4 alkyl is optionally substituted by halo, cyano, heterocyclyl, -OR , -C(O)R , -C(O)OR , -NR 12 R 13 , -NC(O)R 12 or -C(O)NR 12 R 13 ;
  • R 3 , R 4 , R s and R 6 are independently hydrogen or a group selected from C t - ⁇ alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 6 cycloalkyl, C 5 . 6 cycloalkenyl, aryl, heteroaryl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 . alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, C 3 .
  • R 5 and R 6 together with the carbon atom to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO which ring is optionally substituted on carbon by C ⁇ . 4 alkyl, fluoro or C ⁇ - 3 alkoxy and/or on nitrogen by -C(O)C 1 . 3 alkyl or -SO 2 C ⁇ - 3 alkyl or C ⁇ . 4 alkyl;
  • R 7 is hydrogen or a group selected from C ⁇ . 6 alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, heteroalkyl, C 3 . 7 cycloalkyl, aryl, heteroaryl or heterocyclyl which group is optionally substituted by a substituent group selected from halo, C 1 . alkyl, C 1 . alkoxy, C 3 . cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroalkyl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, C ⁇ - 4 alkyl, nitro, haloC 1 .
  • R 3 and R 7 together with the carbon atoms to which they are each attached and (CR 5 R 6 ) n form a saturated 5- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO where the ring is optionally substituted on carbon by C ⁇ . alkyl, fluoro or C ⁇ . 3 alkoxy and/or on nitrogen by -C(O)C 1 . 3 alkyl or -SO 2 C ⁇ _ 3 alkyl or C 1 . alkyl; R is hydrogen or methyl;
  • R 9 and R 10 are independently hydrogen, C ⁇ . 6 alkyl or C 3 _ 6 cycloalkyl; or R 9 and R 10 together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring; R 11 is C ⁇ . 6 alkyl or C 3 . 6 cycloalkyl;
  • R 12 , R 13 and R 16 are independently hydrogen, C ⁇ _ 6 alkyl, aryl and arylC 1 . 4 alkyl and may be optionally substituted by one or more halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, Ci.6alkylsulpb.onyl, C ⁇ - 6 alkylsulphonylamino, C ⁇ . 6 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl,
  • R 14 is hydrogen, C ⁇ . 4 alkyl, -C(O)C 1 . 4 alkyl, -C(O)NH 2 , -SO 2 C 1 . 4 alkyl;
  • R 17 is selected from halo, C ⁇ . 6 alkyl, C 3 . 6 cycloalkyl and C ⁇ _ 6 alkoxy;
  • R 18 is hydrogen or a group selected from C ⁇ - 6 alkyl, C 3 . 6 cycloalkyl, C 5 - 6 cycloalkenyl, saturated heterocyclyl, aryl, heteroaryl, arylC 1 - alkyl and heteroarylC ⁇ . 4 alkyl which group is optionally substituted by one or more halo;
  • R 19 and R 23 are independently a group selected from C 3 . 6 cycloalkyl, C 5 -
  • R is hydrogen, C ⁇ - 6 alkyl or C 3 . 6 cycloalkyl; or R 18 and R 20 together with the nitrogen to which they are attached form a heterocyclic 4- to
  • R 21 and R 22 are independently hydrogen, C ⁇ alkyl, haloC 1 . alkyl, aryl and arylC 1 . 4 alkyl; provided that when z is -NHC(O)- then R 7 is not hydrogen; and provided that when z is -NR -, m is 2;
  • A is phenylene;
  • R is hydrogen, -NR R or C ⁇ . 4 alkyl which C ⁇ . alkyl is optionally substituted by halo, -OR 12 or -NR 12 R 13 ; and r is 0; then X is not
  • optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques known to the skilled person and referred to herein.
  • Compounds of formula (I) are therefore provided as enantiomers, diastereomers, geometric isomers and atropisomers.
  • a compound of formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one ofthe possible tautomeric forms.
  • the invention encompasses any tautomeric form which has metalloproteinases inhibition activity and in particular TACE inhibition activity and/or aggrecanase inhibition activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. It is also to be understood that certain compounds of formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which have metalloproteinases inhibition activity and in particular TACE inhibition activity and/or aggrecanase inhibition activity.
  • compositions of formula (I) may exhibit polymorphism, and that the invention encompasses all such forms which possess metalloproteinases inhibition activity and in particular TACE inhibition activity and/or aggrecanase inhibition activity.
  • the present invention relates to compounds of formula (I) as defined herein as well as to the salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of compounds of formula (I) and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts ofthe invention may, for example, include acid addition salts of compounds of formula (I) as defined herein which are sufficiently basic to form such salts.
  • Such acid addition salts include but are not limited to hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid.
  • salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salts for example triethylamine or tris-(2-hydroxyethyl)amine.
  • the compounds of formula (I) may also be provided as in vivo hydrolysable esters.
  • An in vivo hydrolysable ester of a compound of formula (I) containing a carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol.
  • 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 fluid.
  • Suitable pharmaceutically acceptable esters for carboxy include CT-ealkoxymethyl esters for example methoxymethyl, C ⁇ - 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyC ⁇ .
  • alkyl esters for example 1-cyclohexylcarbonyloxyethyl
  • l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl
  • C ⁇ - 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result ofthe in vivo hydrolysis ofthe ester breakdown to give the parent hydroxy group/s.
  • examples of ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • Ci-ioalkanoyl for example formyl, acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl
  • Ci-ioalkoxycarbonyl to give alkyl carbonate esters
  • alkyl carbonate esters for example ethoxycarbonyl
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, (Ci.. alkyl)aminomethyl and bis(C ⁇ - 4 alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position ofthe benzoyl ring.
  • Other interesting in vivo hydrolysable esters include, for example, R A C(O)O(C 1 . 6 )alkyl- CO-, wherein R A is for example, benzyloxyC ⁇ alkyl, or phenyl).
  • Suitable substituents on a phenyl group in such esters include, for example, 4-C 1 - alkylpiperazinylC 1 - 4 alkyl, piperazinylC ⁇ - alkyl and morpholinoC ⁇ - alkyl.
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as tert-butyl are specific for the branched chain version only.
  • “Ci- 3 alkyl” includes methyl, ethyl, propyl and isopropyl
  • examples of "C h alky! include the examples of "C h alky-” and butyl and tert-butyl and examples of "C ⁇ .
  • C ⁇ - a_kyl include the examples of "C ⁇ - a_kyl”and additionally pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl.
  • An analogous convention applies to other generic terms, for example "C 2 . 4 alkenyl” includes vinyl, allyl and 1-propenyl and examples of “C 2 . 6 alkenyl” include the examples of "C 2 . 4 alkenyl” and additionally 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3- methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • C 2 - 4 alkynyl includes ethynyl, 1-propynyl, 2-propynyl, 3-butynyl and examples of “C 2 . 6 alkynyl”include the examples of “C . 4 alkynyl” and additionally 2-pentynyl, hexynyl and l-methylpent-2-ynyl. Where examples are given for generic terms, it should be noted that these examples are not limiting.
  • Cycloalkyl is a monocyclic, saturated alkyl ring.
  • C 3 - 4 cycloalkyl includes cyclopropyl and cyclobutyl.
  • C 3 - cycloalkyl includes “C 3 . 4 cycloalkyl and cyclopentyl.
  • C 3 - 6 cycloalkyl includes “C 3 . 5 cycloalkyl", and cyclohexyl.
  • C 3 . 7 cycloalkyl includes “C 3 - 6 cycloalkyl” and additionally cycloheptyl.
  • C 3 . locycloalkyl includes “C 3 . 7 cycloalkyl” and additionally cyclooctyl, cyclononyl and cyclodecyl.
  • Cycloalkenyl is a monocyclic ring containing 1, 2, 3 or 4 double bonds.
  • Examples of “C - 6 cycloalkenyl” are cyclopentenyl, cyclohexenyl and cyclohexadiene and examples of “Cs-iocycloalkenyl” include the examples of “Cs- ⁇ cycloalkenyl” and cyclooctatriene.
  • aryl is monocyclic or bicyclic aromatic ring. Examples of “aryl” therefore include phenyl (an example of monocyclic aryl) and naphthyl (an example of bicyclic aryl). Examples of “arylC 1 .
  • alkyl are benzyl, phenylethyl, naphthylmethyl and naphthylethyl.
  • Arylene is a bivalent monocyclic or bicyclic aromatic ring such as phenylene.
  • Carbocyclyl is a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 4 to 12 ring atoms, wherein a -CH 2 - group is optionally be replaced by a -C(O)-. Examples and suitable values ofthe term “carbocyclyl” are 1,2,3,4-tetrahydronaphthyl and indanyl.
  • heteroaryl is a monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised.
  • heteroaryl examples include pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzotbienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl and pyrazolopyridinyl.
  • heteroaryl is pyridyl, imidazolyl, quinolinyl, pyrimidinyl, thienyl, pyrazolyl, thiazolyl, oxazolyl and isoxazolyl. More preferably heteroaryl is pyridyl, imidazolyl and pyrimidinyl. Examples of "monocyclic heteroaryl" are pyridyl, imidazolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl and pyrazinyl.
  • bicyclic heteroaryl examples include quinolinyl, quinazolinyl, cinnolinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl and pyrazolopyridinyl.
  • Preferred examples of B when B is heteroaryl are those examples of bicyclic heteroaryl.
  • heteroarylCi-zialkyl examples are pyridylmethyl, pyridylethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl.
  • Heteroarylene is a bivalent monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised.
  • heteroarylene examples include thiophenylene, pyridinylene, pyrimidinylene, pyrrolylene, oxazolylene, isoxazolylene and thiazolylene.
  • Preferred examples are thiophenylene and pyridinylene.
  • Heterocyclylene is a bivalent is a saturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH - group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring -NH is optionally substituted by acetyl, formyl, methyl or mesyl; and a ring is optionally substituted by one or more halo.
  • heterocyclylene examples and suitable values ofthe term “heterocyclylene” are piperidinylene, piperazinylene, pyrrolidinylene and morpholinylene. Preferred values are piperidinylene and piperazinylene.
  • Heterocyclyl is a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH - group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring -NH is optionally substituted by acetyl, formyl, methyl or mesyl; and a ring is optionally
  • heterocyclyl examples and suitable values ofthe term "heterocyclyl” are piperidinyl, N-acetylpiperidinyl, N- methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5-dioximidazolidinyl, 2,2-dimethyl-l,3- dioxolanyl and 3,4-dimethylenedioxyphenyl.
  • Preferred values are 3,4-dihydro-2H-pyran-5-yl, tetrahydrofuran-2-yl, 2,5-dioximidazolidinyl, 2,2-dimethyl-l,3-dioxolan-2-yl and 3,4- methylenedioxyphenyl.
  • Examples of monocyclic heterocyclyl are piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N- formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, pyranyl, tetrahydrofuranyl, 2,5-dioximidazolidinyl and 2,2-dimethyl-l,3- dioxolanyl.
  • bicyclic heterocyclyl examples include pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl. 2,3- methylenedioxyphenyl, and 3,4-methylenedioxyphenyl.
  • saturated heterocyclyl examples are piperidinyl, pyrrolidinyl, piperazinyl and morpholinyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • C ⁇ - 3 alkoxy and C ⁇ . alkoxy include methoxy, ethoxy, propoxy and isopropoxy.
  • C ⁇ . 6 alkoxy include the examples of "C ⁇ . 4 alkoxy” and additionally pentyloxy, 1-ethylpropoxy and hexyloxy.
  • Heteroalkyl is alkyl containing at least one carbon atom and having at least one carbon atom replaced by a hetero group independently selected from ⁇ , O, S, SO, SO 2 , (a hetero group being a hetero atom or group of atoms). Examples include -CH 2 OCH 3 , -CH SH and -OC 2 H 5 .
  • “HaloC 1 - alkyl” is a C ⁇ - 4 alkyl group substituted by one or more halo. Examples of "haloC ⁇ - alkyr include fluoromethyl, trifluoromethyl, 1-chloroethyl, 2-chloroethyl, 2- bromopropyl, 1-fluoroisopropyl and 4-chlorobutyl.
  • haloC ⁇ . 6 alkyl examples include the examples of “haloC ⁇ . 4 alkyl” and 1-chloropentyl, 3-chloropentyl and 2-fluorohexyl.
  • hydroxyC 1 - alkyl examples include hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 2-hydroxypropyl, 1-hydroxyisopropyl and 4-hydroxybutyl.
  • C 1 - alkoxyC 1 . 4 alkyl include methoxymethyl, ethoxymethyl, 2- methoxy ethyl, 2-methoxypropyl and 4-propoxybutyl.
  • HaloCi- 4 alkoxyCi examples include the examples of "haloC ⁇ . 4 alkyl” and 1-chloropentyl, 3-chloropentyl and 2-fluorohexyl.
  • hydroxyC 1 - alkyl examples include hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 2-hydroxypropyl
  • 4 alky_ is a C 1 - 4 alkoxyC ⁇ . 4 alkyl group substituted on Ci- 4 alkoxy by one or more halo.
  • haloC 1 - alkoxyC 1 - alkyl include l-(chloromethoxy)ethyl, 2- fluoroethoxymethyl, trifluoromethoxymethyl, 2-(4-bromobutoxy)ethyl and 2-(2- iodoethoxy)ethyl.
  • Examples of "carboxyC ⁇ - 4 alkyl” include carboxymethyl, 2-carboxyethyl and 2- carboxypropyl. Heterocyclic rings are rings containing 1, 2 or 3 ring atoms selected from nitrogen, oxygen and sulphur.
  • Heterocyclic 5 to 7-membered rings are pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, thiomorpholinyl , thiopyranyl and morpholinyl.
  • Heterocyclic 4 to 7-membered rings include the examples of “heterocyclic 5 to 7-membered” and additionally azetidinyl.
  • saturated 3- to 7-membered rings optionally containing a heteroatom groups selected from NH, O, S, SO or SO 2 include cyclopropyl, cyclohexane, cyclopentane, piperidine, pyrrolidine, terahydofuran and tetrahydropyran.
  • saturated 5- to 7- membered rings optionally containing a heteroatom groups selected from NH, O, S, SO or SO 2 include cyclohexane, cyclopentane, piperidine, pyrrolidine, terahydofuran and tetrahydropyran.
  • substituents are chosen from “one of more” groups or substituents it is to be understood that this definition includes all substituents being chosen from one ofthe specified groups or the substituents being chosen from two or more ofthe specified groups.
  • substituents Preferably “one or more” means “1, 2 or 3" and this is particularly the case when the group or substituent is halo.
  • One or more may also mean “1 or 2”.
  • Compounds ofthe present invention have been named with the aid of computer software (ACD/Name version 6.0 Name) or Beilstein MDL Crossfire Autonom (MDL Information Sytems).
  • Y 1 , Y 2 , z, n, m, r, t, A, X, B, R 1 , R la , R lb , R lc , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as follows. Such values may be used where appropriate with any ofthe definitions, claims or embodiments defined hereinbefore or hereinafter.
  • Y 1 is O.
  • Y 2 is O.
  • z is -NR 8 -.
  • n is 0. In another aspect n is 1. In another aspect n is 2. In one aspect ofthe invention m is 1, 2 or 3. In another aspect m is 1. hi a further aspect m is 2. In yet another aspect m is 3.
  • r is 0. In another aspect r is 1. In another aspect r is 2. In one aspect ofthe invention t is 0. In another aspect t is 1. In one aspect ofthe invention A is phenylene. In another aspect A is thiophenylene, pyridinylene, pyrimidinylene, pyrrolylene, oxazolylene, isoxazolylene or thiazolylene. In yet another aspect A is thiophenylene or pyridinylene. In one aspect ofthe invention X is -O-.
  • X is absent, -S-, -SO-, -SO 2 - , -NR 14 -, -C(O)NR 14 -, -NR 14 C(O)-, SO 2 NR 14 , -NR 14 SO 2 -, -CH 2 -CH 2 " or -CH ⁇ CH-;
  • B is a group selected from aryl, heteroaryl, carbocyclyl and heterocyclyl where each group is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, C ⁇ .
  • B is C 2 - 4 alkenyl or C 2 . 4 alkynyl optionally substituted by Ci. 4 alkyl, C 3 . 6 cycloalkyl or heterocyclyl.
  • B is a group selected from bicyclic aryl or bicyclic heteroaryl where each group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, Ci- 4 alkyl (optionally substituted by one or more halo), C 2 . 4 alkynyl, heteroaryl, -OR 9 , cyano, - NR 9 R 10 , -C(O)NR 9 R 10 and -NR 9 C(O)R 10 ; or B is C 2 . 4 alkenyl or C 2 . 4 alkynyl optionally substituted by C ⁇ . 4 alkyl, C 3 - 6 cycloalkyl or heterocyclyl.
  • B is phenyl, naphthyl, tetrahydronaphthyl, pyridyl, quinolinyl, isoquinolinyl, thienopyridyl, 1,8- naphthyridinyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 1,6-naphthyridinyl, thienopyrimidinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinolinyl, t
  • 4 alkyl (optionally substituted by one or more fluoro), C 2 . alkynyl, heteroaryl, -OR 9 , cyano, -NR 9 R 10 , -C(O)NR 9 R 10 and -NR 9 C(O)R 10 ; or B is vinyl or ethynyl optionally substituted by C ⁇ - alkyl, hydroxyC ⁇ . 4 alkyl, C 1 . 4 alkoxyC 1 . 4 alkyl or aryl.
  • B is phenyl, naphthyl, tetrahydronaphthyl, pyridyl, quinolinyl, isoquinolinyl, thieno[2,3-b]pyridyl, thieno[3,2-b]pyridyl, 1,8-naphthyridinyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 1,6-naphthyridinyl, thieno[2,3-ct]pyrimidinyl or thieno[3,2- cdpyrimidinyl where each is optionally substituted by one or more groups independently selected from trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, ethynyl, cyano, acetamido, propyloxy, isopropyloxy, methoxy
  • B is a group selected from quinolinyl, pyridyl and phenyl where each group is optionally substituted by one or more methyl, trifluoromethyl, trifluoromethoxy, halo or isoxazolyl.
  • B is aryl, heteroaryl or C2- 4 alkynyl optionally substituted by halo or C ⁇ . alkyl.
  • B is 2-methylquinolin-4-yl, 2,5-dimethylphenyl, 2,5- dimethylpyrid-4-yl, phenyl, 3,5-difluorophenyl or prop-1-ynyl.
  • B is 2-methylquinolin-4-yl, 2,5-dimethylphenyl or 2,5-dimethylpyrid-4-yl. In yet another aspect B is 2-methylquinolin-4-yl or 2,5-dimethylphenyl.
  • R 1 is hydrogen or methyl.
  • R la is hydrogen or methyl. 11".
  • R is hydrogen or methyl.
  • R lc is hydrogen or methyl.
  • R 2 is hydrogen, -OR 12 , -C(O)OR 12 , - ⁇ R 12 R 13 , -
  • R 2 is hydrogen, amino, Ci. 4 alkylamino, di(C 1 - 4 alkyl)amino, cyano, methoxy, hydroxy, carboxy, methyl or ethyl.
  • R is hydrogen, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyano, methoxy, hydroxy, carboxy, methyl or ethyl.
  • R 2 is hydrogen, amino or methyl. In yet a further aspect R 2 is methyl. In a further aspect ofthe present invention R 2 is hydrogen, -OR 12 , -C(O)OR 12 , -NR 12 R 13 , -NR 12 C(O)R 13 ,
  • R 2 is hydrogen, amino, methyl, formyl, acetamido, benzoylamino, benzylcarbonylamino, ureido, 3-methylureido, 3-phenylureido, 3-benzylureido and t-butoxycarbonylamino.
  • R is hydrogen, methyl, ethyl, propyl or phenyl.
  • R 3 is hydrogen or methyl.
  • R 4 is hydrogen or methyl.
  • R 4 is hydrogen.
  • R 3 and R 4 together form a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydropyran ring.
  • R 3 and R 4 together form a pyrrolidine ring or a tetrahydro-2H-pyran ring.
  • R 5 is hydrogen or methyl.
  • R and R together with the carbon atoms to which they are attached form a piperidine ring optionally substituted by methyl.
  • R 6 is hydrogen or methyl.
  • R 7 is hydrogen or a group selected from C ⁇ aHcyl, C 3 . cycloalkyl, aryl, heteroaryl and heterocyclyl which group is optionally substituted by heterocyclyl, aryl and heteroaryl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, C ⁇ alkyl, -C(O)C 1 .
  • R 7 is hydrogen or a group selected from C ⁇ . 4 alkyl, arylC ⁇ . 4 alkyl, heteroarylC ⁇ - 4 alkyl, heterocyclylC 1 - 4 alkyl, aryl, heteroaryl, heterocyclyl and C 3 . 5 cycloalkyl which group is optionally substituted by cyano, Ci.
  • R 7 is hydrogen or a group selected from heterocyclylmethyl, heterocyclylethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, aminomethyl, aminoethyl, Ci. 4 alkylaminomethyl, Ci-zjalkylaminoethyl, di(C 1 . alkyl)aminomethyl and di(C 1 - 4 alkyl)aminoethyl.
  • R 7 is hydrogen or a group selected from C ⁇ - 4 alkyl, tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl and morpholinyl optionally substituted by methyl, ethyl, methoxy, ethoxy, fluoro, -C(O)C ⁇ - 3 alkyl or -SO 2 C 1 - 3 alkyl.
  • R 7 is selected from hydrogen, Ci- alkyl, haloC ⁇ - 4 alkyl, hydroxyC 1 . alkyl, C 1 - 4 alkoxyC 1 . 4 alkyl and aryl.
  • R 7 is hydrogen, methyl, hydroxymethyl or phenyl.
  • R 3 and R 7 together with the carbon atoms to which they are each attached and (CR 5 R 6 ) n form a cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl or piperazine ring.
  • R is hydrogen.
  • R 9 is hydrogen or methyl.
  • R 10 is hydrogen or methyl.
  • R 11 is methyl.
  • R 12 is hydrogen or methyl.
  • R 12 is hydrogen.
  • R is methyl. 19 In another aspect ofthe invention R is hydrogen, C ⁇ .
  • R is hydrogen, methyl, phenyl and benyl and may be optionally substituted by one or more halo, hydroxy, amino.
  • R is hydrogen, methyl, phenyl and benzyl
  • R 13 is hydrogen or methyl. In one aspect ofthe invention R is hydrogen. In one aspect ofthe invention R is methyl.
  • R is hydrogen, C ⁇ - 6 alkyl, aryl and arylC ⁇ - 4 alkyl and may be optionally substituted by one or more halo, hydroxy, amino.
  • R is hydrogen, methyl, phenyl and benyl and may be optionally substituted by one or more halo, hydroxy, amino.
  • R is hydrogen, methyl, phenyl and benzyl.
  • R 14 is hydrogen or methyl.
  • R 16 is hydrogen or methyl.
  • R 17 is selected from fluoro, chloro, methyl or methoxy.
  • R 18 is hydrogen or a group selected from C ⁇ - 6 alkyl, aryl and arylC t ⁇ alkyl which group is optionally substituted by halo. In another aspect R 18 is hydrogen or a group selected from methyl, phenyl and benzyl which group is optionally substituted by chloro. In one aspect ofthe invention R 19 is a group selected from C ⁇ - 6 alkyl, aryl and arylC ⁇ - alkyl where the group is optionally substituted by halo. In another aspect R 19 is a group selected from methyl, phenyl and benzyl where the group is optionally substituted by chloro. In one aspect R 19 is methyl.
  • R 20 is hydrogen or methyl.
  • R 21 is hydrogen, methyl, ethyl, phenyl or benzyl.
  • R 22 is hydrogen, methyl, ethyl, phenyl or benzyl.
  • R 22 is hydrogen or methyl.
  • R 23 is a group selected from C ⁇ . 6 alkyl, aryl and arylC ⁇ alkyl which group is optionally substituted by halo.
  • R is a group selected from methyl, phenyl and benzyl which group is optionally substituted by chloro.
  • R 23 is methyl.
  • a compound of formula (I) as defined herein provided that when z is -NR 8 -; m is 2; A is phenylene; and r is 0; then X is not -O-.
  • a preferred class of compound is of formula (I) wherein:
  • Y 1 is O
  • Y 2 is O; z is -NR 8 -; n is 0, 1 or 2; m is 1 or 3; r is 0; t is 1;
  • A is arylene, heteroarylene or heterocyclylene
  • X is -O-;
  • B is phenyl, naphthyl, tetrahydronaphthyl, pyridyl, quinolinyl, isoquinolinyl, thieno[2,3- b]pyridyl, thieno[3,2-b]pyridyl, 1,8-naphthyridinyl, 2,3-methylenedioxyphenyl, 3,4- methylenedioxyphenyl, 1,6-naphthyridinyl, tMeno[2,3- ⁇ pyrimidinyl or thieno[3,2- - ⁇ pyrimidinyl where each is optionally substituted by one or more groups independently selected from trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, ethynyl, cyano, acetamido, propyloxy, is
  • R 1 is hydrogen or methyl
  • R la is hydrogen or methyl
  • R 2 is hydrogen, -OR 12 , -C(O)OR 12 , - ⁇ R 12 R 13 , -NR 12 C(O)R 13 , -NR 12 C(O)NR 12 R 13 , -NR 12 C(O)OR 13 , methyl or ethyl which methyl or ethyl are optionally substituted by cyano, -OR 12 , -C(O)OR 12 , -NR 12 R 13 or -NR 12 C(O)R 13 ;
  • R 3 is hydrogen, methyl, ethyl, propyl or phenyl
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen or methyl
  • R 3 and R 4 together form a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydropyran ring;
  • R 7 is hydrogen or a group selected from C ⁇ . 6 alkyl, C 3 - cycloalkyl, aryl, heteroaryl or heterocyclyl which group is optionally substituted by heterocyclyl, aryl and heteroaryl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, C 1 . alkyl, -C(O)C 1 - 3 alkyl, -
  • R 3 and R 7 together with the carbon atoms to which they are each attached form a cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl or piperazine ring;
  • R 8 is hydrogen
  • R is hydrogen or methyl
  • Another preferred class of compound is of formula (I) wherein:
  • Y 1 is O
  • Y 2 is O; z is -NR 8 -; n is 0, 1 or 2; m is 1 or 3; r is 0; t is 1;
  • A is phenylene; X is -O-;
  • B is a group selected from bicyclic aryl or bicyclic heteroaryl where each group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, C ⁇ - alkyl (optionally substituted by one or more halo),
  • B is C 2 . alkenyl or C 2 - alkynyl optionally substituted by C ⁇ - alkyl, C 3 - 6 cycloalkyl or heterocyclyl;
  • R 1 is hydrogen or methyl
  • R la is hydrogen or methyl
  • R 2 is hydrogen, -OR 12 , -C(O)OR 12 , -NR 12 R 13 , -NR 12 C(O)R 13 ,
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen or methyl; or R 3 and R 4 together form a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydropyran ring; R 5 is hydrogen or methyl;
  • R 6 is hydrogen or methyl
  • R 7 is selected from hydrogen, C ⁇ . 4 alkyl, haloC 1 . 4 alkyl, hydroxyC 1 . alkyl, C 1 . 4 alkoxyC 1 - alkyl and aryl; or R 3 and R 7 together with the carbon atoms to which they are each attached form a cyclopentyl, cyclohexyl, tetrahydrofyranyl, tetrahydrpyranyl, piperidinyl, pyrrolidinyl or piperazine ring;
  • R 8 is hydrogen; R 9 is hydrogen or methyl; and R 10 is hydrogen or methyl.
  • a further preferred class of compound is of formula (I) wherein: Y s O;
  • Y 2 is O; z is -NR 8 -; n is 0; m is 1 or 3; r is O; t is 1;
  • A is phenylene or heterocyclylene
  • Z is -O-
  • B is 2-methylquinolin-4-yl or 2,5-dimethylphenyl;
  • R 1 is hydrogen or methyl;
  • R la is hydrogen or methyl
  • R is hydrogen, amino, methyl, ethyl, formyl, acetamido, benzoylamino, benzylcarbonylamino, ureido, 3-methylureido, 3-phenylureido, 3-benzylureido and t- butoxycarbonylamino ;
  • R 3 is hydrogen or methyl;
  • R 4 is hydrogen
  • R 7 is hydrogen, methyl, hydroxymethyl or phenyl
  • R 8 is hydrogen.
  • a preferred compound ofthe invention is selected from 5-[(3-Methyl-3- ⁇ 4-[(2-methylquinolin-4-yl)methoxy]phenyl ⁇ -2-oxoazetidin-l- yl)methyl]imidazolidine-2,4-dione;
  • the invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein Y 1 and Y 2 are both O, z is - ⁇ R 8 - and R 8 is hydrogen, which comprises converting a ketone or aldehyde of formula (II) into a hydantoin of formula (I); f ⁇ mJa(ll) fo ⁇ nia(1)
  • the hydantoin can be prepared by a number of methods for example: a) The aldehyde or ketone may be reacted with ammonium carbonate and potassium cyanide in aqueous alcohols using the method of Bucherer and Bergs (Adv. Het. Chem., 1985, 38, 177). b) The aldehyde or ketone could be first converted to the cyanohydrin and then further reacted with ammonium carbonate (Chem.
  • a process for the preparation of a ketone or aldehyde of formula (II) comprises converting a compound of formula (III) into a ketone or aldehyde of formula (II):
  • suitable reagents are Grignard reagents to prepare ketones or diisobutylaluminium hydride in dichloromethane at -78°C under an argon atmosphere to prepare aldehydes.
  • Y is a ketal so that scheme 2 illustrates the reaction:
  • a suitable reagent is an aqueous acid (e.g. a mineral acid such as hydrochloric acid) to hydrolyse the ketal to the diol (Protective Groups in Organic Synthesis; Theordora Greene and
  • suitable reagents are oxidising agents, d) when Y is an alkene group so that scheme 2 illustrates the reaction: formula (111) formula (II) Scheme 2d suitable reagents include reagents for ozonolysis, sodium periodate, osmium tetraoxide and ruthenium calalysts with a suitable oxidant. 5
  • Scheme 3 An alternative to scheme 2a, for the preparation ofthe aldehyde or ketone of formula (II) from an ester of formula (III) is shown in Scheme 3 which comprises:
  • a compound of formula (III) wherein m is 1 may be prepared as shown in Scheme 4;
  • the process of Scheme 4 comprises the steps of: a) reacting an ester of formula (NI), where R is a protected leaving group such as benzyloxy or trimethylsilyloxy or R is -X-(R 1 R la ) t B, with a base such as sodium methoxide in dimethylsulphoxide, lithium diisopylamide or lithium bis(trimethylsilyl)amide in tetrahydrofuran at a temperature of -78°C to 0°C followed by reaction with paraformaldehyde for 30 minutes to 2 hours to give a hydroxymethylated product of formula (Nil); b) reacting the product of formula (Nil) with aqueous base, until no more starting compound can be observed by thin layer chromatography or high performance liquid chromatography/mass spectrometry to give an acid of formula (NIII); c) reacting the acid of formula (VIII) with an amine or amine salt of formula (IX) (where Y is an ester group, a
  • the process of Scheme 5 comprises the steps of: a) reacting an ester of formula (NI), where R is a protected leaving group such as benzyloxy or trimethylsilyloxy or R is -X-(R 1 R la ) t B, with a base such sodium methoxide in dimethylsulphoxide, lithium diisopylamide or lithium bis(trimethylsilyl)amide in tetrahydrofuran at a temperature of-78°C to 0°C followed by reaction with 2-bromo-l- chloroethane, 3-bromo-l-chloropropane or 4-bromo-l-chlorobutane for 30 minutes to 2 hours to give a hydroxymethylated product of formula (XIII); b) reacting the product of formula (XIII) with an amine or amine salt of formula (IX) (where Y is an ester group, a ketal, an alcohol group or an alkene group as defined above or a hydantoin group or
  • the process of Scheme 6 comprises the steps of: a) reacting an ester of formula (VI), where R is a protected leaving group such as benzyloxy or trimethylsilyloxy, with a base such lithium diisopropylamide or lithium bis(trimethylsilyl)amide in tetrahydrofuran at a temperature of -78°C to 0°C followed by reaction with allyl bromide, 4-bromo-but-l-ene or 5-bromopent-l-ene for 30 minutes to 2 hours to give an allylated product of formula (XVI); b) reacting the allylated product of formula (XVI) with ozone, until no more starting compound can be observed by thin layer chromatography or high performance liquid chromatography/mass spectrometry followed by reducing the resultant ozonide with e.g.
  • Y and Y are both O and z is -NH(CO)- (as described herein), which comprises converting a diester of formula (III) wherein Y is -CR 7 (C(O)OC 1 _ 1 oalkyl) 2 into a pyrimidine- 2,4,6(lH,3H,5H)-trione of formula (I);
  • reaction comprises treating a diester of formula (III) with urea in the presence of a base such as sodium methoxide, magnesium methoxide or potassium tert-butoxide to generate a pyrimidine-2,4,6(lH,3H,5H)-trione group. Examples of reactions of this type can be found in Heterocyclic Chemistry, 1993, 4, 55, J. Chem. Soc. Perkin Trans.
  • a compound of formula (III) may be prepared as shown in scheme 4, scheme 5 or scheme 6.
  • a compound of formula (I) can be prepared by removal of protecting groups on the hydantoin directly.
  • the protecting group can be tert-butyloxycarbonyl (BOC), benzyl (Bn) or benzyloxycarbonyl (cbz). These can be removed by treatment with trifluoroacetic acid or hydrogen chloride in dioxane for the former or by treatment with palladium/hydrogen for the latter two.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • the compounds defined in the present invention possesses metalloproteinases inhibitory activity, and in particular TACE inhibitory activity and/or aggrecanase inhibitory activity. These properties may be assessed, for example, using the procedures set out below.
  • Matrix Metalloproteinase family including for example MMP13.
  • Recombinant human proMMP13 may be expressed and purified as described by
  • 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 MMP 13 (11.25ng per assay) is incubated for 4-5 hours at 35°C in assay buffer
  • APMA ImM amino phenyl mercuric acid
  • TACE proTNF- ⁇ convertase enzyme
  • 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.Nal.Arg.Ser.Ser.Ser.Arg.Cys(4-(3- succinimid-l-yl)-fluorescein)- ⁇ H 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 4 hours. The amount of inhibition is determined as for MMP 13 except ⁇ ex 485nm and ⁇ em 538nm were used.
  • the substrate was 5 synthesised as follows.
  • the peptidic part ofthe 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-l-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU) as coupling agent with at least a 4- or 5- fold excess of Fmoc-amino acid and HBTU. Ser and Pro 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
  • Aggrecanase may be prepared from the media of bovine nasal cartilage stimulated for 48 hours with interleukin-1. The media is fractionated by heparin sepharose chromatography using a 0-1 M NaCl gradient. Contaminating gelatinases are removed by passing through a
  • Inhibition is calculated as a percentage ofthe controls. 0% inliibition controls contain aggrecanase and aggrecan alone (maximum activity/luminescence). 100% inhibition controls contain aggrecan substrate alone (minimum activity/luminescence).
  • Other assays The activity ofthe compounds ofthe 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.
  • T ⁇ F- ⁇ production may be assessed in THP-1 cells using an ELISA to detect released T ⁇ F 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.
  • Test as an agent to inhibit cell based invasion The ability ofthe 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
  • Test as an agent to inhibit whole blood TNF sheddase activity The ability ofthe 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- ⁇ . 160 ⁇ l of heparinized (lOUnits/ml) human blood obtained from volunteers, was added to the plate and incubated with 20 ⁇ l of test compound (duplicates), in RPMI1640 + bicarbonate, penicillin, streptomycin, glutamine and 1% DMSO, 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 neat blood incubated with medium alone or LPS (6 wells/plate of each). 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 ofthe compounds of this invention to inhibit the degradation ofthe aggrecan or collagen components of cartilage can be assessed essentially as described by K.
  • Test as an anti-TNF agent The ability ofthe compounds of this invention as in vivo TNF- ⁇ inhibitors is assessed in the rat. Briefly, groups of female Wistar Alderley Park (AP) rats (90-100g) are dosed with compound (5 rats) or drug vehicle (5 rats) by the appropriate route e.g. peroral (p.o.), intraperitoneal (i.p.), subcutaneous (s.c.) 1 hour prior to lipopolysaccharide (LPS) challenge
  • compositions which comprises a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the composition may also be in a form suitable for inhalation.
  • compositions may be prepared in a conventional manner using conventional excipients.
  • 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 0.5 to 30 mg/kg body weight) is received.
  • This daily dose may be given in divided doses as necessary, the precise amount ofthe compound received and the route of administration depending on the weight, age and sex ofthe patient being treated and on the particular disease 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 further aspect ofthe invention provides a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use in a method of treatment of a warm-blooded animal such as man by therapy. Also provided is a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use in a method of treating a disease condition mediated by one or more metalloproteinase enzymes. In particular the disease condition may be mediated by TNF ⁇ and/or aggrecanase.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein is provided for use in a method of treating rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis in a warm-blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is also provided for use in a method of treating a respiratory disorder such as asthma or COPD in a warm-blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is also provided for use in a method of treating osteoarthritis in a warm-blooded animal such as man.
  • the disease condition may be mediated by TNF- ⁇ and/or aggrecanase.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein is provided for use as a medicament in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, is provided for use as a medicament in the treatment of a respiratory disorder such as asthma or COPD.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein is also provided for use as a medicament in the treatment of osteoarthritis.
  • the disease condition may be mediated by TNF- ⁇ and/or aggrecanse.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof as defined herein in the manufacture of a medicament for use in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein is provided in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis.
  • the use of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is also provided in the manufacture of a medicament for use in the treatment of a respiratory disorder such as asthma or COPD.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is further provided in the manufacture of a medicament for use in the treatment of osteoarthritis.
  • the disease condition may be mediated by TNF- ⁇ and/or aggreanase.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein for use in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein is provided for use in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is also provided for use in the treatment of a respiratory disorder such as asthma or COPD.
  • a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is further provided for use in the treatment of osteoarthritis.
  • a method of producing a metalloproteinase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I).
  • a method of producing a TACE inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I).
  • a method of treating autoimmune disease, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I).
  • a method of producing an aggrecanase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I).
  • a method of treating a osteoarthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I).
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is also useful as a pharmacological tool in the development and standardisation of in vitro and in vivo test systems for the evaluation ofthe effects of inhibitors of metalloproteinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part ofthe search for new therapeutic agents.
  • the alternative and preferred embodiments ofthe compounds ofthe invention described herein also apply.
  • the compounds of this invention may be used in combination with other drugs and therapies used in the treatment of various immunological, inflammatory or malignant disease states which would benefit from the inhibition of TACE, aggrecanse or the combination thereof. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate. Examples
  • IsoluteTM SCX column a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK.
  • Flashmaster II is referred to, this means a UN driven automated chromatography unit supplied by Jones.
  • sica Redisep a column containing 40 g or 120 g of silica of 35-60 micron particle size, (230-400 mesh) the silica being contained in a disposable polypropylene column and supported by porous discs and Luer locks either end, obtained from Isco Inc.
  • Companion is referred to, this means a UN driven automated chromatography unit supplied by Isco Ine;
  • Preparative HPLC refers to purification using either an acidic system (General conditions and gradients for each method as follows: 5-95 Method 5 - 95% MeC ⁇ : H2O, 21 ml/min;
  • LCMS liquid chromatography mass spectrometry
  • Potassium carbonate (1.011 g, 3.491 mmol) was added and the mixture was heated at reflux for 48 h, allowed to cool to RT and stirred for a further 72 h. The mixture was diluted with ethyl acetate (50 ml) and filtered.
  • reaction mixture was heated at 60 °C for 2 h, allowed to cool, diluted with ethyl acetate (50 ml), washed with a mixture of brine (15 ml) and water (15 ml), dried (MgSO ), filtered and the filtrate was evaporated in vacuo.
  • Ethanolamine (0.98 ml, 16.3 mmol) and tetrabutylammonium iodide (0.60 g, 1.63 mM) were added to a solution of methyl 5-chloro-2-methyl ⁇ 2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (0.67 g 1.63 mmol) in toluene (15 ml) and the reaction was stirred for 18 h at 105 °C. After cooled and toluene layer was decanted off to leave a red oil.
  • Butanolamine (1.01 ml, 10.90 mmol) and tetrabutylammonium iodide (0.40 g, 1.09 mM) were added to a solution of methyl 5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (0.45 g 1.09 mmol) in toluene (15 ml).
  • the reaction mixture was stirred for 18 h at 105 °C. After cooling, the toluene layer was decanted off to leave a red oil.
  • the starting material 3 -methyl-3 -[4-(2-methy lquinolin-4-ylmethoxy)phenyl]-(2-oxo-propyl)- piperidin-2-one was prepared as follows :
  • reaction solution was poured onto a 5 g silica bond elute column and eluted with EtOAc to give 3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-(2-oxo-propyl)-piperidin-2-one (0.20 g, 0.48 mmol), as a yellow gum.
  • Diisoproylethylamine (0.174 ml, 1.002 mmol) was added followed by 5-(aminomethyl)-5- methyl-3- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ imidazolidine-2,4-dione acetate (prepared below) (0.33 g, 1.002 mmol) in DMF (1 ml) and DIPEA (0.174 ml, 1.002mmol), stirring continued for 10 mins. The solution was poured into a mixture of water (30 ml) and brine (30 ml) and the aqueous phase was extracted with EtOAc (3 x 30 ml).
  • Methanesulphonyl chloride (0.092 ml, 1.184 mmol) was added dropwise and stirring continued at RT for 40 mins. The pyridine was removed in vacuo and the residue re-dissolved in DMA (10 ml). Potasshim carbonate (0.504 g, 3.644 mmol) was added and the mixture was heated at 80 °C for 16 h, allowed to cool to RT. The mixture was diluted with brine (30ml) and water (30ml) and extracted with EtOAc (3 x 30 ml).
  • tert-butyl [3- ⁇ 4-[(2,5-dimethylbenzyl)oxy]phenyl ⁇ -2-oxo-l-(2- oxopropyl)pyrrolidin-3-yl] carbamate was prepared as follows: i) Methyl 2-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate (0.450 g, 1.09 mmol, CAS no. 223407-41-8) was dissolved in 1,2-dichloroethane (10 ml) and (2R)-1- aminopropan-2-ol (0.117 ml, 1.5 mmol) was added.
  • reaction mixture was then heated to reflux and stirred for 2h, at which point the reaction was complete by TLC.
  • the reaction mixture was then cooled to 15°C, basified with 0.880 ammonia to pH 8-9 (approximately 0.770 L) and diluted with water (1.08 L), to aid mobility.
  • the precipitate was filtered, washed with water and dried at 40°C in air to give the desired product / hydroxyphenylglycine methyl ester (673 g, 3.72 mol).
  • Example 10 The procedure described in Example 10 was followed using N- ⁇ 3- ⁇ 4-[(2,5- dimethylbenzyl)oxy]phenyl ⁇ - 1 -[(4-methyl-2,5-dioxo- 1 - ⁇ [2-
  • Example 10 The procedure described in Example 10 was followed using ⁇ 3- ⁇ 4-[(2,5- dimethylbenzyl)oxy]phenyl ⁇ - 1 -[(4-methyl-2,5-dioxo- 1 - ⁇ [2-
  • Example 10 The procedure described in Example 10 was followed using N-benzyl-N'- ⁇ 3- ⁇ 4-[(2,5- dimethylbenzyl)oxy]phenyl ⁇ - 1 - [(4-methyl-2,5 -dioxo- 1 - ⁇ [2-
  • Example 10 The procedure described in Example 10 was followed using N- ⁇ 3- ⁇ 4-[(2,5- dimethylbenzyl)oxy]phenyl ⁇ - 1 -[(4-methyl-2,5-dioxo- 1 - ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl ⁇ -2- phenylacetamide (prepared below) (0.379 g) to give N- ⁇ 3- ⁇ 4-[(2,5- dimethylbenzyl)oxy]phenyl ⁇ -l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-2- oxopyrrolidin-3-yl ⁇ -2-phenylacetamide (0.0553 g, 0.010 mmol).
  • the starting material 2,2-dimethylpropanoic phenylacetic anhydride was prepared using the method provided in Tet Lett, 1990, 31 , (7), 995
  • the starting material (3- ⁇ 4-[(2-methylquinolin-4-yl)methoxy]piperidin-l-yl ⁇ -2-oxopyrrolidin- l-yl)acetaldehyde was prepared as follows : (i) To a stirred solution of [(2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl]amine (1.94g, 14.8mmole), triethylamine (5.16ml, 37mmole) in DMA (20ml) at 0°C under an inert atmosphere was added 2,4-dibromobutanoyl chloride (2.15ml, 16.3mmole) drop-wise.
  • the crude product was purified by flash silica chromatography eluting with a gradient of 10% to 100% EtOAc in iso-hexane, to yield as a mixture of diastereoisomers, 3-bromo-l-[(2,2-dimethyl- l,3-dioxolan-4-yl)methyl]pyrrolidin-2-one as an orange gum (2.044g, 80% yield).
  • the crude product was purified by flash silica chromatography eluting with a gradient of 0% to 50% MeOH in EtOAc to yield as a mixture of diastereoisomers, l-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]-3- ⁇ 4-[(2- methylquinolin-4-yl)methoxy]piperidin-l-yl ⁇ pyrrolidin-2-one as a yellow gum (164mg, 47% yield).

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Abstract

Hydantoin derivatives of formula (I) that are useful in the inhibition of metalloproteinases and in particular in the inhibition of TNF-α Converting Enzyme (TACE), aggrecanase or the combination thereof.

Description

HYDANTOIN DERIVATIVES FOR USE AS TACE AND AGGRECANASE INHIBITORS
The present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising them, as well as their use. The compounds of this invention are inhibitors of one or more metalloproteinase enzymes. They are particularly effective as inhibitors of TNF-α (Tumour Necrosis Factor-α) production, as inhibitors of aggrecan breakdown or the combination thereof. 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 inN.M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMP) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP 10, MMP 11), matrilysin (MMP7), metalloelastase (MMP 12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF-α converting enzymes (AD AMI 0 and TACE); aggrecanases such as the ADAM-TS family (for example ADAM-TS 1 and ADAM-TS4); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as 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 ofthe 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 biologically important cell mediators, such as tumour necrosis factor-α (TNF-α); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al, (1997) Biochem J. 321:265-279). Metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these disease conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation ofthe gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation ofthe skin (especially psoriasis, eczema and dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation ofthe 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 ofthe skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases ofthe central and peripheral nervous systems (such as multiple sclerosis); Alzheimer's disease; and extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis. A number of metalloproteinase inhibitors are known; different classes of compounds may have different degrees of potency and selectivity for inhibiting various metalloproteinases. We have discovered a class of compounds that are inhibitors of metalloproteinases. The compounds are of particular interest in inhibiting TACE but are also useful in the inhibition of aggrecanse or the combination thereof. The compounds of this invention also have beneficial potency and/or pharmacokinetic properties. TACE (also known as ADAM 17) which has been isolated and cloned [R.A. Black et al. (1997) Nature 385:729-733; M.L. Moss et al. (1997) Nature 385:733-736] is a member of the admalysin family of metalloproteins. TACE has been shown to be responsible for the cleavage of pro-TNF-α, a 26kDa membrane bound protein to release 17kDa biologically active soluble TNF-α. [Schlondorff et al. (2000) Biochem. J. 347: 131-138]. TACE mRNA is found in most tissues, however TNF-α is produced primarily by activated monocytes, macrophages and T lymphocytes. TNF-α has been implicated in a wide range of pro- inflammatory biological processes including induction of adhesion molecules and chemokines to promote cell trafficking, induction of matrix destroying enzymes, activation of fibroblasts to produce prostaglandins and activation ofthe immune system [Aggarwal et al (1996) Eur. Cytokine Netw. 7: 93-124]. Clinical use ofthe anti-TNF-α biologicals has shown TNF-α to play an important role in a range of inflammatory diseases including rheumatoid arthritis, Crohn's disease and psoriasis [Onrust et al (1998) Biodrugs 10: 397-422, Jarvis et al (1999) Drugs 57:945-964]. TACE activity has also been implicated in the shedding of other membrane bound proteins including TGFα, p75 and p55 TNF receptors, L-selectin and amyloid precursor protein [Black (2002) Int. J. Biochem. Cell Biol. 34: 1-5]. The biology of TACE inhibition has recently been reviewed and shows TACE to have a central role in TNF- α production and selective TACE inhibitors to have equal, and possibly greater, efficacy in the collagen induced arthritis model of rheumatoid arthritis than strategies that directly neutralise TNF-α [Newton et al (2001) Ann. Rheum. Dis. 60: iii25-iii32]. A TACE inhibitor might therefore be expected to show efficacy in all disease where TNF-α has been implicated including, but not limited to, inflammatory diseases including rheumatoid arthritis and psoriasis, autoimmune diseases, allergic/atopic diseases, transplant rejection and graft versus host disease, cardiovascular disease, reperfusion injury, malignancy and other proliferative diseases. A TACE inhibitor might also be useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary diseases (referred to herein as COPD). Aggrecanase is a proteinase which is responsible for the cleavage ofthe large, hydrophilic aggregating proteoglycan, aggrecan. A network of collagen fibres and aggrecan are the principal components of articulate cartilage, which allows for the almost frictionless articulation of joints and acts as a shock absorber by recovering from deformation after loading. Aggrecan is composed of a central protein core to which glycosaminoglycan (GAG) chains are attached. At the amino terminal there are two globular domains, known as Gl and G2 that are separated by a short interglobular domain. At the carboxy terminus is another globular domain G3. Association of aggrecan with hyaluronan, through an interaction between its Gl domain and link protein, fixes the aggrecan molecule within the cartilage matrix. The breakdown of aggrecan is a proteolytic process catalysed by extracellular matrix metalloproteases. Aggrecan can be cleaved at multiple sites along the aggrecan molecule but in human aggrecan the critical cleavage site is between the Gl and G2 globular domains at the Glu - Ala bond resulting in fragments with neo-epitopes of GI-NITEGE-CO2H and
NH2ARGSN-G2. Several members ofthe ADAM-TS family can cleave aggrecan generating these neo-epitopes. Synovial fluid from patients with joint injury, inflammatory arthritis and osteoarthritis contains both fragments indicating aggrecan cleavage at the Glu - Ala peptide bond. Excessive aggrecanase activity can destroy the cartilage matrix since most GAG bearing aggrecan fragments are released from the tissue into the synovial fluid following cleavage of the Glu373 -Ala374 peptide bond. Analysis of aggrecan in human knee cartilage and synovial fluid indicates that aggrecanase activity is responsible for the loss of aggrecan from cartilage (Sandy JD, et al. Biochem J 358:615-626 (2001)). The presence ofthe intact aggrecan within the cartilage appears to protect the collagen from enzymatic attack. Therefore an inhibitor of aggrecan breakdown should help to retain the integrity ofthe articular cartilage. The thinning of articular cartilage and hence narrowing of joint spaces is a common feature of destructive anthropathies and hence it is expected that an aggrecanse inhibitor will be useful in the treatment of musculo-skeletal disease such as osteoarthritis. TACE and aggrecanase inhibitors are known in the art. WO 02/096426 describes hydantoin derivatives which are useful as inhibitors of matrix metalloproteinases, TACE, aggrecanase, or a combination thereof. We are able to provide further compounds that have metalloproteinase inhibitory activity against one or more metalloproteinase, and are in particular inhibitors of TACE (AD AMI 7), aggrecanase ofthe combination thereof.
The present invention provides a compound of formula (I):
Figure imgf000005_0001
formula (I) or a pharmaceutically acceptable salt thereof: wherein: 1
Y and Y are independently O or S; z is -NR8- or -NHC(O)- which -NHC(O)- is bonded to C=Y2 through N and to CR7(CR5R6)n through C; n is 0, 1 or 2; m is 1, 2, 3 or 4; r is 0, 1 or 2; t is 0 or 1 ;
A is arylene, heteroarylene or heterocyclylene;
X is absent, -O-, -S-, -SO-, -SO2-, -NR14-, -C(O)NR14-, -NR14C(O)-, SO2NR14, -NR14SO2-,
-CH2-CH2- or -CH≡CH-; B is a group selected from aryl, heteroaryl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, cyano, C1.4alkyl (optionally substituted by R9 or Cι.
4alkoxy or one or more halo), C2.4alkenyl (optionally substituted by halo or R9), C2.4alkynyl
(optionally substituted by halo or R9), C3.6cycloalkyl (optionally substituted by R9 or one or more halo), Cs-6cycloalkenyl (optionally substituted by halo or R9), aryl (optionally substituted by halo or Cι-4alkyl), heteroaryl (optionally substituted by halo or Cι.4alkyl), heterocyclyl
(optionally substituted by C1.4alkyl), -SR11, -SOR11, -SO2Rπ, -SO2NR9R10, -NR9SO2Rπ, -
NHC(O)NR9R10, -OR9, -NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is C2-4alkenyl or C2. alkynyl, each being optionally substituted by a substituent group selected from C1.4alkyl, C3.6cycloalkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl which substituent group is optionally substituted by one or more halo, nitro, cyano, trifluoromethyl, trifluoromethoxy,
-C(O)NHR9, -C(O)NR9R10, -SO2Rπ, -SO2NR9R10, -NR9SO2Rn, Ci-4alkyl or C1 alkoxy groups;
R1, Rla, Rlb and Rlc are independently selected from hydrogen, Cι.6alkyl and C3.6cycloalkyl; R2 is selected from hydrogen, halo, heterocyclyl, -OR12, -C(O)R12, -C(O)OR12, -NR12R13, -
NR12C(O)R13, -C(O)NR12R13, -NR12C(O)NR12R13, -NR12C(O)OR13 and d^alkyl which 19 1 19
C1.4alkyl is optionally substituted by halo, cyano, heterocyclyl, -OR , -C(O)R , -C(O)OR , -NR12R13, -NC(O)R12 or -C(O)NR12R13;
R3, R4, Rs and R6 are independently hydrogen or a group selected from Ct-βalkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C5.6cycloalkenyl, aryl, heteroaryl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1. alkyl, C2.4alkenyl, C2.4alkynyl, C3.6cycloalkyl (optionally substituted by one or more R ), aryl (optionally substituted by one 17 17 15Ϊ or more R ), heteroaryl (optionally substituted by one or more R ), heterocyclyl, -OR , - -SSRR1199,, --SSOORR1199,, --SSOO22RR1199,, --CC((OO))RR1199,, --CC((OO))OR18, -C(O)NR18R20, -NR16C(O)R18, - SO2NR18R20, -NR16SO2R19 and-NR18R19; or R3 and R4 together with the carbon atom to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO which ring is optionally substituted on carbon by C1.4alkyl, fluoro or Cι. alkoxy and/or on nitrogen by -C(O)C1-3alkyl or -SO2C1.3alkyl or Cι-4alkyl; or R3 and R5 together with the carbon atoms to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 which ring is optionally substituted on carbon by Cι_4alkyl, fluoro or Cι. alkoxy and/or on nitrogen by -C(O)C1.3alkyl or -SO2Ci-3alkyl or Cι.4alkyl; or R5 and R6 together with the carbon atom to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO which ring is optionally substituted on carbon by Cι.4alkyl, fluoro or Cι-3alkoxy and/or on nitrogen by -C(O)C1.3alkyl or -SO2Cι-3alkyl or Cι.4alkyl;
R7 is hydrogen or a group selected from Cι.6alkyl, C2.6alkenyl, C2_6alkynyl, heteroalkyl, C3.7cycloalkyl, aryl, heteroaryl or heterocyclyl which group is optionally substituted by a substituent group selected from halo, C1. alkyl, C1. alkoxy, C3. cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroalkyl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, Cι-4alkyl, nitro, haloC1.4alkyl, heteroalkyl, aryl, heteroaryl, hydroxyC1. alkyl, C3.7cycloalkyl, heterocyclyl, C1-4alkoxyC1.4alkyl, haloC1.4alkoxyC1-4alkyl, -C(O)C1.4alkyl, -OR21, -NR21R22, -C(O)OR21, -SR23, -SOR23, -SO2R23, -NR21C(O)R22, -C(O)NR21R22 and -NHC(O)NR21R22; or R3 and R7 together with the carbon atoms to which they are each attached and (CR5R6)n form a saturated 5- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO where the ring is optionally substituted on carbon by Cι. alkyl, fluoro or Cι.3alkoxy and/or on nitrogen by -C(O)C1.3alkyl or -SO2Cι_3alkyl or C1. alkyl; R is hydrogen or methyl;
R9 and R10 are independently hydrogen, Cι.6alkyl or C3_6cycloalkyl; or R9 and R10 together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring; R11 is Cι.6alkyl or C3.6cycloalkyl;
R12, R13 and R16 are independently hydrogen, Cι_6alkyl, aryl and arylC1.4alkyl and may be optionally substituted by one or more halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, Ci.6alkylsulpb.onyl, Cι-6alkylsulphonylamino, Cι.6alkyl, C2.6alkenyl, C2-6alkynyl,
Cι-6alkoxy, Cι_6alkylamino and di-tCi-δalkyllamino;
R14 is hydrogen, Cι.4alkyl, -C(O)C1.4alkyl, -C(O)NH2, -SO2C1.4alkyl;
R17 is selected from halo, Cι.6alkyl, C3.6cycloalkyl and Cι_6alkoxy; R18 is hydrogen or a group selected from Cι-6alkyl, C3.6cycloalkyl, C5-6cycloalkenyl, saturated heterocyclyl, aryl, heteroaryl, arylC1- alkyl and heteroarylCι.4alkyl which group is optionally substituted by one or more halo;
R19 and R23 are independently a group selected from
Figure imgf000008_0001
C3.6cycloalkyl, C5-
6cycloalkenyl, saturated heterocyclyl, aryl, heteroaryl, arylCι-4alkyl and heteroarylC1- alkyl which group is optionally substituted by one or more halo;
R is hydrogen, Cι-6alkyl or C3.6cycloalkyl; or R18 and R20 together with the nitrogen to which they are attached form a heterocyclic 4- to
7- membered ring;
R21 and R22 are independently hydrogen, C^alkyl, haloC1. alkyl, aryl and arylC1.4alkyl; provided that when z is -NHC(O)- then R7 is not hydrogen; and provided that when z is -NR -, m is 2; A is phenylene; R is hydrogen, -NR R or Cι.4alkyl which Cι. alkyl is optionally substituted by halo, -OR12 or -NR12R13; and r is 0; then X is not
-O-. Also provided is a compound of formula (I) as defined herein provided that when z is - NR8-; r is 0; and X is -O-; then A is not pheneylene. As a further aspect an in vivo hydrolysable ester of a compound of formula (I) is provided. It is to be understood that, insofar as certain compounds of formula (I) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon or sulphur atoms, the invention includes in its definition any such optically active or racemic form which possesses metalloproteinases inhibition activity and in particular TACE inhibition activity and/or aggrecanase inhibition activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques known to the skilled person and referred to herein. Compounds of formula (I) are therefore provided as enantiomers, diastereomers, geometric isomers and atropisomers. Within the present invention it is to be understood that a compound of formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one ofthe possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which has metalloproteinases inhibition activity and in particular TACE inhibition activity and/or aggrecanase inhibition activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. It is also to be understood that certain compounds of formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which have metalloproteinases inhibition activity and in particular TACE inhibition activity and/or aggrecanase inhibition activity. It is also to be understood that certain compounds of formula (I) may exhibit polymorphism, and that the invention encompasses all such forms which possess metalloproteinases inhibition activity and in particular TACE inhibition activity and/or aggrecanase inhibition activity. The present invention relates to compounds of formula (I) as defined herein as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of compounds of formula (I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts ofthe invention may, for example, include acid addition salts of compounds of formula (I) as defined herein which are sufficiently basic to form such salts. Such acid addition salts include but are not limited to hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In addition where compounds of formula (I) are sufficiently acidic, salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salts for example triethylamine or tris-(2-hydroxyethyl)amine. The compounds of formula (I) may also be provided as in vivo hydrolysable esters. An in vivo hydrolysable ester of a compound of formula (I) containing a carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol. 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 fluid. Suitable pharmaceutically acceptable esters for carboxy include CT-ealkoxymethyl esters for example methoxymethyl, Cι-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxyCι.6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Cι-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result ofthe in vivo hydrolysis ofthe ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include Ci-ioalkanoyl, for example formyl, acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, Ci-ioalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; bis(C1- alkyl)carbamoyl andN-(bis(Cι-4alkyl)aminoethyl)-N- (Ci^alky^carbamoyl (to give carbamates); bis(Cι- alkyl)am_noacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, (Ci.. alkyl)aminomethyl and bis(Cι-4alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position ofthe benzoyl ring. Other interesting in vivo hydrolysable esters include, for example, RAC(O)O(C1.6)alkyl- CO-, wherein RA is for example, benzyloxyCι~ alkyl, or phenyl). Suitable substituents on a phenyl group in such esters include, for example, 4-C1- alkylpiperazinylC1-4alkyl, piperazinylCι- alkyl and morpholinoCι- alkyl.
In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as tert-butyl are specific for the branched chain version only. For example, "Ci-3alkyl" includes methyl, ethyl, propyl and isopropyl, examples of "Chalky!" include the examples of "Chalky-" and butyl and tert-butyl and examples of "Cι.6alkyl" include the examples of "Cι- a_kyl"and additionally pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl. An analogous convention applies to other generic terms, for example "C2.4alkenyl" includes vinyl, allyl and 1-propenyl and examples of "C2.6alkenyl" include the examples of "C2.4alkenyl" and additionally 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3- methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Examples of "C2-4alkynyl" includes ethynyl, 1-propynyl, 2-propynyl, 3-butynyl and examples of "C2.6alkynyl"include the examples of "C .4alkynyl" and additionally 2-pentynyl, hexynyl and l-methylpent-2-ynyl. Where examples are given for generic terms, it should be noted that these examples are not limiting. "Cycloalkyl" is a monocyclic, saturated alkyl ring. The term "C3-4cycloalkyl" includes cyclopropyl and cyclobutyl. The term "C3- cycloalkyl" includes "C3.4cycloalkyl and cyclopentyl. The term "C3-6cycloalkyl" includes "C3.5cycloalkyl", and cyclohexyl. The term "C3.7cycloalkyl" includes "C3-6cycloalkyl" and additionally cycloheptyl. The term "C3. locycloalkyl" includes "C3.7cycloalkyl" and additionally cyclooctyl, cyclononyl and cyclodecyl. "Cycloalkenyl" is a monocyclic ring containing 1, 2, 3 or 4 double bonds. Examples of "C -6cycloalkenyl" are cyclopentenyl, cyclohexenyl and cyclohexadiene and examples of "Cs-iocycloalkenyl" include the examples of "Cs-δcycloalkenyl" and cyclooctatriene. Unless otherwise specified "aryl" is monocyclic or bicyclic aromatic ring. Examples of "aryl" therefore include phenyl (an example of monocyclic aryl) and naphthyl (an example of bicyclic aryl). Examples of "arylC1. alkyl" are benzyl, phenylethyl, naphthylmethyl and naphthylethyl. "Arylene" is a bivalent monocyclic or bicyclic aromatic ring such as phenylene. "Carbocyclyl" is a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 4 to 12 ring atoms, wherein a -CH2- group is optionally be replaced by a -C(O)-. Examples and suitable values ofthe term "carbocyclyl" are 1,2,3,4-tetrahydronaphthyl and indanyl. Unless otherwise specified "heteroaryl" is a monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised. Examples of heteroaryl are pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzotbienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl and pyrazolopyridinyl. Preferably heteroaryl is pyridyl, imidazolyl, quinolinyl, pyrimidinyl, thienyl, pyrazolyl, thiazolyl, oxazolyl and isoxazolyl. More preferably heteroaryl is pyridyl, imidazolyl and pyrimidinyl. Examples of "monocyclic heteroaryl" are pyridyl, imidazolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl and pyrazinyl. Examples of "bicyclic heteroaryl" are quinolinyl, quinazolinyl, cinnolinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl and pyrazolopyridinyl. Preferred examples of B when B is heteroaryl are those examples of bicyclic heteroaryl. Examples of "heteroarylCi-zialkyl" are pyridylmethyl, pyridylethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl. "Heteroarylene" is a bivalent monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised. Examples of "heteroarylene" are thiophenylene, pyridinylene, pyrimidinylene, pyrrolylene, oxazolylene, isoxazolylene and thiazolylene. Preferred examples are thiophenylene and pyridinylene. "Heterocyclylene" is a bivalent is a saturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH - group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring -NH is optionally substituted by acetyl, formyl, methyl or mesyl; and a ring is optionally substituted by one or more halo. Examples and suitable values ofthe term "heterocyclylene" are piperidinylene, piperazinylene, pyrrolidinylene and morpholinylene. Preferred values are piperidinylene and piperazinylene. "Heterocyclyl" is a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH - group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring -NH is optionally substituted by acetyl, formyl, methyl or mesyl; and a ring is optionally substituted by one or more halo. Examples and suitable values ofthe term "heterocyclyl" are piperidinyl, N-acetylpiperidinyl, N- methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5-dioximidazolidinyl, 2,2-dimethyl-l,3- dioxolanyl and 3,4-dimethylenedioxyphenyl. Preferred values are 3,4-dihydro-2H-pyran-5-yl, tetrahydrofuran-2-yl, 2,5-dioximidazolidinyl, 2,2-dimethyl-l,3-dioxolan-2-yl and 3,4- methylenedioxyphenyl. Other values are pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinoline, tetrahydroisoquinoline and isoindolinyl. Examples of monocyclic heterocyclyl are piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N- formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, pyranyl, tetrahydrofuranyl, 2,5-dioximidazolidinyl and 2,2-dimethyl-l,3- dioxolanyl. Examples of bicyclic heterocyclyl are pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl. 2,3- methylenedioxyphenyl, and 3,4-methylenedioxyphenyl. Examples of saturated heterocyclyl are piperidinyl, pyrrolidinyl, piperazinyl and morpholinyl. The term "halo" refers to fluoro, chloro, bromo and iodo. Examples of "Cι-3alkoxy" and "Cι. alkoxy" include methoxy, ethoxy, propoxy and isopropoxy. Examples of "Cι.6alkoxy" include the examples of "Cι.4alkoxy" and additionally pentyloxy, 1-ethylpropoxy and hexyloxy. "Heteroalkyl" is alkyl containing at least one carbon atom and having at least one carbon atom replaced by a hetero group independently selected from Ν, O, S, SO, SO2, (a hetero group being a hetero atom or group of atoms). Examples include -CH2OCH3, -CH SH and -OC2H5. "HaloC1- alkyl" is a Cι-4alkyl group substituted by one or more halo. Examples of "haloCι- alkyr include fluoromethyl, trifluoromethyl, 1-chloroethyl, 2-chloroethyl, 2- bromopropyl, 1-fluoroisopropyl and 4-chlorobutyl. Examples of "haloCι.6alkyl" include the examples of "haloCι.4alkyl" and 1-chloropentyl, 3-chloropentyl and 2-fluorohexyl. Examples of "hydroxyC1- alkyl" include hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 2-hydroxypropyl, 1-hydroxyisopropyl and 4-hydroxybutyl. Example of "C1- alkoxyC1.4alkyl" include methoxymethyl, ethoxymethyl, 2- methoxy ethyl, 2-methoxypropyl and 4-propoxybutyl. "HaloCi-4alkoxyCi.4alky_" is a C1-4alkoxyCι.4alkyl group substituted on Ci-4alkoxy by one or more halo. Examples of "haloC1- alkoxyC1- alkyl" include l-(chloromethoxy)ethyl, 2- fluoroethoxymethyl, trifluoromethoxymethyl, 2-(4-bromobutoxy)ethyl and 2-(2- iodoethoxy)ethyl. Examples of "carboxyCι-4alkyl" include carboxymethyl, 2-carboxyethyl and 2- carboxypropyl. Heterocyclic rings are rings containing 1, 2 or 3 ring atoms selected from nitrogen, oxygen and sulphur. "Heterocyclic 5 to 7-membered" rings are pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, thiomorpholinyl , thiopyranyl and morpholinyl. "Heterocyclic 4 to 7-membered" rings include the examples of "heterocyclic 5 to 7-membered" and additionally azetidinyl. Examples of saturated 3- to 7-membered rings optionally containing a heteroatom groups selected from NH, O, S, SO or SO2 include cyclopropyl, cyclohexane, cyclopentane, piperidine, pyrrolidine, terahydofuran and tetrahydropyran. Examples of saturated 5- to 7- membered rings optionally containing a heteroatom groups selected from NH, O, S, SO or SO2 include cyclohexane, cyclopentane, piperidine, pyrrolidine, terahydofuran and tetrahydropyran. Where optional substituents are chosen from "one of more" groups or substituents it is to be understood that this definition includes all substituents being chosen from one ofthe specified groups or the substituents being chosen from two or more ofthe specified groups. Preferably "one or more" means "1, 2 or 3" and this is particularly the case when the group or substituent is halo. "One or more" may also mean "1 or 2". Compounds ofthe present invention have been named with the aid of computer software (ACD/Name version 6.0 Name) or Beilstein MDL Crossfire Autonom (MDL Information Sytems). Preferred values of Y1, Y2, z, n, m, r, t, A, X, B, R1, Rla, Rlb, Rlc, R2, R3, R4, R5, R6 and R7 are as follows. Such values may be used where appropriate with any ofthe definitions, claims or embodiments defined hereinbefore or hereinafter. In one aspect ofthe invention Y1 is O. In one aspect ofthe invention Y2 is O. hi one aspect ofthe invention z is -NR8-. In a further aspect z is -NHC(O)- which - NHC(O)- is bonded to C=Y2 through N and to CR7(CR5R6)„ through C .
In one aspect ofthe invention n is 0. In another aspect n is 1. In another aspect n is 2. In one aspect ofthe invention m is 1, 2 or 3. In another aspect m is 1. hi a further aspect m is 2. In yet another aspect m is 3.
In one aspect ofthe invention r is 0. In another aspect r is 1. In another aspect r is 2. In one aspect ofthe invention t is 0. In another aspect t is 1. In one aspect ofthe invention A is phenylene. In another aspect A is thiophenylene, pyridinylene, pyrimidinylene, pyrrolylene, oxazolylene, isoxazolylene or thiazolylene. In yet another aspect A is thiophenylene or pyridinylene. In one aspect ofthe invention X is -O-. In another aspect X is absent, -S-, -SO-, -SO2- , -NR14-, -C(O)NR14-, -NR14C(O)-, SO2NR14, -NR14SO2-, -CH2-CH2 " or -CH≡CH-; In one aspect ofthe invention, B is a group selected from aryl, heteroaryl, carbocyclyl and heterocyclyl where each group is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, Cι.4alkyl (optionally substituted by one or more halo), C2- alkynyl, heteroaryl, -OR9, cyano, -NR9R10, - C(O)NR9R10 and -NR9C(O)R10; or B is C2-4alkenyl or C2.4alkynyl optionally substituted by Ci.4alkyl, C3.6cycloalkyl or heterocyclyl. In another aspect B is a group selected from bicyclic aryl or bicyclic heteroaryl where each group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, Ci-4alkyl (optionally substituted by one or more halo), C2.4alkynyl, heteroaryl, -OR9, cyano, - NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is C2.4alkenyl or C2.4alkynyl optionally substituted by Cι.4alkyl, C3-6cycloalkyl or heterocyclyl. In another aspect, B is phenyl, naphthyl, tetrahydronaphthyl, pyridyl, quinolinyl, isoquinolinyl, thienopyridyl, 1,8- naphthyridinyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 1,6-naphthyridinyl, thienopyrimidinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or isoindolinyl, where each is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, Cι.4alkyl (optionally substituted by one or more fluoro), C2. alkynyl, heteroaryl, -OR9, cyano, -NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is vinyl or ethynyl optionally substituted by Cι- alkyl, hydroxyCι.4alkyl, C1.4alkoxyC1.4alkyl or aryl. In another aspect B is phenyl, naphthyl, tetrahydronaphthyl, pyridyl, quinolinyl, isoquinolinyl, thieno[2,3-b]pyridyl, thieno[3,2-b]pyridyl, 1,8-naphthyridinyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 1,6-naphthyridinyl, thieno[2,3-ct]pyrimidinyl or thieno[3,2- cdpyrimidinyl where each is optionally substituted by one or more groups independently selected from trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, ethynyl, cyano, acetamido, propyloxy, isopropyloxy, methoxy, ethoxy, nitro, pyrrolidinylcarbonyl, N-propylcarbamoyl, pyrrolidinyl, piperidinyl, isoxazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl and pyridyl; or B is vinyl or ethynyl optionally substituted by methyl, ethyl, hydroxmethyl, methoxymethyl or phenyl. In another aspect of the invention B is a group selected from quinolinyl, pyridyl and phenyl where each group is optionally substituted by one or more methyl, trifluoromethyl, trifluoromethoxy, halo or isoxazolyl. In a further aspect B is aryl, heteroaryl or C2-4alkynyl optionally substituted by halo or Cι. alkyl. In another aspect B is 2-methylquinolin-4-yl, 2,5-dimethylphenyl, 2,5- dimethylpyrid-4-yl, phenyl, 3,5-difluorophenyl or prop-1-ynyl. In a further aspect ofthe invention B is 2-methylquinolin-4-yl, 2,5-dimethylphenyl or 2,5-dimethylpyrid-4-yl. In yet another aspect B is 2-methylquinolin-4-yl or 2,5-dimethylphenyl. In one aspect ofthe invention R1 is hydrogen or methyl. In one aspect ofthe invention Rla is hydrogen or methyl. 11". In one aspect ofthe invention R is hydrogen or methyl. In one aspect ofthe invention Rlc is hydrogen or methyl. In one aspect ofthe invention R2 is hydrogen, -OR12, -C(O)OR12, -ΝR12R13, -
NR12C(O)R13, methyl or ethyl which methyl or ethyl are optionally substituted by cyano, - OR12, -C(O)OR12, -NR1 R13 or -NR12C(O)R13. In a further aspect R2 is hydrogen, amino, Ci. 4alkylamino, di(C1-4alkyl)amino, cyano, methoxy, hydroxy, carboxy, methyl or ethyl. In another aspect R is hydrogen, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyano, methoxy, hydroxy, carboxy, methyl or ethyl. In yet another aspect R2 is hydrogen, amino or methyl. In yet a further aspect R2 is methyl. In a further aspect ofthe present invention R2 is hydrogen, -OR12, -C(O)OR12, -NR12R13, -NR12C(O)R13,
-NR12C(O)NR12R13, -NR1 C(O)OR13, methyl or ethyl which methyl or ethyl are optionally substituted by cyano, -OR12, -C(O)OR12, -NR12R13 or -NR12C(O)R13. In yet another aspect R2 is hydrogen, amino, methyl, formyl, acetamido, benzoylamino, benzylcarbonylamino, ureido, 3-methylureido, 3-phenylureido, 3-benzylureido and t-butoxycarbonylamino. In one aspect of the invention R is hydrogen, methyl, ethyl, propyl or phenyl. In another aspect R3 is hydrogen or methyl. In one aspect ofthe invention R4 is hydrogen or methyl. In another aspect R4 is hydrogen. In one aspect ofthe invention R3 and R4 together form a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydropyran ring. In another aspect R3 and R4 together form a pyrrolidine ring or a tetrahydro-2H-pyran ring. In one aspect ofthe invention R5 is hydrogen or methyl. hi one aspect ofthe invention R and R together with the carbon atoms to which they are attached form a piperidine ring optionally substituted by methyl. In one aspect ofthe invention R6 is hydrogen or methyl. In one aspect ofthe invention R7 is hydrogen or a group selected from C^aHcyl, C3. cycloalkyl, aryl, heteroaryl and heterocyclyl which group is optionally substituted by heterocyclyl, aryl and heteroaryl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, C^alkyl, -C(O)C1.3alkyl, -SOzC^alkyl, -OR21, -NR21R22, -C(O)OR21, - NR21C(O)R22, -NR21C(O)OR22 and -C(O)NR21R22. In another aspect R7 is hydrogen or a group selected from Cι.4alkyl, arylCι.4alkyl, heteroarylCι-4alkyl, heterocyclylC1-4alkyl, aryl, heteroaryl, heterocyclyl and C3.5cycloalkyl which group is optionally substituted by cyano, Ci. 4alkyl, halo, -OR21, -NR21R22, -C(O)C1.3alkyl and -SO2Ci.3alkyl. In yet another aspect R7 is hydrogen or a group selected from heterocyclylmethyl, heterocyclylethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, aminomethyl, aminoethyl, Ci.4alkylaminomethyl, Ci-zjalkylaminoethyl, di(C1. alkyl)aminomethyl and di(C1-4alkyl)aminoethyl. In a further aspect R7 is hydrogen or a group selected from Cι-4alkyl, tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl and morpholinyl optionally substituted by methyl, ethyl, methoxy, ethoxy, fluoro, -C(O)Cι-3alkyl or -SO2C1-3alkyl. In one aspect R7 is selected from hydrogen, Ci- alkyl, haloCι-4alkyl, hydroxyC1. alkyl, C1-4alkoxyC1.4alkyl and aryl. In another aspect R7 is hydrogen, methyl, hydroxymethyl or phenyl. In one aspect ofthe invention R3 and R7 together with the carbon atoms to which they are each attached and (CR5R6)n form a cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl or piperazine ring. In one aspect ofthe invention R is hydrogen. In one aspect ofthe invention R9 is hydrogen or methyl. In one aspect ofthe invention R10 is hydrogen or methyl. In one aspect ofthe invention R11 is methyl. In one aspect ofthe invention R12 is hydrogen or methyl. In one aspect ofthe invention R12 is hydrogen. In one aspect ofthe invention R is methyl. 19 In another aspect ofthe invention R is hydrogen, Cι.6alkyl, aryl and arylC1-4alkyl and may be optionally substituted by one or more halo, hydroxy, amino. 19 In yet another aspect ofthe invention R is hydrogen, methyl, phenyl and benyl and may be optionally substituted by one or more halo, hydroxy, amino. In yet another aspect ofthe invention R is hydrogen, methyl, phenyl and benzyl In one aspect ofthe invention R13 is hydrogen or methyl. In one aspect ofthe invention R is hydrogen. In one aspect ofthe invention R is methyl. 1 "λ In another aspect ofthe invention R is hydrogen, Cι-6alkyl, aryl and arylCι-4alkyl and may be optionally substituted by one or more halo, hydroxy, amino. 1 In yet another aspect ofthe invention R is hydrogen, methyl, phenyl and benyl and may be optionally substituted by one or more halo, hydroxy, amino. In yet another aspect ofthe invention R is hydrogen, methyl, phenyl and benzyl. In one aspect ofthe invention R14 is hydrogen or methyl. In one aspect ofthe invention R16 is hydrogen or methyl. In one aspect ofthe invention R17 is selected from fluoro, chloro, methyl or methoxy. In one aspect ofthe invention R18 is hydrogen or a group selected from Cι-6alkyl, aryl and arylCt^alkyl which group is optionally substituted by halo. In another aspect R18 is hydrogen or a group selected from methyl, phenyl and benzyl which group is optionally substituted by chloro. In one aspect ofthe invention R19 is a group selected from Cι-6alkyl, aryl and arylCι- alkyl where the group is optionally substituted by halo. In another aspect R19 is a group selected from methyl, phenyl and benzyl where the group is optionally substituted by chloro. In one aspect R19 is methyl. In one aspect ofthe invention R20 is hydrogen or methyl. In one aspect ofthe invention R21 is hydrogen, methyl, ethyl, phenyl or benzyl. In 91 another aspect R is hydrogen. In one aspect R22 is hydrogen, methyl, ethyl, phenyl or benzyl. In another aspect R22 is hydrogen or methyl. In one aspect ofthe invention R23 is a group selected from Cι.6alkyl, aryl and arylC^alkyl which group is optionally substituted by halo. In another aspect R is a group selected from methyl, phenyl and benzyl which group is optionally substituted by chloro. In one aspect ofthe invention R23 is methyl. In one aspect ofthe invention there is provided a compound of formula (I) as defined herein provided that when z is -NR8-; m is 2; A is phenylene; and r is 0; then X is not -O-. A preferred class of compound is of formula (I) wherein:
Y1 is O;
Y2 is O; z is -NR8-; n is 0, 1 or 2; m is 1 or 3; r is 0; t is 1;
A is arylene, heteroarylene or heterocyclylene;
X is -O-; B is phenyl, naphthyl, tetrahydronaphthyl, pyridyl, quinolinyl, isoquinolinyl, thieno[2,3- b]pyridyl, thieno[3,2-b]pyridyl, 1,8-naphthyridinyl, 2,3-methylenedioxyphenyl, 3,4- methylenedioxyphenyl, 1,6-naphthyridinyl, tMeno[2,3-<^pyrimidinyl or thieno[3,2- -^pyrimidinyl where each is optionally substituted by one or more groups independently selected from trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, ethynyl, cyano, acetamido, propyloxy, isopropyloxy, methoxy, ethoxy, nitro, pyrrolidinylcarbonyl, N-propylcarbamoyl, pyrrolidinyl, piperidinyl, isoxazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl and pyridyl; or B is vinyl or ethynyl optionally substituted by methyl, ethyl, hydroxymethyl, methoxymethyl or phenyl;
R1 is hydrogen or methyl;
Rla is hydrogen or methyl;
R2 is hydrogen, -OR12, -C(O)OR12, -ΝR12R13, -NR12C(O)R13, -NR12C(O)NR12R13, -NR12C(O)OR13, methyl or ethyl which methyl or ethyl are optionally substituted by cyano, -OR12, -C(O)OR12, -NR12R13 or -NR12C(O)R13;
R3 is hydrogen, methyl, ethyl, propyl or phenyl;
R4 is hydrogen or methyl;
R5 is hydrogen or methyl; R6 is hydrogen or methyl; or R3 and R4 together form a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydropyran ring;
R7 is hydrogen or a group selected from Cι.6alkyl, C3- cycloalkyl, aryl, heteroaryl or heterocyclyl which group is optionally substituted by heterocyclyl, aryl and heteroaryl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, C1. alkyl, -C(O)C1-3alkyl, -
SO2C1.3alkyl, -OR21, -NR21R22, -C(O)OR21, -NR21C(O)R22, -NR 1C(O)OR22 and -
C(O)NR21R22; or R3 and R7 together with the carbon atoms to which they are each attached form a cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl or piperazine ring;
R8 is hydrogen;
R is hydrogen or methyl;
R13 is hydrogen or methyl; 91 R is hydrogen, methyl, ethyl, phenyl or benzyl; and R22 is hydrogen, methyl, ethyl, phenyl or benzyl. Another preferred class of compound is of formula (I) wherein:
Y1 is O;
Y2 is O; z is -NR8-; n is 0, 1 or 2; m is 1 or 3; r is 0; t is 1;
A is phenylene; X is -O-;
B is a group selected from bicyclic aryl or bicyclic heteroaryl where each group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, Cι- alkyl (optionally substituted by one or more halo),
C2-4alkynyl, heteroaryl, -OR9, cyano, -NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is C2. alkenyl or C2- alkynyl optionally substituted by Cι- alkyl, C3-6cycloalkyl or heterocyclyl;
R1 is hydrogen or methyl;
Rla is hydrogen or methyl;
R2 is hydrogen, -OR12, -C(O)OR12, -NR12R13, -NR12C(O)R13,
-NR12C(O)NR12R13, -NR12C(O)OR13, methyl or ethyl which methyl or ethyl are optionally substituted by cyano, -OR12, -C(O)OR12, -NR12R13 or -NR12C(O)R13;
R3 is hydrogen or methyl;
R4 is hydrogen or methyl; or R3 and R4 together form a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydropyran ring; R5 is hydrogen or methyl;
R6 is hydrogen or methyl;
R7 is selected from hydrogen, Cι.4alkyl, haloC1.4alkyl, hydroxyC1. alkyl, C1.4alkoxyC1- alkyl and aryl; or R3 and R7 together with the carbon atoms to which they are each attached form a cyclopentyl, cyclohexyl, tetrahydrofyranyl, tetrahydrpyranyl, piperidinyl, pyrrolidinyl or piperazine ring;
R8 is hydrogen; R9 is hydrogen or methyl; and R10 is hydrogen or methyl.
A further preferred class of compound is of formula (I) wherein: Y s O;
Y2 is O; z is -NR8-; n is 0; m is 1 or 3; r is O; t is 1;
A is phenylene or heterocyclylene;
Z is -O-;
B is 2-methylquinolin-4-yl or 2,5-dimethylphenyl; R1 is hydrogen or methyl;
Rla is hydrogen or methyl;
R is hydrogen, amino, methyl, ethyl, formyl, acetamido, benzoylamino, benzylcarbonylamino, ureido, 3-methylureido, 3-phenylureido, 3-benzylureido and t- butoxycarbonylamino ; R3 is hydrogen or methyl;
R4 is hydrogen;
R7 is hydrogen, methyl, hydroxymethyl or phenyl; and
R8 is hydrogen. A preferred compound ofthe invention is selected from 5-[(3-Methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)methyl]imidazolidine-2,4-dione;
5 - { 3 -Methyl-3 - [4-(2-methylquinolin-4-ylmethoxy)phenyl] -2-oxo-piperidin- 1 - ylmethyl}imidazolidine-2,4-dione;
5 -(3 - { 3 -Methyl-3 - [4-(2-methylquinolin-4-ylmethoxy)phenyl] -2-oxo-piperidin- 1 - yl}propylimidazolidine-2,4-dione;
5 -Methyl-5 - { 3 -Methyl-3 - [4-(2-methylquinolin-4-ylmethoxy)phenyl] -2-oxo-piperidin- 1 - ylmethyl}imidazolidine-2,4-dione; 5-Methyl-5-[(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)methyl]imidazolidine-2,4-dione;
5-[2-(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxopiperidin-l- yl)ethyl]imidazolidine-2,4-dione; 5-[2-(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)ethyl]imidazolidine-2,4-dione; tert-butyl {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4- yl)methyl] -2-oxopyrrolidin-3 -yl } carbamate ;
5-[3-Methyl-2-oxo-3-(4-phenylethynyl-phenyl)-pyrrolidin-l-ylmethyl]-imidazolidine-2,4- dione;
N- {3- {4-[(2,5-dimethylbenzyl)oxy]phenyl} - 1 -[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-
2-oxopyrrolidin-3-yl}acetamide;
N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-
2-oxopyrrolidin-3 -yl } -N-methylurea; {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-2- oxopyrrolidin-3-yl}formamide;
N-benzyl-N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4- yl)methyl]-2-oxopyrrolidin-3-yl}urea;
N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]- 2-oxopyrrolidin-3-yl}-2-phenylacetamide;
5-[(3- {4-[(2-methylquinolin-4-yl)methoxy]piperidin- 1 -yl} -2-oxopyrrolidin- 1 - yl)methyl]imidazolidine-2,4-dione; and
Carbamic acid, [ 1 - [(2,5 -dioxo-4-imidazolidinyl)methyl] -3 - [4- [(2-methyl-4- quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidinyl]-, 1,1-dimethylethyl ester. In another aspect the invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein Y1 and Y2 are both O, z is -ΝR8- and R8 is hydrogen, which comprises converting a ketone or aldehyde of formula (II) into a hydantoin of formula (I);
Figure imgf000024_0001
fαmJa(ll) foαnia(1)
Scheme 1 and thereafter if necessary: i) converting a compound of formula (I) into another compound of formula (I); and/or ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester. The hydantoin can be prepared by a number of methods for example: a) The aldehyde or ketone may be reacted with ammonium carbonate and potassium cyanide in aqueous alcohols using the method of Bucherer and Bergs (Adv. Het. Chem., 1985, 38, 177). b) The aldehyde or ketone could be first converted to the cyanohydrin and then further reacted with ammonium carbonate (Chem. Rev, 1950, 56, 403). c) The aldehyde or ketone could be converted to the alpha-amino nitrile and then either reacted with ammonium carbonate or aqueous carbon dioxide or potassium cyanate followed by mineral acid (Chem. Rev, 1950, 56, 403).
A process for the preparation of a ketone or aldehyde of formula (II) comprises converting a compound of formula (III) into a ketone or aldehyde of formula (II):
Figure imgf000024_0002
formula (III) formula (II) Scheme 2
wherein Y is an ester group such as -C(O)OC1.10alkyl; a ketal such as A> ° where R' and R" are C oalkyl; an alcohol group such as -CHR7OH; or an alkene group such as CR7=CH2. a) when Y is an ester group so that scheme 2 illustrates the reaction:
Figure imgf000025_0001
formula (III) formula (II)
Scheme 2a suitable reagents are Grignard reagents to prepare ketones or diisobutylaluminium hydride in dichloromethane at -78°C under an argon atmosphere to prepare aldehydes. b) when Y is a ketal so that scheme 2 illustrates the reaction:
Figure imgf000025_0002
formula (III) formula (II) Scheme 2b a suitable reagent is an aqueous acid (e.g. a mineral acid such as hydrochloric acid) to hydrolyse the ketal to the diol (Protective Groups in Organic Synthesis; Theordora Greene and
Peter Wuts, Wiley-InterScience), followed by treatment with sodium periodate or osmium tetraoxide to generate the aldehyde. This can be converted directly to the hydantoin as described above, or reacted with Grignard reagents or alkyl lithiums to prepare secondary alcohols, which can be oxidised to the ketones with an oxidising agent. c) when Y is an alcohol group so that scheme 2 illustrates the reaction:
Figure imgf000025_0003
formula (111) formula (II) Scheme 2c suitable reagents are oxidising agents, d) when Y is an alkene group so that scheme 2 illustrates the reaction:
Figure imgf000026_0001
formula (111) formula (II) Scheme 2d suitable reagents include reagents for ozonolysis, sodium periodate, osmium tetraoxide and ruthenium calalysts with a suitable oxidant. 5 An alternative to scheme 2a, for the preparation ofthe aldehyde or ketone of formula (II) from an ester of formula (III) is shown in Scheme 3 which comprises:
Figure imgf000026_0002
formula (111) formula (IV)
Figure imgf000026_0003
formula (V) formula (II) Scheme 3 a) reacting the ester of formula (III) with a base such as sodium hydroxide, potassium 10 hydroxide or potassium carbonate in alcohols or aqueous alcohols at room temperature to 100°C followed by neutralisation with e.g. acetic acid, to give an acid of formula (IV); b) reacting the acid of formula (IN) with Ν, O-dimethlyhydroxylamine hydrochloride under standard amide coupling conditions or by reacting with triphenylphosphine, carbon tetrabromide and triethylamine in dichlormethane for 10 to 60 minutes (Synth. Commun.,
15 1990, 20, 1105), to give an amide of formula (N); and c) reacting the amide of formula (N) with a reducing agent such as diisobutylaluminium hydride or lithium aluminium hydride to give an aldehyde of formula (II) or reacting with Grignard reagents to give a ketone of formula (II). A compound of formula (III) wherein m is 1 may be prepared as shown in Scheme 4;
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
formula (X)
Figure imgf000027_0004
formula (III)
Scheme 4
The process of Scheme 4 comprises the steps of: a) reacting an ester of formula (NI), where R is a protected leaving group such as benzyloxy or trimethylsilyloxy or R is -X-(R1Rla)tB, with a base such as sodium methoxide in dimethylsulphoxide, lithium diisopylamide or lithium bis(trimethylsilyl)amide in tetrahydrofuran at a temperature of -78°C to 0°C followed by reaction with paraformaldehyde for 30 minutes to 2 hours to give a hydroxymethylated product of formula (Nil); b) reacting the product of formula (Nil) with aqueous base, until no more starting compound can be observed by thin layer chromatography or high performance liquid chromatography/mass spectrometry to give an acid of formula (NIII); c) reacting the acid of formula (VIII) with an amine or amine salt of formula (IX) (where Y is an ester group, a ketal, an alcohol group or an alkene group as defined above or, a hydantoin group, -CR7(C(O)OC1.10alkyl)2 or a pyrimidinetrione group) in a solvent such as dimethylformamide in the presence of a base such as triethylamine or Ν,Ν- diisopropylethylamine and a coupling agent such as O-7-azabezotriazol-l-yl)-N,N,N'N'- tetramethyluronium hexafluorophosphate at room temperature for 2 to 24 hours to give an hydroxyamine of formula (X); d) reacting the product of formula (X) with, for example a sulphonyl chloride (e.g. methanesulphonyl chloride or paratoluenesulphonyl chloride) in the presence of a weak base such as pyridine to convert the hydroxy group into a leaving group which after work up is cyclised in the presence of a base such as potassium carbonate in a solvent such as propanone to give a lactam of formula (XI) or formula (III) (if R is -X-(R1Rla)tB); and thereafter if necessary e) deprotecting R (if necessary), activating the resultant alcohol with methanesulphonyl chloride or paratoluenesulphonyl chloride and reacting this compound of fonnula (XN) with a compound of formula (XII) to give a compound of formula (III).
A compound of formula (III) wherein m is 2, 3 or 4 may be prepared as shown in Scheme 5;
Figure imgf000028_0001
formula (XII)
Scheme 5
The process of Scheme 5 comprises the steps of: a) reacting an ester of formula (NI), where R is a protected leaving group such as benzyloxy or trimethylsilyloxy or R is -X-(R1Rla)tB, with a base such sodium methoxide in dimethylsulphoxide, lithium diisopylamide or lithium bis(trimethylsilyl)amide in tetrahydrofuran at a temperature of-78°C to 0°C followed by reaction with 2-bromo-l- chloroethane, 3-bromo-l-chloropropane or 4-bromo-l-chlorobutane for 30 minutes to 2 hours to give a hydroxymethylated product of formula (XIII); b) reacting the product of formula (XIII) with an amine or amine salt of formula (IX) (where Y is an ester group, a ketal, an alcohol group or an alkene group as defined above or a hydantoin group or -CR7(C(O)OC1.10alkyl)2) followed by addition of a base such as 1,8- diazobicyclo[5.4.0]undec-7-ene and an activator such as tetrabutylammonium iodide until no more starting material can be observed by thin layer chromatography or high performance liquid chromatography/mass spectrometry to give an amine of formula (XIV); c) heating an amine of formula (XIN) in an inert solvent such as toluene to give a lactam of formula (XN) or formula (III) if R is -X-(R1Rla)tB; and thereafter if necessary d) deprotecting R (if necessary), activating the resultant alcohol with methanesulphonyl chloride or paratoluenesulphonyl chloride in the presence of a base such as pyridine and reacting this compound of formula (XV) with a compound of formula (XII) to give a compound of formula (III) .
Alternatively a compound of formula (III) wherein m is 2, 3 or 4 can be prepared as shown in Scheme 6;
Figure imgf000029_0001
formula (VI) formula (XVI) formula (XVII) formula (IX)
Figure imgf000029_0002
formula (XIX) formula (XVIII)
Figure imgf000029_0003
formula (III) Scheme 6
The process of Scheme 6 comprises the steps of: a) reacting an ester of formula (VI), where R is a protected leaving group such as benzyloxy or trimethylsilyloxy, with a base such lithium diisopropylamide or lithium bis(trimethylsilyl)amide in tetrahydrofuran at a temperature of -78°C to 0°C followed by reaction with allyl bromide, 4-bromo-but-l-ene or 5-bromopent-l-ene for 30 minutes to 2 hours to give an allylated product of formula (XVI); b) reacting the allylated product of formula (XVI) with ozone, until no more starting compound can be observed by thin layer chromatography or high performance liquid chromatography/mass spectrometry followed by reducing the resultant ozonide with e.g. dimethylsulphide, triphenylphosphine or polymer supported triphenylphosphine to give an aldehyde of formula (XVII); c) reacting the aldehyde of formula (XVII) with an amine or amine salt of formula (IX) (where Y is an ester group, a ketal, an alcohol group or an alkene group as defined above or - CR7(C(O)OC1-10alkyl)2) in a solvent such as dichloromethane or dichloroethylene in the presence of a base such as triethylamine or N,N-diisopropylethylamine for 30 minutes to 2 hours before adding a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride and reacted at room temperature for 2 to 24 hours to give an amine of formula (XVIII); d) cyclising the amine of formula (XVIII) by heating in an inert solvent such as toluene to 90-110°C for 1 to 4 hour to give a lactam of formula (XIX); e) deprotecting R (if necessary), activating the resultant alcohol with methanesulphonyl chloride or paratoluenesulphonyl chloride and reacting this compound of formula (XV) with a compound of formula (XII) to give a compound of formula (III). In a further aspect the invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein 1 9
Y and Y are both O and z is -NH(CO)- (as described herein), which comprises converting a diester of formula (III) wherein Y is -CR7(C(O)OC1_1oalkyl)2 into a pyrimidine- 2,4,6(lH,3H,5H)-trione of formula (I);
Figure imgf000030_0001
formula (111) for ula ('> Scheme 7 and thereafter if necessary: i) converting a compound of formula (I) into another compound of formula (I); and/or ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester. The reaction comprises treating a diester of formula (III) with urea in the presence of a base such as sodium methoxide, magnesium methoxide or potassium tert-butoxide to generate a pyrimidine-2,4,6(lH,3H,5H)-trione group. Examples of reactions of this type can be found in Heterocyclic Chemistry, 1993, 4, 55, J. Chem. Soc. Perkin Trans. 1, 1990, 3137 or J. Am. Chem. Soc, 1941, 63, 2945. A compound of formula (III) may be prepared as shown in scheme 4, scheme 5 or scheme 6. A compound of formula (I) can be prepared by removal of protecting groups on the hydantoin directly. The protecting group can be tert-butyloxycarbonyl (BOC), benzyl (Bn) or benzyloxycarbonyl (cbz). These can be removed by treatment with trifluoroacetic acid or hydrogen chloride in dioxane for the former or by treatment with palladium/hydrogen for the latter two. It will be appreciated that certain ofthe various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect ofthe invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. It will also be appreciated that in some ofthe reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some ofthe reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. As stated herein the compounds defined in the present invention possesses metalloproteinases inhibitory activity, and in particular TACE inhibitory activity and/or aggrecanase inhibitory activity. These properties may be assessed, for example, using the procedures set out below.
Isolated Enzyme Assays
Matrix Metalloproteinase family including for example MMP13. 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 MMP 13 (11.25ng per assay) is incubated for 4-5 hours at 35°C in assay buffer
(0.1M Tris-HCl, pH 7.5 containing O.lMNaCl, 20mM CaCl2, 0.02 mM ZnCl and 0.05%
(w/v) Brij 35 using the synthetic substrate 7-methoxycoumarin-4- yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg.NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 328nm and λem 393nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescencβpius 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 ofthe compounds to inhibit proTNF-α convertase enzyme (TACE) 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.Nal.Arg.Ser.Ser.Ser.Arg.Cys(4-(3- succinimid-l-yl)-fluorescein)-ΝH2 in assay buffer (50mM Tris HCl, pH 7.4 containing 0.1% (w/v) Triton X-100 and 2mM CaCl2), at 26°C for 4 hours. The amount of inhibition is determined as for MMP 13 except λex 485nm and λem 538nm were used. The substrate was 5 synthesised as follows. The peptidic part ofthe 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-l-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU) as coupling agent with at least a 4- or 5- fold excess of Fmoc-amino acid and HBTU. Ser and Pro were double-coupled. The 1 ^ R 19
10 following side chain protection strategy was employed; Ser (But), Gin (Trityl), Arg ' (Pmc or Pbf), Ser9'10'1 ^Trityl), Cys1 (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 1.5-2 hours at 70°C with 1.5-2 equivalents of 4,,5'-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna & Ullman, (1980) Anal Biochem.
15 108: 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
20 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 compounds of this invention have been found to be active against TACE and/or Aggrecanase (causing greater than 30% inhibition) at less than 100 μM and in particular
25 example 1 caused 50% inhibition of TACE at 44 nM. Aggrecanase Aggrecanase may be prepared from the media of bovine nasal cartilage stimulated for 48 hours with interleukin-1. The media is fractionated by heparin sepharose chromatography using a 0-1 M NaCl gradient. Contaminating gelatinases are removed by passing through a
30 gelatin sepharose column. 0.01% Brij 35 is added to the flow through and aggrecanase is purified using a wheat germ column. The enzyme is eluted from this column in 300mM N- Acetyl D-Glucosamine. Aggrecanase activity is measured by incubating the purified enzyme with bovine nasal cartilage aggrecan (prepared as described in JBC 244:2384 (1969)) for 16 hours at 37°C in 0.1M Tris-HCl, 5μM ZnCl, ImM CaCl in the absence or presence of inhibitors. Specific aggrecanase cleavage of aggrecan is detected as follows : The aggrecanase/aggrecan reactions are immobilised onto a polyvinylidene fluoride (PNDF) microporous membrane using a dot blot apparatus (BioRad). Non-specific binding is blocked by incubating with 8% dried milk in 0.01M Tris-HCl pH 7.5, 0.15M NaCl and 0.1% tween-20 (blocking buffer) for 1 hour. Detection ofthe NITEGE neo-epitope generated by aggrecanase cleavage is detected by incubating the PDNF with the anti ΝITEGE antibody RAM 3-2 (M.T. Bayliss et al, Osteoarthritis and Cartilage (2001) 9, 553-560) diluted 1/20,000 in blocking buffer and incubating for 2 hours. Unbound antibody is removed by washing the PNDF membrane 3 times in blocking buffer containing 0% milk. The bound RAM 3-2 is detected by incubating with an anti-rabbit HRP conjugated antibody (Sigma) diluted 1/5000 in blocking buffer for 1 hour. The PNDF membrane is washed as above, incubated with ECL reagent (Amersham) for 2 minutes and luminescence measured using a microplate scintillation and luminescence counter.
Inhibition is calculated as a percentage ofthe controls. 0% inliibition controls contain aggrecanase and aggrecan alone (maximum activity/luminescence). 100% inhibition controls contain aggrecan substrate alone (minimum activity/luminescence). Other assays The activity ofthe compounds ofthe 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 TΝF convertase The ability ofthe compounds of this invention to inhibit the cellular processing of
TΝF-α production may be assessed in THP-1 cells using an ELISA to detect released TΝF 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 ofthe 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 ofthe compounds of this invention to inhibit TNF-α production is assessed in a human whole blood assay where LPS is used to stimulate the release of TNF-α. 160μl of heparinized (lOUnits/ml) human blood obtained from volunteers, was added to the plate and incubated with 20μl of test compound (duplicates), in RPMI1640 + bicarbonate, penicillin, streptomycin, glutamine and 1% DMSO, 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 neat blood incubated with medium alone or LPS (6 wells/plate of each). The plates are then incubated for 6 hours at 37°C (humidified incubator), centrifuged
(2000rpm for 10 min; 4°C ), plasma harvested (50-100μl) and stored in 96 well plates at
70°C before subsequent analysis for TNF-α concentration by ELISA.
Test as an agent to inhibit in vitro cartilage degradation The ability ofthe compounds of this invention to inhibit the degradation ofthe aggrecan or collagen components of cartilage can be assessed essentially as described by K.
M. Bottomley et al, (1997) Biochem J. 323:483-488.
In vivo assessment
Test as an anti-TNF agent The ability ofthe compounds of this invention as in vivo TNF-α inhibitors is assessed in the rat. Briefly, groups of female Wistar Alderley Park (AP) rats (90-100g) are dosed with compound (5 rats) or drug vehicle (5 rats) by the appropriate route e.g. peroral (p.o.), intraperitoneal (i.p.), subcutaneous (s.c.) 1 hour prior to lipopolysaccharide (LPS) challenge
(30μg/rat i.v.). Sixty minutes following LPS challenge rats are anaesthetised and a terminal blood sample taken via the posterior vena cavae. Blood is allowed to clot at room temperature for 2hours and serum samples obtained. These are stored at -20°C for TNF-α ELISA and compound concentration analysis. Data analysis by dedicated software calculates for each compound/dose: Percent inhibition of TNF-α= Mean TNF-α (Nehicle controD - Mean TΝF-α (Treated) X 100 Mean TΝF-α (Nehicle control) 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.
Pharmaceutical Compositions According to a further aspect ofthe invention there is provided a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein in association with a pharmaceutically-acceptable diluent or carrier. The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The composition may also be in a form suitable for inhalation. In general the above compositions may be prepared in a conventional manner using conventional excipients. 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 0.5 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount ofthe compound received and the route of administration depending on the weight, age and sex ofthe patient being treated and on the particular disease condition being treated according to principles known in the art. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. Therefore a further aspect ofthe invention provides a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use in a method of treatment of a warm-blooded animal such as man by therapy. Also provided is a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use in a method of treating a disease condition mediated by one or more metalloproteinase enzymes. In particular the disease condition may be mediated by TNFα and/or aggrecanase. Further provided is a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use in a method of treating inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal such as man. In particular a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, is provided for use in a method of treating rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis in a warm-blooded animal such as man. A compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is also provided for use in a method of treating a respiratory disorder such as asthma or COPD in a warm-blooded animal such as man. A compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is also provided for use in a method of treating osteoarthritis in a warm-blooded animal such as man. According to an additional aspect ofthe invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use as a medicament. Also provided is a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use as a medicament in the treatment of a disease condition mediated by one or more metalloproteinase enzymes. In particular the disease condition may be mediated by TNF- α and/or aggrecanase. Further provided is a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, for use as a medicament in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy. In particular a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, is provided for use as a medicament in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis. A compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, is provided for use as a medicament in the treatment of a respiratory disorder such as asthma or COPD. A compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, is also provided for use as a medicament in the treatment of osteoarthritis. According to this aspect ofthe invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein in the manufacture of a medicament for use in the treatment of a disease condition mediated by one or more metalloproteinase enzymes. In particular the disease condition may be mediated by TNF-α and/or aggrecanse. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein in the manufacture of a medicament for use in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy. In particular the use of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, is provided in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis. The use of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is also provided in the manufacture of a medicament for use in the treatment of a respiratory disorder such as asthma or COPD. The use of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is further provided in the manufacture of a medicament for use in the treatment of osteoarthritis. According to another aspect ofthe invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein for use in the treatment of a disease condition mediated by one or more metalloproteinase enzymes. In particular the disease condition may be mediated by TNF-α and/or aggreanase. Also provided is a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein for use in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy. In particular a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein, is provided for use in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis. A compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is also provided for use in the treatment of a respiratory disorder such as asthma or COPD. A compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is further provided for use in the treatment of osteoarthritis. According to a further feature of this aspect ofthe invention there is provided a method of producing a metalloproteinase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I).
According to a further feature of this aspect ofthe invention there is provided a method of producing a TACE inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I). According to this further feature of this aspect ofthe invention there is provided a method of treating autoimmune disease, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I). Also provided is a method of treating rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I). Further provided is a method of treating a respiratory disorder such as asthma or COPD in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I). According to another feature of this aspect ofthe invention there is provided a method of producing an aggrecanase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I). Further provided is a method of treating a osteoarthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I). In addition to their use in therapeutic medicine, a compound of formula (I) or a pharmaceutically acceptable salt thereof is also useful as a pharmacological tool in the development and standardisation of in vitro and in vivo test systems for the evaluation ofthe effects of inhibitors of metalloproteinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part ofthe search for new therapeutic agents. In the above pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments ofthe compounds ofthe invention described herein also apply. The compounds of this invention may be used in combination with other drugs and therapies used in the treatment of various immunological, inflammatory or malignant disease states which would benefit from the inhibition of TACE, aggrecanse or the combination thereof. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate. Examples
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C; (ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60°C; (iii) chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a "Bond Elut" column is referred to, this means a column containing 10 g or 20 g of silica of 40 micron particle size, the silica being contained in a 60 ml disposable syringe and supported by a porous disc, obtained from Narian, Harbor City, California, USA under the name "Mega Bond Elut SI". Where an "Isolute™ SCX column" is referred to, this means a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK. Where Flashmaster II is referred to, this means a UN driven automated chromatography unit supplied by Jones. Where a "silica Redisep" column is referred to, this means a column containing 40 g or 120 g of silica of 35-60 micron particle size, (230-400 mesh) the silica being contained in a disposable polypropylene column and supported by porous discs and Luer locks either end, obtained from Isco Inc. Where Companion is referred to, this means a UN driven automated chromatography unit supplied by Isco Ine;
(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only; (v) yields, when given, are for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vi) when given, 1H ΝMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using CDC13 as the solvent imless otherwise stated; coupling constants (J) are given in Hz;
(vii) chemical symbols have their usual meanings; SI units and symbols are used;
(viii) solvent ratios are given in percentage by volume;
(ix) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (APCI) mode using a direct exposure probe; where indicated ionisation was effected by electrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+;
(x) Preparative HPLC refers to purification using either an acidic system (General conditions and gradients for each method as follows: 5-95 Method 5 - 95% MeCΝ: H2O, 21 ml/min;
Early Method 5- 50% MeCΝ: H2O, 21 ml/min; Mid Method 25-70% MeCΝ: H2O, 21 ml/min; Late Method 40-90% MeCΝ: H2O, 21 ml/min using a 150 mm x 21.2 mm,
Phenomenex Luna, lOmicron C18 (2), 100 A column) or a basic system (General conditions and gradients for each method as follows: 5-95 Method 5 - 95% MeCΝ: H2O, 21 ml/min; Early Method 5- 50%MeCΝ: H2O, 21 ml/min; Mid Method 25-70% MeCN: H2O, 21 ml/min; Late Method 40-90% MeCN: H2O, 21 ml/min using a 100 mm x 19 mm, Waters
Xterra, 5micron RP18 OBD column);
(xi) LCMS (liquid chromatography mass spectrometry) characterisation was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer. The LC comprised water symmetry 4.6x50 column CI 8 with 5 micron particle size. The eluents were: A, water with 0.05% formic acid and B, acetonitrile with 0.05% formic acid. The eluent gradient went from 95% A to 95% B in 6 minutes. Where indicated ionisation was effected by elecfrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+ and (xii) the following abbreviations may be used: min minute(s); h hour(s); d day(s); DMSO dimethyl sulphoxide; DBU 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]-azepine; DMA N-dimethylacetamide; DMF N-dimethylformamide; DCM dichloromethane; ΝMP N-methylpyrrolidinone; DIAD di-.SOpropylazodicarboxylate; LHMDS or LiHMDS lithium bis(trimethylsilyl)amide; MeOH methanol; RT room temperature; TFA trifluoroacetic acid; EtOH ethanol; EtOAc ethyl acetate; THF tetrahydrofuran; DIBAL di-.sobutylaluminium hydride; ΝMO 4-methylmorpholine N-oxide; TPAP tetra-n-propylammonium perruthenate (Nil); HATU O-(7-azabenzotriazol- 1 -yl)-Ν,Ν,Ν' ,N' -tetramethyluronium hexafluorophosphate ; DIPEA diisopropylethylamine; and Ar argon EXAMPLE 1
5-[(3-Methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)methyl]imidazolidine-2,4-dione
Figure imgf000044_0001
(3-Methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l-yl)acetaldehyde (115 mg, 0.307 mmol) was stirred in ethanol (4 ml) and water (3.6 ml). Ammonium carbonate (118 mg, 1.23 mmol) was added followed by potassium cyanide (20 mg, 0.307 mmol) and the mixture was heated at 60 °C for 2 h 40 min. The mixture was poured into water (50 ml) and extracted with ethyl acetate (3 x 40 ml). The combined extracts were dried (MgSO ), filtered and evaporated. The residue was purified by column chromatography (lOg silica bond elut, eluent 0 - 4% MeOH in CH2C12) to give the product, 5 -[(3 -methyl-3 -{4- [(2- methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l-yl)methyl]imidazolidine-2,4-dione, as a white solid (29 mg, 0.065 mmol) as a mixture of diastereoisomers. NMR: 1.52 (s, A or B, 3H), 1.54 (s, A or B, 3H), 2.67 (s, 3H), 3.33 - 3.55 (m, 4H), 4.21 (s, A or B, IH), 4.23 (s, A or B, IH), 5.60 (s, 2H), 7.10 (d, 2H), 7.32 (d, 2H), 7.55 (s, IH), 7.60 (t, IH), 7.75 (t, IH), 7.97 (d, IH), 8.06 (s, A or B, IH), 8.09 (s, A or B, IH), 8.11 (d, IH), 10.73 (s, A or B, IH), 10.75 (s, A or B, IH); MS (M+H) 445. A further portion ofthe product was isolated as an HCl salt following precipitation from the aqueous phase; this was collected by filteration, washed with water and dried in vacuo (18 mg, 0.041 mmol).
The starting material, (3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2- oxoazetidin-l-yl)acetaldehyde, was prepared as follows:
(i) Sodium methoxide (0.5M solution in methanol, 2.22 ml, 1.11 mmol) was added dropwise to a solution of methyl 2-[4-(benzyloxy)phenyl]propanoate (prepared as described in J. Med . Chem. 2002, 45, 4954) (3 g, 11.10 mmol) and paraformaldehyde (0.40 g, 13.32 mmol) in DMSO (50 ml) under argon. The solution was stirred at RT for 1.5 h, then diluted with water (300 ml) and acidified with IN HCl. The precipitated product was collected by filtration, washed with water and dried in vacuo to give the product, methyl 2- [4- (benzyloxy)phenyl]-3-hydroxy-2-methylpropanoate, as a crystalline white solid (3.21 g, 10.69 mmol). NMR: 1.47 (s, 3H), 3.59 (s, 3H), 3.54 - 3.61 (m, IH), 3.93 - 4.00 (m, IH), 4.95 (t, IH), 5.08 (s, 2H), 6.96 (d, 2H), 7.19 (d, 2H), 7.29 - 7.47 (m, 5H); MS (M-H2O+H) 283. (ii) Methyl 2- [4-(benzyloxy)phenyl] -3 -hydroxy-2-methylpropanoate (2.16 g, 7.19 mmol) was stirred in methanol (54 ml) and to this was added a solution of lithium hydroxide (0.604 g, 14.38 mmol) in water (11 ml). The reaction solution was stirred at 40 °C for 15 h, allowed to cool and poured into IM HCl (240 ml). The precipitated white solid was collected by filtration, washed with water and dried in vacuo to give 2-[4-(benzyloxy)phenyl]-3-hydroxy-2- methylpropanoic acid (1.73g, 6.04 mmol). NMR: 1.43 (s, 3H), 3.55 (d, IH), 3.91 (d, IH), 5.06 (s, 2H), 6.93 (d, 2H), 7.23 (d, 2H), 7.29 - 7.48 (m, 5H); MS (M-H) 285.
(iii) 2-[4-(Benzyloxy)phenyl]-3-hydroxy-2-methylpropanoic acid (0.582 g, 2.033 mmol) and HATU (0.850 g, 2.236 mmol) were stirred in DMF (12 ml) at RT. Diisoproylethylamine (0.390 ml, 2.236 mmol) was added followed by 2,2-dimethyl-l,3-dioxolane-4-methanamine (0.290 ml, 2.236 mmol) and stirring continued for 1 h. The solution was poured into a mixture of water (20 ml) and brine (20 ml) and the aqueous phase was extracted with ethyl acetate (3 x 30 ml). The combined extracts were washed with brine (30 ml), dried (MgSO ), filtered and evaporated. The residue was purified by column chromatography (20g silica bond elut, eluent 0 - 2% MeOH in CH2C12) to give the product, 2-[4-(benzyloxy)ρhenyl]-N-[(2,2- dimethyl-l,3-dioxolan-4-yl)methyl]-3-hydroxy-2-methylpropanamide, as a colourless oil (0.812 g, 2.033 mmol) as a mixture of diastereoisomers. ΝMR: 1.23 (s, A or B, 6H), 1.27 (s, 3H), 1.40 (s, A or B, 6H), 3.10 - 3.20 (m, IH), 3.23 - 3.33 (m, IH), 3.51 - 3.59 (m, 2H), 3.81
- 3.89 (m, 2H), 4.03 - 4.11 (m, IH), 4.90 (t, IH), 5.08 (s, 2H), 6.94 (d, 2H), 7.20 (d, 2H), 7.30
- 7.48 (m, 6H); MS (M+H) 400.
(iv) 2-[4-(Benzyloxy)phenyl]-N-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]-3-hydroxy-2- methylpropanamide (0.730 g, 1.827 mmol) was stirred in pyridine (10 ml) under argon. Methanesulphonyl chloride (0.184 ml, 2.375 mmol) was added dropwise and stirring continued at RT for 1.5 h. The pyridine was removed in vacuo and the residue re-dissolved in acetone (20 ml). Potassium carbonate (1.011 g, 3.491 mmol) was added and the mixture was heated at reflux for 48 h, allowed to cool to RT and stirred for a further 72 h. The mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (20g silica bond elut, eluent 0 - 1.5% MeOH in CH2C12) to give the product, 3-[4-(benzyloxy)phenyl]-l-[(2,2-dimethyl-l,3- dioxolan-4-yl)methyl]-3-methylazetidin-2-one, as a pale yellow oil (0.479 g, 1.256 mmol) as a mixture of diastereoisomers. NMR: 1.25 (s, A or B, 6H), 1.28 (s, A or B, 3H), 1.35 (s, A or B, 3H), 1.52 (s, A or B, 6H), 3.25 - 3.36 (m, 2H), 3.42 - 3.54 (m, 2H), 3.57 - 3.66 (m, IH), 3.97 - 4.04 (m, IH), 4.18 - 4.27 (m, IH), 5.10 (s, 2H), 6.99 (d, 2H), 7.25 - 7.48 (m, 7H); MS (M+H) 382.
(v) 3 - [4-(Benzyloxy)phenyl] - 1 - [(2,2-dimethyl- 1 ,3 -dioxolan-4-yl)methyl] -3 - methylazetidin-2-one (0.411 g, 1.077 mmol) was stirred in ethanol (40 ml). Cyclohexene (1.09 ml, 10.77 mmol) was added followed by 10% Pd/C (60 mg) and the reaction mixture was heated at reflux for 2.5 h, then allowed to cool, filtered and washed through with ethanol. The filtrate was evaporated in vacuo to give the product, l-[(2,2-dimethyl-l,3-dioxolan-4- yl)methyl]-3-(4-hydroxyphenyl)-3-methylazetidin-2-one, as a colourless viscous oil (0.314 g, 1.077 mmol) as a mixture of diastereoisomers. NMR: 1.25 (s, A or B, 6H), 1.29 (s, A or B, 3H), 1.35 (s, A or B, 3H), 1.50 (s, A or B, 6H), 3.24 - 3.35 (m, 2H), 3.39 - 3.51 (m, 2H), 3.57 - 3.66 (m, IH), 3.96 - 4.04 (m, IH), 4.17 - 4.26 (m, IH), 6.73 (dd, 2H), 7.16 (dd, 2H), 9.30 (s, IH); MS (M+H) 292.
(vi) l-[(2,2-Dimethyl-l,3-dioxolan-4-yl)methyl]-3-(4-hydroxyphenyl)-3-methylazetidin-2- one (0.310 g, 1.064 mmol) was stirred with 4-chloro-2-methylquinolinef (0.243 g, 1.064 mmol) in DMSO (14 ml) under argon and to this was added tetrabutylammonium iodide (0.393 g, 1.064 mmol) and caesium carbonate (0.693 g, 2.128 mmol). The reaction mixture was heated at 60 °C for 2 h, allowed to cool, diluted with ethyl acetate (50 ml), washed with a mixture of brine (15 ml) and water (15 ml), dried (MgSO ), filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography (20g silica bond elut, eluent 0 - 2% MeOH in CH2C12) to give the product, 1 -[(2,2-dimethyl- l,3-dioxolan-4- yl)methyl]-3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}azetidin-2-one, as a pale yellow gum (0.271 g, 0.607 mmol) as a mixture of diastereoisomers. NMR: 1.25 (s, A or B, 6H), 1.28 (s, A or B, 3H), 1.35 (s, A or B, 3H), 1.54 (s, A or B, 6H), 2.67 (s, 3H), 3.23 - 3.67 (m, 5H), 3.96 - 4.04 (m, IH), 4.16 - 4.27 (m, IH), 5.59 (s, 2H), 7.13 (d, 2H), 7.34 (dd, 2H), 7.55 (s, IH), 7.59 (t, IH), 7.75 (t, IH), 7.98 (d, IH), 8.11 (d, IH); MS (M+H) 447. (vii) l-[(2,2-Dimethyl-l,3-dioxolan-4-yl)methyl]-3-methyl-3-{4-[(2-methylquinolin-4- yl)methoxy]phenyl}azetidin-2-one (0.265 g, 0.5934 mmol) was stirred in methanol (10 ml). 2M HCl (10 ml) was added and stirring was continued at RT for 30 min. The solution was then concentrated in vacuo and diluted with brine (25 ml). The aqueous solution was allowed to stand for 30 min, during which time a precipitate formed which was then collected by filtration and dried in vacuo. The solid was then purified by column chromatography (lOg silica bond elut, eluent 0 - 10% MeOH in CH2C12) to give the product, l-(2,3- dihydroxypropyl)-3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}azetidin-2-one, as a white solid (0.153 g, 0.376 mmol) as a mixture of diastereoisomers. NMR: 1.52 (s, 3H), 2.72 (s, 3H), 3.02 - 3.68 (m, 7H, partially obscured by water), 5.64 (s, 2H), 7.13 (d, 2H), 7.36 (d, 2H), 7.59 - 7.70 (m, 2H), 7.81 (t, IH), 8.04 (d, IH), 8.16 (d, IH); MS (M+H) 407. (viii) l-(2,3-Dihydroxypropyl)-3-methyl-3-{4-[(2-methylquinolin-4- yl)methoxy]phenyl}azetidin-2-one (0.125 g, 0.3075 mmol) was stirred in methanol (9.4 ml) and cooled in an ice-bath. Sodium periodate (0.132 g, 0.6150 mmol) was dissolved in water (1.6 ml) and added to the methanol solution. Stirring was continued at RT for 30 min, the reaction mixture was then diluted with water (50 ml) and extracted with CH C12 (3 x 40 ml). The combined extracts were dried (MgSO ), filtered, evaporated and dried in vacuo to give the product, (3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)acetaldehyde, which was then used directly for the next reaction. MS (M+H): 375.
f The synthesis ofthe 4-chloromethyl-2-methylquinoline has been described in WO99/65867 and has CAS Registry number 288399-19-9
EXAMPLE 2
5-{3-Methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo-piperidin-l- ylmethyl}imidazolidine-2,4-dione
Figure imgf000047_0001
To a stirred solution of 3-{3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo- piperidin-l-yl}acetaldehyde (prepared below) (70 mg, 0.174 mmol) in ethanol (4 ml) and water (4 ml) was added ammonium carbonate (167 mg, 1.74 mmol) and potassium cyanide (23 mg, 0.348 mmol). The mixture was heated to 60 °C for 16 h, then evaporated under reduced pressure to give a yellow gum. The residue was partitioned between ethyl acetate (10 ml) and brine (10 ml). The aqueous phase extracted with ethyl acetate (2 x 10 ml) and the combined organic phases dried (MgSO4) and evaporated. The crude product was purified by reverse phase HPLC to give the product (a TFA salt), as a mixture of 4 diastereoisomers and as an off-white solid (83 mg, 0.14 mmol). NMR: 1.45 (s, 3H), 1.55 (m, IH), 1.70 (m, IH), 1.90 ( , IH), 2.10 (m, IH), 2.90 (s, 3H), 3.40 (m, 4H), 3.80 (m, 2H), 4.45 (m, IH), 5.75 (s, 2H), 7.10 (m, 2H), 7.25 (m, 2H), 7.80 (t, IH), 7.90 (s, IH), 8.00 (m, IH), 8.15 (d, IH), 8.35 (d, IH), 10.70 (s, IH); MS (M+H)+ 473.
The starting material 3-{3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo- piperidin-l-yl}acetaldehyde was prepared as follows :
(i) To a solution of 2-(4-hydroxyphenyl)propionic acid (11.68 g, 70.36 mmol) in methanol (50 ml) was added 10 drops of concentrated sulphuric acid. The resultant solution was stirred at 65 °C for 3.5 h. The reaction mixture was allowed to cool, evaporated to a straw coloured oil, redissolved in ethyl acetate (50 ml) and washed with IM NaHCO3 (50 ml) and brine (50 ml). The organic phase was dried (MgSO ) and evaporated to give methyl 2-(4- hydroxyphenyl)proρionate (13.02 g, 72.33 mmol) as an oil. NMR(CDC13): 1.40 (d, 3H), 3.60 (s, 3H), 5.10 (s, IH), 6.70 (d, 2H), 7.10 (d, 2H).
(ii) To a solution of methyl 2-(4-hydroxyphenyl)propionate (5.0 g, 27.7 mmol) in DMSO (60 ml) was added 4-chloromethyl-2-methylquinolinef (6.33 g, 27.7 mmol), caesium carbonate (9.04 g, 27.7 mmol) and tetra-«-butylammonium iodide (10.25 g, 27.7 mmol). The resultant solution was stirred at 50 °C for 60 min. The reaction mixture was allowed to cool then diluted with ethyl acetate (450 ml) and washed with brine (3 x 50 ml). The organic phase was dried (MgSO4), evaporated and purified by chromatography (Companion, 120g silica Redisep column, eluent 0→75% EtOAc / isohexane) to give methyl 2-[4-(2-methyl-quinolin- 4-ylmethoxy)-phenyl]propionate (3.81 g, 11.36 mmol) as an oil. NMR(CDC13): 1.45 (d, 3H), 2.70 (s, 3H), 3.60 (s, 3H), 3.65 (m, IH), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+ 336. (iii) A solution of methyl 2-[4-(2-methylquinolin-4-ylmethoxy)phenyl]propionate (1.0 g 2.98 mmol) in anhydrous THF (25 ml), under argon, was cooled to -10°C, and to this was added dropwise LHMDS (IM solution in THF, 3.58ml). The solution was stirred for 10 min. 3-bromochloropropane (324 μl, 3.28 mmol) was then added and stirring was continued for 2 h while warming to RT. The solution was evaporated to a yellow gum, dissolved in ethyl acetate (25 ml), washed with saturated NHLiCl (2 x 25 ml) and the organic phase was dried (MgSO4) and evaporated to give methyl 5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (1.34 g, 3.25 mmol), a yellow oil. NMR(CDC13): 1.50 (s, 3H), 1.60 (m, 2H), 2.05 (m, 2H), 2.70 (s, 3H), 3.45 (m, 2H), 3.60 (s, 3H), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.50 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+412.
(iv) Ethanolamine (0.98 ml, 16.3 mmol) and tetrabutylammonium iodide (0.60 g, 1.63 mM) were added to a solution of methyl 5-chloro-2-methyl~2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (0.67 g 1.63 mmol) in toluene (15 ml) and the reaction was stirred for 18 h at 105 °C. After cooled and toluene layer was decanted off to leave a red oil. The residual oil was washed with toluene (2 x 15 ml) and the toluene decants combined containing methyl 5-(2-hydroxyethylamino)-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate, MS (M+H)+ 437, which was used directly in the next reaction step. (v) The toluene solution of methyl 5-(2-hydroxyethylamino)-2-methyl-2-[4-(2- methylquinolin-4-ylmethoxy)phenyl]pentanoate (1.63 mmol) from the previous step was heated at 105 °C for 18 h. The solution was evaporated to a yellow gum and purified by chromatography (Companion, 40 g silica Redisep column, eluent 0-→T0% MeOH/EtOAc ) to give l-(2-hydroxyethyl)-3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]piperidin-2- one (0.21 g, 0.52 mmol), as a yellow gum. NMR(CDC13): 1.50 (s, 3H), 1.60 (m, 2H), 1.85 (m, IH), 2.10 (m, IH), 2.70 (s, 3H), 3.35 (m, 3H), 3.85 (m, 3H), 5.40 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+ 405. (vi) l-(2-hydroxyethyl)-3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]piperidin-2- one (0.21 g 0.52 mmol) was stirred in dry dichloromethane (12 ml), under argon. 4A molecular sieves (0.90 g) and N-methyl morpholine oxide (0.105 g, 0.78 mmol) were added and the reaction mixture was stirred at RT for 10 min. Tetrapropylammonium peruthenate (0.018 g, 10 mol%) was added and stirring continued for 30 min at RT. The reaction solution was poured onto a 5 g silica bond elute column and eluted with ethyl acetate to give 3-{3- methyl-3 - [4-(2-methylquinolin-4-ylmethoxy)phenyl] -2-oxo-piperidin- 1 -yl} acetaldehyde (0.07 g, 0.17 mmol), as a colourless oil. NMR(CDC13): 1.50 (s, 3H), 1.70 (m, 2H), 1.95 (m, IH), 2.15 (m, IH), 2.70 (s, 3H), 3.30 (m, 2H), 4.05 (d, IH), 4.30 (d, IH), 5.40 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH), 9.60 (s, IH); MS (M+H)+403.
EXAMPLE 3 5-(3-{3-Methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo-piperidin-l- yl}propylimidazolidine-2,4-dione
Figure imgf000050_0001
To a stirred solution of 3-{3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo- piperidin-l-yl}butyraldehyde (prepared below) (47 mg, 0.109 mmol) in ethanol (2ml) and water (2 ml) was added ammonium carbonate (105 mg, 1.09 mmol) and potassium cyanide 14 mg, 0.218 mmol). The mixture was heated to 60 °C for 16 h, then evaporated under reduced pressure to give a yellow gum. The residue was partitioned between ethyl acetate (10 ml) and brine (10 ml). The aqueous phase extracted with ethyl acetate (2 x 10 ml) and the combined organic phases were dried (MgSO ) and evaporated. The crude product was purified by reverse phase HPLC to give the product (a TFA salt), as a mixture of 4 diastereoisomers and as an off-white solid (47 mg, 0.076 mmol). NMR: 1.45 (s, 3H), 1.50 (m, 2H), 1.60 (m, 2H), 1.70 (m, 2H), 1.85 (t, IH), 2.15 (d, IH), 2.85 (s, 3H), 3.35 (m, 4H), 4.05 (m, IH), 5.75 (s, 2H), 7.10 (m, 2H), 7.25 (m, 2H), 7.85 (t, IH), 7.90 (s, IH), 8.00 (m, IH), 8.05 (d, IH), 8.15 (d, IH), 8.35 (d, IH), 10.60 (s, IH); MS (M+H)+ 501.
The starting material 3-{3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo- piperidin-l-yl}butyraldehyde was prepared as follows :
(i) To a solution of 2-(4-hydroxyphenyl)propionic acid (11.68 g, 70.36 mmol) in methanol (50 ml) was added 10 drops of concentrated sulphuric acid. The resultant solution was stirred at 65 °C for 3.5 h. The reaction mixture was allowed to cool, evaporated to a straw coloured oil, redissolved in ethyl acetate (50 ml) and washed with IM NaHCO3 (50 ml) and brine (50 ml). The organic phase was dried (MgSO ) and evaporated to give methyl 2-(4- hydroxyphenyl)proρionate (13.02 g, 72.33 mmol) as an oil. NMR(CDC13): 1.40 (d, 3H), 3.60 (s, 3H), 5.10 (s, IH), 6.70 (d, 2H), 7.10 (d, 2H).
(ii) To a solution of methyl 2-(4-hydroxyphenyl)propionate (5.0 g, 27.7 mmol) in DMSO (60 ml) was added 4-chloromethyl-2-methylquinolinef (6.33 g, 27.7 mmol), caesium carbonate (9.04 g, 27.7 mmol) and tetra-«-butylammonium iodide (10.25 g, 27.7 mmol). The resultant solution was stirred at 50 °C for 60 min. The reaction mixture was allowed to cool then diluted with ethyl acetate (450 ml) and washed with brine (3 x 50 ml). The organic phase was dried (MgSO4), evaporated and purified by chromatography (Companion, 120g silica Redisep column, eluent 0→75% EtOAc / isohexane) to give methyl 2-[4-(2-methylquinolin-4- ylmethoxy)ρhenyl]propionate (3.81 g, 11.36 mmol) as an oil. NMR(CDC13): 1.45 (d, 3H), 2.70 (s, 3H), 3.60 (s, 3H), 3.65 (m, IH), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+ 336. (iii) A solution of methyl 2-[4-(2-methylquinolin-4-ylmethoxy)phenyl]propionate (1.0 g 2.98 mmol) in anhydrous THF (25 ml), under argon, was cooled to -10°C, and to this was added dropwise LHMDS (IM solution in THF, 3.58ml). The solution was then stirred for 10 min. 3-bromochloropropane (324 μl 3.28 mmol) was added and stirring was continued for 2 h while warming to RT. The solution was evaporated to a yellow gum, dissolved in ethyl acetate (25 ml), washed with saturated NH4C1 (2 x 25 ml), and the organic phase was dried (MgSO4), and evaporated to give methyl 5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (1.34 g, 3.25 mmol), a yellow oil. NMR(CDC13): 1.50 (s, 3H), 1.60 (m, 2H), 2.05 (m, 2H), 2.70 (s, 3H), 3.45 (m, 2H), 3.60 (s, 3H), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.50 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+412. (iv) Butanolamine (1.01 ml, 10.90 mmol) and tetrabutylammonium iodide (0.40 g, 1.09 mM) were added to a solution of methyl 5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (0.45 g 1.09 mmol) in toluene (15 ml). The reaction mixture was stirred for 18 h at 105 °C. After cooling, the toluene layer was decanted off to leave a red oil. The residual oil was washed with toluene (2 x 15ml) and the toluene decants was were combined, containing methyl 5-(4-hydroxybutylamino)-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate, MS (M+H)+ 465, which was used directly in the next reaction step. (v) The toluene solution of methyl 5-(4-hydroxybutylamino)-2-methyl-2-[4-(2- methylquinolin-4-ylmethoxy)phenyl]pentanoate (1.09 mmol) from the previous step was heated at 105 °C for 18 h. The solution was evaporated to a yellow gum and purified by chromatography (Companion, 40 g silica Redisep column, eluent 0— 10% MeOH/EtOAc ) to give l-(4-hydroxybutyl)-3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]piperidin-2- one (0.21 g, 0.52 mmol), as a yellow oil. MS (M+H)+ 433.
(vi) l-(4-hydroxybutyl)-3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]piperidin-2- one (0.11 g 0.25 mmol) was stirred in dry dichloromethane (8 ml), under argon. 4A molecular sieves (0.40 g) and N-methyl morpholine oxide (0.052 g, 0.38 mmol) were added and the reaction mixture was stirred at RT for 10 min. Tetrapropylammonium peruthenate (0.009 g, 10 mol%) was then added and stirring was continued for 45 min at RT. The reaction solution was poured onto a 5 g silica bond elute column and eluted with ethyl acetate to give 3-{3- methyl-3 - [4-(2-methylquinolin-4-ylmethoxy)phenyl] -2-oxo-piperidin- 1 -yl} butyraldehyde (0.047 g, 0.109 mmol), as a colourless oil. NMR(CDC13):1.45 (s, 3H), 1.65 ( , 2H), 1.85 (m, 3H), 2.15 (m, IH), 2.45 (t, 2H), 2.70 (s, 3H), 3.30 (m, 3H), 3.45 (m, IH), 5.40 (s, 2H), 6.90 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH), 9.70 (s, 1H); MS (M+H)+431
EXAMPLE 4 5-Methyl-5-{3-Methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo-piperidin-l- ylmethyl}imidazolidine-2,4-dione
Figure imgf000052_0001
To a stirred solution of 3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-(2-oxo- propyl)-piperidin-2-one (prepared below) (200 mg, 0.48 mmol) in EtOH (10 ml) and water (10 ml) was added ammonium carbonate (461 mg, 4.80 mmol) and potassium cyanide (62 mg, 0.96 mmol). The mixture was heated to 60 °C for 16 h, then evaporated under reduced pressure to give a yellow gum. The residue was partitioned between EtOAc (25 ml) and brine (25 ml). The aqueous phase extracted with EtOAc (2 x 25 ml) and the combined organic phases dried (MgSO4) and evaporated. The crude product was purified by reverse phase HPLC to give the product (a TFA salt), as a mixture of diastereoisomers and as a pale yellow solid (167 mg, 0.28 mmol). NMR: 1.30 (s, 3H), 1.40 (d, 3H), 1.50 (m, IH), 1.70 (m, IH), 1.80 (m, IH), 2.15 (m, IH), 2.85 (s, 3H), 3.30 (m, IH), 3.45 (d, IH), 3.80 (d, IH), 4.00 5 (d, IH), 5.75 (s, 2H), 7.10-7.25 (m, 4H), 7.75 (s, IH), 7.85 (t, IH), 7.90 (s, IH), 8.00 (t, IH), 8.15 (d, IH), 8.35 (d, IH), 11.65 (d, IH); MS (M+H)+ 487.
The starting material 3 -methyl-3 -[4-(2-methy lquinolin-4-ylmethoxy)phenyl]-(2-oxo-propyl)- piperidin-2-one was prepared as follows :
10 (i) To a solution of 2-(4-hydroxyphenyl)propionic acid (11.68 g, 70.36 mmol) in MeOH (50 ml) was added 10 drops of concentrated sulphuric acid. The resultant solution was stirred at 65 °C for 3.5 h. The reaction mixture was allowed to cool, evaporated to a straw coloured oil, redissolved in EtOAc (50 ml) and washed with IM NaHCO3 (50 ml) and brine (50 ml). The organic phase was dried (MgSO4) and evaporated to give methyl 2-(4-
15 hydroxyphenyl)propionate (13.02 g, 72.33 mmol) as an oil. NMR(CDC13): 1.40 (d, 3H), 3.60 (s, 3H), 5.10 (s, IH), 6.70 (d, 2H), 7.10 (d, 2H). (ii) To a solution of methyl 2-(4-hydroxyphenyl)propionate (5.0 g, 27.7 mmol) in DMSO (60 ml) was added 4-chloromethyl-2-methylquinoline (described at the end of Example 1) (6.33 g, 27.7 mmol), caesium carbonate (9.04 g, 27.7 mmol) and tetra-π-butylammonium
20 iodide (10.25 g, 27.7 mmol). The resultant solution was stirred at 50 °C for 60 min. The reaction mixture was allowed to cool then diluted with EtOAc (450 ml) and washed with brine (3 x 50 ml). The organic phase was dried (MgSO4), evaporated and purified by chromatography (Companion, 120g silica Redisep column, eluent 0→75% EtOAc / isohexane) to give methyl 2-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]propionate (3.81 g,
25 11.36 mmol) as an oil. NMR(CDC13): 1.45 (d, 3H), 2.70 (s, 3H), 3.60 (s, 3H), 3.65 (m, IH), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+ 336. (iii) A solution of methyl 2-[4-(2-methylquinolin-4-ylmethoxy)phenyl]propionate (0.5 g 1.49 mmol) in anhydrous THF (10 ml), under Ar, was cooled to -10°C, and to this was added
30 dropwise LHMDS (IM solution in THF, 1.79ml). The solution was stirred for 10 min. 3- bromochloropropane (162 μl, 1.64 mmol) was then added and stirring was continued for 1 h while warming to RT. The solution was evaporated to a yellow oil, dissolved in EtOAc (15 ml), washed with saturated NH C1 (2 x 15 ml) and the organic phase was dried (MgSO4) and evaporated to give methyl 5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (0.62 g, 1.51 mmol), a yellow oil. NMR(CDC13): 1.50 (s, 3H), 1.60 (m, 2H), 2.05 (m, 2H), 2.70 (s, 3H), 3.45 (m, 2H), 3.60 (s, 3H), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.50 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+412.
(iv) 2-hydroxypropylamine (1.16 ml, 15.1 mmol) and tetrabutylammonium iodide (0.56 g, 1.51 mM) were added to a solution of methyl-5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (0.62 g 1.51 mmol) in toluene (15 ml) and the reaction was stirred for 18 h at 105 °C. After cooling, the toluene layer was decanted off to leave a red oil. The residual oil was washed with toluene (2 x 15 ml) and the toluene decants combined containing methyl 5-(2-hydroxypropylamino)-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate, MS (M+H)+ 451 , which was used directly in the next reaction step. (v) The toluene solution of methyl-5-(2-hydroxypropylamino)-2-methyl-2-[4-(2- methylquinolin-4-ylmethoxy)phenyl] pentanoate (1.51 mmol) from the previous step and DBU (0.23g 1.51mmol) were heated at 105 °C for 90 h. The solution was evaporated to a brown oil and purified by chromatography (Companion, 40 g silica Redisep column, eluent 0→20% MeOH/EtOAc ) to give l-(2-hydroxypropyl)-3-methyl-3-[4-(2-methylquinolin-4- ylmethoxy)phenyl]piperidin-2-one (0.24 g, 0.57 mmol), NMR(CDC13): 1.20 (d, 3H), 1.50 (d, 3H), 1.70 (m, 2H), 1.85 (m, IH), 2.15 (m, IH), 2.70 (s, 3H), 3.00 (d, IH), 3.35 (m, 3H), 3.70- 4.05 (m, 2H), 5.40 (s, 2H), 6.90 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+ 419. (vi) l-(2-hydroxypropyl)-3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]piperidin- 2-one (0.24 g 0.57 mmol) was stirred in dry DCM (12 ml), under Ar. 4A molecular sieves (0.90 g) and NMO (0.116 g, 0.86 mmol) were added and the reaction mixture was stirred at RT for 10 min. TPAP (0.020 g, 10 mol%) was added and stirring continued for 30 min at RT. The reaction solution was poured onto a 5 g silica bond elute column and eluted with EtOAc to give 3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-(2-oxo-propyl)-piperidin-2-one (0.20 g, 0.48 mmol), as a yellow gum. NMR(CDC13): 1.50 (s, 3H), 1.70 (m, 2H), 1.90 (m, IH), 2.10 (m, IH), 2.15 (s, 3H), 2.70 (s, 3H), 3.30 (m, 2H), 3.95 (d, IH), 4.30 (d, IH), 5.40 (s, 2H), 6.90 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, 1H); MS (M+H)+417.
EXAMPLE 5 5-Methyl-5-[(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)methyl]imidazolidine-2,4-dione
Figure imgf000055_0001
5-methyl-5-[(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)methyl]-3-{ [2-(trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (prepared below) (0.911 mmol) was stirred in DCM, (20 ml) under Ar and boron trifluoride diethyl ether (0.924ml, 7.288mmol) was added dropwise and stirred at RT for 6h. The mixture was quenched with MeOH (2mls), stirred for 16h, then evaporated and the residue purified by column chromatography (Companion, 40g silica Redisep column, eluent 0→20% MeOH in DCM) to give a pale yellow solid, which was dissolved in water (4mls) MeOH (20mls). To this solution 2.5M ammonia in MeOH (0.15ml) was added and stirred at RT for lh. Solvent evaporated and the residue washed with water (2 x 5mls), triturated in diethyl ether (lOmls), filtered off a pale yellow solid and dried in vacuo to give 5-methyl-5-[(3-methyl-3-{4-[(2- methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l-yl)methyl]imidazolidine-2,4-dione (69 mg, 0.150 mmol) as a mixture of diastereoisomers. NMR: 1.30 (s, 3H), 1.50 (s, 3H), 2.70 (s, 3H), 3.30 - 3.60 (m, 4H), 5.65 (s, 2H), 7.15 (d, 2H), 7.35 (d, 2H), 7.60 (s, IH), 7.65 (t, IH), 7.80 (t, IH), 8.00 (d, IH), 8.15 (m, 2H), 10.80 (d, IH); MS (M+H) 459.
The starting material, 5-methyl-5-[(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}- 2-oxoazetidin- 1 -yl)methyl] -3- { [2-(trimethylsilyl)ethoxy]methyl} imidazolidine-2,4-dione, was prepared as follows:
(i) To a solution of 2-(4-hydroxyphenyl)propionic acid (11.68 g, 70.36 mmol) in MeOH (50 ml) was added 10 drops of concentrated sulphuric acid. The resultant solution was stirred at 65 °C for 3.5 h. The reaction mixture was allowed to cool, evaporated to a straw coloured oil, redissolved in EtOAc (50 ml) and washed with IM NaHCO3 (50 ml) and brine (50 ml). The organic phase was dried (MgSO ) and evaporated to give methyl 2-(4- hydroxyphenyl)proρionate (13.02 g, 72.33 mmol) as an oil. NMR(CDC13): 1.40 (d, 3H), 3.60 (s, 3H), 5.10 (s, IH), 6.70 (d, 2H), 7.10 (d, 2H).
(ii) To a solution of 4-chloromethyl-2-methylquinoιine (described at the end of Example 1) (1.06g, 6.2mmo_), methyl 2-(4-hydroxyphenyl)propionate (1.0 g, 5.6 mmol), triphenylphosphine (2.56g, 9.8mmol) in DCM (15ml), under Ar, di-tert-butyl (E)-diazene-l,2- dicarboxylate (2.26g, 9.8mmol) in DCM (10ml) was added dropwise and stirred for 4h at RT. Evaporated to a residue and purified by chromatography (Companion, 40g silica Redisep column, eluent 15— >40% EtOAc / isohexane) to give methyl 2-[4-(2-methyl-quinolin-4- ylmethoxy)-phenyl]propionate (1.25 g, 3.73 mmol) as an orange solid. NMR(CDC13): 1.45 (d, 3H), 2.70 (s, 3H), 3.60 (s, 3H), 3.65 (m, IH), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H) 336. (iii) Sodium methoxide (0.5M solution in MeOH, 2.39 ml, 1.19 mmol) was added dropwise to a solution of methyl 2-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]propionate (4 g, 11.93 mmol) and paraformaldehyde (0.43 g, 14.31 mmol) in DMSO (70 ml) under Ar. The solution was stirred at RT for 1.5 h, then diluted with water (350 ml) and acidified with IN HCl and extracted into EtOAc (4 x 100ml). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (Companion, 40g silica Redisep column, eluent 25→75% EtOAc / isohexane) to give the product, methyl 3-hydroxy-2-methyl-2-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}propanoate (3.05 g, 8.35 mmol). NMR: 1.50 (s, 3H), 2.70 (s, 3H), 3.60 (s, 3H), 3.60 (m, IH), 3.95 (m, IH), 5.00 (t, IH), 5.60 (s, 2H), 7.10 (d, 2H), 7.20 (d, 2H), 7.55 (s, IH), 7.60 (t, IH), 7.75 (t, IH), 8.00 (d, lH), 8.10 (d, IH); MS (M+H) 366.
(iv) Methyl 3 -hydroxy-2-methyl-2- {4- [(2-methylquinolin-4-yl)methoxy]phenyl} propanoate (3.05 g, 8.35 mmol) was stirred in MeOH (100 ml) and to this was added a solution of lithium hydroxide (0.701 g, 16.70 mmol) in water (18 ml). The reaction solution was stirred at 45 °C for 15 h, evaporated to low volume and neutralised with 2M HCl . Brine (20ml) was added and extracted with EtOAc (3 x 75ml). The combined extracts were dried (MgSO4), filtered and evaporated to give 3-hydroxy-2-methyl-2-{4-[(2-methylquinolin-4- yl)methoxy]phenyl}propanoic acid (1.86g, 5.29 mmol). NMR: 1.35 (s, 3H), 2.65 (s, 3H), 3.50 (d, IH), 3.80 (d, IH), 5.55 (s, 2H), 7.00 (d, 2H), 7.30 (d, 2H), 7.50 (s, IH), 7.55 (t, IH), 7.75 (t, IH), 7.95 (d, IH), 8.05 (d, IH); MS (M+H) 352.
(v) 3-Hydroxy-2-methyl-2-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}propanoic acid (0.32 g, 0.911 mmol) and HATU (0.38 g, 1.002 mmol) were stirred in DMF (10 ml) at RT. Diisoproylethylamine (0.174 ml, 1.002 mmol) was added followed by 5-(aminomethyl)-5- methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione acetate (prepared below) (0.33 g, 1.002 mmol) in DMF (1 ml) and DIPEA (0.174 ml, 1.002mmol), stirring continued for 10 mins. The solution was poured into a mixture of water (30 ml) and brine (30 ml) and the aqueous phase was extracted with EtOAc (3 x 30 ml). The combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to a pale yellow gum 3- hydroxy-2-methyl-N-[(4-methyl-2,5-dioxo-l-{[2-(trimethylsilyl)ethoxy]methyl} imidazolidin- 4-yl)methyl]-2-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}propanamide, MS (M+H) 607, which was used directly in the next reaction step, (vi) 3-Hydroxy-2-methyl-N-[(4-methyl-2,5-dioxo-l-{[2-(trimethylsilyl)ethoxy]methyl} imidazolidin-4-yl)methyl]-2-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}propanamide (0.911 mmol) from the previous step was stirred in pyridine (5 ml) under Ar. Methanesulphonyl chloride (0.092 ml, 1.184 mmol) was added dropwise and stirring continued at RT for 40 mins. The pyridine was removed in vacuo and the residue re-dissolved in DMA (10 ml). Potasshim carbonate (0.504 g, 3.644 mmol) was added and the mixture was heated at 80 °C for 16 h, allowed to cool to RT. The mixture was diluted with brine (30ml) and water (30ml) and extracted with EtOAc (3 x 30 ml). The combined extracts were dried (MgSO ), filtered and evaporated to a golden liquid 5-methyl-5-[(3-methyl-3-{4-[(2-methylquinolin-4- yl)methoxy]phenyl } -2-oxoazetidin- 1 -yl)methyl] -3 - { [2- (trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione, MS (M+H) 589, which was used directly in the next reaction step.
The starting material 5 -(aminomethyl)-5 -methyl-3 -{[2-
(trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione acetic acid salt was prepared as follows: i) Dibenzylamine (200 g, 1.02 mol) was dissolved in THF (1.4 L) and chloroacetone (163 ml, 2.04 mol) added, followed by triethylamine (170 ml, 1.22 mol). The reaction mixture was stirred for 40h at approximately 20°C. The batch was filtered to remove triethylamine hydrochloride, the cake washed with THF (774 ml) and the combined mother and wash liquors evaporated in-vacuo to dryness. The resulting oil was taken up in chloroform (903 ml), washed with saturated aqueous sodium hydrogen carbonate (516 ml), then brine (516 ml), dried over magnesium sulphate and evaporated in-vacuo to give an oil. The latter was purified by flash chromatography through a silica pad, using DCM as eluent. The product-containing fractions were combined and evaporated in-vacuo to give N-acetonyl-dibenzylamine (180 g, 711 mmol) as a pale yellow oil.
ii) The N-acetonyl-dibenzylamine (171.4 g, 677 mmol) was dissolved in ethanol/ water (1.54 L) with stirring. A solution of potassium cyanide (88 g, 1.354 mol) in water (132 ml) was added, followed by ammonium carbonate (260 g, 2.71 mol). The reaction mixture was stirred at 50-55°C for 3h and then cooled overnight. The batch was poured into ice/water (2.73 L) and the solid product filtered, washed with water (3 x 656 ml), then with diethyl ether (2 x 656 ml) and air dried to give 5-(N,N-dibenzylaminomethyl)-5-methyl-lH-imidazolin-2,4- dione (187.5 g, 580 mmol).
iii) 5-(N,N-dibenzylaminomethyl)-5-methyl-lH-imidazolin-2,4-dione (226 g, 700 mmol) was suspended in DCM (7.46 L) under nitrogen. DIPEA (426 ml, 2.45 mol) was added, followed by trimethylsilylethoxymethyl chloride (186 ml, 1.05 mol) and the reaction mixture stirred for 18h at RT. The batch was washed with water (2 x 1.58 L), saturated sodium hydrogen carbonate (1.58 L) and brine (1.58 L), dried with magnesium sulphate and evaporated in- vacuo to give an oil. High vacuum evaporation removed residual DIPEA. The crude product was flash chromatographed through a silica pad, using hexane, then 9:1 hexane/ethyl acetate, and then 4:1 iso-hexane/ethyl acetate as eluent. Fractions containing clean product were vacuum concentrated in-vacuo to give an oil. Impure fractions were also concentrated and the resulting oil was purified on a Biotage column to provide further pure product. The crops were combined to give 5-[(dibenzylamino)methyl]-5-methyl-3-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (276 g, 609 mmol).
iv) 5-[(dibenzylamino)methyl]-5-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}imidazolidine- 2,4-dione (270 g, 596 mmol) was dissolved in ethanol (2.24 L), charged to an autoclave and purged with nitrogen. 10% palladium / charcoal (50 % wet, 29.8 mmol) was added and the batch hydrogenated at 30-40 p.s.i. at RT. Hydrogenolysis was complete after 100 mins and the batch was discharged after 200 mins. The catalyst was removed by filtration and washed with ethanol (0.89 L) until product-free. The filtrate was concentrated to a residual oil, which was purged with diethyl ether (2 x 198 ml) and then evaporated to a solid residue. The latter was dissolved, with warming, in diethyl ether (1.18 L) and filtered through a glass sinter to clarify to a clear yellow solution. Acetic acid (198 ml) was added with stirring and a precipitate rapidly developed. The batch was cooled to 10°C and the product filtered, washed with diethyl ether (198 ml) and dried under vacuum to yield 5-(aminomethyl)-5-methyl-3-{[2- (trimethylsilyl)ethoxy]metl yl}imidazolidine-2,4-dione acetic acid salt (167.5 g, 503 mmol) as a white powder.
NMR: 1HNMR: -0.01 (s, 9H), 0.94 (m, 2H), 1.41 (s, 3H), 2.07 (s, 3H), 2.88 (d, IH), 3.05 (d, IH), 3.49 (s, 3H), 3.63 (m, 2H), 4.93 (s, 2H), 6.22 (s, IH)
EXAMPLE 6 5-{3-Methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo-piperidin-l-ylethyl}- imidazolidine-2,4-dione
Figure imgf000059_0001
To a stirred solution of 3-{3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-(2-oxo- piperidin-l-yl}propanal (prepared below) (80 mg, 0.19 mmol) in EtOH (4 ml) and water (4 ml) was added ammonium carbonate (184 mg, 1.92 mmol) and potassium cyanide (25 mg, 0.38 mmol). The mixture was heated to 60 °C for 16 h, then evaporated under reduced pressure to give a yellow gum. The residue was partitioned between EtOAc (50 ml) and brine (10 ml). The aqueous phase extracted with EtOAc (2 x 20 ml) and the combined organic phases dried (MgSO4) and evaporated. The crude product was purified by reverse phase HPLC to give the product (a TFA salt), as a mixture of 4 diastereoisomers and as an off-white solid 86 mg, 0.14 mmol). NMR: 1.40 (d, 3H), 1.50 (m, IH), 1.70 (m, 2H), 1.85 (m, IH), 2.00 (m, IH), 2.10 (m, IH), 2.90 (s, 3H), 3.25-3.60 (m, 4H), 4.05 (m, IH), 5.75 (s, 2H), 7.10 (d, 2H), 7.20 (d, 2H), 7.80 (t, IH), 7.90 (s, IH), 8.00 (t, IH), 8.15 (d, IH), 8.35 (d, IH), 10.65 (s, IH); MS (M+H)+ 487.
The starting material 3-{3-methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-(2-oxo- piperidin-l-yl}propanal was prepared as follows :
(i) To a solution of 2-(4-hydroxyphenyl)propionic acid (11.68 g, 70.36 mmol) in MeOH (50 ml) was added 10 drops of concentrated sulphuric acid. The resultant solution was stirred at 65 °C for 3.5 h. The reaction mixture was allowed to cool, evaporated to a straw coloured oil, redissolved in EtOAc (50 ml) and washed with IM NaHCO3 (50 ml) and brine (50 ml). The organic phase was dried (MgSO ) and evaporated to give methyl 2-(4- hydroxyphenyl)propionate (13.02 g, 72.33 mmol) as an oil. NMR(CDC13): 1.40 (d, 3H), 3.60 (s, 3H), 5.10 (s, IH), 6.70 (d, 2H), 7.10 (d, 2H).
(ii) To a solution of methyl 2-(4-hydroxyphenyl)propionate (5.0 g, 27.7 mmol) in DMSO (60 ml) was added 4-chloromethyl-2-methylquinoline (described at the end of Example 1) (6.33 g, 27.7 mmol), caesium carbonate (9.04 g, 27.7 mmol) and tetra-π-butylammonium iodide (10.25 g, 27.7 mmol). The resultant solution was stirred at 50 °C for 60 min. The reaction mixture was allowed to cool then diluted with EtOAc (450 ml) and washed with brine (3 x 50 ml). The organic phase was dried (MgSO4), evaporated and purified by chromatography (Companion, 120g silica Redisep column, eluent 0→75% EtOAc / isohexane) to give methyl 2-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]propionate (3.81 g, 11.36 mmol) as an oil. NMR(CDC13): 1.45 (d, 3H), 2.70 (s, 3H), 3.60 (s, 3H), 3.65 (m, IH), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+ 336. (iii) A solution of methyl 2-[4-(2-methylquinolin-4-ylmethoxy)phenyl]propionate (0.5 g 1.49 mmol) in anhydrous THF (10 ml), under Ar, was cooled to -10°C, and to this was added dropwise LHMDS (IM solution in THF, 1.79ml). The solution was stirred for 10 min. 3- bromochloropropane (162 μl, 1.64 mmol) was then added and stirring was continued for 1 h while warming to RT. The solution was evaporated to a yellow oil, dissolved in EtOAc (15 ml), washed with saturated NH4C1 (2 x 15 ml) and the organic phase was dried (MgSO4) and evaporated to give methyl 5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]ρentanoate (0.62 g, 1.51 mmol), a yellow oil. NMR(CDC13): 1.50 (s, 3H), 1.60 (m, 2H), 2.05 (m, 2H), 2.70 (s, 3H), 3.45 (m, 2H), 3.60 (s, 3H), 5.45 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.50 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+412. (iv) 3-aminopropan-l-ol (1.25 ml, 16.3 mmol) and tetrabutylammonium iodide (0.60 g, 1.63 mM) were added to a solution of methyl-5-chloro-2-methyl-2-[4-(2-methylquinolin-4- ylmethoxy)phenyl]pentanoate (0.67 g 1.63 mmol) in toluene (15 ml) and the reaction was stirred for 18 h at 105 °C. After cooled and toluene layer was decanted off to leave a red oil. The residual oil was washed with toluene (2 x 15 ml) and the toluene decants combined containing methyl 5 - [(3 -hydroxypropyl)amino] -2-methyl-2- {4- [(2-methylquinolin-4- yl)methoxy]phenyl}pentanoate MS (M+H)+ 451 , which was used directly in the next reaction step.
(v) The toluene solution of methyl 5-[(3-hydroxypropyl)amino]-2-methyl-2-{4-[(2- methylquinolin-4-yl)methoxy]phenyl}pentanoate from the previous step was heated at 105 °C for 90 h. The solution was evaporated to a yellow gum and purified by chromatography (Companion, 40 g silica Redisep column, eluent 0— 10% MeOH/EtOAc ) to give l-(3- hydroxypropyl)-3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}piperidin-2-one (0.18 g, 0.43 mmol), NMR(CDC13): 1.50 (d, 3H), 1.70 (m, 4H), 1.85 (m, IH), 2.20 (m, IH), 2.70 (s, 3H), 3.25 (m, 2H), 3.50 (m, 4H), 3.95 (m, IH), 5.40 (s, 2H), 6.90 (d, 2H), 7.20 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH); MS (M+H)+ 419. (v) l-(3-hydroxypropyl)-3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy] phenyl} piperidin-2-one (0.18 g 0.43 mmol) was stirred in dry DCM (12 ml), under Ar. 4A molecular sieves (0.90 g) and NMO (0.087 g, 0.65 mmol) were added and the reaction mixture was stirred at RT for 10 min. TPAP (0.015 g, 10 mol%) was added and stirring continued for 90 mins at RT. The reaction solution was poured onto a 5 g silica bond elute column and eluted with EtOAc to give 3-(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2- oxopiperidin-l-yl)propanal (0.08 g, 0.19 mmol), as a colourless oil. NMR(CDC13): 1.45 (s, 3H), 1.65 (m, 2H), 1.80 (m, IH), 2.15 (m, IH), 2.70 (s, 3H), 2.75 (t, 2H), 3.30 (m, 2H), 3.55 (m, IH), 3.70 (m, IH), 5.40 (s, 2H), 6.90 (d, 2H), 7.10 (d, 2H), 7.40 (s, IH), 7.45 (t, IH), 7.65 (t, IH), 7.85 (d, IH), 8.00 (d, IH), 9.80 (s, IH); MS (M+H)+417. EXAMPLE 7
5-[2-(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)ethyl]imidazolidine-2,4-dione;
Figure imgf000062_0001
3-(3-methyl-3- {4-[(2-methylquinolin-4-yl)methoxy]phenyl} -2-oxoazetidin- 1 -yl)propanal (23 mg, 0.059 mmol) was stirred in ethanol (1.2 ml) and water (1.0 ml). Ammonium carbonate (23 mg, 0.237 mmol) was added followed by potassium cyanide (4 mg, 0.059 mmol). The reaction mixture was heated at 60°C for 6.5 h. A further portion each of potassium cyanide (4 mg, 0.059 mmol) and ammonium carbonate (23 mg, 0.059 mmol) was added and heating was continued at 60°C for a further 11 h. The mixture was allowed to stand at RT for ~ 72h, then evaporated to dryness in vacuo and purified by column chromatography (lOg silica bond elut, eluent 0 - 4% MeOH in CH2C12) to give the product, 5-[2-(3-methyl-3-{4-[(2-methylquinolin- 4-yl)methoxy]phenyl}-2-oxoazetidin-l-yl)ethyl]imidazolidine-2,4-dione as a white solid (6 mg, 22%). NMR: 1.52 (d, 3H), 1.69 - 2.04 (m, 2H), 2.67 (s, 3H), 3.16 - 3.53 (m, 4H), 4.04 (t, IH), 5.59 (s, 2H), 7.12 (d, 2H), 7.33 (d, 2H), 7.56 (s, IH), 7.59 (t, IH), 7.75 (t, IH), 7.96 (s, IH), 7.97 (d, IH), 8.11 (d, IH), 10.65 (s, IH); MS (M+H) 459.
The starting material, 3-(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2- oxoazetidin-l-yl)propanal, was prepared as follows:
(i) N-(3-tert-Butoxypropyl)-3-hydroxy-2-methyl-2-{4-[(2-methylquinolin-4- yl)methoxy]phenyl}propanamide (600 mg, 1.29 mmol) (prepared as described for EXAMPLE 1 (iii), from 2-[4-(benzyloxy)phenyl]-3-hydroxy-2-methylpropanoate and l-tert-butoxy-3-propylamine hydrochloride) was stirred in pyridine (7 ml) under Ar. Methanesulfonyl chloride (0.13 ml, 1.68 mmol) was added dropwise and stirring continued at RT for 40 min. The reaction mixture was then evaporated to dryness in vacuo to give the product, 3-[(3-tert-butoxypropyl)amino]-2-methyl-2-{4-[(2- methylquinolin-4-yl)methoxy]phenyl}-3-oxopropyl methanesulfonate, used directly for subsequent reaction. MS (M+H) 543. (ii) 3-[(3-tert-Butoxypropyl)amino]-2-methyl-2-{4-[(2-methylquinolin-4- yl)methoxy]phenyl}-3-oxopropyl methanesulfonate (700 mg, 1.29 mmol) was heated with potassium carbonate (712 mg, 5.15 mmol) in DMA (12 ml) under Ar at 80°C for ~20 h. The reaction mixture was poured into a mixture of water / brine (1:1, 30 ml) and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with brine (20 ml), dried (MgSO ), filtered and evaporated. The residue was purified by column chromatography (20g silica bond elut column, eluent 0 - 2.5% MeOH in CH2C12) to give the product, l-(3-tert-butoxypropyl)-3-methyl-3-{4- [(2-methylquinolin-4-yl)methoxy]phenyl}-azetidin-2-one, as a pale yellow oily gum (389 mg, 67%). NMR: 1.10 (s, 9H), 1.52 (s, 3H), 1.62 - 1.71 (m, 2H), 2.67 (s, 3H), 3.16 - 3.32 (m, 4H), 3.36 (d, IH), 3.43 (d, IH), 5.60 (s, 2H), 7.12 (d, 2H), 7.33 (d, 2H), 7.53 - 7.62 (m, 2H), 7.72 - 7.78 (m, IH), 7.97 (d, IH), 8.11 (d, IH); MS (M+H) 447 (iii) 1 -(3-tert-Butoxypropyl)-3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}- azetidin-2-one (261 mg, 0.584 mmol) was stirred in CH2C12 (4 ml). TFA (4 ml) was added dropwise and stirring was continued for 40 min. The solution was evaporated in vacuo and the residue was taken up in MeOH (8 ml). Triethylamine (0.6 ml) was added and the solution was stirred at RT for 1 h then evaporated to dryness. The residue was purified by column chromatography (20g silica bond elut, eluent 0 - 2.5% MeOH in CH2C12) to give the product, l-(3-hydroxypropyl)-3-methyl-3-{4-[(2- methylquinolin-4-yl)methoxy]phenyl}azetidin-2-one, as a colourless gum (147 mg, 64%). NMR: 1.52 (s, 3H), 1.60 - 1.69 (m, 2H), 2.67 (s, 3H), 3.22 (t, 2H), 3.33 - 3.47 (m, 4H), 4.53 (t, IH), 5.60 (s, 2H), 7.13 (d, 2H), 7.33 (d, 2H), 7.56 (s, IH), 7.59 (t, IH), 7.75 (t, IH), 7.97 (d, IH), 8.11 (d, IH); MS (M+H) 391
(iv) 1 -(3-Hydroxypropyl)-3-methyl-3- {4-[(2-methylquinolin-4- yl)methoxy]phenyl}azetidin-2-one (26 mg, 0.067 mmol) was dissolved in DCM (4 ml) under Ar. 4 A Molecular sieves (110 mg) and NMO (12 mg, 0.100 mmol) were added and the mixture was stirred at RT for 10 min, before addition of TPAP (1.2 mg, 0.0033 mmol). Stirring was continued for 30 min, then the mixture was poured onto a 5g silica isolute column and eluted with EtOAc. The product fractions were evaporated to give the product, 3-(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2- oxoazetidin-l-yl)propanal, used directly for subsequent reaction. NMR: 1.49 (s, 3H), 2.67 (s, 3H), 2.72 - 2.79 (m, 2H), 3.28 - 3.48 (m, 4H), 5.60 (s, 2H), 7.12 (d, 2H), 7.31 (d, 2H), 7.56 (s, IH), 7.59 (t, IH), 7.75 (t, IH), 7.97 (d, IH), 8.11 (d, IH), 9.68 (s, IH); MS (M+H) 389
EXAMPLE 8 tert-but l {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4- yl)methyl]-2-oxopyrrolidin-3-y_}carbamate
Figure imgf000064_0001
tert-Butyl [3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-2-oxo-l-(2-oxopropyl)pyrrolidin-3- yl]carbamate (described below) (0.122 g, 0.262 mmol), ammonium carbonate (0.427 g, 4.189 mmol) and potassium cyanide (0.136 g, 2.094 mmol) were all dissolved in EtOH (3 ml) and water (1 ml) in a sealed microwave tube and heated at 80°C for 0.5h. The reaction mixture was dry loaded onto silica and purified by column chromatography (5-10% MeOH: DCM, 20 g Bond Elut), then triturated with diethyl ether to give a white solid (0.062 g, 0.125 mmol) as a mixture of diastereoisomers. LCMS: retention time = 2.6 min, (M+H) 537, (M-H) 535. NMR: 1HNMR (DMSO) 1.17 (d, 3H), 1.34 (s, 9H), 2.27 (s, 6H), 2.61 - 2.67 (m, 2H), 3.17 (d, IH), 3.42 (m, IH), 3.53 (m, IH), 3.76 (d, IH), 5.02 (d, 2H), 6.71 - 6.86 (m, 2H), 6.97 (t, 2H), 7.06 (d, IH), 7.11 (d, IH), 7.22 (s, IH), 7.33 (t, 2H), 7.99 (d, IH).
The starting material tert-butyl [3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-2-oxo-l-(2- oxopropyl)pyrrolidin-3-yl] carbamate was prepared as follows: i) Methyl 2-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate (0.450 g, 1.09 mmol, CAS no. 223407-41-8) was dissolved in 1,2-dichloroethane (10 ml) and (2R)-1- aminopropan-2-ol (0.117 ml, 1.5 mmol) was added. The reaction was then stirred at RT for 2h. Sodium triacetoxyborohydride (0.316 g, 1.5 mmol) was added and the suspension stirred at RT for a further lh. The reaction was quenched with saturated brine solution (5 ml). The layers were separated and the aqueous phase extracted with DCM (1 x 5 ml). The combined organic extracts were then dried, (MgSO ), filtered and concentrated in vacuo to give tert- butyl { 3 - [4-(benzyloxy)phenyl] - 1 - [(2R)-2-hydroxypropyl] -2-oxopyrrolidin-3 -yl} carbamate (0.385 g) as a colourless foam that was used without further purification. LCMS: retention time = 2.76, (M+Na) 463
ii) tert-Butyl { 3 - [4-(benzyloxy)phenyl] - 1 - [(2i_)-2-hydroxypropyl] -2-oxopyrrolidin-3 - yl}carbamate (0.378 g, 0.859 mmol) was dissolved in EtOH (25 ml) and then cyclohexene (0.869 ml, 8.591 mmol) and 10% palladium on carbon (0.2 g, 50%w/w) were carefully added and heated at reflux under Ar for 26h. The mixture was filtered and the filtrate reduced in vacuo and subjected to column chromatography (20 g BondElut, 20 - 50% EtOAc: isohexane) to give tert-butyl {3-(4-hydroxyphenyl)-l-[(27?)-2-hydroxypropyl]-2-oxopyrrolidin-3- yl}carbamate (0.211 g, 0.603 mmol), as a white solid. LCMS: retention time = 1.68 - 1.77, (M+Na) 373 diastereoisomers visible. NMR: 1H NMR (DMSO) 0.92 (s, 3H), 1.33 (s, 9H), 2.14 - 2.34 (m, IH), 2.59 (m, IH), 3.01 (m, IH), 3.22 (m, IH), 3.33 (m, IH), 3.41 (m, IH), 3.55 (s, IH), 3.73 (s, 0.5H), 3.80 (quintet, 0.5H), 6.53 - 6.65 (m, IH), 6.70 (dd, 2H), 7.21 (s, IH), 7.24 (dd, IH), 9.35 (s, 0.5H), 9.38 (s, 0.5H).
iii) tert-Butyl { 3 -(4-hydroxyphenyl)- 1 - [(2i-)-2-hydroxypropyl] -2-oxopyrrolidin-3 - yl}carbamate (0.204 g, 0.583 mmol) was dissolved in acetone (20 ml), caesium carbonate (0.76 g, 2.331 mmol) was added and the reaction mixture cooled under Ar to 0°C and stirred for 10 mins. To this suspension was then added 2,5-dimethylbenzyl chloride (0.094 ml, 0.641 mmol) and tetrabutylammonium iodide (0.228 g, 0.641 mmol). The reaction was stirred at RT for 5h then filtered and solvent removed in vacuo. The residue was triturated with diethyl ether, the solid removed by filtration and the filtrate reduced in vacuo to give the crude tert- butyl {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(2i_)-2-hydroxypropyl]-2-oxopyrrolidin-3- yl}carbamate (0.263 g, 0.562 mmol). LCMS: retention time = 2.86, (M+Na) 491. NMR: 1H NMR (DMSO) 0.96 (s, 3H), 1.34 (s, 9H), 2.27 (s, 6H), 2.56 - 2.67 (m, IH), 2.97 - 3.09 (m, IH), 3.15 - 3.27 (m, IH), 3.40 (m, IH), 3.59 (m, IH), 3.78 (m, IH), 4.63 (d, IH), 4.66 (d, IH), 5.02 (s, 2H), 6.63 - 6.79 (m, IH), 6.98 (dd, 2H), 7.05 (dd, IH), 7.11 (d, IH), 7.21 (s, IH), 7.38 (dd, 2H). iv) tert-Butyl {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(2i-)-2-hydroxypropyl]-2- oxopyrrolidin-3-yl}carbamate (0.263 g, 0.562 mmol) was dissolved in DCM (20 ml), NMO (0.114 g, 0.843 mmol), 4A powdered molecular sieves (0.3 g) were added and stirred under Ar for 30 mins. TPAP (0.039 g, 0.112 mmol) was added and stirred at RT for 2h. The reaction mixture was filtered, reduced in vacuo and purified by column chromatography (50% EtOAc: isohexane, 20 g Bond Elut) to give tert-butyl [3-{4-[(2,5- dimethylbenzyl)oxy]phenyl}-2-oxo-l-(2-oxopropyl)pyrrolidin-3-yl]carbamate (0.122 g, 0.262 mmol) as a white solid. LCMS: retention time = 3.02, (M+Na) 489, (M-H) 465. NMR: 1H NMR (DMSO) δ 1.34 (s, 9H), 2.05 (s, 3H), 2.27 (s, 6H), 2.42 - 2.49 (m, IH), 2.57 - 2.66 (m, IH), 3.30 - 3.36 (m, 2H), 4.00 (d, IH), 4.22 (d, IH), 5.03 (s, 2H), 6.77 - 6.88 (bs, IH), 6.99 (d, 2H), 7.06 (dd, IH), 7.11 (d, IH), 7.22 (s, IH), 7.41 (d, 2H).
EXAMPLE 9
5-[3-Methyl-2-oxo-3-(4-phenylethynyl-phenyl)-pyrrolidin-l-ylmethyl]-imidazolidine-2,4- dione
Figure imgf000066_0001
[3-Methyl-2-oxo-3-(4-phenylethynyl-phenyl)-pyrrolidin- 1 -yl]-acetaldehyde (described below) (396 mg, 1.25 mmol) was stirred in EtOH (10 ml) and water (10 ml). Ammonium carbonate (720 mg, 7.5 mmol) was added followed by potassium cyanide (162 mg, 2.5 mmol) and the mixture was heated at 60 °C for 3 h and then stirred at RT overnight. Silica gel (5g) was added and the reaction mixture evaporated. The residue was purified by column chromatography using a Flashmaster II (20g silica bond elut, eluent 80 - 100% EtOAc in isohexane) to give the product, 5-[3-methyl-2-oxo-3-(4-phenylethynyl-phenyl)-pyrrolidin-l- ylmethyl]-imidazolidine-2,4-dione, as a yellow foam (330 mg, 0.85 mmol) as a mixture of diastereoisomers. NMR: 1.52 - 1.53 (m, 3H), 2.13 - 2.24 (m, IH), 2.37 - 2.51 (m, IH), 3.32 - 3.44 (m, 2H), 3.53 - 3.63 (m, IH), 3.91 - 4.02 (m, IH), 4.24 - 4.27 (m, IH), 6.17 - 6.34 (m, IH), 7.22 - 7.54 (m, 9H), 8.02 - 8.12 (m, IH); MS (M+H) 388.
The starting material, [3-methyl-2-oxo-3-(4-phenylethynyl-phenyl)-pyrrolidin-l-yl]- acetaldehyde, was prepared as follows:
(i) l-(2,2-Dimethyl-[l,3]dioxolan-4-ylmethyl)-3-(4-hydroxy-phenyl)-3-methyl- pyrrolidin-2-one (790 mg, 2.6 mmol) and pyridine (0.63 ml, 7.8 mmol) were dissolved in anhydrous DCM (50 ml)and cooled in an ice/water bath, trifluoromethane sulphonic anhydride (0.48 ml, 2.86 mmol) was added and the resultant solution stirred at 0°C for lh. The reaction mixture was poured into 2M HCl (50 mL). The organic phase was separated and washed with saturated sodium bicarbonate (50 ml), dried (Na2SO ) and evaporated. The residue was purified by column chromatography using a Flashmaster II (50g silica bond elut, eluent 50 - 100% EtOAc in isohexane) to give the product, trifluoromethanesulfonic acid 4-[l- (2,2-dimethyl-[l ,3]dioxolan-4-ylmethyl)-3-methyl-2-oxo-pyrrolidin-3-yl]-phenyl ester, as a yellow solid which was a mixture of diastereoisomers (916mg, 2.1 mmol), MS (M++H) 438.
(ii) To a solution of trifluoromethanesulfonic acid 4-[l-(2,2-dimethyl-[l,3]dioxolan-4- ylmethyl)-3-methyl-2-oxo-pyrrolidin-3-yl] -phenyl ester (550 mg, 1.3 mmol) in DMF was added bis(triphenylphosphine)-palladium(II) chloride (27mg, 0.04mmol), triethylamine (0.78 ml, 5.5 mmol) and phenylacetylene (0.215 ml, 1.95 mmol). The reaction mixture was stirred at 90°C for 90 min and at RT for 2 days. The reaction mixture was diluted with EtOAc (50 ml) and washed with water (2 x 50 ml) and brine (2 x 50 ml). The organic phase was dried (Na2SO ) and evaporated to a dark brown oil. This was purified by column chromatography using a Flashmaster II (20g silica bond elut, eluent 0 - 60% EtOAc in isohexane) to give the product, 1- (2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-3-methyl-3-(4-phenylethynyl-phenyl)- pyrrolidin-2-one as a brown oil which was a mixture of diastereoisomers (535mg, 1.3mmol), MS (M +H) 390. (iii) To a solution of l-(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-3-methyl-3-(4- ρhenylethynyl-phenyl)-pyrrolidin-2-one (535 mg, 1.3 mmol) in ethanol (10 ml) was added 2M HCl (10 ml). The reaction mixture was stirred at RT for 1 h and then neutralised with saturated sodium bicarbonate solution. This was then extracted with DCM (2 x 50 ml). The combined organic phases were dried (Na2SO4) and evaporated to a brown oil, (500mg), MS (M++H) 350. The oil was dissolved in MeOH (20 ml). To this was added water (4 ml) and sodium periodate (610mg, 2.86 mmol) and the reaction mixture stirred at RT for lh. The reaction mixture was evaporated and the residue partitioned between water (50 ml) and DCM (50 ml). The organic phase was separated, dried (Na2SO4) and evaporated to give crude [3- methyl-2-oxo-3-(4-phenylethynyl-phenyl)-pyrrolidin-l-yl]-acetaldehyde (396 mg, 1.25 mmol) which was used without purification.
EXAMPLE 10 N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4- yl)methy_]-2~oxopyrrolidin-3-yl}acetamide
Figure imgf000068_0001
N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}acetamide (prepared below) (0.215 g, 0.353 mmol) was dissolved in DCM (10 ml) and cooled to 0°C. Boron trifluoride diethyl etherate (0.222 ml, 1.77 mmol) was added under Ar and the mixture stirred at RT for 21h. The reaction mixture was quenched carefully with sat. ΝaHCθ3 (10 ml), and extracted into EtOAc (50 ml), washed with brine, then dried (MgSO ) and reduced in vacuo. Purification by prep HPLC gave the title compound (0.016 g) as a white solid. LCMS: retention time = 1.94, (M-H) 477. NMR: 1H NMR (DMSO) 1.20 (d, 3H), 1.85 (d, 3H), 2.25 (s, 6H), 2.55 (m, IH), 2.70 (m, IH), 3.25 (m, IH), 3.35 (d, IH), 3.45 (d, IH), 3.47 (m, IH), 5.00 (s, 2H), 6.80 (s, IH), 6.99 (dd, 2H), 7.04 (dd, IH), 7.09 (d, IH), 7.21 (s, IH), 7.34 (dd, 2H), 8.01 (d, IH), 10.65 (s, IH). The starting N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}acetamide was prepared as shown below: i) Concentrated sulphuric acid (0.568 L) was added to a solution of hydroxyphenylglycine (710 g, 4.25 mol) in methanol (2.84 L) over 75 mins, allowing the exotherm to raise the reaction temperature from 18°C to 57°C. The reaction mixture was then heated to reflux and stirred for 2h, at which point the reaction was complete by TLC. The reaction mixture was then cooled to 15°C, basified with 0.880 ammonia to pH 8-9 (approximately 0.770 L) and diluted with water (1.08 L), to aid mobility. The precipitate was filtered, washed with water and dried at 40°C in air to give the desired product / hydroxyphenylglycine methyl ester (673 g, 3.72 mol).
ii) -Hydroxyphenylglycine methyl ester (673 g, 3.72 mol) and triethylamine (6.14 mol) were dissolved in DMF (4.71 L) under nitrogen and cooled to 5°C. A solution of Boc anhydride (4.09 mol) in DMF (0.327 L) was added, slowly, over lh, maintaining the internal temperature at 0-5°C. The reaction mixture was then warmed to RT and stirred overnight. The reaction was quenched by addition of 4M hydrochloric acid to pH 3 (approximately 2.30 L), and then ethyl acetate (7.63 L), brine (2.30 L) and water (1.57 L) were added. The separated organic phase was washed with water (3.14 L) and brine (3.14 L), dried over magnesium sulphate, filtered and concentrated in-vacuo to a semi-crystalline residue. This material was slurried in diethyl ether (3.14 L) and filtered. The filtrate was concentrated in-vacuo to give a second crop and the crystalline materials blended to give the product N-butoxycarbonyl-p- hydroxyphenylglycine methyl ester (964 g, 3.43 mol).
iii) 2,5-Dimethylbenzyl chloride (201 ml, 1.36 mol) was added to a stirred suspension of cesium carbonate (442 g, 1.36 mol) in andN-butoxycarbonyl-p-hydroxyphenylglycine methyl ester (367 g, 1.30 mol) in acetone (3.67 L) followed by tetrabutylammonium iodide (86.3 g 0.234 mol). The reaction mixture was stirred and heated to reflux overnight (16h) and cooled to RT. The cool reaction mixture was then filtered and the filtrate concentrated in-vacuo to give the desired product N-butoxycarbonyl-p-(2,5 -dimethylbenzyl)oxyphenylglycine methyl ester (615 g, 1.54 mol). iv) Allyl bromide (75.0 ml, 0.855 mol) was added to a stirred suspension of freshly ground cesium carbonate (350 g, 1.076 mol) and N-butoxycarbonyl-p-(2,5- dimethylbenzyl)oxyphenylglycine methyl ester (294 g, 0.737 mol) in acetone (4.41 L) under nitrogen, followed by tetrabutylammonium iodide (70.7 g, 0.191 mol). The reaction mixture 5 was stirred and heated at reflux overnight. The cooled reaction mixture was filtered to remove inorganics and the filtrate concentrated in-vacuo to give the crude product. Crude purification was accomplished by eluting through a silica pad with hexane/ethyl acetate (99:1), to remove fast-running and baseline impurities. Final purification was carried out on a 75L Biotage system, eluting with hexane/ethyl acetate (93:7), in eight batches, to give the desired product
10 methyl 2-[4-(2,5-dimethylbenzyl)oxyphenyl]-2-tert-butoxycarbonylaminopent-4-enoate (260 g, 0.592 mol). LCMS: retention time = 3.55, (M-H) 438. ΝMR: 1HΝMR: 1.33 - 1.46 (m, 9H), 2.32 (s, 6H), 3.16 (m, IH), 3.36 - 3.49 (m, IH), 3.68 (s, 3H), 4.97 (s, 2H), 5.13 (m, IH), 5.17 (s, IH), 5.59 - 5.74 (m, IH), 5.95 (s, IH), 6.95 (d, 2H), 7.06 (d, IH), 7.10 (d, IH), 7.20 (s, IH), 7.36 (d, 2H)
15 v) Methyl 2-[(tert-butoxycarbonyl)amino]-2-{4-[(2,5-dimethylbenzyl)oxy]phenyl}pent-4- enoate (42.6 g, 97.04 mmol) was dissolved in DCM (500 ml) and cooled to -78°C (dry ice/IP A). O was bubbled through the reaction mixture for 5 mins and then O3 for a further 8.5h. The reaction was then flushed with O2 again for 5 mins and then PS-PPI13 (3mmol/g,
20 32.3 g, 97.04 mmol) was added and stirred at RT for 4 days. The suspension was filtered and reduced in vacuo to give the crude methyl 2-[(tert-butoxycarbonyl)amino]-2-{4-[(2,5- dimethylbenzyl)oxy]phenyl}-4-oxobutanoate (45.01 g) as a yellow gum. LCMS: retention time = 3.20, (M+Na) 464
25 vi) Sodium cyanoborohydride (1.0 M solution in THF, 22.5 ml, 22.52 mmol) was added after 1.5h to a premixed solution of 5-(aminomethyl)-5-methyl-3-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (described in Example 5) (7.5 g, 22.52 mmol), methyl 2-[(tert-butoxycarbonyl)amino]-2-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-4- oxobutanoate (10 g, 22.52 mmol), 4A molecular sieves (0.3 g) and acetic acid (5 ml) in 1,2-
30 dichloroethane (110 ml) at RT and then heated at reflux for 0.5h. The reaction mixture was filtered and reduced in vacuo then purified by column chromatography (20 - 50% EtOAc: isohexane, 20 mins then 50% for 10 mins, 120 g Redisep) to give tert-butyl {3-{4-[(2,5- dimethylbenzyl)oxy]phenyl} - 1 -[(4-methyl-2,5-dioxo- 1 - { [2-
(trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}carbamate (6.421 g, 9.641 mmol) as a yellow foam. LCMS: (MonitorLate method) 1.80-1.88, (M+H) 667.
vii) tert-Butyl {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}carbamate (5.0 g, 7.51 mmol) was dissolved in MeOH (50 ml) and HCl in dioxane (18.77 ml, 75.08 mmol) added. The reaction mixture was stirred at RT for lh. The reaction mixture was basified to pH 12 with 2M NaOH and the MeOH removed in vacuo. The residue was redissolved in EtOAc and extracted with water. The aqueous was then extracted with EtOAc and the organics washed with brine, dried (MgSO4) then reduced in vacuo and purified by SCX-2 (20 g column, eluted with DCM then MeOH then NH3/MeOH) to give 5-[(3-amino-3-{4-[(2,5- dimethylbenzyl)oxy]phenyl}-2-oxopyrrolidin-l-yl)methyl]-5-methyl-3-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (2.403 g, 4.25 mmol) as a white foam. LCMS: retention time = 1.71, (M-H) 565. NMR: 1HNMR: -0.01 (d, 9H), 0.82 (m, 2H), 1.34 (s, 3H), 2.15 (m, 2H), 2.30 (s, 6H), 3.15 - 3.89 (m, 6H), 4.72 (d, 2H), 5.04 (s, 2H), 6.98 (m, 2H), 7.09 (d, IH), 7.14 (d, IH), 7.25 (s, IH), 7.33 (m, 2H), 8.51 (d, IH).
viii) 5 - [(3 -amino-3 - {4- [(2, 5 -dimethylbenzyl)oxy]phenyl} -2-oxopyrrolidin- 1 -yl)methyl] -5 - methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (0.25 g, 0.44 mmol) was dissolved in pyridine (5 ml) and cooled to 0°C. Acetic anhydride (0.414 ml, 4.42 mmol) was added dropwise and the reaction stirred at RT for 18h. The reaction mixture was reduced in vacuo then taken up in EtOAc and washed with water (2 x 20 ml). The organics reduced in vacuo to give N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (ttimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyι olidin-3-yl}acetamide (0.215 g) as a yellow foam. LCMS: retention time = 2.64, (M+H) 609, (M-H) 607. ι> ,,-,„„ PCT/GB2005/000759 71
EXAMPLE 11
N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4- yl)methyl]-2-oxopyrrolidin-3-yl}-iY-methylurea
Figure imgf000072_0001
The procedure described in Example 10 was followed using N-{3-{4-[(2,5- dimethylbenzyl)oxy]phenyl} - 1 -[(4-methyl-2,5-dioxo- 1 - { [2-
(trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}-N'-methylurea (described below) (0.102 g, 0.164 mmol) to give N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}- 1 - [(4-methyl-2, 5 -dioxoimidazolidin-4-yl)methyl] -2-oxopyrrolidin-3 -yl} -N-methylurea (0.0097 g, 0.020 mmol). LCMS: retention time = 1.69, (M-H) 492. ΝMR: 1H ΝMR (500, DMSO) 1.2 (dd, 3H), 2.25 (s, 6H), 2.5 (m, 2H), 3.2 (m, 2H), 3.35 (m, 2H), 3.75 (m, 3H), 4.60 (s, 2H), 6.75 (s, 2H), 6.80 (m, 2H), 6.85 (d, IH), 6.95 (d, IH), 7.00 (m, 2H), 7.9- 8.3 (m, IH), 9.30 (d, IH), 10.6 (s, IH).
The preparation of N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}-N'-methylιιrea was as follows: i) Methyl isocyanate (0.500 ml, 8.83 mmol) was added to a solution of 5-[(3-amino-3-{4- [(2,5-dimethylbenzyl)oxy]phenyl}-2-oxopyrrolidin-l-yl)methyl]-5-methyl-3-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (prepared as described under Example 10) (0.01 g, 0.18 mmol) in 1,4-dioxane (5 ml) and the mixture stirred for 19h. The mixture was reduced in vacuo and taken up in EtOAc and washed with (3 x 5 ml) and brine (5 ml). Organics reduced in vacuo to give title compound (0.102 g, 0.164 mmol). LCMS: retention time = 2.76, (M-H) 622, (M+H) 624 EXAMPLE 12
{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-
2-oxopyrrolidin-3-yl}formamide
Figure imgf000073_0001
The procedure described in Example 10 was followed using {3-{4-[(2,5- dimethylbenzyl)oxy]phenyl} - 1 -[(4-methyl-2,5-dioxo- 1 - { [2-
(trimethylsilyl)ethoxy]methyl} imidazolidin-4-yl)methyl] -2-oxopyrrolidin-3 -yl} formamide (prepared below) (0.098g, 0.165 mmol) to give {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l- [(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl} formamide (0.0087 g, 0.019 mmol). LCMS: retention time = 1.67, (M-H) 463. NMR: 1H NMR (500MHz, DMSO) δ 1.20 (d, 3H), 2.25 (s, 6H), 2.55 (m, 2H), 3.25 (m, 2H), 3.75 (s, 2H), 4.60 (s, 2H), 6.80 (s, 2H), 6.99 (dd, 2H), 7.04 (dd, 2H), 7.09 (d, IH), 7.90 (dd, IH), 8.31 (d, IH), 9.40 (s, IH), 10.65 (s, IH).
The preparation of {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}formamide is described as follows: i) 5-[(3-amino-3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-2-oxopyrrolidin-l-yl)methyl]-5- methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (prepared as described under Example 10) (0.10 g, 0.18 mmol) was dissolved in THF (5 ml) and a premixed solution of formic acid (3.33 ml) and acetic anhydride (1.66 ml) was added under Ar and stirred at RT for 19h. The mixture was reduced in vacuo and redissolved in EtOAc then washed with sat. aHCO3 (2 x 5 ml), water (3 x 5 ml) and brine (5 ml). Organics reduced in vacuo to give {3- {4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}formamide (0.098g, 0.165 mmol) as a yellow gum. LCMS: retention time = 2.76, (M-H) 593 EXAMPLE 13
N-benzyl-_V-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-
4-yl)methyl]-2-oxopyrrolidin-3-yl}urea
Figure imgf000074_0001
The procedure described in Example 10 was followed using N-benzyl-N'-{3-{4-[(2,5- dimethylbenzyl)oxy]phenyl } - 1 - [(4-methyl-2,5 -dioxo- 1 - { [2-
(frimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}urea (prepared below) (0.294 g, 0.421 mmol) to give N-benzyl-N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}- l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}urea (0.0357 g, 0.063 mmol). LCMS: retention time = 2.30-2.32, (M-H) 568. ΝMR: 1H ΝMR (400MHz, DMSO): 1.2 (dd, 3H), 2.25 (s, 6H), 2.7 (m, 2H), 3.2 (m, IH), 3.35 (m, IH), 3.53 (m, IH), 3.75 (m, IH), 4.15 (s, 2H), 5.00 (s, 2H), 6.55 (s, IH), 6.65 (s, IH), 6.98 (m, 2H), 7.05 (d, IH), 7.10 (d, IH), 7.20 (m, 4H), 7.3 (m, 4H), 7.9- 8.3 (m, 2H).
The preparation of Ν-benzyl-Ν'-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5- dioxo- 1 - { [2-(trimethylsilyl)ethoxy]methyl} imidazolidin-4-yl)methyl] -2-oxopyrrolidin-3- yl}urea is described as follows: i) Benzyl isocyanate (0.054 ml, 0.44 mmol) was added to a solution of 5-[(3-amino-3-{4- [(2,5-dimethylbenzyl)oxy]phenyl}-2-oxopyrrolidin-l-yl)methyl]-5-methyl-3-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (prepared as described under Example 10) (0.25 g, 0.44 mmol) in 1,4-dioxane (12 ml) and the mixture stirred for 1.5h. The mixture was taken up in EtOAc and washed with water. The organics were dried (MgSO4) and reduced in vacuo to give N-benzyl-N'-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl- 2,5-dioxo-l-{[2-(trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3- yl}urea (0.294 g, 0.421 mmol) as a yellow foam. LCMS: retention time = 3.11, (M+H) 700, (M-H) 698. EXAMPLE 14
N-{3-{4-[(2,5-dimethylbenzyl)o__y]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4- yl)methyl]-2-oxopyrrolidin-3-yl}-2-phenylacetamide
Figure imgf000075_0001
The procedure described in Example 10 was followed using N-{3-{4-[(2,5- dimethylbenzyl)oxy]phenyl} - 1 -[(4-methyl-2,5-dioxo- 1 - { [2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}-2- phenylacetamide (prepared below) (0.379 g) to give N-{3-{4-[(2,5- dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-2- oxopyrrolidin-3-yl}-2-phenylacetamide (0.0553 g, 0.010 mmol). LCMS: retention time = 2.36, (M-H) 553. ΝMR: 1H ΝMR (DMSO) 1.19 (dd, 3H), 2.25 (s, 6H), 2.6 (m, IH), 3.1 - 3.35 (m, 2H), 3.4 - 3.55 (m, 3H), 3.7 (dd, IH), 4.6 (d, IH), 5.0 (s, 2H), 6.98 (m, 2H), 7.04 (d, IH), 7.1 (d, IH), 7.17 - 7.30 (m, 6H), 7.35 (m, 2H), 7.98 (d, IH), 8.33 (dd, IH), 10.6 (d, IH).
The preparation of Ν-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}-2- phenylacetamide is described as follows: i) 5-[(3-amino-3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-2-oxopyrrolidin-l-yl)methyl]-5- methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}imidazolidine-2,4-dione (prepared as described in Example 10) (0.25 g, 0.44 mmol) was dissolved in pyridine (5 ml) and cooled to 0°C. 2,2- dimethylpropanoic phenylacetic anhydride (0.486 g, 2.21 mmol) was added slowly and the reaction stirred at RT for 1.5h. The reaction mixture was partitioned between EtOAc and water, the organics reduced in vacuo and then redissolved in EtOAc and washed again with water (2 x 20 ml), 2M HCl (20 ml) then water (3 x 20 ml) and finally brine (20 ml). The organics were dried (MgSO4) and reduced in vacuo to give N-{3-{4-[(2,5- dimethylbenzyl)oxy]phenyl} - 1 - [(4-methyl-2,5-dioxo- 1 - { [2- (trimethylsilyl)ethoxy]methyl}imidazolidin-4-yl)methyl]-2-oxopyrrolidin-3-yl}-2- phenylacetamide (0.379 g) as a yellow gum. LCMS: retention time = 3.16, (M-H) 683, (M+H) 685
The starting material 2,2-dimethylpropanoic phenylacetic anhydride was prepared using the method provided in Tet Lett, 1990, 31 , (7), 995
EXAMPLE 15
5-[(3-{4-[(2-methylquinolin-4-yl)methoxy]piperidin-l-yl}-2-oxopyrrolidin-l- yl)methyl]imidazolidine-2,4-dione
Figure imgf000076_0001
To a stirred solution of (3-{4-[(2-methylquinolin-4-yl)methoxy]piperidin-l-yl}-2- oxopyrrolidin-l-yl)acetaldehyde (prepared below) (60 mg, 0.157 mmol) in EtOH (2 ml) and water (2 ml) was added ammonium carbonate (90 mg, 0.945 mmol) and potassium cyanide (20 mg, 0.314 mmol). The mixture was heated to 60 °C for 16h, then evaporated under reduced pressure to give a yellow gum. The crude product was purified by flash silica chromatography eluting with a gradient of 25% to 50% (5% triethylamine in MeOH) in EtOAc, to yield as a mixture of diastereoisomers the title compound as an off-white solid (51.5 mg, 73% yield). NMR: 1.53 (m, 2H), 1.80 - 2.10 (m, 4H), 2.25 (m, IH), 2.56 - 2.73 (m, 2H), 2.65 (s, 3H), 3.17 - 3.56 (m, 6H), 4.98 (s, 2H), 7.43 (s, IH), 7.54 (t, IH), 7.94 (d, IH), 7.97 (d, IH), 8.04 (d, IH), 10.80 (br s, IH). MS (M+H)+ 452.
The starting material (3-{4-[(2-methylquinolin-4-yl)methoxy]piperidin-l-yl}-2-oxopyrrolidin- l-yl)acetaldehyde was prepared as follows : (i) To a stirred solution of [(2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl]amine (1.94g, 14.8mmole), triethylamine (5.16ml, 37mmole) in DMA (20ml) at 0°C under an inert atmosphere was added 2,4-dibromobutanoyl chloride (2.15ml, 16.3mmole) drop-wise. The mixture was allowed to warm to RT and stirred for 2h, sodium hydride (1.77g, 29.6mmole) was added and the resultant mixture stirred for 2h and evaporated under reduced pressure. The residue was partitioned between EtOAc (2 x 200 ml) and saturated aqueous sodium hydrogen carbonate solution (200 ml), water (200ml) and brine (200ml), the combined organic phases were dried (Na2SO ) and evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with a gradient of 10% to 100% EtOAc in iso-hexane, to yield as a mixture of diastereoisomers, 3-bromo-l-[(2,2-dimethyl- l,3-dioxolan-4-yl)methyl]pyrrolidin-2-one as an orange gum (2.044g, 80% yield). IH NMR (400.132 MHz, CDC13) δ 1.34 (s, 3H), 1.44 (d, 3H), 2.32 (m, IH), 2.59 (m, IH), 3.33 (m, IH), 3.46 - 3.79 (m, 4H), 4.06 (m, IH), 4.28 (m, IH), 4.42 (m, IH). MS (M+H)+ 277.95. (ii) To a stirred solution of 3-bromo-l-[(2,2-dimethyl-l,3-dioxolan-4- yl)methyl]pyrrolidin-2-one (215mg, 0.77mmole) and 2-methyl-4-[(piperidin-4- yloxy)methyl]quinoline§ (198mg, 0.77mmole) inNMP (2ml) under an inert atmosphere was added DIPEA (0.335ml, 1.92mmole). The mixture was allowed to stir at RT for 3h, heated to 100°C for 16h, then allowed to cool and partitioned between EtOAc (2 x 100ml) and water (2 x 100ml), the organic phases were combined, washed with brine (100ml), dried (Na2SO4) and evaporated under reduced pressure to yield a brown oil. The crude product was purified by flash silica chromatography eluting with a gradient of 0% to 50% MeOH in EtOAc to yield as a mixture of diastereoisomers, l-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]-3-{4-[(2- methylquinolin-4-yl)methoxy]piperidin-l-yl}pyrrolidin-2-one as a yellow gum (164mg, 47% yield). IHNMR (400.132 MHz, DMSO) δ 1.25 (s, 3H), 1.33 (d, 3H), 1.56 (m, 2H), 1.92 (m, 3H), 2.07 (m, IH), 2.29 (m, IH), 2.66 (s, 3H), 2.68 (m, 2H), 2.99 (m, IH), 3.19 - 3.47 (m, 5H), 3.55 (m, 2H), 3.96 (t, IH), 4.19 (m, IH), 4.98 (s, 2H), 7.44 (s, IH), 7.54 (t, IH), 7.70 (t, IH), 7.94 (d, IH), 8.03 (d, IH). MS (M+H)+ 454. (iii) l-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]-3-{4-[(2-methylquinolin-4- yl)methoxy]piperidin-l-yl}pyrrolidin-2-one (300mg, 0.66mmole) was solubilised in 2M aqueous hydrochloric acid (5ml) and stirred at RT for 90min. Saturated aqueous sodium hydrogen carbonate solution (100 ml) was added then the product extracted with DCM (2 x 100ml), the combined organic extracts were washed with brine (100ml) dried (MgSO4) and evaporated under reduced pressure to yield as a mixture of 4 diastereoisomers l-(2,3- dihydroxypropyl)-3-{4-[(2-methylquinolin-4-yl)methoxy]piperidin-l-yl}pyrrolidin-2-one as a yellow gum (192mg, 70% yield). IH NMR (400.132 MHz, DMSO) δ 1.55 (m, 2H), 1.80 - 2.10 (m, 4H), 2.25 (m, IH), 2.66 (s, 3H), 2.66 (m, 2H), 2.96 (m, IH), 3.02 - 3.33 (m, 5H), 3.37 (t, 2H), 3.50 (m, IH), 3.62 (m, IH), 4.53 (t, IH), 4.73 (d, IH), 4.98 (s, 2H), 7.44 (s, IH), 7.54 (t, IH), 7.70 (t, IH), 7.94 (d, IH), 8.03 (d, IH). MS (M+H)+ 414. (iv) To a stirred solution of l-(2,3-dihydroxypropyl)-3-{4-[(2-methylquinolin-4- yl)methoxy]piperidin-l-yl}pyrrolidin-2-one (162mg, 0.39mmole) in MeOH (5ml) was added sodium periodate (168mg, 0.79mmole) as a suspension in water (1ml). The mixture was allowed to stir at RT for 2h then evaporated under reduced pressure and the residue partitioned between DCM (2 x 75ml) and water (2 x 75ml), the organic phases were combined, washed with brine (100ml), dried (MgSO4) and evaporated under reduced pressure to yield (3- {4-[(2-methylquinolin-4-yl)methoxy]piperidin- 1 -yl} -2-oxopyrrolidin- 1 - yl)acetaldehyde as a yellow gum (149mg, 100% yield).
§ CAS Registry number 647036-81-5, synthesis of TFA salt described in WO2004024698.
EXAMPLE 16 Carbamic acid, [l-[(2,5-dioxo-4-imidazolidinyl)methyl]-3-[4-[(2-methyl-4- quinolinyl)_nethoxy]phenyl]-2-oxo~3-pyrrolidinyl]-, 1,1-dimethylethyl ester
Figure imgf000078_0001
The title compound (CAS registry 675199-46-9) was prepared according to the route described in WO2004024721.

Claims

CLAIMSWe claim:
1. A compound of formula (I):
formula (I) or a pharmaceutically acceptable salt thereof: wherein:
Y1 and Y2 are independently O or S; z is -NR8- or -NHC(O)- which -NHC(O)- is bonded to C=Y2 through N and to CR7(CR5R6)n through C; n is 0, 1 or 2; m is 1, 2, 3 or 4; r is 0, 1 or 2; t is O or l;
A is arylene, heteroarylene or heterocyclylene;
X is absent, -O-, -S-, -SO-, -SO2-, -NR14-, -C(O)NR14-, -NR14C(O)-, SO2NR14, -NR14SO2-,
-CH2-CH2- or -CH≡CH-;
B is a group selected from aryl, heteroaryl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, cyano, Cι.4alkyl (optionally substituted by R9 or Ci. alkoxy or one or more halo), C2- alkenyl (optionally substituted by halo or R9), C2-4alkynyl
(optionally substituted by halo or R9), C3-6cycloalkyl (optionally substituted by R9 or one or more halo), C5-6cycloalkenyl (optionally substituted by halo or R9), aryl (optionally substituted by halo or C1- alkyl), heteroaryl (optionally substituted by halo or C1-4alkyl), heterocyclyl (optionally substituted by Cwalkyl), -SR11, -SOR11, -SO2Ru, ~SO2NR9R10, -NR9SO2Rπ, -
NHC(O)NR9R10, -OR9, -NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is C2.4alkenyl or C2.
4alkynyl, each being optionally substituted by a substituent group selected from Cι. alkyl,
C3.6cycloalkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl which substituent group is optionally substituted by one or more halo, nitro, cyano, trifluoromethyl, trifluoromethoxy,
-C(O)NHR9, -C(O)NR9R10, -SO2Rn, -SO2NR9R10, -NR9SO2Rn, C^alkyl or Cι.4alkoxy groups;
R1, Rla, Rlb and Rlc are independently selected from hydrogen, Cι.6alkyl and C3.6cycloalkyl;
R2 is selected from hydrogen, halo, heterocyclyl, -OR12, -C(O)R12, -C(O)OR12, -NR12R13, - NR12C(O)R13, -C(O)NR1 R13, -NR1 C(O)NR12R13, -NR12C(O)OR13 and Cι.4alkyl which
Cι.4alkyl is optionally substituted by halo, cyano, heterocyclyl, -OR12, -C(O)R12, -C(O)OR12,
-NR12R13, -NC(O)R12 or -C(O)NR1 R13;
R3, R4, R5 and R6 are independently hydrogen or a group selected from Cι.6alkyl, C2-6alkenyl,
C2.6alkynyl, C3.6cycloalkyl, C5.6cycloalkenyl, aryl, heteroaryl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cι.4alkyl, C2.4alkenyl, C2_4alkynyl,
C3.6cycloalkyl (optionally substituted by one or more R17), aryl (optionally substituted by one 17 1 1 R or more R ), heteroaryl (optionally substituted by one or more R ), heterocyclyl, -OR , -SR19, -SOR19, -SO2R19, -C(O)R19, -C(O)OR18, -C(O)NR18R20, -NR16C(O)R18, - SO2NR18R20, -NR16SO2R19 and -NR18R19; or R3 and R4 together with the carbon atom to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 which ring is optionally substituted on carbon by Cι.4alkyl, fluoro or Cι.3alkoxy and/or on nitrogen by -C(O)Cι_3alkyl or -SO2Ci-3alkyl or Cι- alkyl; or R3 and R5 together with the carbon atoms to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 which ring is optionally substituted on carbon by Cι.4alkyl, fluoro or Cι_3alkoxy and/or on nitrogen by -C(O)C1.3alkyl or -SO2Cι.3alkyl or C1.4alkyl; or R5 and R6 together with the carbon atom to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 which ring is optionally substituted on carbon by Cι_4alkyl, fluoro or Cι.3a_koxy and/or on nitrogen by -C(O)C1.3alkyl or -SO2Cι.3alkyl or Cι.4alkyl; R7 is hydrogen or a group selected from Cι-6alkyl, C2.6alkenyl, C2.6alkynyl, heteroalkyl, C3- cycloalkyl, aryl, heteroaryl or heterocyclyl which group is optionally substituted by a substituent group selected from halo, Cι.4alkyl, Cι.4alkoxy, C3- cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroalkyl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, C1.4alkyl, nitro, haloCι. alkyl, heteroalkyl, aryl, heteroaryl, hydroxyC1.4alkyl, C3.7cycloalkyl, heterocyclyl, C1.4alkoxyC1.4alkyl, haloC1. alkoxyC1.4alkyl, -C(O)C1. alkyl, -OR21, -NR21R22, -C(O)OR21, -SR23, -SOR23, -SO2R23, -NR21C(O)R22, -C(O)NR21R22 and -NHC(O)NR21R22; ^ e £: or R and R together with the carbon atoms to which they are each attached and (CR R )n form a saturated 5- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 where the ring is optionally substituted on carbon by Cι. alkyl, fluoro or Cι_3alkoxy and/or on nitrogen by -C(O)C1-3alkyl or -SO2C1-3alkyl or Cι. alkyl;
R8 is hydrogen or methyl; R9 and R10 are independently hydrogen, Cι.6alkyl or C3-6cycloalkyl; or R9 and R10 together with the nitrogen to which they are attached form a heterocyclic 4- to
7-membered ring;
R11 is Cι.6alkyl or C3-6cycloalkyl;
R12, R13 and R16 are independently hydrogen, Cι.6alkyl, aryl and arylCι.4alkyl and may be optionally substituted by one or more halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, Cι.6alkylsulphonyl, Cι-6alkylsulphonylamino, Cι. alkyl, C .6alkenyl, C2-6alkynyl,
Cι.6alkoxy, Cι.6alkylamino and di-[Cι.6alkyl] amino;
R14 is hydrogen, C,.4alkyl, -C(O)Cι.4alkyl, -C(O)NH2, -SO2Cι.4alkyl;
R17 is selected from halo, Cι.6alkyl, C3-6cycloalkyl and Cι_6alkoxy; R18 is hydrogen or a group selected from Cι.6alkyl, C3.6cycloalkyl, C5.6cycloalkenyl, saturated heterocyclyl, aryl, heteroaryl, arylCι.4alkyl and heteroarylCi- alkyl which group is optionally substituted by one or more halo;
R19 and R23 are independently a group selected from Cμ6alkyl, C3.6cycloalkyl, C5-
6cycloalkenyl, saturated heterocyclyl, aryl, heteroaryl,
Figure imgf000081_0001
and heteroarylCι. alkyl which group is optionally substituted by one or more halo;
R20 is hydrogen, Cι-6alkyl or C3.6cycloalkyl; or R18 and R together with the nitrogen to which they are attached form a heterocyclic 4- to 7- membered ring;
R21 and R22 are independently hydrogen, Cι-4alkyl, haloC1- alkyl, aryl and arylCι. alkyl; provided that when z is -NHC(O)- then R7 is not hydrogen; and provided that when z is -NR8-, m is 2; A is phenylene; R2 is hydrogen, -NR12R13 or Cι. alkyl 1 1 1 which Cι.4alkyl is optionally substituted by halo, -OR or -NR R ; and r is 0; then X is not -O-.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Claim 1 wherein:
Y1 and Y2 are independently O or S; z is -NR8- or -NHC(O)- which -NHC(O)- is bonded to C=Y2 through N and to CR7(CR5R6)„ tlirough C; n is 0, 1 or 2; m is 1, 2, 3 or 4; r is 0, 1 or 2; t is O or 1;
A is arylene or heteroarylene;
X is absent, -O-, -S-, -SO-, -SO2-, -NR14-, -C(O)NR14-, -NR14C(O)-, SO2NR14, -NR14SO2-, -CH2-CH2- or -CH≡CH-;
B is a group selected from aryl, heteroaryl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, cyano, C1. alkyl (optionally substituted by R9 or C
4alkoxy or one or more halo), C2. alkenyl (optionally substituted by halo or R ), C2. alkynyl (optionally substituted by halo or R9), C3_6cycloalkyl (optionally substituted by R9 or one or more halo), Cs.6cycloalkenyl (optionally substituted by halo or R9), aryl (optionally substituted by halo or C1-4alkyl), heteroaryl (optionally substituted by halo or Cι. alkyl), heterocyclyl (optionally substituted by Cι_4alkyl), -SR11, -SOR11, -SO2Rn, -SO2NR9R10, -NR9SO2Ru, - NHC(O)NR9R10, -OR9, -NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is C2- alkenyl or C2_ alkynyl, each being optionally substituted by a substituent group selected from Cι-4alkyl, C3. 6cycloalkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl which substituent group is optionally substituted by one or more halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, - ι> ,,-,„„ PCT/GB2005/000759 82
C(O)NHR9, -C(O)NR9R10, -SO2Rn, -SO2NR9R10, -NR9SO2Rπ,
Figure imgf000083_0001
groups;
R1, Rla, Rlb and Rlc are independently selected from hydrogen, C1.6alkyl and C3.6cycloalkyl; R2 is selected from hydrogen, halo, heterocyclyl, -OR12, -C(O)R12, -C(O)OR12, -NR12R13, - NR12C(O)R13, -C(O)NR12R13 and Ci-4alkyl which Cι.4alkyl is optionally substituted by halo, cyano, heterocyclyl, -OR12, -C(O)R12, -C(O)OR12, -NR12R13, -NC(O)R12 or-C(O)NR12R13; R3, R4, Rs and R6 are independently hydrogen or a group selected from Cι.6alkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C5-6cycloalkenyl, aryl, heteroaryl and heterocyclyl which group is optionally substituted by one or more substituent groups independently selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cι.4alkyl, C2-4alkenyl, C2- alkynyl, 17
C3-6cycloalkyl (optionally substituted by one or more R ), aryl (optionally substituted by one 17 1 1 R or more R ), heteroaryl (optionally substituted by one or more R ), heterocyclyl, -OR , -SR19, -SOR19, -SO2R19, -C(O)R19, -C(O)OR18, -C(O)NR18R20, -NR16C(O)R18, - SO2NR18R20, -NR16SO2R19 and -NR18R19; or R3 and R4 together with the carbon atom to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 which ring is optionally substituted on carbon by Cι.4alkyl, fluoro or Cι-3alkoxy and/or on nitrogen by -C(O)Cι_3alkyl or -SO2C1.3alkyl or Cι.4alkyl; or R3 and R5 together with the carbon atoms to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 which ring is optionally substituted on carbon by Cι.4alkyl, fluoro or C1.3a.koxy and/or on nitrogen by -C(O)Cι.3alkyl or -SO2Cι_3alkyl or Cι. alkyl; or R5 and R6 together with the carbon atom to which they are attached form a saturated 3- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 which ring is optionally substituted on carbon by Cι. alkyl, fluoro or C^alkoxy and/or on nitrogen by -C(O)C1.3alkyl or -SO2C1.3alkyl or Cι.4alkyl;
R7 is hydrogen or a group selected from C^a-kyl, C2-6alkenyl, C2.6alkynyl, heteroalkyl, C3-7cycloalkyl, aryl, heteroaryl or heterocyclyl which group is optionally substituted by a substituent group selected from halo, Cι.4alkyl, C1.4alkoxy, C3.7cycloalkyl, heterocyclyl, aryl, heteroaryl and heteroalkyl; and which group is optionally substituted on the group and/or on its optional substituent group by one or more substituents independently selected from halo, cyano, Cι.4alkyl, nitro, haloCι_ alkyl, heteroalkyl, aryl, heteroaryl,
Figure imgf000083_0002
C3.7cycloalkyl, heterocyclyl,
Figure imgf000084_0001
haloC1- alkoxyC1-4alkyl, -C(O)Ci.4alkyl, -OR21, -NR21R22, -C(O)OR21, -SR23, -SOR23, -SO2R23, -NR21C(O)R22, -C(O)NR21R22 and -NHC(O)NR21R22; or R3 and R7 together with the carbon atoms to which they are each attached and (CR5R6)n form a saturated 5- to 7-membered ring optionally containing a heteroatom group selected from NH, O, S, SO and SO2 where the ring is optionally substituted on carbon by Cι.4alkyl, fluoro or Cι-3alkoxy and/or on nitrogen by -C(O)Cι-3alkyl or -SO2C1-3alkyl or Cι.4alkyl; R8 is hydrogen or methyl;
R9 and R10 are independently hydrogen, Cι.6alkyl or C3.6cycloalkyl; or R9 and R10 together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring; R11 is Cι_6alkyl or C3.6cycloalkyl; R12, R13 and R16 are independently hydrogen or Cι.6alkyl; R14 is hydrogen, Ci.4alkyl, -C(O)C1.4alkyl, -C(O)NH2, -SOzC^alkyl; 1 R is selected from halo, Chalk ., C3.6cycloalkyl and Cι.6alkoxy;
R18 is hydrogen or a group selected from Cι.6alkyl, C3.6cycloalkyl, C5.6cycloalkenyl, saturated heterocyclyl, aryl, heteroaryl, arylCι.4alkyl and heteroarylCι.4alkyl which group is optionally substituted by one or more halo;
R19 and R23 are independently a group selected from Chalky., C3.6cycloalkyl, C5. 6cycloalkenyl, saturated heterocyclyl, aryl, heteroaryl, arylCι_ alkyl and heteroarylCι_4alkyl which group is optionally substituted by one or more halo; 9Ω
R is hydrogen, Cι.6alkyl or C3_6cycloalkyl; or R18 and R20 together with the nitrogen to which they are attached form a heterocyclic 4- to 7- membered ring; R21 and R22 are independently hydrogen, Cι.4alkyl, haloCι_4alkyl, aryl and arylCι.4alkyl; provided that when z is -NHC(O)- then R is not hydrogen; and provided that when z is -NR8-, m is 2; A is phenylene; R2 is hydrogen, -NR12R13 or Cι- alkyl which
Figure imgf000084_0002
; and r is 0; then X is not -O-.
3. A compound according to claim 1 or claim 2 wherein Y is O, Y is O, z is -NR - and
R is hydrogen.
4. A compound according to any preceding claim wherein n is 0.
5. A compound according to any one ofthe preceding claims wherein t is 1.
6. A compound according to any one ofthe preceding claims wherein B is a group selected from aryl, heteroaryl, carbocyclyl and heterocyclyl where each group is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, Cι.4alkyl (optionally substituted by one or more halo), C2- alkynyl, heteroaryl, -OR9, cyano, -NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is C2.4alkenyl or C2.4alkynyl optionally substituted by Cι- alkyl, C3-6cycloalkyl or heterocyclyl.
7. A compound according to any one of claims 1 to 5 wherein B is a group selected from bicyclic aryl or bicyclic heteroaryl where each group is optionally substituted by one or more substituent groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, Cι. alkyl (optionally substituted by one or more halo), C2.4alkynyl, heteroaryl, -OR9, cyano, - NR9R10, -C(O)NR9R10 and -NR9C(O)R10; or B is C2. alkenyl or C2.4alkynyl optionally substituted by Cι.4alkyl, C3-6cycloalkyl or heterocyclyl.
8. A compound according to any one of claims 1 to 5 wherein B is 2-methylquinolin-4-yl or 2,5-dimethylphenyl.
9. A compound according to any one ofthe preceding claims wherein R is hydrogen, - OR12, -C(O)OR12, -NR12R13, -NR12C(O)R13, -NR12C(O)NR12R13, -NR12C(O)OR13, methyl or ethyl which methyl or ethyl are optionally substituted by cyano, -OR12, -C(O)OR12, -NR12R13 or -NR12C(O)R13.
10. A compound according to claim 9 wherein R2 is hydrogen, amino, methyl, formyl, acetamido, benzoylamino, benzylcarbonylamino, ureido, 3-methylureido, 3-phenylureido, 3-benzylureido and t-butoxycarbonylamino.
11. A compound according to any one ofthe preceding claims wherein R is selected from hydrogen, Cι.4alkyl, haloC1. alkyl,
Figure imgf000085_0001
and aryl.
12. A compound ofthe formula (I) according to claim 1 selected from:
5-[(3-Methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)methyl]imidazolidine-2,4-dione; 5-{3-Methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo-piperidin-l- ylmethyl}imidazolidine-2,4-dione;
5-(3-{3-Methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo-piperidin-l- yl}propylimidazolidine-2,4-dione;
5-Methyl-5-{3-Methyl-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxo-piperidin-l- ylmethyl} imidazolidine-2,4-dione;
5-Methyl-5-[(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)methyl]imidazolidine-2,4-dione;
5 - { 3 -Methyl-3 - [4-(2-methylquinolin-4-ylmethoxy)phenyl] -2-oxo-piperidin- 1 -ylethyl } - imidazolidine-2,4-dione; 5-[2-(3-methyl-3-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2-oxoazetidin-l- yl)ethyl]imidazolidine-2,4-dione; tert-butyl {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4- yl)methyl] -2-oxopyrrolidin-3 -yl} carbamate ;
5-[3-Methyl-2-oxo-3-(4-phenylethynyl-phenyl)-pyrrolidin-l-ylmethyl]-imidazolidine-2,4- dione;
N- {3- {4- [(2,5 -dimethylbenzyl)oxy]phenyl} - 1 -[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl] -
2-oxopyrrolidin-3-yl} acetamide;
N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-
2-oxopyrrolidin-3-yl}-N-methylurea; {3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]-2- oxopyrrolidin-3-yl}formamide;
N-benzyl-N- { 3- {4- [(2,5-dimethylbenzyl)oxy]phenyl} - 1 - [(4-methyl-2,5-dioxoimidazolidin-4- yl)methyl] -2-oxopyrrolidin-3 -yl} urea;
N-{3-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-l-[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]- 2-oxopyrrolidin-3 -yl} -2-phenylacetamide ;
5 - [(3 - {4- [(2-methylquinolin-4-yl)methoxy]piperidin- 1 -yl} -2-oxopyrrolidin- 1 - yl)methyl]imidazolidine-2,4-dione; and Carbamic acid, [ 1 - [(2,5 -dioxo-4-imidazolidinyl)methyl] -3 - [4- [(2-methyl-4- quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidinyl]-, 1,1-dimethylethyl ester.
13. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically-acceptable diluent or carrier.
14. A compound according to claim 1 for use as a medicament.
15. The use of a compound according to claim 1 in the manufacture of a medicament for use in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy.
16. A method of treating autoimmune disease, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound according to claim 1.
17. A process for the preparation of a compound of formula (I) or a pharmaceutically 1 9 R acceptable salt or in vivo hydrolysable ester thereof wherein Y and Y are both O, z is -NR - and R8 is hydrogen, which comprises converting a ketone or aldehyde of formula (II) into a hydantoin of formula (I);
Figure imgf000087_0001
- , /u formula (I) formula (II) ' or wherein Y1 and Y2 are both O and z is -NH(CO)- (as described herein), which comprises converting a diester of formula (III) wherein Y is -CR7(C(O)OC1.1oalkyl)2 into a pyrimidine- 2,4,6(lH,3H,5H)-trione of formula (I);
Figure imgf000088_0001
formula (III) formula (') and thereafter if necessary: i) converting a compound of formula (I) into another compound of formula (I); and/or ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
PCT/GB2005/000759 2004-03-06 2005-03-01 Hydantoin derivatives for use as tace and aggrecanase inhibitors WO2005085232A1 (en)

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