WO2003053958A1 - Derives de quinazolinedione - Google Patents

Derives de quinazolinedione Download PDF

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WO2003053958A1
WO2003053958A1 PCT/GB2002/005770 GB0205770W WO03053958A1 WO 2003053958 A1 WO2003053958 A1 WO 2003053958A1 GB 0205770 W GB0205770 W GB 0205770W WO 03053958 A1 WO03053958 A1 WO 03053958A1
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group
optionally substituted
alk
methoxy
oxazol
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PCT/GB2002/005770
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English (en)
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Hazel Joan Dyke
Marianna Dilani Richard
Alan Findlay Haughan
Andrew Sharpe
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Celltech R & D Limited
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Priority claimed from GB0130585A external-priority patent/GB0130585D0/en
Priority claimed from GB0204137A external-priority patent/GB0204137D0/en
Application filed by Celltech R & D Limited filed Critical Celltech R & D Limited
Priority to AU2002352444A priority Critical patent/AU2002352444A1/en
Publication of WO2003053958A1 publication Critical patent/WO2003053958A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to a series of quinazolinediones and their derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • IMPDH lnosine-5'-monophosphate dehydrogenase
  • NAD ⁇ -nicotinamide adenine dinucleotide
  • XMP xanthosine-5'-monophosphate
  • Guanine nucleotides are essential to the cell for RNA and DNA synthesis, intermediates in signalling pathways and as energy sources for metabolic pathways.
  • IMPDH is ubiquitous in eukaryotes, bacteria and protozoa (Y. Natsumeda & S.F. Carr, Ann. N.Y. Acad.. 696, pp. 88-93, (1993)).
  • IMPDH type I and type II form active tetramers in solution, with subunit molecular weights of 56 kDa (Y. Yamada et. al., Biochemistry, 27, pp. 2737-2745, (1988)). It is thought that type I is the predominant isoform expressed in normal cells, whilst type II is upregulated in neoplastic and replicating cells. Studies have postulated that selective inhibition of type II IMPDH could provide a therapeutic advantage by reducing potential toxicity effects caused by inhibiting the type I isoform (Pankiewicz K.W, Expert Opin. Ther. Patents 11 (7) pp 1161 -1170, (2001)).
  • IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
  • MPA Mycophenolic acid
  • Kj 33 nM
  • MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen (A.C. Allison et. al., Ann. N. Y. Acad. Sci.. 696, 63, (1993) ).
  • Immunosuppressants such as MPA are useful drugs in the treatment of transplant rejection and autoimmune diseases.
  • MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity.
  • Mycophenolate mofetil a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute allograft rejection following kidney transplantation (i.e. renal allograft failure) and heart transplantation.
  • kidney transplantation i.e. renal allograft failure
  • heart transplantation i.e. renal allograft failure
  • Mycophenolate mofetil has also been used for the treatment of rheumatoid arthritis.
  • mycophenolate mofetil has also been described (R. Bentley, Chem. Rev.. 100, pp. 3801-3825, (2000)).
  • Mycophenolate mofetil has also been postulated to be of use for the treatment of atopic dermatitis (Grundmann-Kollman M et al, Archives of Dermatology. 137 (7), pp.
  • Nucleoside analogues such as tiazofurin, bavirin and mizoribine also inhibit IMPDH (L. Hedstrom, et. al., Biochemistry. 29, pp. 849-854, (1990) ). These nucleoside analogues are competitive inhibitors of IMPDH, but also inhibit other NAD dependant enzymes. This lack of specificity limits the therapeutic application of these compounds. New agents with improved selectivity for IMPDH would represent a significant improvement over these nucleoside analogues.
  • Mizorbine (Bredinin®) has been approved in Japan for multiple indications in transplantation and autoimmune diseases including prevention of rejection after renal transplantation, idiopathic glomerulonephritis, lupus nephritis and rheumatoid arthritis.
  • Vertex has recently disclosed a series of novel IMPDH inhibitors (WO 97/40028), of which VX-497 has been evaluated for the treatment of psoriasis.
  • IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumour cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy (M. Nagai et. al., Cancer Res.. 51 , pp. 3886-3890, (1991), Pankiewicz K.W., Exp. Opin. Ther. Patents. 11 , pp. 1161-1170, (2001) ). IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases (CR. Gregory et. al., Transplantation. 59, pp. 655-61 , (1995); PCT publication WO 94/12184; and PCT publication WO 94/ 01105).
  • IMPDH has been shown to play a role in viral replication in some virus-infected cell lines. (S.F. Carr, J. Biol. Chem.. 268, pp. 27286-27290, (1993) ). VX-497 is currently being evaluated for the treatment of hepatitis C in humans. Thus, there remains a need for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-inflammatory agents, antipsoriatic and anti-viral agents.
  • WO98/56770 generally discloses the synthesis of a class of substituted quinazolinediones. However, these are not disclosed for use as IMPDH inhibitors.
  • the present inventors disclose new potent IMPDH inhibitors based on substituted quinazolinedione derivatives.
  • X and Y which may be the same or different, is each an O or S atom;
  • R 1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group;
  • R 2 is an optionally substituted heteroaromatic group;
  • R 3 is the group -Alk 1 -L 1 -Alk 2 -R 4 in which Alk 1 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain, L 1 is a covalent bond or a linker atom or group, Alk 2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and
  • R 4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers or N-oxides thereof.
  • certain compounds of formula (1 ) may exist as geometric isomers (E or Z isomers).
  • the compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers.
  • the invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates.
  • Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
  • Quinazolinediones may also exist as tautomers, one possible example is illustrated below:
  • the compounds of the invention may be administered in a pharmaceutically acceptable pro-drug form, for example, as a protected carboxylic acid derivative, e.g. as an acceptable ester.
  • the pro-drugs may be converted in vivo to the active compounds of formula (1), and the invention is intended to extend to such pro-drugs.
  • Such prodrugs are well known in the literature, see for example International Patent Application No. WO 00/23419, Bodor N. (Alfred Benson Symposium, 1982, 17, 156-177), Singh G. et al (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard H. (Design of Prodrugs, 1985, Elsevier, Amsterdam).
  • aliphatic group is intended to include optionally substituted straight or branched C M oalkyl, e.g. C 1 - 6 alkyl, C 2 - ⁇ oalkenyl e.g. C ⁇ -ealkenyl or C- 2 - 10 alkynyi e.g. C 2 - 6 alkynyl groups.
  • Optional substituents when present on these groups include those optional substituents mentioned hereinafter.
  • alkyl whether present as a group or part of a group includes straight or branched d-ioalkyl groups, for example Ci- ⁇ alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl or neopentyl groups.
  • Optional substituents when present on those groups include those optional substituents mentioned hereinafter.
  • alkenyl or “alkynyi” are intended to mean straight or branched C 2 - 10 alkenyl or C- 2 - ⁇ oalkynyl groups such as or C 2 - 6 alkynyl groups such as -CHCH 2 , -CHCHCH 3 , -CH 2 CHCHCH 3 , -CCH, -CH 2 CCH and -CH 2 CCCH 3 groups. Such groups may be substituted by those optional substituents mentioned hereinafter.
  • aliphatic groups include optionally substituted C ⁇ -6 alkyl groups such as -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2> - CH 2 C(CH 3 ) 3 , -C(CH 3 ) 3 , -(CH 2 ) 4 CH 3 , -(CH 2 ) 5 CH 3 , or or C 2 - 6 alkynyl groups such as -CHCH 2 , -CHCHCH 3 , -CH 2 CHCH 2 , -CHCHCH 2 CH 3 , -CH 2 CHCHCH 3 , -(CH 2 ) 2 CHCH 2 , -CCH, -CCCH 3 , -CH 2 CCH, -CCCH 2 CH 3 , -CH 2 CCCH 3
  • aliphatic chain is intended to include those alkyl, alkenyl or alkynyi groups as just described where a terminal hydrogen atom is replaced by a covalent bond to give a divalent chain.
  • aliphatic chains include optionally substituted Ci- 6 alkylene chains such as -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -,-(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 -,
  • More particular examples include optionally substituted d- 3 alkylene chains selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 - and -CH 2 CH(CH 3 )- chains.
  • Heteroaliphatic chains represented by Alk 1 or Alk 2 in the compounds of formula (1) include the aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L 3 where L 3 is a linker atom or group.
  • L 3 is a linker atom or group.
  • Each L 3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
  • Particular examples include optionally substituted -L 3 CH 2 -, -CH 2 L 3 -, -L 3 CH(CH 3 )-, -CH(CH 3 )L 3 -, -CH 2 L 3 CH 2 -, -L 3 CH 2 CH 2 -, -L 3 CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 L 3 -, -CH 2 CH 2 L 3 -, -CH 2 L 3 CH 2 CH 2 -, -CH 2 L 3 CH 2 CH 2 L 3 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 -, -L 3 (CH 2 ) 2 CH 2 -, -L 3 CH 2 CHCH-, -CHCHCHCH 2 L 3 -, -(CH 2 ) 2 L 3 CH 2 -, -(CH 2 ) 3 L 3 CH 2 -, -L 3 (CH 2 ) 2 CH 2 -, -
  • L 3 When L 3 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(S)-, -S(O)-, -S(0) 2 -, -C(O)0-, -OC(O)-, -N(R 5 )- [where R 5 is a hydrogen atom or a straight or branched C h alky!
  • cycloaliphatic group includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C 3- ⁇ o ring systems, such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbomyl, norbomenyl, bicyclo[2.2.1]heptanyl or bicyclo[2.2.1]heptenyl.
  • Particular examples include optionally substituted C 3-6 cycloalkyl ring systems such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • Optional substituents present on those groups include those substituents mentioned hereinafter.
  • cycloalkyl-alkyl- group refers to a C ⁇ -6 alkyl group (as described herein) where a terminal hydrogen atom is replaced by a C3-6 cycloalkyl ring (as described herein). Examples include -(CH 2 ) ⁇ -6 -cyclopropyl, -(CH 2 ) 1-6 - cyclobutyl, -(CH 2 ) ⁇ -6 -cyclopentyl or -(CH 2 ) ⁇ - 6 -cyclohexyl.
  • heterocycloaliphatic group refers to an optionally substituted 3 to 10 membered saturated or partially saturated monocyclic or saturated or partially saturated multicyclic hydrocarbon ring system containing one, two, three or four L 2 linker atoms or groups.
  • L 2 atoms or groups include -O- or -S- atoms or -C(O)-, -C(0)O-, -OC(O)-, -C(S)-,
  • Optional substituents present on the heterocycloaliphatic groups include those substituents mentioned hereinafter.
  • heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e.g. 1 ,3- dioxolanyl, imidazolinyl, e.g.
  • 2-imidazolinyl imidazolidinyl, pyrazolinyl, e.g. 2- pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g.
  • Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom.
  • Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon or, where available, ring nitrogen atom.
  • R 4 in compounds of formula (1) is an optionally substituted heterocycloaliphatic or cycloaliphatic ring, these may optionally be fused to an optionally substituted monocyclic C 6-12 aromatic group, such as phenyl or an optionally substituted monocyclic C 1-9 heteroaromatic group, such as a 5 or 6 membered heteroaromatic group, containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • the optional substituents which may be present on the aliphatic, alkyl, alkenyl, alkynyi, cycloaliphatic or heterocycloaliphatic groups, described above and generally herein include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino(-NH 2 ), substituted amino, optionally substituted C 6-12 arylamino, -CN, -C0 2 H, -CO 2 R 6 (where R 6 is an optionally substituted C- ⁇ -6 alkyl group), -SO 3 H, -SOR 7 (where R 7 is a C 1 - 6 alkyl group) -SO 2 R 7 , -S0 3 R 7 , -OC0 2 R 7 , -C(0)H, -C(O)R 7 , -OC
  • the optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk 1 or Alk 2 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or -OH, -CN,
  • C 1-6 alkyl group e.g -CO 2 CH 3 or -CO 2 C(CH 3 ) 3 ; -CONHR 11 , e.g. -CONHCH 3 ; -CON(R 11 ) 2 , e.g. -CON(CH 3 ) 2 ; -COR 11 , e.g. -COCH 3 ; C ⁇ -6 alkoxy, e.g. methoxy or ethoxy; haloCi- ⁇ alkoxy, e.g. trifluoromethoxy or difluoromethoxy; thiol (-SH); -S(0)R 11 , e.g.
  • -S(O)CH 3 ; -S(O) 2 R 11 e.g. -S(0) 2 CH 3 ; C ⁇ -6 alkylthio e.g. methylthio or ethylthio; amino; -NHR 11 , e.g. -NHCH 3 or -N(R 11 ) 2 , e.g.
  • L 1 is present in compounds of formula (1) as a linker atom or group it may be any such atom or group as hereinbefore described in relation to L 3 linker atoms and groups.
  • Alk 1 in compounds of formula (1) is a covalent bond then L 1 , when present, is a -C(O)-, -C(S)-, -S(0) 2 -, -CON(R 5 )-, -CSN(R 5 )- or -S(0) 2 N(R 5 )- group, where R 5 is as herein defined.
  • R 5 , R 5a , R 7 , R 8 , R 9 or R 10 is present as a C ⁇ -6 alkyl group it may be a straight or branched C ⁇ - 6 alkyl group e.g. a C ⁇ - 3 alkyl group such as methyl, ethyl or /-propyl.
  • Optional substituents which may be present on R 11 include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or C ⁇ - 6 alkoxy e.g. methoxy or ethoxy groups.
  • halogen atom is intended to include fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF 3) -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, and -CH 2 CI groups.
  • alkoxy as used herein is intended to include straight or branched C M0 alkoxy for example C 1-6 alkoxy such as methoxy, ethoxy, ⁇ -propoxy, /-propoxy and f-butoxy.
  • "Haloalkoxy” as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCF 3 , -OCCI 3 , -OCHF 2 , -OCHCI 2 , -OCH 2 F and -OCH 2 CI groups.
  • alkylthio is intended to include straight or branched C 1-10 alkylthio, e.g. C 1-6 alkylthio such as methylthio or ethylthio groups.
  • aromatic group and "aryl group” are intended to include for example optionally substituted monocyclic ring C 6-12 aromatic groups, such as phenyl, or bicyclic fused ring C 6-12 aromatic groups, such as, 1- or 2-naphthyl groups.
  • heteroaromatic group and “heteroaryl group” are intended to include for example optionally substituted C- ⁇ -9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms (or oxidised versions thereof).
  • the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups.
  • Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example eight- to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Each of these aromatic or heteroaromatic groups may be optionally substituted by one, two, three or more R 12 atoms or groups as defined below.
  • monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.
  • bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl or phthalazinyl.
  • R 2 or R 4 heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
  • Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R 12 in which R 12 is -R 12a or -Alk 3 (R 12a ) f , where R 12a is a halogen atom, or an amino (-NH 2 ), substituted amino, nitro, cyano, hydroxyl (-OH), substituted hydroxyl, amidino, formyl, carboxyl (-CO 2 H), esterified carboxyl, thiol (-SH), substituted thiol, -COR 13 [where R 13 is an -Alk 3 (R 1 a ) f , heterocycloaliphatic, cycloaliphatic, aryl or heteroaryl group], -CSR 13 , -S0 3 H, -SOR 13 , -S0 2 R 13 , -S0 3 R 13 , -SO 2 NH 2 , -S
  • Alk 3 is a straight or branched C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(O) g - [where g is an integer 1 or 2] or -N(R 14 )- groups; and f is zero or an integer 1 , 2 or 3. It will be appreciated that when two R 13 or R 14 groups are present in one of the above substituents, the R13 or R groups may be the same or different.
  • t f is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R 12a may be present on any suitable carbon atom in -Alk 3 . Where more than one R 12a substituent is present these may be the same or different and may be present on the same or different atom in -Alk 3 . Clearly, when f is zero and no substituent R 12a is present the chain represented by Alk 3 becomes a corresponding group.
  • R 1 a is a substituted amino group it may be for example a group -NHR 13 [where R 13 is as defined above] or a group -N(R 13 ) 2 wherein each R 13 group is the same or different.
  • R 1 a is a substituted hydroxyl or substituted thiol group it may be for example a group -OR 13 or a -SR 13 group respectively.
  • Esterified carboxyl groups represented by the group R 12a include groups of formula -CO 2 Alk 4 wherein Alk 4 is an optionally substituted C 1 - 6 alkyl group.
  • Alk 3 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, /-propylene, n-butylene, /-butylene, s-butylene, t- butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O)-, -S(0) 2 - or -N(R 15 )- groups.
  • f is the integer 1
  • 2 or 3 more particular examples include C ⁇ -3 alkylene chains, especially -CH 2
  • each may be for example an optionally substituted 2- or 3-pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, imidazolinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group.
  • Het 2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group.
  • Optional substituents which may be present on -NHet 1 or -Het 2 include those substituents described above in relation to aromatic groups.
  • Particularly useful atoms or groups represented by R 12 include fluorine, chlorine, bromine or iodine atoms, or C -6 alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl or piperidinyl, C ⁇ ehydroxyalkyl, e.g.
  • carboxyC 1-6 alkyl e.g. carboxyethyl, C -6 alkylthio e.g. methylthio or ethylthio, carboxyC 1-6 alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3- carboxypropylthio, C 1-6 alkoxy, e.g. methoxy or ethoxy, hydroxyC ⁇ alkoxy, e.g.
  • 2-hydroxyethoxy optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C 5-7 cycloalkoxy, e.g. cyclopentyloxy, haloC ⁇ alkyl, e.g. trifluoromethyl, haloC 1-6 alkoxy, e.g. thfluoromethoxy, C 1-6 alkylamino, e.g. methylamino or ethylamino, amino (-NH2), aminoC 1-6 alkyl, e.g. aminomethyl or aminoethyl, C 1-6 dialkylamino, e.g.
  • aminoC 1-6 alkylamino e.g. aminoethylamino, Het 1 NC ⁇ - 6 alkylamino e.g. morpholinopropylamino, C 1-6 alkylaminoC 1-6 alkyl, e.g. ethylaminoethyl, C 1-6 dialkylaminoC 1-6 alkyl, e.g. diethylaminoethyl, aminoC 1-6 alkoxy, e.g. aminoethoxy, C 1-6 alkylaminoC 1-6 alkoxy, e.g.
  • methylaminoethoxy C 1-6 dialkylaminoCi- ⁇ alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, hydroxyC 1-6 alkylamino e.g. hydroxyethylamino, imido, such as phthalimido or naphthalimido, e.g. 1 ,8- naphthalimido, nitro, cyano, amidino, formyl [HC(O)-], carboxyl (-C0 2 H), -C ⁇ 2 Alk 4 [where Alk 4 is as defined above], C-
  • C 1-6 alkylaminosulphonyl e.g. methylamino-sulphonyl or ethylaminosulphonyl
  • C 1-6 dialkylaminosulphonyl e.g. dimethyl-aminosulphonyl or diethylaminosulphonyl, optionally substituted phenylamino-sulphonyl, carboxamido (-CONH 2 )
  • C 1-6 alkylaminocarbonyl e.g. methylamino-carbonyl or ethylaminocarbonyl
  • C -6 dialkylaminocarbonyl e.g.
  • dimethylaminocarbonylamino or diethyl- aminocarbonylamino C 1-6 alkylaminocabonylC 1-6 alkylamino, e.g. methylamino- carbonylmethylamino, aminothiocarbonylamino, C 1-6 alkylaminothiocarbonyl- amino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C ⁇ . 6 dialkylaminothiocarbonylamino, e.g.
  • Ci- ⁇ alkyl- sulphonylamino e.g. methylsulphonylamino or ethylsulphonylamino
  • C 1-6 dialkyl sulphonylamino e.g.
  • dimethylsulphonylamino or diethylsulphonyl-amino optionally substituted phenylsulphonylamino, aminosulphonylamino (-NHSO 2 NH 2 ), C ⁇ alkylaminosulphonylamino, e.g. methylamino sulphonylamino or ethylaminosulphonylamino, C 1-6 dialkylamino sulphonylamino, e.g. dimethylaminosulphonylamino or diethylamino sulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC ⁇ .
  • two adjacent R 12 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 - 6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • a cyclic group such as a cyclic ether, e.g. a C ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 - 6 cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • R 12 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
  • Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
  • Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
  • optionally substituted alkyl groups present in ester groups of formulae -C0 2 R 6 and -C0 2 Alk 4 include C ⁇ -6 alkyl groups as herein described, in particular C ⁇ -3 alkyl groups.
  • Optional substituents, which may be present on these alkyl groups include optionally substituted cycloaliphatic, aromatic or heteroaromatic groups as herein defined.
  • Particular examples include optionally substituted C 3 - 6 cycloalkyl wherein the optional substituents include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or Ci-e alkoxy e.g.
  • substituents include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine, straight or branched Ci- ⁇ alkyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CO 2 CH 3) C0 2 CH 2 CH 3 , -CO 2 C(CH3) 3) or -COCH 3 , -NHCOCH3, -N(CH 3 )COCH 3 or CO 2 H.
  • One useful group of compounds of the invention has the formula (1) wherein both X and Y is each a S atom.
  • a particularly preferred group of compounds has the formula (1) wherein X is an O atom and Y is a S atom.
  • Another preferred group of compounds has the formula (1) wherein both X and Y is each an O atom.
  • Examples of aliphatic groups, which may represent R 1 include C ⁇ -6 alkyl groups as herein described. More particular examples include C ⁇ -3 alkyl groups, such as -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 )CH 3 .
  • Examples of cycloaliphatic groups which may represent R 1 include C 3-6 cycloalkyl groups, such as those described previously.
  • cycloalkyl-alkyl- groups which may represent R 1 include C ⁇ -3 alkyl groups (as described herein) where a terminal hydrogen atom is replaced by a C 3-6 cycloalkyl ring (as described herein), for example, cyclopropylCH 2 -.
  • R 1 is in particular a Ci-e alkyl group. Especially preferred is when R 1 is a C ⁇ -3 alkyl group. Most especially preferred is when R 1 is a methyl group.
  • R 1 is in particular a haloalkyl group. Especially preferred is when R 1 is a CHF 2 or CH 2 F group.
  • a particularly preferred group of compounds of the invention has the formula (1) wherein R 2 is an optionally substituted monocyclic heteroaromatic group, especially a five-membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Particular preferred heteroaromatic groups which may represent R 2 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or pyrazolyl.
  • R 2 is an oxazolyl group.
  • R 3 is preferably represented by the groups -Alk 1 - L 1 -Alk 2 -R 4 , -Alk 1 -L 1 -R 4 , -Alk 1 -R 4 , -L 1 -Alk 2 -R 4 , -L 1 -R 4 or -R 4 wherein Alk 1 , L 1 , Alk 2 and R 4 are as herein defined.
  • a particularly preferred group of compounds of the invention has the formula (1) wherein R 3 is the group -Alk 1 -L 1 -R 4 .
  • Another group of compounds of the invention has the formula (1) wherein R 3 is the group -Alk 1 -L 1 -Alk 2 -R 4 .
  • Alk 1 is a covalent bond or an optionally substituted aliphatic chain, in particular a C ⁇ -6 alkylene chain, especially an optionally substituted -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )- chain, most especially a C ⁇ -3 alkylene chain such as -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Alk 2 when present in compounds of formula (1), is preferably a C ⁇ -3 alkyl chain as defined herein.
  • One particular group of compounds of the invention has the formula (1 ) wherein Alk 2 is a covalent bond.
  • L 1 when present in compounds of formula (1), include -O- or -S- atoms or -C(0>, -C(S)-, -S(O)-, -S(O) 2 -, -C(0)0-, -OC(O)-, -N(R 5 )- [where R 5 is as defined hereinbefore], -CON(R 5 )-, -CSN(R 5 )-, -N(R 5 )CO-, -N(R 5 )CS-, -S(0) 2 N(R 5 )- or -N(R 5 )S(O) 2 - groups.
  • R 5 is especially a hydrogen atom or a C ⁇ -3 alkyl group, particularly a methyl group.
  • R 4 in one particular group of compounds of formula (1 ), is a hydrogen atom or an optionally substituted C 3-6 cycloalkyl, 3 to 10 membered saturated monocyclic heterocycloaliphatic, especially 3 to 6 membered, phenyl or 5 to 6 membered heteroaromatic group.
  • More particular examples include a hydrogen atom or an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C ⁇ - 6 alkylpiperazinyl, especially N- methylpiperazinyl, ⁇ /-C ⁇ -6 alkylpyrrolidinyl, especially ⁇ /-methylpyrrolidinyl, N- Ci- 6 alkylpiperidinyl, especially ⁇ /-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imi
  • R 3 is the group -Alk 1 -L 1 -R 4 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a covalent bond and R 4 is a hydrogen atom.
  • Alk 1 in compounds of this type preferably forms an optionally substituted straight or branched C ⁇ -6 alkyl chain such as those as herein defined, especially optionally substituted -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 - or -CH 2 C(CH 3 ) 2 -.
  • Optional substituents which may be present on these groups include those as herein defined for Alk 1 substituents, especially -CN, -C0 2 H, -CO 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , C ⁇ -6 alkoxy, particularly methoxy or ethoxy; haloC ⁇ -6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R 11 , -S(O) 2 R 11 , amino, -NHR 11 or -N(R 11 ) 2 , groups.
  • R 11 is in particular a C ⁇ -3 alkyl group.
  • Alk 1 is an optionally substituted -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 - chain and the optional substituent is a -NH(CH 3 ) or -N(CH 3 ) 2 group, especially a -N(CH 3 ) 2 group.
  • Further preferred substituents include -CN, -CO 2 H, -C0 2 CH 3 , -CO 2 CH 2 CH 3 , -C0 2 C(CH 3 ) 3 , -CONH 2 , -CONHCH 3 or -CON(CH 3 ) 2 .
  • R 3 in another particular group of compounds of this type is a -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or - CH 2 C(CH 3 ) 3 group, especially a -CH 3 group.
  • R 3 is the group -Alk 1 -L 1 -R 4 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a covalent bond and R 4 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group especially an optionally substituted heterocycloaliphatic, aromatic or heteroaromatic group.
  • Alk 1 in compounds of this type is in particular a C ⁇ -3 alkyl chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • R 4 in compounds of this type is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or monocyclic heteroaromatic group.
  • Particular R 4 examples include optionally substituted azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C 1-6 alkylpiperazinyl, especially ⁇ /-methylpiperazinyl, ⁇ /-C ⁇ - 6 alkylpyrrolidinyl, especially ⁇ /-methylpyrrolidinyl, ⁇ /-C1-6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl
  • R 4 is a morpholinyl, pyrrolidinonyl, ⁇ /-methylpiperazinyl, tetrahydropyranyl, imidazolyl, pyridyl, pyrrolidinyl, pyrazolyl, piperidinyl or N- methylpyrrolidinyl group.
  • R 3 in another group of compounds of formula (1) is the group -Alk 1 -L 1 -R 4 in which Alk 1 is a covalent bond or an optionally substituted aliphatic chain, L 1 is a linker group and R 4 is an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • L 1 in compounds of this type is especially a -C(O)-, -C(S)- or -S(0) 2 group or a -CON(R 5 )- or - N(R 5 )CO- group.
  • R 4 is an optionally substituted phenyl or monocyclic heteroaromatic group, especially a 5 to 6 membered heteroaromatic group.
  • R 4 is in particular an optionally substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group.
  • R 3 is the group -Alk 1 -L 1 -Alk 2 -R 4 in which Alk 1 is an optionally substituted aliphatic chain, L 1 is a linker atom or group, Alk 2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and R 4 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group.
  • Alk 1 in compounds of this type preferably forms an optionally substituted straight or branched C ⁇ -6 alkylene chain such as those as herein defined, especially optionally substituted -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 2 CH 2 -, -(CH 2 ) 3 CH 2 - or -CH 2 C(CH 3 ) 2 -;
  • L 1 is preferably -O-, -C(O)-, -C(S)-, -S(O) 0 - 2 -, -N(R 5 )- [where R 5 is a hydrogen atom or a straight or branched C 1 - 6 alkyl group, especially methyl], -CON(R 5 )-, -CSN(R 5 )-, -N(R 5 )CO-, -N(R 5 )CS-, -S(0) 2 N(R 5 )- or -N(R 5 )S(O) 2 -;
  • Alk 1 is most preferably a C ⁇ -3 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; L 1 is most preferably -O-, - N(R 5 )-, -CON(R 5 )- or -N(R 5 )CO- [where R 5 is especially a hydrogen atom or a methyl group] and Alk 2 is most preferably a covalent bond or an optionally substituted C ⁇ - 3 alkylene chain, especially -CH 2 -, CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Optional substituents which may in particular be present on Alk 2 include -CN, -C0 2 H, -C0 2 R 11 [where R 11 is as herein defined] -CONHR 11 , -CON(R 11 ) 2 , -COR 11 , d- ⁇ alkoxy, particularly methoxy or ethoxy; haloC ⁇ . 6 alkoxy, particularly trifluoromethoxy or difluoromethoxy; -S(O)R 11 , -S(O) 2 R 11 , amino, -NHR 11 or -N(R 11 ) 2 , groups.
  • R 11 is in particular a C 1-3 alkyl group.
  • One group of optional substituents which may be present on cycloaliphatic or heterocycloaliphatic groups in compounds of formula (1) and in particular on the group R 4 are one, two, three or more groups selected from Ci- 3 alkoxy, OCF 3 , OCF 2 H, CF 3 , Ci -3 alkylthio, -CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , C0 2 CH 3 , CO 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , or -COCH 3 , -NHCOCH 3 , -N(CH 3 )COCH 3> CO 2 H or optionally substituted straight or branched C 1-3 alkyl, wherein the optional alkyl substituent is in particular a CN, C ⁇ -3 alkoxy, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 )
  • One group of optional substituents which may be present on aromatic or heteroaromatic groups in compounds of formula (1) and in particular in R 4 aromatic or heteroaromatic groups, are one, two, three or more atoms or groups selected from fluorine, chlorine, bromine, straight or branched C ⁇ -6 alkyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2> C0 2 CH 3 , C0 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , or -COCH 3 , - NHCOCH 3 , -N(CH 3 )COCH 3 , -SCH 3 , -SO 2 CH 3 , C0 2 H or optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, wherein the optional substituent is
  • Particular compounds of the invention include:
  • Compounds of formula (1) are potent inhibitors of IMPDH.
  • the ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
  • the compounds of the invention may be used in the treatment of IMPDH- associated disorders.
  • the invention extends to such a use and in general to the use of the compounds of formula (1) for the manufacture of a medicament for treating such diseases and disorders.
  • IMPDH-associated disorders refers to any disorder or disease state in which inhibition of the enzyme IMPDH (inosine monphosphate dehydrogenase, EC1.1.1.205, of which there are presently two known isozymes referred to as IMPDH type 1 and IMPDH type 2) would modulate the activity of cells (such as lymphocytes or other cells) and thereby ameliorate or reduce the symptoms or modify the underlying cause(s) of that disorder or disease. There may or may not be present in the disorder or disease an abnormality associated directly with the IMPDH enzyme.
  • IMPDH inosine monphosphate dehydrogenase
  • IMPDH-associated disorders include transplant rejection and autoimmune disorders, such as rheumatoid arthritis, lupus, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory disorders, cancer and tumors, T-cell mediated hypersensitivity diseases, ischemic or reperfusion injury, viral replication diseases, proliferative disorders and vascular diseases.
  • Use of the compounds of the present invention is exemplified by, but is not limited to, treating a range of disorders such as: treatment of transplant rejection (e.g. kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • transplant rejection e.g. kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitus), pyoderma gangrenum, lupus (systemic lupus erythematosis), myasthenia gravis, psoriasis, eczema, dermatitis, dermatomyosis, atopic dermatitis; multiple sclerosis, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, Addison's disease (autoimmune disease of the adrenal glands), idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as
  • IMPDH is also known to be present in bacteria and thus may regulate bacterial growth.
  • the IMPDH-inhibitor compounds of the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.
  • the compounds of the present invention are useful for the treatment of the afore mentioned exemplary disorders irrespective of their etiology, for example, for the treatment of lupus, psoriasis, inflammatory bowl disease, multiple sclerosis, atopic dermatitis, transplant rejection or rheumatoid arthritis.
  • the compounds of the present invention are of particular use for the treatment of DNA or RNA viral replication diseases, such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • the compounds of the present invention are of particular use for the treatment of cancer and tumour disorders, such as solid tumors, lymphoma, leukemia and other forms of cancer.
  • the compounds of formula (1) can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.
  • therapeutic or prophylactic agents such as anti-virals, anti-inflammatory agents, antibiotics, anticancer agents and immunosuppressants.
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions of this invention comprise a compound formula (1) or a salt thereof; an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, anti-inflammatory agent, anti-fungal agent, anti-vascular hyperproliferation agent or an antibiotic agent; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, OKT3, ATAG, interferon and mizoribine.
  • Additional anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxantheres.
  • Additional anti-viral agents include, but are not limited to, Cytovene, Ganiclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT and acyclovir.
  • Additional anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, and rapamycin.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, vaginal or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • compositions for oral administration may be suitably formulated to give controlled release of the active compound
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen- free water, before use.
  • the compounds of formula (1) may be coated on particles such as microscopic gold particles.
  • the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • suitable propellant e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • the compounds of formula (1) may be formulated as a suppository.
  • These formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at room temperature but liquid at the body temperature.
  • suitable non-irritating excipient include for example cocoa butter and polyethylene glycols.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-known standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.
  • R 1 -R 3 when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated.
  • reactive functional groups for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in “Protective Groups in Organic Synthesis", John Wiley and Sons, (1999) and the examples herein].
  • deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
  • Compounds of formula (1 ) in which X is O and Y is S may be prepared according to one of several general methods, including the methods shown in Scheme B and Scheme C. The starting materials for these routes are the amines of formula (ii).
  • Amines of general formula (ii) may be prepared in a variety of ways.
  • the amine of formula (ii) where R 1 is a methyl group and R 2 is an oxazole group may be prepared using methods known in the literature, (CAS 198821-79-3).
  • a compound of formula (iii), where Z is a halogen atom e.g. CI or Br or a suitable leaving group e.g. trifluoromethylsulfonyloxy (OTf) and - NRR' is a nitro group or an amine group (which may be suitably protected), may be reacted with a derivative of the desired heteroaromatic group (R 2 -W, where W is as described below) utilising a palladium catalysed cross coupling reaction.
  • R 2 -W where W is as described below
  • the resulting coupled product may require further manipulation, depending on the nature of the -NRR' group, in order to obtain an amine of formula (ii).
  • an amine of formula (ii) For example, when -NRR' is a nitro group this may be reduced to an amine using standard techniques, or when -NRR' is a protected amine the protecting group may be removed using standard methodology.
  • the various R 2 -W derivatives are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compounds of formula (iii) are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compound of formula (iii) may be prepared by alkylation of the phenol precursor of (iii) using standard techniques.
  • bromides of formula (iv) may be treated with zinc cyanide in the presence of a suitable catalyst, e.g. a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), in an appropriate solvent, such as DMF ( ⁇ /, ⁇ /-dimethylformamide). It may be appropriate to carry out such a reaction at elevated temperature, such as 100°C.
  • a suitable catalyst e.g. a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • an appropriate solvent such as DMF ( ⁇ /, ⁇ /-dimethylformamide).
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • Nitriles of formula (v) may be converted into amides of formula (vi) by hydrolysis, for example using sodium perborate tetrahydrate in aqueous methanol at elevated temperature, for example 50°C.
  • Thioureas of formula (vii) may be obtained from amides of formula (vi) by treatment with an isothiocyanate of formula (viii) in a suitable solvent, such as acetone, at an appropriate temperature, such as reflux temperature.
  • Thioureas of formula (vii) may be converted into compounds of formula (1) by cyclisation. Cyclisation may be achieved using an adaptation of the method described by Chan and Shish (Heterocycles, 1987, 26, 3193). Thus, heating a thiourea of formula (vii) with sodium hydroxide in aqueous ethanol provides a compound of formula (1).
  • R a in a thiourea of formula (vii) is an acyl group, such as p-tolylmethanoyl, it is lost during the reaction and a compound of formula (1) in which R 3 is H will be produced.
  • Amides of formula (vi) may be prepared using a variety of alternative procedures known to those skilled in the art, including the methods described in a recent patent application, WO0181340. Standard functional group interconversions known to those skilled in the art may be employed.
  • esters of formula (ix) may be treated with thiophosgene in the presence of a suitable base, such as triethylamine, in an appropriate solvent such as dichloromethane to provide an isothiocyanate of formula (x). Heating an isothiocyanate of formula (x) with an amine of formula (xi) in an appropriate solvent, such as THF, at a suitable temperature, such as reflux temperature, provides a compound of formula (1).
  • Esters of formula (ix) may be prepared by any suitable method known to those skilled in the art, including the methods described in a recent patent application, WO0181340. Amines of formula (xi) may be commercially available, previously described compounds, or prepared using any standard method known to those skilled in the art.
  • amines of formula (ix) may be treated with triphosgene in the presence of a suitable base such as triethylamine in an appropriate solvent such as dichloromethane to afford intermediate isocyanate (xii). This may be reacted, without isolating, with an amine of formula (xi) to yield ureas of formula (xiii). The urea thus formed may then be heated to reflux in a mixture of ethanol and water in the presence of sodium hydroxide to afford the desired quinazolinedione of general formula (1).
  • a suitable base such as triethylamine in an appropriate solvent such as dichloromethane
  • ureas of formula (xiii) may then be heated to reflux in a mixture of ethanol and water in the presence of sodium hydroxide to afford the desired quinazolinedione of general formula (1).
  • the ureas of formula (xiii) may be heated to reflux in a solvent such as ethylene glycol dimethyl ether with a non-nucleophilic, non-hydrolysing base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene to yield the diones of formula (1 ).
  • a solvent such as ethylene glycol dimethyl ether
  • a non-nucleophilic, non-hydrolysing base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene
  • amines of formula (xiv) may be treated with a commercially available chloroformate of formula (xv) using a suitable base such as di/sopropylethylamine in an appropriate solvent such as dichloromethane to give a carbamate of formula (xvi).
  • a suitable base such as di/sopropylethylamine in an appropriate solvent such as dichloromethane
  • the free acid in compounds of formula (xvi) may then be coupled with amines of formula (xi) using standard conditions known to those skilled in the art to give an amide of formula (xvii).
  • Appropriate coupling conditions may involve the use of a coupling reagent such as pyBOP ® (benzotriazol-1-yloxytris (pyrrolidino)phosphonium hexafluorophosphate) in the presence of suitable base such as diisopropylethylamine in a suitable solvent such as dichloromethane.
  • suitable base such as diisopropylethylamine
  • suitable solvent such as dichloromethane.
  • the amides of formula (xv) may then be heated in an appropriate solvent such as DMF to afford the desired quinazolinediones of general formula (1).
  • amines of formula (xiv) may be reacted with an acylating reagent attached to an inert support (represented by the black circle in Scheme F), such as a polystyrene resin, employing for example hydroxymethyl polystyrene p-nitrophenylcarbonate (xviii) and N- methylmorpholine (NMM) in DCM, to give an intermediate resin-bound carbamate (xix).
  • an acylating reagent attached to an inert support (represented by the black circle in Scheme F)
  • an inert support represented by the black circle in Scheme F
  • an inert support represented by the black circle in Scheme F
  • the free acids (xix) may then coupled with amines of formula (xi) using standard conditions such as PyBOP in the presence of a suitable base such as di-/so-propylethylamine in a suitable solvent such as dichloromethane or ⁇ /-methylpyrrolidinone to give resin-bound amides of formula (xx). Heating compounds of formula (xx) in an appropriate solvent such as DMF cleaves the desired quinazolinediones of formula (1) from the resin.
  • a suitable base such as di-/so-propylethylamine
  • a suitable solvent such as dichloromethane or ⁇ /-methylpyrrolidinone
  • substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of any of formula (1) or any preceding intermediates where appropriate functional groups exist in these compounds.
  • ester groups such as -C0 2 R 6 , -C0 2 R 11 or -C0 2 Alk 4 in the compounds may be converted to the corresponding acid [-CO 2 H] by acid- or base-catalysed hydrolysis depending on the nature of the groups R 6 , R 1 or Alk 4 .
  • Acid- or base- catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
  • an acid [-CO 2 H] may be prepared by hydrolysis of the corresponding nitrile [-CN], using for example a base such as sodium hydroxide in a refluxing alcoholic solvent, such as ethanol.
  • -OH groups may be generated from the corresponding ester [e.g. CO 2 Alk 4 or C0 2 R 11 ] or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
  • a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
  • an alcohol may be prepared by reduction of the corresponding acid [-C0 2 H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.
  • trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon e.g., dichloromethane to yield the corresponding chloride.
  • a base e.g., triethylamine may also be used in the reaction.
  • alcohol or phenol groups may be converted to ether groups groups by coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine
  • an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • ether groups may be prepared by deprotonation of an alcohol, using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkylhalide.
  • Aldehyde [-CHO] groups may be obtained by oxidation of a corresponding alcohol using well known conditions.
  • an oxidising agent such as a periodinane e.g. Dess Martin
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane.
  • An alternative oxidation may be suitably activating dimethyl sulfoxide using for example, oxalyl chloride, followed by addition of an alcohol, and subsequent quenching of the reaction by the addition of an amine base, such as triethylamine.
  • Suitable conditions for this reaction may be using an appropriate solvent, for example, a halogenated hydrocarbon, e.g. dichloromethane at -78°C followed by subsequent warming to room temperature.
  • primary amine (-NH 2 ) or secondary amine (-NH-) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • amine [-NH 2 ] groups may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
  • a nitro [-N0 2 ] group may be reduced to an amine [-NH 2 ], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol
  • an acid such as hydrochloric acid
  • amine (-CH 2 NH 2 ) groups may be obtained by reduction of nitriles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic an ether, e.g. a cyclic ether such as tetrahydrofuran, at a temperature from -78°C to the reflux temperature.
  • a metal catalyst for example palladium on a support such as carbon, or Raney nickel
  • Aromatic halogen substituents in the compounds may be subjected to halogen- metal exchange by treatment with a base, for example a lithium base such as n-butyl or t- butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a base for example, a lithium base such as n-butyl or t- butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using dimethylformamide as the electrophile
  • a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
  • Aromatic halogen substituents may also be subjected to palladium
  • sulphur atoms in the compounds may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3- chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
  • an oxidising agent such as a peroxy acid, e.g. 3- chloroperoxybenzoic acid
  • an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane
  • N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid
  • an elevated temperature for example around 70°C to 80°C
  • a peracid such as peracetic acid in a solvent, e.g. dichloromethane
  • Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base or acid in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol or an aqueous solvent using conventional procedures. Salts of compounds of formula (1) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.
  • a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol or an aqueous solvent using conventional procedures.
  • Salts of compounds of formula (1) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.
  • diastereomeric derivatives e.g. salts
  • a mixture of enantiomers of formula (1) e.g. a racemate
  • an appropriate chiral compound e.g. a chiral base
  • the diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • 2-lsothiocvanato-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester To a solution of 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (1.0g) in dry DCM (60ml) under nitrogen cooled to -78°C was added TEA (1.2ml) followed by thiophosgene (0.34ml) dropwise. The reaction mixture was allowed to warm to 0°C and stirred for 30 mins.
  • Example 15 3-(7-Methoxy- ⁇ -oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-,2/-/-quinazolin-3-vD-propionic acid ethyl ester From Intermediate 5 (300mg), ⁇ -alanine ethyl ester hydrochloride (158mg) and TEA (0.29ml). Triturating with water afforded the title compound as an off- white solid (361 mg, 93%).
  • Example 23 r2-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4- dihvdro-2H-quinazolin-3-yl)-ethylamino1-acetic acid ethyl ester From Intermediate 5 (40mg), ⁇ /- ⁇ -aminoethylglycine ethyl ester.2HCI (30mg) and TEA (0.1 ml). Triturating with water and then purification by preparative HPLC afforded the title compound as an off-white solid (2mg).
  • Example 13 (87mg), lithium hydroxide hydrate (21 mg), water (1 ml), THF (2ml) and MeOH (2ml) were combined and stirred at room temperature for 16 hrs. Then heated to reflux for 6 hrs. The solvents were then removed in vacuo and the residue triturated with aqueous 1 N HCI to give the title compound as an off-white solid (82mg, 98%).
  • Example 27.4-(7-Methoxy-6-oxazol-5-yl-4-oxo-2-thioxo-1.4-dihvdro-2H- quinazolin-3-yl)-butyric acid From Example 14 (348mg), and lithium hydroxide (76mg). Triturating with aqueous 1 N HCI gave the title compound as an off-white solid (323mg, 96%).
  • Example 25 (20mg), 4-aminopyridine (6mg), TEA (10 drops), EDC (12mg), DMAP (1mg) and DMF (3ml) were combined and stirred at room temperature for 2 days. The reaction was then evaporated to dryness and purified by preparative HPLC to give the title compound as an off-white solid (2mg).
  • 1 H NMR 300MHz (d 6 -DMSO) 8.25 (3H, m), 8.15 (3H, m), 7.5 (2H, d), 7.4 (1 H, s), 6.75 (1 H, s), 5.25 (2H, s), 3.95 (3H, s).
  • Example 29 3-(3-Amino-propyh-7-methoxy-6-oxazol-5-yl-2-thioxo-
  • Example 24 To a suspension/solution of Example 24 (100mg) in DCM (20ml) was added trifluoroacetic acid (5ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue triturated in DCM/Et 2 O to afford the title compound as an off-white solid (97mg, 95%).
  • Example 29 To a suspension of Example 29 (50mg) in dry DCM (10ml) was added TEA (0.02ml) followed by nicotinic acid (14mg), EDC (26mg) and HOBT (18mg). DMF (5ml) was added and the mixture stirred at room temperature overnight. Trituration in water followed by trituration in DCM afforded the title compound as an off-white solid (28mg, 57%).
  • Example 37 7-Methoxy-6-oxazol-5-yl-3-(tetrahvdro-pyran-2- ylmethyl)-7H-quinazoline-2.4-dione
  • EtOH/water 15ml/2ml
  • NaOH NaOH
  • water 2ml
  • the resulting clear solution was heated at reflux for 3 hours.
  • the EtOH was removed in vacuo and the aqueous residue acidified to pH7 with aqueous 2M HCI.
  • the resulting precipitate was filtered off and dried in vacuo to yield by the title compound as a yellow solid (72mg, 75%).
  • Example 40 (7-Methoxy-6-oxazol-5-yl-2,4-dioxo-1,4-dihvdro-2H- quinazolin-3-yl)-acetonitrile From Intermediate 14 (98mg) and DBN (0.044ml). The resulting precipitate was filtered off, washed with DME and washed with Et 2 0 to yield the title compound as a white solid (56mg, 63%). TLC R f 0.40 (5% MeOH/DCM).
  • Example 42 ⁇ H7-Methoxy-6-oxazol-5-yl-2.4-dioxo-1.4-dihvdro-2H- quinazolin-3-yl)-ethyll-acetamide From Intermediate 16 (220mg) and DBN (0.086ml). The resulting precipitate was filtered off and triturated in hot MeOH to afford the title compound as a solid (175mg, 87%). TLC R f 0.29 (EtOAc).
  • Example 46 7-Methoxy-3-r3-(5-methyl-7H-pyrazol-4-yl)-propy ⁇ -6- oxazol-5-yl-7H-quinazoline-3.4-dione
  • 2-amino-4-methoxy-5-oxazol-5-yl-benzoic acid methyl ester (CAS 371251-37-5) (200mg) in dry THF (20ml) under nitrogen cooled to -78°C was added triphosgene (84mg) followed by TEA (0.23ml) dropwise.
  • the reaction mixture was allowed to warm to 0°C and stirred for 30 mins.
  • Hydroxymethylpolystyrene resin (10.2g, 100-2— mesh, 0.98gmol "1 ) was suspended in anhydrous DCM (120ml), treated with ⁇ /-Methylmorpholine (2.20ml) and cooled in an ice-bath. 4-Nitrophenylchloroformate (4.03g) was added in one portion and the mixture stirred in the ice bath for 5 minutes, then at room temperature for 18 hours. The resin was filtered under a nitrogen atmosphere, washed with DCM (4 x 40ml), and dried overnight in a vacuum desiccator. The resultant pale pink resin (12.3g) was placed in a round-bottomed flask.
  • DIPEA (10.5ml), HOBT (4.05g) and 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid (CAS 371251-38-6) (11.71g) were dissolved in a 1 :1 mixture of anhydrous DCM/DMF (200ml) and transferred onto the resin via cannular. After stirring at room temperature for 18 hours, the mixture was filtered, and the resin was washed with DMF (4 x 30ml) followed by DCM (4 x 30ml), then dried in a vacuum desiccator to constant weight, as a beige solid (11.56 g).
  • the resin thus produced was placed in a glass tube with DMF (1 ml), and heated to 125°C under an atmosphere of nitrogen for 16 hours.
  • the reaction mixture was then filtered into a tared flask, and the resin washed with DMF (2 x 2ml), then 1 :1 MeOH/DCM (3 x 2ml). Evaporation of the filtrate yielded the title compound as beige solid (4.6mg, 11%).
  • Example 55 3-Cvclopropylmethyl-7-methoxy-6-oxazol-5-yl-1 H- quinazoline-2.4-dione From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and aminomethylcyclopropane (71 mg). The title compound was obtained as an off-white solid (5.8mg, 19%). LCMS 314 [M+1] + , RT 2.86 mins.
  • Example 57 7-Methoxy-3-r2-(6-methoxy-1 H-indol-3-yl ⁇ ethvn-6- oxazol-5-yl-1 H-quinazoline-2.4-dione From the 2-amino-4-methoxy-5-oxazol-5-ylbenzoic acid loaded resin (116mg), and 6-methoxytryptamine (190mg). The title compound was obtained as an off-white solid (7.4mg, 17%). LCMS 433 [M+1] + , RT 3.08 mins.
  • Example 58 7-Methoxy-3-(2-methoxyethylj-6-oxazol-5-yl-1 H- quinazoline-2.4-dione
  • Example 40 To a solution of Example 40 (20mg) in dry DMF (3ml) was added sodium azide (5mg) and ammonium chloride (4mg). The mixture was heated at 120°C overnight. The solvent was removed in vacuo and the residue taken up in aqueous Na 2 CO 3 (20ml) and washed with EtOAc (20ml). The aqueous layer was acidified with aqueous 1N HCI and extracted with EtOAc (2 x 30ml). The combined organic layers were died over MgS04, filtered and the solvent removed in vacuo to afford the title compound as a solid (10mg, 44%).
  • Example 44 A solution of Example 44 (315mg) in formic acid (8ml) was stirred at room temperature for 4 hours. The mixture was taken up in water (20ml) and washed with Et 2 0 (20ml). The aqueous layer was basified with solid Na 2 C0 3 and washed with EtOAc (20ml). The aqueous layer was acidified to pH7 with aqueous 1 N HCI and the resulting solid filtered off and dried in vacuo to yield the title compound as a solid (150mg, 62%). TLC R f 0.03 (10% MeOH/DCM).
  • Example 64 2H-quinazolin-3-yl)-butv ⁇ -methanesulphonamide
  • methyl sulphonyl chloride 0.2ml
  • TEA 0.2ml
  • the mixture was heated at 60°C for 5 hours.
  • the mixture was concentrated in vacuo and the residue dissolved in EtOAc (50ml), washed with aqueous 1 N HCI, the organic layer was separated, dried over MgS0 4 , filtered and the solvent removed in vacuo. Purification by preparative HPLC afforded the title compound as a solid (1 mg, 1%).
  • Example 64 To a solution of Example 64 (56mg) in dry DCM / DMF (15ml / 3ml) under nitrogen was added TEA (0.04ml). The mixture was cooled to 0°C and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester (3S)-tetrahydro-furan-3-yl ester (CAS 138499-08-8) (43mg) was added in a single portion. The reaction mixture was allowed to warm to room temperature and stirred over the weekend. The solvents were removed in vacuo. Trituration in Et 2 0, trituration in MeOH, followed by purification by preparative HPLC afforded the title compound as a white solid (6.8mg, 9%).
  • the ability of the compounds of the invention to inhibit the IMPDH enzymes may be determined using the following assays:
  • IMPDH catalyses the NAD dependent oxidation of IMP to XMP with concomitant reduction of the cofactor.
  • IMPDH activity was determined by monitoring the production of the fluorescent product, NADH. Assays were performed in a final volume of 200/yl containing IMPDH (2/yg), NAD (100 /M), IMP (100/yM), 1% DMSO, 30mM KCl and 100mM Tris/HCI, pH7.5. Fluorescence (excitation 340nm / emission 465nm) was read continuously at 25°C for 30 minutes. From this data, initial rates (i.e. change in fluorescence intensity per minute) were calculated.
  • test compounds were prepared at an initial concentration of 1.0mM in 100% DMSO, then diluted in assay buffer to 0.2mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 20-fold into the assay, to allow testing across the range 0.3nM to 10 M.
  • Peripheral blood mononuclear cells were isolated from freshly taken human blood using standard procedures. Cells were plated out in RPMI medium containing 5% human serum in the presence and absence of inhibitor. PHA (25 ⁇ l of 30 ⁇ g/ml solution to each well) was added and the plates were incubated at 37°C in an atmosphere of 95% air/5% C0 for 48 hours. O. ⁇ Ci of tritiated thymidine was added to each well and the plates were incubated for a further 18 hours. The contents of the plate were transferred to a filter plate and the cells washed with saline. The plates were dried, microscintillation fluid was added to each well and the plate was counted on a scintillation counter. IC 50 values were calculated by plotting inhibitor concentration versus %inhibition.
  • the assay described above can be carried out using anti-CD3 (40 ⁇ l of 3750ng/ml concentration to each well) stimulation instead of PHA.

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Abstract

L'invention concerne un composé de formule (1), y compris les sels, solvates, hydrates, tautomères, isomères et N-oxydes correspondants. Dans ladite formule, X et Y, qui peuvent être identiques ou différents, représentent chacun un atome O ou S; R1 repésente un groupe aliphatique, cycloaliphatique ou cycloalkyle-alkyle; R2 représente un groupe hétéroaromatique éventuellement substitué; R3 représente le groupe Alk1-L1-Alk2-R4, dans lequel Alk1 est une liaison covalente ou bien une chaîne aliphatique ou hétéroaliphatique éventuellement substituée, L1 est une liaison covalente ou bien un bras ou un groupe de liaison, Alk2 est une liaison covalente ou bien une chaîne aliphatique ou hétéroaliphatique éventuellement substituée, et R4 est un atome d'hydrogène ou bien un groupe cycloaliphatique, hétérocycloaliphatique, aromatique ou hétéroaromatique éventuellement substitué. Ce type de composé est un puissant inhibiteur de l'inosine-5'-monophosphate déshydrogénase (IMPDH).
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US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
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