WO2003045901A2 - Guanidine derivatives - Google Patents

Guanidine derivatives Download PDF

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Publication number
WO2003045901A2
WO2003045901A2 PCT/GB2003/000339 GB0300339W WO03045901A2 WO 2003045901 A2 WO2003045901 A2 WO 2003045901A2 GB 0300339 W GB0300339 W GB 0300339W WO 03045901 A2 WO03045901 A2 WO 03045901A2
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Prior art keywords
phenyl
group
methoxy
optionally substituted
oxazol
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PCT/GB2003/000339
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French (fr)
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WO2003045901A3 (en
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Hazel Joan Dyke
George Martin Buckley
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Celltech R & D Limited
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Priority to AU2003202091A priority Critical patent/AU2003202091A1/en
Publication of WO2003045901A2 publication Critical patent/WO2003045901A2/en
Publication of WO2003045901A3 publication Critical patent/WO2003045901A3/en

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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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a series of guanidines, 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, ribavirin 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 (C.R. 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.
  • United States patent 6,420,403 (published 16 July 2002) discloses a class of guanidine derivatives as IMPDH inhibitors.
  • the present inventors disclose new potent IMPDH inhibitors based on substituted guanidine derivatives.
  • R 1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group
  • R 2 is an optionally substituted aromatic, heteroaromatic group, aryl- fused cycloaliphatic, heteroaryl-fused cycloaliphatic, aryl-fused heterocycloaliphatic or heteroaryl-fused heterocycloaliphatic group;
  • R 3 is a -CN, -COR 5 , -OR 6 , -CON(R 7 )R 8 , S0 2 R 5 or SO 2 N(R 7 )R 8 group, in which R 5 is an optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, R 6 is a hydrogen atom or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group and R 7 and R 8 , which may be the same or different, is each a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;
  • R 4 is an optionally substituted heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.
  • 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.
  • Guanidines may also exist as tautomers, for example compounds of formula (1) may exist in the tautomeric forms as 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).
  • formula (1) certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless specified otherwise.
  • aliphatic group is intended to include optionally substituted straight or branched C-i-ioalkyl, e.g. C -
  • Optional substituents when present on those groups include those optional substituents mentioned hereinafter.
  • aliphatic groups include optionally substituted C 1-6 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 C 2 - 6 alkenyl or C 2-6 alkynyl groups such as -CHCH 2 , -CHCHCHg, -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 1-6 al
  • aliphatic chain is intended to include those alkyl, alkenyl or alkynyl 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 C- ⁇ -6 alkylene chains such as -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH2-,-(CH 2 )2CH 2 -, -(CH 2 ) 3 CH 2 -,
  • heteroaliphatic group is intended to include the optionally substituted aliphatic groups just described but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L where L is a linker atom or group.
  • Each L 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.
  • suitable L 1 atoms or groups include -O- or -S- atoms or -C(O)-, -C(0)0-, -OC(O)-, -C(S)-, -S(O)-, - S(0) 2 -, -N(R 13 )- [where R 13 is a hydrogen atom or a C 1-6 alkyl group], - N(R13)N(R13)-, -N(R 3 )0-, -0N(R13)-, -CON(R 13 )-, -OC(0)N(Ri3)-, -CSN(R13)-, -N(R 3 )CO-, -N(R 13 )C(O)0-, -N(R 3 )CS-, -S(0) 2 N(R 13 )-,
  • 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 C 3 . 6 cycloalkyl ring (as described herein). Examples include -(CH 2 ) ⁇ -6-cyclopropyl, -(CH 2 ) ⁇ - 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 1 linker atoms or groups.
  • L 1 linker atoms or groups include those as just described.
  • 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.
  • the optional substituents which may be present on the aliphatic, alkyl, alkenyl, alkynyl, 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- i 2 arylamino, -CN, -CO 2 H, -C0 2 R 9a (where R 9a is an optionally substituted d- ⁇ alkyl group), -SO 3 H, -SOR 9 (where R 9 is a C 1 - 6 alkyl group) -S0 2 R 9 , -S0 3 R 9 , -OCO 2 R 9 , -C(0)H, -C(0)R 9 ,
  • R 9a , R 9 , R 10 , R 11 , R 12 or R 13 is present as a C 1-6 alkyl group it may be a straight or branched C 1 - 6 alkyl group e.g. a C1- 3 alkyl group such as methyl, ethyl or i-propyl.
  • Optional substituents which may be present on R 9a 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 , - CH 2 F, and -CH 2 CI groups.
  • alkoxy as used herein is intended to include straight or branched C 1-10 alkoxy for example C 1-6 alkoxy such as methoxy, ethoxy, n-propoxy, i- propoxy and t-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. Each of these aromatic groups may be optionally substituted by one, two, three or more R 14 atoms or groups as defined below.
  • heteroaromatic group and “heteroaryl group” are intended to include for example optionally substituted C 1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms (or oxidised versions therof).
  • 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, sulphur 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.
  • 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, pyridyl-N-oxide, tetrazolyl, or triazinyl.
  • 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.
  • aryl-fused cycloaliphatic group is intended to include for example optionally substituted monocyclic ring C 6-12 aromatic groups, such as phenyl fused to optionally substituted non-aromatic monocyclic, saturated or partially saturated C 3-10 ring systems.
  • monocyclic cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • Particular examples of aryl-fused cycloaliphatic groups of this type include indanyl or indenyl groups.
  • Optional substituents which may be present on these groups include the optional aryl or cycloaliphatic group substituents as previously described herein. It will be appreciated that an aryl-fused cycloaliphatic group may be attached to the remainder of the compound of formula (1) by any available carbon atom.
  • aryl-fused heterocycloaliphatic group is intended to include for example optionally substituted monocyclic ring C 6- 2 aromatic groups, such as phenyl fused to optionally substituted 3 to 10 membered saturated or partially saturated monocyclic hydrocarbon ring systems containing one, two, three or four L 1 linker atoms or groups as defined herein.
  • the monocyclic heterocycloaliphatic groups include those groups as previously described for the term heterocycloaliphatic group.
  • Particular heterocycloaliphatic groups include, optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, pyranyl, e.g.
  • aryl or heterocycloaliphatic groups include those substituents as defined herein. It will be appreciated that an aryl-fused heterocycloaliphatic group may be attached to the remainder of the compound of formula (1) by any available carbon or nitrogen atom.
  • heteroaryl-fused cycloaliphatic group is intended to include for example optionally substituted monocyclic C 1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms fused to optionally substituted non- aromatic monocyclic, saturated or partially saturated C 3- ⁇ o ring systems.
  • examples of monocyclic cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • examples of heteroaryl groups include the monocyclic heteroaryl groups as previously described.
  • heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.
  • Optional substituents which may be present on these groups include the optional heteroaryl or cycloaliphatic group substituents as previously described herein. It will be appreciated that an heteroaryl-fused cycloaliphatic group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom.
  • heteroaryl-fused heterocycloaliphatic group is intended to include for example optionally substituted monocyclic C 1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms fused to optionally substituted 3 to 10 membered saturated or partially saturated monocyclic hydrocarbon ring systems containing one, two, three or four L 1 linker atoms or groups as defined herein.
  • the monocyclic heterocycloaliphatic groups include those groups as previously described for the term heterocycloaliphatic group.
  • Particular heterocycloaliphatic groups include, optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, pyranyl, e.g.
  • heteroaryl groups include the monocyclic heteroaryl groups as previously described. Particular examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, N-Ci- ⁇ alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.
  • Optional substituents which may be present on the heteroaryl or heterocycloaliphatic groups include those substituents as defined herein. It will be appreciated that an heteroaryl-fused heterocycloaliphatic group may be attached to the remainder of the compound of formula (1) by any available carbon or nitrogen atom.
  • R 2 , R 3 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 14 in which R 14 is -R 14a or -Alk 1 (R 14a ) f , where R 14a is a halogen atom, or an amino (-NH 2 ), -NHR 15 [where R 15 is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl, heteroaryl group or -Alk 1 (R 15a ) f where R 15a is the same as R 15 ], -N(R 15 ) 2 , nitro, cyano, amidino, formyl, hydroxy (OH), carboxyl (-C0 2 H), -C0 2 R 15 , thiol (-SH
  • 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 14 include fluorine, chlorine, bromine or iodine, d- ⁇ alkyl, haloC 1-6 alkyl, e.g. -CF 3 , haloC 1-6 alkoxy, e.g.
  • -Alk 1 N(R 16 )C(0)OR 15 -Alk 1 S0 2 NHet 1 , -Alk 1 CONHet 1 , -Alk 1 CSNHet 1 , optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic, -Alk 1 phenyl, -Alk 1 monocyclic heteroaryl, -Alk 1 monocyclic heterocycloaliphatic or -Alk 1 cycloaliphatic.
  • R 15 groups include -Alk 1 (where f is zero), optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic, -Alk 1 phenyl, -Alk 1 monocyclic heteroaryl, -Alk 1 monocyclic heterocycloaliphatic or -Alk 1 cycloaliphatic.
  • R 16 is particularly hydrogen or methyl.
  • Alk 1 When Alk 1 is present it may be for example a methylene, ethylene, n- propylene, i-propylene, n-butylene, i-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 16 )- groups.
  • Particular examples of Alk 1 include Ci- 6 alkylene chains especially C1.
  • alkylene chains e.g. methylene, ethylene or propylene or when f is zero C ⁇ -6 alkyl groups especially C ⁇ - alkyl groups e.g methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl.
  • aryl, heteroaryl, heterocycloaliphatic or cycloaliphatic groups which may represent -R 1 a , R 15 or -R 15a include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, N-C 1 - 6 alkylpiperazinyl, especially N-methylpiperazinyl, N-d- ⁇ alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-d- ⁇ alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydro
  • Optional substituents which may in particular be present on the aryl or heteroaryl groups represented by -R 14a , R 15 or -R 15a include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, OCH 3 , 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 , -COCH3, -NHCOCH3, -N(CH 3 )COCH 3 , -SCH 3 , -S0 2 CH 3 or C0 2 H.
  • Optional substituents which may in particular be present on the heterocycloaliphatic or cycloaliphatic groups represented by -R 14a , R 15 or -R 15a include one, two, three or more atoms or groups selected from -OCH 3 , OCF 3 , OCF 2 H, CF 3 , C ⁇ -3 alkylthio, straight or branched C ⁇ -3 alkyl, -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 , -C0 2 C(CH 3 ) 3 , or -COCH3, -NHCOCH3, -N(CH 3 )COCH 3 or CO 2 H.
  • R 14 substituents need not necessarily be the same atoms and/or groups.
  • the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
  • Examples of aliphatic groups, which may represent R 1 include Ci- 6 alkyl groups as herein described. More particular examples include C 1 . 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.
  • Examples of cycloalkyl-alkyl- groups which may represent R 1 include C 1 - 3 alkyl groups (as described herein) where a terminal hydrogen atom is replaced by a C3-6 cycloalkyl ring (as described herein), for example, cyclopropylCH 2 -.
  • optionally substituted aliphatic groups which may represent R 5 , R 6 , R 7 or R 8 include d -6 alkyl groups as herein described. More particular examples include optionally substituted C ⁇ - 3 alkyl groups, such as -CH 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 )CH 3 .
  • optionally substituted cycloaliphatic groups which may represent R 5 , R 6 , R 7 or R 8 include C 3-6 cycloalkyl groups, such as those described previously.
  • Optional substituents which may be present on these alkyl and cycloaliphatic groups include one, two, three or more optional substituents selected from optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic groups as herein defined.
  • Particular examples of R 15 groups present in esterified carboxyl groups of formula -C0 2 R 15 include C ⁇ -6 alkyl groups optionally substituted with R 15a as herein defined.
  • 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.
  • R 1 is in particular a Ci- 6 alkyl goup. 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.
  • R 4 is an optionally substituted monocyclic ring heteroaromatic, especially a five-membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Particular heteroaromatic groups which may represent R 4 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N- C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, ozadiazolyl, thiadiazolyl, triazolyl or pyrazolyl. Especially preferred is when R 4 is an oxazolyl group.
  • R 2 is an optionally substituted aromatic or heteroaromatic group, especially a monocyclic aromatic or monocyclic heteroaromatic group.
  • R 2 is in particular an optionally substituted phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridyl-N- oxide, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl or triazinyl group.
  • R 2 is an optionally substituted phenyl, pyridyl, pyridyl-N-oxide, thiazolyl or
  • aryl or heteroaryl substituents which may be present on compounds of this type include one, two, three or more atoms or groups selected from fluorine, chlorine, optionally substituted straight or branched Ci- 6 alkyl, optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , C0 2 CH 3 , CO 2 CH 2 CH 3 , -C0 2 C(CH 3 ) 3 , -COCH 3 , -NHCOCH3, -N(CH 3 )COCH 3 , -SCH 3 , -SO 2 CH3, C0 2 H or an optionally substituted monocyclic heteroaryl group.
  • Ci-6 alkyl groups include C ⁇ -3 alkyl groups especially methyl, ethyl or propyl optionally substituted with CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH2, CONHCH 3 , CON(CH 3 ) 2 , CO 2 CH 3 , C0 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH3, -NHCOCH3, -N(CH 3 )COCH 3 , -N(CH 3 )C(0)OC(CH 3 ) 3 ,
  • Particular optionally substituted monocyclic heteroaryl groups include pyridyl, pyrimidinyl or pyrazinyl, where the optional substituent includes one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched C ⁇ -6 alkyl e.g methyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NHCH 3 , N(CH 3 ) , CONH 2 , CONHCH3, CON(CH 3 ) 2 , CO2CH3, C0 2 CH 2 CH 3 , -C0 2 C(CH 3 ) 3 , -COCH 3 , -NHCOCH 3 , -N(CH 3 )COCH 3 , -SCH 3) -S0 2 CH 3 or C0 2 H.
  • One particular group of substitutents includes one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, -CH 2 NHC(0)OC(CH 3 ) 3 , methoxy, methylpyrimidinyl, morpholinyl or piperidinyl.
  • R 2 is an optionally substituted aryl-fused cycloaliphatic, heteroaryl- fused cycloaliphatic, aryl-fused heterocycloaliphatic or heteroaryl-fused heterocycloaliphatic group.
  • Particular examples of cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl groups present in compounds of this type include optionally substituted C . 6 cycloalkyl groups e.g. cyclobutyl, cyclopentyl, cyclohexyl, 4 to 6 membered saturated heterocycloaliphatic ring systems e.g.
  • cyclobutanonyl cyclopentanonyl, cyclohexanonyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, 1 ,4-dioxanyl, imidazolidinyl, thiazolidinyl, piperazinyl, homopiperazinyl, morpholinyl, morpholinonyl, thiomorpholinyl, oxazolidinyl, dihydrofuran-2-onyl, tetrahydropyran-2-onyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C 1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, ox
  • R 2 in one particular group of compounds is an optionally substituted aryl-fused cycloaliphatic or heteroaryl-fused cycloaliphatic group.
  • R 2 in compounds of this type is especially an optionally substituted cyclopentyl or cyclohexyl group fused to an optionally substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl group.
  • One preferred group of compounds of the invention has the formula (1) wherein R 2 is an optionally substituted indanyl group.
  • Particular aryl or heteroaryl substituents which may be present on compounds of this type include one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched Ci- 6 alkyl, optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, 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 , -C0 2 C(CH 3 ) 3) -COCH 3 , -NHCOCH 3 , -N(CH 3 )COCH 3) -SCH 3 , -S0 2 CH 3 or C0 2 H.
  • R 3 in one group of compounds of formula (1) is in particular a CN, CON(R 7 )R 8 or OR 6 group.
  • R 6 , R 7 and R 8 which may be the same or different, is each in particular a hydrogen atom or a C ⁇ -3 alkyl group, most particularly a hydrogen atom.
  • R 3 is most especially a CN group.
  • One particular group of aliphatic, alkyl, alkenyl, alkynyl, cycloaliphatic or heterocycloaliphatic substituents which may be present on the compounds of formula (1), are one, two, three or more groups selected from C1- 3 alkoxy, OCF 3 , OCF 2 H, CF 3 , C ⁇ -3 alkylthio, optionally substituted straight or branched C ⁇ -3 alkyl (wherein the optional alkyl substituent is in particular an optionally substituted phenyl or monocyclic heteroaromatic group), -CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , C0 2 CH 3 , C0 2 CH 2 CH 3 , -C0 2 C(CH 3 ) 3 , or -COCH 3 , -NHCOCH 3 , -N(CH 3 )COCH 3 or C0 2 H.
  • the optional phenyl or heteroaromatic substituents which may be present in compounds of this type include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, 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 , -COCH3, -NHCOCH3, -N(CH 3 )COCH 3 , -SCH 3 , -SO 2 CH 3 or CO 2 H.
  • 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 syndrome, 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
  • 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 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.
  • viruses such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • HIV human immundeficiency virus
  • influenza influenza
  • 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.
  • HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, and rapamycin.
  • the above other therapeutic agents when employed
  • 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.
  • Preparations 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.
  • the quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, 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 8 , R 9a , L 1 and Alk 2 etc 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.
  • the compounds of formula (1) may be prepared in a variety of ways depending on the nature of substituent R 3 .
  • R 3 is a CN group
  • the compounds of formula (1) where R 3 is a CN group may be prepared by the following general route as shown in scheme A:
  • the compounds of formula (1) where R 3 is a CN group, may be prepared in a similar way to that reported by Parmee et al (Bioorganic & Medicinal Chemistry Letters 11 , 2001 , 379-382).
  • diphenyl ⁇ /-cyanocarbonimidate (ii) may be treated with an amine of formula (iii), under appropriate conditions such as room temperature in acetonitrile, to afford an isourea of general formula (iv).
  • This isourea may then be converted to the desired guanidine (1), for example, by either heating with an amine of formula (v) at 80°C for 2 hours or by treatment with an amine of formula (v) in refluxing dioxane for 18 hours.
  • the order of reactions may be reversed so that amine (v) may be first reacted with diphenyl ⁇ /-cyanocarbonimidate (ii) and the resulting isourea then treated with an amine of general formula (iii).
  • the guanidines of formula (1) where R 3 is a CONH 2 group may be prepared by hydrolysis of the corresponding cyanoguanidine of formula (1) (where R 3 is a CN group) using aqueous trifluoroacetic acid in a similar manner to the method of Garrett et al (Tetrahedron, 1993, 49, 6885-6898).
  • the primary amides thus formed may then be further functionalised using methods known to those skilled in the art.
  • R 3 in compounds of formula (1), is an OR 6 group these may be prepared using the general route as shown in scheme B:
  • a thiourea of formula (vii) may be reacted with an Osubstituted hydroxylamine of formula (viii) in the presence of a carbodiimide e.g. 1 ,3- dicyclohexylcarbodiimide (DCC) in, for example, dichloromethane in a manner similar to that used by Townsend et al (J. Org. Chem. 1988, 53, 5622-5628) to give a compound of formula (1).
  • a carbodiimide e.g. 1 ,3- dicyclohexylcarbodiimide (DCC) in, for example, dichloromethane in a manner similar to that used by Townsend et al (J. Org. Chem. 1988, 53, 5622-5628) to give a compound of formula (1).
  • Thioureas of general formula (vii) may be prepared by treatment of an amine of formula (iii) with a thioisocyanate
  • the thiourea of general formula (vii) may also be used to prepare compounds of formula (1) where R 3 is a -COR 5 , -S0 2 R 5 or -S0 2 N(R 7 )R 8 group, as illustrated in the general Scheme C shown below:
  • a compound of formula (1) may be prepared by reaction of a guanidine of general formula (ix) with an acid chloride or sulfonyl chloride of formula (x), in which R 3 is a -COR 5 , -S0 2 R 5 or -S0 2 N(R 7 )R 8 group, using methods known in the literature.
  • R 3 is a -S0 2 R 5 or -SO 2 N(R 7 )R 8 group
  • the following literature methodology may be used (Bull. Soc. Chim. Fr. 1973, 985- 991 ; Tetrahedron, 1970, 26, 1805-1820; Indian J. Chem. Sect. B, 1990, 29, 1041-1043).
  • R 3 is a -COR 5 group
  • the following literature methodology may be used (Talaty E.R. et al Synth. Commun. 1987, 17, 9, 1063-1070).
  • the compound of formula (ix) may be prepared by reaction of a thiourea of formula (vii) with, for example, ammonia and DCC in dichloromethane according to the method of Townsend et al (J. Org. Chem. 1988, 53, 5622-5628).
  • Appropriate conditions may include the use of refluxing ethanol as solvent to give a compound of formula (xia).
  • the compound of formula (xia) may then be reacted with a compound of formula (v) in, for example, refluxing ethanol to give a compound of formula (1).
  • the compounds of formula (xi) may be commercially available or prepared using methods known to those skilled in the art.
  • amines of general formula (iii) may be prepared in a variety of ways.
  • the compound of formula (iii) where R 1 is a methyl group and R 4 is an oxazole group may be prepared using methods known in the literature, see, for example, WO 97-40028.
  • a halide of formula (xii) where X is a halogen atom e.g. CI or Br and -NRR' is a nitro group or an amine group (which may be suitably protected)
  • R 4 -Y a derivative of the desired heteroaromatic group utilising a palladium catalysed cross coupling reaction.
  • the following literature methodology may be used to perform this coupling reaction according to the nature of the Y group; e.g.
  • the resulting coupled product may require further manipulation, depending on the nature of the -NRR' group, in order to obtain an amine of formula (iii).
  • an amine of formula (iii) 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 4 -Y derivatives are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compounds of formula (xii) are either commercially available or may be prepared using methods known to those skilled in the art.
  • the compound of formula (xii) may be prepared by alkylation of the phenol precursor of (xii) using standard techniques.
  • 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 may be converted to the corresponding acid [- CO 2 H] by acid- or base-catalysed hydrolysis depending on the nature of the ester group.
  • 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 [-C0 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 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 [-CO 2 H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as an halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to the skilled artisan.
  • 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 period inane 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.
  • a halogenated hydrocarbon e.g. dichloromethane
  • ketone such as acetone
  • alcohol e.g. ethanol
  • 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.
  • CDCI 3 deuterated chloroform DMSO-d 6 - deuterated dimethylsulfoxide DMF - ⁇ /,/V-dimethylformamide
  • Example 1 N-cvano-N'-(3-Methoxy-4-oxazol-5-yl-phenvD-N"-phenyl- quanidine A suspension of intermediate 1 (80mg) in aniline (3ml) was heated at 80°C for 3 hours. The reaction was allowed to cool and the residue purified by column chromatography on silica eluting with 50% to 100% ethyl acetate/hexane to yield the title compound as an off white solid (46mg, 52%).
  • Example 9 /v ⁇ Cvano- ⁇ /-(3-methoxy-4-oxazol-5-yl-phenyl)- ⁇ /"-(4- morpholin-4-yl-phenyl)-quanidine
  • Example 16 r(3-Methoxy-4-oxazol-5-yl-phenylamino)- phenylamino-methylenel-urea Trifluoroacetic acid (0.5 ml) was added to a suspension of example 1 (22 mg) in a mixture of THF (1 ml) and water (0.5 ml). The resulting solution was heated to reflux for 4 hours, then cooled and evaporated to dryness. The residue was then purified by silica gel chromatography, eluting with 75% ethyl acetate/hexane, rising to 100% ethyl acetate, to yield the title compound as a white solid (19 mg, 82%). MS 352 [M+1] + . TLC R f 0.50 (ethyl acetate)
  • the ability of the compounds of the invention to inhibit the IMPDH enzymes may be determined using the following assays: Abbreviatons used: IMPDH Inosine 5'monophosphate dehydrogenase
  • IMPDH catalyses the NAD dependent oxidation of IMP to XMP with the concomitant production of NADH.
  • IMPDH activity was determined in a coupled assay, where the NADH produced by IMPDH is utilised by the enzyme Diaphorase to reduce it's substrate, MTT, to give a purple product. The appearance of this product is monitored as an increase in absorbance at 580nm. Assays were performed in a final volume of 100 ⁇ l containing IMPDH (25 g), NAD (1.1 mM), IMP (2.6mM), Diaphorase (40 ⁇ g), MTT (0.12mM), 2% DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5.
  • test compounds were prepared at an initial concentration of 1.5 mM in 100% DMSO, then diluted in assay buffer to 0.3mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 10-fold into the assay, to allow testing across the range 1nM to 30 ⁇ M.
  • Diaphorase assay To exclude the possibility of identifying compounds that inhibit the Diaphorase component of the coupled assay, all compounds showing inhibition in the IMPDH assay were screened again in a Diaphorase only assay. Assays were performed in a final volume of 100 ⁇ l containing Diaphorase (0.6 ⁇ g), NADH (159 ⁇ M), MTT (0.12mM), 2% DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5. The change in absorbance at 540 nm is read after incubation at 37°C for 60 minutes. Compounds were included at the concentrations used in the coupled assay.
  • IMPDH catalyses the NAD dependent oxidation of IMP to XMP with concomitant reduction of the coenzyme.
  • IMPDH activity was determined by monitoring the production of the fluorescent product, NADH.
  • Assays were performed in a final volume of 200 ⁇ l containing IMPDH (2 ⁇ g), NAD (100 ⁇ M), IMP (100 ⁇ M), 1 % DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5. Fluorescence (excitation 340nm / emission 465nm) was read continuously at 25°C for 30 minutes. From these data, initial rates (i.e. change in fluorescence intensity per minute) were calculated.
  • test compounds were prepared at an initial concentration of 1.OmM 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 2 for 48 hours. 0.5 ⁇ 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

Guanidine derivatives of formula (I) are described: wherein: R' is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group; R2 is an optionally substituted aromatic, heteroaromatic group, aryl-fused cycloaliphatic, heteroaryl-fused cycloaliphatic, aryl-fused heterocycloaliphatic or heteroaryl-fused heterocycloaliphatic group; R3 is a -CN, -COR5, -OR6, -CON(R7)R8, S02R5 or S02N(R7)R8 group; R4 is an optionally substituted heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof. The compounds are potent inhibitors of IMPDH and are of use as immunosuppressants, anti-cancer agents, anti-inflammatory agents, antipsoriatic and anti-viral agents.

Description

GUANIDINE DERIVATIVES
This invention relates to a series of guanidines, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
lnosine-5'-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) is an enzyme involved in the de novo synthesis of guanine nucleotides. IMPDH catalyses the β-nicotinamide adenine dinucleotide (NAD)-dependant oxidation of inosine-5'-monophosphate (IMP) to xanthosine-5'-monophosphate (XMP) (Jackson R.C. et al., Nature. 256, pp. 331-333, (1975)). 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)). Two isoforms of human IMPDH, designated type I and type II, have been identified and sequenced (F.R. Collart and E. Huberman, J. Biol. Chem.. 263, pp. 15769-15772, (1988); Y. Natsumeda et al J. Biol. Chem.. 265, pp 5292-5295, (1990)). Each is 514 amino acids and they share 84% sequence identity. Both 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)).
The de novo synthesis of guanine nucleotides, and thus the activity of IMPDH, is particularly important in B and T-lymphocytes. These cells depend on the de novo, rather than the salvage pathway to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen (A.C. Allison et. al., Lancet II. 1179, (1975) and A.C. Allison et. al., Ciba Found. Svmp.. 48, 207, (1977) ). Thus, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
Mycophenolic acid (MPA) and some of its derivatives have been described in United States patents 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 as potent, uncompetitive, reversible inhibitors of human IMPDH type I (Kj = 33 nM) and type II (Kι = 9 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. (R.E. Morris, Kidney Intl.. 49, Suppl. 53, S-26, (1996) ). However, MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity. (L.M. Shaw, et. al., Therapeutic Drug Monitoring. 17, pp. 690-699, (1995) ).
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. (L.M. Shaw, et. al., Therapeutic Drug Monitoring. 17, pp. 690-699, (1995); H.W. Sollinger, Transplantation. 60, pp. 225-232, (1995); J. Kobashigawa Transplant, 66, pp. 507, (1998) ). Mycophenolate mofetil has also been used for the treatment of rheumatoid arthritis. The experimental use of mycophenolate mofetil in the treatment of systemic lupus erythematosus, lupus nephritis, myasthenia gravis, inflammatory eye disease, autoimmune and inflammatory skin disorders (including psoriasis) and glomerular disease 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. 870-873, (2001) ) and has been shown to be effective in predictive animal models of multiple sclerosis (Tran G.T et al, International Immunopharmacoloov. 1 (9-10) pp. 1709-1723, (2001) ). Several clinical observations, however, limit the therapeutic potential of this drug. (L.M. Shaw, et. al., Therapeutic Drug Monitoring. 17, pp. 690-699, (1995) ).
Nucleoside analogues such as tiazofurin, ribavirin 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.
It is also known that 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 (C.R. Gregory et. al., Transplantation, 59, pp. 655-61 , (1995); PCT publication WO 94/12184; and PCT publication WO 94/ 01105).
Additionally, 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.
The International Patent Applications WO 01-04102, WO 97-45111 , WO 97- 45400 and WO 97-45108 all generally disclose substituted guanidine derivatives.
United States patent 6,420,403 (published 16 July 2002) discloses a class of guanidine derivatives as IMPDH inhibitors.
The present inventors disclose new potent IMPDH inhibitors based on substituted guanidine derivatives.
Thus according to one aspect of the invention we provide a compound of formula (1):
Figure imgf000005_0001
wherein: R1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group;
R2 is an optionally substituted aromatic, heteroaromatic group, aryl- fused cycloaliphatic, heteroaryl-fused cycloaliphatic, aryl-fused heterocycloaliphatic or heteroaryl-fused heterocycloaliphatic group;
R3 is a -CN, -COR5, -OR6, -CON(R7)R8, S02R5 or SO2N(R7)R8 group, in which R5 is an optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, R6 is a hydrogen atom or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group and R7 and R8, which may be the same or different, is each a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;
R4 is an optionally substituted heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.
It will be appreciated that 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. In addition, compounds of formula (1) may exist as tautomers, for example keto (CH2C=O) - enol (CH=CHOH) tautomers. Guanidines may also exist as tautomers, for example compounds of formula (1) may exist in the tautomeric forms as illustrated below:
Figure imgf000006_0001
Formula (1) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.
It will also be appreciated that where desired 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. It will be further appreciated that 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). In the compounds of the invention as represented by formula (1) and the more detailed description hereinafter certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless specified otherwise.
The term "aliphatic group" is intended to include optionally substituted straight or branched C-i-ioalkyl, e.g. C -|.6 alkyl, C2-ιoa'kenyl e.g. C2-6alkenyl or C2-ιo alkynyl e.g. C2-6alkynyl groups. Optional substituents when present on those groups include those optional substituents mentioned hereinafter.
Particular examples of aliphatic groups include optionally substituted C1-6 alkyl groups such as -CH3, -CH2CH3, -CH(CH3)2, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, - CH2C(CH3)3, -C(CH3)3, -(CH2)4CH3, -(CH2)5CH3, or C2-6alkenyl or C2-6alkynyl groups such as -CHCH2, -CHCHCHg, -CH2CHCH2, -CHCHCH2CH3, -CH2CHCHCH3, -(CH2)2CHCH2, -CCH, -CCCH3, -CH2CCH, -CCCH2CH3, -CH2CCCH3, or -(CH2)2CCH groups.
The term "aliphatic chain" is intended to include those alkyl, alkenyl or alkynyl groups as just described where a terminal hydrogen atom is replaced by a covalent bond to give a divalent chain.
Examples of aliphatic chains include optionally substituted C-ι-6 alkylene chains such as -CH2-, -CH2CH2-, -CH(CH3)CH2-,-(CH2)2CH2-, -(CH2)3CH2-,
-CH(CH3)(CH2)2CH2-, -CH2CH(CH3)CH2-, -C(CH3)2-, -C(CH3)2CH2-, -CH2C(CH3)2CH2-, -(CH2)2CH(CH3)CH2-, -CH(CH3)CH2CH2-,
-CH(CH3)CH2CH(CH3)CH2-, -CH2CH(CH3)CH2CH2-, -(CH2)2C(CH3)2CH2-, -(CH )4CH2-, -(CH2)5CH2 or C2-6alkenylene or C2-6alkynylene chains such as -CHCH-, -CHCHCH2 -CH2CHCH-, -CHCHCH2CH2-, -CH2CHCHCH2-, -(CH2)2CHCH-, -CC-, -CCCH2) -CH2CC-, -CCCH2CH2-, -CH2CCCH2- or -(CH2)2CCH- chains. More particular examples include optionally substituted Cι-3 alkylene chains selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH(CH3)CH2-, -C(CH3)2- and -CH2CH(CH3)- chains. The term "heteroaliphatic group" is intended to include the optionally substituted aliphatic groups just described but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L where L is a linker atom or group. Each L 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 of suitable L1 atoms or groups include -O- or -S- atoms or -C(O)-, -C(0)0-, -OC(O)-, -C(S)-, -S(O)-, - S(0)2-, -N(R13)- [where R13 is a hydrogen atom or a C1-6alkyl group], - N(R13)N(R13)-, -N(R 3)0-, -0N(R13)-, -CON(R13)-, -OC(0)N(Ri3)-, -CSN(R13)-, -N(R 3)CO-, -N(R13)C(O)0-, -N(R 3)CS-, -S(0)2N(R13)-, -N(R13)S(0)2-, - N(R13)C0N(R13)-, -N(R13)CSN(R 3)-, or -N(R13)S02N(R 3)- groups. Where the linker group contains two R13 substituents, these may be the same or different. Optional substituents present on the heteroaliphatic groups include those substituents mentioned hereinafter.
The term "cycloaliphatic group" includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C3-ιo 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 C3-6 cycloalkyl ring systems such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituents present on those groups include those substituents mentioned hereinafter.
The term "cycloalkyl-alkyl- group" refers to a Cι-6 alkyl group (as described herein) where a terminal hydrogen atom is replaced by a C3.6 cycloalkyl ring (as described herein). Examples include -(CH2)ι-6-cyclopropyl, -(CH2)ι-6- cyclobutyl, -(CH2)ι-6-cyclopentyl or -(CH2)ι-6-cyclohexyl.
The term "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 L1 linker atoms or groups. Particular examples of suitable L1 atoms or groups include those as just described. Optional substituents present on the heterocycloaliphatic groups include those substituents mentioned hereinafter.
Particular examples of 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. 2- or 4-pyranyl, pyranonyl, piperidinyl, piperidinonyl, quinuclidinyl, 1 ,4-dioxanyl, morpholinyl, morpholinonyl, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydrofuran-2-onyl, tetrahydropyran-2-onyl, isothiazolidinyl 1 ,1-dioxide, [1 ,2]thiazinanyl 1 ,1-dioxide, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrazolidin-3-onyl, tetrahydrothiopyranyl 1 ,1-dioxide, tetrahydrothiophenyl 1 ,1- dioxide, 1 ,3,5-trithianyl, oxazinyl, e.g. 2H-1 ,3-, 6H-1.3-, 6H-1.2-, 2H-1 ,2- or 4H-1.4- oxazinyl, 1 ,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1 ,2,5 or 1 ,2,6-oxathiazinyl, or 1 ,3,5,-oxadiazinyl groups.
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.
The optional substituents which may be present on the aliphatic, alkyl, alkenyl, alkynyl, 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 (-NH2), substituted amino, optionally substituted C6-i2arylamino, -CN, -CO2H, -C02R9a (where R9a is an optionally substituted d-βalkyl group), -SO3H, -SOR9 (where R9 is a C1- 6alkyl group) -S02R9, -S03R9, -OCO2R9, -C(0)H, -C(0)R9, -0C(O)R9, -C(S)R9, -C(O)N(R10)(R11) (where R10 and R11, which may be the same or different is each a hydrogen atom or a Cι-6alkyl group), -OC(O)N(R10)(R11), -N(R1°)C(0)R11, -CSN(R10)(R11), -N(R1o)C(S)(RH), -SO2N(R10)(R11), -N(R1°)SO2R11, -N(Ri°)C(O)N(R11)(Ri2) (where R12 js a hydrogen atom or a Cι-6alkyl group), -N(R °)C(S)N(R1 )(R12), -N(Rio)S02N(R11)(R12), or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group or a Cι-6alkyl group optionally substituted by one, two, three or more of the same or different halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH2), substituted amino, optionally substituted C6-12arylamino, -CN, -C02H, -CO2R9a, -S03H, -SOR9, -S02R9, -S03R9, -OCO2R9, -C(0)H, -C(0)R9, -OC(O)R9, -C(S)R9, -C(0)N(Rio)(R11), -OC(O)N(R °)(R11), -N(R1°)C(0)R11, -CSN(R10)(RH), -N(R10)C(S)(R11), -S02N(Rio)(RH), -N(R10)SO2R11, -N(R1°)C(0)N(RH)(R12), -N(R10)C(S)N(R )(R12), -N(Rio)S02N(R11)(R12), or optionally substituted aromatic or heteroaromatic groups. Substituted amino groups include -NHR9 and -N(R9)(R10) groups. Optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic and heteroaromatic groups include those groups described herein.
When R9a, R9, R10, R11, R12 or R13 is present as a C1-6alkyl group it may be a straight or branched C1-6 alkyl group e.g. a C1-3 alkyl group such as methyl, ethyl or i-propyl. Optional substituents which may be present on R9a 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 Cι-6 alkoxy e.g. methoxy or ethoxy groups.
The term "halogen atom" is intended to include fluorine, chlorine, bromine or iodine atoms.
The term "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 -CF3, -CCI3, -CHF2, -CHCI , - CH2F, and -CH2CI groups.
The term "alkoxy" as used herein is intended to include straight or branched C1-10alkoxy for example C1-6alkoxy such as methoxy, ethoxy, n-propoxy, i- propoxy and t-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 -OCF3, -OCCI3, -OCHF2, -OCHCI2) - OCH2F and -OCH2CI groups.
As used herein the term "alkylthio" is intended to include straight or branched C1-10alkylthio, e.g. C1-6alkylthio such as methylthio or ethylthio groups.
The terms "aromatic group" and "aryl group" are intended to include for example optionally substituted monocyclic ring C6-12 aromatic groups, such as phenyl, or bicyclic fused ring C6-12 aromatic groups, such as, 1- or 2-naphthyl groups. Each of these aromatic groups may be optionally substituted by one, two, three or more R14 atoms or groups as defined below.
The terms "heteroaromatic group" and "heteroaryl group" are intended to include for example optionally substituted C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms (or oxidised versions therof). In general, 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, sulphur 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.
Particular examples of monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridyl-N-oxide, tetrazolyl, or triazinyl.
Particular examples of 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.
The term "aryl-fused cycloaliphatic group" is intended to include for example optionally substituted monocyclic ring C6-12 aromatic groups, such as phenyl fused to optionally substituted non-aromatic monocyclic, saturated or partially saturated C3-10 ring systems. Examples of monocyclic cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. Particular examples of aryl-fused cycloaliphatic groups of this type include indanyl or indenyl groups. Optional substituents which may be present on these groups include the optional aryl or cycloaliphatic group substituents as previously described herein. It will be appreciated that an aryl-fused cycloaliphatic group may be attached to the remainder of the compound of formula (1) by any available carbon atom.
The term "aryl-fused heterocycloaliphatic group" is intended to include for example optionally substituted monocyclic ring C6- 2 aromatic groups, such as phenyl fused to optionally substituted 3 to 10 membered saturated or partially saturated monocyclic hydrocarbon ring systems containing one, two, three or four L1 linker atoms or groups as defined herein.
In compounds of this type the monocyclic heterocycloaliphatic groups include those groups as previously described for the term heterocycloaliphatic group. Particular heterocycloaliphatic groups include, optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, pyranonyl, piperidinyl, piperidinonyl, 1 ,4-dioxanyl, morpholinyl, morpholinonyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydrofuran-2-onyl, tetrahydropyran-2-onyl, isothiazolidinyl 1 ,1-dioxide, [1 ,2]thiazinanyl 1 ,1-dioxide, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrazolidin-3-onyl, tetrahydrothiopyranyl 1 ,1-dioxide or tetrahydrothiophenyl 1 ,1-dioxide groups. Optional substituents which may be present on the aryl or heterocycloaliphatic groups include those substituents as defined herein. It will be appreciated that an aryl-fused heterocycloaliphatic group may be attached to the remainder of the compound of formula (1) by any available carbon or nitrogen atom.
The term "heteroaryl-fused cycloaliphatic group" is intended to include for example optionally substituted monocyclic C1-9heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms fused to optionally substituted non- aromatic monocyclic, saturated or partially saturated C3-ιo ring systems.
In compounds of this type examples of monocyclic cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. Examples of heteroaryl groups include the monocyclic heteroaryl groups as previously described. Particular examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl. Optional substituents which may be present on these groups include the optional heteroaryl or cycloaliphatic group substituents as previously described herein. It will be appreciated that an heteroaryl-fused cycloaliphatic group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom. The term "heteroaryl-fused heterocycloaliphatic group" is intended to include for example optionally substituted monocyclic C1-9heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms fused to optionally substituted 3 to 10 membered saturated or partially saturated monocyclic hydrocarbon ring systems containing one, two, three or four L1 linker atoms or groups as defined herein.
In compounds of this type the monocyclic heterocycloaliphatic groups include those groups as previously described for the term heterocycloaliphatic group. Particular heterocycloaliphatic groups include, optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, pyranonyl, piperidinyl, piperidinonyl, 1 ,4-dioxanyl, morpholinyl, morpholinonyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydrofuran-2-onyl, tetrahydropyran-2-onyl, isothiazolidinyl 1 ,1-dioxide, [1 ,2]thiazinanyl 1 ,1-dioxide, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrazolidin-3-onyl, tetrahydrothiopyranyl 1 ,1-dioxide or tetrahydrothiophenyl 1 ,1-dioxide groups. Examples of heteroaryl groups include the monocyclic heteroaryl groups as previously described. Particular examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, N-Ci-βalkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl. Optional substituents which may be present on the heteroaryl or heterocycloaliphatic groups include those substituents as defined herein. It will be appreciated that an heteroaryl-fused heterocycloaliphatic group may be attached to the remainder of the compound of formula (1) by any available carbon or nitrogen atom.
The R2, R3 or R4 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 R14 in which R14 is -R14a or -Alk1(R14a)f, where R14a is a halogen atom, or an amino (-NH2), -NHR15 [where R15 is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl, heteroaryl group or -Alk1(R15a)f where R15a is the same as R15], -N(R15)2, nitro, cyano, amidino, formyl, hydroxy (OH), carboxyl (-C02H), -C02R15, thiol (-SH), -SR15, -OR15, -CORis -CSR *, -S03H, -SOR1s, -S02R15, -SO3R15, -S02NH2, -SO2NHR15, S02N(R15)2> -CONH2, -CSNH2, -CONHR 5, -CSNHRis, -CON(Ris)2) -CSN(R15)2, -N(R16)SO2R15, [where R16 is a hydrogen atom or an alkyl group] -N(SO2R15)2, -N(R16)S02NH2, -N(R16)S02NHR15, -N(R15)SO2N(R16)2, -N(R16)C0R15, -N(R16)CONH2, -N(R16)CONHR s, -N(Riβ)CON(Ri5)2, -N(R16)CSNH2, -N(R16)CSNHR15, -N(R16)CSN(Ris)2ι -N(R 6)CSR15, - N(R16)C(O)OR15, -S02NHet1 [where -NHet1 is an optionally substituted C 3-7 heterocycloaliphatic group optionally containing one or more other -O- or -S- atoms or -N(R 6)-, -C(O)- or -C(S)- groups], -CONHefi, -CSNHet1, -N(R 6)SO2NHet1 , -N(Rie)CONHet1, -N(R 6)CSNHefi, -S02N(Riβ)Het2 [where Het2 is an optionally substituted monocyclic C3-7 cycloaliphatic group optionally containing one or more -O- or -S- atoms or -N(R16)-, -C(O)- or -C(S)- groups], -CON(Ri6)Het2, -CSN(R16)Hef2, -N(Ri6)CON(R16)Het2, -N(R16)CSN(Ri6)Het , optionally substituted aryl, heteroaryl, cycloaliphatic or heterocycloaliphatic group; Alk1 is a straight or branched C1-6alkylene, C^alkenylene or C2-6 alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(0)g- [where g is an integer 1 or 2] or -N(R16)- groups; and f is zero or an integer 1 , 2 or 3. It will be appreciated that when two R15 or R16 groups are present in one of the above substituents, the R15 or R16 groups may be the same or different.
When in the group -Alk1(R14a)f or -Alk1(R15a)f f is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R14a or R15a may be present on any suitable carbon atom in -Alk1. Where more than one R1 a or R15a substituent is present these may be the same or different and may be present on the same or different atom in -Alk1. Clearly, when f is zero and no substituent R14a or R15a is present the alkylene, alkenylene or alkynylene chain represented by Alk1 becomes an alkyl, alkenyl or alkynyl group.
When -NHet1 or -Het2 forms part of a substituent R14 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. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or -Het2 include those substituents described above in relation to aromatic groups.
Particularly useful atoms or groups represented by R14 include fluorine, chlorine, bromine or iodine, d-β alkyl, haloC1-6alkyl, e.g. -CF3, haloC1-6 alkoxy, e.g. -OCF3> -OCF2H, -NH2, -NHR15, -N(R15)2, -CN, -C02H, -C02R15, -SR15, -OR15, -COR15, -CSR15, -S02R15, -S02NH2, -S02NHR15, S02N(R15)2) -CONH2, -CSNH2, -CONHR15, -CSNHR15, -CON(R15)2, -CSN(R15)2, -N(R16)SO2R15, -N(R16)COR15, -N(R16)CONH2, -N(R16)CONHR1s, -N(R16)CSR15, - N(R 6)C(0)OR1s, -S02NHet1, -CONHet1, -CSNHet1, -Alk1NH2, -Alk1NHR15, -Alk1N(R15)2, -Alk1CN, -Alk1C02H, -Alk1C02R15, -Alk1SR15, -Alk1OR15, -Alk1COR15 -Alk1CSR15, -Alk1S02R15, -Alk1SO2NH2, -Alk1S02NHR15,
-Alk1S02N(R15)2, -Alk1CONH2, -Alk1CSNH2, -Alk1CONHR1s, -Alk1CSNHR1s, -Alk1CON(R 5)2, -Alk1CSN(R15)2, -Alk1N(R16)SO2R15, -Alk1N(R16)COR1s, -Alk1N(R16)CONH2, -Alk1N(R16)CONHR15, -Alk1N(R16)CSR15,
-Alk1N(R16)C(0)OR15, -Alk1S02NHet1, -Alk1CONHet1, -Alk1CSNHet1, optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic, -Alk1 phenyl, -Alk1 monocyclic heteroaryl, -Alk1 monocyclic heterocycloaliphatic or -Alk1cycloaliphatic.
Particularly useful R15 groups include -Alk1 (where f is zero), optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic, -Alk1 phenyl, -Alk1 monocyclic heteroaryl, -Alk1 monocyclic heterocycloaliphatic or -Alk1 cycloaliphatic. R16 is particularly hydrogen or methyl.
When Alk1 is present it may be for example a methylene, ethylene, n- propylene, i-propylene, n-butylene, i-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(R16)- groups. Particular examples of Alk1 include Ci-6 alkylene chains especially C1.3 alkylene chains e.g. methylene, ethylene or propylene or when f is zero Cι-6 alkyl groups especially Cι- alkyl groups e.g methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl.
Particular examples of aryl, heteroaryl, heterocycloaliphatic or cycloaliphatic groups which may represent -R1 a, R15 or -R15a include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, N-C1-6 alkylpiperazinyl, especially N-methylpiperazinyl, N-d-β alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-d-β alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-Cι-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.
Optional substituents which may in particular be present on the aryl or heteroaryl groups represented by -R14a, R15 or -R15a include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, OCH3, OCF3, OCF2H, CF3, CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, C02CH2CH3, -CO2C(CH3)3, -COCH3, -NHCOCH3, -N(CH3)COCH3, -SCH3, -S02CH3 or C02H. Optional substituents which may in particular be present on the heterocycloaliphatic or cycloaliphatic groups represented by -R14a, R15 or -R15a include one, two, three or more atoms or groups selected from -OCH3, OCF3, OCF2H, CF3, Cι-3 alkylthio, straight or branched Cι-3 alkyl, -CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, CO2CH2CH3, -C02C(CH3)3, or -COCH3, -NHCOCH3, -N(CH3)COCH3 or CO2H.
It will be appreciated that where two or more R14 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.
Examples of aliphatic groups, which may represent R1 include Ci-6 alkyl groups as herein described. More particular examples include C1.3 alkyl groups, such as -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)CH3. Examples of cycloaliphatic groups which may represent R1 include C3-6 cycloalkyl groups, such as those described previously. Examples of cycloalkyl-alkyl- groups which may represent R1 include C1-3 alkyl groups (as described herein) where a terminal hydrogen atom is replaced by a C3-6 cycloalkyl ring (as described herein), for example, cyclopropylCH2-.
Examples of optionally substituted aliphatic groups, which may represent R5, R6, R7 or R8 include d-6 alkyl groups as herein described. More particular examples include optionally substituted Cι-3 alkyl groups, such as -CH3, - CH2CH3, -CH2CH2CH3 or -CH(CH3)CH3. Examples of optionally substituted cycloaliphatic groups which may represent R5, R6, R7 or R8 include C3-6 cycloalkyl groups, such as those described previously. Optional substituents which may be present on these alkyl and cycloaliphatic groups include one, two, three or more optional substituents selected from optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic groups as herein defined. Particular examples of R15 groups present in esterified carboxyl groups of formula -C02R15 include Cι-6 alkyl groups optionally substituted with R15a as herein defined.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. 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.
In one group of compounds of the invention R1 is in particular a Ci-6 alkyl goup. Especially preferred is when R1 is a Cι-3 alkyl group. Most especially preferred is when R1 is a methyl group.
In another group of compounds of the invention R1 is in particular a haloalkyl group. Especially preferred is when R1 is a CHF2 or CH2F group. In particular in compounds of formula (1) R4 is an optionally substituted monocyclic ring heteroaromatic, especially a five-membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Particular heteroaromatic groups which may represent R4 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N- C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, ozadiazolyl, thiadiazolyl, triazolyl or pyrazolyl. Especially preferred is when R4 is an oxazolyl group.
One group of compounds of the invention has the formula (1 ) wherein R2 is an optionally substituted aromatic or heteroaromatic group, especially a monocyclic aromatic or monocyclic heteroaromatic group. In compounds of this type R2 is in particular an optionally substituted phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridyl-N- oxide, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl or triazinyl group. Especially preferred is when R2 is an optionally substituted phenyl, pyridyl, pyridyl-N-oxide, thiazolyl or thiadiazolyl group.
Particular aryl or heteroaryl substituents which may be present on compounds of this type include one, two, three or more atoms or groups selected from fluorine, chlorine, optionally substituted straight or branched Ci-6 alkyl, optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, methoxy, OCF3, OCF2H, CF3, CN, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, CO2CH2CH3, -C02C(CH3)3, -COCH3, -NHCOCH3, -N(CH3)COCH3, -SCH3, -SO2CH3, C02H or an optionally substituted monocyclic heteroaryl group. Particular optionally substituted straight or branched Ci-6 alkyl groups include Cι-3 alkyl groups especially methyl, ethyl or propyl optionally substituted with CN, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, CO2CH3, C02CH2CH3, -CO2C(CH3)3, -COCH3, -NHCOCH3, -N(CH3)COCH3, -N(CH3)C(0)OC(CH3)3,
-NHC(0)OC(CH3)3, -SCH3, -SO2CH3 or C02H. Particular optionally substituted monocyclic heteroaryl groups include pyridyl, pyrimidinyl or pyrazinyl, where the optional substituent includes one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched Cι-6 alkyl e.g methyl, methoxy, OCF3, OCF2H, CF3, CN, NHCH3, N(CH3) , CONH2, CONHCH3, CON(CH3)2, CO2CH3, C02CH2CH3, -C02C(CH3)3, -COCH3, -NHCOCH3, -N(CH3)COCH3, -SCH3) -S02CH3 or C02H. One particular group of substitutents includes one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, -CH2NHC(0)OC(CH3)3, methoxy, methylpyrimidinyl, morpholinyl or piperidinyl.
Another particular group of compounds of the invention has the formula (1) wherein R2 is an optionally substituted aryl-fused cycloaliphatic, heteroaryl- fused cycloaliphatic, aryl-fused heterocycloaliphatic or heteroaryl-fused heterocycloaliphatic group. Particular examples of cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl groups present in compounds of this type include optionally substituted C .6 cycloalkyl groups e.g. cyclobutyl, cyclopentyl, cyclohexyl, 4 to 6 membered saturated heterocycloaliphatic ring systems e.g. cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, 1 ,4-dioxanyl, imidazolidinyl, thiazolidinyl, piperazinyl, homopiperazinyl, morpholinyl, morpholinonyl, thiomorpholinyl, oxazolidinyl, dihydrofuran-2-onyl, tetrahydropyran-2-onyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl or triazinyl groups.
R2 in one particular group of compounds is an optionally substituted aryl-fused cycloaliphatic or heteroaryl-fused cycloaliphatic group. R2 in compounds of this type is especially an optionally substituted cyclopentyl or cyclohexyl group fused to an optionally substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl group. One preferred group of compounds of the invention has the formula (1) wherein R2 is an optionally substituted indanyl group.
Particular aryl or heteroaryl substituents which may be present on compounds of this type include one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched Ci-6 alkyl, optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, methoxy, OCF3, OCF2H, CF3, CN, NHCH3, N(CH3)2) CONH2, CONHCH3, CON(CH3)2, C02CH3, C02CH2CH3, -C02C(CH3)3) -COCH3, -NHCOCH3, -N(CH3)COCH3) -SCH3, -S02CH3 or C02H.
R3 in one group of compounds of formula (1) is in particular a CN, CON(R7)R8 or OR6 group. In compounds of this type R6, R7 and R8, which may be the same or different, is each in particular a hydrogen atom or a Cι-3 alkyl group, most particularly a hydrogen atom. R3 is most especially a CN group.
One particular group of aliphatic, alkyl, alkenyl, alkynyl, cycloaliphatic or heterocycloaliphatic substituents, which may be present on the compounds of formula (1), are one, two, three or more groups selected from C1-3 alkoxy, OCF3, OCF2H, CF3, Cι-3 alkylthio, optionally substituted straight or branched Cι-3 alkyl (wherein the optional alkyl substituent is in particular an optionally substituted phenyl or monocyclic heteroaromatic group), -CN, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, C02CH2CH3, -C02C(CH3)3, or -COCH3, -NHCOCH3, -N(CH3)COCH3 or C02H. The optional phenyl or heteroaromatic substituents which may be present in compounds of this type include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, methoxy, OCF3, OCF2H, CF3, CN, NHCH3, N(CH3)2, CONH2, CONHCH3, CON(CH3)2, C02CH3, C02CH2CH3, -CO2C(CH3)3, -COCH3, -NHCOCH3, -N(CH3)COCH3, -SCH3, -SO2CH3 or CO2H.
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.
Thus 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. Examples of 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. host disease, in the treatment of 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 syndrome, 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 autoimmune polyglandular syndrome) glomerulonephritis, scleroderma, morphea, lichen planus, viteligo (depigmentation of the skin), alopecia areata, autoimmune alopecia, autoimmune hypopituatarism, cicatricial pemphigoid, Gullivan-Barre syndrome, and alveolitis; in the treatment of T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis (including that due to poison ivy), urticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease); in the treatment of inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, acute respiratory distress syndrome, Sezary's syndrome and vascular diseases which have an inflammatory and or a proliferatory component such as restenosis, stenosis and artherosclerosis; in the treatment of cancer and tumor disorders, such as solid tumors, lymphomas and leukemia; in the treatment of fungal infections such as mycosis fungoides; in protection from ischemic or reperfusion injury such as ischemic or reperfusion injury that may have been incurred during organ transplantation, myocardial infarction, stroke or other causes; in the treatment of DNA or RNA viral replication diseases, such as herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, Epstein-Barr, human immundeficiency virus (HIV) and influenza.
Additionally, IMPDH is also known to be present in bacteria and thus may regulate bacterial growth. As such, 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.
In a particular embodiment, 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 or rheumatoid arthritis.
In another particular embodiment 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. In an additional particular embodiment 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.
For the prophylaxis or treatment of disease 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.
Alternate 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.
Thus, for example, 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. The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physician's Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
Pharmaceutical 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.
For oral administration, 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). The tablets may be coated by methods well known in the art. 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.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound
For buccal administration the 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. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen- free water, before use. For particle mediated administration the compounds of formula (1 ) may be coated on particles such as microscopic gold particles.
In addition to the formulations described above, 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.
For nasal administration or administration by inhalation, 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.
For vaginal or rectal administration 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. Such materials include for example cocoa butter and polyethylene glycols.
The 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. The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, 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.
In the following process description, the symbols R1-R8, R9a, L1 and Alk2 etc when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect 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]. In some instances, 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.
The compounds of formula (1) may be prepared in a variety of ways depending on the nature of substituent R3. Thus, for example, the compounds of formula (1) where R3 is a CN group may be prepared by the following general route as shown in scheme A:
Figure imgf000029_0001
Scheme A.
Figure imgf000029_0002
(1 )
Thus, the compounds of formula (1), where R3 is a CN group, may be prepared in a similar way to that reported by Parmee et al (Bioorganic & Medicinal Chemistry Letters 11 , 2001 , 379-382). For example, commercially available diphenyl Λ/-cyanocarbonimidate (ii) may be treated with an amine of formula (iii), under appropriate conditions such as room temperature in acetonitrile, to afford an isourea of general formula (iv). This isourea may then be converted to the desired guanidine (1), for example, by either heating with an amine of formula (v) at 80°C for 2 hours or by treatment with an amine of formula (v) in refluxing dioxane for 18 hours. Alternatively the order of reactions may be reversed so that amine (v) may be first reacted with diphenyl Λ/-cyanocarbonimidate (ii) and the resulting isourea then treated with an amine of general formula (iii).
The guanidines of formula (1) where R3 is a CONH2 group may be prepared by hydrolysis of the corresponding cyanoguanidine of formula (1) (where R3 is a CN group) using aqueous trifluoroacetic acid in a similar manner to the method of Garrett et al (Tetrahedron, 1993, 49, 6885-6898). The primary amides thus formed may then be further functionalised using methods known to those skilled in the art. When R3, in compounds of formula (1), is an OR6 group these may be prepared using the general route as shown in scheme B:
Figure imgf000030_0001
H2N— OR6 (viii) OCC
CH2CI2
Scheme B
Figure imgf000030_0002
(1 )
Thus a thiourea of formula (vii) may be reacted with an Osubstituted hydroxylamine of formula (viii) in the presence of a carbodiimide e.g. 1 ,3- dicyclohexylcarbodiimide (DCC) in, for example, dichloromethane in a manner similar to that used by Townsend et al (J. Org. Chem. 1988, 53, 5622-5628) to give a compound of formula (1). Thioureas of general formula (vii) may be prepared by treatment of an amine of formula (iii) with a thioisocyanate of formula (vi) using standard methods known to those skilled in the art. The thioisocyanates of formula (vi) may either be commercially available or made using methods known to those skilled in the art.
The thiourea of general formula (vii) may also be used to prepare compounds of formula (1) where R3 is a -COR5, -S02R5 or -S02N(R7)R8 group, as illustrated in the general Scheme C shown below:
Figure imgf000030_0003
Thus a compound of formula (1) may be prepared by reaction of a guanidine of general formula (ix) with an acid chloride or sulfonyl chloride of formula (x), in which R3 is a -COR5, -S02R5 or -S02N(R7)R8 group, using methods known in the literature. For example when R3 is a -S02R5 or -SO2N(R7)R8 group the following literature methodology may be used (Bull. Soc. Chim. Fr. 1973, 985- 991 ; Tetrahedron, 1970, 26, 1805-1820; Indian J. Chem. Sect. B, 1990, 29, 1041-1043). Alternatively when R3 is a -COR5 group the following literature methodology may be used (Talaty E.R. et al Synth. Commun. 1987, 17, 9, 1063-1070). The compound of formula (ix) may be prepared by reaction of a thiourea of formula (vii) with, for example, ammonia and DCC in dichloromethane according to the method of Townsend et al (J. Org. Chem. 1988, 53, 5622-5628).
Alternatively the compounds of formula (1) where R3 is a -COR5 or -S0 R5 group may be prepared using the following litetrature methodology (Farmaco Ed. Sci. 1988, 43, 575-596). Thus a compound of formula (xi) may be reacted with a compound of formula (iii) as shown in the general Scheme D below:
Figure imgf000031_0001
(1 )
Appropriate conditions may include the use of refluxing ethanol as solvent to give a compound of formula (xia). The compound of formula (xia) may then be reacted with a compound of formula (v) in, for example, refluxing ethanol to give a compound of formula (1). The compounds of formula (xi) may be commercially available or prepared using methods known to those skilled in the art. Intermediates of formulae (iii), (v), (vi), (viii) and (x) and any other intermediates required to obtain compounds of formulae (1), if not available commercially, may be prepared by methods known to those skilled in the art following procedures set forth in references such as Rodd's Chemistry of Carbon Compounds, Volumes 1-15 and Supplementals (Eisevier Science Publishers, 1989), Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al, Volumes 1-8, 1984 and Volumes 1-11 , 1994 (Pergamon), Comprehensive Organic Functional Group Transformations, Ed. Katritzky et al, Volumes 1-7, 1995 Pergamon), Comprehensive Organic Synthesis, Ed. Trost and Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents for Organic Synthesis Ed. Paquette, Volumes 1-8 (John Wiley and Sons, 1995), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) and March's Advanced Organic Chemistry (John Wiley and Sons, 1992).
Thus amines of general formula (iii) may be prepared in a variety of ways. For example, the compound of formula (iii) where R1 is a methyl group and R4 is an oxazole group may be prepared using methods known in the literature, see, for example, WO 97-40028.
Alternatively amines of formula (iii) may be prepared using the route as shown in Scheme E:
Scheme E
Figure imgf000032_0001
X=CI or Br R=R'=H or R=R'=0 or R=H, R'=Protecting I group For example, a halide of formula (xii), where X is a halogen atom e.g. CI or Br 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 (R4-Y, where Y is as described below) utilising a palladium catalysed cross coupling reaction. The following literature methodology may be used to perform this coupling reaction according to the nature of the Y group; e.g. when Y is a hydrogen atom (Heterocycles, 1990, 31 , 1951-1958); the zinc species (Y=ZnCI) (J Organomet. Chem. 1990, 390, 389-398; Tetrahedron 1997, 53, 7237-7254); the mercury species (Y=HgBr) (Chem. Heterocycl. Compd. 1983, 19, 1159-1162) or a boron derivative (Y=B(OH)2, Y=Et2) (J. Med. Chem. 1997, 40, 3542-3550; J. Org. Chem. 1998, 63, 8295-8303). The resulting coupled product may require further manipulation, depending on the nature of the -NRR' group, in order to obtain an amine of formula (iii). 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. It will be appreciated that the various R4-Y derivatives are either commercially available or may be prepared using methods known to those skilled in the art. In a similar manner the compounds of formula (xii) are either commercially available or may be prepared using methods known to those skilled in the art. For example, the compound of formula (xii) may be prepared by alkylation of the phenol precursor of (xii) using standard techniques.
It will be appreciated that compounds of formula (1) or any preceding intermediates may be further derivatised by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions.
Particular 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.
For example, ester groups may be converted to the corresponding acid [- CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the ester group. 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. Similarly an acid [-C02H] 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.
In another example, -OH groups may be generated from the corresponding ester 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. Alternatively an alcohol may be prepared by reduction of the corresponding acid [-CO2H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.
Alcohol groups may be converted into leaving groups, such as an halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to the skilled artisan. For example, 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.
In another example, 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. Alternatively 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. For example using an oxidising agent such as a period inane e.g Dess Martin, in 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.
In a further example primary amine (-NH2) 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.
In a further example, amine [-NH2] 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.
In another example, a nitro [-N02] group may be reduced to an amine [-NH2], 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.
In a further example amine (-CH2NH2) 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.
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. Thus, for example, 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 catalysed reactions, to introduce, for example, acid, ester, cyano or amino substituents.
In another example, sulphur atoms in the compounds, for example when present in a linker group L1 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.
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.
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.
Where it is desired to obtain a particular enantiomer of a compound of (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and 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.
In another resolution process a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired 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.
The following Examples illustrate the invention. All temperatures are in °C. Where experimental detail is not given for the preparation of a reagent it is either commercially available, or it is known in the literature, for which the CAS number is quoted. The compounds are named with the aid of Beilstein Autonom. 1H NMR spectra were obtained at 300MHz unless otherwise indicated.
LCMS conditions:
HP1050 (Diode Array) linked tc i a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionization
Column: Luna C18(2) 100x4.6mm, 5μm particle size Analytical column
Column Temp: 35° C Mobile Phase: A: Water + 0.08% formic acid
B: Acetonitrile + 0.08% formic acid
Flow rate: 3ml/min
Gradient: Time (mins): % Composition B:
0 5
0.05 5
4.50 95
5.0 95
5.02 5
6.00 5
Run time: 6.00mins
Typical Injection Vol: 5μl Detector Wavelength: DAD 205-330nm Preparative LC conditions:
Gilson 215 liquid handler setup.
Column: Luna C18(2) 250x21.2mm, 5μn particle size PREP column Column Temp: Ambient Mobile Phase: A: Water + 0.08% formic acid
B: Acetonitrile + 0.1% formic acid Gradient: Variable - depends on retention of sample in LCMS screen
Run Time: 20 mins
Flow rate: 20ml/min
Typical Injection Vol: 750μl of 25mg/ml solution Detector Wavelength: 210 and 254nm
Abbreviations used:
DCC - dicyclohexylcarbodiimde; THF - tetrahydrofuran;
CDCI3 - deuterated chloroform DMSO-d6 - deuterated dimethylsulfoxide DMF - Λ/,/V-dimethylformamide
Intermediate 1. 1-(3-Methoxy-4-oxazol-5-yl-phenyl)-3-cvano-2-phenyl- isourea A mixture of 3-methoxy-4-oxazol-5-yl-phenylamine (CAS198821 -79-3) (1.0g) and diphenylcyanocarbon imidate (1.25g) in acetonitrile (50ml) was heated at reflux overnight. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (100ml). The organic solution was washed with water (50ml), saturated aqueous sodium chloride (50ml), separated, dried over magnesium sulphate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography on silica eluting with 50% ethyl acetate/hexane to yield the title compound as an off white solid (0.9g, 52%).
Rf 0.41 (50% ethyl acetate/hexane). 1H NMR 300MHz (CDCI3) 8.1-8.3 (1 H, s, br), 7.9 (1 H, s), 7.7-78 (1 H, d), 7.55(1 H, s), 7.4-7.5 (2H, m), 7.25-7.4 (1 H, m), 7.15-7.2 (2H, m), 7.0-7.1 (2H, m), 3.95 (3H, s). Intermediate 2. 1-Cvano-2-phenyl-3-pyridin-3-yl-isourea. A suspension of diphenylcyanocarbon imidate (4.76g) in isopropanol (25ml) was treated with 3-aminopyridine (1.88g) and the mixture stirred at room temperature for 24 hours. The reaction was cooled to 0°C, filtered and washed with cold isopropanol (10ml). The solid obtained was dried in a vacuum oven to give the title compound as a white solid (3.07g, 68%).
Rf 0.27 (ethyl acetate). 1H NMR 300MHz (DMSO-d6) 8.50 (1 H, s), 8.20-8.30 (1 H, s), 7.70-7.85 (1 H, dd), 7.10-7.35 (5H, m). Intermediate 3 1-(3-Methoxy-4-oxazol-5-yl-phenvh-3-phenyl-thiourea To a solution of 3-methoxy-4-oxazol-5-yl-phenylamine (CAS198821 -79-3) (3.0g, 15.8mmol) in dichloromethane (40ml) was added slowly phenyl isothiocyanate (1.9ml, 15.8mmol). The reaction mixture was stirred at room temperature for 18 hours. Hexane (40ml) was added and the resulting precipitate was filtered off and dried in vacuo to afford the title compound as a yellow solid (4.0g, 78%).
TLC R, 0.62 (ethyl acetate). 1H NMR 300MHz (CDCI3) 8.03 (1 H, s, br), 7.90 (1 H, s, br), 7.88 (1 H, s), 7.73-7.76 (1 H, d), 7.56 (1 H, s), 7.27-7.49 (6H, m), 6.90-6.95 (1 H, dd), 3.98 (3H, s).
Example 1. N-cvano-N'-(3-Methoxy-4-oxazol-5-yl-phenvD-N"-phenyl- quanidine A suspension of intermediate 1 (80mg) in aniline (3ml) was heated at 80°C for 3 hours. The reaction was allowed to cool and the residue purified by column chromatography on silica eluting with 50% to 100% ethyl acetate/hexane to yield the title compound as an off white solid (46mg, 52%).
Rf 0.41 (50% ethyl acetate/hexane). 1H NMR 300MHz (CDCI3) 8.10-8.30 (1 H, s, br), 7.90 (1 H, s), 7.70-7.80 (1 H, d), 7.55 (1 H, s), 7.40-7.50 (2H, m), 7.25-7.40 (1 H, m), 7.15-7.20 (2H, m), 7.00-7.1 0(2H, m), 3.95 (3H, s). MS 334 [M+1]+
The following example was prepared in a similar manner to the above:- Example 2. N-cvano-f3-rN'-(3-Methoxy-4-oxazol-5-yl-phenvO- quanidinolbenzvD-carbamic acid tert-butyl ester From intermediate 1 (50mg) and (3-aminobenzyl)-carbamic acid- e/ -butyl ester (68621 -88-5) (1 OOmg) as a tan oil (46mg, 67%).
Rf 0.42 (50% ethyl acetate/hexane). 1H NMR 300MHz (CDCI3) 7.90 (1 H, s), 7.70-7.80 (1 H, d), 7.55 (1 H, s), 7.40-7.50 (2H, m), 7.25-7.40 (1 H, m), 7.15-7.20 (2H, m), 7.00-7.10 (1 H, m), 6.85-6.90 (1 H, d), 5.00-5.10 (1 H, s, br), 4.30 (2H, d), 3.95 (3H, s), 1.40 (3H, s). MS 463 [M+1]+ Example 3. N-cvano-N'-(3-Methoxy-4-oxazol-5-yl-phenyl)-N"-pyridin-
3-yl-quanidine
A solution of intermediate 2 (100mg) in dioxane (5ml) was treated with 3- methoxy-4-oxazol-5-yl-phenylamine (CAS198821 -79-3) (100mg) and heated at reflux for 12 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with 10% methanol/ethyl acetate to yield the title compound as an off white solid (57mg, 37%). Rf 0.41 (50% ethyl acetate/hexane). 1H NMR 300MHz (CDCI3) 8.45-8.55 (2H, m), 7.80-8.00 (3H, m), 7.60 (1 H, s), 7.45-7.55(1 H, m), 7.30-7.40 (1 H, m), 6.90-7.05 (3H, m), 4.00 (3H, s). MS 335 [M+1]+
Example 4 Λ^Benzyloxy-Λf-(3-methoxy-4-oxazol-5-yl- henyl)-Λ/',- phenyl-quanidine To a solution of intermediate 3 (0.5g, 1.54mmol) in dry THF (10ml) under nitrogen was added a solution of DCC (0.38g, 1.85mmol) in dry THF (5ml). O Benzylhydroxylamine hydrochloride (0.3g, 1.85mmol) was added in a single portion followed by triethylamine (0.26ml, 1.85mmol). The reaction mixture was stirred at room temperature overnight. The resulting precipitate (triethylamine hydrochloride) was filtered off and the filtrate concentrated in vacuo. Purification by flash chromatography on silica afforded the title compound as a yellow solid (0.44g, 69%).
TLC Rf 0.57 (50% ethyl acetate/hexane). 1H NMR 300MHz (CDCI3) 7.85, 7.83 (1 H, 2 X s), 6.50-7.63 (13H, m), 5.58, 5.61 (1 H, 2 X s), 5.04, 5.06 (2H, 2 X s), 3.73, 3.78 (3H, 2 X s). MS 415 [M+1]+.
The following example was prepared in a similar manner to that described for Example 4:-
Example 5 iV-Hvdroxy-Λ/ -(3-methoxy-4-oxazol-5-yl-phenyl)-ιV"- phenyl-quanidine
From intermediate 3 (0.5g, 1.54mmol) and hydroxylamine hydrochloride (0.12g, 1.85mmol). Preparative HPLC afforded the title compound as an off- white solid (0.017g, 3%).
TLC Rf 0.56 (20% methanol/dichloromethane). 1H NMR 300MHz (CDCI3) 7.84 (1 H, s), 7.56-7.60 (1 H, d), 7.42 (1 H, s), 6.66-7.33 (7H, m), 3.84 (3H, s). MS 324 [M+1]+. Example 6 /v-Cvano-Λ - 3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-p- tolyl-quanidine
A solution of intermediate 1 (25 mg) in DMF (0.5 ml) was treated with p- toluidine (12 mg) and sodium methanesulfinate (1.25 mg, as a solution in 100 μl DMF), and heated to 100°C for 6 hours. The reaction was then stirred at room temperature overnight, then treated with polystyrene-piperazine resin (70 mg), stirred at room temperature for a further 3 hours, then at 60°C for 3 hours, and left to cool overnight. Water (4 ml) was added to a Waters Oasis® MCX 6cc extraction cartridge, followed by the reaction mixture. The cartridges were then eluted with 4 ml fractions of 20, 40, 60 then 100% methanol/water to yield the title compound (4 mg, 15%). MS 348 [M+1]+.
The following example was prepared in a similar manner to that described for Example 6:-
Example 7 Λ^Cvano-/V-(3-methoxy-4-oxazol-5-yl-phenvO-Λ "-(4- methoxy-phenvD-quanidine
From intermediate 1 (25 mg), p-anisidine (14 mg) and sodium methanesulfinate (1.25 mg). Purification with a Waters Oasis® MCX 6cc extraction cartridge afforded the title compound (8 mg, 29%). MS 364 [M+1]+.
Example 8 ΛK vano-Λ -indan-1-yl-Λ/"-(3-methoxy-4-oxazol-5-yl- phenvD-quanidine
Intermediate 1 (25 mg) and 1-aminoindan (15 mg) were combined in DMF (0.5 ml) and heated to 60°C for 6 hours, then held at room temperature overnight. The reaction mixture was then loaded onto a Waters Oasis® MCX
6cc extraction cartridge, rinsing first with water (2 ml) then eluting with methanol (2 ml) to give crude product. Purification by preparative HPLC gave the title compound (7.8 mg, 28%). MS 374 [M+1]+.
The following examples were prepared in a similar manner to that described for Example 8:- Example 9 /v^Cvano-Λ/-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-(4- morpholin-4-yl-phenyl)-quanidine
From intermediate 1 (25 mg) and 4-morpholinoaniline (20 mg). Preparative
HPLC afforded the title compound (4.8 mg, 15%). MS 419 [M+1]+. Example 10 /V-Cvano-Λf-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ "-(4- piperidin-1-yl-phenv0-quanidine
From intermediate 1 (25 mg) and 4-piperidinoaniline (20 mg). Preparative
HPLC yielded the title compound (10.4 mg, 33%). MS 417 [M+1]+.
Example 11 Λ Cvano-Λr-(3-fluoro-phenyl)-Λ -(3-methoxy-4- oxazol-5-yl-phenyl)-quanidine
From intermediate 1 (25 mg) and 3-fluoroaniline (12 mg). Preparative HPLC gave the title compound (2.2 mg, 8%). MS 352 [M+1]+.
Example 12 ιV-Cvano-Λ -(3-methoxy-4-oxazol-5-yl-phenyl)-Λ "- T3-
(2-methyl-pyrimidin-4-yl)-phenyll-quanidine From intermediate 1 (25 mg) and 3-(2-methylpyrimidin-4-yl)aniline (21 mg).
Preparative HPLC gave the title compound (4.3 mg, 14%). MS 426 [M+1]+.
Example 13 *W-Cvano-Λ/'-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ - thiazol-2-yl-quanidine
Intermediate 1 (100 mg) and 2-aminothiazole (30 mg) were combined in 1 ,4- dioxane (5 ml) and heated to reflux for 48 hours. After cooling, the solvent was evaporated, and a portion of the residue was purified by preparative HPLC to afford the title compound (3 mg, 3%). MS 341 [M+1]+.
The following example was prepared in a similar manner to that described for Example 13:-
Example 14 /v Cvano-Λf-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ "- ri,3.41thiadiazol-2-yl-quanidine
From intermediate 1 (100 mg) and 2-amino-1 ,3,4-thiadiazole (30 mg).
Preparative HPLC gave the title compound (3.6 mg, 4%). MS 342 [M+1]+. Example 15 M-Cvano-Λf -(3-methoxy-4-oxazol-5-yl-phenyl)-/V' - (1 - oxy-Pyridin-3-vO-quanidine
Peracetic acid (0.21 ml) was added to a solution/suspension of example 3 (54 mg) in dichloromethane 10 ml), and the mixture heated to reflux for 24 hours.
After cooling, the reaction mixture was concentrated under reduced pressure, and the residue purified by preparative HPLC to provide the title compound (1.4 mg, 2.5%). MS 351 [M+1]+.
Example 16 r(3-Methoxy-4-oxazol-5-yl-phenylamino)- phenylamino-methylenel-urea Trifluoroacetic acid (0.5 ml) was added to a suspension of example 1 (22 mg) in a mixture of THF (1 ml) and water (0.5 ml). The resulting solution was heated to reflux for 4 hours, then cooled and evaporated to dryness. The residue was then purified by silica gel chromatography, eluting with 75% ethyl acetate/hexane, rising to 100% ethyl acetate, to yield the title compound as a white solid (19 mg, 82%). MS 352 [M+1]+. TLC Rf 0.50 (ethyl acetate)
The ability of the compounds of the invention to inhibit the IMPDH enzymes may be determined using the following assays: Abbreviatons used: IMPDH Inosine 5'monophosphate dehydrogenase
IMP Inosine 5'monophosphate
XMP Xanthosine 5'-monophosphate
NAD β- Nicotinamide adenine dinucleotide
NADH β- Nicotinamide adenine dinucleotide, reduced form MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Assay Protocol 1
IMPDH catalyses the NAD dependent oxidation of IMP to XMP with the concomitant production of NADH. IMPDH activity was determined in a coupled assay, where the NADH produced by IMPDH is utilised by the enzyme Diaphorase to reduce it's substrate, MTT, to give a purple product. The appearance of this product is monitored as an increase in absorbance at 580nm. Assays were performed in a final volume of 100μl containing IMPDH (25 g), NAD (1.1 mM), IMP (2.6mM), Diaphorase (40μg), MTT (0.12mM), 2% DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5. The change in absorbance at 540 nm is read after incubation at 37°C for 60 minutes. To determine the IC5o values, test compounds were prepared at an initial concentration of 1.5 mM in 100% DMSO, then diluted in assay buffer to 0.3mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 10-fold into the assay, to allow testing across the range 1nM to 30μM.
Diaphorase assay To exclude the possibility of identifying compounds that inhibit the Diaphorase component of the coupled assay, all compounds showing inhibition in the IMPDH assay were screened again in a Diaphorase only assay. Assays were performed in a final volume of 100μl containing Diaphorase (0.6μg), NADH (159μM), MTT (0.12mM), 2% DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5. The change in absorbance at 540 nm is read after incubation at 37°C for 60 minutes. Compounds were included at the concentrations used in the coupled assay.
Assay Protocol 2 IMPDH catalyses the NAD dependent oxidation of IMP to XMP with concomitant reduction of the coenzyme. IMPDH activity was determined by monitoring the production of the fluorescent product, NADH. Assays were performed in a final volume of 200μl containing IMPDH (2μg), NAD (100μM), IMP (100μM), 1 % DMSO, 30mM KCI and 100mM Tris/HCI, pH7.5. Fluorescence (excitation 340nm / emission 465nm) was read continuously at 25°C for 30 minutes. From these data, initial rates (i.e. change in fluorescence intensity per minute) were calculated. To determine the IC5o values, test compounds were prepared at an initial concentration of 1.OmM 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 10μM.
The functional effect of the compounds of the invention may be demonstrated using the following assay:
PBMC Proliferation Assay
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 (25μl of 30μg ml solution to each well) was added and the plates were incubated at 37°C in an atmosphere of 95% air/5% C02 for 48 hours. 0.5μCi 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. IC50 values were calculated by plotting inhibitor concentration versus %inhibition.
The assay described above can be carried out using anti-CD3 (40μl of 3750ng/ml concentration to each well) stimulation instead of PHA.

Claims

1. A compound of formula (1):
Figure imgf000046_0001
wherein: R1 is an aliphatic, cycloaliphatic or cycloalkyl-alkyl- group;
R2 is an optionally substituted aromatic, heteroaromatic group, aryl- fused cycloaliphatic, heteroaryl-fused cycloaliphatic, aryl-fused heterocycloaliphatic or heteroaryl-fused heterocycloaliphatic group;
R3 is a -CN, -COR5, -OR6, -CON(R7)R8, S02R5 or S02N(R7)R8 group, in which R5 is an optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, R6 is a hydrogen atom or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group and R7 and R8, which may be the same or different, is each a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;
R4 is an optionally substituted heteroaromatic group; and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.
2. A compound according to Claim 1 , wherein R1 is a Ci-6 alkyl group.
3. A compound according to Claim 2, wherein R1 is a methyl group.
4. A compound according to any one of Claims 1 - 3, wherein R4 is a five- membered heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen.
5. A compound according to Claim 4, wherein R4 is an oxazole group.
6. A compound according to any one of Claims 1 - 5, wherein R2 is an optionally substituted aromatic or heteroaromatic group.
7. A compound according to Claim 6, wherein R2 is an optionally substituted phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl or triazinyl group.
8. A compound according to any one of Claims 1 - 7 wherein R2 is an optionally substituted phenyl, pyridyl, pyridyl-N-oxide, thiazolyl or thiadiazolyl group.
9. A compound according to any one of Claims 1 - 5 wherein R2 is an optionally substituted aryl-fused cycloaliphatic, heteroaryl-fused cycloaliphatic, aryl-fused heterocycloaliphatic or heteroaryl-fused heterocycloaliphatic group.
10. A compound according to Claim 9 wherein R2 is an optionally substituted aryl-fused cycloaliphatic or heteroaryl-fused cycloaliphatic group.
11. A compound according to Claim 9 or Claim 10 wherein R2 is an optionally substituted indanyl group.
12. A compound according to any one of Claims 1 - 11 wherein R3 is a CN, CON(R7)R8 or OR6 group.
13. A compound according to Claim 12 wherein R3 is a CN group.
14. A compound which is:
Λ/-Cyano-N'-(3-Methoxy-4-oxazol-5-yl-phenyl)-N"-phenyl-guanidine;
Λ/-Cyano-{3-[N'-(3-Methoxy-4-oxazol-5-yl-phenyl)-guanidino]benzyl}-carbamic acid fert-butyl ester; Λ/-Cyano-N'-(3-Methoxy-4-oxazol-5-yl-phenyl)-N"-pyridin-3-yl-guanidine;
Λ/-Benzyloxy-/V-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-phenyl-guanidine;
Λ/-Hydroxy-Λ/-(3-methoxy-4-oxazol-5-yl-phenyl)-/V"-phenyl-guanidine;
Λ/-Cyano-Λ/'-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-p-tolyl-guanidine;
Λ/-Cyano-Λ/'-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-(4-methoxy-phenyl)- guanidine;
Λ/-Cyano-/V'-indan-1-yl-Λ/"-(3-methoxy-4-oxazol-5-yl-phenyl)-guanidine;
Λ/-Cyano-/V'-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-(4-morpholin-4-yl-phenyl)- guanidine;
Λ/-Cyano-/V-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-(4-piperidin-1-yl-phenyl)- guanidine
Λ/-Cyano-Λ/-(3-fluoro-phenyl)-Λ/"-(3-methoxy-4-oxazol-5-yl-phenyl)-guanidine;
Λ/-Cyano-/V-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"- [3-(2-methyl-pyrimidin-4-yl)- phenyl]-guanidine;
Λ/-Cyano-/V-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-thiazol-2-yl-guanidine; Λ/-Cyano-/V-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-[1 ,3,4]thiadiazol-2-yl- guanidine;
Λ/-Cyano-/V-(3-methoxy-4-oxazol-5-yl-phenyl)-Λ/"-(1-oxy-pyridin-3-yl)- guanidine; and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.
15. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 14, together with one or more pharmaceutically acceptable carriers, excipients or diluents.
16. A compound according to any one of Claims 1 to 14 for use in the treatment of cancer, inflammatory disorders, autoimmune disorders, psoriatic disorders and viral disorders.
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