WO2003087071A1 - Derives de sulfamide - Google Patents

Derives de sulfamide Download PDF

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Publication number
WO2003087071A1
WO2003087071A1 PCT/GB2003/001418 GB0301418W WO03087071A1 WO 2003087071 A1 WO2003087071 A1 WO 2003087071A1 GB 0301418 W GB0301418 W GB 0301418W WO 03087071 A1 WO03087071 A1 WO 03087071A1
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alk
group
atom
compound according
optionally substituted
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PCT/GB2003/001418
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English (en)
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Alan Findlay Haughan
Hazel Joan Dyke
Sophie Caroline Williams
Christopher Lowe
Alistair George Draffan
David Alan Owen
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Celltech R & D Limited
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Priority to AU2003214472A priority Critical patent/AU2003214472A1/en
Publication of WO2003087071A1 publication Critical patent/WO2003087071A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to a series of sulfonamides, 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. NN. 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. Qpin. Ther. Patents. 11 , pp. 1161-1170, (2001) ). IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases (CR. Gregory et. al., Transplantation. 59, pp. 655-61 , (1995); PCT publication WO 94/12184; and PCT publication WO 94/ 01105).
  • IMPDH has been shown to play a role in viral replication in some virus-infected cell lines. (S.F. Carr, J. Biol. Chem.. 268, pp. 27286-27290, (1993) ). VX-497 is currently being evaluated for the treatment of hepatitis C in humans. Thus, there remains a need for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-inflammatory agents, antipsoriatic and anti-viral agents.
  • the present inventors disclose new potent IMPDH inhibitors based on substituted sulfonamide derivatives.
  • X is an O or S atom
  • Y is an O or S atom
  • A is a group -S0 2 NR R 2 ; m is zero or the integer 1 ; n is zero or the integer 1 ; provided that at least one but not both of m and n are the integer 1 ;
  • R 3 is a hydrogen atom or an alkyl or cycloalkyl group
  • R 1 is the group -Alk 1 -L 1 -Alk 2 -R 4 , in which Alk 1 is a covalent bond or an optionally substituted aliphatic chain, L 1 is a covalent bond or a linking atom or group, Alk 2 is a covalent bond or an optionally substituted aliphatic or heteroaliphatic chain and R 4 is hydrogen atom or an optionally substituted aromatic, heteroaromatic, cycloaliphatic, heterocycloaliphatic group; provided that R 1 is other than a hydrogen atom;
  • R 2 is a hydrogen atom or an alkyl group; or NR 1 R 2 forms an optionally substituted heterocycloaliphatic ring of formula (1a), which may be optionally fused to an optionally substituted aromatic or heteroaromatic group:
  • W is a C or N atom or a N-C- ⁇ -6 alkyl group
  • R 5 which may be attached to any available C or N atom including W, is the group -Alk 1a -L 1a -Alk 2a -R 4a wherein Alk 1a is as herein defined for Alk 1 , L 1a is as herein defined for L 1 , Alk 2a is as herein defined for Alk 2 and R 4a is as herein defined for R 4 ; when two R 5 substituents are attached to the same C atom or to two adjacent C atoms on the group (1a), they may be joined together to form a cycloaliphatic or heterocycloaliphatic 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.
  • R 3 in compounds of formula (1) is a hydrogen atom the following tautomers may also exist as illustrated below:
  • Formula (1) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.
  • 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 pro-drugs 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).
  • Alk 1 , L 1 , Alk 2 , Alk 1a , L 1a or Alk 2a is a covalent bond that the group R 1 or R 5 then consists of one, two or three members.
  • aliphatic group is intended to include optionally substituted straight or branched C ⁇ _ 10 alkyl, e.g. C 1 - 6 alkyl, C 2 - ⁇ oalkenyl e.g. C 2 - 6 alkenyl or C 2 - 10 alkynyl e.g. C 2 - 6 alkynyl groups.
  • Optional substituents when present on those groups include those optional substituents mentioned hereinafter.
  • aliphatic groups include optionally substituted C ⁇ - 6 alkyl groups such as -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , - CH 2 C(CH 3 ) 3 , -C(CH 3 ) 3 , -(CH 2 ) 4 CH 3 , -(CH 2 ) 5 CH 3 , or C- 2 - 6 alkenyl or C 2 - 6 alkynyl groups such as -CHCH 2) -CHCHCH 3 , -CH 2 CHCH 2 , -CHCHCH 2 CH 3 , -CH 2 CHCHCH 3 , -(CH 2 ) 2 CHCH , -CCH, -CCCH 3 , -CH 2 CCH, -CCCH 2 CH 3 ,
  • aliphatic chains include optionally substituted C 1 - 6 alkylene chains such as -CH2-, -CH2CH2-, -CH(CH 3 )CH2-,-(CH 2 )2CH2-, -(CH 2 ) 3 CH2-,
  • -(CH 2 ) 2 CCH- chains More particular examples include optionally substituted C 1 - 3 alkylene chains selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - CH(CH 3 )CH 2 -, -C(CH 3 ) 2 - and -CH 2 CH(CH 3 )- chains.
  • Heteroaliphatic chains represented by Alk 2 or Alk 2a in the compounds of formula (1) include the aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L 3 where L 3 is a linker atom or group.
  • L 3 is a linker atom or group.
  • Each L 3 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
  • Particular examples include optionally substituted -L 3 CH 2 -, -CH 2 L 3 -, -L 3 CH(CH 3 )-, -CH(CH 3 )L 3 -, -CH 2 L 3 CH 2 -, -L 3 CH 2 CH 2 -, -L 3 CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 L 3 -, -CH 2 CH 2 L 3 -, -CH 2 L 3 CH2CH 2 -, -CH 2 L 3 CH 2 CH 2 L 3 -,
  • L 3 When L 3 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(S)-, -S(O)-, -S(0) 2 -, -N(R 6 )- [where R 6 is a hydrogen atom or a straight or branched C*,- 6 alkyl group], -N(R 6 )0- ( -N(R 6 )N-, -C(0)0-, -OC(O) -, -CON(R 6 )-, -OC(0)N(R 6 )-, -CSN(R 6 )-, -N(R 6 )CO-, -N(R 6 )C(0)0-, -N(R 6 )CS-, -S(0) 2 N(R 6 )-, -N(R 6 )S(0) 2 -, -N(R
  • cycloaliphatic group includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C 3 - 10 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.
  • heterocycloaliphatic group refers to an optionally substituted 3 to 10 membered saturated or partially saturated monocyclic or saturated or partially saturated multicyclic hydrocarbon ring system containing one, two, three or four L 2 linker atoms or groups.
  • L 2 atoms or groups include any atom or linker group as described hereinbefore in relation to L 3 .
  • Optional substituents present on the heterocyloaliphatic groups include those substituents mentioned hereinafter.
  • heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyciopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e.g. 1 ,3- dioxolanyl, imidazolinyl, e.g.
  • 2-imidazolinyl imidazolidinyl, pyrazolinyl, e.g. 2- pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g.
  • Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom.
  • Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon or, where available, ring nitrogen atom.
  • R 4 or R 4a in compounds of formula (1) is an optionally substituted heterocycloaliphatic or cycloaliphatic ring, these may optionally be fused to an optionally substituted monocyclic C 6 . 12 aromatic group, such as phenyl or an optionally substituted monocyclic C* ⁇ - 9 heteroaromatic group containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • the optional substituents which may be present on the aliphatic, cycloaliphatic or heterocycloaliphatic groups or chains include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH 2 ), substituted amino, optionally substituted C 6 - 12 arylamino, optionally substituted C* ⁇ - 6 alkyl, -CN, -C0 2 H, -C0 2 R 7 (where R 7 is an optionally substituted Ci- ⁇ alkyl group), -S0 3 H, -SOR 8 (where R 8 is a C-
  • R 9 and R 10 which may be the same or different is each a hydrogen atom or a C* ⁇ - 6 alkyl group
  • R 9 and R 10 which may be the same or different is each a hydrogen atom or a C* ⁇ - 6 alkyl group
  • R 9 and R 10 which may be the same or different is each a hydrogen atom or a C* ⁇ - 6 alkyl group
  • -OC(0)N(R 9 )(R 10 ) -N(R 9 )C(0)R 1 °
  • -CSN(R ⁇ )(R i o) -N(R 9 )C(S)(R 10 ), -S0 2 N(R 9 )(R 1 °)
  • R 6 , R 6a , R 7 , R 8 , R 9 , R 10 or R 11 is present as a C*
  • 6 alkyl group it may be a straight or branched C-i-e alkyl group e.g. a C 1 - 3 alkyl group such as methyl, ethyl or i-propyl.
  • Optional substituents which may be present on R 7 include for example one, two or three substituents which may be the same or different selected from fluorine, chlorine, bromine or iodine atoms or hydroxy or C ⁇ - 6 alkoxy e.g. methoxy or ethoxy groups.
  • halogen atom is intended to include fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, and -CH 2 C1 groups.
  • alkoxy as used herein is intended to include straight or branched C ⁇ _ ⁇ 0 alkoxy for example C* ⁇ - 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 t - 10 alkylthio, e.g. C ⁇ alky-lt-hio such as methylthio or ethylthio groups.
  • aromatic group and "aryl group” are intended to include for example optionally substituted monocyclic ring C 6 -** 2 aromatic groups, such as phenyl, or bicyclic fused ring C 6 - 12 aromatic groups, such as, 1- or 2-naphthyl groups.
  • heteroaryl 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, sulfur or nitrogen atoms (or oxidised versions thereof). 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, sulfur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example eight- to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Each of these aromatic or heteroaromatic groups may be optionally substituted by one, two, three or more R 12 atoms or groups as defined below.
  • monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl or imidazolonyl.
  • bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo[1 ,2-a]pyridyI, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl or phthalazinyl.
  • R 4 or R 4a heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
  • Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R 12 in which R 12 is -R 12 a or -Alk 3 (R 2 * a ) f , where R 12a is a halogen atom, or an amino (-NH 2 ), -NHR 13 [where R 13 is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl, heteroaryl group or -Alk 3 (R 13a ) f where R 13a is the same as R 13 ], -N(R 13 ) 2 , nitro, cyano, amidino, formyl, hydroxy (OH), carboxyl (-C0 2 H), -C0 2 R 13 , 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 12 include fluorine, chlorine, bromine or iodine, C- ⁇ - 6 alkyl, haloC ⁇ alkyl, e.g. -CF 3 , haloC* ⁇ - 6 alkoxy, e.g.
  • R 13 groups include -Alk 3 (where f is zero), optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic, -Alk 3 phenyl, -Alk 3 monocyclic heteroaryl, -Alk 3 monocyclic heterocycloaliphatic or -Alk 3 cycloaliphatic.
  • R 4 is particularly hydrogen or methyl.
  • Alk 3 When Alk 3 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 14 )- groups.
  • Alk 3 include C-i- ⁇ alkylene chains especially C 1 -3 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 12a , R 13 or -R 13a include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, N-C 1 - 6 alkylpiperazinyl, especially N-methylpiperazinyl, N-C- ⁇ - 6 alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-C 1 -6 alkylpiperidinyl, especially N- methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetra
  • Optional substituents which may in particular be present on the aryl or heteroaryl groups represented by -R 12a , R 13 or -R 13a 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 , -C0 2 C(CH 3 )3, -COCH 3 , -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 1 a , R 13 or -R 13a 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 d- 3 alkyl, -CN, NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCHs, 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.
  • two adjacent R 12 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C ⁇ - 6 alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 - ⁇ cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • a cyclic ether e.g. a C ⁇ - 6 alkylenedioxy group such as methylenedioxy or ethylenedioxy or a C 3 - ⁇ cycloalkyl or 3-10 membered monocylic heterocycloaliphatic group as defined herein.
  • R 12 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
  • Examples of aliphatic chains which may represent Alk 1 , Alk 1a , Alk 2 or Alk 2a include C*i- 6 alkylene chains (wherein the terminal hydrogen atom of a C ⁇ - 6 alkyl group is replaced by a covalent bond), as herein described. More particular examples include C* ⁇ - 3 alkylene chains, such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-.
  • alkyl groups which may represent R 3 include C ⁇ - 6 alkyl groups as herein described. More particular examples include C* ⁇ - 3 alkyl groups, such as -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 )CH 3 .
  • cycloalkyl groups which may represent R 3 include C 3 - ⁇ cycloalkyl groups, such as those described previously.
  • alkyl groups which may represent R 2 are as defined herein for R 3 alkyl groups.
  • Particular examples of R 13 groups present in esterified carboxyl groups of formula -C0 2 R 13 include C* ⁇ - 6 alkyl groups optionally substituted with R 13a 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.
  • One particular group of compounds of the invention has the formula (1) wherein X is a S atom.
  • One particular group of compounds has the formula (1) wherein Y is an O atom.
  • Another group of compounds of the invention has the formula (1) wherein Y is a S atom.
  • a particular group of compounds of the invention has the formula (1) wherein n is zero and m is the integer 1.
  • a particularly useful group of compounds of the invention has the formula (2):
  • R 1 , R 2 and R 3 are as described for formula (1); and the salts, solvates, hydrates, tautomers, isomers, N-oxides thereof.
  • R is the group -Alk 1 -L 1 -Alk 2 -R 4 and R 2 is a hydrogen atom or a C 1 - 3 alkyl group, especially a methyl group.
  • R 1 is most especially the group -Alk 1 -R 4 .
  • Another particularly preferred group of compounds of formulae (1) or (2) has the formula (3):
  • R 3 is a hydrogen atom or a C- ⁇ - 6 alkyl group. Especially preferred is when R 3 is a C 1 - 3 alkyl group, particularly methyl or isopropyl.
  • One particular group of compounds of the invention has the formulae (1), (2) or (3) in which the sum of s + 1 is zero, 1 , 2 or 3.
  • Alk 1 or Alk 1 is each particularly a covalent bond or an optionally substituted C 1-6 alkylene chain. Especially preferred is when Alk 1 or Alk 1a is a covalent bond or an optionally substitued C-1-3 alkylene chain, particularly, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Optional substituents which may in particular be present on Alk 1 or Alk 1a include d- 3 alkoxy e.g.
  • L 1 in compounds of formulae (1) or (2) is especially a covalent bond or a linking atom or group selected from -0-, -C(O)-, -NH- or -NCH 3 -.
  • L 1a is a -0-, -C(O)-, -S(0) 2 -, -C(0)0- or -CON(R 6 )- group.
  • R 6 and R 6a are especially a hydrogen atom or a methyl group.
  • Alk 2 in the group R 1 is especially a covalent bond or a C ⁇ - 3 alkylene chain, particularly -CH 2 -, -CH 2 CH 2 - or -(CH 2 ) 2 CH 2 -.
  • Alk 2a in the group R 5 is particularly a covalent bond or a straight or branched C 1 - 6 alkylene chain.
  • Particular examples include -CH 2 -, -CH 2 CH 2 -, - CH(CH 3 )CH 2 -, -(CH 2 ) CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 - or -CH 2 C(CH 3 ) 2 CH 2 -.
  • R ⁇ 4 in one particular group of compounds of the invention is a hydrogen atom.
  • R 4 in one class of compounds of formulae (1) or (2) is in particular an optionally substituted aromatic, heteroaromatic or heterocycloaliphatic group.
  • R 4 in compounds of this type is especially an optionally substituted 3-10 membered saturated monocyclic heterocycloaliphatic, phenyl or heteroaromatic group.
  • Particular R 4 examples include optionally substituted azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, N-C- ⁇ - 6 alkylpiperazinyl, especially N-methylpiperazinyl, N-C 1 - 6 alkylpyrrolidinyl, especially N-methylpyrrolidinyl, N-C 1 .
  • alkylpiperidinyl especially N-methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-d.
  • R 4 is an optionally substituted morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N- C ⁇ - 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or pyridyl-N-oxide group.
  • R 4a in one particular group of compounds of the invention is a hydrogen atom.
  • R 4a is an optionally substituted aromatic or heteroaromatic group.
  • Particular R 4a examples include optionally substituted phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C* ⁇ - 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl or iso
  • heterocycloaliphatic ring of formula (1a) is fused to an optionally substituted phenyl ring.
  • the heterocycloaliphatic ring of formula (1a) contains two R 5 substituents attached to the same C atom which link to form a heterocycloaliphatic ring, especially 1 ,3-dioxolanyl.
  • Particular aryl or heteroaryl substituents which may be present on compounds of formulae (1), (2) or (3), in particular on the groups R 4 or R 4a include one, two, three or more atoms or groups selected from fluorine, chlorine, bromine, iodine, optionally substituted straight or branched C ⁇ _ 6 alkyl, 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) 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 , C0 2 H; optionally substituted morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl
  • C ⁇ - 3 alkyl groups especially methyl, ethyl or propyl optionally substituted with CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCHs, 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 , -N(CH 3 )C(0)OC(CH 3 ) 3 , -NHC(0)OC(CH 3 ) 3 , -SCH 3 , -S0 2 CH 3 or C0 2 H.
  • optionally substituted aryl or monocyclic heteroaryl groups in substituents of this type include phenyl, pyrrolyl, furyl, thienyl, imidazolyl, N-C ⁇ - 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl or pyridyl-N-oxide, where the optional substituent includes one, two, three or more atoms or groups selected from fluorine, chlorine, straight or branched C 1 - 6 alkyl e.g methyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, NHCH 3 , N(CH 3 , N
  • One group of compounds of the invention has the formulae (1), (2) or (3) wherein R 4 or R 4a is optionally substituted with one, two, three or more atoms or groups selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, OCF 3 , OCF 2 H, CF 3 , CN, C0 2 CH 3 , oxazolyl, phenyl, or two adjacent substituents link to form a methylenedioxy or dihydrofuranonyl group.
  • One particular group of aliphatic, especially alkyl, cycloaliphatic or heterocycloaliphatic substituents, which may be present on the compounds of formulae (1), (2) or (3) are one, two, three or more groups selected from C 1 - 3 alkoxy, OCF 3 , OCF 2 H, CF 3 , C ⁇ - 3 alkyithio, optionally substituted straight or branched C 1 .
  • 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 , -NHCOCH3, -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, phenyl, 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 ,
  • Particular compounds of the invention include: 2-methyl-3-oxo-2,3-dihydrobenzo[c/]isothiazole-5-sulfonic acid (2-ethyl- phenyl)amide;
  • 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 formulae (1), (2) or (3) 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, multiple sclerosis, atopic dermatitis, transplant rejection or rheumatoid arthritis.
  • the compounds of the present invention are of particular use for the treatment of DNA or RNA viral replication diseases, such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • DNA or RNA viral replication diseases such as hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, human immundeficiency virus (HIV) and influenza.
  • the compounds of the present invention are of particular use for the treatment of cancer and tumour disorders, such as solid tumors, lymphoma, leukemia and other forms of cancer.
  • the compounds of formulae (1), (2) or (3) 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 formulae (1), (2) or (3) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions of this invention comprise a compound of formulae (1), (2) or (3) 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-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, ciprostene, trapidil, eicosapentanoic acid, ACE inhibitors, low molecular weight heparin, and rapamycin.
  • Additional anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, amsacrine, mitoxantrone, doxorubicin, vincristine, vinblastine, etoposide, 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.
  • therapeutic agents when employed in combination with the compounds of the present invention, may be used, for example, in amounts generally indicated for use in standard formularies (e.g. in the Physician's Desk Reference (PDR)) or as determined using routine pharmaceutical dosing methods.
  • PDR Physician's Desk Reference
  • 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 formulae (1), (2) or (3) 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 formulae (1), (2) or (3) may be coated on particles such as microscopic gold particles.
  • the compounds of formulae (1), (2) or (3) 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 formulae (1), (2) or (3) 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 which is a solid at room temperature but liquid at the body temperature.
  • Such materials include for example cocoa butter and polyethylene glyco
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-known standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.
  • R 1 , R 2 , R 3 etc when used in the formulae depicted are to be understood to represent those groups described above in relation to formulae (1), (2) or (3) 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 formulae (1), (2) or (3) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
  • a compound of formulae (1), (2) or (3) where Y is an O atom may be prepared by following the general route as shown in Scheme A:
  • an amine of formula (ii) may be reacted with a sulfonyl chloride of formula (i) using appropriate conditions to give a compound of formula (1).
  • R 2 in the amine of formula (ii) is a hydrogen atom
  • a base such as pyridine in a halogenated hydrocarbon e.g. dichloromethane may be used.
  • R 2 in amines of formula (ii) is an alkyl group
  • a base such as sodium hydride in a solvent such as ⁇ /, ⁇ /-dimethylformamide (DMF) may be employed.
  • a compound of formula (1) where R 2 is a hydrogen atom may be further manipulated by alkylation of the sulfonamide using standard conditions to give a compound of formula (1) where R 2 is an alkyl group.
  • the amines of formula (ii) may be available commercially or prepared using methods known to those skilled in the art.
  • a compound of formula (i) may be prepared using a variety of conditions.
  • X is a S atom and Y is an O atom
  • the general Scheme B may be used:
  • a compound of formula (iii) (which may be commercially available or made using methods known to those skilled in the art) may be reacted with an activating agent such as thionyl chloride, to give an intermediate acid choride.
  • the resulting acid chloride may then be reacted with an amine of formula (iv) (which may be commercially available or made using methods known to those skilled in the art), using standard methodology or methods as described herein for sulfonamide formation to give an amide of formula (v).
  • the compound of formula (v) may be cyclised using appropriate conditions such as treatment with bromine in carbon tetrachlo ide followed by reflux in acetic acid to yield a compound of formula (vi). See also US 6, 191 , 275.
  • the nitro group in compounds of formula (vi) may be reduced to an amine, for example using hydrogen in the presence of palladium on carbon, to give an amine of formula (vii).
  • These amines may converted to compounds of formula (i) for example, by initial diazotization using sodium nitrite in the presence of concentrated hydrochloric acid, acetic acid and water at a suitable temperature e.g. -5-0°C followed by addition of acetic acid saturated with sulfur dioxide, copper (I) chloride and warming to room temperature.
  • the analogues of the compounds of formula (vi) where Y is an O atom may be prepared using literature methodology. See, for example, Wr ⁇ bel et al Z. Chem. 1980, 20(1), 18 or Chem. Ber. 1967, 100(3), 954-960.
  • a compound of formula (viii) may be reacted with excess chlorosulfonic acid to give a sulfonyl chloride of formula (i) as shown.
  • Appropriate conditions may include treatment of the compound of formula (ix) with oxalyl chloride in dioxane in the presence of catalytic DMF followed by addition of excess methylamine in DMF to afford the corresponding analogue of the compound of formula (vi).
  • compounds of formulae (1), (2) or (3) 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 formulae (1), (2) or (3) or any preceding intermediates where appropriate functional groups exist in these compounds.
  • the compounds where Y is an O atom may be converted to compounds where Y is a S atom, for example, by reaction with Lawesson's reagent in a suitable solvent, such as tetrahydrofuran.
  • ester groups when present may be converted to the corresponding acid [-C0 2 H] by acid- or base-catalysed hydrolysis depending on the nature of the ester.
  • 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 [-C0 2 H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as 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 formulae (1), (2) or (3) 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 formulae (1), (2) or (3) may be prepared by reaction of a compound of formulae (1), (2) or (3) 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 formulae (1), (2) or (3) 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.
  • diastereomeric derivatives e.g. salts
  • a mixture of enantiomers of formulae (1), (2) or (3) 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 formulae (1), (2) or (3) 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.
  • the ability of the compounds of the invention to inhibit the IMPDH enzymes may be determined using the following assays: Abbreviatons used:
  • 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 /I 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 1 nM to 30 ⁇ M.
  • IMPDH activity was determined by monitoring the production of the fluorescent product, NADH. Assays were performed in a final volume of 200//I containing IMPDH (2/yg), NAD (100//M), IMP (100/vM), 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 this data, initial rates (i.e. change in fluorescence intensity per minute) were calculated. To determine the IC 50 values, test compounds were prepared at an initial concentration of 1.0mM in 100% DMSO, then diluted in assay buffer to 0.2mM. Further dilutions were made in assay buffer containing 20% DMSO, prior to diluting 20-fold into the assay, to allow testing across the range 0.3nM to 10 /M.
  • Peripheral blood mononuclear cells were isolated from freshly taken human blood using standard procedures. Cells were plated out in RPMI medium containing 5% human serum in the presence and absence of inhibitor. PHA (25 ⁇ l of 30 ⁇ g/ml solution to each well) was added and the plates were incubated at 37°C in an atmosphere of 95% air/5% C0 2 for 48 hours. O. ⁇ Ci of tritiated thymidine was added to each well and the plates were incubated for a further 18 hours. The contents of the plate were transferred to a filter plate and the cells washed with saline. The plates were dried, microscintillation fluid was added to each well and the plate was counted on a scintillation counter. IC 5 o values were calculated by plotting inhibitor concentration versus %inhibition.
  • the assay described above can be carried out using anti-CD3 (40 ⁇ l of 3750ng/ml concentration to each well) stimulation instead of PHA.

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Abstract

L'invention concerne des dérivés de sulfamide de formule (1), dans laquelle X représente un atome d'oxygène ou de soufre, Y représente un atome d'oxygène ou de soufre, A représente un groupe -S02NR1R2, m est égal à zéro ou est le nombre entier 1, n est égal à zéro ou est le nombre entier 1, à condition qu'au moins m ou n soit le nombre entier 1, R3 représente un atome d'hydrogène ou un groupe alkyle ou cycloalkyle. Cette invention a également trait aux sels, aux solvates, aux hydrates, aux tautomères, aux isomères, aux N-oxydes associés. Ces composés sont de puissants inhibiteurs de l'IMPDH et sont utilisés en tant qu'immunosuppresseurs, agents anticancéreux, agents anti-inflammatoires, agents antipsoriasiques et agents antiviraux.
PCT/GB2003/001418 2002-04-10 2003-04-01 Derives de sulfamide WO2003087071A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide
CN110128369A (zh) * 2019-05-27 2019-08-16 东南大学 苯并[d]异噻唑-3(2H)-酮衍生物及其制备方法和应用

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1996038144A1 (fr) * 1995-05-31 1996-12-05 Warner-Lambert Company Isothiazolones
WO1998040381A1 (fr) * 1997-03-14 1998-09-17 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme impdh

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038144A1 (fr) * 1995-05-31 1996-12-05 Warner-Lambert Company Isothiazolones
WO1998040381A1 (fr) * 1997-03-14 1998-09-17 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme impdh

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Title
A. M. BADAWI ET AL.: "Studies on amebicidal agents: II. Synthesis and amebicidal activity of toluene-2,4-bis-sulfon-N-anilides", ORIENTAL JOURNAL OF CHEMISTRY, vol. 2, no. 1, 1986, IQBAL, BHOPAL,, IN, pages 40 - 44, XP008086305, ISSN: 0970-020X *
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002246520 *
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002246521 *
I. B. HANNOUT ET AL.: "Sulfonamides of expected biological activity. I. Disulfonamides active against cotton leaf worm, Spodoptra littoralis", JOURNAL FUER PRAKTISCHE CHEMIE, vol. 316, no. 5, 1974, LEIPZIG, DE, pages 866 - 874, ISSN: 0021-8383 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide
CN110128369A (zh) * 2019-05-27 2019-08-16 东南大学 苯并[d]异噻唑-3(2H)-酮衍生物及其制备方法和应用

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