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WO2009136144A1 - Dérivés de purine appropriés pour le traitement du cancer, des maladies auto-immunes et inflammatoires - Google Patents

Dérivés de purine appropriés pour le traitement du cancer, des maladies auto-immunes et inflammatoires Download PDF

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WO2009136144A1
WO2009136144A1 PCT/GB2009/001115 GB2009001115W WO2009136144A1 WO 2009136144 A1 WO2009136144 A1 WO 2009136144A1 GB 2009001115 W GB2009001115 W GB 2009001115W WO 2009136144 A1 WO2009136144 A1 WO 2009136144A1
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group
alkyl
fused
unsubstituted
phenyl
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David Charles Festus Moffat
Kenneth William John Baker
Alistair David Graham Donald
Francesca Ann Day
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Chroma Therapeutics Ltd
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Chroma Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • This invention relates to a series of amino acid derivatives, to compositions containing them, to processes for their preparation and to their use in medicine as HSP90 inhibitors.
  • the compounds may also be of use in the treatment of cell proliferative diseases such as cancer which are mediated by inappropriate HSP90 activity as well as inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and endometriosis.
  • the compounds may also be of use in the protection of normal cells against the action of cytotoxic agents.
  • the present invention encompasses compounds that are derivatives of adenine.
  • HSPs heat shock proteins
  • HSP90 Heat shock protein 90
  • HSP90 comprises as much as 1-2% of total cellular protein content, whereas in tumour cells it is expressed at levels 2- to 10-fold higher in comparison to normal cells.
  • These chaperone proteins are required for essential housekeeping functions, such as de novo protein folding during nascent polypeptide-chain synthesis, translocation of proteins across membranes and normal protein turnover.
  • HSPs also participate in higher-order functions such as post-translational regulation of signalling molecules [Csermelt et al, Pharmacol. Ther, 1998, 79, 129-168], the assembly and disassembly of transcriptional complexes [Science 2002, 296, 2232-2235] and the processing of immunogenic peptides by the immune system.
  • HSPs function as components of multi-protein complexes which contain other chaperones, co-chaperones, modulators of ATPase activity and various accessory proteins.
  • the components of the HSP90 chaperone complex include HSP70 ,HSP40, HIP, HOP, CDC37/p50, AHAl, p23 and immunophilin. Chaperones typically interact with client proteins in a cyclical, iterative fashion which is driven by ATP hydrolysis, [Smith et al, MoI. Cell Biol. 1995, 15, 6804-6812]. Targeting the nucleotide-binding pockets of HSP90 with small molecules may therefore provide a method of modulating the activity of the chaperone complex.
  • HSP90 is unique amongst the chaperones as it is not required for biogenesis of most polypeptides. Many of its client proteins are conformationally labile signal transducers which are critical to cell growth and survival, [Pratt et al, Proc. Soc. Exp. Biol. Med., 1998, 217, 420-431]. Post-translational interactions with its clients allows HSP90 to couple stress response to changes in signal transduction pathways and transcriptional responses, [Morimoto et al, Cell, 2002, 110, 281-284]. Studies in
  • HSP90 Drosophila melanogaster have demonstrated that compromising the function of HSP90 can induce epigenetic alteration in gene expression as well as heritable alterations in chromatin state [Solars et al, Nature Genet. 2003, 33, 70-74 and Sangster et al, Cell Cycle, 2003, 2, 166-168].
  • a common feature of both solid and haematological malignancies is increased expression of one or more HSPs.
  • Overexpression of HSP90 in breast cancer correlates with poor prognosis [Jameel et al, hit. J. Cancer 1992, 50, 409-415].
  • Increased chaperone expression contributes to oncogenesis at several levels.
  • Increased abundance of HSPs in advanced cancers reflects an appropriate cytoprotective stress response to hypoxic and acidotic microenvironment of the tumour.
  • increased chaperone activities appear to allow tumour cells to tolerate the deregulation in intracellular signalling associated with neoplastic transformation and thereby provide a mechanism for tumour cells to avoid apoptosis [Mosser et al, Oncogene 2004, 23, 2907].
  • the modulation of tumour cell apoptosis by HSP90 and its co-chaperones is mediated through effects on AKT, [Basso et al, J. Biol. Chem., 2003, 277, 39858-39866], tumour necrosis factor (TNF) receptors [Vanden Bergh et al, J. Biol. Chem. 2003, 278, 5622-5629] and NF- ⁇ B function [Chen et al, MoI. Cell, 2002, 9, 401-410].
  • kinases are client proteins of HSP90 including several which play a significant role in the progression of malignant phenotype such as HER2, AKT and RAF-I, [Neckers et al, Trends MoI. Med. 2002, 8, S55-S61].
  • Ligand-dependent transcription factors e.g. steroid receptors
  • transcription factors e.g. HIF- l ⁇
  • mutated or chimeric signalling proteins mutated p53, NPM-ALK kinase, p210 Bcr"AbI
  • client proteins are involved other fundamental processes of tumorigenesis, namely apoptosis evasion (e.g. Apaf-1, RIP), immortality (e.g. hTert), angiogenesis (e.g. VEGFR, Flt-3, FAK, HIF-I) and metastasis (c-Met).
  • HSP90 resides predominantly in the cytoplasm, where it exists at a homodimer. Each monomer is comprised of three main domains.
  • the N-terminal domain contains an unusual adenine nucleotide-binding pocket defined by a Bergerat fold, [Dutta et al, Trends Biochem. Sci., 2000, 25, 24-28].
  • Structural alterations driven by the hydrolysis of ATP in this fold appear to have an essential role in the chaperoning activity of the HSP90 dimer.
  • a highly charged linker sequence connects the N-terminal domain to the 'middle region' of HSP90.
  • This middle region indicates that is has an important role in modulating ATP hydrolysis by interacting with the ⁇ -phosphate of ATP molecules bound to the protein, [Meyer et al, MoI. Cell 2003, 11, 647-658].
  • the N-terminal ATP- binding site is also the site of interaction of the structurally unrelated natural products geldanamycin and radicicol. These compounds prevent the chaperone from cycling between its ADP- and ATP-bound conformations.
  • Drug binding at the N-terminus of HSP90 seems to recruit E3 ubiquitin ligases such as CHIP (carboxy terminus of HSP70- interacting protein) to the many client proteins that are normally expressed by HSP90 protein complexes [Xu et al, Proc. Natl. Acad. Sci., 2002, 99, 12847-12852]. This recruitment leads to proteosomal degradation of the clients and depletion of their cellular levels.
  • HSP90 inhibitors induce a predominant Gl cell-cycle arrest in a p53-independent manner, [Mcllwrath et al, Cancer Chemother. Pharmacol. 1996, 37, 423-428].
  • Disruption of anti-apoptotic signalling in tumour cells occurs following exposure to HSP90 inhibitors and can enhance the pro-apoptotic effects of cytotoxic agents [Basso et al, Oncogene 2002, 21, 1159-1162].
  • the compounds are thus of use in medicine, for example in the treatment of a variety of proliferative disease states, where inappropriate action of HSP90 may be involved such as cancer, inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and endometriosis.
  • the compounds may also be of use in the protection of normal cells against the action of cytotoxic agents.
  • the invention provides a compound which is (a) an amino acid derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:
  • R 1 represents a hydrogen or halogen atom, or a cyano, nitro, -N 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, C 2-6 alkenyloxy, hydroxyl, -SR', Ci -6 alkylthio, C 2-6 alkenylthio, guanidine, amidine, -NR'R", -NR" OR' or -NR'"R'R” group wherein each R', R" and R'" group is the same or different and represents hydrogen or Ci -4 alkyl, or represents a group of formula -COOH, -COOR A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -C0NHR A , -SO 2 NHR A , -C0NR A R B , -SO 2 NR A R B , -OCONH 2 ,
  • A represents a C 6- Io aryl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further C 6-I0 aryl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group;
  • W is a group of formula -[CH 2 ] Z -Y 1 -L 2 -R, wherein: z is 0 or 1 ;
  • Q either (i) represents a phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-metnbered heterocyclyl group; or (ii) in the case where p is 0, represents a group of formula -Q 1 Ot 1 - wherein X 1 represents -O-, -S- or -NR 5 - wherein R 5 is hydrogen or C 1-4 alkyl, and Q 1 represents a phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; AIk 1 and AIk 2 are the same or different and represent C 3-7
  • R 7 is a group -COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group;
  • R 9 represents hydrogen, a Ci -6 alkyl group, a phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, or R 9 represents a group of formula
  • AIk 4 represents a C 1-6 alkylene group and Cyc represents a phenyl, 5- to 10-membered heteroaryl or 5- to 10- membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, and R 10 represents hydrogen or Ci -6 alkyl, or wherein R 8 represents a phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; and
  • R 19 represents a Ci -6 alkyl group or a group -L 3 -B where L 3 represents a bond or a Ci -6 alkylene and B represents a C 6-10 aryl or 5- to 10-membered heteroaryl group; wherein the alkyl, alkylene, alkenyl and alkynyl moieties in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 19 , AIk 1 , AIk 2 and AIk 3 are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, C 2-4 alkenyloxy, Ci -4 haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -
  • R 9 , R 19 , A, B, Q, Q 1 and D are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 1-4 alkylene, C 2-4 alkenyl, C 1-4 alkoxy, C 2 ⁇ alkenyloxy, C 1-4 haloalkyl, C 2 ⁇ haloalkenyl, C 1-4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C 1-4 hydroxyalkyl, C 2-4 hydroxyalkenyl, Ci -4 alkylthio, C 2- 4 alkenylthio, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl, and groups of formula -COOH, -COOR A , -COR A , -SO 2 R A , -
  • R A and R B are the same or different and represent Ci -6 alkyl, C 3-6 cycloalkyl, phenyl or a non-fused 5- to 6-membered heteroaryl, or R A and R B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group.
  • the compounds of the invention are characterised by the presence in the molecule of an amino acid motif or an amino acid ester motif which is hydrolysable by an intracellular carboxylesterase.
  • Compounds of the invention can cross the cell membrane, and, if in the ester form, can be hydrolysed to the acid by the intracellular carboxylesterases.
  • the polar hydrolysis product accumulates in the cell since it does not readily cross the cell membrane. Hence the HSP90 activity of the compound is prolonged and enhanced within the cell.
  • the compounds of the invention are compounds of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound as defined above in the manufacture of a medicament for inhibiting the activity of HSP90. More preferably, the invention provides the use of a compound as defined above in the manufacture of a medicament for use in treating a disorder mediated by HSP90.
  • the compounds with which the invention is concerned may be used for the inhibition of HSP90 activity ex vivo or in vivo.
  • the compounds of the invention may be used in the preparation of a composition for treatment of cancer, inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and endometriosis.
  • the compounds may also be of use in the protection of normal cells against the action of cytotoxic agents.
  • the invention provides a method for the treatment of the foregoing disease types, which comprises administering to a subject suffering such disease an effective amount of a compound as defined above.
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene moieties in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 19 , AIk 1 , AIk 2 and AIk 3 are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C M alkyl, C 2 -4 alkenyl, C M alkoxy, C 2 ⁇ alkenyloxy, CM haloalkyl, C 2-4 haloalkenyl, C M haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C M hydroxyalkyl, C 2 ⁇ hydroxyalkenyl, C M alkylthio, C 2 _4 alkenylthio, -NR'R" groups
  • Preferred substituents include halogen atoms and C 1-4 alkyl, C 2 ⁇ t alkenyl, C M alkoxy, C 2-4 alkenyloxy, C M haloalkyl, C 2-4 haloalkenyl, C M haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C M hydroxyalkyl, C 2-4 hydroxyalkenyl, C M alkylthio, C 2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl.
  • substituents include halogen, C 1-4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, hydroxyl, C M haloalkyl, C 2-4 haloalkenyl, C 1-4 haloalkyloxy, C 2-4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl. More preferred substituents are halogen, C 1-2 alkoxy, C 1-2 haloalkyl, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl. In particular, it is preferred that R' and R" are unsubstituted.
  • alkyl, alkylene, alkenylene and alkynylene moieties are substituted by two or three substituents, it is preferred that not more than two substituents are selected from cyano and nitro. More preferably, not more than one substituent is selected from cyano and nitro.
  • alkyl, alkylene, alkenylene and alkynylene moieties are substituted by two or three substituents
  • a C 1-6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example a C M alkyl group or moiety containing from 1 to 4 carbon atoms.
  • Examples Of Ci -4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • the alkyl moieties may be the same or different.
  • a C 2-6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, for example a C 2-4 alkynyl group or moiety containing from 2 to 4 carbon atoms.
  • two alkynyl moieties are present in a group, they may be the same or different.
  • a Ci -6 alkylene group or moiety is a linear or branched alkylene group or moiety, for example a C M alkylene group or moiety.
  • Examples include methylene, n-ethylene, n-propylene and -C(CH 3 ) 2 - groups and moieties.
  • a C 2-6 alkenylene group or moiety is a linear or branched alkenylene group or moiety, for example a C 2-4 alkenylene group or moiety.
  • a halogen atom is typically chlorine, fluorine, bromine or iodine.
  • a C 1-6 alkoxy group or C 2 ⁇ alkenyloxy group is typically a said C 1-6 alkyl (e.g. a C 1-4 alkyl) group or a said C 2-6 alkenyl (e.g. a C 2-4 alkenyl) group respectively which is attached to an oxygen atom.
  • a haloalkyl, haloalkenyl, haloalkoxy or haloalkenyloxy group is typically a said alkyl, alkenyl, alkoxy or alkenyloxy group respectively which is substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX 3 and -OCX 3 wherein X is a said halogen atom, for example chlorine and fluorine.
  • a Ci -4 alkylthio or C 2-4 alkenylthio group is typically a said C M alkyl group or a C 2-4 alkenyl group respectively which is attached to a sulphur atom, for example -S-CH 3 .
  • a Ci -4 hydroxyalkyl group is a Ci -4 alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group.
  • a phenyl ring When a phenyl ring is fused to a further phenyl, 5- to 10-membered heterocyclyl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, it is preferably fused to a further phenyl, 5- to 6-membered heterocyclyl, C 3-7 carbocyclyl or 5- to 6-membered heterocyclyl group, more preferably to a 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group.
  • preferred 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, dithiolanyl, dioxolanyl, oxazolidinyl, imidazolyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, thioxolanyl, thiazolidinyl and isothiazolidinyl, more preferably oxazolidinyl, imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl and dithiolanyl, most preferably dioxolanyl.
  • a 5- to 10- membered heteroaryl group or moiety is a monocyclic 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2, 3 or 4 heteroatoms, selected from O, S and N. When the ring contains 4 heteroatoms these are preferably all nitrogen atoms.
  • Examples include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazolyl groups.
  • Thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups are preferred, e.g. pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups.
  • More preferred groups are imidazolyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, e.g. imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl.
  • a particularly preferred group is imidazolyl.
  • a heteroaryl group or moiety When a heteroaryl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-7 carbocyclyl group. Preferably it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring, more preferably it is fused to a phenyl group.
  • Examples include benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benztriazolyl, indolyl, isoindolyl and indazolyl groups.
  • Preferred groups include indolyl, isoindolyl, benzimidazolyl, indazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzisothiazolyl groups, more preferably indolyl, benzimidazolyl, benzoxazolyl and benzothiazolyl, more preferably indolyl and benzothiazolyl, most preferably indolyl.
  • a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C 5- io carbocyclic ring in which one or more, for example 1, 2, 3 or 4, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O) 2 , and wherein one or more of the remaining carbon atoms is optionally replaced by a group -C(O)- or -C(S)-.
  • one or more of the remaining carbon atoms is replaced by a group -C(O)- or -C(S)-, preferably only one or two (more preferably two) such carbon atoms are replaced.
  • the 5- to 10- membered heterocyclyl ring is a 5- to 6- membered ring.
  • Suitable heterocyclyl groups and moieties include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, methylenedioxyphenyl, ethylenedioxyphenyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S,S-dioxo-thi
  • Preferred heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, thiomorpholinyl and morpholinyl groups and moieties.
  • heterocyclyl groups are tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl and pyrrolidinyl groups, and variants where one or two ring carbon atoms are replaced with -C(O)- groups.
  • Particularly preferred groups include tetrahydrofuranyl and pyrrolyl-2,5- dione.
  • heterocyclyl group or moiety When a heterocyclyl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-7 carbocyclyl group, more preferably to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group. Preferably it is monocyclic (i.e. it is unfused).
  • heteroaryl and heterocyclyl groups refer to an "N" moiety which can be present in the ring, as will be evident to a skilled chemist the N atom will be protonated (or will carry a substituent as defined below) if it is attached to each of the adjacent ring atoms via a single bond.
  • a C 3-7 carbocyclic group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 7 carbon atoms.
  • it is a saturated or mono-unsaturated hydrocarbon ring (i.e. a cycloalkyl moiety or a cycloalkenyl moiety) having from 3 to 7 carbon atoms, more preferably having from 3 to 6 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their mono- unsaturated variants, more particularly cyclopentyl and cyclohexyl.
  • a C 3-7 carbocyclyl group or moiety also includes C 3-7 carbocyclyl groups or moieties described above but wherein one or more ring carbon atoms are replaced by a group -C(O)-. More preferably one or two ring carbon atoms (most preferably two) are replaced by -C(O)-.
  • a preferred such group is benzoquinone.
  • a carbocyclyl group or moiety When a carbocyclyl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3-7 carbocyclyl group, more preferably to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl ring. For example it may be fused to a further phenyl ring.
  • An exemplary fused carbocyclyl group is indanyl. More preferably carbocyclyl groups are monocyclic (i.e. non-fused).
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R 1 , R 2 , R 8 , R 9 , R 19 , A, B, Q, Q 1 and D are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 1-4 alkylene, C 2-4 alkenyl, C M alkoxy, C 2-4 alkenyloxy, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 1-4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci -4 hydroxyalkyl, C 2-4 hydroxyalkenyl, C M alkylthio, C 2-4 alkenylthio, -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C 1-4
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two, three or four substituents, it is preferred that not more than two substituents are selected from C 1-4 alkylene, cyano and nitro. More preferably, not more than one substituent is selected from C 1-4 alkylene, cyano and nitro.
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two or three substituents, it is preferred that not more than one substituent is selected from -COOH, -C00R A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO 2 NHR A , -CONR A R B , -SO 2 NRV 3 , -OCONH 2 , -OCONHR A , -0C0NR A R B , -NHCOR A , NHCOOR A ,
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R 1 , R 2 , R 8 , R 9 , R 19 , A, B, Q, Q 1 and D are unsubstituted or substituted by 1, 2, 3 or 4 substituents, for example by 1, 2 or 3 substituents.
  • Preferred substituents include halogen atoms and Ci -4 alkyl, C 2 ⁇ alkenyl, C 1-4 alkoxy, C 2-4 alkenyloxy, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 1-4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C M hydroxyalkyl, C 2-4 hydroxyalkenyl, C 1-4 alkylthio, C 2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, and groups of formula COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -C0NHR A , -SO 2 NHR A , -C0NR A R B and -SO 2 NR A R 3 wherein R A and R B are the same or different and
  • R 1 , R 2 , R 8 , R 9 , R 19 , A, B, Q, Q 1 and D include halogen atoms and Cj -4 alkyl, Q- 4 alkoxy, Ci -4 alkylthio, C M haloalkyl, hydroxyl, cyano, nitro and -NR 'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl, and groups of formula COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -C0NHR A , -SO 2 NHR A , -C0NR A R B and -SO 2 NR A R B wherein R A and R B are the same or different and represent C 1-2 alkyl.
  • substituents include halogen atoms and C 1-4 alkyl, C 1-4 alkoxy, Ci -4 alkylthio and hydroxyl groups. More preferred substituents include halogen atoms, C 1-4 alkyl, Ci -2 alkoxy, Ci -2 alkylthio and hydroxy.
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl pipe
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.
  • R 1 is the group characterising the ester, notionally derived from the alcohol R 1 '-OH.
  • R 1 represents a hydrogen or halogen atom, or an unsubstituted Ci -4 alkyl, hydroxyl, C 1-4 alkoxy, -SR', Ci -4 alkylthio, -NR'R" or -CONR A R B group where R', R", R A and R B are the same or different and represent hydrogen or unsubstituted Ci -4 alkyl group. More preferably R 1 represents a halogen atom (preferably chlorine) or an unsubstituted Ci -4 alkyl or -NR'R" group wherein R' and R" are the same or different and represent hydrogen or unsubstituted Ci -2 alkyl.
  • R 1 represents an -NR'R" group wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl. Most preferably R 1 represents -NH 2 . It is preferred that the alkyl groups and moieties in R 1 are unsubstituted or substituted by 1, 2 or 3 substituents which are themselves unsubstituted and are selected from halogen, C M alkyl, C 2-4 alkenyl, Ci -4 alkoxy, hydroxyl, Ci -4 haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkyloxy, C 2-4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl.
  • the alkyl groups and moieties in R 1 are unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci -2 alkoxy, Ci -2 haloalkyl, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl. hi particular, it is preferred that R' and R" are unsubstituted. More preferably, the alkyl groups and moieties in R 1 are unsubstituted.
  • R 2 represents a hydrogen or halogen atom, an unsubstituted Ci -4 alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci -2 alkyl. More preferably R 2 represents a hydrogen or halogen atom (preferably fluorine or chlorine) or an -NH 2 group. Most preferably R 2 represents a hydrogen atom.
  • Group -(L 1 VfHety x and y are the same or different and represent zero or 1.
  • x is zero, L 1 is absent, and when y is 1, Het is absent.
  • L 1 preferably represents unsubstituted C M alkylene, more preferably unsubstituted C 1-2 alkylene, most preferably -CH 2 -.
  • Het preferably represents -S-, -S(O)- or -S(O) 2 -. More preferably, Het represents -S- or -S(O)-. Most preferably Het represents -S-.
  • A represents an unsubstituted or substituted phenyl, 5- to 6-membered heteroaryl, C 3-7 carbocyclyl or 5- to 6-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 6-membered heteroaryl, C 3-7 carbocyclyl or 5- to 6- membered heterocyclyl group. More preferably A represents an unsubstituted or substituted phenyl, 5- to 6-membered heteroaryl, C 3-7 carbocyclyl or 5- to 6-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group.
  • A represents an unsubstituted or substituted non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non- fused C 3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group.
  • preferred 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, dithiolanyl, dioxolanyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, thioxolanyl, thiazolidinyl and isothiazolidinyl, more preferably oxazolidinyl, imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl and dithiolanyl, most preferably dioxolanyl.
  • A represents a non-fused 5- to 6-membered heteroaryl group
  • preferred groups include pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • A is a 5- to 6-membered heteroaryl group fused to a phenyl group
  • preferred groups include indolyl, isoindolyl, benzimidazolyl, indazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, more preferably benzimidazolyl, benzoxazolyl or benzothiazolyl, most preferably benzothiazolyl.
  • suitable groups include 5- to 6-membered heterocyclyl groups where 1, 2, 3 or 4, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O) 2 , and wherein one or more of the remaining carbon atoms is optionally replaced by a group -C(O)- or -C(S)-.
  • one or more of the remaining carbon atoms is replaced by a group -C(O)- or -C(S)-, preferably only one or two (more preferably two) such carbon atoms are replaced.
  • suitable 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl, and variants where one or two of the ring carbon atoms are replaced with -C(O)- groups.
  • Particularly preferred 5- to 6-membered heterocyclyl groups include tetrahydrofuranyl and pyrrolyl-2,5-dione.
  • A is a non-fused C 3-7 carbocyclyl group
  • preferred groups include C 3-7 carbocyclyl groups wherein one or two ring carbon atoms are replaced by -C(O)- or -S(O)-, more preferably wherein two ring carbon atoms are replaced by -C(O)-. More preferably, when A is a non-fused C 3-7 carbocyclyl group it is a benzoquinone group.
  • A represents an unsubstituted or substituted phenyl ring, wherein the phenyl ring is optionally fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6-membered heterocyclyl group.
  • A is fused, it is preferably fused to a further 5- to 6-membered heterocyclyl group, more preferably to an imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl or dithiolanyl group, most preferably to a dioxolanyl group.
  • A represents an unsubstituted or substituted phenyl ring.
  • group A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are themselves unsubstituted, which are the same or different, and which are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, Ci -4 alkoxy, C 2 ⁇ alkenyloxy, C M haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci -4 hydroxyalkyl, C 2-4 hydroxyalkenyl, Ci -4 alkylthio, C 2-4 alkenylthio and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, and groups of formula COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -C0NHR A ,
  • substituents on group A include 1, 2, 3 or 4 unsubstituted substituents which are the same or different and represent halogen atoms and C 1-4 alkyl, C M alkoxy, C M alkylthio, Ci -4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl.
  • substituents on group A include 1, 2, 3 or 4 unsubstituted substituents which are the same or different and represent halogen atoms and C 1-4 alkyl, C M alkoxy, C M alkylthio, Ci -4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl.
  • Even more preferred substituents include halogen atoms, C M alkyl, C 1-2 alkoxy, Ci -2 alkylthi
  • Preferred C 1-2 alkoxy substituents include methoxy groups.
  • Preferred C 1-4 alkyl substituents include methyl, ethyl and propyl, more preferably ethyl and propyl.
  • Preferred Ci -2 alkylthio substituents include -S-CH 3 .
  • group A is substituted by a single halogen atom (preferably a fluorine or bromine atom, more preferably a bromine atom) and a C 1-2 alkoxy group (preferably a methoxy group).
  • W is a group of formula -[CH 2 ] Z -Y 1 -L 2 -R.
  • the group W contains the alpha amino acid or alpha amino acid ester moiety of formula (X) linked through a linker radical to ring A.
  • W terminates in an ester group the compounds of the invention are converted by intracellular esterases to the corresponding carboxylic acid.
  • Both the esters and carboxylic acids may have HSP90 inhibitory activity in their own right.
  • the compounds of the invention therefore include not only the ester, but also the corresponding carboxylic acid hydrolysis products.
  • the group R is represented by formula (X):
  • R 7 is either a carboxylic acid group -COOH or an ester group -COOR 11 . Where R 7 is an ester group, it must be one which in the compound of the invention is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group.
  • Intracellular carboxylesterase enzymes capable of hydrolysing the ester group of a compound of the invention to the corresponding acid include the three known human enzyme isotypes hCE-1, hCE-2 and hCE-3. Although these are considered to be the main enzymes other enzymes such as biphenylhydrolase (BPH) may also have a role in hydrolysing the conjugates.
  • BPH biphenylhydrolase
  • R 13 represents hydrogen or a group of formula -[C 1-4 alkylene] b -(Z 1 ) a -[C 1-4 alkyl] or -[Ci -4 alkylene]b-(Z 1 ) a -[C 2-4 alkenyl] wherein a and b are the same or different and represent 0 or 1, and Z 1 represents -O-, -S-, or -NR 17 - wherein R 17 is hydrogen or Ci -4 alkyl, R 14 represents hydrogen or Ci -4 alkyl, and R 12 represents hydrogen or Ci -4 alkyl;
  • R 13 represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group
  • R 14 represents hydrogen or C M alkyl
  • R 12 represents hydrogen
  • R 13 represents a group of formula -(Alk 3 )-NR 15 R 16 wherein AIk 3 represents a C M alkylene group and either (a) R 15 and R 16 are the same or different and represent hydrogen or C M alkyl, or (b) R 15 and R 16 , together with the nitrogen atom to which they are bonded, form a 5- to 10- membered heteroaryl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group; R 14 represents hydrogen or C 1-4 alky
  • R 16 , R 17 and AIk 3 groups include one or two substituents which are the same or different and are selected from halogen, CM alkyl, C 2-4 alkenyl, Ci -4 alkoxy, hydroxyl and -NR 'R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl. More preferred substituents are halogen, C 1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl. Most preferably the alkyl, alkylene and alkenyl groups in R 13 , R 14 and AIk 3 are unsubstituted.
  • Preferred substituents on the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 13 , R 14 , R 15 and R 16 groups include one or two substituents which are the same or different and are selected from halogen atoms and Cj -4 alkyl, C 1-4 alkylene, Ci -4 alkoxy, Ci -4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, more preferably halogen atoms and Ci -2 alkyl, Ci -2 alkylene, Ci -2 alkoxy and hydroxyl groups.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 13 , R 14 , R 15 and R 16 are unsubstituted or substituted by a Ci -2 alkylene group, in particular a methylene group.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 13 , R 14 , R 15 , R 16 are unsubstituted.
  • R 13 represents a group of formula -[C M alkylene] b -(Z 1 ) a -[Ci -4 alkyl], preferably either a or b is zero, for example both a and b are zero.
  • [Ci -4 alkylene] is present, it is preferably a Ci -3 alkylene, more preferably a Ci -2 alkylene such as a group -CH 2 -CH 2 -.
  • R 13 represents a group of formula -[CM alkylene]b-(Z') a -[C ⁇ -4 alkyl]
  • C M alkyl is a Ci -3 alkyl group such as methyl, ethyl or n-propyl, most preferably methyl.
  • Z 1 is preferably -O- or -NR 17 - wherein R 17 is hydrogen or C 1-2 alkyl, more preferably Z 1 is -O-.
  • R 13 represents a group of formula -[C 1-4 alkylene] b -(Z 1 ) a -[C 2 . 4 alkenyl], preferably either a or b is zero, more preferably both a and b are zero.
  • [C M alkylene] is present, it is preferably a C 1-3 alkylene, more preferably a Ci -2 alkylene.
  • Z 1 is preferably -O- or -NR 17 - wherein R 17 is hydrogen or Ci -2 alkyl, more preferably Z 1 is -O-. Most preferably Z 1 is absent (i.e. a is zero).
  • R 13 represents hydrogen or a group of formula -[Ci -4 alkyl] or -[C M alkylene] b -(Z 1 ) a -[C 2-4 alkenyl]
  • R 13 represents hydrogen or a group of formula -[CM alkylene]b-(Z 1 ) a -[CM alkyl] or -[C M alkylene] b -(Z 1 ) a -[C 2-4 alkenyl]
  • R 14 represents hydrogen or Ci -2 alkyl, more preferably hydrogen or methyl, most preferably hydrogen.
  • R 13 represents hydrogen or a group of formula -[Ci -4 alkylene]b-(Z 1 ) a -[CM alkyl] or -[C M alkylene] b -(Z 1 ) a -[C 2-4 alkenyl]
  • R 12 represents hydrogen or Ci -2 alkyl, more preferably R 12 represents hydrogen or methyl, most preferably hydrogen.
  • R 13 represents hydrogen or a group of formula -[Ci -4 alkylene]b-(Z 1 ) a -[Ci -4 alkyl] or -[C M alkylene] b -(Z 1 ) a -[C 2-4 alkenyl], preferably the alkyl, alkylene and alkenyl groups in both R 13 and R 14 are unsubstituted.
  • R 13 represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, preferably it represents a non-fused phenyl or a non-fused 5- to 6-membered heteroaryl group.
  • Preferred heteroaryl groups include pyridyl, pyrrolyl, isothiazolyl, pyrazolyl and isoxazolyl, most preferably pyridyl.
  • R 13 represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10- membered heterocyclyl group, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R 13 are unsubstituted .
  • R 14 preferably represents hydrogen or C 1-4 alkyl, more preferably hydrogen or C 1-2 alkyl, most preferably hydrogen.
  • the C 1-4 alkyl groups of R 14 are unsubstituted.
  • AIk 3 preferably represents a C 1-2 alkylene group, preferably either -CH 2 - or -CH 2 CH 2 -.
  • R 13 represents a group of formula -(Alk ⁇ -NR 15
  • R 16 and R 15 and R 16 are the same or different and represent hydrogen or C 1-4 alkyl, preferably R 15 represents hydrogen or C 1-2 alkyl, more preferably R 15 represents a methyl group.
  • R 13 represents a group of formula -(Alk 3 )-NR 15
  • R 16 and R 15 and R 16 are the same or different and represent hydrogen or C 1 ⁇ alkyl, preferably R 16 represents hydrogen or C 1-2 alkyl, more preferably R 16 represents a methyl group.
  • R 13 represents a group of formula -(Alk 3 )-NR l5 R 16 and R 15 and R 16 , together with the nitrogen atom to which they are bonded, form a 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10- membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, preferably they form a non-fused 5- to 6-membered heteroaryl or non-fused 5- to 6- membered heterocyclyl group. More preferably they form a 5- to 6-membered heterocyclyl group.
  • Preferred heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, most preferably morpholinyl.
  • AIk 3 preferably represents a C 1-2 alkylene group, more preferably a group -CH 2 CH 2 -.
  • R 14 preferably represents hydrogen or Ci -2 alkyl, most preferably hydrogen.
  • R 13 represents a group of formula -(Alk 3 )-NR I5 R 16 , preferably the alkyl and alkylene groups in AIk 3 , R 15 and R 16 are unsubstituted.
  • R 13 represents a group of formula -(Alk 3 )-NR 15 R 16 , preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R 15 and R 16 are unsubstituted.
  • R 13 represents a group of formula -(Alk 3 )-NR 15 R 16
  • preferred groups include
  • R 13 and R 14 together with the carbon atom to which they are bonded, form a phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group
  • preferred groups include non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused 5- to 6-membered heterocyclyl, non-fused C 3-7 carbocyclyl and C 3-7 carbocyclyl fused to a phenyl ring, more preferably non-fused phenyl, non-fused 5- to 6-membered heterocyclyl, non-fused C 3-7 carbocyclyl and C 3-7 carbocyclyl fused to a phenyl ring.
  • preferred non-fused 5- to 6-membered heterocyclyl groups include piperidinyl, tetrahydrofuranyl, piperazinyl, morpholinyl and pyrrolidinyl groups, more preferably piperidinyl and tetrahydrofuranyl groups.
  • preferred non-fused C 3-7 carbocyclyl groups include cyclopentyl and cyclohexyl, more preferably cyclopentyl.
  • preferred C 3-7 carbocyclyl groups fused to a phenyl ring include indanyl.
  • R 13 and R 14 form a cyclic group together with the carbon atom to which they are bonded, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups formed are unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and C M alkyl, C 1-4 alkylene, C 1-4 alkoxy, C M haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl, more preferably selected from halogen atoms or Ci -2 alkyl, Ci -2 alkylene, Ci -2 alkoxy and hydroxyl groups.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups formed are unsubstituted or substituted by a Ci -2 alkyl group (such as a methyl group) or by a Ci -2 alkylene group (such as by a methylene group). Even more preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups so formed are unsubstituted.
  • R 11 groups include C 1-4 alkyl groups (such as methyl, ethyl, n- or iso-propyl and n-, sec- and tert-butyl, most preferably methyl), C 3-7 carbocyclyl groups (such as cyclopentyl and cyclohexyl), C 2-4 alkenyl groups (such as allyl), and also phenyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridyhnethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbonyl, dimethylaminoethyl and mo ⁇ holinoethyl groups, more preferably R 11 represents C 1-4 alkyl or C 3-7 carbocyclyl. Most preferred groups include where R 11 is methyl, cyclopentyl or t-butyl, more preferably where R 11 is
  • R 7 represents -COOH or -COOR 11 wherein R 11 is C 1-4 alkyl or C 3-7 carbocyclyl
  • R 7 is -COOR 18 and R 18 is hydrogen, Ci -4 alkyl or C 3-7 carbocyclyl.
  • R 7 is -COOR 18 where R 18 is hydrogen, methyl or C 3-7 carbocyclyl, more preferably where R 18 is hydrogen, methyl or cyclopentyl, most preferably where R 18 is hydrogen or methyl.
  • R 8 represents a Ci -6 alkyl group, it is preferably a Ci -4 alkyl group such as methyl, ethyl or n-or iso-propyl.
  • R represents a C 3-7 carbocyclyl group
  • it is preferably a C 3-6 carbocyclyl group, more preferably a C 3-6 cycloalkyl group such as cyclopropyl, cyclopentyl or cyclohexyl.
  • R 8 represents a 5- to 6-membered heteroaryl group
  • preferred groups include pyridyl.
  • R 9 is Ci -6 alkyl, non-fused phenyl, non- fused 5- to 6-membered heteroaryl, non-fused C 3-7 carbocyclyl or a group -Alk 4 -Cyc.
  • R 9 is Ci -6 alkyl, it is preferably a C 1-4 alkyl group such as methyl, ethyl, n- or iso- propyl, or n-, iso- or sec-butyl.
  • R 9 is C 3-7 carbocyclyl it is preferably C 3-6 carbocyclyl, more preferably C 3-6 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl.
  • R 9 is 5- to 6-membered heteroaryl, preferred groups include pyridyl and thienyl.
  • AIk 4 is preferably a C 1-4 alkylene group, more preferably C 1-2 alkylene, most preferably methylene.
  • Cyc is preferably a non- fused phenyl, a non-fused 5- to 6-membered heteroaryl or a non-fused 5- to 6-membered heterocyclyl group.
  • Cyc is a 5- to 6-membered heteroaryl it is preferably thienyl or pyridyl.
  • Preferred -Alk 4 -Cyc groups include benzyl, 4-methoxyphenylmethylcarbonyl, thienylmethyl and pyridylmethyl.
  • R 10 is hydrogen or C i- 4 alkyl, more preferably hydrogen, methyl, ethyl, or n- or iso-propyl.
  • the alkyl and alkylene groups in R 8 , R 9 , R 10 and AIk 4 are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C M alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl, more preferably selected from halogen, C 1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl. Most preferably the alkyl and alkylene groups in R 8 , R 9 , R 10 and AIk 4 are unsubstituted.
  • the phenyl, heteroaryl, heterocyclyl, carbocyclyl and heterocyclyl in R 8 and R 9 are preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, Ci -4 alkoxy, C 1-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl, more preferably the substituents are selected from halogen atoms and C 1-2 alkyl, C 1-2 alkoxy and hydroxyl groups.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R 8 are unsubstituted.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R 9 are unsubstituted or substituted by a single Ci -2 alkoxy group, more preferably by a single methoxy group.
  • R 8 is hydrogen.
  • esters with a slow rate of esterase cleavage are preferred, since they are less susceptible to pre-systemic metabolism. Their ability to reach their target tissue intact is therefore increased, and the ester can be converted inside the cells of the target tissue into the acid product.
  • ester for local administration, where the ester is either directly applied to the target tissue or directed there by, for example, inhalation, it will often be desirable that the ester has a rapid rate of esterase cleavage, to minimise systemic exposure and consequent unwanted side effects. If a carbon atom to which the group R is attached is unsubstituted, i.e.
  • R is attached to a methylene (-CH 2 -) radical, then the esters tend to be cleaved more rapidly than if that carbon is substituted, or is part of a ring system such as a phenyl or cyclohexyl ring.
  • p is 1 and AIk 2 terminates in a methylene radical
  • n and p are both zero
  • m is 1 and AIk 1 terminates in a methylene radical
  • Y 1 is a bond and z is 1, then the ester (i.e. when R 7 is not -COOH) is likely to be cleaved more rapidly.
  • the subscript z may be 0 or 1, so that a methylene group linked to ring A is optional. Preferably z is zero and the methylene group is absent.
  • R 3 is an alkyl group, it is preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from Ci -4 alkyl, C 2 ⁇ alkenyl, C M alkoxy, C 2-4 alkenyloxy, Ci -4 haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci -4 hydroxyalkyl, C 2-4 hydroxyalkenyl, Ci -4 alkylthio, C 2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, more preferably selected from halogen, Ci -2 alkyl, Ci -2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl
  • Y 1 represents -0-, -S- or -NR 3 -, preferably either m is zero (i.e. AIk 1 is absent) and n is 1 (i.e. Q is present), or m is 1 (i.e. AIk 1 is present) and n and p are zero (i.e. Q and AIk 2 are absent). Most preferably Y 1 is a bond.
  • L 2 represents a group of formula -(Alk 1 ) m -(Q) n -(Alk 2 ) p -.
  • the subscripts m, n and p are independently zero or 1. Specifically, in some embodiments of the invention, m and p may be O with n being 1. In other embodiments, n and p may be O with m being 1. In further embodiments, m, n and p may be all O. In still further embodiments m may be O, n may be 1 with Q being a monocyclic aryl, heteroaryl, carbocyclyl or heterocyclyl radical, and p may be O or 1 , more preferably p is 1.
  • n and p are zero and m is 1; or m is zero, n is 1 with Q being a monocyclic aryl, heteroaryl, carbocyclyl or heterocyclyl radical, and p is 1 ; for example n and p are zero and m is 1.
  • Preferred AIk 1 groups include C 3-6 cycloalkyl groups and Ci -4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene groups which may optionally contain or terminate in an ether, thioether or amino -NR 6 - link wherein R 6 represents hydrogen or Ci -2 alkyl.
  • R 6 represents hydrogen or Ci -2 alkyl.
  • R 6 is Ci -2 alkyl, it is preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, Ci -2 alkyl, Ci -2 alkoxy, hydroxyl and -NR 'R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl.
  • Most preferred substituents on the R 6 group are halogen, Ci -2 alkoxy and hydroxyl, in particular hydroxyl.
  • AIk 1 is a C 3-6 cycloalkyl group
  • preferred groups include divalent cyclopropyl, cyclopentyl and cyclohexyl groups which optionally contain an ether, thioether or amino -NR 6 - link wherein R 6 represents hydrogen or Ci -2 alkyl.
  • R 6 represents hydrogen or Ci -2 alkyl.
  • the group R 6 when present, is unsubstituted. More preferably, when AIk 1 is a C 3-6 cycloalkyl group it is a 5- or 6-membered ring optionally containing an ether or amino -NR 6 - link.
  • Suitable examples include cyclopentyl, cyclohexyl and heterocyclic groups selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl. More preferred examples include cyclopentyl, cyclohexyl and pyrrolidinyl.
  • AIk 1 is a Ci -4 alkylene group
  • preferred groups include -CH 2 -, -CH 2 CH 2 -,
  • AIk 1 is a C 2-4 alkenylene group
  • AIk 1 is a C 2-4 alkynylene group
  • AIk 1 is a Ci -4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene group terminating in an ether (-O-), thioether (-S-) or amino (-NR 6 )- wherein R 6 represents hydrogen or Ci -2 alkyl
  • preferred groups include (in either orientation) -CH 2 W-, -CH 2 CH 2 W-, -CH 2 CH 2 WCH 2 -, -CH 2 CH 2 WCH(CH 3 ) -, -CH 2 WCH 2 CH 2 -, -CH 2 WCH 2 CH 2 WCH 2 -, and -WCH 2 CH 2 - where W is -O-, -S-, -NH-, -N(CH 3 )-, or -CH 2 CH 2 N(CH 2 CH 2 OH)CH 2 -.
  • suitable groups include -0-CH 2 -, -S-CH 2 - and -0-CH 2 -CH 2 -.
  • AIk 1 is a C 1-4 alkylene group, more preferably it is selected from -CH 2 -, -CH 2 CH 2 - and -CH 2 -CH 2 -CH 2 -, more preferably AIk 1 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, most preferably AIk 1 is -CH 2 CH 2 -.
  • AIk 1 groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2 ⁇ alkenyl, C 1-4 alkoxy, C 2-4 alkenyloxy, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 1-4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C 1-4 hydroxyalkyl, C 2-4 hydroxyalkenyl, C M alkylthio, C 2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl.
  • AIk 1 groups are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, C 1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl. Most preferably AIk 1 groups are unsubstituted.
  • Preferred Q groups include phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl and 5- to 10-membered heterocyclyl groups optionally fused to a further phenyl, 5- to 10- membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group. More preferably Q represents a phenyl optionally fused to a further phenyl, a 5- to 10-membered heteroaryl optionally fused to a further phenyl, a non-fused C 3-7 carbocyclyl or a non-fused 5- to 10-membered heterocyclyl group.
  • Q represents a phenyl optionally fused to a further phenyl, it represents phenyl or naphthyl, with phenyl groups being preferred.
  • Q represents a phenyl it is preferably linked to the rest of the molecule in a 1,4-relationship.
  • Q represents a C 3-7 carbocyclyl group it is preferably a cyclopropyl, cyclopentyl or cyclohexyl group, more preferably a cyclohexyl group.
  • Q represents a 5- to 10-membered heteroaryl group optionally fused to a further phenyl it is preferably a 5- to 6-membered heteroaryl group optionally fused to a further phenyl.
  • Q represents a non-fused 5- to 6-membered heteroaryl group it is preferably a pyridyl, thienyl, furyl or pyrrolyl group, more preferably a pyridyl, thienyl or pyrrolyl group.
  • Q represents a 5- to 6-membered heteroaryl group fused to a phenyl, it is preferably an indolyl, benzimidazolyl, benzofuryl or benzothienyl group, more preferably an indolyl group.
  • Q represents a 5- to 10-membered heterocyclyl group it is preferably a non- fused 5- to 6-membered heterocyclyl group, for example a piperidinyl or piperazinyl group.
  • Q groups when present, include phenyl, pyridinyl, thienyl and cyclohexyl, e.g. phenyl and cyclohexyl, more preferably phenyl.
  • subscript n is zero and the group Q is absent.
  • Q groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl, and groups of formula COR ⁇ , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO 2 NHR A , -C0NR A R B , -SO 2 NR A R B wherein R A and R B are the same or different and represent Ci -2 alkyl.
  • Q groups are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C M alkoxy and hydroxyl groups. Most preferably Q groups are unsubstituted.
  • Preferred AIk 2 groups include C 3-6 cycloalkyl groups, and Ci -4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene groups which may optionally contain or terminate in an ether, thioether or amino -NR 6 - link wherein R 6 represents hydrogen or C 1-2 alkyl.
  • R 6 is Ci -2 alkyl, it is preferably unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, C 1-2 alkyl, C 1-2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl. Most preferred substituents on the R 6 group are halogen, Ci -2 alkoxy and hydroxyl, in particular hydroxyl.
  • AIk 2 is a C 3-6 cycloalkyl group
  • preferred groups include divalent cyclopropyl, cyclopentyl and cyclohexyl groups.
  • AIk 2 is a Ci -4 alkylene group
  • preferred groups include -CH 2 -, -CH 2 CH 2 -,
  • -CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 - as well as branched variants such as -CH(CH 3 )-, -C(CH 3 ) 2 -, or in either orientation -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -.
  • Most preferred groups are -CH 2 - and -CH 2 -CH 2 -.
  • AIk 2 is a C 2-4 alkenylene group
  • AIk 2 is a C 2-4 alkynylene group
  • AIk 2 is a Ci -4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene group terminating in an ether (-O-), thioether (-S-) or amino (-NR 6 - wherein R 6 represents hydrogen or Ci -2 alkyl)
  • preferred groups include (in either orientation) -CH 2 W-, -CH 2 CH 2 W-, -CH 2 CH 2 WCH 2 -, -CH 2 CH 2 WCH(CH 3 ) -, -CH 2 WCH 2 CH 2 -, -CH 2 WCH 2 CH 2 WCH 2 -, and -WCH 2 CH 2 - where W is -O-, -S-, -NH-, -N(CH 3 )-, or -CH 2 CH 2 N(CH 2 CH 2 OH)CH 2 -. More preferably AIk 2 does not terminate in or contain an ether, thioether or amino group.
  • AIk 2 groups are Ci -4 alkylene groups, in particular -CH 2 - and -CH 2 CH 2 -. However, in one preferred embodiment subscript p is zero and the group AIk 2 is absent.
  • AIk 2 groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen atoms and C M alkyl, C 2-4 alkenyl, Ci -4 alkoxy, C 2-4 alkenyloxy, C M haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, Ci -4 hydroxyalkyl, C 2 ⁇ hydroxyalkenyl, C M alkylthio, C 2-4 alkenylthio, and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • AIk 2 groups are preferably unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci -2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl. Most preferably AIk 2 groups are unsubstituted.
  • m is 1, n andp are zero and L 2 preferably represents
  • Ci -4 alkylene more preferably -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, more preferably -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, most preferably -CH 2 CH 2 -.
  • m is zero
  • n and p are 1
  • L 2 represents -Cyc'-Alk 2 - wherein Cyc' represents a non-fused phenyl or a non-fused C 3-6 cycloalkyl group, substituted as described for Q above and AIk 2 represents Ci -4 alkylene, more preferably -CH 2 - or -CH 2 CH 2 -.
  • m is zero, n andp are 1 and L 2 represents -Cyc'-Alk 2 - wherein Cyc' represents a non-fused phenyl or a non-fused 5- to 10- membered heteroaryl and AIk 2 represents Ci -4 alkylene, more preferably -CH 2 - Or -CH 2 CH 2 -.
  • Preferred examples of the group -[CH 2 ] Z -Y 1 -L 2 - in its entirety include -CH 2 CH 2 -,
  • exemplary R 19 groups include side chains of natural amino acids and close structural variants thereof.
  • R 19 is a C 1-4 alkyl group preferably it is a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, most preferably a methyl group.
  • R 19 represents a group of formula -L 3 -B, preferably L 3 is a bond or a C 1-4 alkylene group, more preferably a Ci -2 alkylene group, most preferably a methylene group.
  • R 19 represents a group of formula -L 3 -B, preferably B represents a phenyl group or a 5- tolO-membered heteroaryl group.
  • B represents a 5- to 10-membered heteroaryl group preferred heteroaryl groups include imidazolyl and indolyl.
  • R 19 represents a group of formula -L 3 -B, preferably B represents a phenyl group.
  • R 19 is a Ci -6 alkyl group it is preferably unsubstituted or substituted with one or two, preferably one, unsubstituted substituent selected from halogen, Ci -2 alkoxy, C 1-2 haloalkyl, hydroxyl, -COOR', -COONR'R", -SR' and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl.
  • R 19 is a C 1-6 alkyl group most preferably it is unsubstituted.
  • R 19 represents a group of formula -L 3 -B, preferably L 3 is unsubstituted.
  • R 19 represents a group of formula -L 3 -B
  • B is unsubstituted or substituted with one, two or three, more preferably with one or two, unsubstituted substituents selected from halogen atoms, C M alkyl, C 1-2 alkoxy, C 1-2 alkylthio and hydroxy.
  • R 19 represents a group of formula -L 3 -B, most preferably B is unsubstituted or substituted with one substituent selected from a halogen atom or a C 1-4 alkyl, C 1-2 alkoxy, C 1-2 alkylthio or hydroxy group.
  • R 19 represents an unsubstituted C 1-6 alkyl group or a C 1-6 alkyl group substituted with one halogen atom or a C 1-2 alkoxy, C 1-2 haloalkyl, hydroxyl,
  • R 19 represents a group -L 3 -B where L 3 represents a bond or an unsubstituted Ci -6 alkylene group and B represents an unsubstituted or substituted C 6- Io aryl or 5- to 10-membered heteroaryl group, the substituents on the aryl or heteroaryl group being independently selected from 1, 2, 3 or 4 halogen atoms or Ci -2 alkyl, Ci -2 alkoxy, Ci -2 alkylthio or hydroxy groups.
  • R 19 represents an unsubstituted Ci -4 alkyl group or a group -L 3 -B where L 3 represents a bond or an unsubstituted Ci -2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci -2 alkyl, C 1-2 alkoxy, Ci -2 alkylthio or hydroxy group.
  • Most preferred R 19 groups include unsubstituted methyl groups and unsubstituted methylphenyl groups, more preferably unsubstituted methyl groups.
  • Preferred compounds of the invention are (a) amino acid derivatives of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof, wherein:
  • R 1 represents hydrogen or halogen atom, or an unsubstituted Ci -4 alkyl, hydroxyl, C M alkoxy, -SR', Ci -4 alkylthio, -NR'R" or -CONR A R B group where R', R", R A and R B are the same or different and represent hydrogen or unsubstituted Ci -4 alkyl group, and wherein the alkyl groups or moieties in R 1 are unsubstituted or substituted by 1, 2 or 3 substituents which are themselves unsubstituted and are selected from halogen, C M alkyl, C 2-4 alkenyl, C M alkoxy, hydroxyl, C M haloalkyl, C 2-4 haloalkenyl, C 1-4 haloalkyloxy, C 2 _4 haloalkenyloxy and -NR'R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl;
  • R 2 represents a hydrogen or halogen atom, an unsubstituted C 1-4 alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted Ci -2 alkyl; x is zero and y is one; - Het represents -S-, -S(O)- or -S(O) 2 -;
  • - A represents an unsubstituted or substituted group selected from non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused C 3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C M alkyl, C 2-4 alkenyl, C M alkoxy, C 2 ⁇ alkenyloxy, C M haloalkyl, C 2-4 haloalkenyl, C M haloalkoxy, C 2-4 haloalken
  • - AIk 2 represents a Ci -4 alkylene group which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Ci -2 alkoxy, hydroxyl and -NR'R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl;
  • - R 7 represents -COOH or is an ester group -COOR 1 ' wherein the ester group is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group;
  • R represents a hydrogen or halogen atom, an unsubstituted C] -4 alkyl group or a group of formula -NR'R" where R' and R" are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl;
  • A represents an unsubstituted or substituted group selected from non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused C 3-7 carbocyclyl, non-fused 5- to 6-membered heterocyclyl group, a phenyl group which is fused to a further 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group which is fused to a further phenyl group, and wherein the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2 ⁇ alkenyl, C 1-4 alkoxy, C 2-4 alkenyloxy, Ci -4 haloalkyl, C 2-4 haloalkenyl, Ci -4 haloalkoxy, C 2-4 halo
  • R 7 represents -COOH or is an ester group -COOR 11 wherein the ester group is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group;
  • R 2 represents a hydrogen or halogen atom or an -NH 2 group, more preferably a hydrogen atom.
  • A represents a group selected from phenyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, pyrrolyl-2,5-dione and benzoquinone, or A represent a phenyl ring fused to a 5- to 6- membered heterocyclyl group selected from oxazolidinyl, imidazolidinyl, thiazolidinyl, thioxolanyl, dioxolanyl
  • R 7 represents a group -COOH or -COOR 11 , wherein R 11 represents -CR 12 R 13 R 14 and:
  • R 13 represents hydrogen or a group of formula -[Ci -4 alkylene] b -(Z 1 ) a -[Ci -4 alkyl] or -[Ci -4 alkylene]b-(Z 1 ) a -[C 2- 4 alkenyl] wherein a and b are the same or different and represent O or 1, and Z 1 represents -0-, -S-, or -NR 17 - wherein R 17 is hydrogen or C M alkyl, R 14 represents hydrogen or Ci ⁇ alkyl, and R 12 represents hydrogen or C 1-4 alkyl;
  • R 13 represents a phenyl or a 5- to 10-membered heteroaryl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10-membered heterocyclyl group, R 14 represents hydrogen or Ci -4 alkyl, and R 12 represents hydrogen;
  • R 13 represents a group of formula -(Alk 3 )-NR 15 R 16 wherein AIk 3 represents a C M alkylene group and either (a) R 15 and R 16 are the same or different and represent hydrogen or Ci -4 alkyl, or (b) R 15 and R 16 , together with the nitrogen atom to which they are bonded, form a 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl group optionally fused to a further phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10- membered heterocyclyl group; R 14 represents hydrogen or C M alkyl, and R 12 represents hydrogen; or (iv) R 13 and R 14 , together with the carbon atom to which they are bonded, form a phenyl, 5- to 10-membered heteroaryl, C 3-7 carbocyclyl or 5- to 10- membered heterocyclyl group which is optionally fused to a further phenyl, 5-
  • R 1 ' represents -CR 12 R 13 R 14 , and either: (i) R 12 represents hydrogen or C 1-2 alkyl; R 13 represents hydrogen, C 1-4 alkyl, C 2-4 alkenyl or a group -(Ci -4 alkyl)-O-(Ci-4 alkyl); and R 14 represents hydrogen or Ci -2 alkyl; or
  • R 12 represents hydrogen or Ci -2 alkyl, and R 13 and R 14 form a cyclic group together with the carbon atom to which they are bonded, form a non-fused
  • C 3-7 carbocyclyl groups which is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and Ci -4 alkyl, C 1-4 alkylene, Ci -4 alkoxy, C 1-4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or Ci -4 alkyl.
  • R 7 represents a group -COOR 18 where R 18 is hydrogen, C 1-4 alkyl or C 3-7 carbocyclyl.
  • R 19 represents an unsubstituted Ci -4 alkyl group.
  • A represents a non-fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1, 2, 3 or 4 substituents which are the same or different and represent halogen atoms or Ci -4 alkyl, Ci -2 alkoxy,
  • Ci -2 alkylthio or hydroxy groups and W represent a group of formula -Y'-IAR wherein:
  • R 12 represents hydrogen or C 1-2 alkyl
  • R 13 represents hydrogen, C 1-4 alkyl, C 2-4 alkenyl or a group -(Ci -4 alkyl)-O-(C 1-4 alkyl); and
  • R 14 represents hydrogen or Ci -2 alkyl; or
  • R 12 represents hydrogen or Ci -2 alkyl, and R 13 and R 14 form a cyclic group together with the carbon atom to which they are bonded, form a non-fused C 3-7 carbocyclyl groups which is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and C M alkyl, Ci -4 alkylene, C M alkoxy, Cj -4 haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C M alkyl;
  • R 19 represents an unsubstituted C M alkyl group or a group -L 3 -B where L 3 represents an unsubstituted Ci -2 alkylene group and B represents an unsubstituted phenyl group or a phenyl group substituted with one substituent selected from a halogen atom or a Ci -2 alkyl, Ci -2 alkoxy, Ci -2 alkylthio or hydroxy group.
  • A represents a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents which are the same or different and represent halogen atoms or C i- 4 alkyl, Ci -2 alkoxy, Ci -2 alkylthio or hydroxy groups.
  • Y 1 is a bond.
  • R 7 represents -COOH or -COOR 1 ' and R 1 ! represents a C M alkyl or a C 3-7 carbocyclyl group.
  • R 8 represents hydrogen.
  • L 2 represents a group -AIk 1 - and AIk 1 represents an unsubstituted Ci -4 alkylene group.
  • R 19 represents an unsubstituted C M alkyl group.
  • A represents a non-fused phenyl ring or a phenyl ring fused to a dioxolanyl ring, and wherein A is unsubstituted or substituted by 1 or 2 substituents which are the same or different and represent halogen atoms or C M alkyl, C 1-2 alkoxy, C 1-2 alkylthio or hydroxy groups; AIk 1 represents a Ci -4 alkylene group; and R 18 represents hydrogen, Ci -4 alkyl or a C 3-7 carbocyclyl. More preferably in formula (IC) R 18 represents hydrogen, t-butyl or cyclopentyl, most preferably hydrogen or cyclopentyl.
  • AIk 1 represents -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, most preferably -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. More preferably in formula (IC) R 19 represents an unsubstituted Ci -4 alkyl group.
  • Particularly preferred compounds of formula (I) are: - Methyl 4- ⁇ 6-amino-8-[(2 -bromo-5-methoxyphenyl)thio]-9H-purin-9- yl ⁇ isovalinate; and 4- ⁇ 6-Amino-8-[(2-bromo-5-methoxyphenyl)thio]-9H-purin-9-yl ⁇ isovaline.
  • the compounds of the invention comprise a derivatised purine core, with a side chain (W) which terminates in an amino acid or amino acid ester end group.
  • the purine cores of the compounds are similar to a number of known purine analogues which have HSP90 inhibition activity.
  • Cancer cell lines e.g. U937 and HUT
  • U937 and HUT can be grown in log phase then harvested and seeded at 1000 cells/well (200 ⁇ l final volume) into 96- well tissue culture plates.
  • SRB sulphorhodamine B
  • Data from the assay can be expressed as a percentage inhibition of the control, measured in the absence of inhibitor, as follows:
  • % inhibition 100-((SVS°)xl00) where S 1 is the signal in the presence of inhibitor and S 0 is the signal in the presence of
  • the compounds with which the invention is concerned are inhibitors of HSP90 activity and are therefore of use for treatment of cancer, autoimmune and inflammatory diseases, including chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease, systemic lupus erythematosis and others.
  • a preferred utility of the compounds of the invention is for use in the treatment of cancer.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, but an exemplary dosage would be 0.1-lOOOmg per day
  • the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propy
  • Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the drug may be formulated for aerosol delivery for example, by pressure-driven jet atomizers or ultrasonic atomizers, or preferably by propellant-driven metered aerosols or propellant-free administration of micronized powders, for example, inhalation capsules or other "dry powder" delivery systems.
  • Excipients such as, for example, propellants (e.g.
  • Frigen in the case of metered aerosols surface-active substances, emulsifiers, stabilizers, preservatives, flavourings, and fillers (e.g. lactose in the case of powder inhalers) may be present in such inhaled formulations.
  • emulsifiers emulsifiers
  • stabilizers emulsifiers
  • preservatives e.g. lactose in the case of powder inhalers
  • flavourings e.g. lactose in the case of powder inhalers
  • fillers e.g. lactose in the case of powder inhalers
  • inhalation a large number of apparata are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient.
  • adaptors spacers, expanders
  • pear-shaped containers e.g.
  • Nebulator®, Volumatic®), and automatic devices emitting a puffer spray for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described in European Patent Application EP 0 505 321).
  • the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
  • Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
  • buffers such as sodium metabisulphite or disodium edeate
  • preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the compounds of the invention may be used in conjunction with a number of known pharmaceutically active substances.
  • the compounds of the invention may be used with cytotoxics, HDAC inhibitors, kinase inhibitors, aminopeptidase inhibitors and monoclonal antibodies (for example those directed at growth factor receptors).
  • Preferred cytotoxics include, for example, taxanes, platins, anti-metabolites such as 5- fluoracil, topoisomerase inhibitors and the like.
  • the medicaments of the invention comprising amino acid derivatives of formula (I), tautomers thereof or pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof therefore typically further comprise a cytotoxic, an HDAC inhibitor, a kinase inhibitor, an aminopeptidase inhibitor and/or a monoclonal antibody.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) an amino acid derivative of formula (I), a tautomer thereof or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof;
  • a cytotoxic agent an HDAC inhibitor, a kinase inhibitor, an aminopeptidase inhibitor and/or a monoclonal antibody
  • a cytotoxic agent for the separate, simultaneous or sequential use in the treatment of the human or animal body.
  • the compounds of the invention may be prepared by a number of processes generally described below and more specifically in the Examples hereinafter.
  • reactive functional groups for example hydroxyl, amino and carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions [see for example Greene, T. W., "Protecting Groups in Organic Synthesis", John Wiley and Sons, 1999].
  • Conventional protecting groups may be used in conjunction with standard practice.
  • deprotection may be the final step in the synthesis of a compound of general formula (T), and the processes according to the invention described herein after are understood to extend to such removal of protecting groups.
  • amino acid ester intermediates may be prepared by, but not restricted to, the methods outlined in Scheme 1.
  • amino acid ester compounds of the invention may be prepared by, but not restricted to, the methods outlined in Scheme 2.
  • linking group (W) between the central purine core and the R 7 group is an ethylene group.
  • a large number of other linking groups are, of course, encompassed by formula (I).
  • the skilled person would readily be able to choose suitable starting materials in order to produce amino acid ester compounds of the invention having a wide range of other W groups, and the ethylene group of Scheme 2 is used for clarity purposes only.
  • Scheme 3 shows a generic scheme for preparing the amino acids derivatives according to the invention, starting from the corresponding amino acid ester.
  • Hydrolysis of esters to the corresponding carboxylic acids by hCE-1 can be measured using the following procedure. At zero time, lOO ⁇ l of recombinant hCE-1 at a concentration of 6 ⁇ g/ml in phosphate assay buffer (K 2 PO 4 10OmM, KCl 4OmM, PH 7.4) was added to an equal volume of assay buffer containing 5 ⁇ M ester substrate. After thorough mixing, triplicate samples were incubated for 0, 20 or 80minutes at 37 0 C. At the appropriate time, hydrolysis was stopped by the addition of 600 ⁇ l of acetonitrile. For zero time samples, the acetonitrile was added prior to the enzyme.
  • phosphate assay buffer K 2 PO 4 10OmM, KCl 4OmM, PH 7.4
  • the compound may be tested in the following assay: Preparation of cell extract
  • the resulting supernatant was used as a source of esterase activity and was stored at -80 0 C until required.
  • Cells (8xlO 4 /ml) were incubated at 37 0 C in culture medium containing 6 ⁇ M compound in a 5% (v/v) CO 2 -humidified atmosphere. Incubations were terminated after 6h by centrifugation of 25ml aliquots of the cell suspension at 300g for 5 minutes at 4 0 C.
  • 0.2ml samples of the culture media supernatants were added to 4 volumes of acetonitrile (Sigma-Aldrich). After decanting the supernatant, the residual cell pellet (2xlO 6 cells) was extracted into ImI of acetonitrile. Samples were then analysed for the ester and acid metabolite at room temperature by LC/MS/MS (Sciex API3000). Chromatography was based on an AcCN (75x2 lmm) column with a 5-95% (v/v) acetonitrile, 0.1% (v/v) formic acid mobile phase. For the zero time samples, the cell suspension was chilled and centrifuged as soon as the ester had been added and then extracted into acetonitrile as described. Levels in cells are expressed as ng/ml.
  • UV spectra were recorded at 215 nm using a G1214A single wavelength UV detector. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per second or 1 scan per 1.2 seconds using LC/MSD Quad SW ESI interface. Data were integrated and reported using OpenLynx and OpenLynx Browser software.
  • Example 2 was prepared from Example 1 using the methodology described in scheme 3 above. To a solution of Example 1 (17mg, 0.029mmol) in diethyl ether (5ml) was added potassium trimethyl silanolate (32mg, 0.25mmol). The mixture was heated at 40 0 C for 12 hours, cooled to RT and then concentrated. The mixture was purified by preparative HPLC to yield the title compound as a white solid (2.6mg, 19%).
  • HTRP homogeneous time resolved fluorescence assay
  • HSP90 human recombinant his-tagged HSP90 ⁇
  • HSP90 Prospec Technogene, #HSP90, lot: 260HSP9001
  • a signal is generated by fluorescence resonance energy transfer from an Europium-cryptate labeled anti-his antibody (anti-his-K; Cisbio International, # 6 IHISKLA, lot: 33V) via the HSP90-GM-biotin complex to a fluorescence acceptor (allophycocyanin) linked to streptavidin (SA-XL; Cisbio International, # 61 OSAXLB, lot: 089).
  • Unlabeled GM or compounds compete with the bio-GM for binding to HSP90 resulting in reduced fluorescence energy transfer/assay signal.
  • a preformed (Ih incubation) complex of HSP90 with the anti-his-K is added to the compound solution in a 384 well microplate (Corning, # 3710) and incubated for 15 min.
  • a preformed (Ih incubation) complex of bio-GM with the SA-XL was added to the wells and incubated for 20 h. All incubations were performed at room temperature. The final assay volume was 50 ⁇ l/well.
  • the final concentrations in the assay were: 50 mM Hepes pH 7.3, 50 mM NaCl, 100 mM KF, 1 mM EDTA, 1 mM DTT, 0.1% Triton-X-100, 1 nM anti-his-K, 40 nM HSP90, 40 nM SA-XL, 40 nM bio-GM.
  • Test compounds were dissolved in DMSO, prediluted in assay buffer and tested at a final concentration between 5000 nM and 0.3 nM. The resulting DMSO concentration was 0.5% and included in all controls. High controls were without test compounds, low controls without test compounds, without HSP90 and without bio-GM.
  • IC 50 values were calculated by non-linear least squares fitting to the standard dose-response model using GraphPad Prism (GraphPad Software Inc).
  • the corresponding cancer cell lines (U937 and HUT) growing in log phase were harvested and seeded at 1000 cells/well (200 ⁇ l final volume) into 96- well tissue culture plates. Following 24h of cell growth cells were treated with compounds (final concentration of 20 ⁇ M). Plates were then re-incubated for a further 72h before a sulphorhodamine B (SRB) cell viability assay was conducted according to Skehan 1990 J Natl Cane Inst 82, 1107-1112.
  • SRB sulphorhodamine B
  • % inhibition 100-((SVS°)xl 00) where S 1 is the signal in the presence of inhibitor and S 0 is the signal in the presence of DMSO.
  • IC50 values were determined by non-linear regression analysis, after fitting the results of eight data points to the equation for sigmoidal dose response with variable slope (% activity against log concentration of compound), using Graphpad Prism software.
  • Range A IC50 ⁇ 1000nM
  • Range B IC50 from 100OnM to 500OnM
  • Range C IC50 >5000nM.

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Abstract

L'invention porte sur un composé qui est (a) un dérivé d'acide aminé de formule (I) ou un tautomère de celui-ci, ou (b) un sel, N-oxyde, hydrate ou solvate pharmaceutiquement acceptable de celui-ci : formule dans laquelle R1, R2, L1, Het, A, x, y et W sont tels que définis dans la description. Les composés sont utiles dans le traitement de maladies médiées par HSP90.
PCT/GB2009/001115 2008-05-07 2009-05-05 Dérivés de purine appropriés pour le traitement du cancer, des maladies auto-immunes et inflammatoires Ceased WO2009136144A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8217050B2 (en) * 2006-11-06 2012-07-10 Chroma Therapeutics Limited Adenine derivative as inhibitors of HSP90 for the treatment of cancer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084030A2 (fr) * 2005-02-01 2006-08-10 Sloan-Kettering Institute For Cancer Research Petites molecules inhibitrices du hsp90

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084030A2 (fr) * 2005-02-01 2006-08-10 Sloan-Kettering Institute For Cancer Research Petites molecules inhibitrices du hsp90

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8217050B2 (en) * 2006-11-06 2012-07-10 Chroma Therapeutics Limited Adenine derivative as inhibitors of HSP90 for the treatment of cancer

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