WO2009060215A1 - Polyamides - Google Patents

Polyamides Download PDF

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Publication number
WO2009060215A1
WO2009060215A1 PCT/GB2008/003767 GB2008003767W WO2009060215A1 WO 2009060215 A1 WO2009060215 A1 WO 2009060215A1 GB 2008003767 W GB2008003767 W GB 2008003767W WO 2009060215 A1 WO2009060215 A1 WO 2009060215A1
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group
formula
optionally substituted
polyamide
moiety
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PCT/GB2008/003767
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English (en)
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Philip Howard
Luke Masterson
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Spirogen Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a 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
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to polyamides, i.e. compounds comprising a number of amide linkages, their synthesis and binding pattern with certain DNA sequences.
  • Wnt Signalling has been identified as an important factor in a variety of human tumour types.
  • the family of Wnt secreted factors control numerous biological processes including proliferation, differentiation and morphogenesis.
  • Canonical Wnt signalling ultimately regulates the activity of ⁇ -catenin-Tcf/LEF transcriptional complexes.
  • Wnt controls the availability of ⁇ -catenin for its transcriptional binding partners (Tcf/Lef) through an Axin-APC (axin-adenomatous polyposis coli) complex that controls the ubiquitination and proteosomal degradation of free intracellular ⁇ -catenin.
  • GSK-3 ⁇ is highly active, leading to the phosphorylation dependent degradation of ⁇ -catenin via the Axin-APC destruction complex.
  • Wnt signakGSK- ⁇ is disabled allowing ⁇ -catenin to escape degradation, enter the nucleus and form trans-activation complexes with Tcf/LEF DNA binding proteins.
  • these transcription factors enable the expression of a suite of genes that block differentiation and encourage proliferation.
  • the suite includes the known proto-oncogenes c-Myc, Cyclin D1 and Ets. More recently, three Tcf/Lef binding elements (TBEs 1 , 2 and 3) have been found in the androgen receptor (AR) promoter.
  • Tcf and LEF genes themselves contain TBEs allowing autoregulation to take place.
  • Both Tcf and LEF genes contain dual promoter regions, the second of which is located in intronic DNA.
  • the secondary promoters are responsible for the transcription of truncated versions of the transcription factor which are still capable of binding to DNA but are unable to capture ⁇ -catenin.
  • these truncated proteins act as natural dominant negatives opposing the action of the full length transcription factors.
  • Significantly LEF-1 is not observed in normal colon cells (even in stem cells in the crypt), however in cancerous cells Tcf-4/ ⁇ -catenin binds to the primary promoter, whilst the second is repressed, aberrantly producing full length transcriptionally active Lef-1.
  • a feature of the Wnt signalling pathway is the lack of drugable kinase targets, with signal transduction being mediated through protein-protein interactions. Since the pathway lacks obvious kinase targets, there remains a need for pathway modulators.
  • the present inventors have realised that the ultimate effectors of the pathway are the sequence selective minor groove binding transcription factors of the Tcf/Lef family.
  • minor groove binding agents such as heterocyclic polyamides and pyrrolobenzodiazepines (PBDs)
  • PBDs pyrrolobenzodiazepines
  • TCF binding element 3 TCF binding element 3
  • TCF-4 can be displaced by Lef-1.
  • the Lef-1/ ⁇ -catenin transcription complex cannot be dismantled and deactivated via TGF- ⁇ signalling (unlike TCF-4/ ⁇ -catenin).
  • TBE3 has the sequence 5'- CTCCTCTCCTCTTCTTTG ATC-3 1 .
  • the novel compounds of the present invention may bind to this sequence in competition with TCF-4 and LeM .
  • These compounds may block transcription factor binding and may have therapeutic use, for example in colon cancer.
  • colon cancer studies have shown that blocking c-Myc expression with dominant negative Tcfs causes the tumour to differentiate, abolishing the tumour phenotype [Clevers, Cancer Cell, 5(1), 91-102, Jan 2004; van de Werering et al, Cell, 111(2), 241-250, Oct 2002].
  • the invention provides a polyamide moiety of formula I: -P 1 -X 1 -Y 1 -X 3 -X 4 -P 3 . (i) wherein:
  • Yi is either X 2 - ⁇ 2 or ⁇ 2 -X 2 ; ⁇ i is -R ⁇ -CH 2 -NH- ⁇ a -, wherein ⁇ a is a ⁇ -alanine residue and R p is chosen from optionally substituted Ci -7 alkylene, Ci -7 alkenylene and Ci -7 alkynylene groups; ⁇ 2 and ⁇ 3 are ⁇ -alanine residues; and Xi ⁇ X 2 , X 3 and X 4 are independently fragments of formula II: wherein E is an optionally substituted C 5 - 6 heteroarylene group.
  • a second aspect of the invention provides a polyamido moiety of formula III:
  • Y 2 is X 5 , X 5 -X 6 or X 5 -X 6 -P 4 .
  • Y 2 is preferably X 5 -X 6 or X 5 -X 6 -P 4 and most preferably X 5 -X 6 -P 4 .
  • X 5 and X 6 are independently fragments of formula II: wherein E is an optionally substituted C 5-6 heteroarylene group.
  • ⁇ 4 is a ⁇ -alanine residue.
  • a third aspect provides a polyamido moiety of formula IV:
  • Z is an optionally substituted C 5-2O cyclic group. In preferred embodiments of this set, Z is optionally substituted C 5-20 heterocyclyl or heteroaryl. In a second set of embodiments, Z is an optionally substituted pyrrolobenzodiazepine (PBD) moiety of formula Via or VIb:
  • R 8 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', nitro, Me 3 Sn and halo;
  • R 6 , R 7 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', nitro, Me 3 Sn and halo; where R and R' are independently selected from optionally substituted Ci -7 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; or R 6 and R 7 together form a group -O-(CH 2 ) P -O-, where p is 1 or 2; R 10 and R 11 either together form a double bond, or are selected from H and YR Y , where
  • Y is selected from O, S and NH and R ⁇ is H or C 1-7 alkyl or H and SO x M, where x is 2 or
  • M is a monovalent pharmaceutically acceptable cation
  • R 2L is X 2 , where X 2 is C 1-7 alkylene or C 1-7 alkenylene;
  • R 8L is Q-X 8 , where Q is selected from O, S, NH or a single bond and X 8 is C 1-7 alkylene or C 1-7 alkylene-CONH-C 1-7 alkylene.
  • the moiety of formula Via or VIb may be in a protected form, wherein R 10 is a nitrogen protecting group and R 11 is 0-R 12 , wherein R 12 is H or a hydroxyl protecting group.
  • a fourth aspect provides a polyamido the moiety of formula VII:
  • A taken with -R ⁇ -CH 2 -NH-, is preferably an optionally substituted amino or amido capping group. More preferably it forms a group of formula IX:
  • R D is an optionally substituted C 1-7 alkyl group or a group of formula Via or VIb.
  • A when taken with -R P -CH 2 -NH-, A forms a dimethylaminopropylamino (Dp) group.
  • a fifth aspect of the invention provides a compound of formula VIII: A-P 1 -X 1 -Y 1 -X 3 -X 4 -Ps-Y 2 -B (VIII) wherein A and B are as described above. It is preferred that only one of A and B contains a PBD moiety.
  • a sixth aspect of the invention provides a compound comprising a polyamido moiety according to the first, second, third or fourth aspect.
  • a seventh aspect provides a pharmaceutical composition containing a compound of the fifth or sixth aspect, as well as a compound of the fifth or sixth aspect for use in a method of medical treatment.
  • An eighth aspect provides the use of a compound according to the fifth or sixth aspect in the manufacture of a medicament for treating a proliferative disease, as well as a compound of the fifth or sixth aspect for use in a method of treatment of a proliferative disease.
  • a ninth aspect provides a method of treatment of a proliferative disease, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to the fifth or sixth aspect, preferably in the form of a pharmaceutical composition.
  • Figure 1 shows the footprint of four of the compounds of the invention (compounds 6, 7, 11 and 12) against TBE3 of the human MYC gene promoter. Lanes are labelled according to the identity and concentration of compound tested.
  • Figure 2 shows the footprint of a further four of the compounds of the invention (compounds 15, 19, 18 and 20) against TBE3 of the human MYC gene promoter. Lanes are labelled according to the identity and concentration of compound tested.
  • Figure 3 shows the footprint of a further two of the compounds of the invention (compounds 25 and 26) against TBE3 of the human MYC gene promoter. Lanes are labelled according to the identity and concentration of compound tested. Definitions Points of connection
  • ⁇ -Alanine residue refers to a moiety of formula: Cs-20 Cyclic, C ⁇ 20 Cyclyl
  • C5-20 cyclic and C 5-2 O cyclyl refer to groups which form a complete ring in their structure.
  • C 5-2 o refers to the number of ring atoms, whether they are carbon (carbocyclic, carbocyclyl) or heteroatoms (heterocyclic, heterocyclyl).
  • Such cyclic or cyclyl groups may be saturated or unsaturated (partially or fully).
  • cyclic and “cyclyl” include, but are not limited to, the subclasses carbocyclic, aryl and heterocyclic discussed below.
  • C 1-7 alkylene as used herein, pertains to a monovalent moiety obtained by removing two hydrogen atoms from carbon atoms of a hydrocarbon compound having from 1 to 7 carbon atoms, which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated).
  • alkylene includes the sub-classes alkenylene, alkynylene, cycloalkylene, etc., discussed below.
  • saturated alkylene groups include, but are not limited to, methylene (Ci), ethylene (C 2 ), propylene (C 3 ), butylene (C 4 ), pentylene (C 5 ), hexylene (C 6 ) and heptylene (C 7 ).
  • saturated linear alkylene groups include, but are not limited to, methylene (Ci), ethylene (C 2 ), n-propylene (C 3 ), n-butylene (C 4 ), n-pentylene (C 5 ), n-hexylene (C 6 ) and n-heptylene (C 7 ).
  • saturated branched alkylene groups include iso-propylene (C 3 ), iso-butylene (C 4 ), sec-butylene (C 4 ), tert-butylene (C 4 ), iso-pentylene (C 5 ), and neo-pentylene (C 5 ).
  • C 5-6 heteroarylene refers to a monovalent moiety obtained by removing two hydrogen atoms from aromatic ring atoms of a heteroaromatic compound, which moiety has from 3 to 20 ring atoms.
  • each ring has from 5 to 7 ring atoms.
  • C 5-6 denotes the number of ring atoms, whether carbon atoms or heteroatoms.
  • C 5-6 heteroarylene as used herein therefore pertains to a heteroarylene group having 5 or 6 ring atoms.
  • Examples of monocyclic C 5-6 heteroarylene groups include, but are not limited to, those derived from:
  • N 1 pyrrole (azole) (C 5 ), pyridine (azine) (C 6 );
  • S 1 thiophene (thiole) (C 5 ); N 1 Oi: oxazole (C 5 ), isoxazole (C 5 ), isoxazine (C 6 );
  • N 1 Si thiazole (C 5 ), isothiazole (C 5 );
  • N 2 imidazole (1 ,3-diazole) (C 5 ), pyrazole (1 ,2-diazole) (C 5 ), pyridazine (1 ,2-diazine) (C 6 ), pyrimidine (1 ,3-diazine) (C 6 ) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) (C 6 );
  • the pharmaceutically acceptable cation may be inorganic or organic.
  • Examples of pharmaceutically acceptable monovalent inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + .
  • Examples of pharmaceutically acceptable divalent inorganic cations include, but are not limited to, alkaline earth cations such as Ca 2+ and Mg 2+ .
  • Examples of pharmaceutically acceptable organic cations include, but are not limited to, ammonium ion (i.e. NH 4 + ) and substituted ammonium ions (e.g. NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 J 4 + .
  • Nitrogen protecting groups are well known in the art.
  • Preferred nitrogen protecting groups are carbamate protecting groups that have the general formula: R' 10 -O '. ⁇ y - ⁇ 3-
  • R' 10 is an optionally substituted alkyl (e.g. C 1 . 2 0 alky!), aryl (e.g. C 5-2 O aryl) or heteroaryl (e.g. C 3-20 heterocyclyl) group.
  • alkyl e.g. C 1 . 2 0 alky!
  • aryl e.g. C 5-2 O aryl
  • heteroaryl e.g. C 3-20 heterocyclyl
  • Particularly preferred protecting groups include Alloc, Troc, Teoc, BOC, Doc, Hoc, TcBOC, Fmoc, 1-Adoc and 2-Adoc.
  • nitrogen protecting groups which can be removed in vivo (e.g. enzymatically, using light) as described in WO 00/12507, which is incorporated herein by reference.
  • these protecting groups include:
  • ADEPT/GDEPT nitroreductase labile
  • Protected hydroxyl groups are of the formula -O-Prot, where Prot is an oxygen protecting group as discussed below. Oxygen protecting groups
  • Oxygen protecting groups are well known in the art. A large number of suitable groups are described on pages 23 to 200 of Greene, T.W. and Wuts, G. M., Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, Inc., 1999, which is incorporated herein by reference.
  • Classes of particular interest include silyl ethers, methyl ethers, alkyl ethers, benzyl ethers, esters, benzoates, carbonates, and sulfonates.
  • substituted refers to a parent group which bears one or more substituents.
  • substituted is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, or if appropriate, fused to, a parent group.
  • substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.
  • C 1-7 alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 7 carbon atoms, which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated).
  • alkyl includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc., discussed below.
  • saturated alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), butyl (C 4 ), pentyl (C 5 ), hexyl (C 6 ) and heptyl (C 7 ).
  • saturated linear alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C 5 ), n-hexyl (C 6 ) and n-heptyl (C 7 ).
  • saturated branched alkyl groups include iso-propyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neo-pentyl (C 5 ).
  • C 2-7 Alkenyl The term "C 2 - 7 alkenyl" as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds.
  • C 2- 7 alkynyl The term "C 2-7 alkynyl" as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds.
  • C 3-7 cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 carbon atoms, including from 3 to 7 ring atoms.
  • cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C 3 ), cyclobutane (C 4 ), cyclopentane (C 5 ), cyclohexane (C 6 ), cycloheptane (C 7 ), methylcyclopropane (C 4 ), dimethylcyclopropane (C 5 ), methylcyclobutane (C 5 ), dimethylcyclobutane (C 6 ), methylcyclopentane (C 6 ), dimethylcyclopentane (C 7 ) and methylcyclohexane (C 7 ); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C 3 ), cyclobutene (C 4 ), cyclopentene (C 5 ), cyclohexene (C 6 ), methylcyclopropene (C 4 ), dimethylcyclopropene (C 5 ), methylcycloprop
  • C 3-20 heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • the prefixes e.g. C 3-2O , C 3-7 , C 5-6 , etc.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C 5-6 heterocyclyl as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.
  • monocyclic heterocyclyl groups include, but are not limited to, those derived from:
  • N 1 aziridine (C 3 ), azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C 5 ), pyrroline (e.g.,
  • O 1 oxirane (C 3 ), oxetane (C 4 ), oxolane (tetrahydrofuran) (C 5 ), oxole (dihydrofuran) (C 5 ), oxane (tetrahydropyran) (C 6 ), dihydropyran (C 6 ), pyran (C 6 ), oxepin (C 7 );
  • O 3 trioxane (C 6 ); N 2 : imidazolidine (C 5 ), pyrazolidine (diazolidine) (C 5 ), imidazoline (C 5 ), pyrazoline
  • N 1 O 1 tetrahydrooxazole (C 5 ), dihydrooxazole (C 5 ), tetrahydroisoxazole (C 5 ), dihydroisoxazole (C 5 ), morpholine (C 6 ), tetrahydrooxazine (C 6 ), dihydrooxazine (C 6 ), oxazine (C 6 ); N 1 S 1 : thiazoline (C 5 ), thiazolidine (C 5 ), thiomorpholine (C 6 );
  • O 1 S 1 oxathiole (C 5 ) and oxathiane (thioxane) (C 6 ); and,
  • N 1 O 1 S 1 oxathiazine (C 6 ).
  • substituted monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C 5 ), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C 6 ), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.
  • furanoses C 5
  • arabinofuranose such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse
  • pyranoses C 6
  • allopyranose altropyranose
  • glucopyranose glucopyranose
  • mannopyranose gulopyranose
  • idopyranose galactopyranose
  • C 5-2 O aryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms. Preferably, each ring has from 5 to 7 ring atoms.
  • the prefixes e.g. C 3-2O , C 5-7 , C 5-6 , etc.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • the term "C 5-6 aryl” as used herein, pertains to an aryl group having 5 or 6 ring atoms.
  • the ring atoms may be all carbon atoms, as in "carboaryl groups".
  • carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C 6 ), naphthalene (C 10 ), azulene (Ci 0 ), anthracene (Ci 4 ), phenanthrene (Ci 4 ), naphthacene (Ci 8 ), and pyrene (Ci 6 ).
  • aryl groups which comprise fused rings include, but are not limited to, groups derived from indane (e.g. 2, 3-d i hydro- 1H- indene) (C 9 ), indene (C 9 ), isoindene (C 9 ), tetraline (1,2,3,4-tetrahydronaphthalene (Ci 0 ), acenaphthene (Ci 2 ), fluorene (Ci 3 ), phenalene (Ci 3 ), acephenanthrene (Ci 5 ), and aceanthrene (Ci 6 ).
  • indane e.g. 2, 3-d i hydro- 1H- indene
  • indene C 9
  • isoindene C 9
  • tetraline (1,2,3,4-tetrahydronaphthalene Ci 0
  • acenaphthene Ci 2
  • fluorene Ci 3
  • phenalene Ci 3
  • the ring atoms may include one or more heteroatoms, as in "heteroaryl groups".
  • heteroaryl groups include, but are not limited to, those derived from:
  • N 1 pyrrole (azole) (C 5 ), pyridine (azine) (C 6 ); O 1 : furan (oxole) (C 5 );
  • Ni ⁇ i oxazole (C 5 ), isoxazole (C 5 ), isoxazine (C 6 );
  • N 3 O 1 oxatriazole (C 5 );
  • N 1 S 1 thiazole (C 5 ), isothiazole (C 5 );
  • N 2 imidazole (1 ,3-diazole) (C 5 ), pyrazole (1 ,2-diazole) (C 5 ), pyridazine (1 ,2-diazine) (C 6 ), pyrimidine (1 ,3-diazine) (C 6 ) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) (C 6 );
  • heteroaryl which comprise fused rings include, but are not limited to: C 9 (with 2 fused rings) derived from benzofuran (O 1 ), isobenzofuran (Oi), indole (N 1 ), isoindole (N 1 ), indolizine (N 1 ), indoline (N 1 ), isoindoline (N 1 ), purine (N 4 ) (e.g., adenine, guanine), benzimidazole (N 2 ), indazole (N 2 ), benzoxazole (N 1 O 1 ), benzisoxazole (N 1 O 1 ), benzodioxole (O 2 ), benzofurazan (N 2 O 1 ), benzotriazole (N 3 ), benzothiofuran (S 1 ), benzothiazole (N 1 S 1 ), benzothiadiazole (N 2 S);
  • C 13 (with 3 fused rings) derived from carbazole (N 1 ), dibenzofuran (O 1 ), dibenzothiophene (S 1 ), carboline (N 2 ), perimidine (N 2 ), pyridoindole (N 2 ); and,
  • C 14 (with 3 fused rings) derived from acridine (N-i), xanthene (O 1 ), thioxanthene (S 1 ), oxanthrene (O 2 ), phenoxathiin (O 1 S 1 ), phenoxazine (N 1 O 1 ), phenothiazine (N 1 S 1 ), thianthrene (S 2 ), phenanthridine (N 1 ), phenanthroline (N 2 ), phenazine (N 2 ).
  • C 2-7 Alkenylene The term "C 2-7 alkenylene” as used herein, pertains to an alkylene group having one or more carbon-carbon double bonds.
  • C 2-7 alkynylene The term "C 2-7 alkynylene” as used herein, pertains to an alkylene group having one or more carbon-carbon triple bonds.
  • C 3-7 cycloalkylene refers to an alkylene group which is also a cyclyl group; that is, a monovalent moiety obtained by removing two hydrogen atoms from alicyclic ring atoms of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 carbon atoms, including from 3 to 7 ring atoms.
  • cycloalkylene groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C 3 ), cyclobutane (C 4 ), cyclopentane (C 5 ), cyclohexane (C 6 ), cycloheptane (C 7 ), methylcyclopropane (C 4 ), dimethylcyclopropane (C 5 ), methylcyclobutane (C 5 ), dimethylcyclobutane (C 6 ), methylcyclopentane (C 6 ), dimethylcyclopentane (C 7 ) and methylcyclohexane (C 7 ); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C 3 ), cyclobutene (C 4 ), cyclopentene (C 5 ), cyclohexene (C 6 ), methylcyclopropene (C 4 ), dimethylcyclopropene (C 5 ), methylcycloprop
  • C 3-2 O heterocyclylene refers to a monovalent moiety obtained by removing two hydrogen atoms from ring atoms of a heterocyclic compound, which moiety has from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • C 3-2 O, C 3-7 , C 5- 6, etc. denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C 5-6 heterocyclylene as used herein, pertains to a heterocyclylene group having 5 or 6 ring atoms.
  • monocyclic heterocyclylene groups include, but are not limited to, those derived from:
  • N 1 aziridine (C 3 ), azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C 5 ), pyrroline (e.g.,
  • O 2 dioxolane (C 5 ), dioxane (C 6 ), and dioxepane (C 7 );
  • O 3 trioxane (C 6 );
  • N 2 imidazolidine (C 5 ), pyrazolidine (diazolidine) (C 5 ), imidazoline (C 5 ), pyrazoline (dihydropyrazole) (C 5 ), piperazine (C 6 );
  • N 1 Oi tetrahydrooxazole (C 5 ), dihydrooxazole (C 5 ), tetrahydroisoxazole (C 5 ), dihydroisoxazole (C 5 ), morpholine (C 6 ), tetrahydrooxazine (C 6 ), dihydrooxazine (C 6 ), oxazine (C 6 );
  • NiS 1 thiazoline (C 5 ), thiazolidine (C 5 ), thiomorpholine (C 6 ); N 2 Oi: oxadiazine (C 6 );
  • OiSi oxathiole (C 5 ) and oxathiane (thioxane) (C 6 ); and, N 1 O 1 S 1 : oxathiazine (C 6 ).
  • substituted monocyclic heterocyclylene groups include those derived from saccharides, in cyclic form, for example, furanoses (C 5 ), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C 6 ), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.
  • furanoses C 5
  • arabinofuranose such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse
  • pyranoses C 6
  • allopyranose altropyranose
  • glucopyranose glucopyranose
  • mannopyranose gulopyranose
  • idopyranose galactopyranose
  • C 5-2O arylene refers to a monovalent moiety obtained by removing two hydrogen atoms from aromatic ring atoms of an aromatic compound, which moiety has from 3 to 20 ring atoms. Preferably, each ring has from 5 to 7 ring atoms.
  • the prefixes e.g. C 3-20 , C 5-7 , C 5-6 , etc.
  • the term "C 5-6 arylene” as used herein, pertains to an arylene group having 5 or 6 ring atoms.
  • the ring atoms may be all carbon atoms, as in "carboarylene groups".
  • carboarylene groups include, but are not limited to, those derived from benzene (i.e. phenylene) (C 6 ), naphthalene (C 10 ), azulene (C 10 ), anthracene (C 14 ), phenanthrene (C 14 ), naphthacene (C 18 ), and pyrene (C 16 ).
  • arylene groups which comprise fused rings include, but are not limited to, groups derived from indane (e.g. 2,3- dihydro-1 H-indene) (C 9 ), indene (C 9 ), isoindene (C 9 ), tetraline (1 ,2,3,4-tetrahydronaphthalene (C 10 ), acenaphthene (C 12 ), fluorene (C 13 ), phenalene (C 13 ), acephenanthrene (C 15 ), and aceanthrene (C 16 ).
  • the ring atoms may include one or more heteroatoms, as in "heteroarylene groups".
  • monocyclic heteroarylene groups include, but are not limited to, those derived from: N 1 : pyrrole (azole) (C 5 ), pyridine (azine) (C 6 );
  • N 1 O 1 oxazole (C 5 ), isoxazole (C 5 ), isoxazine (C 6 );
  • N 2 O 1 oxadiazole (furazan) (C 5 ); N 3 O ⁇ OXaWaZoIe (C 5 );
  • N 1 S 1 thiazole (C 5 ), isothiazole (C 5 );
  • N 2 imidazole (1 ,3-diazole) (C 5 ), pyrazole (1 ,2-diazole) (C 5 ), pyridazine (1 ,2-diazine) (C 6 ), pyrimidine (1 ,3-diazine) (C 6 ) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) (C 6 );
  • N 3 triazole (C 5 ), triazine (C 6 ); and, N 4 : tetrazole (C 5 ).
  • heteroarylene which comprise fused rings, include, but are not limited to:
  • C 13 (with 3 fused rings) derived from carbazole (N 1 ), dibenzofuran (O 1 ), dibenzothiophene (S 1 ), carboline (N 2 ), perimidine (N 2 ), pyridoindole (N 2 ); and, C 14 (with 3 fused rings) derived from acridine (N 1 ), xanthene (O 1 ), thioxanthene
  • Halo -F, -Cl, -Br, and -I.
  • Ether -OR, wherein R is an ether substituent, for example, a Ci -7 alkyl group (also referred to as a C 1-7 alkoxy group, discussed below), a C 3-2O heterocyclyl group (also referred to as a C 3-2O heterocyclyloxy group), or a C 5-20 aryl group (also referred to as a C 5-20 aryloxy group), preferably a d -7 alkyl group.
  • a Ci -7 alkyl group also referred to as a C 1-7 alkoxy group, discussed below
  • C 3-2O heterocyclyl group also referred to as a C 3-2O heterocyclyloxy group
  • C 5-20 aryl group also referred to as a C 5-20 aryloxy group
  • Alkoxy -OR, wherein R is an alkyl group, for example, a C 1-7 alkyl group.
  • C 1-7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), - O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), -O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy).
  • Acetal -CH(OR 1 J(OR 2 ), wherein R 1 and R 2 are independently acetal substituents, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group, or, in the case of a "cyclic" acetal group, R 1 and R 2 , taken together with the two oxygen atoms to which they are attached, and the carbon atoms to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • Examples of acetal groups include, but are not limited to, -CH(OMe) 2 , -CH(OEt) 2 , and -CH(OMe)(OEt).
  • Hemiacetal -CH(OH)(OR 1 ), wherein R 1 is a hemiacetal substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • R 1 is a hemiacetal substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • hemiacetal groups include, but are not limited to, -CH(OH)(OMe) and - CH(OH)(OEt).
  • Ketal -CR(OR 1 J(OR 2 ), where R 1 and R 2 are as defined for acetals, and R is a ketal substituent other than hydrogen, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • Examples ketal groups include, but are not limited to, -C(Me)(OMe) 2 , -C(Me)(OEt) 2 , -C(Me)(OMe)(OEt), -C(Et)(OMe) 2 , - C(Et)(OEt) 2 , and -C(Et)(OMe)(OEt).
  • R 1 is as defined for hemiacetals, and R is a hemiketal substituent other than hydrogen, for example, a C 1-7 alkyl group, a C 3-2 O heterocyclyl group, or a C 5-2 O aryl group, preferably a Ci -7 alkyl group.
  • hemiacetal groups include, but are not limited to, -C(Me)(OH)(OMe), -C(Et)(OH)(OMe), -C(Me)(OH)(OEt), and -C(Et)(OH)(OEt).
  • lmino (imine): NR, wherein R is an imino substituent, for example, hydrogen, Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably hydrogen or a Ci -7 alkyl group.
  • R is an acyl substituent, for example, a Ci -7 alkyl group (also referred to as Ci -7 alkylacyl or Ci -7 alkanoyl), a C 3-20 heterocyclyl group (also referred to as C 3-20 heterocyclylacyl), or a C 5-20 aryl group (also referred to as C 5-20 arylacyl), preferably a Ci -7 alkyl group.
  • a Ci -7 alkyl group also referred to as Ci -7 alkylacyl or Ci -7 alkanoyl
  • C 3-20 heterocyclyl group also referred to as C 3-20 heterocyclylacyl
  • C 5-20 aryl group also referred to as C 5-20 arylacyl
  • Carboxy (carboxylic acid): -C( O)OH.
  • Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C( O)OR, wherein R is an ester substituent, for example, a Ci -7 alkyl group, a C 3-2 o heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • Acyloxy (reverse ester): -OC( O)R, wherein R is an acyloxy substituent, for example, a Ci -7 alkyl group, a C 3-2O heterocyclyl group, or a C 5-2O aryl group, preferably a Ci -7 alkyl group.
  • R is an acyloxy substituent, for example, a Ci -7 alkyl group, a C 3-2O heterocyclyl group, or a C 5-2O aryl group, preferably a Ci -7 alkyl group.
  • Oxycarboyloxy: -OC( O)OR, wherein R is an ester substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a Ci -7 alkyl group (also referred to as Ci -7 alkylamino or di-Ci -7 alkylamino), a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably H or a Ci -7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • a Ci -7 alkyl group also referred to as Ci -7 alkylamino or di-Ci -7 alkylamino
  • C 3-20 heterocyclyl group or a C 5-20 aryl group, preferably H or a Ci -7 alkyl group
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • Amino groups may be primary (-NH 2 ), secondary (-NHR 1 ), or tertiary (-NHR 1 R 2 ), and in cationic form, may be quaternary (- + NR 1 R 2 R 3 ).
  • Examples of amino groups include, but are not limited to, -NH 2 , -NHCH 3 , -NHC(CH 3 ) 2 , -N(CH 3 J 2 , -N(CH 2 CH 3 ) 2 , and -NHPh.
  • Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.
  • Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C( O)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • Thioamido (thiocarbamyl): -C( S)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amide substituent, for example, hydrogen, a C 1-7 alkyl group, a C 3-2O heterocyclyl group, or a Cs -2O aryl group, preferably hydrogen or a C 1-7 alkyl group
  • R 2 is an acyl substituent, for example hydrogen, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C
  • R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:
  • R 2 and R 3 are independently amino substituents, as defined for amino groups, and R 1 is a ureido substituent, for example, hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably hydrogen or a C 1-7 alkyl group.
  • ureido groups include, but are not limited to, -NHCONH 2 , - NHCONHMe, -NHCONHEt, -NHCONMe 2 , -NHCONEt 2 , -NMeCONH 2 , -NMeCONHMe, -NMeCONHEt, -NMeCONMe 2 , and -NMeCONEt 2 .
  • Tetrazolyl a five membered aromatic ring having four nitrogen atoms and one carbon atom
  • N ⁇ N Imino: NR
  • R is an imino substituent, for example, for example, hydrogen, a C 1 - 7 alkyl group, a C 3-2O heterocyclyl group, or a C 5-2 o aryl group, preferably H or a C 1-7 alkyl group.
  • C 1-7 alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3 .
  • Disulfide -SS-R, wherein R is a disulfide substituent, for example, a Ci -7 alkyl group, a C3-20 heterocyclyl group, or a C 5-2O aryl group, preferably a Ci -7 alkyl group (also referred to herein as Ci -7 alkyl disulfide).
  • R is a disulfide substituent, for example, a Ci -7 alkyl group, a C3-20 heterocyclyl group, or a C 5-2O aryl group, preferably a Ci -7 alkyl group (also referred to herein as Ci -7 alkyl disulfide).
  • Ci -7 alkyl disulfide groups include, but are not limited to, -SSCH 3 and -SSCH 2 CH 3 .
  • Sulfine (sulfinyl, sulfoxide): -S( O)R, wherein R is a sulfine substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • R is a sulfine substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • R is a sulfinate substituent, for example, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • R is a sulfonate substituent, for - example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • R is a sulfinyloxy substituent, for example, a Ci -7 alkyl group, a C 3-2 O heterocyclyl group, or a C 5-2O aryl group, preferably a Ci -7 alkyl group.
  • R is a sulfonyloxy substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group.
  • R is a sulfate substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfonamino substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a C 1-7 alkyl group.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfinamino substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-2O aryl group, preferably a Ci -7 alkyl group.
  • phosphino groups include, but are not limited to, -PH 2 , -P(CH 3 J 2 , -P(CH 2 CH 3 ) 2 , -P(t-Bu) 2 , and -P(Ph) 2 .
  • R is a phosphinyl substituent, for example, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably a Ci -7 alkyl group or a C 5-20 aryl group.
  • R is a phosphonate substituent, for example, -H, a Ci -7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably -H, a Ci -7 alkyl group, or a C 5-20 aryl group.
  • Phosphate (phosphonooxy ester): -OP( O)(OR) 2 , where R is a phosphate substituent, for example, -H, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably -H, a Ci -7 alkyl group, or a C 5-20 aryl group.
  • Phosphorous acid -OP(OH) 2 .
  • Phosphite -OP(OR) 2 , where R is a phosphite substituent, for example, -H, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably -H, a C 1-7 alkyl group, or a C5-20 aryl group.
  • R is a phosphite substituent, for example, -H, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 aryl group, preferably -H, a C 1-7 alkyl group, or a C5-20 aryl group.
  • Examples of phosphite groups include, but are not limited to, -OP(OCH 3 ) 2 , -OP(OCH 2 CHs) 2 , -OP(O-t-Bu) 2 , and -OP(OPh) 2 .
  • Phosphoramidite -OP(OR 1 )-NR 2 2 , where R 1 and R 2 are phosphoramidite substituents, for example, -H, a (optionally substituted) C 1-7 alkyl group, a C 3-2O heterocyclyl group, or a C 5-20 aryl group, preferably -H, a Ci -7 alkyl group, or a C 5-2 O aryl group.
  • Examples of phosphoramidite groups include, but are not limited to, -OP(OCH 2 CH 3 )-N(CH 3 ) 2 , -OP(OCH 2 CH 3 )-N(i-Pr) 2 , and -OP(OCH 2 CH 2 CN)-N(J-Pr) 2 .
  • proliferative disease pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g. histocytoma, glioma, astrocyoma, osteoma), cancers (e.g. lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g.
  • any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
  • capping group refers to any group which terminates one end of a polyamide chain.
  • a complete chain has two capping groups.
  • Flanking Sequence A "flanking sequence” as used herein describes a short sequence of DNA which is positioned next to a transcription unit. Usually the flanking sequence itself is not transcribed.
  • the present invention provides as an eighth aspect the use of a compound in a method of therapy.
  • a method of treatment comprising administering to a subject in need of treatment a therapeutically- effective amount of a compound of the fifth or sixth aspect, preferably in the form of a pharmaceutical composition, which is the seventh aspect of the present invention.
  • therapeutically effective amount is an amount sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time-course of administration will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.
  • a compound may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs); surgery; and radiation therapy.
  • compositions according to the present invention may comprise, in addition to the active ingredient, i.e. a compound of the sixth aspect, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such a gelatin.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO ' ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 " ), a salt or solvate thereof, as well as conventional protected forms.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and I- forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. d -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below.
  • a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
  • a pharmaceutically-acceptable salt examples are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e. NH 4 + ) and substituted ammonium ions (e.g. NH 3 R + , NH 2 (V, NHR 3 + , NR 4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 J 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • Suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • Solvates of particular relevance to the present invention are those where the solvent adds across the imine bond present in some PBD moieties of formula Via or VIb, which is illustrated below where the solvent is water or an alcohol (R A OH, where R A is an ether substituent as described above):
  • carbinolamine and carbinolamine ether forms of the PBD can be called the carbinolamine and carbinolamine ether forms of the PBD.
  • the balance of these equilibria depends on the conditions in which the compounds are found, as well as the nature of the moiety itself.
  • nucleophilic solvent in general any nucleophilic solvent is capable of forming such solvates as illustrated above for hydroxylic solvents.
  • nucleophilic solvents include thiols and amines.
  • solvates may be isolated in solid form, for example, by lyophilisation.
  • Ala alanine, or a derivative fragment thereof
  • succinimide or succinimidyl (succinimidyl being the deprotonated derivative of succinimide)
  • DIPEA N.N-diisopropylethylamine
  • HOBt 1-hydroxybenzotriazole
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
  • DTT dithiothreitol
  • EDTA ethylenediaminetetraacetic acid
  • the group ⁇ i is -R p -CH 2 -NH- ⁇ a -, ⁇ a being a ⁇ -alanine residue.
  • R ⁇ is chosen from optionally substituted Ci -7 alkylene, C 1-7 alkenylene and C 1-7 alkynylene groups.
  • R p is prefereably and optionally substituted Ci -7 alkylene groups, more preferably optionally substituted C 3 alkylene. Most preferably, R p is substituted by a tertiary amine group.
  • E is an optionally substituted C 5-6 heteroarylene group.
  • This group is preferably an optionally substituted C 5 heteroarylene group.
  • the group preferably has one or two ring heteroatoms, which are preferably selected from N, S and O. If the heteroarylene group is substituted, it is preferably substituted with an optionally substituted Ci -7 alkylene group, most preferably with a methyl group. If the heteroarylene group is substituted with a methyl group, the substitution is preferably on the atom ⁇ to that which is bonded to the acyl carbon of the fragment of formula II.
  • Xi is a pyrrole (Py) based residue.
  • Xi, X 2 , X 3 , X 4 , Xs and X 6 are selected from:
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are Pyrrole (Py) or Imidazole (Im) based residues.
  • X 1 and X 3 are preferably Py.
  • X 2 , X 4 , X 5 and X 6 are preferably Im.
  • the cyclic group when Z is an optionally substituted C 5-20 cyclic group, the cyclic group preferably has one or more ring heteroatoms (that is, it is preferably a heterocyclic group). More preferably, the optionally substituted heterocycle has one or two heteroatoms. The heteroatoms are preferably chosen from N, O and S. Z can be made up of any number of optionally substituted fused ring systems, for example bicyclic or tricyclic. If the optionally substituted cyclic or heterocyclic group is substituted, it is preferably substituted by one or more Cw alkyl substituents.
  • Z is an optionally substituted heterocyclic group, it is preferably an optionally substituted C 5-2 O heterocyclic group, more preferably an optionally substituted C 5- I 0 heterocyclic group.
  • Z comprises an optionally substituted C 5 or C 6 heterocycle optionally fused to a further optionally substituted C 5 or C 6 cyclic group.
  • Z is an optionally substituted C 5 or C 6 heterocyclic group fused to a further optionally substituted C 6 cyclic group. If the fused ring is substituted, it is preferably substituted with -NRR', more preferably -N(C 1-7 alkyl) 2 .
  • B is most preferably selected from the following groups (which are shown with abbreviated names):
  • 3M2Pic 2Py 2ABz 7DMAC B is more preferably selected from the following groups (which are shown with abbreviated names):
  • the most preferred groups for B are 2Pic and 2Pyz.
  • Z is based around an optionally substituted pyrrolobenzodiazepine (PBD) moiety of formula Via or VIb
  • Q is preferably O and X 8 is preferably optionally substituted Ci -7 alkylene.
  • R 2 is preferably H or optionally substituted Ci -7 alkyl, most preferably H.
  • R 8 is preferably OR, more preferably optionally substituted 0-Ci -7 alkyl, most preferably OCH 3 .
  • R 2L is preferably optionally substituted Ci -7 alkylene or optionally substituted Ci -7 alkenylene, most preferably optionally substituted Ci -7 alkenylene.
  • R 7 R 7 is preferably selected from H, OH, OR, SH, SR, NH 2 , NHR, NRR", and halo, and more preferably independently selected from H, OH and OR, where R is preferably selected from optionally substituted Ci -7 alkyl, C 3-I0 heterocyclyl and C 5-10 aryl groups.
  • Particularly preferred substituents at the 7- position are OMe and OCH 2 Ph.
  • R 3 is preferably H or optionally substituted Ci -7 alkyl, most preferably H.
  • R 9 R 9 is preferably H.
  • R 6 is preferably selected from H, OH, OR, SH, NH 2 , nitro and halo, and is more preferably H or halo, and most preferably is H.
  • R 2 is H.
  • R is an optionally substituted C 5-2 O aryl group. It may be selected from: an optionally substituted C 5-7 aryl group, for example phenyl; an optionally substituted C 9-I2 aryl group, for example for example naphthyl (e.g napthy-1-yl, napth-2-yl) and quinolinyl (e.g. quinolin-2-yl, quinolin-3-yl,quinolin-6-yl); an optionally substituted C 5-7 heteroaryl group, for example furanyl (e.g. furan-2-yl, furan-3- yl), thiophenyl (e.g. thiophen-2-yl, thiophen-3-yl) and pyridyl (e.g. pyrid-2-yl, pyrid-3-yl).
  • an optionally substituted C 5-7 aryl group for example phenyl
  • an optionally substituted C 9-I2 aryl group for
  • the C 5-20 aryl group may bear any substituent group. It may bear from 1 to 3, 1 to 2 or 1 substituent groups.
  • C 5-20 aryl substituents, particularly for phenyl include, but are not limited to: halo (e.g. F, Cl, Br); Ci -7 alkoxy (e.g. methoxy, ethoxy); C 1-7 alkyl (e.g. methyl, trifluoromethyl, ethyl, propyl, t-butyl); bis-oxy-alkylene (e.g. bis-oxy-methylene, -0-CH 2 - O-).
  • C 5-20 aryl groups of particular interest include, but are not limited to, phenyl, 4-methyl- phenyl, 4-methoxy-phenyl, 3-methoxyphenyl, 4-fluoro-phenyl, 3,4-bisoxymethylene- phenyl, 4-triflouoromethylphenyl, 4-methylthiophenyl, 4-cyanophenyl, 4-phenoxyphenyl, thiophen-2-yl, napth-2-yl, quinolin-3-yl and quinolin-6-yl.
  • R may be Ci -7 alkyl (e.g. methyl, ethyl).
  • the C 1-7 alkyl group may contain one or more unsaturated bonds conjugated to the double bond bound to the C-ring.
  • R may be C 5-2O aryl, in particular C 5-6 aryl (e.g. phenyl, pyridyl, thiophenyl, furanyl).
  • R 2 may be Ci -7 alkyl containing one or more unsaturated bonds conjugated to the double bond in the C-ring.
  • R 10 and R 11 preferably together form a double bond between N10 and C11.
  • M is preferably Na + .
  • B is selected from the following groups (which are shown with abbreviated names):
  • polyamido moiety of formula I is: - ⁇ rPy-lm- ⁇ -Py-lm- ⁇ -
  • Triethylamine (15.99 g, 22 ml, 158.4 mmol, 1.1 eq) was added to a solution of amine 1a HCI salt (27.44 g, 144 mmol, 1 eq) and Boc Ala succinimide (45.4 g, 158.4 mmol, 1.1 eq) in DCM (400 ml). The solution was stirred at room temperature for 1.5 hours. The reaction mixture was washed with H 2 O (2 x 250 ml), 1 M citric acid (2 x 200 ml), saturated NaHCO 3 (2 x 200 ml), H 2 O (250 ml) and brine (250 ml).
  • Compound 3(b) is available from commercial sources.
  • 2-Amino-5-methyl-thiazole-4- carboxylic acid methyl ester 8 (10.33 g, 60 mmol, 1 eq) was added portionwise followed by DIPEA (7.75 g, 9.73 ml, 60 mmol, 1 eq), and DMAP (2.2 g, 18 mmol, 0.3 eq) and the reaction mixture was allowed to stir at room temperature for 18 hours.
  • the mixture was filtered and extracted with 1M citric acid (3 x 200 ml), sat. NaHCO 3 (3 x 200 ml), water (200 ml), brine (200 ml), dried (MgSO 4 ) and evaporated under reduced pressure to give a yellow foam.
  • the product was contaminated with dicyclohexylcarbodiimide and was used without further purification assuming 100% yield.
  • the compound to be tested and buffer (20 mM HEPES pH 7.9, 20 mM NaCI, 2 mM MgCI 2 , 1 mM DTT, 10% glycerol; 388 ⁇ l) were mixed with 2 ⁇ l of 32 P-radiolabelled DNA (128 base pairs containing TBE3 and flanking sequences of the human MYC gene promoter) and incubated overnight at room temperature.
  • Each compound was tested at five different concentrations: 0.0003 ⁇ M, 0.001 ⁇ M, 0.003 ⁇ M, 0.01 ⁇ M and 0.03 ⁇ M.
  • Digestion was initiated by the addition, at timed intervals, of 10 ⁇ l of DNase I solution (200 mM NaCI 1 20 mM MgCI 2 , 20 mM MnCI 2 ; containing 0.02 U/ ⁇ l DNase I [Promega]). Each reaction was stopped after exactly eight minutes by the addition of 40 ⁇ l of DNase I Stop solution (2.25 M NaCI, 150 mM EDTA 1 pH 8.0, 0.57 ⁇ g/ ⁇ l glycogen and 19.3 ng/ ⁇ l poly(dl-dC)»poly(dl-dC) DNA).
  • Single-stranded DNA fragments were resolved to a difference of one nucleotide by denaturing polyacrylamide gel electrophoresis.
  • Denaturing gels (0.4 mm thick, 10%) were prepared using a National Diagnostics Sequencing Gel Kit according to the manufacturer's instructions. The gel was set by the addition of 300 ⁇ l of 10% APS (w/v) and 30 ⁇ l of TEMED. Electrophoresis was performed for around 150 minutes at 90 W ( ⁇ 2000-2250 V) in 1x TBE buffer until the bromophenol blue marker dye had run out of the gel, thus resolving the DNA sites 20-120 nucleotides from the labeled end. Gels were fixed by soaking in 10% acetic acid for 15 minutes and then dried onto Whatman 3MM paper under vacuum at 8O 0 C for 90 minutes.
  • Dried gels were apposed at room temperature to GE Healthcare phosphor storage screens for a minimum period of 48 hours. Data were collected from exposed screens using a Storm 840 Phosphorlmager (GE Healthcare) and transferred to ImageQuant TL V2003.03 software (GE Healthcare) for visual inspection.
  • Storm 840 Phosphorlmager GE Healthcare
  • ImageQuant TL V2003.03 software GE Healthcare
  • the target site in the MYC promoter comprises 5'-AAAGAAG AG-3'.
  • W A or T.
  • Reference herein to a 'match' or a 'mismatch' site is with respect to this generic target.
  • the compounds with the highest apparent affinity were 7, 8 and 9 representing C2- linked benzofuran, pyridine and pyrazine variations respectively. These three compounds exhibited inhibition of DNase l-mediated cleavage at the predicted match site at ⁇ 1 nM. In contrast, the standard pyrrole-imidazole molecule (1) bound to the same site at ⁇ 10 nM. The remaining nine compounds in this class (spanning nine base pairs) had apparent C 50 values in the range 3-30 nM.
  • both 8 and 9 exhibited high levels of selectivity.
  • selectivity ratio of 50-100. This value is calculated as C50 S ec/C50p rim where C50 sec is the concentration required to inhibit 50% of DNase l-mediated cleavage at the secondary (non-match) drug-binding site and C50p r i m is the equivalent at the primary (match) site.
  • C50 sec is the concentration required to inhibit 50% of DNase l-mediated cleavage at the secondary (non-match) drug-binding site
  • C50p r i m is the equivalent at the primary (match) site.
  • the selectivity ratio does not provide a full indication of sequence-selectivity.
  • the selectivity ratio of 1 (a typical pyrrole-imidazole polyamide) on the same fragment was 10-30.
  • the pyrrole-imidazole 'parent' of the set had an approximate C 5 o of 3-10 nM.
  • the C2- linked pyridine- and pyrazine-containing compounds (20 and 21 respectively) showed no easily discernible differences from 14.
  • the secondary binding sites of 14 were different to those of the nine base pair-spanning compounds, presumably due to the additional heterocycle causing a shift in sequence preference. 14 bound to an A 7 tract at -30 nM (selectivity ratio of 10).
  • 25 and 26 were designed to bind over an eleven base pair region of DNA. Both compounds bound to the predicted preferred site ((5'-AAAGAAGAGAG-3') at 0.3-1 nM, as shown in the table below:
  • the mismatched molecule 26 (which contains a pyrrole unit juxtaposed to a guanine) exhibited the slightly higher affinity. From the images of footprinting gels, it is clear that as the molecules are extended from spanning nine base pairs to twelve base pairs, that the visible footprint widens accordingly. Both 25 and 26 bind to lengthy regions of DNA at concentrations above their C 5 o values. Secondary binding over much of the studied fragment was apparent at 30 nM.

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Abstract

L'invention concerne un fragment de polyamide comprenant au moins une unité représentée par la formule I: -β1-X1-Y1-X3-X4-β3- (I) dans laquelle Y1 est X2-β2 ou β2-X2; β1 est -Rβ -CH2-NH- βa-, βa étant un reste de β-alanine et Rβ étant sélectionné parmi des groupes alkylène C1-7, alkénylène C1-7 et alkynylène C1-7 éventuellement substitués; β2 et β3 sont des restes de β-alanine; et X1, X2, X3 et X4 sont des fragments indépendants représentés par la formule (II) dans laquelle E est un groupe hétéroarylène C5-6 éventuellement substitué.
PCT/GB2008/003767 2007-11-09 2008-11-07 Polyamides WO2009060215A1 (fr)

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US11160872B2 (en) 2017-02-08 2021-11-02 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
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US11612665B2 (en) 2017-02-08 2023-03-28 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
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