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WO2008015429A2 - Pharmaceutical compounds - Google Patents

Pharmaceutical compounds Download PDF

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Publication number
WO2008015429A2
WO2008015429A2 PCT/GB2007/002926 GB2007002926W WO2008015429A2 WO 2008015429 A2 WO2008015429 A2 WO 2008015429A2 GB 2007002926 W GB2007002926 W GB 2007002926W WO 2008015429 A2 WO2008015429 A2 WO 2008015429A2
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WO
WIPO (PCT)
Prior art keywords
carbocyclic
substituents
optionally substituted
alkyl
group
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PCT/GB2007/002926
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French (fr)
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WO2008015429A3 (en
Inventor
Robert George Boyle
Stuart Travers
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Sentinel Oncology Limited
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Priority claimed from GB0615299A external-priority patent/GB0615299D0/en
Application filed by Sentinel Oncology Limited filed Critical Sentinel Oncology Limited
Publication of WO2008015429A2 publication Critical patent/WO2008015429A2/en
Publication of WO2008015429A3 publication Critical patent/WO2008015429A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • C07D253/10—Condensed 1,2,4-triazines; Hydrogenated condensed 1,2,4-triazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
    • C07D241/52—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to N-oxide compounds that can be reduced under hypoxic cellular conditions such as those found in many solid tumour cells, and to compounds that inhibit or modulate the activity of PARP and which are activated under hypoxic conditions. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds.
  • PARP Poly(ADP-ribose) polymerases
  • the family contains both nuclear and cytoplasmic enzymes including PARP 1 , P ARP2, P ARP3 , Tankyrase 1 , Tankyrase2, vault PARP and TiPARP.
  • Inhibitors of PARP proteins are considered useful for several disease states including DNA repair, chromosomal stability, cell survival, proliferation, inflammation and ischaemia-reperfusion injury.
  • PARP-I and PARP -2 taken together are essential for life ⁇ Expert Opin. Ther. Patents, 2004, 14, 1531-1551) and their role in the modulation of DNA response illustrates their potential as targets in cancer intervention ⁇ Expert Rev. Anticancer Ther. 2005, 5, 333- 342). They are DNA binding proteins that sense and bind to nicks in the DNA via a zinc finger domain and subsequently undergo a conformational change leading to their activation. Once activated, they consume nicotinamide adenine dinucleotide (NAD) producing ADP ribose and nicotinamide and ultimately polymerise ADP ribose onto target proteins at glutamic acid residues.
  • NAD nicotinamide adenine dinucleotide
  • PARP itself is modified by these polymer chains driving the release of PARP from the DNA and thus allowing the DNA repair enzymes access to the sites of DNA Damage.
  • the translated signal instructs the cell to initiate DNA repair mechanisms and therefore inhibitors of PARP are considered important as adjuvants to DNA damaging chemotherapeutics and ionising radiation.
  • Solid tumours which make up more than 90% of all human cancers, typically have areas of very low oxygenation, or hypoxia (Brown, Molecular Medicine Today, 2000 (vol 6), 157-161).
  • hypoxia Brown, Molecular Medicine Today, 2000 (vol 6), 157-161).
  • the aggressive growth of solid tumours exerts pressure on surrounding vasculature to maintain a sufficient supply of blood and nutrients to these cells.
  • the growing distance of cells from the blood supply (>150 ⁇ M) ultimately leads to regions of very low oxygen concentrations that are said to be hypoxic.
  • tumour hypoxia There are a number of consequences associated with tumour hypoxia including: resistance to killing by ionising radiation (Movsas et al., Cancer, 2000, 89, 2018; Rudat et al., Radiother.
  • tumour hypoxia is a key factor associated with tumour aggressiveness, its existence provides an opportunity that has been exploited by tumour targeting agents ⁇ Anti- Cancer Agents in Medicinal Chemistry, 2006, 6, 281-286).
  • One such compound is 3- amino-l,2,4-benzotriazine 1,4-dioxide, named Tirapazamine (TPZ - Denny and Wilson, Exp Opin. Invest. Drugs, 2000, 9, 2889).
  • TPZ is showing promising indications of clinical activity, it also displays considerable toxicity such as nausea, vomiting, diarrhoea, neutropenia, thrombocytopenia and muscle cramping. Given these toxic limitations, TPZ cannot be given at doses sufficient enough to fully exploit tumour hypoxia.
  • the ease of bioreduction is governed by the one electron reduction potentials (El) of the dioxide and can be influenced by the substituents on the ring: see the article in Zhongguo Yaowu Huctxue Zazhi 1997, 7(3), 157-161).
  • the presence of electron withdrawing groups as subsituents makes the El/2 more positive and hence potentially more selective for hypoxia.
  • the one-electron reduction potential is a key parameter for the successful bioreduction under hypoxia is the E(Y). If the E(I) value is too high, reduction will not be limited to hypoxic conditions, and the compound may be toxic to normal cells. Conversely, if the E(I) value is too low, the rate of reduction may be too slow to provide therapeutic benefit.
  • the optimal range for hypoxic selective bioreduction appears to be between about -45OmV and -51 OmV. Values higher than -30OmV have been found to induce aerobic toxicity, and values lower than -51OmV reduce slowly (Hay MP. J. Med. Chem., 2003, 46:169-182). It has been reported that mono-N-oxides of substituted 3-amino-l,2,4-benzotriazine 1,4-dioxides have E(Y) values in the range required for hypoxic bioreduction, and that these values change in line with the substitution patterns (Anderson RF. Org. Biomol Chem.., 2005, 3:2167-2174).
  • EP 1468688 (Auckland Uniservices) discloses benzotriazine and quinoxaline N-oxides and dioxides as cytotoxic agents.
  • One object of this invention to provide a range of N-oxide compounds that can act against tumour cells and in particular hypoxic tumour cells.
  • the compounds will act against tumour cells by a two step mechanism involving firstly, the selective induction of DNA damage under tumour hypoxia, and secondly the inhibition of proteins essential for DNA repair.
  • both of these steps are achieved from the action of a single molecule that is inert under normal (aerobic) conditions.
  • the present invention discloses methods of selectively activating inhibitors of poly(ADP-ribose) by the process outlined above.
  • Such a mechanism provides a means for selective activation in the tumour, the potential for synergy with DNA damage and the potential for an overall increased therapeutic index.
  • Another object of the invention is to provide substituted benzotriazines as inhibitors of PARP for the treatment of PARP associated disease states
  • the invention provides a compound of the formula (1):
  • Q is CN or CONH 2 and is attached at either position "a” or position "b” on the benzene ring; YMs N OrN + -O " ;
  • Y 2 is N or CR 3 ; Y 3 Is N OrN + -O " ; provided that when Y 2 is CR 3 , then Y 3 is N + -O " ; m is 0, 1 or 2; R 1 is halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy wherein the C 1-4 alkyl and C 1-4 alkoxy moieties are each optionally substituted by fluorine or C 1-2 alkoxy; when Y 2 is N, then R 2 is a group R 4 ; and when Y 2 is CR 3 , then one of R 2 and R 3 is R 4 and the other of R 2 and R 3 is hydrogen, C 1-4 alkyl, halogen or cyano; R 4 is NR 5 R 6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more
  • R 5 is hydrogen, C 1-4 alkyl or C 1-4 acyl wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C 1-2 alkoxy; or R 5 is a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O 5 N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R 7 ; R 6 is hydrogen, C 1-4 alkyl or C 1-4 acyl, wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents R 7 ;
  • R 7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C 1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R 8 ; or a group R a -R b ;
  • R a is a bond, O, CO, X 1 C(X 2 ), C(X ⁇ X 1 , X 1 C(X ⁇ X 1 , S 3 SO, SO 2 , NR 0 , SO 2 NR 0
  • R b is:
  • R 9 is selected from R 7 except that any carbocyclic or heterocyclic groups constituting or forming part of R 9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluorornethyl; cyano; nitro; amino; mono- or di-C ⁇ hydrocarbylamino; or a group R a -R bb ; where R a is as hereinbefore defined and R bb is hydrogen or a C 1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4 saturated hydrocarbylamino and wherein one or more carbon atoms of the C 1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR 0 , X 1 C(X 2 ), C(X 2
  • Formula (1) above covers both quinoxalines (Y is CR ) and benzotriazines (Y is N).
  • Y is CR .
  • Y 2 is N.
  • Q is CONH 2 and hence the compounds are compounds of the formula (Ia)
  • R 1 , R 2 , Y 1 , Y 2 , Y 3 and m are as hereinbefore defined.
  • the compound of the invention is a compound of the formula (2):
  • R 1 is halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy wherein the C 1-4 alkyl and C 1-4 alkoxy moieties are each optionally substituted by fluorine or C 1-2 alkoxy;
  • R 2 is a group R 4 ;
  • R 4 is NR 5 R 6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R 7 ;
  • R 5 is hydrogen, C 1-4 alkyl or C 1-4 acyl wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C 1-2 alkoxy;
  • R 6 is hydrogen, C 1-4 alkyl or C 1-4 acyl, wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents R 7 ;
  • R 7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C 1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R 8 ; or a group R a -R b ;
  • R a is a bond, O, CO, X 1 C(X 2 ), C(X ⁇ X 1 , X 1 C(X ⁇ X 1 , S, SO, SO 2 , NR C , SO 2 NR 0 Or NR 0 SO 2 ;
  • R b is:
  • an acyclic C 1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-Q.s non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R 8 ; wherein one or more carbon atoms of the acyclic C 1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR 0 , X 1 C(X 2 ), C(X ⁇ X 1 or X 1 C(X ⁇ X 1 ;
  • R° is R b , hydrogen or C 1-4 hydrocarbyl;
  • X 1 is O, S or NR 0 ; and
  • R 8 is selected from R 7 provided that when the substituents R 8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R 9 ; and
  • R 9 is selected from R 7 except that any carbocyclic or heterocyclic groups constituting or forming part of R 9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-Ci -4 hydrocarbylamino; or a group R a -R bb ; where R a is as hereinbefore defined
  • the compound of the invention is a compound of the formula (3):
  • R 1 is halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy wherein the C 1-4 alkyl and C 1-4 alkoxy moieties are each optionally substituted by fluorine or C 1-2 alkoxy; one of R 2 and R 3 is R 4 and the other of R 2 and R 3 is hydrogen, C 1-4 alkyl, halogen or cyano;
  • R 4 is NR 5 R 6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R 7 ;
  • R 5 is hydrogen, C 1-4 alkyl or C 1-4 acyl wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C 1-2 alkoxy;
  • R 6 is hydrogen, C 1-4 alkyl or C 1-4 acyl, wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents R 7 ;
  • R 7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C 1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R 8 ; or a group R a -R b ;
  • R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X ⁇ X 1 C(X ⁇ X 1 , S 5 SO, SO 2 , NR 0 , SO 2 NR 0 Or NR 0 SO 2 ;
  • R b is: • hydrogen
  • a C 1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C 1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R 8 ; wherein one or more carbon atoms of the C 1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR 0 , X 1 C(X 2 ), C(X 2 X 1 or X 1 C(X 2 X 1 ; R c is R b , hydrogen or C 1-4 hydrocarbyl;
  • the invention also provides inter alia:
  • a method of treating a cancer which method comprises administering to a subject need thereof a therapeutically effective amount of a compound of formula (1), (Ia), (2) or (3), optionally together with another anti-cancer agent or radiation therapy.
  • a method of causing DNA damage in hypoxic tumour cells which method comprises bringing a compound of the formula (I) 5 (Ia), (2) or (3) as defined herein into contact with the hypoxic tumour cells.
  • a method for the prophylaxis or treatment of a proliferative disease such as cancer which method comprises administering to a patient in combination with radiotherapy or chemotherapy a compound of the formula (1), (Ia), (2) or (3) as defined herein.
  • a pharmaceutical composition comprising a compound of the formula (1), (Ia), (2) or (3) as defined herein and a pharmaceutically acceptable carrier.
  • references to a compound of formula (1) includes formulae (Ia), (2), (3), and all other subgroups thereof as defined herein, and the term 'subgroups' includes all preferences, embodiments, examples and particular compounds defined herein.
  • references to "carbocyclic” and “heterocyclic” groups as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems.
  • such groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 ring members, more usually 5 to 10 ring members.
  • monocyclic groups are groups containing 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, and preferably 5 or 6 ring members.
  • Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10 ring members.
  • the carbocyclic or heterocyclic groups can be aryl or heteroaryl groups having from 5 to 12 ring members, more usually from 5 to 10 ring members.
  • aryl refers to a carbocyclic group having aromatic character and the term “heteroaryl” is used herein to denote a heterocyclic group having aromatic character.
  • aryl and heteroaryl embrace polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group may be attached by the aromatic ring, or by a non-aromatic ring.
  • non-aromatic group embraces unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems.
  • the term “fully saturated” refers to rings where there are no multiple bonds between ring atoms.
  • Saturated carbocyclic groups include cycloalkyl groups as defined below.
  • Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring will be less than five.
  • five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an imidazole ring fused to a
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, benzodioxole and pyrazolopyridine groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring examples include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiene, dihydrobenzofuran, 2,3-dihydro- benzo[l,4]dioxine, benzo[l,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoline and indane groups.
  • carbocyclic aryl groups examples include phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.
  • non-aromatic heterocyclic groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ring members), usually selected from nitrogen, oxygen and sulphur.
  • the heterocylic groups can contain, for example, cyclic ether moieties (e.g as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), cyclic sulphones (e.g. as in sulpholane and sulpholene), cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g. thiomorpholine).
  • Other examples of non-aromatic heterocyclic groups include cyclic amide moieties (e.g. as in pyrrolidone) and cyclic ester moieties (e.g. as in butyrolactone).
  • Examples of monocyclic non-aromatic heterocyclic groups include 5-, 6-and 7- membered monocyclic heterocyclic groups.
  • Particular examples include morpholine, thiomorpholine and its S-oxide and S,S-dioxide, piperidine (e.g. 1-piperidinyl, 2- piperidinyl, 3-piperidinyl and 4-piperidinyl), N-alkyl piperidines such as N-methyl piperidine, piperidone, pyrrolidine (e.g.
  • non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.
  • halogen substituents include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred.
  • hydrocarbyl is a generic term encompassing aliphatic, alicyclic and aromatic groups having an all-carbon backbone, except where otherwise stated.
  • acyclic hydrocarbyl refers to a hydrocarbyl group that contains no cyclic moieties.
  • one or more of the carbon atoms making up the carbon backbone may be replaced by a specified atom or group of atoms.
  • hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, can be substituted by one or more substituents as defined herein.
  • the examples and preferences expressed below apply to each of the hydrocarbyl substituent groups or hydrocarbyl-containing substituent groups referred to in the various definitions of substituents for compounds of the formula (I) unless the context indicates otherwise.
  • the hydrocarbyl groups can have up to twelve carbon atoms, unless the context requires otherwise.
  • hydrocarbyl groups having 1 to 12 carbon atoms particular examples are Ci -10 hydrocarbyl groups, Ci -8 hydrocarbyl groups, C 1-6 hydrocarbyl groups, C 1-4 hydrocarbyl groups (e.g. C 1-3 hydrocarbyl groups or C 1-2 hydrocarbyl groups), specific examples being any individual value or combination of values selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 and C 8 hydrocarbyl groups.
  • alkyl covers both straight chain and branched chain alkyl groups.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers.
  • C 1-6 alkyl groups such as C 1-4 alkyl groups (e.g. C 1-3 alkyl groups or C 1-2 alkyl groups).
  • Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the sub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8 carbon atoms, particular examples being C 3-6 cycloalkyl groups.
  • Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-l,4-dienyl, pentenyl, and hexenyl. Within the sub-set of alkenyl groups the alkenyl group will have 2 to 8 carbon atoms, particular examples being C 2-6 alkenyl groups, such as C 2-4 alkenyl groups.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. Within the sub-set of cycloalkenyl groups the cycloalkenyl groups have from 3 to 8 carbon atoms, and particular examples are C 3-6 cycloalkenyl groups.
  • alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within the sub-set of alkynyl groups having 2 to 8 carbon atoms, particular examples are C 2-6 alkynyl groups, such as C 2-4 alkynyl groups.
  • carbocyclic aryl groups include substituted and unsubstituted phenyl, naphthyl, indane and indene groups.
  • cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl groups.
  • one or more carbon atoms of a hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR 0 , X 1 C(X 2 ), C(X ⁇ X 1 or X 1 C(X ⁇ X 1 (or a sub-group thereof) wherein X 1 and X 2 are as hereinbefore defined, provided that at least one carbon atom of the hydrocarbyl group remains.
  • 1, 2, 3 or 4 carbon atoms of the hydrocarbyl group may be replaced by one of the atoms or groups listed, and the replacing atoms or groups may be the same or different.
  • the number of linear or backbone carbon atoms replaced will correspond to the number of linear or backbone atoms in the group replacing them.
  • Examples of groups in which one or more carbon atom of the hydrocarbyl group have been replaced by a replacement atom or group as defined above include ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (C-C replaced by X 1 C(X 2 ) or C(X 2 )X 1 ), sulphones and sulphoxides (C replaced by SO or SO 2 ), amines (C replaced by NR C ). Further examples include ureas, carbonates and carbamates (C-C-C replaced by X 1 C(X 2 )X 1 ).
  • an amino group has two hydrocarbyl substituents, if the context permits they may, together with the nitrogen atom to which they are attached, and optionally with another heteroatom such as nitrogen, sulphur, or oxygen, link to form a ring structure of 4 to 7 ring members.
  • R a -R b as used herein, either with regard to substituents present on a carbocyclic or heterocyclic moiety, or with regard to other substituents present at other locations on the compounds of the formula (I), includes inter alia compounds wherein R a is selected from a bond, O, CO, OC(O), SC(O), NR 0 C(O), OC(S), SC(S), NR 0 C(S), OC(NR 0 ), SC(NR 0 ), NR 0 C(NR 0 ), C(O)O, C(O)S, C(O)NR 0 , C(S)O, C(S)S, C(S) NR 0 , C(NR°)0, C(NR°)S, C(NR°)NR°, OC(O)O, SC(O)O, NR 0 C(O)O, OC(S)O, SC(O)O, NR 0 C(O)O, OC(S)O
  • the moiety R b can be hydrogen or it can be a group selected from carbocyclic and heterocyclic groups having from 3 to 12 ring members (typically 3 to 10 and more usually from 5 to 10), and a C 1-12 hydrocarbyl group (e.g. a C 1-10 hydrocarbyl group or a C 1-8 hydrocarbyl group) optionally substituted as hereinbefore defined.
  • a C 1-12 hydrocarbyl group e.g. a C 1-10 hydrocarbyl group or a C 1-8 hydrocarbyl group
  • Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as set out above.
  • hydrocarbyloxy groups include saturated hydrocarbyloxy such as alkoxy (e.g. C 1-6 alkoxy, more usually C 1-4 alkoxy such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (e.g. C 3-6 cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy (e.g.
  • alkoxy e.g. C 1-6 alkoxy, more usually C 1-4 alkoxy such as ethoxy and methoxy, particularly methoxy
  • cycloalkoxy e.g. C 3-6 cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy
  • cycloalkyalkoxy e.g.
  • the hydrocarbyloxy groups can be substituted by various substituents as defined herein.
  • the alkoxy groups can be substituted by halogen (e.g. as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g. as in hydroxyethoxy), C 1-2 alkoxy (e.g. as in methoxyethoxy), hydroxy-C 1-2 alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. a cycloalkyl group or non-aromatic heterocyclic group as hereinbefore defined).
  • alkoxy groups bearing a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C 1-4 -alkyl-piperazines, C 3 . 7 -cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkoxy group is a C 1-4 alkoxy group, more typically a C 1-3 alkoxy group such as methoxy, ethoxy or n- propoxy.
  • the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C 1-4 -alkyl-piperazines, C 3 . 7 -cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran
  • the alkoxy group is a C 1-4 alkoxy group, more typically
  • Alkoxy groups may be substituted by, for example, a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and N-substituted derivatives thereof such as N-benzyl, N-C 1-4 acyl and N-C 1-4 alkoxycarbonyl.
  • a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and N-substituted derivatives thereof such as N-benzyl, N-C 1-4 acyl and N-C 1-4 alkoxycarbonyl.
  • Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.
  • hydrocarbyl groups R a -R b are as hereinbefore defined.
  • the hydrocarbyl groups may be saturated groups such as cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl.
  • the hydrocarbyl (e.g. alkyl) groups can be substituted by various groups and atoms as defined herein.
  • substituted alkyl groups include alkyl groups substituted by one or more halogen atoms such as fluorine and chlorine (particular examples including bromoethyl, chloroethyl, difluoromethyl, 2,2,2- trifiuoroethyl and perfluoroalkyl groups such as trifluoromethyl), or hydroxy (e.g. hydroxymethyl and hydroxyethyl), C 1-8 acyloxy (e.g. acetoxymethyl and benzyloxymethyl), amino and mono- and dialkylamino (e.g.
  • halogen atoms such as fluorine and chlorine
  • hydroxy e.g. hydroxymethyl and hydroxyethyl
  • C 1-8 acyloxy e.g. acetoxymethyl and benzyloxymethyl
  • amino and mono- and dialkylamino e.g.
  • aminoethyl methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and tert- butylaminomethyl
  • alkoxy e.g. C 1-2 alkoxy such as methoxy - as in methoxyethyl
  • cyclic groups such as cycloalkyl groups, aryl groups, heteroaryl groups and non- aromatic heterocyclic groups as hereinbefore defined).
  • alkyl groups substituted by a cyclic group are those wherein the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C 1-4 -alkyl-piperazines, C 3-7 -cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is a C 1-4 alkyl group, more typically a C 1-3 alkyl group such as methyl, ethyl or n-propyl.
  • a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C 1-4 -alkyl-piperazines, C 3-7 -cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran
  • the alkyl group is a C 1-4 alkyl group, more typically a C 1-3 alkyl group such as methyl, eth
  • alkyl groups substituted by a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N- substituted forms thereof as defined herein.
  • alkyl groups substituted by aryl groups and heteroaryl groups include benzyl, phenethyl and pyridylmethyl groups.
  • R b can be, for example, hydrogen or an optionally substituted C 1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group.
  • R a -R b where R a is SO 2 NR 0 include aminosulphonyl, C 1-4 alkylaminosulphonyl and di-C 1-4 alkylaminosulphonyl groups, and sulphonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine such as N-methyl piperazine.
  • R a -R b where R a is SO 2 examples include alkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups, particularly monocyclic aryl and heteroaryl sulphonyl groups. Particular examples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl.
  • R b can be, for example, hydrogen or an optionally substituted C 1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group.
  • R a -R b where R a is NR 0 include amino, C 1-4 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, te/t-butylamino), di-C 1-4 alkylamino (e.g. dimethylamino and diethylamino) and cycloalkylamino (e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino) .
  • C 1-4 alkylamino e.g. methylamino, ethylamino, propylamino, isopropylamino, te/t-butylamino
  • di-C 1-4 alkylamino e.
  • the moiety Q can be either CN or CONH 2 .
  • Q is CONH 2 .
  • the CN or CONH 2 moiety can be attached at either position "a” or position "b” on the benzene ring.
  • the CONH 2 moiety is attached at position "a" on the benzene ring.
  • the CONH 2 moiety is attached at position "b" on the benzene ring.
  • the CN moiety is attached at position "a" on the benzene ring.
  • the CN moiety is attached at position "b" on the benzene ring.
  • n is O or 1.
  • n is O and hence R 1 is absent.
  • n 1
  • each substituent R 1 is independently selected from halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy wherein the C 1-4 alkyl and C 1-4 alkoxy moieties are each optionally substituted by fluorine or C 1-2 alkoxy.
  • each R 1 is halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy, cyano, C 1-4 alkyl or C 1-4 alkoxy.
  • each R 1 can be methyl, ethyl, isopropyl, chlorine, fluorine, bromine, cyano, methoxy, ethoxy or isopropoxy.
  • R 1 may be attached to any of the carbon atoms in the benzene ring apart from the carbon atom to which the moiety Q is attached.
  • each R 1 when present is attached to a carbon atom between positions "a" and "b" on the benzene ring, i.e. at the 6- and/or 7-positions of the quinoxaline or benzotriazine ring.
  • R 1 or the combination of R 1 groups is selected so that the one electron reduction potential E(I) of the quinoxaline group is between -300 mV and -510 mV, and more preferably from -450 mV to -510 mV.
  • Y 1 is N or N + -O " ;
  • Y 2 is N or CR 3 ; and
  • Y 3 Is N Or N + -CT ; provided that when Y 2 is CR 3 , then Y 3 is N + -O ' .
  • one particular subgroup of compounds is the subgroup wherein Y 1 and Y 3 are both N + -O " .
  • a further subgroup of compounds is the subgroup wherein Y 1 is N and Y 3 is N + -O " .
  • a further subgroup of compounds is the subgroup wherein Y 1 is N + -O " and Y 3 is N.
  • the group CONH 2 is attached at location "a" on the benzene ring, Y 1 is N; Y 2 is CR 3 and Y 3 is N + -O-.
  • R 2 is a group R 4 ; and when Y 2 is CR 3 , then one of R 2 and R 3 is R 4 and the other of R 2 and R 3 is hydrogen, C 1-4 alkyl, halogen or cyano.
  • R 2 and R 3 are R 4 and the other is hydrogen, methyl, ethyl or cyano.
  • R 2 and R 3 are R 4 and the other is hydrogen or cyano.
  • R 2 is R 4
  • R 3 is, for example, hydrogen, methyl, ethyl or cyano.
  • R 3 is R 4
  • R 2 is, for example, hydrogen, methyl, ethyl or cyano.
  • R 4 is NR 5 R 6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R 7 .
  • the carbocyclic and heterocyclic ring can be any of the carbocyclic and heterocyclic rings set out in the Definitions and General Preferences above.
  • Preferred carbocyclic and heterocyclic rings are monocyclic rings of 5 or 6 ring members.
  • the carbocyclic or heterocyclic rings can be monocyclic non-aromatic or aryl or heteroaryl rings of 5 or 6 ring members containing up to 2 heteroatomic ring members selected from O, N and S.
  • examples of such rings are: (a) optionally substituted aryl and heteroaryl rings selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, diazinyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and pyrazolyl; (b) optionally substituted non-aromatic monocyclic rings selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, morpholinyl, thiomorpholiny
  • carbocyclic or heterocyclic rings are optionally substituted phenyl, piperidinyl, piperazinyl and morpholinyl rings.
  • R 4 may be other than an unsubstituted or N-substituted azepin-4-yl or azepine-5-yl group.
  • R 4 is NR 5 R 6
  • R 5 is hydrogen, C 1-4 alkyl or C 1-4 acyl wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C 1-2 alkoxy
  • R 6 is hydrogen, C 1-4 alkyl or C 1-4 acyl, wherein the C 1-4 alkyl or C 1-4 acyl moieties are each optionally substituted by one or more substituents R 7 .
  • R 5 can be a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R 7 .
  • examples of C 1-4 alkyl or C 1-4 acyl groups are methyl, ethyl, ⁇ -propyl, isopropyl, «-butyl, isobutyl, tert-bntyl, formyl, acetyl, propanoyl, butanoyl and 2- methylbutanoyl.
  • R 5 is hydrogen or methyl and R 6 is hydrogen, C 1-4 alkyl or C 1-4 acyl optionally substituted by one or more substituents R 7 .
  • R 6 is optionally substituted C 1-4 alkyl or C 1-4 acyl, there may be 0, 1, 2 or 3 substituents, for example 0, 1 or 2 substituents, and more usually 0 or 1 substituent.
  • R 5 is a carbocyclic or heterocyclic ring, preferably it is a monocyclic 5- or 6- membered aryl or heteroaryl group, for example a phenyl group.
  • the carbocyclic and heterocyclic rings are optionally substituted by one or more substituents R 7 .
  • substituents R 7 there may be 0, 1, 2 or 3 substituents, for example 0, 1 or 2 substituents.
  • R 7a is halogen; hydroxy; trifluoromethyl; cyano; amino; mono- or di-Ci. 4 alkylamino; monocyclic carbocyclic or heterocyclic groups having from 3 to 7 ring members and optionally substituted by one or more substituents R 8a ; or a group R a' -R b' ;
  • R a' is a bond, O, CO, X 1 C(X 2 ), S, SO, SO 2 , NR C> , SO 2 NR 0 Or NR 0 SO 2 ;
  • R b' is:
  • a C 1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-Ci- 4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R 8 ; wherein one or more carbon atoms of the C 1-8 hydrocarbyl group may optionally be replaced by O 5 S, SO, SO 2 , NR 0' , X 1 C(X 2 ), C(X 2 )X !
  • R° is R b , hydrogen or C 1-4 hydrocarbyl
  • X 1 is O, S or NR 0'
  • R 8a is selected from R 7a provided that when the substituents R 8a contain a carbocyclic or heterocyclic group having from 3 to 7 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R 9a
  • R 9a is selected from R 7a but is other than a carbocyclic or heterocyclic group.
  • the carbocyclic and heterocyclic rings may be optionally substituted by one or more substituents R ; wherein R is chlorine; fluorine; bromine; hydroxy; trifluoromethyl; cyano; amino; mono- or di-C 1-4 alkylamino; monocyclic carbocyclic or heterocyclic groups having from 3 to 7 ring members and optionally substituted by one or more substituents R 8a ; or a group R a -R b ;
  • R a" is a bond, O, CO, OC(O), NR C" (CO), C(O)NR 0" , OC(O)O, OC(O)NR 0" , NR° “ (CO)O, S 5 SO 5 SO 25 NR 0" , SO 2 NR 0" orNR° " SO 2 ;
  • R b is:
  • a C 1-8 alkyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C 1-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R 8b ; wherein one or more carbon atoms of the C 1-8 alkyl group may optionally be replaced by O 5 S 5 SO 5 SO 2 , CO 5 OC(O) 5 NR° " (CO) 5 C(O)NR 0" , OC(O)O 5 OC(O)NR 0" ,
  • R° is hydrogen or C 1-2 alkyl; wherein R 8b is selected from R 7a provided that R 8a is other than a carbocyclic or heterocyclic group.
  • R 7 is represented by R 7 °, where R 7c is:
  • R a>" is a bond, O, CO, OC(O), NR° '" (CO), C(O)NR 0'" , OC(O)O, OC(O)NR 0"' , NR° '" (CO)O, NR 0"' ;
  • ⁇ R b>" is: o hydrogen; o a monocyclic carbocyclic or heterocyclic groups selected from phenyl, piperazinyl, piperidinyl, and morpholinyl, each being optionally substituted by one or more substituents R 8 °; o a C 1-6 alkyl group optionally substituted by one or more substituents selected from hydroxy; oxo; chlorine; fluorine; bromine; cyano; carboxy; amino; mono- or di-C 1-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R 8c ; wherein one or more carbon atoms of the C 1-6 alkyl group may optionally be replaced by O, CO, OC(O),
  • NR C (CO), C(O)NR 0 , OC(O)NR 0 , NR°(CO)O, NR 0 , and R 0 is hydrogen or C 1-2 alkyl; wherein R 8 ° is selected from R 7 ° provided that R 8 ° is other than a carbocyclic or heterocyclic group.
  • substituents R 7 include C 1-4 alkyl, chlorine, fluorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, hydroxy, amino-C 1-2 alkyl, mono- or dimethylamino-C 1-2 alkyl, piperazinylcarbonyl, morpholinylcarbonyl, piperazinyl-C 1-2 alkyl, morpholinyl-C 1-2 alkyl, piperidinyl-C ⁇ -2 alkyl,, pyrrolidinyl-C 1-2 alkyl, hydroxy-Q ⁇ alkyl, methoxy-C 1-2 alkyl, cyano-Ci. 2 alkyl and Cj -4 alkylsulphonyl.
  • Preferred compounds of the present invention are those having a one electron reduction potential E(I) of between -300 mV and -510 mV, and more preferably from -450 mV to -510 mV.
  • E(I) can be measured by a number of techniques including pulse radiolysis, see for example (i) M. P Hay et al. J. Med. Chem., 2003, 46:169-182 (ii) E. J Land et al., Arch Biochem Biophys. 1983 Aug; 225(1):116-21; (iii) Patel and Willson (K B Patel and R L Willson. Journal of the Chemical Society, Faraday Transactions 1, 1973, 69, 814-825); (iv) D Meisel and P Neta.
  • the various functional groups and substituents making up the compounds of the formula (1) are typically chosen such that the molecular weight of the compound of the formula (1) does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.
  • a reference to a compound of the formula (1) and sub-groups thereof also includes ionic forms, salts, solvates, isomers, tautomers, prodrugs, isotopes and protected forms thereof, for example, as discussed below.
  • salts for example acid addition salts or, in certain cases salts of organic and inorganic bases such as phenolate, carboxylate, sulphonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (1) include the salt forms of the compounds.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • 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 metal 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 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 ) 4 + .
  • the compounds of the formula (1) contain an amine function
  • these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person.
  • Such quaternary ammonium compounds are within the scope of formula (1).
  • the salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et ah, 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1- 19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
  • tautomeric forms include, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto enol enolate as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • references to compounds of the formula (I) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
  • optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and / isomers) or they may be characterised in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl, 1966, 5, 385-415.
  • Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.
  • optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)- pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulphonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.
  • chiral acids such as (+)-tartaric acid, (-)- pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulphonic
  • compositions containing a compound of the formula (I) having one or more chiral centres wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (I) is present as a single optical isomer (e.g.
  • 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).
  • the compounds of the invention include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element.
  • a reference to hydrogen includes within its scope
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use.
  • the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
  • formula (1) Also encompassed by formula (1) are any polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds, and pro-drugs of the compounds.
  • solvates e.g. hydrates
  • complexes e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals
  • pro-drugs is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1).
  • C ⁇ alkyl e.g., -Me 5 -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu;
  • acyloxy-C ⁇ alkyl e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • the compounds of the formulae (1), (Ia), (2) and (3) wherein both Y 1 and Y 3 are N-oxide groups will be reduced to the mono-N-oxides in hypoxic tumour cells and that the reduction process will result in damage to the DNA of the tumour cell and therefore cell death.
  • the mono-N-oxides may undergo further reduction to the parent heterocycle, thereby causing further DNA damage in the hypoxic tumour cell and consequent cell death.
  • the parent heterocycle and in many cases the mono-N-oxides
  • the compounds of the invention are believed to act against hypoxic cancer cells in two ways. Firstly, they are reduced in hypoxic conditions and the act of reduction results in damage to the DNA of the tumour cell. Secondly, the reduced products block the normal cell repair processes thereby enhancing the cytotoxic effect of the N-oxides.
  • the compounds of the invention will be useful in treating a range of proliferative diseases and in particular solid tumours containing a significant mass of hypoxic cells.
  • the compounds of the invention will also act in a synergistic or additive manner with other chemotherapeutic agents and cancer treatments such as radiotherapy against a wide spectrum of proliferative disorders.
  • proliferative disorders include, but are not limited to carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin, hematopoieitic tumours such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoieitic tumours of myeloid lineage, for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocyte leukaemia; thyroid follicular cancer; tumours of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; tumours of the central or peripheral nervous system, for example
  • the PARP inhibitor compounds of the invention may be used in combination with
  • a cancer is considered to be resistant to a drug when it resumes a normal rate of tumour growth while undergoing treatment with the drug after the tumour had initially responded to the drug.
  • a tumour is considered to "respond to a drag" when it exhibits a decrease in tumor mass or a decrease in the rate of tumour growth.
  • Compounds of the invention having PARP inhibiting activity should also be useful in the treatment of other disease states and conditions where inhibition of PARP has a beneficial effect.
  • the compounds may be useful in the treatment of inflammation and ischaemia-reperfusion injury, and diseases arising from or mediated by NMDA- and NO-induced toxicity.
  • Examples of uses in connection with diseases arising from or mediated by NMDA- and NO-induced toxicity include treating neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Parkinson's disease; epilepsy; Amyotrophic Lateral Sclerosis (ALS); Huntington's disease; schizophrenia; chronic pain; ischaemia; hypoxia; hypoglycaemia; ischaemia; trauma; nervous insult; skin aging; atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy; degenerative diseases of skeletal muscle involving replicative senescence; age-related macular degeneration; AIDS; and other immune deficiency diseases; inflammatory bowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock; and septic shock.
  • inflammatory bowel disorders e.g., colitis
  • arthritis e.g., colitis
  • diabetes endotoxic shock
  • septic shock e.g.
  • the ability of the compounds of the invention to inhibit PARP can be determined by using commercially available assay kits and following the manufacturers' instructions. Examples of such assay kits include:
  • the PARP inhibiting activity of the compounds can be determined using the methods described in on page 23 of WO 03/007959 (Fujisawa), the disclosure in which is incorporated herein by reference.
  • references to Formula (1) also include Formula (Ia), Formula (2) and Formula (3) and all sub-groups and examples therof as defined herein unless the context indicates otherwise.
  • the 5-cyano-benzotriazine (18) is then partially hydrolysed using aqueous HCl to give the amide (2a).
  • Oxidation of the amide (2a) with H 2 O 2 /acetic acid yields the amide mono-N-oxide (2b) which can be further oxidized to the di-N-oxide using an oxidizing agent such as hydrogen peroxide/trifluoroacetic acid or other oxidising agents as described below in relation to Scheme 7.
  • Scheme 2 the amine (19) is cyclised to the 3-amino-5-fluorobenzotriazine mono-N- oxide (20) by reaction with cyanamide/HCl followed by treatment with sodium hydroxide.
  • the 3-amino-5-fluorobenzotriazine (20) is oxidised to the di-N-oxide (21) using a suitable oxidizing agent such as hydrogen peroxide/trifluoroacetic acid, and the di-N-oxide is then reacted with sodium cyanide to displace the fluorine atom with cyanide and give the nitrile (22).
  • Hydrolysis of the nitrile (22) using aqueous hydrochloric acid gives the amide di-N-oxide (2d) which can be reduced to the parent heterocycle (2e) using sodium dithionite in ethanol.
  • Scheme 3 illustrates an alternative route to 3-aminobenzotriazoles starting from the 2- iodo-acetamidobenzene (23) which can be obtained from Maybridge of Tintagel, UK
  • the 2-iodo-acetamidobenzene (23) is nitrated using a standard nitrating mixture of nitric and sulphuric acids to give (24) which is then converted to the amine (25) using sodium methoxide in methanol or concentrated sulphuric acid to remove the acetyl group.
  • the amine (25) is then cyclised to the 3-amino-5- iodobenzotriazine mono-N-oxide (26) by reaction with cyanamide/HCl followed by treatment with sodium hydroxide.
  • the 3-amino-5-iodobenzotriazine mono-N-oxide (26) is then reacted with cuprous cyanide (CuCN) in dimethylformamide to displace the iodine atom with cyanide and reduce the N-oxide to give the 3-amino-5-cyano- benzotriazine (27).
  • Hydrolysis of the 3-amino-5-cyano-benzotriazine (27) using aqueous hydrochloric acid gives the amide (2e) which can be oxidized to the mono-N- oxide (2f) and/or di-N-oxide using a suitable oxidising agent such as H 2 O 2 /acetic acid or another oxidising agent as described below in relation to Scheme 7.
  • Scheme 4 illustrates a route to compounds of the formula (2) wherein R 2 is introduced either by nucleophilic displacement of halogen from the 3-position of the benzotriazine ring or by means of the Suzuki reaction.
  • the 3-chloro-benzotriazine (31) can then be converted to a wide range of compounds of formula (2) via the nitrile (32)) using the Suzuki reaction to introduce aryl and heteroaryl groups at the 3-position.
  • a Suzuki coupling procedure a compound of formula (31) is reacted with a boronate ester or a boronic acid R 2 -B(OH) 2 in the presence of a palladium (0) catalyst and base to give the nitrile (32).
  • Many boronates suitable for use in preparing compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or from Combi- Blocks Inc, of San Diego, USA.
  • boronates are not commercially available, they can be prepared by methods known in the art, for example as described in the review article by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457.
  • boronates can be prepared by reacting the corresponding bromo-compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester.
  • the resulting boronate ester derivative can, if desired, be hydrolysed to give the corresponding boronic acid.
  • the 3-chloro-benzotriazine (31) can be subjected to nucleophilic displacement of the chlorine atom by an amine to give substituted amino compounds of formula (33) wherein R 2 is NR 5 R 6 and at least one of R 5 and R 6 is other than hydrogen.
  • the amino compounds (33) and the aryl/heteroaryl compounds (32) can then be hydrolysed using hydrochloric acid to give the carboxamides (2h) and (2g) respectively.
  • the carboxamides can be oxidized to the mono-N-oxide or di-N-oxide using the methods described above.
  • the 3-chloro-2-nitro-benzoic acid (34) is converted to the amide (35) by reaction with CDI in dichloromethane to form an activated acid derivative and then reacting with ammonia.
  • the mono-N-oxide can either be reduced to the parent heterocycle (2j) using sodium dithionite or can be be oxidised to the di-N-oxide (2k) using hydrogen peroxide/trifluoroacetic acid.
  • Compounds of the formula (3) may be prepared by forming the parent heterocycle using the methods described in WO 03/062234 (Yamanouchi) and WO 03/007959 (Fujisawa) and then oxidising the compounds to the corresponding di-N-oxides of the formula (3) using an appropriate oxidising agent.
  • the group R 10 is either an NH 2 group or a methoxy or ethoxy group and hence C(O)R 10 is either a carboxamide or ester group.
  • the starting material for Scheme 7 is the substituted nitro-aniline derivative (39a) which is reduced to the corresponding diamine (40) by catalytic hydrogenation over palladium on charcoal.
  • the reaction is typically carried out in ethanol at room temperature.
  • the group C(O)R 10 is an ester group
  • this can be converted to the corresponding carboxamide group either before or after the reduction of the nitro group.
  • the ester group can be left in place throughout the synthesis and then converted to the amide at a later stage.
  • Conversion of the ester to an amide may be carried out by reaction with ammonia in a polar solvent such as methanol under conditions of elevated temperature and pressure (for example in a sealed tube with heating to about 100 0 C)
  • a polar solvent such as methanol
  • the 2,3-diaminobenzoic acid amide/ester (40) is reacted with the ⁇ -bromoketone (41) to give a mixture of quinoxalines (42) and (43) which are separated by HPLC.
  • C(O)R 10 is an ester group
  • the quinoxaline esters (42) and (43) can be converted to the corresponding amides using the conditions described above.
  • the amides may then be oxidised using a suitable oxidising agent to give initially the mono-N-oxides (not shown) and then, following further oxidation, the di-N-oxides (3a) and (3b).
  • oxidising agents include:
  • peroxycarboxylic acids such as wet ⁇ -chloroperbenzoic acid (mCPBA), peracetic acid/sodium acetate and diperoxymaleic acid (see Organic and Bioorganic Chem., 1973, 22, 2707-2713)
  • peroxysulphuric acid Caro's acid
  • salts thereof such as potassium peroxymonosulphate (e.g. Oxone ® /dimethyldioxirane - J. Org. Chem., 1977, 1869-1871 and 3367-3369)
  • oxidising agents set out above may also be used to oxidise compounds of formula (2) wherein Y 1 and Y 2 are both N to give compounds of the formula (2) wherein Y 1 and Y 2 are both N + -O-.
  • R 2 is NR 5 R 6 wherein R 5 is an aryl or heteroaryl group
  • R 5 is an aryl or heteroaryl group
  • the reaction is carried out in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), together with a further ligand such as 9,9-dimethyl-4,5-bis(diphenylphosphino)- xanthene (Xantphos), a metal carbonate base such as caesium carbonate, and a non- protic solvent such as toluene.
  • a palladium catalyst for example tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), together with a further ligand such as 9,9-dimethyl-4,5-bis(diphenylphosphino)- xanthene (Xantphos), a metal carbonate base such as caesium carbonate, and a non- protic solvent such as toluene.
  • the reaction may be carried out in a sealed tube at an elevated temperature (e.
  • one compound of the formula (1), (Ia), (2) or (3) or a protected derivative thereof can be converted into another compound of the formula (1), (Ia), (2) or (3) by methods well known to the skilled person.
  • Examples of synthetic procedures for converting one functional group into another functional group are set out in standard texts such as Advanced Organic Chemistry, by Jerry March, 4 th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1- 17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8)).
  • the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound of the invention together with a pharmaceutically acceptable carrier, and optionally one or more additional excipients.
  • a pharmaceutical composition e.g. formulation
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (1) and a pharmaceutically acceptable carrier.
  • compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.
  • compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
  • the delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient.
  • aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels,
  • compositions for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, VoI 21(2) 2004, p 201-230).
  • a drug molecule that is ionizable can be solubilized to the desired concentration by pH adjustment if the drug's pK a is sufficiently away from the formulation pH value.
  • the acceptable range is pH 2-12 for intravenous and intramuscular administration, but subcutaneously the range is pH 2.7-9.0.
  • the solution pH is controlled by either the salt form of the drug, strong acids/bases such as hydrochloric acid or sodium hydroxide, or by solutions of buffers which include but are not limited to buffering solutions formed from glycine, citrate, acetate, maleate, succinate, histidine, phosphate, tris(hydroxymethyl)- aminomethane (TRIS), or carbonate.
  • the combination of an aqueous solution and a water-soluble organic solvent/surfactant is often used in injectable formulations.
  • the water-soluble organic solvents and surfactants used in injectable formulations include but are not limited to propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP; Pharmasolve), dimethylsulphoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60, and polysorbate 80.
  • Such formulations can usually be, but are not always, diluted prior to injection.
  • Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, and polysorbate 80 are the entirely organic water-miscible solvents and surfactants used in commercially available injectable formulations and can be used in combinations with each other.
  • the resulting organic formulations are usually diluted at least 2-fold prior to IV bolus or IV infusion.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections
  • the pharmaceutical formulation can be prepared by lyophilising a compound of Formula (1) or acid addition salt thereof.
  • Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms.
  • a typical process is to solubilise the compound and the resulting formulation is clarified, sterile filtered and aseptically transferred to containers appropriate for lyophilisation (e.g. vials). In the case of vials, they are partially stoppered with lyo-stoppers.
  • the formulation can be cooled to freezing and subjected to lyophilisation under standard conditions and then hermetically capped forming a stable, dry lyophile formulation.
  • the composition will typically have a low residual water content, e.g. less than 5% e.g. less than 1% by weight based on weight of the lyophile.
  • the lyophilisation formulation may contain other excipients for example, thickening agents, dispersing agents, buffers, antioxidants, preservatives, and tonicity adjusters.
  • Typical buffers include phosphate, acetate, citrate and glycine.
  • antioxidants include ascorbic acid, sodium bisulphite, sodium metabisulphite, monothioglycerol, thiourea, butylated hydroxytoluene, butylated hydroxyl anisole, and ethylenediaminetetraacetic acid salts.
  • Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of /? ⁇ r ⁇ -hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzalkonium chloride and cetylpyridinium chloride.
  • the buffers mentioned previously, as well as dextrose and sodium chloride, can be used for tonicity adjustment if necessary.
  • Bulking agents are generally used in lyophilisation technology for facilitating the process and/or providing bulk and/or mechanical integrity to the lyophilized cake.
  • Bulking agent means a freely water soluble, solid particulate diluent that when co- lyophilised with the compound or salt thereof, provides a physically stable lyophilized cake, a more optimal freeze-drying process and rapid and complete reconstitution.
  • the bulking agent may also be utilised to make the solution isotonic.
  • the water-soluble bulking agent can be any of the pharmaceutically acceptable inert solid materials typically used for lyophilisation.
  • Such bulking agents include, for example, sugars such as glucose, maltose, sucrose, and lactose; polyalcohols such as sorbitol or mannitol; amino acids such as glycine; polymers such as polyvinylpyrrolidine; and polysaccharides such as dextran.
  • the ratio of the weight of the bulking agent to the weight of active compound is typically within the range from about 1 to about 5, for example of about 1 to about 3, e.g. in the range of about 1 to 2.
  • dosage forms may be via filtration or by autoclaving of the vials and their contents at appropriate stages of the formulation process.
  • the supplied formulation may require further dilution or preparation before delivery for example dilution into suitable sterile infusion packs.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. In another preferred embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.
  • Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
  • compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
  • tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
  • swellable crosslinked polymers such as crosslinked carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as citrate/bicarbonate mixtures.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
  • Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • the solid dosage forms can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating.
  • a protective film coating e.g. a wax or varnish
  • the coating e.g. a Eudragit TM type polymer
  • the coating can be designed to release the active component at a desired location within the gastrointestinal tract.
  • the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
  • the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • a release controlling agent for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
  • the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations may be prepared in accordance with methods well known to those skilled in the art.
  • the pharmaceutical formulations may be presented to a patient in "patient packs" containing an entire course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
  • compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
  • compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
  • formulations for rectal or intra- vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound.
  • Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
  • the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
  • a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient.
  • particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).
  • a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.
  • the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
  • the compounds of the formula (1) and sub-groups as defined herein will be useful either as sole chemotherapeutic agents or, more usally, in combination therapy with chemotherapeutic agents or radiation therapy in the prophylaxis or treatment of a range of proliferative disease states or conditions. Examples of such disease states and conditions are set out above.
  • chemotherapeutic agents that may be co-administered with the compounds of formula (1) include: • Topoisomerase I inhibitors
  • the compounds may also be administered in conjunction with radiotherapy.
  • the compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a pulsatile or continuous manner.
  • an effective amount can be a quantity of compound which, when administered together with a chemotherapeutic agent to a subject suffering from cancer, slows tumour growth, ameliorates the symptoms of the disease and/or increases longevity.
  • an effective amount of the PARP inhibitor of the invention is the quantity in which a greater response is achieved when the PARP inhibitor is co-administered with the DNA damaging anti-cancer drug and/or radiation therapy compared with when the DNA damaging anti-cancer drug and/or radiation therapy is administered alone.
  • an "effective amount" of the DNA damaging drug and/or an “effective” radiation dose are administered to the subject, which is a quantity in which anti-cancer effects are normally achieved.
  • the PARP inhibitors of the invention and the DNA damaging anticancer drug can be co-administered to the subject as part of the same pharmaceutical composition or, alternatively, as separate pharmaceutical compositions.
  • the PARP inhibitor of the invention and the DNA-damaging anti-cancer drug (and/or radiation therapy) can be administered simultaneously or at different times, provided that the enhancing effect of the PARP inhibitor is retained.
  • the amount of PARP inhibitor compound of the invention, and the DNA damaging anti-cancer drug and radiation dose administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors. Effective dosages for commonly used anti-cancer drugs and radiation therapy are well known to the skilled person.
  • the compounds are generally administered to a subject in need of such administration, for example a human or animal patient, preferably a human.
  • a typical daily dose of the compound of formula (1) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of body weight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of body weight although higher or lower doses may be administered where required.
  • the compound can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.
  • a patient will be given an infusion of a compound for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.
  • a patient may be given an infusion of a compound for periods of one hour daily for 5 days and the treatment repeated every three weeks.
  • a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.
  • a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.
  • the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.
  • 3-(4-Chloro-phenyl)-quinoxaline-5-carboxylic acid amide 120 mg was suspended in a mixture of 30% peracetic acid (3 ml) and sodium acetate (200 mg). The mixture was heated at 60 0 C for 3 days then allowed to cool to room temperature. The precipitate formed was then filtered, washed (with water) and dried to yield the title compound.
  • a re-sealable microwave tube is charged with tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) (0.1 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) (0.15 mmol), 3-amino-benzo[l,2,4]triazine-5-carbonitrile (1.0 mmol), Cs 2 CO 3 (fine powder, 1.4 mmol), bromobenzene (1.0 mmol), and toluene (4 mL).
  • the tube is capped and carefully subjected to three cycles of evacuation-backfilling with nitrogen.
  • the tube is then immersed into a 100 0 C oil bath and left overnight. After cooling, the mixture is diluted with THF 5 filtered, concentrated, and subjected to chromatography to give the title compound.
  • Example 44B 3-Phenylamino-benzori,2,4 ⁇
  • the product of Example 44 A is treated with aqueous concentrated hydrochloric acid as described in Example 1C to give the title compound.
  • a tablet composition containing a compound of the formula (1) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.
  • BP lactose
  • Capsule Formulation A capsule formulation is prepared by mixing 100 mg of a compound of the formula (1) with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.
  • a parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (1) in water containing 10% propylene glycol to give a concentration of active compound of 1.5 % by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.
  • a parenteral composition for injection is prepared by dissolving in water a compound of the formula (1) (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules.
  • a formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilised by autoclaving.
  • a formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg/ml. The vial is then sealed and sterilised by autoclaving.
  • a buffer e.g. 0.2 M acetate pH 4.6
  • composition for sub-cutaneous administration is prepared by mixing a compound of the formula (1) with pharmaceutical grade corn oil to give a concentration of 5 mg/ml.
  • the composition is sterilised and filled into a suitable container.
  • Aliquots of formulated compound of formula (1) are put into 50 ml vials and lyophilized.
  • the compositions are frozen using a one-step freezing protocol at (-45 0 C).
  • the temperature is raised to -10 0 C for annealing, then lowered to freezing at -45 0 C, followed by primary drying at +25 0 C for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50 0C.
  • the pressure during primary and secondary drying is set at 80 millitor.
  • the ability of the compounds of the invention to inhibit PARP was determined using an in vitro assay kit available from Trevigen, Gaithersburg, MD, USA.
  • the PARP inhibiting activities of compounds of the invention were found to be as follows:

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Abstract

The invention provides a compound of the formula (1) or a salt, solvate or tautomer thereof, having PARP inhibitor activity. In formula (1), Q is CN or CONH2 and is attached at either position 'a' or position 'b' on the benzene ring; Y1 is N or N+-O-; Y2 is N or CR3; Y3 is N or N+-O-; provided that when Y2 is CR3, then Y3 is N+-O-; m is 0, 1 or 2; and R1 and R2 are as defined in the claims.

Description

PHARMACEUTICAL COMPOUNDS
This invention relates to N-oxide compounds that can be reduced under hypoxic cellular conditions such as those found in many solid tumour cells, and to compounds that inhibit or modulate the activity of PARP and which are activated under hypoxic conditions. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds.
Background of the Invention
Poly(ADP-ribose) polymerases (PARP) belong to a family of enzymes that function by the post translational modification of their target proteins. The family contains both nuclear and cytoplasmic enzymes including PARP 1 , P ARP2, P ARP3 , Tankyrase 1 , Tankyrase2, vault PARP and TiPARP. Inhibitors of PARP proteins are considered useful for several disease states including DNA repair, chromosomal stability, cell survival, proliferation, inflammation and ischaemia-reperfusion injury.
PARP-I and PARP -2 taken together are essential for life {Expert Opin. Ther. Patents, 2004, 14, 1531-1551) and their role in the modulation of DNA response illustrates their potential as targets in cancer intervention {Expert Rev. Anticancer Ther. 2005, 5, 333- 342). They are DNA binding proteins that sense and bind to nicks in the DNA via a zinc finger domain and subsequently undergo a conformational change leading to their activation. Once activated, they consume nicotinamide adenine dinucleotide (NAD) producing ADP ribose and nicotinamide and ultimately polymerise ADP ribose onto target proteins at glutamic acid residues. PARP itself is modified by these polymer chains driving the release of PARP from the DNA and thus allowing the DNA repair enzymes access to the sites of DNA Damage. The translated signal instructs the cell to initiate DNA repair mechanisms and therefore inhibitors of PARP are considered important as adjuvants to DNA damaging chemotherapeutics and ionising radiation.
Quinoxaline compounds having PARP-inhibiting activity are disclosed in WO 03/062234 (Yamanouchi) and WO 03/007959 (Fujisawa).
Solid tumours, which make up more than 90% of all human cancers, typically have areas of very low oxygenation, or hypoxia (Brown, Molecular Medicine Today, 2000 (vol 6), 157-161). The aggressive growth of solid tumours exerts pressure on surrounding vasculature to maintain a sufficient supply of blood and nutrients to these cells. The growing distance of cells from the blood supply (>150 μM) ultimately leads to regions of very low oxygen concentrations that are said to be hypoxic. There are a number of consequences associated with tumour hypoxia including: resistance to killing by ionising radiation (Movsas et al., Cancer, 2000, 89, 2018; Rudat et al., Radiother. Oncol, 2000, 57, 31), resistance to chemotherapy (Brown and Giaccia, Cancer Res., 1998, 58, 1408) and the promotion of a malignant phenotype. Whilst tumour hypoxia is a key factor associated with tumour aggressiveness, its existence provides an opportunity that has been exploited by tumour targeting agents {Anti- Cancer Agents in Medicinal Chemistry, 2006, 6, 281-286). One such compound is 3- amino-l,2,4-benzotriazine 1,4-dioxide, named Tirapazamine (TPZ - Denny and Wilson, Exp Opin. Invest. Drugs, 2000, 9, 2889). Although TPZ is showing promising indications of clinical activity, it also displays considerable toxicity such as nausea, vomiting, diarrhoea, neutropenia, thrombocytopenia and muscle cramping. Given these toxic limitations, TPZ cannot be given at doses sufficient enough to fully exploit tumour hypoxia.
Quinoxaline dioxides are known to undergo bioreductions under hypoxia causing DNA damage (Scheme A) - see for example (i) Bioorg. Med. Chem. 2001, 9, 2395-2401, (ii) Chem. Res. Toxicol. 2004, 17(11), 1399-1405 (TX-402), and (iii) Mutagenesis 2005, 20(3), 165-171 (Q85).
Scheme A
Figure imgf000003_0001
1 TX-402 Q85
In a similar manner to tirapazamine, the bioreduction leads to the formation of mono- N-oxides and potentially to the parent heterocycle. The Chem. Res. Toxicol. 2004, 17(11), 1399-1405 paper discusses the metabolism of TX-402 and the one-electron reduction that leads to mono-N-oxide metabolite. Although not discussed in the paper, it would seem likely, based on knowledge of the properties of TPZ, that further reduction will lead to the heterocycle (but may not be accompanied by DNA damage).
Hypoxia
Figure imgf000004_0002
Figure imgf000004_0001
The ease of bioreduction is governed by the one electron reduction potentials (El) of the dioxide and can be influenced by the substituents on the ring: see the article in Zhongguo Yaowu Huctxue Zazhi 1997, 7(3), 157-161). The presence of electron withdrawing groups as subsituents makes the El/2 more positive and hence potentially more selective for hypoxia. The one-electron reduction potential is a key parameter for the successful bioreduction under hypoxia is the E(Y). If the E(I) value is too high, reduction will not be limited to hypoxic conditions, and the compound may be toxic to normal cells. Conversely, if the E(I) value is too low, the rate of reduction may be too slow to provide therapeutic benefit. Consequently, the optimal range for hypoxic selective bioreduction appears to be between about -45OmV and -51 OmV. Values higher than -30OmV have been found to induce aerobic toxicity, and values lower than -51OmV reduce slowly (Hay MP. J. Med. Chem., 2003, 46:169-182). It has been reported that mono-N-oxides of substituted 3-amino-l,2,4-benzotriazine 1,4-dioxides have E(Y) values in the range required for hypoxic bioreduction, and that these values change in line with the substitution patterns (Anderson RF. Org. Biomol Chem.., 2005, 3:2167-2174).
EP 1468688 (Auckland Uniservices) discloses benzotriazine and quinoxaline N-oxides and dioxides as cytotoxic agents.
Summary of the Invention One object of this invention to provide a range of N-oxide compounds that can act against tumour cells and in particular hypoxic tumour cells. Without wishing to be bound by any theory, it is envisaged that the compounds will act against tumour cells by a two step mechanism involving firstly, the selective induction of DNA damage under tumour hypoxia, and secondly the inhibition of proteins essential for DNA repair. Importantly, both of these steps are achieved from the action of a single molecule that is inert under normal (aerobic) conditions. In particular, the present invention discloses methods of selectively activating inhibitors of poly(ADP-ribose) by the process outlined above. Such a mechanism provides a means for selective activation in the tumour, the potential for synergy with DNA damage and the potential for an overall increased therapeutic index.
Another object of the invention is to provide substituted benzotriazines as inhibitors of PARP for the treatment of PARP associated disease states
Accordingly, in a first aspect, the invention provides a compound of the formula (1):
Figure imgf000005_0001
or a salt, solvate or tautomer thereof; wherein:
Q is CN or CONH2 and is attached at either position "a" or position "b" on the benzene ring; YMs N OrN+-O" ;
Y2 is N or CR3; Y3 Is N OrN+-O" ; provided that when Y2 is CR3, then Y3 is N+-O" ; m is 0, 1 or 2; R1 is halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the C1-4 alkyl and C1-4 alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy; when Y2 is N, then R2 is a group R4; and when Y2 is CR3, then one of R2 and R3 is R4 and the other of R2 and R3 is hydrogen, C1-4 alkyl, halogen or cyano; R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7;
R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy; or R5 is a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O5 N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7; R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7;
R7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R8; or a group Ra-Rb; Ra is a bond, O, CO, X1C(X2), C(X^X1, X1C(X^X1, S3 SO, SO2, NR0, SO2NR0
Or NR0SO2;
Rb is:
• hydrogen;
• a carbocyclic and heterocyclic group having from 3 to 12 ring members and being optionally substituted by one or more substituents R8;
• a C1-I2 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-Ci-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R ; wherein one or more carbon atoms of the Ci-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X^X1 or X1C(X^X1; R0 is Rb, hydrogen or C1-4 hydrocarbyl; X1 is O, S or NR0; and X2 is =O, =S or =NRc; wherein R8 is selected from R7 provided that when the substituents R8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9; and
R9 is selected from R7 except that any carbocyclic or heterocyclic groups constituting or forming part of R9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluorornethyl; cyano; nitro; amino; mono- or di-C^ hydrocarbylamino; or a group Ra-Rbb; where Ra is as hereinbefore defined and Rbb is hydrogen or a C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 saturated hydrocarbylamino and wherein one or more carbon atoms of the C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2)X! or X1C(X^X1.
Formula (1) above covers both quinoxalines (Y is CR ) and benzotriazines (Y is N).
In one general embodiment, Y is CR .
In another general embodiment, Y2 is N.
Preferably Q is CONH2 and hence the compounds are compounds of the formula (Ia)
Figure imgf000007_0001
or salts, solvates or tautomer thereof; wherein R1, R2, Y1, Y2, Y3 and m are as hereinbefore defined.
In one embodiment, the compound of the invention is a compound of the formula (2):
Figure imgf000007_0002
or a salt, solvate or tautomer thereof; wherein: the CONH2 moiety is attached at either position "a" or position "b" on the benzene ring;
YMs N Or N+-(J ; Y3 Is N OrN+-O" ; m is 0, 1 or 2;
R1 is halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the C1-4 alkyl and C1-4 alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy;
R2 is a group R4; R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7;
R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy;
R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7;
R7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R8; or a group Ra-Rb;
Ra is a bond, O, CO, X1C(X2), C(X^X1, X1C(X^X1, S, SO, SO2, NRC, SO2NR0 Or NR0SO2;
Rb is:
• hydrogen; • a carbocyclic and heterocyclic group having from 3 to 12 ring members and being optionally substituted by one or more substituents R8;
• an acyclic C1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-Q.s non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R8; wherein one or more carbon atoms of the acyclic C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X^X1 or X1C(X^X1;
R° is Rb, hydrogen or C1-4 hydrocarbyl; X1 is O, S or NR0; and X2 is =0, =S or =NR°; wherein R8 is selected from R7 provided that when the substituents R8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9; and R9 is selected from R7 except that any carbocyclic or heterocyclic groups constituting or forming part of R9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-Ci-4 hydrocarbylamino; or a group Ra-Rbb; where Ra is as hereinbefore defined and Rbb is hydrogen or an acyclic C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 saturated hydrocarbylamino and wherein one or more carbon atoms of the C1- 6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X^X1 Or X1C(X^X1.
In another embodiment, the compound of the invention is a compound of the formula (3):
Figure imgf000009_0001
or a salt, solvate or tautomer thereof; wherein: the CONH2 moiety is attached at either position "a" or position "b" on the benzene ring;
YMs N OrN+-O" ; m is 0, 1 or 2;
R1 is halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the C1-4 alkyl and C1-4 alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy; one of R2 and R3 is R4 and the other of R2 and R3 is hydrogen, C1-4 alkyl, halogen or cyano;
R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7;
R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy;
R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7;
R7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R8; or a group Ra-Rb;
Ra is a bond, O, CO, X1C(X2), C(X2)X\ X1C(X^X1, S5 SO, SO2, NR0, SO2NR0 Or NR0SO2;
Rb is: • hydrogen;
• a carbocyclic and heterocyclic group having from 3 to 12 ring members and being optionally substituted by one or more substituents R8;
• a C1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R8; wherein one or more carbon atoms of the C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2X1 or X1C(X2X1; Rc is Rb, hydrogen or C1-4 hydrocarbyl;
X1 is O, S or NR0; and X2 is =O, =S or =NRc; wherein R8 is selected from R7 provided that when the substituents R8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9; and R9 is selected from R7 except that any carbocyclic or heterocyclic groups constituting or forming part of R9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C^ hydrocarbylamino; or a group Ra-Rbb; where Ra is as hereinbefore defined and Rbb is hydrogen or a C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C^ saturated hydrocarbylamino and wherein one or more carbon atoms of the C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X^X1 Or X1C(X^X1.
The invention also provides inter alia:
• A compound of the formula (1), (Ia), (2) or (3) as defined herein for use as an anti-cancer agent.
• The use of a compound of the formula (1), (Ia), (2) or (3) for the manufacture of a medicament for the treatment of cancer.
• A method of treating a cancer, which method comprises administering to a subject need thereof a therapeutically effective amount of a compound of formula (1), (Ia), (2) or (3), optionally together with another anti-cancer agent or radiation therapy.
• A compound of the formula (1), (Ia), (2) or (3) as defined herein for use as a DNA damaging agent in hypoxic tumour cells.
• A method of causing DNA damage in hypoxic tumour cells, which method comprises bringing a compound of the formula (I)5 (Ia), (2) or (3) as defined herein into contact with the hypoxic tumour cells. • A compound of the formula (1), (Ia), (2) or (3) as defined herein for use in enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer.
• The use of a compound of the formula (1), (Ia), (2) or (3) for the manufacture of a medicament for enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer.
• A method for the prophylaxis or treatment of a proliferative disease such as cancer, which method comprises administering to a patient in combination with radiotherapy or chemotherapy a compound of the formula (1), (Ia), (2) or (3) as defined herein.
• A pharmaceutical composition comprising a compound of the formula (1), (Ia), (2) or (3) as defined herein and a pharmaceutically acceptable carrier.
• A compound of the formula (1), (Ia), (2) or (3) as defined herein for use in medicine.
General Preferences and Definitions
In this section, as in all other sections of this application, unless the context indicates otherwise, references to a compound of formula (1) includes formulae (Ia), (2), (3), and all other subgroups thereof as defined herein, and the term 'subgroups' includes all preferences, embodiments, examples and particular compounds defined herein.
References to "carbocyclic" and "heterocyclic" groups as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. In general, such groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 ring members, more usually 5 to 10 ring members. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, and preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10 ring members. The carbocyclic or heterocyclic groups can be aryl or heteroaryl groups having from 5 to 12 ring members, more usually from 5 to 10 ring members. The term "aryl" as used herein refers to a carbocyclic group having aromatic character and the term "heteroaryl" is used herein to denote a heterocyclic group having aromatic character. The terms "aryl" and "heteroaryl" embrace polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group may be attached by the aromatic ring, or by a non-aromatic ring.
The term non-aromatic group embraces unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "unsaturated" and "partially saturated" refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C≡C or N=C bond. The term "fully saturated" refers to rings where there are no multiple bonds between ring atoms. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cycloheptenyl and cyclooctenyl.
Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; i) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; j) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; 1) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; m) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; n) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and o) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.
Examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, benzodioxole and pyrazolopyridine groups.
Examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiene, dihydrobenzofuran, 2,3-dihydro- benzo[l,4]dioxine, benzo[l,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoline and indane groups.
Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.
Examples of non-aromatic heterocyclic groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ring members), usually selected from nitrogen, oxygen and sulphur.
The heterocylic groups can contain, for example, cyclic ether moieties (e.g as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), cyclic sulphones (e.g. as in sulpholane and sulpholene), cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g. thiomorpholine). Other examples of non-aromatic heterocyclic groups include cyclic amide moieties (e.g. as in pyrrolidone) and cyclic ester moieties (e.g. as in butyrolactone).
Examples of monocyclic non-aromatic heterocyclic groups include 5-, 6-and 7- membered monocyclic heterocyclic groups. Particular examples include morpholine, thiomorpholine and its S-oxide and S,S-dioxide, piperidine (e.g. 1-piperidinyl, 2- piperidinyl, 3-piperidinyl and 4-piperidinyl), N-alkyl piperidines such as N-methyl piperidine, piperidone, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine, and N-alkyl piperazines such as N-methyl piperazine, N-ethyl piperazine and N- isopropylpiperazine.
Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.
Examples of halogen substituents include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred.
In the definition of the compounds of the formula (1) above and as used hereinafter, the term "hydrocarbyl" is a generic term encompassing aliphatic, alicyclic and aromatic groups having an all-carbon backbone, except where otherwise stated. Thus, for example, the term "acyclic hydrocarbyl" refers to a hydrocarbyl group that contains no cyclic moieties.
In certain cases, as defined herein, one or more of the carbon atoms making up the carbon backbone may be replaced by a specified atom or group of atoms. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, can be substituted by one or more substituents as defined herein. The examples and preferences expressed below apply to each of the hydrocarbyl substituent groups or hydrocarbyl-containing substituent groups referred to in the various definitions of substituents for compounds of the formula (I) unless the context indicates otherwise.
Generally by way of example, the hydrocarbyl groups can have up to twelve carbon atoms, unless the context requires otherwise. Within the sub-set of hydrocarbyl groups having 1 to 12 carbon atoms, particular examples are Ci-10 hydrocarbyl groups, Ci-8 hydrocarbyl groups, C1-6 hydrocarbyl groups, C1-4 hydrocarbyl groups (e.g. C1-3 hydrocarbyl groups or C1-2 hydrocarbyl groups), specific examples being any individual value or combination of values selected from C1, C2, C3, C4, C5, C6, C7 and C8 hydrocarbyl groups.
The term "alkyl" covers both straight chain and branched chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers. Within the sub-set of alkyl groups having 1 to 8 carbon atoms, particular examples are C1-6 alkyl groups, such as C1-4 alkyl groups (e.g. C1-3 alkyl groups or C1-2 alkyl groups).
Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the sub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8 carbon atoms, particular examples being C3-6 cycloalkyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-l,4-dienyl, pentenyl, and hexenyl. Within the sub-set of alkenyl groups the alkenyl group will have 2 to 8 carbon atoms, particular examples being C2-6 alkenyl groups, such as C2-4 alkenyl groups.
Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. Within the sub-set of cycloalkenyl groups the cycloalkenyl groups have from 3 to 8 carbon atoms, and particular examples are C3-6 cycloalkenyl groups.
Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within the sub-set of alkynyl groups having 2 to 8 carbon atoms, particular examples are C2-6 alkynyl groups, such as C2-4 alkynyl groups.
Examples of carbocyclic aryl groups include substituted and unsubstituted phenyl, naphthyl, indane and indene groups.
Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl groups.
Where present and where stated, one or more carbon atoms of a hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X^X1 or X1C(X^X1 (or a sub-group thereof) wherein X1 and X2 are as hereinbefore defined, provided that at least one carbon atom of the hydrocarbyl group remains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl group may be replaced by one of the atoms or groups listed, and the replacing atoms or groups may be the same or different. In general, the number of linear or backbone carbon atoms replaced will correspond to the number of linear or backbone atoms in the group replacing them. Examples of groups in which one or more carbon atom of the hydrocarbyl group have been replaced by a replacement atom or group as defined above include ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (C-C replaced by X1C(X2) or C(X2)X1), sulphones and sulphoxides (C replaced by SO or SO2), amines (C replaced by NRC). Further examples include ureas, carbonates and carbamates (C-C-C replaced by X1C(X2)X1).
Where an amino group has two hydrocarbyl substituents, if the context permits they may, together with the nitrogen atom to which they are attached, and optionally with another heteroatom such as nitrogen, sulphur, or oxygen, link to form a ring structure of 4 to 7 ring members.
The definition "Ra-Rb" as used herein, either with regard to substituents present on a carbocyclic or heterocyclic moiety, or with regard to other substituents present at other locations on the compounds of the formula (I), includes inter alia compounds wherein Ra is selected from a bond, O, CO, OC(O), SC(O), NR0C(O), OC(S), SC(S), NR0C(S), OC(NR0), SC(NR0), NR0C(NR0), C(O)O, C(O)S, C(O)NR0, C(S)O, C(S)S, C(S) NR0, C(NR°)0, C(NR°)S, C(NR°)NR°, OC(O)O, SC(O)O, NR0C(O)O, OC(S)O, SC(S)O, NR0C(S)O, 0C(NR°)0, SC(NR°)O, NR°C(NR°)0, OC(O)S, SC(O)S, NR0C(O)S, OC(S)S, SC(S)S, NR0C(S)S, OC(NR°)S, SC(NR°)S, NR°C(NRC)S, OC(O)NR0, SC(O)NR0, NR0C(O) NR0, OC(S)NR0, SC(S) NR0, NR0C(S)NR0, 0C(NR°)NR°,
SC(NR°)NR°, NR0C(NR0NR0, S, SO, SO2 ,NR0, SO2NR0 and NR0SO2 wherein R° is as hereinbefore defined.
The moiety Rb can be hydrogen or it can be a group selected from carbocyclic and heterocyclic groups having from 3 to 12 ring members (typically 3 to 10 and more usually from 5 to 10), and a C1-12 hydrocarbyl group (e.g. a C1-10 hydrocarbyl group or a C1-8 hydrocarbyl group) optionally substituted as hereinbefore defined. Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as set out above.
When Ra is O and Rb is a C1-12 hydrocarbyl group, Ra and Rb together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groups include saturated hydrocarbyloxy such as alkoxy (e.g. C1-6 alkoxy, more usually C1-4 alkoxy such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (e.g. C3-6 cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy (e.g. C3-6 cycloalkyl-C1-2 alkoxy such as cyclopropylmethoxy). The hydrocarbyloxy groups can be substituted by various substituents as defined herein. For example, the alkoxy groups can be substituted by halogen (e.g. as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g. as in hydroxyethoxy), C1-2 alkoxy (e.g. as in methoxyethoxy), hydroxy-C1-2 alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. a cycloalkyl group or non-aromatic heterocyclic group as hereinbefore defined). Examples of alkoxy groups bearing a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4-alkyl-piperazines, C3.7-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkoxy group is a C1-4 alkoxy group, more typically a C1-3 alkoxy group such as methoxy, ethoxy or n- propoxy.
Alkoxy groups may be substituted by, for example, a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and N-substituted derivatives thereof such as N-benzyl, N-C1-4 acyl and N-C1-4 alkoxycarbonyl. Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.
When Ra is a bond and Rb is a C1-12 hydrocarbyl group, examples of hydrocarbyl groups Ra-Rb are as hereinbefore defined. The hydrocarbyl groups may be saturated groups such as cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl. The hydrocarbyl (e.g. alkyl) groups can be substituted by various groups and atoms as defined herein. Examples of substituted alkyl groups include alkyl groups substituted by one or more halogen atoms such as fluorine and chlorine (particular examples including bromoethyl, chloroethyl, difluoromethyl, 2,2,2- trifiuoroethyl and perfluoroalkyl groups such as trifluoromethyl), or hydroxy (e.g. hydroxymethyl and hydroxyethyl), C1-8 acyloxy (e.g. acetoxymethyl and benzyloxymethyl), amino and mono- and dialkylamino (e.g. aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and tert- butylaminomethyl), alkoxy (e.g. C1-2 alkoxy such as methoxy - as in methoxyethyl), and cyclic groups such as cycloalkyl groups, aryl groups, heteroaryl groups and non- aromatic heterocyclic groups as hereinbefore defined). Particular examples of alkyl groups substituted by a cyclic group are those wherein the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4-alkyl-piperazines, C3-7-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is a C1-4 alkyl group, more typically a C1-3 alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted by a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N- substituted forms thereof as defined herein.
Particular examples of alkyl groups substituted by aryl groups and heteroaryl groups include benzyl, phenethyl and pyridylmethyl groups.
When Ra is SO2NR0, Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of Ra-Rb where Ra is SO2NR0 include aminosulphonyl, C1-4 alkylaminosulphonyl and di-C1-4 alkylaminosulphonyl groups, and sulphonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine such as N-methyl piperazine.
Examples of groups Ra-Rb where Ra is SO2 include alkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups, particularly monocyclic aryl and heteroaryl sulphonyl groups. Particular examples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl.
When Ra is NR0, Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of Ra-Rb where Ra is NR0 include amino, C1-4 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, te/t-butylamino), di-C1-4 alkylamino (e.g. dimethylamino and diethylamino) and cycloalkylamino (e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino) .
Specific Embodiments and Preferences The moiety Q can be either CN or CONH2. Preferably Q is CONH2.
The CN or CONH2 moiety can be attached at either position "a" or position "b" on the benzene ring.
In one embodiment, the CONH2 moiety is attached at position "a" on the benzene ring.
In another embodiment, the CONH2 moiety is attached at position "b" on the benzene ring.
In a further embodiment, the CN moiety is attached at position "a" on the benzene ring.
In another embodiment, the CN moiety is attached at position "b" on the benzene ring.
In formulae (1), (Ia)5 (2) and (3), m is 0, 1 or 2.
Preferably m is O or 1.
In one embodiment, m is O and hence R1 is absent.
In another embodiment, m is 1.
When R1 is present, each substituent R1 is independently selected from halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the C1-4 alkyl and C1-4 alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy.
More typically, each R1 is halogen, cyano, C1-4 alkyl or C1-4 alkoxy, cyano, C1-4 alkyl or C1-4 alkoxy.
For example, each R1 can be methyl, ethyl, isopropyl, chlorine, fluorine, bromine, cyano, methoxy, ethoxy or isopropoxy.
When present, R1 may be attached to any of the carbon atoms in the benzene ring apart from the carbon atom to which the moiety Q is attached. Preferably, each R1 when present is attached to a carbon atom between positions "a" and "b" on the benzene ring, i.e. at the 6- and/or 7-positions of the quinoxaline or benzotriazine ring.
Preferably R1 or the combination of R1 groups is selected so that the one electron reduction potential E(I) of the quinoxaline group is between -300 mV and -510 mV, and more preferably from -450 mV to -510 mV.
Y1, Y2 & Y3
In formulae (1) and (Ia), Y1 is N or N+-O" ; Y2 is N or CR3; and Y3 Is N Or N+-CT ; provided that when Y2 is CR3, then Y3 is N+-O'.
In one embodiment wherein Q is CONH2, Y1 is N or N+-O' ; Y2 is N and Y3 is N or N+- O". This embodiment is represented by formula (2) above.
Within this embodiment, one particular subgroup of compounds is the subgroup wherein Y1 and Y3 are both N+-O".
Another particular subgroup of compounds is the subgroup wherein Y1 and Y3 are both
N.
A further subgroup of compounds is the subgroup wherein Y1 is N and Y3 is N+-O".
A further subgroup of compounds is the subgroup wherein Y1 is N+-O" and Y3 is N.
In another embodiment wherein Q is CONH2, Y1 is N or N+-O" ; Y2 is CR3 and Y3 is N+-O". This embodiment is represented by formula (3) above.
Within this embodiment, in one subgroup of compounds, Y1 is N; Y2 is CR3 and Y3 is
N+-O".
In another subgroup of compounds, Y1 is N+-O" ; Y2 is CR3 and Y3 is N+-O". In a further sub-group of compounds, the group CONH2 is attached at location "a" on the benzene ring, Y1 is N; Y2 is CR3 and Y3 is N+-O-.
R2 & R3
When Y2 is N, then R2 is a group R4; and when Y2 is CR3, then one of R2 and R3 is R4 and the other of R2 and R3 is hydrogen, C1-4 alkyl, halogen or cyano.
More typically, when Y2 is CR3, one of R2 and R3 is R4 and the other is hydrogen, methyl, ethyl or cyano.
Preferably, when Y2 is CR3, one of R2 and R3 is R4 and the other is hydrogen or cyano.
In one embodiment, R2 is R4, and R3 is, for example, hydrogen, methyl, ethyl or cyano.
In another embodiment, R3 is R4, and R2 is, for example, hydrogen, methyl, ethyl or cyano.
In formulae (1), (Ia), (2) and (3), R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7.
The carbocyclic and heterocyclic ring can be any of the carbocyclic and heterocyclic rings set out in the Definitions and General Preferences above.
Preferred carbocyclic and heterocyclic rings are monocyclic rings of 5 or 6 ring members.
For example, the carbocyclic or heterocyclic rings can be monocyclic non-aromatic or aryl or heteroaryl rings of 5 or 6 ring members containing up to 2 heteroatomic ring members selected from O, N and S. Examples of such rings are: (a) optionally substituted aryl and heteroaryl rings selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, diazinyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and pyrazolyl; (b) optionally substituted non-aromatic monocyclic rings selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, morpholinyl, thiomorpholinyl and S-oxide and S,S-dioxides thereof, tetrahydrofuranyl and tetrahydropyranyl.
Particular examples of carbocyclic or heterocyclic rings are optionally substituted phenyl, piperidinyl, piperazinyl and morpholinyl rings.
When Y2 is CH, R4 may be other than an unsubstituted or N-substituted azepin-4-yl or azepine-5-yl group.
When R4 is NR5R6, R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy; and R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7.
Alternatively, R5 can be a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7.
For R5 and R6, examples of C1-4 alkyl or C1-4 acyl groups are methyl, ethyl, π-propyl, isopropyl, «-butyl, isobutyl, tert-bntyl, formyl, acetyl, propanoyl, butanoyl and 2- methylbutanoyl.
In one embodiment, R5 is hydrogen or methyl and R6 is hydrogen, C1-4 alkyl or C1-4 acyl optionally substituted by one or more substituents R7.
When R6 is optionally substituted C1-4 alkyl or C1-4 acyl, there may be 0, 1, 2 or 3 substituents, for example 0, 1 or 2 substituents, and more usually 0 or 1 substituent.
When R5 is a carbocyclic or heterocyclic ring, preferably it is a monocyclic 5- or 6- membered aryl or heteroaryl group, for example a phenyl group. The carbocyclic and heterocyclic rings are optionally substituted by one or more substituents R7. Typically there may be 0, 1, 2 or 3 substituents, for example 0, 1 or 2 substituents.
One subgroup of optional substituents R7 for the carbocyclic or heterocyclic rings or the group R6 is represented by R7a wherein R7a is halogen; hydroxy; trifluoromethyl; cyano; amino; mono- or di-Ci.4 alkylamino; monocyclic carbocyclic or heterocyclic groups having from 3 to 7 ring members and optionally substituted by one or more substituents R8a; or a group Ra'-Rb';
Ra' is a bond, O, CO, X1C(X2),
Figure imgf000026_0001
S, SO, SO2, NRC>, SO2NR0Or NR0 SO2; Rb' is:
• hydrogen;
• a monocyclic carbocyclic and heterocyclic group having from 3 to 7 ring members and being optionally substituted by one or more substituents R8a;
• a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-Ci-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R8; wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O5 S, SO, SO2, NR0', X1C(X2), C(X2)X! or X1C(X^X1; R° is Rb , hydrogen or C1-4 hydrocarbyl; X1 is O, S or NR0'; and X2 is =O, =S or =NR0'; wherein R8a is selected from R7a provided that when the substituents R8a contain a carbocyclic or heterocyclic group having from 3 to 7 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9a; and R9a is selected from R7a but is other than a carbocyclic or heterocyclic group. More particularly, the carbocyclic and heterocyclic rings may be optionally substituted by one or more substituents R ; wherein R is chlorine; fluorine; bromine; hydroxy; trifluoromethyl; cyano; amino; mono- or di-C1-4 alkylamino; monocyclic carbocyclic or heterocyclic groups having from 3 to 7 ring members and optionally substituted by one or more substituents R8a; or a group Ra -Rb ;
Ra" is a bond, O, CO, OC(O), NRC"(CO), C(O)NR0", OC(O)O, OC(O)NR0", NR°"(CO)O, S5 SO5 SO25 NR0", SO2NR0" orNR°"SO2;
Rb" is:
• hydrogen; • a monocyclic carbocyclic and heterocyclic group having from 3 to 7 ring members of which O5 1 or 2 are heteroatom ring members selected from O5 N and S5 and wherein the monocyclic carbocyclic and heterocyclic group is optionally substituted by one or more substituents R8b;
• a C1-8 alkyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R8b; wherein one or more carbon atoms of the C1-8 alkyl group may optionally be replaced by O5 S5 SO5 SO2, CO5 OC(O)5 NR°"(CO)5 C(O)NR0", OC(O)O5 OC(O)NR0",
NR°"(C0)0, NR0", SO2NR0" or NR°"SO2; and R° is hydrogen or C1-2 alkyl; wherein R8b is selected from R7a provided that R8a is other than a carbocyclic or heterocyclic group.
One subgroup of substituents R7 is represented by R7°, where R7c is:
■ chlorine;
■ fluorine;
■ bromine;
■ hydroxy; ■ trifluoromethyl;
■ cyano; ■ amino;
■ mono- or di-C1-4 alkylamino;
■ monocyclic carbocyclic or heterocyclic groups selected from phenyl, piperazinyl, piperidinyl, and morpholinyl, each being optionally substituted by one or more substituents R8c; or
■ a group Ra"'-Rb>"; wherein Ra>" is a bond, O, CO, OC(O), NR°'"(CO), C(O)NR0'", OC(O)O, OC(O)NR0"', NR°'"(CO)O, NR0"';
■ Rb>" is: o hydrogen; o a monocyclic carbocyclic or heterocyclic groups selected from phenyl, piperazinyl, piperidinyl, and morpholinyl, each being optionally substituted by one or more substituents R8°; o a C1-6 alkyl group optionally substituted by one or more substituents selected from hydroxy; oxo; chlorine; fluorine; bromine; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R8c; wherein one or more carbon atoms of the C1-6 alkyl group may optionally be replaced by O, CO, OC(O),
NRC(CO), C(O)NR0, OC(O)NR0, NR°(CO)O, NR0, and R0 is hydrogen or C1-2 alkyl; wherein R8° is selected from R7° provided that R8° is other than a carbocyclic or heterocyclic group.
Particular examples of substituents R7 include C1-4 alkyl, chlorine, fluorine, C1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, hydroxy, amino-C1-2 alkyl, mono- or dimethylamino-C1-2 alkyl, piperazinylcarbonyl, morpholinylcarbonyl, piperazinyl-C1-2 alkyl, morpholinyl-C1-2 alkyl, piperidinyl-Cϊ-2 alkyl,, pyrrolidinyl-C1-2 alkyl, hydroxy-Q^alkyl, methoxy-C 1-2 alkyl, cyano-Ci.2 alkyl and Cj-4 alkylsulphonyl.
For the avoidance of doubt, it is to be understood that each general and specific preference, embodiment and example of one R group may be combined with each general and specific preference, embodiment and example of each other R group, Y1, Y2 and Y3 as defined herein and that all such combinations are embraced by this application.
Preferred compounds of the present invention are those having a one electron reduction potential E(I) of between -300 mV and -510 mV, and more preferably from -450 mV to -510 mV. One electron reduction potentials can be measured by a number of techniques including pulse radiolysis, see for example (i) M. P Hay et al. J. Med. Chem., 2003, 46:169-182 (ii) E. J Land et al., Arch Biochem Biophys. 1983 Aug; 225(1):116-21; (iii) Patel and Willson (K B Patel and R L Willson. Journal of the Chemical Society, Faraday Transactions 1, 1973, 69, 814-825); (iv) D Meisel and P Neta. Journal of the American Chemical Society, 1975, 97, 5198-5203; (v) P Wardman and E D Clarke. Journal of the Chemical Society, Faraday Transactions 1, 1976, 72, 1377-1390; and (vi) P Wardman. Journal of Physical and Chemical Reference Data, 1989, 18, 1637- 1755.
The various functional groups and substituents making up the compounds of the formula (1) are typically chosen such that the molecular weight of the compound of the formula (1) does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.
Particular and preferred compounds are as set out in the examples.
Salts, Solvates, Tautomers, Isomers, Prodrugs and Isotopes
A reference to a compound of the formula (1) and sub-groups thereof also includes ionic forms, salts, solvates, isomers, tautomers, prodrugs, isotopes and protected forms thereof, for example, as discussed below.
Many compounds of the formula (1) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as phenolate, carboxylate, sulphonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (1) include the salt forms of the compounds.
The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
Acid addition salts may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L- ascorbic), L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(15)-camphor-10-sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane- 1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, (+)-L-lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL- mandelic, methanesulphonic, naphthalene-2-sulphonic, naphthalene- 1,5-disulphonic, 1- hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic, j?-toluenesulphonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.
If the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth metal cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). 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(CH3)4 +.
Where the compounds of the formula (1) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (1).
The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et ah, 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1- 19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
Compounds of the formula (1) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (1).
Examples of tautomeric forms include, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
Figure imgf000032_0001
keto enol enolate
Where compounds of the formula (1) contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to compounds of the formula (I) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and / isomers) or they may be characterised in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl, 1966, 5, 385-415.
Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.
As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)- pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulphonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.
Where compounds of the formula (1) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound of the formula (I) having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (I) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).
The compounds of the invention include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope
I O 1X
H, H (D), and H (T). Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 18O.
The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
Also encompassed by formula (1) are any polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds, and pro-drugs of the compounds. By "prodrugs" is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1).
For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
Examples of such metabolically labile esters include those of the formula -C(=O)OR wherein R is:
C^alkyl (e.g., -Me5 -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);
C1-7 aminoalkyl
(e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C^ alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;
1-acetoxyethyl; 1 -( 1 -methoxy- 1 -methyl)ethyl-carbonyloxyethyl;
1 -(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;
1 -isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;
1 -cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxyniethyl; 1 -cyclohexyloxy-carbonyloxyethyl;
(4-tetrahydropyranyloxy) carbonyloxymethyl; l-(4-tetrahydropyranyloxy)carbonyloxyethyl;
(4-tetrahydropyranyl)carbonyloxymethyl; and l-(4-tetrahydropyranyl)carbonyloxyethyl).
Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Biological Activity
It is envisaged that the compounds of the formulae (1), (Ia), (2) and (3) wherein both Y1 and Y3 are N-oxide groups will be reduced to the mono-N-oxides in hypoxic tumour cells and that the reduction process will result in damage to the DNA of the tumour cell and therefore cell death. The mono-N-oxides may undergo further reduction to the parent heterocycle, thereby causing further DNA damage in the hypoxic tumour cell and consequent cell death. In each case, the parent heterocycle (and in many cases the mono-N-oxides) has PARP inhibiting activity which prevents DNA repair. Thus the compounds of the invention are believed to act against hypoxic cancer cells in two ways. Firstly, they are reduced in hypoxic conditions and the act of reduction results in damage to the DNA of the tumour cell. Secondly, the reduced products block the normal cell repair processes thereby enhancing the cytotoxic effect of the N-oxides.
It is therefore considered that the compounds of the invention will be useful in treating a range of proliferative diseases and in particular solid tumours containing a significant mass of hypoxic cells.
It is envisaged that the compounds of the invention will also act in a synergistic or additive manner with other chemotherapeutic agents and cancer treatments such as radiotherapy against a wide spectrum of proliferative disorders.
Examples of such proliferative disorders include, but are not limited to carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin, hematopoieitic tumours such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoieitic tumours of myeloid lineage, for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocyte leukaemia; thyroid follicular cancer; tumours of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; tumours of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
The PARP inhibitor compounds of the invention may be used in combination with
DNA-damaging anti-cancer drugs and/or radiation therapy to treat subjects with multidrug resistant cancers. A cancer is considered to be resistant to a drug when it resumes a normal rate of tumour growth while undergoing treatment with the drug after the tumour had initially responded to the drug. A tumour is considered to "respond to a drag" when it exhibits a decrease in tumor mass or a decrease in the rate of tumour growth.
Compounds of the invention having PARP inhibiting activity, e.g. compounds of the formula (2) wherein at least one of Y1 and Y3 is N, should also be useful in the treatment of other disease states and conditions where inhibition of PARP has a beneficial effect. For example, the compounds may be useful in the treatment of inflammation and ischaemia-reperfusion injury, and diseases arising from or mediated by NMDA- and NO-induced toxicity.
Examples of uses in connection with diseases arising from or mediated by NMDA- and NO-induced toxicity include treating neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Parkinson's disease; epilepsy; Amyotrophic Lateral Sclerosis (ALS); Huntington's disease; schizophrenia; chronic pain; ischaemia; hypoxia; hypoglycaemia; ischaemia; trauma; nervous insult; skin aging; atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy; degenerative diseases of skeletal muscle involving replicative senescence; age-related macular degeneration; AIDS; and other immune deficiency diseases; inflammatory bowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock; and septic shock.
The ability of the compounds of the invention to inhibit PARP can be determined by using commercially available assay kits and following the manufacturers' instructions. Examples of such assay kits include:
(a) The Trevigen Poly (ADP-ribose) Polymerase Assay Kit.
(b) The Trevigen Universal Colorimetric PARP Assay Kit With Histones and Coating Buffer.
(c) The Trevigen Universal Chemiluminescent PARP Assay Kit With Histone- Coated Strip Wells. Each of the aforementioned kits is available from Trevigen, Inc., of Gaithersburg, MD, USA.
Alternatively, the PARP inhibiting activity of the compounds can be determined using the methods described in on page 23 of WO 03/007959 (Fujisawa), the disclosure in which is incorporated herein by reference.
Methods for the Preparation of Compounds of the Formula (1)
In this section, as in all other sections of this application unless the context indicates otherwise, references to Formula (1) also include Formula (Ia), Formula (2) and Formula (3) and all sub-groups and examples therof as defined herein unless the context indicates otherwise.
Compounds of the formula (1) can be prepared in accordance with synthetic methods well known to the skilled person.
For example, compounds of the formula (2) where the CONH2 group is attached to position "a" of the benzene ring can be prepared by the synthetic route shown in Scheme 1.
Figure imgf000037_0001
Scheme 1
The starting compound in Scheme 1 is the optionally substituted 3-bromo-2-fluoro- nitrobenzene compound (16) which is either commercially available or can readily be prepared by the skilled person using well known methods. In the case of compound (16) where m=0, this is available from Marshallton Research Laboratories of King, North Carolina, USA.
In Scheme 1, the optionally substituted 3-bromo-2-fluoro-nitrobenzene compound (16) is reacted with an amidine or guanidine compound of the formula R4-C(=NH)NH, where R4 is as defined herein to give a bromo-benzotriazine mono-N-oxide (17). The bromo-benzotriazine mono-N-oxide (17) is then reacted with cuprous cyanide (CuCN) which results in replacement of the bromine atom with a nitrile group, and reduction of the N-oxide, to give the 5-cyano-benzotriazine (18). The 5-cyano-benzotriazine (18) is then partially hydrolysed using aqueous HCl to give the amide (2a). Oxidation of the amide (2a) with H2O2/acetic acid yields the amide mono-N-oxide (2b) which can be further oxidized to the di-N-oxide using an oxidizing agent such as hydrogen peroxide/trifluoroacetic acid or other oxidising agents as described below in relation to Scheme 7.
A process for making compounds of the formula (2) wherein R2 is an amino group is illustrated in Scheme 2. In this process, the starting material is the optionally substituted 2-fluoro-6-nitro-aniline (19) which is either commercially available (e.g. from KaironChem of Carry Ie Rouet France, in the case of the compound where m=0) or can be made according to methods well known to the skilled person.
Figure imgf000038_0001
(22) (2d) (2e)
Scheme 2 In Scheme 2, the amine (19) is cyclised to the 3-amino-5-fluorobenzotriazine mono-N- oxide (20) by reaction with cyanamide/HCl followed by treatment with sodium hydroxide. The 3-amino-5-fluorobenzotriazine (20) is oxidised to the di-N-oxide (21) using a suitable oxidizing agent such as hydrogen peroxide/trifluoroacetic acid, and the di-N-oxide is then reacted with sodium cyanide to displace the fluorine atom with cyanide and give the nitrile (22). Hydrolysis of the nitrile (22) using aqueous hydrochloric acid gives the amide di-N-oxide (2d) which can be reduced to the parent heterocycle (2e) using sodium dithionite in ethanol.
Scheme 3 illustrates an altenative route to 3-aminobenzotriazoles starting from the 2- iodo-acetamidobenzene (23) which can be obtained from Maybridge of Tintagel, UK
Figure imgf000039_0001
(27) (2e) (2f)
Scheme 3
(in the case of the compound wherein m=0) or can be synthesised according to well known methods. The 2-iodo-acetamidobenzene (23) is nitrated using a standard nitrating mixture of nitric and sulphuric acids to give (24) which is then converted to the amine (25) using sodium methoxide in methanol or concentrated sulphuric acid to remove the acetyl group. The amine (25) is then cyclised to the 3-amino-5- iodobenzotriazine mono-N-oxide (26) by reaction with cyanamide/HCl followed by treatment with sodium hydroxide. The 3-amino-5-iodobenzotriazine mono-N-oxide (26) is then reacted with cuprous cyanide (CuCN) in dimethylformamide to displace the iodine atom with cyanide and reduce the N-oxide to give the 3-amino-5-cyano- benzotriazine (27). Hydrolysis of the 3-amino-5-cyano-benzotriazine (27) using aqueous hydrochloric acid gives the amide (2e) which can be oxidized to the mono-N- oxide (2f) and/or di-N-oxide using a suitable oxidising agent such as H2O2/acetic acid or another oxidising agent as described below in relation to Scheme 7. Scheme 4 illustrates a route to compounds of the formula (2) wherein R2 is introduced either by nucleophilic displacement of halogen from the 3-position of the benzotriazine ring or by means of the Suzuki reaction.
Figure imgf000040_0001
(33) (2h)
Scheme 4
In Scheme 6, the amino-benzotriazine (28) wherein X is bromine or iodine (see compound (26) above) is converted to the 3 -hydroxy compound (29) by reaction with sodium nitrite and hydrochloric acid. The halogen atom X is then displaced by reaction with cuprous cyanide in dimethylformamide to give the nitrile (30). The nitrile (30) is then reacted with POCl3 to give the 3-chloro-benzotriazine (31).
The 3-chloro-benzotriazine (31) can then be converted to a wide range of compounds of formula (2) via the nitrile (32)) using the Suzuki reaction to introduce aryl and heteroaryl groups at the 3-position. In a Suzuki coupling procedure, a compound of formula (31) is reacted with a boronate ester or a boronic acid R2-B(OH)2 in the presence of a palladium (0) catalyst and base to give the nitrile (32). Many boronates suitable for use in preparing compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or from Combi- Blocks Inc, of San Diego, USA. Where the boronates are not commercially available, they can be prepared by methods known in the art, for example as described in the review article by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. Thus, boronates can be prepared by reacting the corresponding bromo-compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester. The resulting boronate ester derivative can, if desired, be hydrolysed to give the corresponding boronic acid. Alternatively, the 3-chloro-benzotriazine (31) can be subjected to nucleophilic displacement of the chlorine atom by an amine to give substituted amino compounds of formula (33) wherein R2 is NR5R6 and at least one of R5 and R6 is other than hydrogen. The amino compounds (33) and the aryl/heteroaryl compounds (32) can then be hydrolysed using hydrochloric acid to give the carboxamides (2h) and (2g) respectively. The carboxamides can be oxidized to the mono-N-oxide or di-N-oxide using the methods described above.
Compounds of the formula (2) in which the CONH2 group is attached to the 8-position of the benzotriazine ring can be prepared by the synthetic route shown in Scheme 5.
Figure imgf000041_0001
Scheme 5
In Scheme 5, the 3-chloro-2-nitro-benzoic acid (34) is converted to the amide (35) by reaction with CDI in dichloromethane to form an activated acid derivative and then reacting with ammonia. The amide (35) is then reacted with an amidine or guanidine compound of the formula R4-C(=NH)NH to give the benzotriazine mono-N-oxide (2i). The mono-N-oxide can either be reduced to the parent heterocycle (2j) using sodium dithionite or can be be oxidised to the di-N-oxide (2k) using hydrogen peroxide/trifluoroacetic acid.
An alternative route to compounds of the formula (2) in which the CONH2 group is attached to the 8-position of the benzotriazine ring is illustrated in Scheme 6.
Figure imgf000042_0001
Scheme 6
In Scheme 6, the 2,6-difluoronitrobenzene (36) is reacted with an amidine or guanidine compound of the formula R4-C(=NH)NH to give the benzotriazine mono-N-oxide (37) which is then oxidised to the di-N-oxide (38) using hydrogen peroxide/trifluoroacetic acid.The fluorine atom is then displaced with cyanide by reaction with sodium cyanide to give the nitrile (39) which is hydrolysed to the amide (2k) using conditions as described in the preceding Schemes. The compound (2k) can be reduced to the parent heterocycle (2j) as described above.
Compounds of the formula (3) may be prepared by forming the parent heterocycle using the methods described in WO 03/062234 (Yamanouchi) and WO 03/007959 (Fujisawa) and then oxidising the compounds to the corresponding di-N-oxides of the formula (3) using an appropriate oxidising agent.
An example of a synthetic route for preparing compounds of the formula (3) is set out in Scheme 7.
Figure imgf000043_0001
(42) Separated by HPLC
Figure imgf000043_0002
Scheme 7
In Scheme 7, the group R10 is either an NH2 group or a methoxy or ethoxy group and hence C(O)R10 is either a carboxamide or ester group.
The starting material for Scheme 7 is the substituted nitro-aniline derivative (39a) which is reduced to the corresponding diamine (40) by catalytic hydrogenation over palladium on charcoal. The reaction is typically carried out in ethanol at room temperature. Where the group C(O)R10 is an ester group, this can be converted to the corresponding carboxamide group either before or after the reduction of the nitro group. Alternatively, the ester group can be left in place throughout the synthesis and then converted to the amide at a later stage. Conversion of the ester to an amide may be carried out by reaction with ammonia in a polar solvent such as methanol under conditions of elevated temperature and pressure (for example in a sealed tube with heating to about 100 0C) The 2,3-diaminobenzoic acid amide/ester (40) is reacted with the α-bromoketone (41) to give a mixture of quinoxalines (42) and (43) which are separated by HPLC. Where C(O)R10 is an ester group, the quinoxaline esters (42) and (43) can be converted to the corresponding amides using the conditions described above. The amides may then be oxidised using a suitable oxidising agent to give initially the mono-N-oxides (not shown) and then, following further oxidation, the di-N-oxides (3a) and (3b).
Examples of oxidising agents include:
• peroxycarboxylic acids such as wetα-chloroperbenzoic acid (mCPBA), peracetic acid/sodium acetate and diperoxymaleic acid (see Organic and Bioorganic Chem., 1973, 22, 2707-2713)
• sodium tungstate and hydrogen peroxide (Chem. Pharm Bull, 191 A, 22, 2097- 2100)
• peroxysulphuric acid (Caro's acid) and salts thereof such as potassium peroxymonosulphate (e.g. Oxone ®/dimethyldioxirane - J. Org. Chem., 1977, 1869-1871 and 3367-3369)
• dimethyldioxirane (Tetrahedron, 1997, 15877-15888)
• MeReO3 (Synlett., 2001, 2, 73-74)
• hydrogen peroxide, for example in the presence of molecular sieves (J. MoI. Cat., 2002, 109-120) or in combination with acetic acid or trifluoracetic acid (J. Med. Chem., 2003, 46, 169-182
• HOF-CH3CN (J. Org. Chem., 2006, 71, 5761-5765)
The oxidising agents set out above may also be used to oxidise compounds of formula (2) wherein Y1 and Y2 are both N to give compounds of the formula (2) wherein Y1 and Y2 are both N+-O-.
Compounds of the formula (3) wherein one of R2 and R3 is a group NR5R6 can be prepared by the synthetic route shown in Scheme 8.
Figure imgf000045_0001
Scheme 8
In Scheme 8, the nitro-azido-benzoic acid compound (44) is reacted with ammonia in a polar solvent such as methanol in the presence of EDC. The resulting compound is then heated to an elevated temperature (e.g. 180 0C) in a non-protic polar solvent such as sulpholane to bring about cyclisation to form the benzo-oxadiazole derivative (46). Reaction of the benzo-oxadiazole derivative (46) with cyanamide (NH2-CN) gives an aminobenzotriazine amide as a mixture of regioisomers (47) and (48) which can he separated by means of HPLC. The amino group at the 3-position of the benzotriazine ring can then be further functionalized according to methods well known to the skilled person, for example by acylation, alkylation or by arylation using a Buchwald cross- coupling reaction.
Compounds wherein R2 is NR5R6 wherein R5 is an aryl or heteroaryl group can be prepared by the reaction of a benzotriazin-3 -yl-amino compound of the formula (33) wherein R5 and R6 are both hydrogen with an aryl or heteroaryl bromide under Buchwald cross-coupling conditions. The reaction is carried out in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), together with a further ligand such as 9,9-dimethyl-4,5-bis(diphenylphosphino)- xanthene (Xantphos), a metal carbonate base such as caesium carbonate, and a non- protic solvent such as toluene. The reaction may be carried out in a sealed tube at an elevated temperature (e.g. approximately 100 0C). The resulting nitrile product can then be hydrolysed to the corresponding carboxamide using a mineral acid such as aqueous concentrated hydrochloric acid.
Once formed, one compound of the formula (1), (Ia), (2) or (3) or a protected derivative thereof, can be converted into another compound of the formula (1), (Ia), (2) or (3) by methods well known to the skilled person. Examples of synthetic procedures for converting one functional group into another functional group are set out in standard texts such as Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1- 17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8)).
In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
Compounds made by the foregoing methods may be isolated and purified by any of a variety of methods well known to those skilled in the art and examples of such methods include recrystallisation and chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC.
Pharmaceutical Formulations
While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound of the invention together with a pharmaceutically acceptable carrier, and optionally one or more additional excipients.
Accordingly, in another aspect, the invention provides a pharmaceutical composition comprising a compound of the formula (1) and a pharmaceutically acceptable carrier.
The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, VoI 21(2) 2004, p 201-230).
A drug molecule that is ionizable can be solubilized to the desired concentration by pH adjustment if the drug's pKa is sufficiently away from the formulation pH value. The acceptable range is pH 2-12 for intravenous and intramuscular administration, but subcutaneously the range is pH 2.7-9.0. The solution pH is controlled by either the salt form of the drug, strong acids/bases such as hydrochloric acid or sodium hydroxide, or by solutions of buffers which include but are not limited to buffering solutions formed from glycine, citrate, acetate, maleate, succinate, histidine, phosphate, tris(hydroxymethyl)- aminomethane (TRIS), or carbonate.
The combination of an aqueous solution and a water-soluble organic solvent/surfactant (i.e., a cosolvent) is often used in injectable formulations. The water-soluble organic solvents and surfactants used in injectable formulations include but are not limited to propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP; Pharmasolve), dimethylsulphoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60, and polysorbate 80. Such formulations can usually be, but are not always, diluted prior to injection.
Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, and polysorbate 80 are the entirely organic water-miscible solvents and surfactants used in commercially available injectable formulations and can be used in combinations with each other. The resulting organic formulations are usually diluted at least 2-fold prior to IV bolus or IV infusion.
Alternatively increased water solubility can be achieved through molecular complexation with cyclodextrins.
The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
The pharmaceutical formulation can be prepared by lyophilising a compound of Formula (1) or acid addition salt thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms. A typical process is to solubilise the compound and the resulting formulation is clarified, sterile filtered and aseptically transferred to containers appropriate for lyophilisation (e.g. vials). In the case of vials, they are partially stoppered with lyo-stoppers. The formulation can be cooled to freezing and subjected to lyophilisation under standard conditions and then hermetically capped forming a stable, dry lyophile formulation. The composition will typically have a low residual water content, e.g. less than 5% e.g. less than 1% by weight based on weight of the lyophile.
The lyophilisation formulation may contain other excipients for example, thickening agents, dispersing agents, buffers, antioxidants, preservatives, and tonicity adjusters. Typical buffers include phosphate, acetate, citrate and glycine. Examples of antioxidants include ascorbic acid, sodium bisulphite, sodium metabisulphite, monothioglycerol, thiourea, butylated hydroxytoluene, butylated hydroxyl anisole, and ethylenediaminetetraacetic acid salts. Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of /?αrø-hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzalkonium chloride and cetylpyridinium chloride. The buffers mentioned previously, as well as dextrose and sodium chloride, can be used for tonicity adjustment if necessary.
Bulking agents are generally used in lyophilisation technology for facilitating the process and/or providing bulk and/or mechanical integrity to the lyophilized cake. Bulking agent means a freely water soluble, solid particulate diluent that when co- lyophilised with the compound or salt thereof, provides a physically stable lyophilized cake, a more optimal freeze-drying process and rapid and complete reconstitution. The bulking agent may also be utilised to make the solution isotonic.
The water-soluble bulking agent can be any of the pharmaceutically acceptable inert solid materials typically used for lyophilisation. Such bulking agents include, for example, sugars such as glucose, maltose, sucrose, and lactose; polyalcohols such as sorbitol or mannitol; amino acids such as glycine; polymers such as polyvinylpyrrolidine; and polysaccharides such as dextran.
The ratio of the weight of the bulking agent to the weight of active compound is typically within the range from about 1 to about 5, for example of about 1 to about 3, e.g. in the range of about 1 to 2.
Alternatively they can be provided in a solution form which may be concentrated and sealed in a suitable vial. Sterilisation of dosage forms may be via filtration or by autoclaving of the vials and their contents at appropriate stages of the formulation process. The supplied formulation may require further dilution or preparation before delivery for example dilution into suitable sterile infusion packs.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
In one preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. In another preferred embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.
Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
Pharmaceutical compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.
Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
The solid dosage forms (eg; tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit ™ type polymer) can be designed to release the active component at a desired location within the gastrointestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations may be prepared in accordance with methods well known to those skilled in the art.
The pharmaceutical formulations may be presented to a patient in "patient packs" containing an entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
Examples of formulations for rectal or intra- vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
The compounds of the formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within this range, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).
For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.
The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
Methods of Treatment
It is envisaged that the compounds of the formula (1) and sub-groups as defined herein will be useful either as sole chemotherapeutic agents or, more usally, in combination therapy with chemotherapeutic agents or radiation therapy in the prophylaxis or treatment of a range of proliferative disease states or conditions. Examples of such disease states and conditions are set out above.
Particular examples of chemotherapeutic agents that may be co-administered with the compounds of formula (1) include: • Topoisomerase I inhibitors
• Antimetabolites
• Tubulin targeting agents
• DNA binder and topoisomerase II inhibitors • Alkylating Agents
• Monoclonal Antibodies.
• Anti-Hormones
• Signal Transduction Inhibitors
• Proteasome Inhibitors • DNA methyl transferases
• Cytokines and retinoids
• Other hypoxia triggered DNA damaging agents (e.g. Tirapazamine)
The compounds may also be administered in conjunction with radiotherapy.
The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a pulsatile or continuous manner.
The compounds of the invention will be administered in an effective amount, i.e. an amount which is effective to bring about the desired therapeutic effect. For example, the "effective amount" can be a quantity of compound which, when administered together with a chemotherapeutic agent to a subject suffering from cancer, slows tumour growth, ameliorates the symptoms of the disease and/or increases longevity. More particularly, when used in combination with radiation therapy, with a DNA- damaging drug or other anti-cancer drug, an effective amount of the PARP inhibitor of the invention is the quantity in which a greater response is achieved when the PARP inhibitor is co-administered with the DNA damaging anti-cancer drug and/or radiation therapy compared with when the DNA damaging anti-cancer drug and/or radiation therapy is administered alone. When used as a combination therapy, an "effective amount" of the DNA damaging drug and/or an "effective" radiation dose are administered to the subject, which is a quantity in which anti-cancer effects are normally achieved. The PARP inhibitors of the invention and the DNA damaging anticancer drug can be co-administered to the subject as part of the same pharmaceutical composition or, alternatively, as separate pharmaceutical compositions. When administered as separate pharmaceutical compositions, the PARP inhibitor of the invention and the DNA-damaging anti-cancer drug (and/or radiation therapy) can be administered simultaneously or at different times, provided that the enhancing effect of the PARP inhibitor is retained.
The amount of PARP inhibitor compound of the invention, and the DNA damaging anti-cancer drug and radiation dose administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors. Effective dosages for commonly used anti-cancer drugs and radiation therapy are well known to the skilled person.
The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, preferably a human.
A typical daily dose of the compound of formula (1) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of body weight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of body weight although higher or lower doses may be administered where required. The compound can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.
In one particular dosing schedule, a patient will be given an infusion of a compound for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.
More particularly, a patient may be given an infusion of a compound for periods of one hour daily for 5 days and the treatment repeated every three weeks.
In another particular dosing schedule, a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.
In a further particular dosing schedule, a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.
Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.
EXAMPLES
EXAMPLE 1
3-Amino-benzo[l,2,41triazine-5-carboχylic acid amide IA. 5-Bromo-l-oxy-benzo[l,2,41triazin-3-ylamine
Figure imgf000055_0001
A mixture of l-bromo-2-fluoro-3-nitro-benzene (5.0 mmol) and guanidine (20 mmol) in THF (20 ml) was heated at reflux overnight. The reaction mixture was then cooled to room temperature and diluted with water (50 ml) to precipitate out the title compound. The product was filtered and washed with water and dried.
IB. 3-Amino-benzori ,2,41triazine-5-carbonitrile
Figure imgf000056_0001
To a solution of 5-bromo-l-oxy-benzo[l,2,4]triazin-3-ylamine (1 mmol) in NMP (4 ml) was added CuCN (2.0 eq) and the reaction mixture was heated to 2000C for 30 minutes using microwave irradiation. The reaction mixture was poured into water and the resulting precipitate was filtered and washed with water. The aqueous layer was extracted three times with ethyl acetate and the combined organic phases were washed with brine twice. The crude product was purified by column chromatography eluting with a 0-100% gradient of 10% 7N NH3MeOH in DCM to afford the title compound. NMR (DMSO-d6): 8.53 (dd, IH), 8.37 (dd, IH), 7.55 (t, IH) LC/MS RT 1.37 - no ionisation
1C. 3-Amino-berizo[l,2,4]triazine-5-carboxyric acid amide
Figure imgf000056_0002
3-Amino-benzo[l,2,4]triazine-5-carbonitrile (150 mg) was treated with concentrated HCl and warmed to 50 0C overnight. The resulting mixture was concentrated and purified by RP-HPLC to afford the title compound. NMR (DMSO-d6): 9.60 (br s, IH), 8.57 (dd, IH), 8.40 (dd, IH), 8.09 (br s, 2H), 7.99 (br s, IH), 7.56 (t, IH). LC/MS RT 1.10 - no ionisation
EXAMPLE 2
S-M-Chloro-phenvD-l-oxy-quinoxaline-S-carboxylic acid amide 2 A. 2,3-Diamino-benzoic acid methyl ester
Figure imgf000057_0001
2-Amino-3-nitro-benzoic acid methyl ester (10 mmol) was dissolved in ethanol (20ml) and hydrogenated over 10% Pd/C catalyst overnight. Upon completion, the reaction mixture was filtered and washed with ethanol. The filtrate was concentrated to dryness to give the crude product which was used without further purification.
2B. 3-f4-Chloro-phenyl)-quinoxaline-5-carboxylic acid methyl ester & 2-C4-Chloro- phenyl)-quinoxaline-5-carboxylic acid methyl ester
Figure imgf000057_0002
To a suspension of (2,3-diamino-benzoic acid methyl ester) 3-(4-chloro-phenyl)-l-oxy- quinoxalme-5-carboxylic acid amide (332 mg, 2 mmol) in methanol (20 ml) was added triethylamine (2.8 ml, 20 mmol) and 4-chloro-phenacyl bromide (700 mg, 3 mmol) at room temperature. The mixture was stirred overnight and poured into a mixture of water and chloroform. The aqueous layer was separated and the organic layer was washed with brine and dried over magnesium sulphate. After evaporation of the solvent, the residue was purified by column chromatography on silica-gel eluting with dichloromethane-methanol to afford the product as a mixture of isomers.
2C. 3-r4-Chloro-phenyr)-quinoxaline-5-carboxylic acid amide & 2-(4-Chloro-phenylV quinoxaline-5-carboxylic acid amide
Figure imgf000058_0001
2Cii To a mixture of 3-(4-chloro-phenyl)-quinoxaline-5-carboxylic acid methyl ester and 2-
(4-chloro-phenyl)-quinoxaline~5-carboxylic acid methyl ester was added 7N NH3 in MeOH (5 ml) and the mixture was warmed to 1000C in a sealed tube overnight. The reaction mixture was then cooled to room temperature and the resulting precipitate was filtered and washed with methanol to afford 3-(4-chloro-phenyl)-quinoxaline-5- carboxylic acid amide. The filtrate was concentrated and purified by RP-HPLC and the later eluted peak isolated the alternative isomer 2-(4-chloro-phenyl)-quinoxaline-5- carboxylic acid amide.
EXAMPLE 3
3-(4-Chloro-phenylVl-oxy-quinoxaline-5-carboxylic acid amide
Figure imgf000058_0002
3-(4-Chloro-phenyl)-quinoxaline-5-carboxylic acid amide (120 mg) was suspended in a mixture of 30% peracetic acid (3 ml) and sodium acetate (200 mg). The mixture was heated at 60 0C for 3 days then allowed to cool to room temperature. The precipitate formed was then filtered, washed (with water) and dried to yield the title compound.
The 3-(4-chloro-phenyl)-l-oxy-quinoxaline-5-carboxylic acid amide can be oxidised to the di-N-oxide using an oxidising agent as described in the general synthesis section of this application. EXAMPLES 4 TO 43
By using the general methods described above, the following compounds may be prepared:
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0002
EXAMPLE 44 S-Phenylamino-benzor[^Λltriazine-S-carboxylic acid amide
Figure imgf000064_0001
44A. 3-Phenylamino-benzo|"l,2,41triazine-5-carbonitrile
A re-sealable microwave tube is charged with tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (0.1 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) (0.15 mmol), 3-amino-benzo[l,2,4]triazine-5-carbonitrile (1.0 mmol), Cs2CO3 (fine powder, 1.4 mmol), bromobenzene (1.0 mmol), and toluene (4 mL). The tube is capped and carefully subjected to three cycles of evacuation-backfilling with nitrogen. The tube is then immersed into a 100 0C oil bath and left overnight. After cooling, the mixture is diluted with THF5 filtered, concentrated, and subjected to chromatography to give the title compound.
44B. 3-Phenylamino-benzori,2,4~|triazine-5-carboxylic acid amide The product of Example 44 A is treated with aqueous concentrated hydrochloric acid as described in Example 1C to give the title compound.
PHARMACEUTICAL FORMULATIONS
EXAMPLE 45 (ϊ) Tablet Formulation
A tablet composition containing a compound of the formula (1) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.
(ii) Capsule Formulation A capsule formulation is prepared by mixing 100 mg of a compound of the formula (1) with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.
(lip Injectable Formulation I
A parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (1) in water containing 10% propylene glycol to give a concentration of active compound of 1.5 % by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.
(V) Injectable Formulation II
A parenteral composition for injection is prepared by dissolving in water a compound of the formula (1) (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules.
V) Injectable formulation III
A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilised by autoclaving.
vi) Injectable formulation IV A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg/ml. The vial is then sealed and sterilised by autoclaving.
(vii) Subcutaneous Injection Formulation A composition for sub-cutaneous administration is prepared by mixing a compound of the formula (1) with pharmaceutical grade corn oil to give a concentration of 5 mg/ml. The composition is sterilised and filled into a suitable container.
viii) Lyophilised formulation
Aliquots of formulated compound of formula (1) are put into 50 ml vials and lyophilized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (-45 0C). The temperature is raised to -10 0C for annealing, then lowered to freezing at -45 0C, followed by primary drying at +25 0C for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50 0C. The pressure during primary and secondary drying is set at 80 millitor.
EXAMPLE 46
PARP Inhibition Assay
The ability of the compounds of the invention to inhibit PARP was determined using an in vitro assay kit available from Trevigen, Gaithersburg, MD, USA.
By means of the assay, the PARP inhibiting activities of compounds of the invention were found to be as follows:
Figure imgf000066_0001
Equivalents
The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

Claims

1. A compound of the formula (1) :
Figure imgf000068_0001
or a salt, solvate or tautomer thereof; wherein:
Q is CN or CONH2 and is attached at either position "a" or position "b" on the benzene ring;
YMs N OrN+-O" ; Y2 is N or CR3; Y3 Is N Or N+-O" ; provided that when Y2 is CR3, then Y3 is N+-O" ; m is 0, 1 or 2;
R1 is halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the C1-4 alkyl and C1-4 alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy; when Y2 is N, then R2 is a group R4; and when Y2 is CR3, then one of R2 and R3 is R4 and the other of R2 and R3 is hydrogen, C1-4 alkyl, halogen or cyano;
R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7;
R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy; or R5 is a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from
O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7; R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7;
R7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R8; or a group Ra-Rb;
Ra is a bond, O5 CO, X1C(X2), C(X2JK1, X1C(X2JX1, S, SO, SO2, NR0, SO2NR0 Or NR0SO2;
Rb is: • hydrogen;
• a carbocyclic and heterocyclic group having from 3 to 12 ring members and being optionally substituted by one or more substituents R8;
• a C1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C^s non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R8; wherein one or more carbon atoms of the C1-12 hydrocarbyl group may optionally be replaced by O, S,
SO, SO2, NR0, X1C(X2), C(X^X1 or X1C(X^X1; R° is Rb, hydrogen or C1-4 hydrocarbyl; X1 is O, S or NR0; and X2 is =0, =S or =NR°; wherein R8 is selected from R7 provided that when the substituents R8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9; and
R9 is selected from R7 except that any carbocyclic or heterocyclic groups constituting or forming part of R9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; or a group Ra-Rbb; where Ra is as hereinbefore defined and Rbb is hydrogen or a C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 saturated hydrocarbylamino and wherein one or more carbon atoms of the C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X^X1 or X1C(X^X1.
2. A compound according to claim 1 of the formula (1a):
Figure imgf000070_0001
or a salt, solvate or tautomer thereof; wherein: the CONH2 moiety is attached at either position "a" or position "b" on the benzene ring;
Y1 Is N Or N+-O" ; Y2 is N or CR3; Y3 is N Or N+-O" ; provided that when Y2 is CR3, then Y3 is N+-O" ; m is 0, 1 or 2;
R1 is halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the C1-4 alkyl and C1-4 alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy; when Y2 is N, then R2 is a group R4; and when Y2 is CR3, then one of R2 and R3 is R4 and the other of R2 and R3 is hydrogen, C1-4 alkyl, halogen or cyano;
R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7; R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy;
R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7;
R7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-Cϊ-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R8; or a group Ra-Rb; Ra is a bond, O, CO, X1C(X2),
Figure imgf000071_0001
S, SO, SO2, NR0,
SO2NR0 Or NR0SO2;
Rb is:
• hydrogen;
• a carbocyclic and heterocyclic group having from 3 to 12 ring members and being optionally substituted by one or more substituents R8;
• a C1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R ; wherein one or more carbon atoms of the C1-I2 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X^X1 or X1C(X^X1; R° is Rb, hydrogen or C1-4 hydrocarbyl;
X1 Is O, S or NR0; and X2 is =0, =S or =NR°; wherein R8 is selected from R7 provided that when the substituents R8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9; and R9 is selected from R7 except that any carbocyclic or heterocyclic groups constituting or forming part of R9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifiuoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; or a group Ra-Rbb; where Ra is as hereinbefore defined and Rbb is hydrogen or a C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 saturated hydrocarbylamino and wherein one or more carbon atoms of the C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X^X1 or X1C(X^X1.
3. A compound according to claim 2 having the formula (2):
Figure imgf000072_0001
or a salt, solvate or tautomer thereof; wherein: the CONH2 moiety is attached at either position "a" or position "b" on the benzene ring;
Y1 Is N Or N+-O" ; Y3 Is N Or N+-O" ; m is 0, 1 or 2; R1 is halogen, cyano, C1-4 alkyl or C^4 alkoxy wherein the C1-4 alkyl and
C1-4 alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy; R2 is a group R4;
R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7; R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy;
R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7;
R7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1_4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to 12 ring members and optionally substituted by one or more substituents R8; or a group Ra-Rb; Ra is a bond, O, CO, X1C(X2),
Figure imgf000073_0001
S, SO, SO2, NRC,
SO2NRc or NRcSO2;
Rb is:
• hydrogen;
• a carbocyclic and heterocyclic group having from 3 to 12 ring members and being optionally substituted by one or more substituents R8;
• an acyclic C1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R8; wherein one or more carbon atoms of the acyclic C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X! or X1C(X^X1; R° is Rb, hydrogen or C1-4 hydrocarbyl;
X1 is O, S or NR0; and X2 is =O, =S or =NR°; wherein R8 is selected from R7 provided that when the substituents R8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9; and R9 is selected from R7 except that any carbocyclic or heterocyclic groups constituting or forming part of R9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; or a group Ra-Rbb; where Ra is as hereinbefore defined and Rbb is hydrogen or an acyclic C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 saturated hydrocarbylamino and wherein one or more carbon atoms of the C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC,
X1C(X2), C(X^X1 or X1C(X^X1.
4. A compound according to claim 2 having the formula (3):
Figure imgf000074_0001
or a salt, solvate or tautomer thereof; wherein: the CONH2 moiety is attached at either position "a" or position "b" on the benzene ring;
Y^s N Or N+-O" ; m is 0, 1 or 2; R1 is halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the C1-4 alkyl and
CM alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy; one of R2 and R3 is R4 and the other of R2 and R3 is hydrogen, C1-4 alkyl, halogen or cyano;
R4 is NR5R6 or a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7; R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy;
R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7;
R7 is halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; a carbocyclic or heterocyclic group having from 3 to
12 ring members and optionally substituted by one or more substituents R ; or a group Ra-Rb; Ra is a bond, O, CO, X1C(X2),
Figure imgf000075_0001
S, SO, SO2, NR0,
SO2NR0 Or NR0SO2; Rb is:
• hydrogen;
• a carbocyclic and heterocyclic group having from 3 to 12 ring members and being optionally substituted by one or more substituents R ;
• a C1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members optionally substituted by one or more substituents R8; wherein one or more carbon atoms of the C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2)Xl or X1C(X^X1; R° is Rb, hydrogen or C1-4 hydrocarbyl;
X1 is O, S or NR0; and X2 is =O, =S or =NR°; wherein R8 is selected from R7 provided that when the substituents R8 contain a carbocyclic or heterocyclic group having from 3 to 12 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R ; and R9 is selected from R7 except that any carbocyclic or heterocyclic groups constituting or forming part of R9 may not bear a substituent containing or consisting of a carbocyclic or heterocyclic group but may optionally bear one or more substituents selected from halogen; hydroxy; trifluoromethyl; cyano; nitro; amino; mono- or di-C1-4 hydrocarbylamino; or a group Ra-Rbb; where Ra is as hereinbefore defined and Rbb is hydrogen or a C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 saturated hydrocarbylamino and wherein one or more carbon atoms of the C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X^X1 or X1C(X^X1.
5. A compound according to claim 1 wherein Q is attached at position "a" on the benzene ring.
6. A compound according to claim 1 wherein Q is attached at position "b" on the benzene ring.
7. A compound according to any one of claims 2 to 4 wherein the CONH2 moiety is attached at position "a" on the benzene ring.
8. A compound according to any one of claims 2 to 4 wherein the CONH2 moiety is attached at position "b" on the benzene ring.
9. A compound according to any one of the preceding claims wherein m is O or 1.
10. A compound according to claim 9 wherein m is 0 and hence R1 is absent.
11. A compound according to any one of claims 1 to 9 wherein m is 1, 2 or 3 and each substituent R1 is independently selected from halogen, cyano, C1-4 alkyl or C1-4 alkoxy wherein the Ci-4 alkyl and CM alkoxy moieties are each optionally substituted by fluorine or C1-2 alkoxy.
12. A compound according to claim 11 wherein each R1 is independently halogen, cyano, C1-4 alkyl or C1-4 alkoxy, cyano, C1-4 alkyl or Ci-4 alkoxy.
13. A compound according to claim 12 wherein each R1 is independently selected from methyl, ethyl, isopropyl, chlorine, fluorine, bromine, cyano, methoxy, ethoxy and isopropoxy.
14. A compound according to any one of claims 11 to 13 wherein R1 is attached to a carbon atom between positions "a" and "b" on the benzene ring.
15. A compound according to claim 3 and any claim dependent thereon wherein Y1 and Y3 are both N+-O".
16. A compound according to claim 3 and any claim dependent thereon wherein Y1 and Y3 are both N.
17. A compound according to claim 3 and any claim dependent thereon wherein Y1 is N and Y3 is N+-O".
18. A compound according to claim 3 and any claim dependent thereon wherein Y1 is N+-O" and Y3 is N.
19. A compound according to any one of the preceding claims wherein Y2 is N, R2 is a group R4 wherein R4 is a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7.
20. A compound according to claim 19 wherein the carbocyclic or heterocyclic rings are monocyclic non-aromatic or aryl or heteroaryl rings of 5 or 6 ring members containing up to 2 heteroatomic ring members selected from O, N and S.
21. A compound according to claim 20 wherein the carbocyclic or heterocyclic rings are selected from (a) optionally substituted aryl and heteroaryl rings selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, diazinyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and pyrazolyl; and (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, morpholinyl, thiomorpholinyl and S-oxide and S,S-dioxides thereof, tetrahydrofuranyl and tetrahydropyranyl.
22. A compound according to claim 21 wherein the carbocyclic or heterocyclic rings are selected from optionally substituted phenyl, piperidinyl, piperazinyl and morpholinyl rings.
23. A compound according to any one of claims 19 to 22 wherein the carbocyclic and heterocyclic rings are substituted by 0, 1, 2 or 3 substituents, for example 0, 1 or 2 substituents.
24. A compound according to any one of claims 1 to 18 wherein R4 is NR5R6, R5 is hydrogen, C1-4 alkyl or C1-4 acyl wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents selected from halogen, hydroxy and C1-2 alkoxy; and R6 is hydrogen, C1-4 alkyl or C1-4 acyl, wherein the C1-4 alkyl or C1-4 acyl moieties are each optionally substituted by one or more substituents R7.
25. A compound according to claim 24 wherein R5 is hydrogen or methyl and R6 is hydrogen, C1-4 alkyl or C1-4 acyl optionally substituted by one or more substituents R7.
26. A compound according to claim 24 or claim 25 wherein R6 is optionally substituted C1-4 alkyl or C1-4 acyl and there are 0, 1, 2 or 3 substituents R7, for example 0, 1 or 2 substituents, and more usually 0 or 1 substituent.
27. A compound according to claim 1 and any claim dependent thereon wherein R5 is a carbocyclic or heterocyclic ring of 3 to 12 ring members and containing up to 4 heteroatoms selected from O, N and S, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents R7.
28. A compound according to claim 27 wherein the carbocyclic or heterocyclic ring is a monocyclic 5- or 6-membered heteroaryl or aryl group.
29. A compound according to claim 28 wherein the carbocyclic or heterocyclic ring is a phenyl ring.
30. A compound according to any one of the preceding claims wherein the optional substituents R7 for the carbocyclic or heterocyclic rings or the group R6 is selected from R7a wherein R7a is halogen; hydroxy; trifluoromethyl; cyano; amino; mono- or di-C1-4 alkylamino; monocyclic carbocyclic or heterocyclic groups having from 3 to 7 ring members and optionally substituted by one or more substituents R8a; or a group Ra -Rb ;
Ra' is a bond, O, CO, X1C(X2), C(X2)X!, X1CQf)X1, S, SO, SO2, NR0', SO2NR°Or NR°'SO2;
Rb' is: • hydrogen;
• a monocyclic carbocyclic and heterocyclic group having from 3 to 7 ring members and being optionally substituted by one or more substituents R8a;
• a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R8; wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NR0', X1C(X2), C(X^X1 or X1CQf)X1;
R° is Rb , hydrogen or C1-4 hydrocarbyl; X1 Is O, S or NR0'; and X2 is =0, =S or =NRC>; wherein R8a is selected from R7a provided that when the substituents R8a contain a carbocyclic or heterocyclic group having from 3 to 7 ring members, the said carbocyclic or heterocyclic group can be unsubstituted or substituted by one or more substituents R9a; and
R9a is selected from R7a but is other than a carbocyclic or heterocyclic group.
31. A compound according to claim 30 wherein the optional substituents R7 for the carbocyclic or heterocyclic rings or the group R6 are selected from R7b; wherein R7b is chlorine; fluorine; bromine; hydroxy; trifluoromethyl; cyano; amino; mono- or di-C1-4 alkylamino; monocyclic carbocyclic or heterocyclic groups having from 3 to 7 ring members and optionally substituted by one or more substituents R8a; or a group Ra -R ; Ra" is a bond, O, CO, OC(O), NR°"(CO), C(O)NR0", OC(O)O,
OC(O)NR0", NR°"(C0)0, S, SO, SO23 NR0", SO2NR0" or NR°"SO2; Rb" is:
• hydrogen;
• a monocyclic carbocyclic and heterocyclic group having from 3 to 7 ring members of which O, 1 or 2 are heteroatom ring members selected from
O, N and S, and wherein the monocyclic carbocyclic and heterocyclic group is optionally substituted by one or more substituents R8b;
• a C1-8 alkyl group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R8b; wherein one or more carbon atoms of the C1-8 alkyl group may optionally be replaced by O, S, SO, SO2, CO, OC(O), NR°"(C0), C(O)NR0", OC(O)O, OC(O)NR0", NR°"(C0)0, NR0", SO2NR0" or NR°"SO2; and
R° is hydrogen or Ci-2 alkyl; wherein R8b is selected from R7a provided that R8a is other than a carbocyclic or heterocyclic group.
32. A compound according to claim 31 wherein the optional substituents R7 for the carbocyclic or heterocyclic rings or the group R6 are selected from R7c, where
R70 is:
■ chlorine;
■ fluorine;
■ bromine; ■ hydroxy;
■ trifluoromethyl; ■ cyano;
■ amino;
■ mono- or di-C1-4 alkylamino;
■ monocyclic carbocyclic or heterocyclic groups selected from phenyl, piperazinyl, piperidinyl, and morpholinyl, each being optionally substituted by one or more substituents R8°; or a group R aa'" -R1 wherein Ra is a bond, O, CO, OC(O), NRC (CO), C(O)NR0 , OC(O)O, OC(O)NR0'", NR°"'(CO)O, NR0'"; Rb>" is: o hydrogen; o a monocyclic carbocyclic or heterocyclic groups selected from phenyl, piperazinyl, piperidinyl, and morpholinyl, each being optionally substituted by one or more substituents R80; o a C1-6 alkyl group optionally substituted by one or more substituents selected from hydroxy; oxo; chlorine; fluorine; bromine; cyano; carboxy; amino; mono- or di- C1-4 alkylamino; and monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members optionally substituted by one or more substituents R8°; wherein one or more carbon atoms of the C1-6 alkyl group may optionally be replaced by O, CO, OC(O), NR°'"(C0), C(O)NR0'", OC(O)NR0'", NR°"'(C0)0, NR0'", and
R0 is hydrogen or C1-2 alkyl; wherein R8c is selected from R7° provided that R8c is other than a carbocyclic or heterocyclic group.
33. A compound according to any one of the preceding claims wherein R7 is Cj-4 alkyl, chlorine, fluorine, C1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, hydroxy, amino-C1-2 alkyl, mono- or dimethylamino- C1-2 alkyl, piperazinylcarbonyl, morpholinylcarbonyl, piperazinyl-C^ alkyl, morpholinyl-C1-2 alkyl, piperidinyl-Ci.2 alkyl,, pyrrolidinyl-Ci-2 alkyl, hydroxy- C1-2 alkyl, methoxy-C1-2 alkyl, cyano-C1-2 alkyl or C1-4 alkylsulphonyl.
34. A compound according to claim 4 and any claim dependent thereon wherein one of R2 and R3 is R4 and the other of R2 and R3 is hydrogen, methyl, ethyl or cyano.
35. A compound according to claim 4 and any claim dependent on claim 4 wherein Y1 is N.
36. A compound according to claim 4 and any claim dependent on claim 4 wherein Y1 is N+-O" .
37. A compound according to claim 4 and any claim dependent on claim 4 wherein the group CONH2 is attached at location "a" on the benzene ring and Y1 is N.
38. A compound according to any one of the preceding claims having a one electron reduction potential E(Y) of between -300 mV and -510 mV, and more preferably from -450 mV to -510 mV.
39. A compound according to any one of claims 1 to 38 for use as an anti-cancer agent.
40. The use of a compound according to any one of claims 1 to 38 for the manufacture of a medicament for the treatment of cancer.
41. A method of treating a cancer, which method comprises administering to a subject need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 38, optionally together with another anticancer agent or radiation therapy.
42. A compound according to any one of claims 16 to 18 and any claim dependent thereon for use as a PARP inhibitor.
43. A compound according to any one of claims 1 to 38, in the form of an N-oxide or di-N-oxide for use as a DNA damaging agent in hypoxic tumour cells.
44. A method of causing DNA damage in hypoxic tumour cells, which method comprises bringing a compound according to any one of claims 1 to 38 in the form of an N-oxide or di-N-oxide into contact with the hypoxic tumour cells.
45. A compound according to any one of claims 1 to 38 for use in enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer.
46. The use of a compound according to any one of claims 1 to 38 for the manufacture of a medicament for enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer.
47. A method for the prophylaxis or treatment of a proliferative disease such as cancer, which method comprises administering to a patient in combination with radiotherapy or chemotherapy a compound according to any one of claims 1 to 38.
48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38 and a pharmaceutically acceptable carrier.
49. A compound according to any one of claims 1 to 38 for use in medicine.
50. A compound according to any one of claims 1 to 38 for use in the treatment of disease states and conditions where inhibition of PARP has a beneficial effect.
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