EP1742911A1 - 3,4-disubstituted maleimides for use as vascular damaging agents - Google Patents

3,4-disubstituted maleimides for use as vascular damaging agents

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Publication number
EP1742911A1
EP1742911A1 EP05738031A EP05738031A EP1742911A1 EP 1742911 A1 EP1742911 A1 EP 1742911A1 EP 05738031 A EP05738031 A EP 05738031A EP 05738031 A EP05738031 A EP 05738031A EP 1742911 A1 EP1742911 A1 EP 1742911A1
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European Patent Office
Prior art keywords
formula
compound
group
mmol
alkyl
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EP05738031A
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German (de)
French (fr)
Inventor
Jean-Claude AstraZeneca Pharma ARNOULD
Craig Steven AstraZeneca Pharma HARRIS
Francis Thomas AstraZeneca R & D Alderely BOYLE
Keith Hopkinson AstraZeneca R & D Alderley GIBSON
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AstraZeneca AB
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AstraZeneca AB
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Priority to EP05738031A priority Critical patent/EP1742911A1/en
Publication of EP1742911A1 publication Critical patent/EP1742911A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 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 other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • 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
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to vascular damaging agents and their uses.
  • vascular damaging agents relate to certain compounds which may be of use as vascular damaging agents, to methods for preparing the compounds, to their use as medicaments (including methods for the treatment of angiogenesis or disease states associated with angiogenesis) and to pharmaceutical compositions containing them.
  • the invention also relates to the use of such compounds in the manufacture of medicaments for the production of anti-angiogenic and/or. anti- vascular effects.
  • Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function.
  • Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1 : 27-31). Formation of new vasculature by angiogenesis is a key pathological feature of several diseases (J. Folkman, New England Journal of Medicine 333, 1757-1763 (1995)).
  • Neovascularisation is also a clinical feature of skin lesions in psoriasis, of the invasive pannus in the joints of rheumatoid arthritis patients and of atherosclerotic plaques. Retinal neovascularisation is pathological in macular degeneration and in diabetic retinopathy. Reversal of neovascularisation by damaging the newly-formed vascular endothelium is therefore expected to have a beneficial therapeutic effect.
  • Such vascular- damaging activity would clearly be of value in the treatment of disease states associated with angiogenesis such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • angiogenesis such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • Ar 1 is selected from phenyl, heteroaryl or heterocyclyl;
  • Ar 2 is selected from phenyl or heteroaryl;
  • Ar 3 is selected from phenyl or a monocyclic heteroaryl ring comprising between 1 and 3 heteroatoms selected fromN, O or S;
  • R 1 is selected from hydrogen, -C(O)-R 2 , -C(O)-O-R 2 , -C(O)N(R 4 )-R 2 and -CH 2 -R 2 , wherein the group N(R 4 )-R 2 may optionally form a 4-6 membered heterocyclic ring;
  • R 2 is selected from: hydrogen, halo, cyano, amino, hydroxy, -SO 3 , d- 6 alkyl, C ⁇ .
  • R 3 is selected from hydroxy, amino, carbamoyl, -SO 3 , phosphonoxy, -C(O)-O-R 4 , and -N(R 4 )R 5 , wherein the group - N(R 4 )R 5 may optionally form a 4-6 membered heterocyclic ring;
  • R 4 and R 5 are independently selected from: hydrogen, C ⁇ - 4 alkyl and C(O)-R 6 , R 6 is C ⁇ alkyl optionally substituted with carboxy or amino;
  • R 7 is selected from halo, hydroxy, nitro, amino,
  • R is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, C ⁇ - 4 alkyl, liydroxyC M alkyl, aminoC M alkyl, C ⁇ - 4 alkoxy and Ci ⁇ alkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified;
  • R 9 is selected from: cyano, halo and nitro;
  • R 10 is selected from hydrogen or Ci ⁇ alkyl;
  • p is an integer from 0 to 3;
  • q is an integer from 0 to 3;
  • r is an integer from 1 to 3; or a salt thereof.
  • R 7 when p is 0, all positions on the AR 1 ring are substituted by hydrogen, an analogous notation applies to AR 2 and AR 3 when q is 0.
  • the use of the term (R 7 ) p when p is between 1 and 3, 7 1 means that there are 1, 2 or 3 R substituents on the Ar ring, which when p is 2 or 3 can be the same group or different groups.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable diluent or carrier.
  • Compounds of Formula (I) have anti-angiogenic activity by virtue of their vascular damaging activity.
  • a compound of Formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof for the manufacture of a medicament to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis.
  • a method of treatment, in a warm-blooded animal, to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.
  • a therapeutically (including prophylactically) effective amount of a compound of Formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.
  • Compounds of Formula (I) are believed to inhibit the polymerization of tubulin which results in their vascular damaging activity.
  • a compound of Formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof in the manufacture of a medicament for the inhibition of tubulin polymerization.
  • a method of treatment, in a warm-blooded animal, by inhibiting tubulin polymerization comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.
  • a warm-blooded animal is a human.
  • Examples of disease states associated with angiogenesis are solid tumours, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • a preferred disease state associated with angiogenesis is solid tumours.
  • Preferred solid tumours include colon, lung, breast, brain ovary, prostate,skin and metastatic tumours such as live metastases.
  • heteroaryl refers to a 4-10 membered aromatic mono or, bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible tlirough the 1 -nitrogen of a pyrazole ring.
  • heteroaryl preferably refers to a 5-10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring.
  • heteroaryl refers to a 5 or 6 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring.
  • Examples of 5- or 6-membered heteroaryl ring systems include pyrrole, furan, imidazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, 1,2,4 oxadiazole, isothiazole, thiazole, 1,2,4-triazole and thiophene.
  • 5- or 6-membered heteroaryl ring systems include pyrrole, furan, imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, 1,2,4 oxadiazole, isothiazole, thiazole and thiophene.
  • heteroaryl refers to a 9 or 10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring.
  • a 9 or 10 membered bicyclic heteroaryl ring system is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring.
  • Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, 1,3-benzodioxole, indole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
  • 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, indole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
  • heterocyclyl refers to a 5-10 membered saturated or partially saturated mono or bicyclic ring containing up to 5 heteroatoms selected from nitrogen, oxygen or sulphur linked via ring carbon atoms or ring nitrogen atoms.
  • Examples of 'heterocyclyl' include tetrahydrofuranyl, 2,3-dihydro-4H-pyran, pyrrolinyl, pyrrolidinyl, 1,3-thiazolidine, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, dihydropyrimidinyl and azepane.
  • Particular examples of 'heterocyclyl' include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl and dihydropyrimidinyl.
  • carbocyclyl refers to a totally saturated or partially saturated mono, bi or tri cyclic 3-10 membered carbon ring.
  • carbocychc rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo-octane, adamantyl or 2,3-dihydroindene.
  • aryl refers to phenyl or naphthyl.
  • halo refers to fluoro, chloro, bromo or iodo.
  • carbamoyl refers to the group -CONH 2 .
  • amino acid residue is defined as that derived from the coupling of an L-amino acid with an amino group via an amide bond. This bond can either be formed via a carboxylate group on the amino acid backbone or via a side chain carboxylate group, preferably via a carboxylate group on the amino acid backbone.
  • Amino acid residues include those derived from natural and non-natural amino acids, preferably natural amino acids and include ⁇ -amino acids ⁇ -amino acids and ⁇ -amino acids. For the avoidance of doubt amino acids include those with the generic structure:
  • amino acid also includes amino acid analogues which have additional methylene groups within the amino acid backbone, for example ⁇ -alanine and amino acids which are not naturally occurring such as cyclohexylalanine.
  • Preferred amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparaginine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, ⁇ -alanine and ornithine.
  • More preferred amino acids include glutamic acid, serine, threonine, arginine, glycine, alanine, ⁇ -alanine and lysine.
  • Especially preferred amino acids include glutamic acid, serine, and glycine.
  • Basic functions include: amino, morpholino, piperidino, piperazino, pyrrolidino, amino acids and imidazolino.
  • Acidic functions include: carboxy, sulphonic acid, phosphate, sulphate and acid mimetics such as tetrazolyl.
  • Hydrophilic groups include hydroxyl.
  • Suitable R 7 groups wherein hydroxy is esterf ⁇ ed include: C ⁇ - 6 alkanoyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, heteroarylcarbonyloxy wherein the Ri group is optionally substituted with between 1 and 3 groups selected from C M alkanoylC M alkyl, C M alkanoylheterocyclyl, hydroxy, hydroxyC M alkyl, carboxy, carboxyphenyl, phosphono, phosphonoCi ⁇ alkyl, amino, aminoC M alkyl, N-C all-ylamino, N,N-diC ⁇ -- ⁇ alkylamino, carbamoyl, carbamoylC M alkyl, heterocyclyl, heterocyclylC alkyl, heterocycly
  • R groups wherein hydroxy is esterfied include: carboxypentanoyloxy , 4-carboxyphenylpropanoyloxy , 4-(N-methylpiperizin- 1 - ylethy l)pheny lcarbonyloxy , 4-(piperizin- 1 -ylethy l)pheny lcarbonyloxy ,
  • R groups wherein hydroxy is esterfied include:
  • C ⁇ - 4 alkyl and d- ⁇ alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as 'propyl' are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as 'isopropyl' are specific for the branched-chain version only.
  • An analogous convention applies to other generic terms. Examples of C ⁇ .
  • alkyl include methyl, ethyl, propyl, isopropyl, .yec-butyl and tert-butyl;
  • examples of aminoC ⁇ - 4 alkyl include aminomethyl, aminoethyl or aminopropyl;
  • examples of hydroxy Ci ⁇ alkyl include hydroxymethyl, hydroxyethyl,
  • examples of arylC ⁇ - 4 alkyl include benzyl and phenethyl; examples of cycloalkylCi jalkyl include cyclopropylethyl, cyclobutylmethyl and cyclohexylpropy ; examples of heterocyclylC 1 .
  • Examples of C 4 alkyl include piperazinylmethyl, piperazinylethyl, mo ⁇ holinylmethyl or morpholinylethyl;
  • Examples of C 2 - 6 alkenyl include allyl and 2-butenyl;
  • examples of C ⁇ - 4 aIkoxy include methoxy, ethoxy and propoxy;
  • examples of C ⁇ - 4 alkanoyl include formyl or propanoyl;
  • examples of C ⁇ - 6 alkanoyloxy include propanoyloxy or butanoyloxy.
  • the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting and/or reversing and/or alleviating the symptoms of angiogenesis and/or any disease states associated with angiogenesis.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, activity of these compounds may be evaluated using the standard laboratory techniques referred to hereinafter.
  • the invention also relates to any and all tautomeric forms of the compounds of the different features of the invention that possess the property of inhibiting and/or reversing and/or alleviating the symptoms of angiogenesis and/or any disease states associated with angiogenesis.
  • certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the property of inl ibiting and/or reversing and/or alleviating the symptoms of angiogenesis and/or any disease states associated with angiogenesis.
  • the compounds of Formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I).
  • pro-drugs include in- vivo hydrolysable esters of a compound of the Formula (I).
  • Various forms of pro-drugs are known in the art.
  • pro-drug derivatives see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H.
  • An in- vivo hydroly sable ester of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include C ⁇ - 6 alkoxymethyl esters for example methoxymethyl, C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-scycloalkoxycarbonyloxyQ- ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci_ 6 alkoxycarbonyloxy ethyl esters.
  • An in- vivo hydroly sable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in- vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically-acceptable salt of a benzoxazinone derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a preferred group of values of AR 1 in each feature of the invention includes phenyl, a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl.
  • a further preferred group of values for AR 1 in each feature of the invention includes: phenyl, a 6 membered heteroaryl or a 6 membered heterocyclyl.
  • a yet further preferred group of values for AR 1 in each feature of the invention includes: phenyl, a 6 membered heteroaryl or a 6 membered heterocyclyl, wherein the heteroaryl or heterocyclyl rings contain 1-2 heteroatoms selected from nitrogen.
  • a yet further preferred group of values for AR 1 in each feature of the invention includes: phenyl, pyridyl and piperidinyl.
  • a most preferred value for AR 1 in each feature of the invention is phenyl.
  • a preferred group of values of AR in each feature of the invention includes phenyl or 5-6 membered heteroaryl.
  • a further preferred group of values for AR 2 in each feature of the invention includes: phenyl or 6 membered heteroaryl.
  • a yet further preferred group of values for AR 1 in each feature of the invention includes: phenyl or 5-6 membered heteroaryl wherein the heteroaryl ring contain 1-2 heteroatoms selected from nitrogen.
  • a yet further preferred group of values for AR 2 in each feature of the invention includes: phenyl and pyridyl.
  • a most preferred value for AR is phenyl.
  • a preferred group of values of AR in each feature of the invention includes phenyl or 6 membered monocyclic heteroaryl.
  • a further preferred group of values of AR 3 in each feature of the invention includes phenyl, pyridyl and pyrimidinyl.
  • a most preferred value of AR 3 in each feature of the invention is phenyl.
  • a preferred group of values of R 1 in each feature of the invention includes hydrogen, -C(O)N(R 4 )-R 2 , -CH 2 -R 2 , and -C(O)-O-R 2 .
  • a more preferred group of values of R 1 in each feature of the invention includes hydrogen and -CH 2 -R 2 .
  • Most preferably R 1 is hydrogen.
  • a preferred group of values for R 2 in each feature of the invention is hydrogen,
  • a further preferred group of values for R 2 in each feature of the invention is hydrogen, C ⁇ - 6 alkyl optionally substituted by one or more groups selected from R 3 , 6-membered heterocyclyl and 6-membered heterocyclylC M alkyl.
  • a yet further preferred group of values for R in each feature of the invention is hydrogen, C ⁇ aUcyl optionally substituted by R or heterocyclylC ⁇ - 4 alkyl.
  • a most preferred group of values for R in each feature of the invention is hydrogen, methyl substituted by one R group, t-butyl or piperidin-1-ylmethyl.
  • a preferred group of values for R 3 in each feature of the invention is amino, hydroxy and phosphonoxy.
  • a most preferred value for R 3 is phosphonoxy.
  • a preferred group of values for R 4 in each feature of the invention is hydrogen or methyl, most preferably hydrogen.
  • a preferred group of values for R 5 in each feature of the invention is hydrogen or methyl, most preferably hydrogen.
  • a preferred group of values for R 6 in each feature of the invention is hydrogen or methyl, most preferably hydrogen.
  • a preferred group of values for R 7 in each feature of the invention is hydroxy, nitro, amino, halo, phosphonooxy, wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified.
  • a further preferred group of values for R 7 in each feature of the invention is hydroxy, nitro, amino, halo, ⁇ alkoxy wherein the amino group is optionally substituted by an amino acid residue.
  • a yet further preferred group of values for R in each feature of the invention is hydroxy, nitro, amino, glutamyl-NH-, seryl-NH-, alanyl-NH- or glycyl-NH-.
  • a yet further preferred group of values for R in each feature of the invention is hydroxy, nitro, amino or glutamyl-NH-. Most preferably R 7 is hydrogen.
  • a preferred group of amino acids in each feature of the invention when R 7 is amino substituted by an amino acid residue include: glutamic acid, serine, threonine, arginine, glycine, alanine, ⁇ -alanine and lysine.
  • a preferred group of values for R 8 in each feature of the invention is selected from hydrogen or methyl, preferably hydrogen.
  • a preferred group of values for R 9 in each feature of the invention is selected from hydrogen or methyl, preferably hydrogen.
  • a preferred group of values for R 10 in each feature of the invention is selected from hydrogen or C h alky!.
  • a further preferred group of values for R 10 in each feature of the invention is selected from hydrogen or methyl.
  • a most preferred value for R 10 in each feature of the invention is hydrogen.
  • a preferred group of values for p in each feature of the invention is 0, 1 or 2, further preferably p is 1 or 2, most preferably p is 1.
  • a preferred group of values for q in each feature of the invention is 0 or 1, most preferably q is 0.
  • a preferred group of values for r in each feature of the invention is 1 or 2, most preferably r is 1.
  • a preferred group of compounds of each feature of the invention described herein, comprise compounds of Formula (II)
  • Ar 1 is selected from phenyl, heteroaryl or heterocyclyl;
  • Ar 2 is selected from phenyl or heteroaryl;
  • Ar 3 is selected from phenyl or a monocyclic heteroaryl ring comprising between 1 and 3 heteroatoms selected from N, O or S;
  • R 1 is selected from hydrogen, -C(O)-R 2 , -C(O)-O-R 2 , -C(O)N(R 4 )-R 2 and -CH 2 -R 2 , wherein the group N(R 4 )-R 2 may optionally form a 4-6 membered heterocyclic ring;
  • R 2 is selected from: hydrogen, halo, cyano, amino, hydroxy, -SO 3 , C ⁇ 6 alkyl, C ⁇ alkoxy, Ci.
  • R is selected from C h alky 1, CMalkoxy, C M alkanoyl, hydroxy, amino, carbamoyl, -SO 3 , phosphonoxy, -C(O)-O-R 4 , and -N(R )R 5 , wherein the group - N(R 4 )R 5 may optionally form a 4-6 membered heterocyclic ring;
  • R 4 and R 5 are independently selected from: hydrogen, C M alkyl and C(O)-R 6 , R 6 is C M alkyl optionally substituted with carboxy or amino;
  • R is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, C M alkyl, hydroxyC M alkyl, aminoC M alkyl, CMalkoxy and C ⁇ - 4 alkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified;
  • R is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, C M alkyl, hydroxyC M alkyl, aminoC ⁇ . 4 alkyl, CMalkoxy and CMalkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified;
  • R 9 is selected from: cyano, halo and nitro;
  • R 10 is selected from hydrogen or CM lkyl;
  • X is selected from -N(R 10 )-;
  • Y is-O-, p is an integer from 0 to 3; q is an integer from 0 to 3; r is an integer from 0, 1 or 2; or a salt thereof.
  • a preferred group of compounds of each feature of the invention described herein, comprise compounds of Formula (III)
  • Ar is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl; Ar is selected from phenyl or 5-6 membered heteroaryl; R 1 is selected from hydrogen, C ⁇ - 6 alkyl, C M alkoxycarbonyl, hydroxyC ⁇ - 6 alkyl, aminoCi- ⁇ alkyl, heterocyclylC ⁇ .
  • R 7 is selected from halo, hydroxy, nitro, amino, phosphonooxy, and wherein the amino group is optionally substituted by an amino acid residue;
  • R 10 is hydrogen or C M alkyl;
  • X is selected from -N(R 10 )-;
  • Y is selected from -O-,
  • p is an integer from 0 to 3; or a salt thereof.
  • a pharmaceutical composition comprising a compound of Formula (II) or Formula (III) or pharmaceutically- acceptable salt thereof, and a pharmaceuticaHy-acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (II) or Formula (III) or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable diluent or carrier.
  • a compound of Formula (II) or Formula (III) or pharmaceutically-acceptable salt thereof for the manufacture of a medicament to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis.
  • a method of treatment, in a warm-blooded animal, to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (II) or Formula (III), or a pharmaceutically-acceptable salt thereof.
  • a therapeutically (including prophylactically) effective amount of a compound of Formula (II) or Formula (III), or a pharmaceutically-acceptable salt thereof comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (II) or Formula (III), or a pharmaceutically-acceptable salt thereof.
  • a compound of Formula (II) or Formula (III) or pharmaceutically-acceptable salt tliereof in the manufacture of a medicament for the inhibition of tubulin polymerization.
  • a method of treatment, in a warm-blooded animal, by inhibiting tubulin polymerization comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (II) of Formula (III), or a pharmaceutically-acceptable salt thereof.
  • a preferred group of compounds of each feature of the invention comprise compounds wherein: 3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-hydroxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-phoshonoxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-aminophenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-[3-( ⁇ -glutamylamino)
  • a compound of the invention or a pharmaceutically-acceptable salt tliereof may be prepared by any process known to be applicable to the preparation of chemically related compounds. Such processes, when used to prepare a compound of the invention or a salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples in which AR 1 , AR 2 , AR 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, Y, p, q and r have the same meaning as herein before defined. The reader is referred to Advanced Organic Chemistry, 4 Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents.
  • a process for the preparation of compound of Formula (I), or salt thereof comprises: a) Reaction of a compound of Formula (A) with a compound of Formula (B) wherein Z 1 is a leaving group;
  • Formula (A) Formula (B) b) For compounds of Formula (I) wherein R 1 is other than hydrogen, Reaction of a 1 1 compound of Formula (I) wherein R is hydrogen with a compound of formula R -Z , wherein Z is a leaving group;
  • Formula (C) Formula (D) d) for compounds of Formula (I) wherein an R 7 group is an amino group substituted with an amino acid residue, reaction of a compound of Formula (E) with an amino acid or protected amino acid;
  • Process b) reaction of a compounds of Formula (I) wherein R 1 is hydrogen can be reacted with a compound of formula R -Z can be performed either: (i) via a Mitsunobu reaction, for example in the presence of triphenyl phosphine and DEAD or DTAD in a suitable solvent such as methylene chloride at room temperature; or (ii) wherein Z is halo, reaction in the presence of a base such as sodium hydride or potassium carbonate in a suitable solvent such as methylene chloride or DMF at a temperature between room temperature and 80°C.
  • a base such as sodium hydride or potassium carbonate
  • a suitable solvent such as methylene chloride or DMF
  • Process d) Compound of Formula (E) can be reacted with an amino acid or protected amino acid using a suitable amide bond forming reaction.
  • Amide bond forming reactions are well known in the art, for example, a carbodiimide coupling reaction can be performed with EDC1 in the presence of DMAP in a suitable solvent such as methylene chloride, chloroform or DMF at room temperature.
  • MCBDA at a temperature of between -60°C and room temperature for about 2 hours.
  • Examples of protected activated phosphate derivatives include di-tert-butyl diethylphosphoramidite.
  • Process f) Processes for the formation of an ester between a hydroxyl group and a carboxylic acid or an activated carboxylic acid are well know in the art. For example this reaction an acid chloride can be reacted with an alcohol in the presence of a base such as triethylamine.
  • a carboxylic acid derivative is any derivative of a carboxylic acid which when reacted with a hydroxyl under appropriate conditions will form an ester bond.
  • Examples of carboxylic acid derivatives include an acid chloride.
  • Process g) Reaction of a compound of Formula (G) with a compounds of Formula (H) can be performed in the presence of a suitable solvent such as DMF, at a temperature between
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • a compound of the Formula (I), Formula (II) or Formula (III), or a pharmaceutically-acceptable salt thereof, for the therapeutic treatment (including prophylactic treatment) of mammals including humans it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alg
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • the pharmaceutical compositions may also be in the form of a sterile i ⁇ jectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically-acceptable, vehicle or diluent using conventional procedures well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ m or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically-acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inl aler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • intravenous administration a dose in the range of, for example, 0.5 mg to 20 mg per kg body weight will generally be used. Intranvenous administration is however preferred, typically, intravenous doses of about 10 mg to 500 mg per patient of a compound of this invention.
  • the compounds of this invention may be used in combination with other drugs and therapies used to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis.
  • Such disease states include: cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate.
  • the anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iii) Agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor
  • inliibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inl ⁇ bitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7- methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib,
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti- vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • vascular endothelial growth factor for example the anti- vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • vastinTM anti- vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and WO02/08213;
  • antisense therapies for example tliose which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-ma
  • Cell cycle inliibitors including for example CDK inhibitiors (eg flavopiridol) and other inhibitors of cell cycle checkpoints (eg checkpoint kinase); inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation (eg mitotic kinesins); and histone deacetylase inhibitors
  • CDK inhibitiors eg flavopiridol
  • cell cycle checkpoint kinase eg checkpoint kinase
  • aurora kinase and other kinases involved in mitosis and cytokinesis regulation eg mitotic kinesins
  • histone deacetylase inhibitors eg mitotic kinesins
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range
  • a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof preferably in the form of a pharmaceutical composition, which when dosed in divided doses (also known as split doses) produces a greater anti-tumour effect than when a single dose is given.
  • Anti-tumour effects include but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to re- growth of tumour on cessation of treatment, slowing of disease progression.
  • a compound of the present invention when administered to a warm-blooded animal such as a human, in need of treatment for cancer involving a solid tumour, said method of treatment will produce an effect, as measured by, for example, one or more of: the extent of the anti-tumour effect, the response rate, the time to disease progression and the survival rate.
  • a method for the production of a vascular damaging effect in a warm-blooded animal such as a human which comprises administering to said animal in divided doses an effective amount of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition.
  • a method for the treatment of a cancer involving a solid tumour in a warmblooded animal which comprises administering to said animal in divided doses an effective amount of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition.
  • a medicament comprising two or more fractions of doses of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition, which together add up to a total daily dose, for administration in divided doses for use in a method of treatment of a human or animal-body by therapy.
  • kits comprising two or more fractions of doses of a compound of Formula (I) Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition, which together add up to a total daily dose, for administration in divided doses.
  • a kit comprising: a) two or more fractions of doses of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, which together add up to a total daily dose, in unit dosage forms for administration in divided doses; and b) container means for containing said dosage forms.
  • kits comprising: a) two or more fractions of doses of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, which together add up to a total daily dose, together with an excipient or carrier, in unit dosage forms; and b) container means for containing said dosage forms.
  • a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof in the manufacture of a medicament for administration in divided doses for use in the production of a vascular damaging effect in a warm-blooded animal such as a human.
  • a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof in the manufacture of a medicament for administration in divided doses for use in the production of an anti-cancer effect in a warm-blooded animal such as a human.
  • a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof in the manufacture of a medicament for administration in divided doses for use in the production of an anti-tumour effect in a warm-blooded animal such as a human.
  • Divided doses also called split doses, means that the total dose to be administered to a warm-blooded animal, such as a human, in any one day period (for example one 24 hour period from midnight to midnight) is divided up into two or more fractions of the total dose and these fractions are administered with a time period between each fraction of about greater than 0 hours to about 10 hours, preferably about 1 hour to about 6 hours, more preferably about 2 hours to about 4 hours.
  • the fractions of total dose may be about equal or unequal.
  • the total dose is divided into two parts which may be about equal or unequal.
  • the time intervals between doses may be for example selected from: about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours and about 6 hours.
  • the time intervals between doses may be any number (including non-integers) of minutes between greater than 0 minutes and 600 minutes, preferably between 45 and 375 minutes inclusive. If more than two doses are administered the time intervals between each dose may be about equal or unequal.
  • two doses are given with a time interval in between them of greater than or equal to 1 hour and less than 6 hours. More preferably two doses are given with a time interval in between them of greater than or equal to two hours and less than 5 hours.
  • two doses are given with a time interval in between them of greater than or equal to two hours and less than or equal to 4 hours.
  • the total dose is divided into two parts which may be about equal or unequal with a time interval between doses of greater than or equal to about two hours and less than or equal to about 4 hours. More particularly the total dose is divided into two parts which may be about equal with a time interval between doses of greater than or equal to about two hours and less than or equal to about 4 hours.
  • the term 'about' in the description of time periods means the time given plus or minus 15 minutes, thus for example about 1 hour means 45 to 75 minutes, about 1.5 hours means 75 to 105 minutes. Elsewhere the term 'about' has its usual dictionary meaning.
  • the compounds of the Formula (I), Formula (II) or Formula (III) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or. any disease state associated with angiogenesis. Thus, they are useful as pharmacological tools for use in the development of new biological tests and in the search for new pharmacological agents.
  • Colchicine Binding site competitive assay kit The ability of a ligand to bind specifically to the colchicine binding site on tubulin, an indicator of the vascular damaging activity, was assessed using a size exclusion chromatography assay kit from "Cytoskeleton" (1650 Fillmore St. #240, Denver, CO 80206, U.S.A.) Catalogue number of kit: BK023.
  • tubulin buffer to give O.lmM GTP, 0.5mM MgCl 2 , 0.5mM EGTA, 40mM PIPES buffer at pH 6.9 in the final reaction mix
  • purified tubulin protein from bovine brain at lmg/ml in tubulin buffer
  • 0.02mM fluorescent colchicine in tubulin buffer [FITC (fluorescein isothiocyanate)- labelled]
  • 2mM colchicine in tubulin buffer 0.2mM vinblastine in tubulin buffer
  • G-25 SephadexTM Fine - particle size 34-138 ⁇ m The reaction was performed as follows: 8 ⁇ l of test compound (dissolved in DMSO) was gently mixed with 150 ⁇ l of tubulin.
  • the incubation mixture was pipetted onto the column and up to 12 elutions of 160 ⁇ l were collected.
  • the fluorescence of the tubulin-containing fractions was detected on a spectrophotometer which excites at 485nm and emits at 535nm.
  • Example 1 inhibits colchicines binding by 80% at a concentration of lO ⁇ M and Example 9 inhibits colchicine binding by 85% at lO ⁇ M in the above assay.
  • Compounds of Formula (I), Formula (II) or Formula (III) encompass vascular damaging agents and pro-drugs of vascular damaging agents. Pro-drugs of vascular damaging agents are believed to be cleaved in-vivo.
  • pro-drugs may have lower activity in the in- vitro colchicine binding site competitive assay, than would be anticipated when the activity of these compounds is measured in cell based assays or in-vivo.
  • the invention will now be illustrated with the following non-limiting Examples in which, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18- 25 °C and under an atmosphere of an inert gas such as argon or nitrogen; (iii) yields are given for illustration only and are not necessarily the maximum attainable; (iv) the structures of the end-products of the Formula (I) were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d,
  • OASISTM is described in the following patents, US Patent Number No.5882521, US Patent Number No.5976376 and US Patent Number No.6106721.
  • OASISTM sample extraction products were obtained from Waters Corporation (Milford, Massachusetts, USA).
  • celite refers to diatomaceous earth.
  • the starting material was prepared as follows :
  • Example 2 To a stirred solution of Example 1 (0.100 g ; 0.25 mmol) in DMF (0.200 ml) was added NaH as a 60 % dispersion in oil (0.011 g ; 0.28 mmol). After the effervescence subsided, Mel (0.035 g ; 0.28 mmol) added and the reaction mixture was stirred at room temperature for 1 hour. The solution was purified by flash chromatography eluting with pentane / CH 2 C1 2 80/20 to give Example 2.
  • the starting material was prepared as follows
  • the starting material was prepared as follows :
  • Example 4 To a stirred solution of Example 4 (0.55 g ; 1.40 mmol) THF (10 ml) was added di-tert- butyl diethylphosphoramidite (0.66 g ; 2.63 mmol). The solution was stirred at room temperature for 2 hours. The orange solution was cooled to -60 °C and mCPBA (0.63 g ; 3.60 mmol) in CH C1 2 (50 ml) was added over 30 minutes. The reaction mixture was allowed to warm to room temperature, diluted with CH 2 C1 2 (50 ml) and washed with a 10%> (w/v) aqueous solution of Na S 2 O 5 (10 ml) and water (2 x 10 ml).
  • Example 6 To a stirred suspension of 15 (1.00 g ; 3.90 mmol) in cyclohexanol (3 ml) was added 2 (0.83 g ; 3.90 mmol) [see Example 1]. The reaction mixture was heated at 120 °C overnight. The solution was cooled to room temperature and triturated with ether (10 ml). The resulting precipitate was washed with ether (10 ml) and dried to a constant weight to give Example 6 as an dark brown solid.
  • Example 7 To a stirred solution of Example 6 (1.00 g ; 2.30 mmol) in EtOAc-EtO ⁇ (33 ml, 10:1) was added 10%> palladium on carbon (0.100 g). The resulting suspension was exposed to 1 atmosphere of hydrogen for 1 hour. The catalyst was removed by filtration through Celite and the filtrate concentrated to ca. 10 ml on a rotary evaporator. The solution was triturated with ether (30 ml) and the solid collected by filtration, washed with ether (10ml) and dried to a constant weight to give Example 7. Yield : 69 %
  • Example 8 as an orange solid.
  • the starting material was prepared as follows
  • Example 7 To a stirred solution of Example 7 (0.30 g ; 0.76 mmol) in DMF (0.50 ml) were added
  • the starting material was prepared as follows
  • Example 1 To a stirred suspension of Example 1 (0.50 g ; 1.30 mmol) in DCM (5 ml) were added triphenylphosphine (0.38 g ; 1.44 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.19 g ; 1.30 mmol). The solution was cooled to 0 °C and di-tert-butylazido carboxylate (0.33 g ; 1.44 mmol) in DCM (5.00 ml) was added over 10 minutes. The resulting dark brown solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated to ca. 5 ml and purified by flash chromatography eluting with CH 2 C1 / MeOH 97/3 to give 18 as an orange solid. Yield : 86 %
  • Example 9 To a stirred solution of Example 9 (0.40 g ; 0.94 mmol) in THF (10 ml) was added di-tert- butyl diethylphosphoramidite (0.22 g ; 0.85 mmol). The solution was stirred at room temperature for 2 hours. The orange solution was cooled to -60 °C and mCPBA (0.21 g ;
  • Example 11 To a stirred suspension of 22 (0.20 g ; 0.82 mmol) in methanol (5 ml) was added 2 (0.17 g ; 0.82 mmol). The reaction mixture was heated at 70 °C overnight. The resulting orange suspension was cooled to room temperature, evaporated to dryness and purified by flash chromatography eluting with CH 2 C1 2 / MeOH 96/4 to give Example 11 as an orange crystalline solid.
  • the starting material was prepared as follows
  • Example 12 To a stirred solution of 25 (0.10 g ; 0.26 mmol) in DMF (0.20 ml) was added piperidine (0.07 g ; 0.78 mmol). The solution was stirred at 40 °C for 1 hour. The reaction mixture was purified by flash chromatography eluting with CH 2 C1 2 / MeCN 80/20 to give the free base as a red oil. The oil was dissolved in ether (10 ml) and a 4.0M solution of HCl in dioxane (1 ml) was added. The precipitate was collected by filtration, washed with ether (10 ml) and dried to a constant weight to give Example 12 as a HCl salt. Yield : 42 %
  • the starting material was prepared as follows :
  • Example 13 To a stirred slurry of 27 (0.20 g ; 0.94 mmol) in cyclohexanol (2 ml) was added 3-chloro- 4-phenylpyrrole-2,5-dione (0.19 g ; 0.94 mmol). The resulting suspension was heat at 120°C overnight. The reaction mixture was cooled to room temperature and purified by flash cliromatography eluting with C ⁇ 2 C1 2 / MeCN 80/20 to give Example 13 as an orange solid.
  • the starting material was prepared as follows :
  • Example 14 as a HCl salt.
  • the starting material was prepared as follows
  • Example 1 28 To a stirred suspension of Example 1 (0.40 g ; 1.04 mmol) in DCM (4 ml) were added triphenylphosphine (0.30 g ; 1.16 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (0.17 g ; 1.04 mmol). The solution was cooled to -10 °C and DTAD (0.27 g ; 1.16 mmol) in DCM (5 ml) was added over 10 minutes. The resulting dark brown solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated to ca. 5 ml and purified by flash chromatography eluting with CH 2 C1 2 / MeOH 97/3 to give 28 as a dark yellow solid. Yield : 73 %
  • Example 15 To a stirred suspension of Example 1 (0.20 g ; 0.52 mmol) in DCM (2 ml) were added triphenylphosphine (0.153 g ; 0.58 mmol) and 1-piperidinethanol (0.07 g ; 0.52 mmol). The solution was cooled to -10 °C and DTAD (0.13 g ; 0.58 mmol) in DCM (1 ml) was added over 10 minutes. The resulting dark brown solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated to ca. 1.00 ml and purified by flash chromatography eluting with C ⁇ 2 C1 2 / MeOH 97/3 to give Example 15 as a yellow solid. Yield : 52 %
  • Example 17 To a stirred suspension of 3-chloro-4-phenylpyrrole-2,5-dione (0.20 g ; 0.97 mmol) in cyclohexanol (5 ml) was added 34 (0.22 g ; 1.06 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH 2 C1 2 / MeOH 97/3 to give Example 17 as an orange solid. Yield : 57 %
  • the starting material was prepared as follows:
  • Example 18 To a stirred suspension of 3-cl ⁇ loro-4-phenylpyrrole-2,5-dione (0.20 g ; 0.97 mmol). in cyclohexanol (5 ml) was added 36 (0.22 g ; 1.06 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH 2 C1 2 / MeOH 97/3 to give Example 18 as an orange solid. Yield : 67 %
  • the starting material was prepared as follows:
  • the starting material was prepared as follows:
  • Example 1 Example 19 .
  • Example 1 To a stirred solution of Example 1 (1.00 g ; 2.62 mmol) in MeCN (10 ml) were added DMAP (0.016 g, 0.13 mmol) and di-tert-butyl dicarbonate (0.58 g ; 2.67 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was purified by flash chromatography eluting with pentane / CH 2 C1 2 50/50 to give Example 19. Yield : 67 %
  • Example 20 as a dark red solid.
  • the starting material was prepared as follows:
  • Example 19 To a stirred solution of Example 19 (0.20 g ; 0.42 mmol) in THF (1 ml) was added NaH as a 60% dispersion in mineral oil (0.017 g ; 0.42 mmol) at -10 °C. Dimethyl sulfate (0.064 g ; 0.54 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The solution was purified by flash cliromatography eluting with CH 2 C1 2 / MeOH 99/1 to give 37. Yield : 59 %
  • Example 22 To a stirred suspension of 42 (0.05 g ; 0.18 mmol) in cyclohexanol (0.20 ml) was added 2 (0.04 g ; 0.18 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH 2 C1 / MeOH 97/3 to give Example 22 as a yellow solid. Yield : 42 %
  • the starting material was prepared as follows

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Abstract

This invention relates to novel compounds of Formula (I) for use as vascular damaging agents: Formula (I) wherein Rl, R7, R8, R9, ARI, AR2, AR3, p, q and r are as described in the specification. The invention also relates to methods for preparing compounds of Formula (I), to their use as medicaments (including methods for the treatment of angiogenesis or disease states associated with angiogenesis) and to pharmaceutical compositions containing compounds of Formula (I).

Description

3,4-DISUBSTITUTED MA EIMIDES FOR USE AS VASCULAR DAMAGING AGENTS
This invention relates to vascular damaging agents and their uses. In particular it relates to certain compounds which may be of use as vascular damaging agents, to methods for preparing the compounds, to their use as medicaments (including methods for the treatment of angiogenesis or disease states associated with angiogenesis) and to pharmaceutical compositions containing them. The invention also relates to the use of such compounds in the manufacture of medicaments for the production of anti-angiogenic and/or. anti- vascular effects. Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1 : 27-31). Formation of new vasculature by angiogenesis is a key pathological feature of several diseases (J. Folkman, New England Journal of Medicine 333, 1757-1763 (1995)). For example, for a solid tumour to grow it must develop its own blood supply upon which it depends critically for the provision of oxygen and nutrients; if this blood supply is mechanically shut off the tumour undergoes necrotic death. Neovascularisation is also a clinical feature of skin lesions in psoriasis, of the invasive pannus in the joints of rheumatoid arthritis patients and of atherosclerotic plaques. Retinal neovascularisation is pathological in macular degeneration and in diabetic retinopathy. Reversal of neovascularisation by damaging the newly-formed vascular endothelium is therefore expected to have a beneficial therapeutic effect. Such vascular- damaging activity would clearly be of value in the treatment of disease states associated with angiogenesis such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. Certain known compounds that cause selective destruction of tumour vasculature have been reported, in vitro and at non-cytotoxic concentrations, to cause effects on proliferating endothelial cells, ie, cell detachment [Blakey D C et al, Proceedings of the American Association for Cancer Research, 41, 329, 2000 abstract 2086] and changes in cell shape [Davis P D et al, Proceedings of the American Association for Cancer Research, 41, 329, 2000 abstract 2085; Chaplin D J & Dougherty G J, Br J Cancer, 80, Suppl 1, 57- 64, 1999]. It can therefore be expected that these compounds will have damaging effects on newly-formed vasculature, for example the vasculature of tumours. It can reasonably be predicted, for example, that they will be capable of causing selective destruction of tumour vasculature, both in vitro and in vivo. Destruction of tumour vasculature in turn leads to a reduction in tumour blood flow and to tumour cell death due to starvation of oxygen and nutrients, ie, to anti-tumour activity [Davis P D et al; Chaplin D J & Dougherty G J; Blakey D C et al, all supra]. Compounds with this activity have also been described in International Patent Application WO 99/02166 (Angiogene Pharmaceuticals), International Patent Application WO00/40529 (Angiogene Pharmaceuticals) and International Patent Application WO 00/41669 (Angiogene Pharmaceuticals) . We have identified a class of maleimide compounds with vascular damaging activity. Thus, according to the first feature of the present invention there is provided a compound of Formula (I), wherein:
Formula (I)
Ar1 is selected from phenyl, heteroaryl or heterocyclyl; Ar2 is selected from phenyl or heteroaryl; Ar3 is selected from phenyl or a monocyclic heteroaryl ring comprising between 1 and 3 heteroatoms selected fromN, O or S; R1 is selected from hydrogen, -C(O)-R2, -C(O)-O-R2, -C(O)N(R4)-R2 and -CH2-R2, wherein the group N(R4)-R2 may optionally form a 4-6 membered heterocyclic ring; R2 is selected from: hydrogen, halo, cyano, amino, hydroxy, -SO3, d-6alkyl, Cι.6alkoxy, -ealkanoyloxy, phosphonoxy, C -6alkenyl, cycloalkyl, cycloalkylCt^alkyl-, heterocyclyl, wherein an alkyl or alkenyl chain or a carbocyclyl, heterocyclyl or heteroaryl ring in R2 is optionally substituted by one or more groups selected from R3; R3 is selected from hydroxy, amino, carbamoyl, -SO3, phosphonoxy, -C(O)-O-R4, and -N(R4)R5, wherein the group - N(R4)R5 may optionally form a 4-6 membered heterocyclic ring; R4 and R5 are independently selected from: hydrogen, Cι-4alkyl and C(O)-R6, R6 is C^alkyl optionally substituted with carboxy or amino; R7 is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, Chalky 1, hydroxyC1.4alkyl, aminoCMalkyl, CMalkoxy and C^alkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified; R is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, Cι-4alkyl, liydroxyCMalkyl, aminoCMalkyl, Cι-4alkoxy and Ci^alkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified;
R9 is selected from: cyano, halo and nitro; R10 is selected from hydrogen or Ci^alkyl; p is an integer from 0 to 3; q is an integer from 0 to 3; r is an integer from 1 to 3; or a salt thereof. For the avoidance of doubt when p is 0, all positions on the AR1 ring are substituted by hydrogen, an analogous notation applies to AR2 and AR3 when q is 0. For the avoidance of doubt the use of the term (R7)p when p is between 1 and 3, 7 1 means that there are 1, 2 or 3 R substituents on the Ar ring, which when p is 2 or 3 can be the same group or different groups. For example, where (R )p is 3,4-dichloro then p is 2 and the Ar1 ring has a chloro group at the 3-position and a chloro group at the 4-position, in relation to the position wherein the Ar1 group is bound to the pyrrole-2,5-dione group. Whilst pharmaceutically-acceptable salts of compounds of the invention are preferred, other non-pharmaceutically-acceptable salts of compounds of the invention may also be useful, for example in the preparation of pharmaceutically-acceptable salts of compounds of the invention. According to a further aspect of the first feature of the invention there is provided a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically- acceptable salt thereof, and a pharmaceutically-acceptable excipient. According to a further aspect of the first feature of the invention there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable diluent or carrier. Compounds of Formula (I) have anti-angiogenic activity by virtue of their vascular damaging activity. Thus, according to the second feature of the present invention there is provided the use of a compound of Formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, for the manufacture of a medicament to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis. According to a further aspect of the second feature of the invention there is provided a method of treatment, in a warm-blooded animal, to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof. Compounds of Formula (I) are believed to inhibit the polymerization of tubulin which results in their vascular damaging activity. Thus, according to a further aspect of the second feature of the present invention mere is provided the use of a compound of Formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, in the manufacture of a medicament for the inhibition of tubulin polymerization. According to a further aspect of the second feature of the invention there is provided a method of treatment, in a warm-blooded animal, by inhibiting tubulin polymerization comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof. Preferably a warm-blooded animal is a human. Examples of disease states associated with angiogenesis are solid tumours, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. A preferred disease state associated with angiogenesis is solid tumours. Preferred solid tumours include colon, lung, breast, brain ovary, prostate,skin and metastatic tumours such as live metastases. According to a third feature of the invention there is provided the use of a compound of Formula (I) as a medicament. The term "heteroaryl" refers to a 4-10 membered aromatic mono or, bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible tlirough the 1 -nitrogen of a pyrazole ring. The term "heteroaryl" preferably refers to a 5-10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. More preferably, the term "heteroaryl" refers to a 5 or 6 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. Examples of 5- or 6-membered heteroaryl ring systems include pyrrole, furan, imidazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, 1,2,4 oxadiazole, isothiazole, thiazole, 1,2,4-triazole and thiophene. Particular examples of 5- or 6-membered heteroaryl ring systems include pyrrole, furan, imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, 1,2,4 oxadiazole, isothiazole, thiazole and thiophene. More particularly, the term "heteroaryl" refers to a 9 or 10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. A 9 or 10 membered bicyclic heteroaryl ring system is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, 1,3-benzodioxole, indole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine. Particular examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, indole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine. The term "heterocyclyl" refers to a 5-10 membered saturated or partially saturated mono or bicyclic ring containing up to 5 heteroatoms selected from nitrogen, oxygen or sulphur linked via ring carbon atoms or ring nitrogen atoms. Examples of 'heterocyclyl' include tetrahydrofuranyl, 2,3-dihydro-4H-pyran, pyrrolinyl, pyrrolidinyl, 1,3-thiazolidine, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, dihydropyrimidinyl and azepane. Particular examples of 'heterocyclyl' include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl and dihydropyrimidinyl. The term "carbocyclyl" refers to a totally saturated or partially saturated mono, bi or tri cyclic 3-10 membered carbon ring. Examples of carbocychc rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo-octane, adamantyl or 2,3-dihydroindene. The term aryl refers to phenyl or naphthyl. The term halo refers to fluoro, chloro, bromo or iodo. The term carbamoyl refers to the group -CONH2. An amino acid residue is defined as that derived from the coupling of an L-amino acid with an amino group via an amide bond. This bond can either be formed via a carboxylate group on the amino acid backbone or via a side chain carboxylate group, preferably via a carboxylate group on the amino acid backbone. Amino acid residues include those derived from natural and non-natural amino acids, preferably natural amino acids and include α-amino acids β-amino acids and γ-amino acids. For the avoidance of doubt amino acids include those with the generic structure:
where R is the amino acid side chain. The definition of amino acid also includes amino acid analogues which have additional methylene groups within the amino acid backbone, for example β-alanine and amino acids which are not naturally occurring such as cyclohexylalanine. Preferred amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparaginine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, β-alanine and ornithine. More preferred amino acids include glutamic acid, serine, threonine, arginine, glycine, alanine, β-alanine and lysine. Especially preferred amino acids include glutamic acid, serine, and glycine. Esterifying groups at R7 are esterifying groups which increase the solubility of the molecule in water at a pH of approximately pH=7. Such groups include groups with ionisable groups, such as acidic functions or basic functions and groups containing a hydrophilic function. Basic functions include: amino, morpholino, piperidino, piperazino, pyrrolidino, amino acids and imidazolino. Acidic functions include: carboxy, sulphonic acid, phosphate, sulphate and acid mimetics such as tetrazolyl. Hydrophilic groups include hydroxyl. Suitable R7 groups wherein hydroxy is esterfϊed include: Cι-6alkanoyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, heteroarylcarbonyloxy wherein the Ri group is optionally substituted with between 1 and 3 groups selected from CMalkanoylCMalkyl, CMalkanoylheterocyclyl, hydroxy, hydroxyCMalkyl, carboxy, carboxyphenyl, phosphono, phosphonoCi^alkyl, amino, aminoCMalkyl, N-C all-ylamino, N,N-diCι--ιalkylamino, carbamoyl, carbamoylCMalkyl, heterocyclyl, heterocyclylC alkyl, heterocyclylcarbonyl, heterocyclCMalkanoylamino, carbamoylheterocyclyl, [wherein optional substituents comprising heterocyclyl are optionally further substituted by Ci^alkyl, hydroxyCMalkyl, Cι- alkoxyCι- alkyl, C\.
4alkanoyl and formyl, wherein the carbamoyl and amino optional substituents are optionally further N-substituted by Q^a-kyl, di-Cι-4alkyl, hydroxy Chalky 1, di-(hydroxyCMalkyl), carboxy Ci^alkyl, and wherein the amino group is optionally substituted by an amino acid residue] with the proviso that when Ri is Ci-βalkanoyloxy or arylcarbonyloxy Ri is not unsubstituted and Ri is not substituted by Ci^alkyl. More preferred R groups wherein hydroxy is esterfied include: carboxypentanoyloxy , 4-carboxyphenylpropanoyloxy , 4-(N-methylpiperizin- 1 - ylethy l)pheny lcarbonyloxy , 4-(piperizin- 1 -ylethy l)pheny lcarbonyloxy ,
4-[N-di-(hydroxyemyl)aminomethyl]phenylcarbonyloxy,
3 -(N-acetylpiperizin- 1 -ylethy l)pheny lcarbonyloxy,
3 - [N-di-(hy droxyethyl)aminomethyl]pheny lcarbonyloxy ,
4-(N-methylpiperizin- 1 -y lpropanoylamino)phenylcarbonyloxy, N-methylpiperizin- 1 -ylcarbonylpropanoyloxy ,
N-di-(hydroxyethyl)aminocarbonylpropanoyloxy, piperizin- 1 -ylcarbonylpropanoyloxy,
(N-acetylpiperizin- 1 -ylcarbonylpropanoyloxy,
(N-di-(hydroxyethyl)aminocarbonylpropanoyloxy, and
4-(piperizin- 1 -ylmethyl)pheny lcarbonyloxy. Further preferred R groups wherein hydroxy is esterfied include:
4-(N-methylpiperizin- 1 -ylpropanoylamino)pheny lcarbonyloxy ,
N-methylpiperizin- 1 -ylcarbonylpropanoyloxy and
N-di-(hydroxyethyl)aminocarbonylpropanoyloxy. In this specification the generic term 'alkyl' as used in the terms Cι-4alkyl and d-βalkyl includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as 'propyl' are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as 'isopropyl' are specific for the branched-chain version only. An analogous convention applies to other generic terms. Examples of Cι.6alkyl include methyl, ethyl, propyl, isopropyl, .yec-butyl and tert-butyl; examples of aminoCι-4alkyl include aminomethyl, aminoethyl or aminopropyl; examples of hydroxy Ci^alkyl include hydroxymethyl, hydroxyethyl,
2-hydroxypropyl and 2-hydroxy-2-methyl-propyl; examples of arylCι-4alkyl include benzyl and phenethyl; examples of cycloalkylCi jalkyl include cyclopropylethyl, cyclobutylmethyl and cyclohexylpropy ; examples of heterocyclylC1.4alkyl include piperazinylmethyl, piperazinylethyl, moφholinylmethyl or morpholinylethyl; Examples of C2-6alkenyl include allyl and 2-butenyl; examples of Cι-4aIkoxy include methoxy, ethoxy and propoxy; examples of Cι-4alkanoyl include formyl or propanoyl; examples of Cχ-6alkanoyloxy include propanoyloxy or butanoyloxy. It is to be understood that, insofar as certain of the compounds in the different features of the invention may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting and/or reversing and/or alleviating the symptoms of angiogenesis and/or any disease states associated with angiogenesis. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, activity of these compounds may be evaluated using the standard laboratory techniques referred to hereinafter. The invention also relates to any and all tautomeric forms of the compounds of the different features of the invention that possess the property of inhibiting and/or reversing and/or alleviating the symptoms of angiogenesis and/or any disease states associated with angiogenesis. It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the property of inl ibiting and/or reversing and/or alleviating the symptoms of angiogenesis and/or any disease states associated with angiogenesis. The compounds of Formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I). Examples of pro-drugs include in- vivo hydrolysable esters of a compound of the Formula (I). Various forms of pro-drugs are known in the art. For examples of such pro-drug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al.,- Chem Pharm Bull, 32, 692 (1984). An in- vivo hydroly sable ester of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include Cι-6alkoxymethyl esters for example methoxymethyl, C^alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-scycloalkoxycarbonyloxyQ-όalkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci_6alkoxycarbonyloxy ethyl esters. An in- vivo hydroly sable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in- vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a benzoxazinone derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. A preferred group of values of AR1 in each feature of the invention includes phenyl, a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl. A further preferred group of values for AR1 in each feature of the invention includes: phenyl, a 6 membered heteroaryl or a 6 membered heterocyclyl. A yet further preferred group of values for AR1 in each feature of the invention includes: phenyl, a 6 membered heteroaryl or a 6 membered heterocyclyl, wherein the heteroaryl or heterocyclyl rings contain 1-2 heteroatoms selected from nitrogen. A yet further preferred group of values for AR1 in each feature of the invention includes: phenyl, pyridyl and piperidinyl. A most preferred value for AR1 in each feature of the invention is phenyl. A preferred group of values of AR in each feature of the invention includes phenyl or 5-6 membered heteroaryl. A further preferred group of values for AR2 in each feature of the invention includes: phenyl or 6 membered heteroaryl. A yet further preferred group of values for AR1 in each feature of the invention includes: phenyl or 5-6 membered heteroaryl wherein the heteroaryl ring contain 1-2 heteroatoms selected from nitrogen. A yet further preferred group of values for AR2 in each feature of the invention includes: phenyl and pyridyl. A most preferred value for AR is phenyl. A preferred group of values of AR in each feature of the invention includes phenyl or 6 membered monocyclic heteroaryl. A further preferred group of values of AR3 in each feature of the invention includes phenyl, pyridyl and pyrimidinyl. A most preferred value of AR3 in each feature of the invention is phenyl. A preferred group of values of R1 in each feature of the invention includes hydrogen, -C(O)N(R4)-R2, -CH2-R2, and -C(O)-O-R2. A more preferred group of values of R1 in each feature of the invention includes hydrogen and -CH2-R2. Most preferably R1 is hydrogen. A preferred group of values for R2 in each feature of the invention is hydrogen,
Cι-6alkyl optionally substituted by one or more groups selected from R , heterocyclyl and heterocyclylCMalkyl. A further preferred group of values for R2 in each feature of the invention is hydrogen, Cι-6alkyl optionally substituted by one or more groups selected from R3, 6-membered heterocyclyl and 6-membered heterocyclylCMalkyl. A yet further preferred group of values for R in each feature of the invention is hydrogen, C^aUcyl optionally substituted by R or heterocyclylCι-4alkyl. A most preferred group of values for R in each feature of the invention is hydrogen, methyl substituted by one R group, t-butyl or piperidin-1-ylmethyl. A preferred group of values for R3 in each feature of the invention is amino, hydroxy and phosphonoxy. A most preferred value for R3 is phosphonoxy. A preferred group of values for R4 in each feature of the invention is hydrogen or methyl, most preferably hydrogen. A preferred group of values for R5 in each feature of the invention is hydrogen or methyl, most preferably hydrogen. A preferred group of values for R6 in each feature of the invention is hydrogen or methyl, most preferably hydrogen. A preferred group of values for R7 in each feature of the invention is hydroxy, nitro, amino, halo, phosphonooxy, wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified. A further preferred group of values for R7 in each feature of the invention is hydroxy, nitro, amino, halo, ^alkoxy wherein the amino group is optionally substituted by an amino acid residue. A yet further preferred group of values for R in each feature of the invention is hydroxy, nitro, amino, glutamyl-NH-, seryl-NH-, alanyl-NH- or glycyl-NH-. A yet further preferred group of values for R in each feature of the invention is hydroxy, nitro, amino or glutamyl-NH-. Most preferably R7 is hydrogen. A preferred group of amino acids in each feature of the invention when R7 is amino substituted by an amino acid residue include: glutamic acid, serine, threonine, arginine, glycine, alanine, β-alanine and lysine. A preferred group of values for R8 in each feature of the invention is selected from hydrogen or methyl, preferably hydrogen. A preferred group of values for R9 in each feature of the invention is selected from hydrogen or methyl, preferably hydrogen. A preferred group of values for R10 in each feature of the invention is selected from hydrogen or Chalky!. A further preferred group of values for R10 in each feature of the invention is selected from hydrogen or methyl. A most preferred value for R10 in each feature of the invention is hydrogen. A preferred group of values for p in each feature of the invention is 0, 1 or 2, further preferably p is 1 or 2, most preferably p is 1. A preferred group of values for q in each feature of the invention is 0 or 1, most preferably q is 0. A preferred group of values for r in each feature of the invention is 1 or 2, most preferably r is 1. A preferred group of compounds of each feature of the invention described herein, comprise compounds of Formula (II)
Formula (II) Ar1 is selected from phenyl, heteroaryl or heterocyclyl; Ar2 is selected from phenyl or heteroaryl; Ar3 is selected from phenyl or a monocyclic heteroaryl ring comprising between 1 and 3 heteroatoms selected from N, O or S; R1 is selected from hydrogen, -C(O)-R2, -C(O)-O-R2, -C(O)N(R4)-R2 and -CH2-R2, wherein the group N(R4)-R2 may optionally form a 4-6 membered heterocyclic ring; R2 is selected from: hydrogen, halo, cyano, amino, hydroxy, -SO3, Cμ6alkyl, C^alkoxy, Ci.6alkanoyloxy, phosphonoxy, C .6alkenyl, cycloalkyl, cycloalkylCMalkyl-, heterocyclyl, heterocyclylCι-4alkyl-, aryl and arylCMalkyl-, wherein an alkyl or alkenyl chain or a carbocyclyl, heterocyclyl or heteroaryl ring in R is optionally substituted by one or more groups selected from R3; R is selected from Chalky 1, CMalkoxy, CMalkanoyl, hydroxy, amino, carbamoyl, -SO3, phosphonoxy, -C(O)-O-R4, and -N(R )R5, wherein the group - N(R4)R5 may optionally form a 4-6 membered heterocyclic ring;
R4 and R5 are independently selected from: hydrogen, CMalkyl and C(O)-R6, R6 is CMalkyl optionally substituted with carboxy or amino;
R is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, CMalkyl, hydroxyCMalkyl, aminoCMalkyl, CMalkoxy and Cι-4alkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified; R is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, CMalkyl, hydroxyCMalkyl, aminoCι.4alkyl, CMalkoxy and CMalkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified;
R9 is selected from: cyano, halo and nitro; R10 is selected from hydrogen or CM lkyl;
X is selected from -N(R10)-;
Y is-O-, p is an integer from 0 to 3; q is an integer from 0 to 3; r is an integer from 0, 1 or 2; or a salt thereof. A preferred group of compounds of each feature of the invention described herein, comprise compounds of Formula (III)
Formula (III) Ar is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl; Ar is selected from phenyl or 5-6 membered heteroaryl; R1 is selected from hydrogen, Cι-6alkyl, CMalkoxycarbonyl, hydroxyCι-6alkyl, aminoCi-όalkyl, heterocyclylCι.6alkyl and phosphonoxyCι-6alkyl; R7 is selected from halo, hydroxy, nitro, amino, phosphonooxy, and wherein the amino group is optionally substituted by an amino acid residue; R10 is hydrogen or CMalkyl; X is selected from -N(R10)-; Y is selected from -O-, p is an integer from 0 to 3; or a salt thereof. According to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of Formula (II) or Formula (III) or pharmaceutically- acceptable salt thereof, and a pharmaceuticaHy-acceptable excipient. According to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of Formula (II) or Formula (III) or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable diluent or carrier. According to a further feature of the present invention there is provided the use of a compound of Formula (II) or Formula (III) or pharmaceutically-acceptable salt thereof, for the manufacture of a medicament to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis. According to a further feature of the invention there is provided a method of treatment, in a warm-blooded animal, to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (II) or Formula (III), or a pharmaceutically-acceptable salt thereof. According to the further feature of the invention there is provided the use of a compound of Formula (II) or Formula (III) or pharmaceutically-acceptable salt tliereof, in the manufacture of a medicament for the inhibition of tubulin polymerization. According to a further feature of the invention there is provided a method of treatment, in a warm-blooded animal, by inhibiting tubulin polymerization comprising administering to said warm-blooded animal a therapeutically (including prophylactically) effective amount of a compound of Formula (II) of Formula (III), or a pharmaceutically-acceptable salt thereof. A preferred group of compounds of each feature of the invention, comprise compounds wherein: 3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-hydroxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-phoshonoxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-aminophenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-[3-(α-glutamylamino)phenyl]-2,5-dioxo-2,5- dihydro-lH-pyrrole; l-hydroxyethyl-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH- pyrrole; l-(phosphonooxyethyl)-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5- dihydro- lH-pyrrole; or a salt thereof. A compound of the invention or a pharmaceutically-acceptable salt tliereof, may be prepared by any process known to be applicable to the preparation of chemically related compounds. Such processes, when used to prepare a compound of the invention or a salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples in which AR1, AR2, AR3, R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y, p, q and r have the same meaning as herein before defined. The reader is referred to Advanced Organic Chemistry, 4 Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. The reader is referred to Protective Groups in Organic Synthesis 2nd Edition, by Green et al, published by John Wiley & Sons for general guidance on protecting groups. Thus, according to a fourth feature of the invention there is provided a process for the preparation of compound of Formula (I), or salt thereof, which process (wherein AR1, AR2, AR3, R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y, p, q and r are unless otherwise specified as defined above) comprises: a) Reaction of a compound of Formula (A) with a compound of Formula (B) wherein Z1 is a leaving group;
Formula (A) Formula (B) b) For compounds of Formula (I) wherein R1 is other than hydrogen, Reaction of a 1 1 compound of Formula (I) wherein R is hydrogen with a compound of formula R -Z , wherein Z is a leaving group;
c) Reaction of a compound of Formula (C) with a compound of Formula (D) wherein: (i) Z is -Y-H and Z is a leaving group; or (ii) Z3 is a leaving group and Z4 is with a compound of formula H-Y-;
Formula (C) Formula (D) d) for compounds of Formula (I) wherein an R7 group is an amino group substituted with an amino acid residue, reaction of a compound of Formula (E) with an amino acid or protected amino acid;
Formula (E) e) for compounds of Formula (I) wherein an R7 group is phosphonoxy, reaction of a compound of Formula (F) with a protected activated phosphate derivative;
Formula (F) f) for compounds of Formula (I) wherein an R7 group is an esterified hydroxyl group, reaction of a compound of Formula (F) with a carboxylic acid or an activated carboxylic acid derivative; g) Reaction of a compound of Formula (G) with a compound of Formula (H), wherein; (i) Z5 is hydrogen and Z6 is a leaving group; or (ii) Z5 is a leaving group and Z4 is hydrogen;
Formula (G) Formula (H) and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt. Specific reaction conditions for the above reactions are as follows: Process a) Reaction of a compound of Formula (A) with a compound of Formula (B) can be performed in the presence of a suitable solvent, such as an alcohol, DMF, DMSO or methylene chloride at a temperature between 0 and 150°C.
Process b) reaction of a compounds of Formula (I) wherein R1 is hydrogen can be reacted with a compound of formula R -Z can be performed either: (i) via a Mitsunobu reaction, for example in the presence of triphenyl phosphine and DEAD or DTAD in a suitable solvent such as methylene chloride at room temperature; or (ii) wherein Z is halo, reaction in the presence of a base such as sodium hydride or potassium carbonate in a suitable solvent such as methylene chloride or DMF at a temperature between room temperature and 80°C. Process c) A compound of Formula (C) can be reacted with a compound of Formula
(D) in the presence of a suitable solvent such as methylene chloride, DMF or DMA at a temperature between room temperature and 150°C.
Process d) Compound of Formula (E) can be reacted with an amino acid or protected amino acid using a suitable amide bond forming reaction. Amide bond forming reactions are well known in the art, for example, a carbodiimide coupling reaction can be performed with EDC1 in the presence of DMAP in a suitable solvent such as methylene chloride, chloroform or DMF at room temperature.
Process e) Compounds of Formula (F) can be reacted with a protected activated phosphate derivative in a suitable solvent such as methylene chloride in the presence of
MCBDA at a temperature of between -60°C and room temperature for about 2 hours.
Examples of protected activated phosphate derivatives include di-tert-butyl diethylphosphoramidite.
Process f) Processes for the formation of an ester between a hydroxyl group and a carboxylic acid or an activated carboxylic acid are well know in the art. For example this reaction an acid chloride can be reacted with an alcohol in the presence of a base such as triethylamine. A carboxylic acid derivative is any derivative of a carboxylic acid which when reacted with a hydroxyl under appropriate conditions will form an ester bond.
Examples of carboxylic acid derivatives include an acid chloride. Process g) Reaction of a compound of Formula (G) with a compounds of Formula (H) can be performed in the presence of a suitable solvent such as DMF, at a temperature between
0°C and 100°C. Intermediates for the processes a), b), c), d), e), f) and g) may be prepared as outlined in Scheme 1 : Reaction Conditions (i) using ammonia in the presence of a suitable solvent such a DMF or DMSO at a temperature between room temperature and 100°C.
Reaction Conditions (ii) in the presence of a suitable solvent such as DMF, DMA or
DMSO at a temperature between -10°C and 60°C.
Reaction Conditions (iii) in the presence of sulphonyl chloride in a suitable solvent such as methylene chloride in DMF at room temperature.
oxalate
Scheme 1 The compounds used as starting points for the reactions described above are commercially available or they are known compounds or they are prepared by processes known in the art. It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. In order to use a compound of the Formula (I), Formula (II) or Formula (III), or a pharmaceutically-acceptable salt thereof, for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent. The pharmaceutical compositions may also be in the form of a sterile iηjectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically-acceptable, vehicle or diluent using conventional procedures well known in the art. Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30μm or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically-acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inl aler device, such as is used for insufflation of the known agent sodium cromoglycate. Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on formulation the reader is referred to Chapter 25.2 in
Nolume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I), Formula (II) or Formula (III) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In using a compound of the Formula (I), Formula (II) or Formula (III) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range of, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range of, for example, 0.5 mg to 20 mg per kg body weight will generally be used. Intranvenous administration is however preferred, typically, intravenous doses of about 10 mg to 500 mg per patient of a compound of this invention. The compounds of this invention may be used in combination with other drugs and therapies used to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis. Examples of such disease states include: cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate. The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :-
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) Agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
(iv) inliibitors of growth factor function, for example such inliibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inlύbitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7- methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3 -chloro-4-fluorophenyl)-7-(3 -moφholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti- vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and WO02/08213; (vii) antisense therapies, for example tliose which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
(x) Cell cycle inliibitors including for example CDK inhibitiors (eg flavopiridol) and other inhibitors of cell cycle checkpoints (eg checkpoint kinase); inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation (eg mitotic kinesins); and histone deacetylase inhibitors Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. The compounds of the invention may also be used in combination with surgery or radiotherapy. According to the fifth feature of the present invention there is provided a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition, which when dosed in divided doses (also known as split doses) produces a greater anti-tumour effect than when a single dose is given. Anti-tumour effects include but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to re- growth of tumour on cessation of treatment, slowing of disease progression. It is expected that when a compound of the present invention is administered to a warm-blooded animal such as a human, in need of treatment for cancer involving a solid tumour, said method of treatment will produce an effect, as measured by, for example, one or more of: the extent of the anti-tumour effect, the response rate, the time to disease progression and the survival rate. According to a further aspect of the fifth feature of the present invention there is provided a method for the production of a vascular damaging effect in a warm-blooded animal such as a human, which comprises administering to said animal in divided doses an effective amount of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition. According to a further aspect of the fifth feature of the present invention there is provided a method for the treatment of a cancer involving a solid tumour in a warmblooded animal such as a human, which comprises administering to said animal in divided doses an effective amount of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition. According to a further aspect of the fifth feature of the present invention there is provided a medicament comprising two or more fractions of doses of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition, which together add up to a total daily dose, for administration in divided doses for use in a method of treatment of a human or animal-body by therapy. According to a further aspect of the fifth feature of the present invention there, is provided a kit comprising two or more fractions of doses of a compound of Formula (I) Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, preferably in the form of a pharmaceutical composition, which together add up to a total daily dose, for administration in divided doses. According to a further aspect of the fifth feature of the present invention there is provided a kit comprising: a) two or more fractions of doses of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, which together add up to a total daily dose, in unit dosage forms for administration in divided doses; and b) container means for containing said dosage forms. According to a further aspect of the fifth feature of the present invention there is provided a kit comprising: a) two or more fractions of doses of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, which together add up to a total daily dose, together with an excipient or carrier, in unit dosage forms; and b) container means for containing said dosage forms. According to a further aspect of the fifth feature of the present invention there is provided the use of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for administration in divided doses for use in the production of a vascular damaging effect in a warm-blooded animal such as a human. According to a further aspect of the fifth feature of the present invention there is provided the use of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for administration in divided doses for use in the production of an anti-cancer effect in a warm-blooded animal such as a human. According to a further aspect of the fifth feature of the present invention there is provided the use of a compound of Formula (I), Formula (II) or Formula (III), or pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for administration in divided doses for use in the production of an anti-tumour effect in a warm-blooded animal such as a human. Divided doses, also called split doses, means that the total dose to be administered to a warm-blooded animal, such as a human, in any one day period (for example one 24 hour period from midnight to midnight) is divided up into two or more fractions of the total dose and these fractions are administered with a time period between each fraction of about greater than 0 hours to about 10 hours, preferably about 1 hour to about 6 hours, more preferably about 2 hours to about 4 hours. The fractions of total dose may be about equal or unequal. Preferably the total dose is divided into two parts which may be about equal or unequal. The time intervals between doses may be for example selected from: about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours and about 6 hours. The time intervals between doses may be any number (including non-integers) of minutes between greater than 0 minutes and 600 minutes, preferably between 45 and 375 minutes inclusive. If more than two doses are administered the time intervals between each dose may be about equal or unequal. Preferably two doses are given with a time interval in between them of greater than or equal to 1 hour and less than 6 hours. More preferably two doses are given with a time interval in between them of greater than or equal to two hours and less than 5 hours. Yet more preferably two doses are given with a time interval in between them of greater than or equal to two hours and less than or equal to 4 hours. Particularly the total dose is divided into two parts which may be about equal or unequal with a time interval between doses of greater than or equal to about two hours and less than or equal to about 4 hours. More particularly the total dose is divided into two parts which may be about equal with a time interval between doses of greater than or equal to about two hours and less than or equal to about 4 hours. For the avoidance of doubt the term 'about' in the description of time periods means the time given plus or minus 15 minutes, thus for example about 1 hour means 45 to 75 minutes, about 1.5 hours means 75 to 105 minutes. Elsewhere the term 'about' has its usual dictionary meaning. Although the compounds of the Formula (I), Formula (II) or Formula (III) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or. any disease state associated with angiogenesis. Thus, they are useful as pharmacological tools for use in the development of new biological tests and in the search for new pharmacological agents.
Biological Assay
Colchicine Binding site competitive assay kit. The ability of a ligand to bind specifically to the colchicine binding site on tubulin, an indicator of the vascular damaging activity, was assessed using a size exclusion chromatography assay kit from "Cytoskeleton" (1650 Fillmore St. #240, Denver, CO 80206, U.S.A.) Catalogue number of kit: BK023. The following reagents were used: tubulin buffer, to give O.lmM GTP, 0.5mM MgCl2, 0.5mM EGTA, 40mM PIPES buffer at pH 6.9 in the final reaction mix; purified tubulin protein from bovine brain at lmg/ml in tubulin buffer; 0.02mM fluorescent colchicine in tubulin buffer [FITC (fluorescein isothiocyanate)- labelled]; 2mM colchicine in tubulin buffer; 0.2mM vinblastine in tubulin buffer; and G-25 Sephadex™ Fine - particle size 34-138μm. The reaction was performed as follows: 8μl of test compound (dissolved in DMSO) was gently mixed with 150μl of tubulin. This was then incubated at 37°C for 30 minutes. Then 4μl of the fluorescent colchicine was added, the incubation mix vortexed for 5 seconds and then incubated for a further 30 minutes at 37°C. At the end of the reaction incubation size exclusion chromatography was performed to separate the tubulin with fluorescent colchicine bound from the free, unbound colchicine. If a test compound inhibited fluorescent colchicine binding then a reduced signal is measured and the compound is confirmed as a colchicine site binding moiety. Size exclusion chromatography was performed as follows, using chromatography columns filled with 3mls of G-25 Sephadex™ Fine slurry. The incubation mixture was pipetted onto the column and up to 12 elutions of 160μl were collected. The fluorescence of the tubulin-containing fractions was detected on a spectrophotometer which excites at 485nm and emits at 535nm.
Control incubations were also performed, 8μl DMSO (negative control) and 8μl colchicine stock (positive competition control), instead of the 8μl of test compound in the incubation mixture. The degree of competition of colchicine binding by either unlabelled colchicine or test compound was calculated relative to the DMSO negative control. For example, Example 1 inhibits colchicines binding by 80% at a concentration of lOμM and Example 9 inhibits colchicine binding by 85% at lOμM in the above assay. Compounds of Formula (I), Formula (II) or Formula (III) encompass vascular damaging agents and pro-drugs of vascular damaging agents. Pro-drugs of vascular damaging agents are believed to be cleaved in-vivo. Without being bound by theoretical considerations these pro-drugs may have lower activity in the in- vitro colchicine binding site competitive assay, than would be anticipated when the activity of these compounds is measured in cell based assays or in-vivo. The invention will now be illustrated with the following non-limiting Examples in which, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18- 25 °C and under an atmosphere of an inert gas such as argon or nitrogen; (iii) yields are given for illustration only and are not necessarily the maximum attainable; (iv) the structures of the end-products of the Formula (I) were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet; (v) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), infra-red (IR) or NMR analysis; (vi) flash chromatography was performed on silica (Merck Keiselgel: Art.9385); (vii) OASIS™ is a macroporous co-polymer, used to purify hydrophilic compounds, made from a balanced ratio of lipophilic divinylbenzene and hydrophilic N-vinylpyrrolidone. OASIS™ is described in the following patents, US Patent Number No.5882521, US Patent Number No.5976376 and US Patent Number No.6106721. OASIS™ sample extraction products were obtained from Waters Corporation (Milford, Massachusetts, USA). (viii) celite refers to diatomaceous earth.
Abbreviations
Meta chloroperbenzoic acid mCPBA
Dichloromethane DCM Dimethylacetamide DMA
4-Dimethylaminopyridine DMAP
2,3-dichloro-5,6-dicyano-l,4-benzoquinone DDQ
Dimethylformamide DMF di-ter-butyl azodicarboxylate DTAD l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI
Dimethyl sulphoxide DMSO
N-(9-fluorenylmethoxycarbonyl) N-FMOC N-methylpyrrolidine NMP Tetrahydrofuran THF
Example 1 3-[4-(2-cyanophenoxy)aniIino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole
Example 1
To a stirred slurry of 2 (i.84 g ; 8.90 mmol) in cyclohexanol (5 ml) was added 3-chloro-4- phenylpyrrole-2,5-dione (1.80 g ; 8.90 mmol). The resulting suspension was heated at ■ 120°C overnight. The reaction mixture was cooled to room temperature and triturated with diethyl ether (10 ml). The precipitate was collected by filtration, washed with ether (30 ml) and dried to a constant weight to afford Example 1. Yield : 91 % 1H NMR (DMSOd6) : 6.64 (d, 1H) ; 6.85 (2 x merged d, 4H) ; 6.99 (m, 2H ; 7.19 (m, 3H) ; 7.25 (s, 1H) ; 7.67 (t, 1H) ; 7.87 (dd, 1H) ; 9.56 (bs, 1H) ; 10.76 (bs, 1H) MS - ESI : 380 [M-H]"
The starting material was prepared as follows :
HO CN
To a stirred slurry of l-fluoro-4-nitrobenzene (11.9 g ; 85.0 mmol) and 2-cyanophenol (10.0 g ; 84.0 mmol) in DMF (100 ml) was added K2CO3 (15.1 g ; 109 mmol). The mixture was heated at 90 °C overnight. The suspension was cooled to room temperature and the product was precipitated into water (250 ml). The solid was collected by filtration, washed with cold ether (20 ml) and dried to a constant weight to give 1. Yield : 93 %
1H NMR (DMSOd6) : 7.34 (d, 2H) ; 7.37 (d, 1H) ; 7.49 (t, 1H) ; 7.85 (t, 1H) ; 8.03 (dd, 1H) ; 8.34 (d, 2H).
MS - ESI : 241 [M+H]+
To a stirred solution of 1 (22.3 g ; 92.9 mmol) in EtOAc-EtOH (150 ml, 10:1) was added
10 % palladium on carbon (2.23 g). The resulting suspension was exposed to 1 atmosphere of hydrogen for 2.5 h. The catalyst was removed by filtration through a pad of Celite and the filtrate evaporated to afford 2 as a white solid.
Yield : 74 %
1H NMR (DMSOd6) : 5.14 (bs, 2H) ; 6.65 (d,>2H) ; 6.86 (d, 1H) ; 6.89 (d, 2H) ; 7.19 (t,
1H) ; 7.61 (t, 1H) ; 7.83 (dd, 1H). MS - ESI : 211 [M+H]+
Example 2 l-methyl-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole
Example 1 Example 2
To a stirred solution of Example 1 (0.100 g ; 0.25 mmol) in DMF (0.200 ml) was added NaH as a 60 % dispersion in oil (0.011 g ; 0.28 mmol). After the effervescence subsided, Mel (0.035 g ; 0.28 mmol) added and the reaction mixture was stirred at room temperature for 1 hour. The solution was purified by flash chromatography eluting with pentane / CH2C1280/20 to give Example 2. Yield : 37 % 1H NMR (DMSOd6) : 3.01 (s, 3H); 6.63 (d, IH) ; 6.80 (2 merged d, 4H) ; 6.97 (m, 2H) ; 7.18 (m, 3H) ; 7.27 (t, IH); 7.69 (t, IH) ; 7.87 (dd, IH) : 9.73 (bs, IH). MS - ESI : 394 [M-H]~
Example 3
3-[4-(2-cyanophenoxy)anilino]-4-(3-methoxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole
Example 3
To a stirred suspension of 5 (0.20 g ; 0.84 mmol) in cyclohexanol (0.50 ml) was added 2
(0.19 g ; 0.93 mmol) [see Example 1]. The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH C1 /
MeOH 95/5 to give Example 3 as an orange solid.
Yield : 35 % 1H NMR (DMSOd6) : 3.53 (s, 3H) ; 6.40 (s, IH) ; 6.61 (d, IH) ; 6.68 (d, IH) ; 6.76 (dd,
IH) ; 6.84 (m, 4H) ; 7.13 (t, IH) ; 7.27 (t, IH) ; 7.67 (t, IH) ; 7.84 (dd, IH) ; 9.76 (bs, IH)
10.34 (bs, IH).
MS - ESI : 410[M+HT
The starting material was prepared as follows
5
To a stirred solution of 3-methoxyphenylacetyl chloride (3.00 g ; 16.2 mmol) in ether (20 ml) at 0°C, was bubbled ammonia gas for 10 minutes. The solid formed was collected by filtration and re-crystallised from hot water (100 ml) to give 3 as a white crystalline solid. Yield : 44 %
1H NMR (DMSOd6) : 3.34 (s, 3H) ; 3.74 (s, 2H) ; 6.85 (m, 3H) ; 7.21 (t, IH) ; 7.43 (bs, 2H). MS - ESI : 166 [M+H]+
To a stirred solution of 3 (1.00 g ; 6.10 mmol) and diethyl oxalate (0.97 g ; 6.70 mmol) in DMF (10 ml) at -10 °C, was added solid potassium tert-butoxide (0.82 g ; 6.70 mmol). The resulting orange solution was stirred at -10 °C for 30 minutes and further solid potassium tert-butoxide (0.82 g, 6.70 mmol) was added. The resulting suspension was allowed to warm to room temperature and stirred for a further 30 minutes. Water (100 ml) was added and the pH of the solution decreased to 1 with concentrated aqueous HC1. The resulting precipitate was collected by filtration, washed with water (50 ml), ether (50 ml) and dried to a constant weight to give 4. Yield : 77 % 1H NMR (DMSOd6) : 3.78 (s, IH) ; 6.89 (dd, IH) ; 7.35 (t, IH) ; 7.57 (m, 2H) ; 10.67 (bs,
IH).
MS - ESI : 218 [M+H]+
To a stirred suspension of 4 (1.00 g ; 4.50 mmol) and CC14 (2.00 ml) in MeCN (10 ml), was added triphenylphosphine (3.59 g, 13.7 mmol). The solid dissolved in 1 hour and the resulting orange solution was stirred at room temperature for a further 2 hours. The solvent was removed and the residue remaining purified by flash chromatography eluting with pentane / CH C1 50/50 to give 5 as a yellow solid. Yield : 49 %
1H NMR (DMSOd6) : 3.78 (s, 3H) ; 7.14 (dd, IH) ; 7.36 (m, 2H) ; 7.75 (t, IH) ; 11.53 (bs,
IH).
MS - ESI : 236 [M-H]"
Example 4
3-[4-(2-cyanophenoxy)anihno]-4-(3-hydroxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole
Example 4
To a stirred solution of 11 (1.00 g ; 2.10 mmol) in EtOAc-EtOH (50 ml, 10:1) was added Pearlman's catalyst (0.50 g). The suspension was exposed to" 1 atmosphere of hydrogen for
5 hours. The catalyst was removed by filtration through Celite, the filtrate concentrated on a rotary evaporator and the residue purified by flash chromatography eluting with CH2C12 /
MeOH 95/5 to give Example 4 as an orange solid.
Yield : 65 % !H NMR (DMSOd6) : 6.39 (d, IH) ; 6.44 (s, IH) ; 6.56 (d, IH) ; 6.67 (d, IH) ; 6.89 (2 x merged d, 4H) ; 6.95 (t, IH) ; 7.26 (t, IH) ; 7.67 (t, IH) ; 7.86 (dd, IH) ; 9.25 (bs, IH) ;
9.50 (bs, IH) ; 10.72 (bs, IH).
MS - ESI : 398[M+H]+ The starting material was prepared as follows
To a stirred solution of 4-hydroxyphenylacetic acid (25.0 g ; 164 mmol) in MeOH (300 ml) was added concentrated sulphuric acid (1 ml). The solution was heated to reflux for 5 hours. The solvent was evaporated and the residue dissolved in CH2C1 (300 ml) and washed with water (5 x 50 ml). The organic layer was dried over magnesium sulfate and evaporated to dryness to give 6 as a dark brown oil.
Yield : 85 %
1H NMR (DMSOd6) : 3.58 (s, 2H) ; 3.62 (s, 3H) ; 6.68 (m, 3H) ; 7.11 (t, IH) ; 9.39 (bs,
IH).
MS - ESI : 166 [M+H]+
To 6 (23.1 g ; 139 mmol) was added concentrated aqueous NH4OH (150 ml) at 0°C. The reaction mixture was stirred overnight at room temperature. The resulting solution was evaporated and the residue neutralised with AcOH. The resulting solid was re-crystallised from hot n-butyl acetate (100 ml) to give 7 as an off-white solid. Yield : 60 %
1H NMR (DMSO) 3.35 (s, 2H) ; 6.68 (m, 3H) ; 6.85 (bs, IH) ; 7.10 (t, IH) ; 7.41 (bs, IH) ; 9.29 (bs, IH)
MS - ESI : 152 [M+H]+
To a stirred solution of 7 (5.00 g ; 33.0 mmol) and benzyl bromide (5.93 g ; 34.7 mmol) in
DMF (50 ml), was added solid potassium carbonate (6.84 g ; 49.5 mmol). The suspension was stirred at room temperature overnight. The suspension was triturated with water (100 xrύ) and the resulting precipitate was collected by filtration, washed with water (100 ml) and cold ether (10 ml) to give 8 as a white solid.
Yield : 99%
1H NMR (DMSO) 5.09 (s, 2H) ; 6.89 (m, 2H) ; 6.95 (m, IH) ; 7.35 (t, IH) ; 7.50-7.36 (m, 5H) ; 9.29 (bs, IH)
MS - ESI : 242 [M+H]+
To a stirred solution of 8 (6.00 g ; 24.9 mmol) and diethyl oxalate (4.00 g ; 27.4 mmol) in DMF (50 ml) at -10 °C, was added solid potassium tert-butoxide (3.35 g ; 24.7 mmol). The resulting orange solution was stirred at -10 °C for 30 minutes and further solid potassium tert-butoxide (3.35 g, 27.4 mmol) was added. The resulting suspension was allowed to warm to room temperature and stirred for a further 30 minutes. Water (300 ml) was added and the pH of the solution decreased to 1 with concentrated aqueous HC1. The resulting precipitate was collected by filtration, washed with water (3 x 50 ml), ether (50 ml) and dried to a constant weight to give 9. Yield : 83 %
1H NMR (DMSO) : 5.11 (s, 2H) ; 6.97 (dd, IH) ; 7.36 (m, 2H) ; 7.43 (t, 2H) ; 7.49 (m, 2H) ; 7.58 (d, IH) ; 7.66 (m, IH) ; 10.65 (bs, IH). MS - ESI : 294 [M-H]"
To a stirred suspension of 9 (5.00 g ; 16.9 mmol) and SOCl2 (10.1 g ; 84.7 mmol) in CH2C12 (20 ml), was added DMF (1 ml). The solid dissolved in 1 hour and the resulting orange solution was stirred at room temperature for a further 2 hours. The solvent was removed and the residue dissolved in MeOH (25 ml) and triturated with ether (100 ml). The solid was collected by filtration, washed with cold ether (20 ml) and dried to a constant weight to give 10. Yield : 63 %
1H NMR (DMSO) : 5.17 (s, 2H) ; 7.21 (dd, IH) ; 7.36-7.50 (m, 8H) ; 11.53 (bs, IH). MS - ESI : 312 [M-HT
To a stirred suspension of 10 (2.00 g ; 6.40 mmol) in cyclohexanol (5 ml) was added 2 (1.48 g ; 7.00 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH C1 / MeOH 95/5 to give 11 as an orange solid.
Yield : 74 %
1H NMR (DMSOd6) : 4.80 (s, 2H) ; 6.53 (s, IH) ; 6.62 (d, IH) ; 6.68 (d, IH) ; 6.84 (2 x merged d, 4H) ; 7.10 (t, IH) ; 7.21 (t, IH) ; 7.32 (m, IH) ; 7.36 (m, 3H) ; 7.57 (t, IH) ;
7.84 (dd, IH) ; 9.53 (bs, IH) ; 11.22 (bs, IH).
MS - ESI : 488 [M+H]+
Example 5 3-[4-(2-cyanophenoxy)anilino]-4-(3-phoshonoxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole
Example 5
To a stirred solution of 12 (0.47 g ; 0.80 mmol) in DCM (10 ml) at -10°C was added neat TFA (10 ml). The resulting dark orange solution was allowed to warm to room temperature and stirred for 1 hour. The solvent was evaporated to dryness and the residue taken up in MeCN (2.00 ml) and purified using OASIS resin eluting with MeCN / Η2O 30 / 70. The solvent was removed on a rotary evaporator and the pH of the remaining aqueous liquor adjusted to 7. The solution was lyopl ilised to give Example 5 as a yellow solid. Yield : 49 %
Η NMR (DMSOd6 -TFA) : 6.66 (d, IH) ; 6.68 (s, IH) ; 6.78 (t, IH) ; 6.83 (2 x merged d, 4H) ; 6.95 (d, IH) ; 7.14 (t, IH) ; 7.23 (t, IH) ; 7.68 (t, IH) ; 7.83 (dd, IH) ; 13.12 (bs, IH). MS - ESI : 478 [M+H]+
The starting material was prepared as follows :
Example 4 12
To a stirred solution of Example 4 (0.55 g ; 1.40 mmol) THF (10 ml) was added di-tert- butyl diethylphosphoramidite (0.66 g ; 2.63 mmol). The solution was stirred at room temperature for 2 hours. The orange solution was cooled to -60 °C and mCPBA (0.63 g ; 3.60 mmol) in CH C12 (50 ml) was added over 30 minutes. The reaction mixture was allowed to warm to room temperature, diluted with CH2C12 (50 ml) and washed with a 10%> (w/v) aqueous solution of Na S2O5 (10 ml) and water (2 x 10 ml). The organic layer was dried over MgSO , concentrated to ca. 2 ml and purified by flash chromatography eluting with CH2C12 / MeOH 98 / 3 to give 12 as an orange solid. Yield : 57 % 1HNMR (DMSOd6) : 1.43 (s, 18H) ; 6.67 (m, 3H) ; 6.83 (2 x merged d, 4H) ; 6.87 (d, IH) ; 7.15 (s, IH) ; 7.26 (t, IH) ; 7.69 (t, IH) ; 7.87 (dd, IH) ; 9.67 (bs, IH) ; 10.82 (bs, IH). MS - ESI : 588[M-H]" Example 6 3-[4-(2-cyanophenoxy)aniIino]-4-(3-nitrophenyl)-2,5-dioxo-2,5-dihydro-lH-pyrrole
To a stirred suspension of 15 (1.00 g ; 3.90 mmol) in cyclohexanol (3 ml) was added 2 (0.83 g ; 3.90 mmol) [see Example 1]. The reaction mixture was heated at 120 °C overnight. The solution was cooled to room temperature and triturated with ether (10 ml). The resulting precipitate was washed with ether (10 ml) and dried to a constant weight to give Example 6 as an dark brown solid. Yield : 74 % 1H NMR (DMSOd6) : 6.53 (d, 1Η) ; 6.84 (2 x merged d, 4Η) ; 7.25 (t, IH) ; 7.40 (m, IH) ; 7.47 (t, IH) ; 7.65 (t, IH) ; 7.72 (m, IH) ; 7.88 (dd, IH) ; 8.04 (dd, IH) ; 9.91 (bs, IH) ; 10.94 (bs, IH). MS - ESI : 427[M+H]+ The starting material was prepared as follows :
14
15 To a stirred slurry of ethyl 3-nitrophenylacetate (6.00 g ; 28.7 mmol) was added concentrated aqueous NH4OH (100 ml). The resulting suspension was stirred overnight at room temperature. The crystalline solid formed was collected by filtration, washed with water (100 ml), ether (20 ml) and dried to a constant weight in a vacuum oven to give 13. Yield : 52 %
1H NMR (DMSO) : 3.36 (s, 2H) ; 7.02 (bs, 2H) ; 7.64 (t, IH) ; 7.74 (d, IH) ; 8.14 (dd, IH)
; 8.17 (s, IH).
MS - ESI : 179 [M-HT
To a stirred solution of 13 (2.00 g ; 11.0 mmol) and diethyl oxalate (1.78 g, 12.2 mmol) in DMF (20 ml) at -10 °C, was added solid potassium tert-butoxide (1.48 g ; 12.1 mmol). The resulting orange solution was stirred at -10 °C for 30 minutes and further solid potassium tert-butoxide (1.48 g, 12.1 mmol) was added. The resulting suspension was allowed to warm to room temperature and stirred for a further 30 minutes. Water (200 ml) was added and the pH of the solution decreased to 1 with concentrated aqueous HCl. The resulting precipitate was collected by filtration, washed with water (3 x 50 ml), ether (50 ml) and dried to a constant weight to give 14. Yield : 78 % 1H NMR (DMSO) : 7.71 (t, IH) ; 8.10 (dd, IH) ; 8.45 (d, IH) ; 8.89 (s, IH) ; 10.71 (bs, IH).
MS - ESI : 233 [M+H]"
To a stirred suspension of 14 (2.00 g ; 8.50 mmol) and SOCl2 (5.08 g ; 42.7 mmol) in
CH2C12(10 ml), was added DMF (1.00 ml). The solid dissolved in 1 hour and the resulting orange solution was stirred at room temperature for a further 2 hours. The solvent was removed and the residue dissolved in MeOH (25 ml) and triturated with water (100 ml).
The solid was collected by filtration, washed with cold ether (20 ml) and dried to a constant weight to give 15.
Yield : 63 % 1H NMR (DMSO) : 7.90 (t, IH) ; 8.26 (d, IH) ; 8.41 (dd, IH) ; 8.63 (s, IH) ; 11.70 (bs,
IH).
MS - ESI : 251 [M-H]" Example 7 3-[4-(2-cyanophenoxy)anilino]-4-(3-aminophenyl)-2,5-dioxo-2,5-dihydro-lH-pyrrole
Example 6
To a stirred solution of Example 6 (1.00 g ; 2.30 mmol) in EtOAc-EtOΗ (33 ml, 10:1) was added 10%> palladium on carbon (0.100 g). The resulting suspension was exposed to 1 atmosphere of hydrogen for 1 hour. The catalyst was removed by filtration through Celite and the filtrate concentrated to ca. 10 ml on a rotary evaporator. The solution was triturated with ether (30 ml) and the solid collected by filtration, washed with ether (10ml) and dried to a constant weight to give Example 7. Yield : 69 %
1H NMR (DMSOd6) : 4.93 (bs, 2Η) ; 6.26 (d, IH) ; 6.38 (dd, IH) ; 6.81 (m, 7H) ; 7.24 (t, IH) ; 7.71 (t, IH) ; 7.85 (dd, IH) ; 9.43 (bs, IH) ; 10.72 (bs, IH). MS - ESI : 397[M+H]+
Example 8
3-[4-(2-cyanophenoxy)anilino]-4-[3-( α-glutamylamino)phenyl]-2,5-dioxo-2,5- dihydro-lH-pyrrole
Example 8
To a stirred solution of 17 (0.36 g ; 0.52 mmol) in CH2C12 (150 ml) was bubbled HCl gas at room temperature for 4 hours. The reaction was stopped and a 4.0 M solution of HCl in dioxane (20 ml) was added and the suspension was held at 0 °C overnight. The solid was collected by filtration and washed thoroughly with CH2C1 (150 ml). The solid was dissolved in water (5 ml) and the solution was purified using OASIS resin eluting with MeCN / H O 30/70. The organic solvent was removed on a rotary evaporator and the pH of the remaining aqueous liquor adjusted to 2. The solution was lyophilised to give
Example 8 as an orange solid.
Yield : 30 % .
1HNMR (DMSOd6) : 1.97 (m, 2H) ; 2.31 (m, 2H) ; 3.90 (t, IH) ; 6.53 (d, IH) ; 6.56 (d,
IH) ; 6.79 (d, 2H) ; 6.82 (d, 2H) ; 7.08 (t, IH) ; 7.21 (t, IH) ; 7.39 (s, IH) ; 7.52 (d, IH) ;
7.67 (t, IH) ; 7.82 (dd, IH) ; 9.37 (bs, IH) ; 10.45 (bs, IH) ; 10.76 (bs, IH).
MS - ESI : 524 [M-H]"
The starting material was prepared as follows
To a stirred solution of Example 7 (0.30 g ; 0.76 mmol) in DMF (0.50 ml) were added
DMAP (0.05 g ; 0.38 mmol) and Boc-Glu^Bu H (0.25 g ; 0.84 mmol). The resulting solution was cooled to 0 °C and solid EDCI (0.19 g ; 0.99 mmol) was added. The resulting red solution was stirred at room temperature for 2 hours. The reaction mixture was purified by flash chromatography eluting with CH2C12 / MeOH 98/2 to give 17 as a yellow foam.
Yield : 80 %
1H NMR (DMSOd6) : 1.37 (s, 18H) ; 1.72-1.91 (m, 2H) ; 2.21 (m, 2H) ; 4.07 (m, IH) ; 6.54 (d, IH) ; 6.84 (2 x merged d, 4H) ; 6.97 (d, IH) ; 7.08 (t, IH) ; 7.22 (t, IH) ; 7.35 (s,
IH) ; 7.52 (d, IH) ; 7.67 (t, IH) ; 7.84 (dd, IH) ; 9.54 (bs, IH) ; 9.86 (bs, IH) ; 10.45 (bs,
IH).
MS - ESI : 682 [M+H]+ Example 9 l-(l-hydroxyethyI)-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro- lH-pyrrole
18 Example 9
To. a stirred solution of l8 (0.50 g ; 0.98 mmol) in MeOΗ (30 ml) was added pyridinium - toluenesulfonate (0.25 g ; 0.98 mmol). The resulting solution was heated at 60 °C for 2 hours. The solvent was removed and the residue was purified by flash chromatography eluting with CΗ2C12 / MeOH 95/5 to give Example 9 as an orange solid. Yield : 96 %
1H NMR (DMSOd6) : 3.59 (m, 4H) ; 4.87 (t, IH) ; 6.66 (d, IH) ; 6.83 (2 x merged d, 4H) ; 6.96 (m, 2H) ; 7.18 (m, 3H) ; 7.27 (t, IH) ; 7.69 (t, IH) ; 7.87 (dd, IH) ; 9.72 (bs, IH). MS - ESI : 426 [M+H]+
The starting material was prepared as follows
Example 1 18
To a stirred suspension of Example 1 (0.50 g ; 1.30 mmol) in DCM (5 ml) were added triphenylphosphine (0.38 g ; 1.44 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.19 g ; 1.30 mmol). The solution was cooled to 0 °C and di-tert-butylazido carboxylate (0.33 g ; 1.44 mmol) in DCM (5.00 ml) was added over 10 minutes. The resulting dark brown solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated to ca. 5 ml and purified by flash chromatography eluting with CH2C1 / MeOH 97/3 to give 18 as an orange solid. Yield : 86 %
1H NMR (DMSOd6) : 1.46-1.73 (m, 6H) ; 3.61-3.80 (m, 6H) ; 4.63 (m, IH) ; 6.65 (d, IH) ; 6.81 (2 x merged d, 4H) ; 6.96 (m, 2H) ; 7.19 (m, 3H) ; 7.27 (t, IH) ; 7.71 (t, IH) ; 7.87 (dd, IH) ; 9.76 (bs, IH). MS - ESI : 508 [M-H]"
Example 10 l-(l-phosphonooxyethyl)-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5- dihy dro- lH-py rrole
19 Example 10
To a stirred solution of 19 (0.49 g ; 0.79 mmol) in DCM (50 ml) at -10°C was added neat
TFA (50 ml), The resulting dark orange solution was allowed to warm to room temperature and stirred for 1 hour. The solvent was evaporated to dryness and the residue taken up in
MeCN (2 ml) and purified using OASIS resin eluting with MeCN / Η2O 45/55. The organic solvent was removed on a rotary evaporator and the pH of the remaining aqueous liquor adjusted to 7. The solution was lyophihsed to give Example 10 as a yellow solid.
Yield : 28 %
1H NMR (DMSOd6-TFA) : 3.76 (t, 2H) ; 4.05 (m, 2H) ; 6.65 (d, IH) ; 6.83 (2 x merged d,
4H) ; 6.95 (m, 2H) ; 7.17 (m, 3H) ; 7.22 (t, IH) ; 7.66 (t, IH) ; 7.82 (dd, IH).
MS - ESI : 504 [M-H]" The starting material was prepared as follows
Example 9 19
To a stirred solution of Example 9 (0.40 g ; 0.94 mmol) in THF (10 ml) was added di-tert- butyl diethylphosphoramidite (0.22 g ; 0.85 mmol). The solution was stirred at room temperature for 2 hours. The orange solution was cooled to -60 °C and mCPBA (0.21 g ;
1.22 mmol) in CH2C1 (10 ml) was added over 30 minutes. The reaction mixture was allowed to warm to room temperature, diluted with CH C1 (50 ml) and washed with a 10%
(w/v) aqueous solution of Na S2O5 (10 ml) and water (2 x 10 ml). The organic layer was dried over MgSO4, concentrated to ca. 2 ml and purified by flash chromatography eluting with CH2C12 / MeOH 98/3 to give 19 as an orange solid.
Yield : 84 %
1H NMR (DMSOd6) : 1.39 (s, 18H) ; 3.78 (t, 2H) ; 4.09 (m, 2H) ; 6.66 (d, IH) ; 6.81 (2 x merged d, 4H) ; 6.95 (m, 2H) ; 7.18 (m, 3H) ; 7.27 (t, IH) ; 7.68 (t, IH) ; 7.88 (dd, IH) ; 9.76 (bs, IH).
MS - ESI : 616 [M-H]"
Example 11 3-[4-(2-cyanophenoxy)anilino]-4-pyrid-3-yl-2,5-dioxo-2,5-dihydro-lH-pyrrole
22 Example 11 To a stirred suspension of 22 (0.20 g ; 0.82 mmol) in methanol (5 ml) was added 2 (0.17 g ; 0.82 mmol). The reaction mixture was heated at 70 °C overnight. The resulting orange suspension was cooled to room temperature, evaporated to dryness and purified by flash chromatography eluting with CH2C12 / MeOH 96/4 to give Example 11 as an orange crystalline solid. Yield : 43 % 1H NMR (DMSOd6) : 6.84 (dd, IH) ; 6.93 (2 x merged d, 4H) ; 7.28 (t, IH) ; 7.69-7.78 (m, 3H) ; 7.88 (dd, IH) ; 8.29 (s, IH) ; 8.60 (d, IH) ; 10.18 (bs, IH) ; 11.10 (bs, IH). MS - ESI : 383 [M+H]+
The starting material was prepared as follows
To a stirred slurry of the ethyl 3-pyridylacetate (5.00 g ; 30.2 mmol) was added concentrated NH OH (50 ml), the resulting suspension was stirred at room temperature overnight. The solution was evaporated to dryness to afford a solid, which was washed with MeCN-ether (100 ml, 3:1) and dried to a constant weight in a vacuum oven to give 20 as a white solid. Yield : 76 % 1H NMR (DMSOd6) : 3.43 (s, 2H) ; 6.98 (bs, IH) ; 7.33 (m, IH) ; 7.52 (bs, IH) ; 7.69 (d, IH) ; 8.46 (m, 2H). MS - ESI : 137 [M+H]+
To a stirred solution of 20 (3.00 g ; 22.1 mmol) and diethyl oxalate (3.55 g ; 24.0 mmol) in DMF (50 ml) at -10 °C, was added solid potassium tert-butoxide (2.97 g ; 24.3 mmol). The resulting orange solution was stirred at -10 °C for 30 minutes and further solid potassium tert-butoxide (2.97 g, 24.3 mmol) was added. The resulting suspension was allowed to warm to room temperature and stirred for. a further 30 minutes. Water (300 ml) was added and the pH of the solution decreased to 1 with concentrated aqueous HCl. The resulting precipitate was collected by filtration, washed with water (5 x 50 ml), ether (50 ml) and dried to a constant weight to give 21 as a hydrochloride salt. Yield : 78 % MS - ESI : 189 [M+H]+
To a stirred suspension of 21 (1.00 g ; 4.40 mmol) and SOCl (2.63 g ; 22.1 mmol) in CH Ci2 (5 ml), was added DMF (2 ml). The solid dissolved in 2 hours and the resulting orange solution was stirred at room temperature for a further 2 hours. The solvent was , removed and the residue triturated with MeOH (50 ml). The solid was collected by filtration, washed with cold MeOH (10 ml) and dried to a constant weight to give 22. Yield : 87 %
1H NMR (DMSO) : 7.84 (m, IH) ; 8.42 (d, IH) ; 8.84 (dd, IH) ; 9.03 (s, IH) ; 11.75 (bs, IH). MS - ESI : 209 [M+H]+
Example 12 3-[4-(2-cyanophenoxy)anilino]-4-piperidin-l-yl-2,5-dioxo-2,5-dihydro-lH-pyrrole
25 Example 12 To a stirred solution of 25 (0.10 g ; 0.26 mmol) in DMF (0.20 ml) was added piperidine (0.07 g ; 0.78 mmol). The solution was stirred at 40 °C for 1 hour. The reaction mixture was purified by flash chromatography eluting with CH2C12 / MeCN 80/20 to give the free base as a red oil. The oil was dissolved in ether (10 ml) and a 4.0M solution of HCl in dioxane (1 ml) was added. The precipitate was collected by filtration, washed with ether (10 ml) and dried to a constant weight to give Example 12 as a HCl salt. Yield : 42 %
1H NMR (DMSOd6) : 1.39 (m, 4H) ; 1.46 (m, 2H) ; 3.38 (m, 4H) ; 6.79 (m, 3H) ; 7.03 (d, 2H) ; 7.19 (t, IH) ; 7.60 (t, IH) ; 7.62 (bs, IH) ; 7.85 (dd, IH) ; 10.24 (bs, IH). MS - ESI : 389 [M+H]+
The starting material was prepared as follows :
23 24
25
To a stirred solution of maleimide (1.00 g ; 10.3 mmol) in NMP (1 ml) was added 2 (2.16 g ; 10.3 mmol) [see Example 1]. The solution was heated at 110 °C overnight. The reaction mixture was cooled to room temperature and purified by flash chromatography eluting with CH2C12 / MeOH 97/3 to give 23 as an off-white solid. Yield : 90 % 1H NMR (DMSOd6) : 4.59 (m, IH) ; 6.20 (d, IH) ; 6.75 (d, 2H) ; 6.81 (d, IH) ; 7.00 (d, 2H) ; 7.21 (t,.lH) ; 7.63 (t, IH) ; 7.85 (dd, IH) ; 11.32 (bs, IH). MS - ESI : 307 [M+H]+ To a stirred solution of 23 (1.00 g ; 3.30 mmol) in DCM (50 ml) was added DDQ (0.74 g ; 3.30 mmol). The solution was stirred at room temperature overnight. The reaction mixture was filtered through Celite and the filtrate purified by flash chromatography eluting with CH2C12 / MeOH 96/4 to give 24 as a pale yellow solid. Yield : 35 % 1H NMR (DMSOd6) : 5.62 (s, IH) ; 6.95 (d, IH) ; 7.17 (d, 2H) ; 7.31 (t, IH) ; 7.57 (d, 2H) ; 7.69 (t, IH) ; 7.91 (dd, IH) ; 9.64 (bs, IH) ;11.32 (bs, IH). MS - ESI : 306 [M+H]+ To a stirred solution of 24 (1.18 g ; 3.90 mmol) in DMF (10 ml) was added N- bromosuccinimide (0.62 g ;.3.50 mmol). The solution was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography eluting with CH C12 / MeOH 98 / 2 to give 25 as a rust-coloured solid. Yield : 82 % ' 1H NMR (DMSOd6) : 6.96 (d, IH) ; 7.14 (d, 2H) ; 7.25-7.29 (m, 3H) ; 7.68 (t, IH) ; 7.89 (dd, IH) ; 9.68 (bs, IH) ; 11.12 (bs, IH). MS - ESI : 386 [M+H]+
Example 13 3- [6-(2-cyanophenoxy)pyrid-3-ylamino] -4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole
27 Example 13 To a stirred slurry of 27 (0.20 g ; 0.94 mmol) in cyclohexanol (2 ml) was added 3-chloro- 4-phenylpyrrole-2,5-dione (0.19 g ; 0.94 mmol). The resulting suspension was heat at 120°C overnight. The reaction mixture was cooled to room temperature and purified by flash cliromatography eluting with CΗ2C12 / MeCN 80/20 to give Example 13 as an orange solid. Yield : 37 % 1H NMR (DMSOde) : 6.83 (d, IH) ; 6.91 (d, 2H) ; 7.05 (dd, IH) ; 7.16 (m, 3H) ; 7.26 (dd,
IH) ; 7.34 (t, IH) ; 7.56 (m, IH) ; 7.74 (t, IH) ; 7.89 (dd, IH) ; 9.55 (bs, IH) ; 10.34 (bs,
IH).
MS - ESI : 383 [M+H]+
The starting material was prepared as follows :
0-NAA' — 2 NA>° ∞ — H,„A>cA:» 26 27
To a stirred slurry of 2-chloro-5-nitropyridine (2.00 g ; 12.6 mmol) and 2-cyanophenol (1.50 g ; 12.6 mmol) in DMF (5 ml) was added K2CO3 (2.21 g ; 16.4 mmol). The mixture was heated to 80°C for 4 hours. The suspension was cooled to room temperature and the product was precipitated into water (100 ml). The solid was filtered, washed with cold ether (30 ml) and dried to a constant weight to give 26.
Yield : 82 % 1H NMR (DMSOde) : 7.51-7.56 (m, 3H) ; 7.84 (t, IH) ; 8.01 (dd, IH) ; 8.74 (dd, IH) ; 9.07
(d, IH).
MS - ESI : 242 [M+H]+
To a stirred solution of 26 (2.50 g ; 10.4 mmol) in EtOAc-EtOH (100 ml, 10:1) was added 10% palladium on carbon. The resulting suspension was exposed to 1 atmosphere of hydrogen for 1.5 h. The catalyst was removed by filtration through a pad of Celite and the filtrate evaporated to afford 27 as a white solid.
Yield : 83 %
1H NMR (DMSOde) : 5.26 (bs, 2H) ; 6.96 (d, IH) ; 7.07 (d, IH) ; 7.16 (dd, IH) ; 7.30 (t, IH) ; 7.57 (d, IH) ; 7.69 (t, IH) ; 7.87 (dd, IH).
MS - ESI : 212 [M+H]+ Example 14 l-(l-aminoethyl)-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH- pyrrole
28 Example 14
To a stirred solution of 28 (0.25 g ; 0.48 mmol) in DCM (20 ml) at -10°C was added neat
TFA (20 ml). The resulting dark yellow solution was allowed to warm to room temperature and stirred for 1 hour. The solvent was evaporated to dryness and the residue purified by flash chromatography eluting with CΗ2C1 / MeOH-NH3 95/5 to give the free base as a yellow oil. The oil was dissolved in ether (10 ml) and a 4.0M solution of HCl in dioxane
(1.00 ml) was added. The resulting precipitate was collected by filtration and dried to a constant weight to give Example 14 as a HCl salt. ■
Yield : 92 %
1H NMR (DMSOde) : 3.09 (t, 2H) ; 3.79 (t, 2H) ; 6.64 (d, IH) ; 6.83 (2 x merged d, 4H) ;
6.97 (m, 2H) ; 7.20 (m, 3H) ; 7.28 (t, IH) ; 7.72 (t, IH) ; 7.86 (bs, IH) ; 7.88 (dd, IH).
MS - ESI : 423 [M-H]"
The starting material was prepared as follows
Example 1 28 To a stirred suspension of Example 1 (0.40 g ; 1.04 mmol) in DCM (4 ml) were added triphenylphosphine (0.30 g ; 1.16 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (0.17 g ; 1.04 mmol). The solution was cooled to -10 °C and DTAD (0.27 g ; 1.16 mmol) in DCM (5 ml) was added over 10 minutes. The resulting dark brown solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated to ca. 5 ml and purified by flash chromatography eluting with CH2C12 / MeOH 97/3 to give 28 as a dark yellow solid. Yield : 73 %
1H ΝMR (DMSOd6) : 1.39 (m, 9H) ; 3.17 (q, 2H) ; 3.57 (t, 2H) ; 6.66 (d, IH) ; 6.83 (2 x merged d, 4H) ; 6.97 (m, 2H) ; 7.18 (m, 3H) ; 7.27 (t, IH) ; 7.72 (t, IH) ; 7.87 (dd, IH) ; 9.70 (bs, IH). MS - ESI : 525 [M+H]+
Example 15 l-(l-Piperidin-l-ylethyl)-3-[4-(2-cyanophenoxy)aniIino]-4-phenyl-2,5-dioxo-2,5- dihydro-lH-pyrrole
Example 1 Example 15
To a stirred suspension of Example 1 (0.20 g ; 0.52 mmol) in DCM (2 ml) were added triphenylphosphine (0.153 g ; 0.58 mmol) and 1-piperidinethanol (0.07 g ; 0.52 mmol). The solution was cooled to -10 °C and DTAD (0.13 g ; 0.58 mmol) in DCM (1 ml) was added over 10 minutes. The resulting dark brown solution was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated to ca. 1.00 ml and purified by flash chromatography eluting with CΗ2C12 / MeOH 97/3 to give Example 15 as a yellow solid. Yield : 52 %
1H NMR (DMSOde) : 1.39 (m, 2H) ; 1.47 (m, 4H) ; 2.47 (m, 4H) ; 2.50 (m, 2H) ; 3.62 (t,
2H) ; 6.64 (d, IH) ; 6.85 (d, 2H) ; 6.98 (m, IH) ; 7.18 (m, 2H) ; 7.25 (t, IH) ; 7.56-7.69 (m,
4H) ; 7.71 (t, IH) ; 7.88 (dd, IH) ; 9.72 (bs, IH).
MS - ESI : 491 [M-H]"
Example 16
3-[4-(2-cyanophenoxy)anilmo]-4-(4-hydroxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole
32 Example 16
To a stirred solution of 32 (0.50 g ; 1.00 mmol) in EtOAc-EtOΗ (20 ml, 10:1) was added Pearlman's catalyst (0.10 g). The suspension was exposed to 1 atmosphere of hydrogen for 2.5 hours. The catalyst was removed by filtration through Celite, the filtrate concentrated on a rotary evaporator and the residue triturated with CΗ2C1 (30 ml). The solid was collected by filtration and dried to a constant weight in vacuum oven to give Example 16 as an orange solid. Yield : 76 %
1H NMR (DMSOde) : 6.53 (d, 2H) ; 6.63 (d, IH) ; 6.82 (m, 6H) ; 7.22 (t, IH) ; 7.73 (t, IH) ; 7.81 (d, IH) ; 9.29 (bs, IH) ; 9.44 (bs, IH) ; 10.34 (bs, IH). MS - ESI : 398 [M+H]+ The starting material was prepared as follows :
To a stirred solution of 4-hydroxyphenylacetamide (5.00 g ; 33.0 mmol) and benzyl bromide (5.93 g ; 34.7 mmol) in DMF (30 ml), was added solid potassium carbonate (3.86 g ; 36.3 mmol). The suspension was stirred at room temperature overnight. The suspension was triturated with water (100 ml) and the resulting precipitate was collected by filtration, washed with water (100 ml) and cold ether (10 ml) to give 29 as a white solid.
Yield : 91%
1H NMR (DMSO) 3.30 (s, 2H) ; 5.09 (s, 2H) ; 6.82 (bs, 2H) ; 6.96 (d, 2H) ; 7.19 (d, 2H) ;
7.45 (m, 5H).
MS - ESI : 242 [M+H]+
To a stirred solution of 29 (5.70 g ; 23.7 mmol) and diethyl oxalate (3.80 g, 26.0 mmol) in DMF (50 ml) at -10 °C, was added solid potassium tert-butoxide (2.93 g ; 26.0 mmol). The resulting orange solution was stirred at -10 °C for 30 minutes and further solid potassium tert-butoxide (2.93 g, 26.0 mmol) was added. The resulting suspension was allowed to warm to room temperature and stirred for a further 30 minutes. Water (300 ml) was added and the pH of the solution decreased to 1 with concentrated aqueous HCl. The resulting precipitate was collected by filtration, washed with water (3 x 50 ml), ether (50 ml) and dried to a constant weight to give 30. Yield : 82 % 1H NMR (DMSO) : 5.14 (s, 2H) ; 7.09 (d, 2H) ; 7.34-7.48 (m, 5H) ; 7.97 (d, 2H) ; 10.57
(bs, IH).
MS - ESI : 295 [M-H]"
To a stirred suspension of 30 (4.14 g ; 14.0 mmol) and CC14 (20 ml) in MeCN (200 ml), was added solid triphenylphosphine (11.0 g ; 42.0 mmol). The solid dissolved in 1 hour and the resulting orange solution was stirred at room temperature for a further 2 hours. The solvent was removed and the residue purified by flash chromatography eluting with CH2C12 / pentane 50/50 to give 31 as a yellow solid. Yield : 70 %
1H NMR (DMSO) : 5.21 (s, 2H) ; 7.19 (d, 2H) ; 7.38 (m, IH) ; 7.43 (m, 2H) ; 7.49 (d, 2H) ; 7.88 (d, 2H) ; l 1.40 (bs, IH). MS - ESI : 313 [M-H]"
To a stirred suspension of 31 (1.00 g ; 3.20 mmol) in cyclohexanol (5 ml) was added 2 (0.67 g ; 3.20 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH2C12 / MeOH 99/1 to give 32 as an orange solid. Yield : 48 % 1H NMR (DMSOde) : 5.04 (s, 2H) ; 6.71 (d, 2H) ; 6.81 (m, 5H) ; 6.84 (d, 2H) ; 7.19 (t, IH) ; 7.35 (m, 5H) ; 7.61 (t, IH) ; 7.84 (dd, IH) ; 9.03 (bs, IH) ; 11.05 (bs, IH). MS - ESI : 488[M+H]+
Example 17 3-[4-(4-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole
34 Example 17 To a stirred suspension of 3-chloro-4-phenylpyrrole-2,5-dione (0.20 g ; 0.97 mmol) in cyclohexanol (5 ml) was added 34 (0.22 g ; 1.06 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH2C12 / MeOH 97/3 to give Example 17 as an orange solid. Yield : 57 %
1H NMR (DMSOd6) : 6.82 (d, 2H) ; 6.84 (d, 2H) ; 6.96 (m, 4H) ; 7.19 (m, 3H) ; 7.87 (d, 2H) ; 9.57 (bs, IH) ; 10.62 (bs, IH). MS - ESI : 382[M+H]+
The starting material was prepared as follows:
To a stirred slurry of l-fluoro-4-nitrobenzene (3.93 g ; 27.7 mmol) and 4-cyanophenol (3.00 g ; 25.2 mmol) in DMF (10 ml) was added K2CO3 (4.53 g ; 32.8 mmol). The mixture was heated to 90 °C overnight. The suspension was cooled to room temperature and the product was precipitated into water (50 ml). The solid was filtered and washed with cold ether (10 ml) to give 33.
Yield : 93 % 1H NMR (DMSOd6) : 7.35 (m, 4H) ; 7.98 (d, 2H) ; 8.33 (d, 2H).
MS - ESI : 241 [M+H]+
A stirred solution of 33 (5.00 g ; 92.9 mmol) in EtOAc-EtOH (55 ml, 10:1) was added 10% palladium on carbon (0.50 g). The resulting suspension was exposed to 1 atmosphere of hydrogen for 1.5 h. The catalyst was removed by filtration through a pad of Celite and the filtrate evaporated to afford 34 as a white solid. Yield : 74 % 1H NMR (DMSOde) : 5.13 (bs, 2H) ; 6.65 (d, 2H) ; 6.84 (d, 2H) ; 7.00 (d, 2H) ; 7.79 (d,
2H).
MS - ESI : 211 [M+H]+
Example 18
3-[4-(3-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole
36 Example 18 To a stirred suspension of 3-clιloro-4-phenylpyrrole-2,5-dione (0.20 g ; 0.97 mmol). in cyclohexanol (5 ml) was added 36 (0.22 g ; 1.06 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH2C12 / MeOH 97/3 to give Example 18 as an orange solid. Yield : 67 %
1H NMR (DMSOde) : 6.72 (d, 2H) ; 6.82 (d, 2H) ; 6.96 (m, 2H) ; 7.22 (m, 5H) ; 7.61 (m, 2H) ; 9.54 (bs, IH) ; 10.75 (bs, IH). MS - ESI : 382 [M+H]+
The starting material was prepared as follows:
The starting material was prepared as follows:
To a stirred slurry of l-fluoro-4-nitrobenzene (3.93 g ; 27.7 mmol) and 3-cyanophenol (3.00 g ; 25.2 mmol) in DMF (10 ml) was added K2CO3 (4.53 g ; 32.8 mmol). The mixture was heated to 90 °C overnight. The suspension was cooled to room temperature and the product was precipitated into water (50 ml). The solid was filtered and washed with cold ether (10 ml) to give 35. Yield : 96 % 1H NMR (DMSOd6) : 7.26 (d, 2H) ; 7.59 (dd, IH) ; 7.71 (t, IH) ; 7.79 (m, 2H) ; 8.31 (d, 2H). MS - ESI : 241 [M+H]+
To a stirred solution of 35 (5.00 g ; 92.9 mmol) in EtOAc-EtOH (55 ml, 10:1) was added 10%) palladium on carbon. The resulting suspension was exposed to 1 atmosphere of hydrogen for 1.5 hours. The catalyst was removed by filtration through a pad of Celite and the filtrate evaporated and the residue purified by flash chromatography eluting with
CH2C12 / MeOH 97/3 to give 36 as a white solid.
Yield : 85 % 1H NMR (DMSOde) : 5.10 (bs, 2H) ; 6.81 (d, 2H) ; 6.84 (d, 2H) ; 7.21 (dd, IH) ; 7.27 (s,
IH) ; 7.55 (m, 2H).
MS - ESI : 211 [M+H]+
Example 19 l-t-butoxycarbonyl-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro- lH-pyrrole
Example 1 Example 19 .
To a stirred solution of Example 1 (1.00 g ; 2.62 mmol) in MeCN (10 ml) were added DMAP (0.016 g, 0.13 mmol) and di-tert-butyl dicarbonate (0.58 g ; 2.67 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was purified by flash chromatography eluting with pentane / CH2C1250/50 to give Example 19. Yield : 67 %
1 H NMR (DMSOde) 1-56 (s, 9H) ; 6.62 (d, IH) ; 6.79 (d, 2H) ; 6.86 (d, 2H) ; 6.97 (m, IH) ; 7.23 (m, 3H) ; 7.28 (t, IH) ; 7.68 (t, IH); 7.88 (dd, IH) : 9.90 (bs, IH). MS - ESI : 480 [M-H]"
Example 20 3-[N-methyl-4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole
37 Example 20
To a stirred solution of 37 (0.12 g ; 0.24 mmol) in DCM (10 ml) was added TFA (10 ml). The resulting orange solution was stirred at room temperature for 1 hour. The solvent was evaporated and the residue purified by flash chromatography eluting with CH2C1 / MeOH
99/1 to give Example 20 as a dark red solid.
Yield : 43 %
1H NMR (DMSOde) 3.52 (s, 3H) ; 6.53 (d, IH) ; 6.88 (d, 2H) ; 7.12 (m, 4H) ; 7.25 (m, 4H) ; 7.65 (t, IH); 7.85 (dd, IH) : 10.34 (bs, IH).
MS - ESI : 394 [M-H]"
The starting material was prepared as follows:
Example 19 37
To a stirred solution of Example 19 (0.20 g ; 0.42 mmol) in THF (1 ml) was added NaH as a 60% dispersion in mineral oil (0.017 g ; 0.42 mmol) at -10 °C. Dimethyl sulfate (0.064 g ; 0.54 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The solution was purified by flash cliromatography eluting with CH2C12 / MeOH 99/1 to give 37. Yield : 59 %
1H NMR (DMSOde) 1.52 (s, 9H) ; 3.52 (s, 3H) ; 6.48 (d, IH) ; 6.88 (d, 2H) ; 7.11 (d, 2H) ; 7.12-7.29 (m, 6H) ; 7.71 (t, IH); 7.88 (dd, IH). MS - ESI : 396 [M(-Boc)+H]+
Example 21
3-[4-(2-cyanophenoxy)anilino]-4-(3,4-dichIorophenyI)-2,5-dioxo-2,5-dihydro-lH- pyrrole
42 Example 22 To a stirred suspension of 42 (0.05 g ; 0.18 mmol) in cyclohexanol (0.20 ml) was added 2 (0.04 g ; 0.18 mmol). The reaction mixture was heated at 120 °C overnight. The solution was purified by flash chromatography eluting with CH2C1 / MeOH 97/3 to give Example 22 as a yellow solid. Yield : 42 %
1H NMR (DMSOde) : 6.67 (d, IH) ; 6.87-6.95 (m, 5H) ; 7.08 (s, IH) ; 7.28 (t, IH) ; 7.44 (d, IH) ; 7.69 (t, IH) ; 7.87 (dd, IH) ; 9.79 (bs, IH) ; 10.79 (bs, IH). MS - ESI : 450 [M+H]+
The starting material was prepared as follows
40 41
42
To a stirred suspension of 3,4-dichlorophenylacetic acid (0.50 g ; 2.40 mmol) in DMF (0.50 ml) were added K2CO3 (0.41 g ; 2.97 mmol) and dimethylsulfate (0.38 g ; 2.97 mmol). The reaction mixture was stirred at room temperature for 2 hours. Concentrated aqueous NH4OH (20 ml) was added and the resulting suspension stirred at room temperature overnight. The precipitate was collected by filtration, washed with water (10 ml) and dried to a constant weight in a vacuum oven to give 40 as a white solid. Yield : 48 %
1H NMR (DMSOde) : 3.42 (s, 2H) ; 6.98 (bs, IH) ; 7.26 (dd, IH) ; 7.53 (bs, 2H) ; 7.58 (d, IH).
MS - ESI : 202 [M-H]"
To a stirred solution of 40 (0.15 g ; 0.74 mmol) and diethyl oxalate (0.12 g ; 0.81 mmol) in DMF (2 ml) at -10 °C, was added solid potassium tert-butoxide (0.10 g ; 0.81 mmol). The resulting orange solution was stirred at -10 °C for 30 minutes and fiirther solid potassium tert-butoxide (0.10 g, 0.81 mmol) was added. The resulting suspension was allowed to warm to room temperature and stirred for a further 30 minutes. Water (10 ml) was added and the pH of the solution decreased to 1 with concentrated aqueous HCl. The resulting precipitate was collected by filtration, washed with water (3 5 ml), cold ether (1 ml) and dried to a constant weight to give 41. Yield : 82 %
1H NMR (DMSO) : 7.58 (d, IH) ; 8.06 (d, IH) ; 8.30 (s, IH) ; 10.23 (bs, IH). MS - ESI : 256 [M-H]"
To a stirred suspension of 41 (0.14 g ; 0.56 mmol) and SOCl2 (0.18 g ; 2.80 mmol) in CH2C-2 (2 ml), was added DMF (0.5 ml). The solid dissolved in 2 hours and the resulting yellow solution was stirred at room temperature for a further 2 hours. The solvent was removed and the residue dissolved in MeOH (0.50 ml). Water (5 ml) was added and the resulting precipitate was collected by filtration, washed with water (10 ml) and dried to a constant weight to give 42. Yield : 59 %
1H NMR (DMSO) : 7.79 (d, IH) ; 7.88 (d, IH) ; 8.02 (s, IH) ; 11.70 (bs, IH). MS - ESI : 274 [M-H]"

Claims

Claims
1 A compound of Formula (I) , wherein:
Formula (I) Ar is selected from phenyl, heteroaryl or heterocyclyl; Ar is selected from phenyl or heteroaryl; Ar is selected from phenyl or a monocyclic heteroaryl ring comprising between 1 and 3 heteroatoms selected from N, O or S; R1 is selected from hydrogen, -C(O)-R2, -C(O)-O-R2, -C(O)N(R4)-R2 and -CH2-R2, wherein the group N(R4)-R2 may optionally form a 4-6 membered heterocyclic ring; R is selected from: hydrogen, halo, cyano, amino, hydroxy, -SO3, Chalky I, Ci-βalkoxy, Cι-6alkanoyloxy, phosphonoxy, C2-6alkenyl, cycloalkyl, cycloalkylCMalkyl-, heterocyclyl, heterocyclylCι-4alkyl-, aryl and wherein an alkyl or alkenyl chain or a carbocyclyl, heterocyclyl or heteroaryl ring in R2 is optionally substituted by one or more groups selected R is selected from CMalkyl, CMalkoxy, CMalkanoyl, hydroxy, amino, carbamoyl, -SO3, phosphonoxy, -C(O)-O-R4 and -N(R4)R5, wherein the group - N(R4)R5 may optionally form a 4-6 membered heterocyclic ring; R4 and R5 are independently selected from: hydrogen, CMalkyl and C(O)-R6, R is CMalkyl optionally substituted with carboxy or amino; R7 is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, Ci^alkyl, hydroxyCMalkyl, aminoCι-4alkyl, CMalkoxy and CMalkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified; R8 is selected from halo, hydroxy, nitro, amino, cyano, phosphonooxy, CMalkyl, hydroxyCMalkyl, aminoCι-4alkyl, and CM lkanoyl wherein the amino group is optionally substituted by an amino acid residue and the hydroxyl group is optionally esterified; R9 is selected from: cyano, halo and nitro; R10 is selected from hydrogen or CMalkyl; p is an integer from 0 to 3; q is an integer from 0 to 3; r is an integer from 1 to 3; or a salt thereof.
2. A compound according to Claim 1 wherein Ar1 is selected from: phenyl, pyridyl and piperidinyl.
3. A compound according to Claim 1 or Claim 2 wherein Ar2 is selected from: phenyl and pyridyl.
4. A compound according to any one of the preceding claims wherein Ar3 is selected from: phenyl, pyridyl and pyrimidinyl.
5. A compound according to any one of the preceding claims wherein R is amino, CMalko y, hydroxy or phosphonoxy, wherein the amino group is optionally substituted by an amino acid residue and the hydroxy group is optionally esterified.
6. A compound according to Claim 5 wherein the amino acid residue is independently derived from: glutamic acid, serine, threonine, arginine, glycine, alanine, β-alanine or lysine.
7. A compound selected from: 3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH-pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-hydroxyphenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-phoshonoxyphenyl)-2,5-dioxo-2,5-dihydiO-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-(3-aminophenyl)-2,5-dioxo-2,5-dihydro-lH- pyrrole; 3-[4-(2-cyanophenoxy)anilino]-4-[3-(α-glutamylamino)phenyl]-2,5-dioxo-2,5- dihydro-lH-pyrrole; l-hydroxyethyl-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5-dihydro-lH- pyrrole; l-(phosphonooxyethyl)-3-[4-(2-cyanophenoxy)anilino]-4-phenyl-2,5-dioxo-2,5- dihydro- 1 H-pyrrole; or salt thereof.
8. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 7.
9. The use of a compound according to any one of claims 1 to 7, or pharmaceutically-acceptable salt thereof, for the manufacture of a medicament to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis.
10. The use of a compound according to any one of claims 1 to 7, or pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for the inhibition of tubulin polymerization.
11. A process for preparing a compound of Formula (I), or salt thereof, which process (wherein AR1, AR2, AR3, R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y, p, q and r are, unless otherwise specified, as defined in Claim 1), comprises: a) Reaction of a compound of Formula (A) with a compound of Formula (B) wherein Z1 is a leaving group;
Formula (A) Formula (B) b) For compounds of Formula (I) wherein R1 is other than hydrogen, Reaction of a compound of Formula (I) wherein R1 is hydrogen with a compound of formula0 R -Z , wherein Z is a leavmg group; c) Reaction of a compound of Formula (C) with a compound of Formula (D) wherein: (i) Z3 is -Y-H and Z is a leaving group; or (ii) Z is a leaving group and Z4 is with a compound of formula H-Y-;
Formula (D) d) for compounds of Formula (I) wherein an R7 group is an amino group substituted with an amino acid residue, reaction of a compound of Formula (E) with an amino acid or protected amino acid;
Formula (E) n e) for compounds of Formula (I) wherein an R group is phosphonoxy, reaction of a compound of Formula (F) with a protected activated phosphate derivative;
Formula (F) f) for compounds of Formula (I) wherein an R7 group is an esterified hydroxyl group, reaction of a compound of Formula (F) with a carboxylic acid or an activated carboxylic acid derivative; g) Reaction of a compound of Formula (G) with a compound of Formula (H), wherein; (i) Z5 is hydrogen and Z6 is a leaving group; or (ii) Z5 is a leaving group and Z is hydrogen;
Formula (G) Formula (H) and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (i); ii) removing any protecting groups; iii) foπning a salt.
EP05738031A 2004-04-26 2005-04-22 3,4-disubstituted maleimides for use as vascular damaging agents Withdrawn EP1742911A1 (en)

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