WO2004046123A1 - Benzoxazole, benzthiazole and benzimidazole derivatives useful as heparanase inhibitors - Google Patents

Abstract

Compounds of formula (I): wherein R1, R2 and R3 are independently, hydrogen, halogen, CF3, OR6, NR7 R8, NR8COR10, NR8SO2R10 or C 1-6 alkyl optionally substituted by hydroxy, C 1-6 alkoxy or NR7R8; R4 is NR8CONR8R9; and R5 formula (Ia) is methods for their synthesis, pharmaceutical compositions comprising them and their use in medicine, in particular for the treatment of cancer.

Description

BENZOXAZOLE , BENZTHIAZOLE AND BENZIMIDAZOLE DERIVATIVES USEFUL AS HEPARANASE . INHIBITORS

The present invention relates to novel compounds useful as inhibitors of heparanase, methods for their synthesis, pharmaceutical compositions comprising the novel compounds and their use in medicine, in particular for the treatment of cancer.

The extracellular matrix (ECM) is not only the structural surround for cells in a multicellular organism but also acts as a key modulator and mediator of their physiology, differentiation, organisation and repair. Receptor ligands are stored, concentrated, processed and presented to the cell surface by components of the ECM, which include free and protein-bound heparan sulfate proteoglycans, free and protein-bound chondroitins, collagens, and a variety of cell-adhesive integrins, such as, fibronectin. As such, the ECM is in a constant flux of degradation and synthesis by neighbouring cells.

The ECM is also the principal barrier to tumour growth and metastasis. For a tumour cell to penetrate this barrier it must sufficiently degrade the ECM components so that there is ample space to traverse. The ECM must also be degraded in order to provide avenues for new blood vessel formation (angiogenesis) which are needed to supply the increased nutrient requirements of rapidly growing tumours.

A broad spectrum of degradative enzymes are secreted by tumor cells to break down the ECM's complex composition. However, recent studies have demonstrated that inhibiting even just one ECM degrading enzyme appears to provide significant benefit in treating cancer. For example, inhibitors of certain proteases that degrade ECM protein component have been studied in preclinical and clinical trials as anticancer agents.

Carbohydrates represent a large fraction of the total mass of all ECM. Therefore, tumour cells secrete large quantities of carbohydrate degrading enzymes as they penetrate the ECM. In fact, there is good correlation between raised levels of carbohydrate processing enzymes, such as heparanases, secreted by tumour cells and their metastatic potential (e.g. Nlodavsky et al., (1994) Invasion Metastasis, 14:290- 302; (1999) Nature Medicine, 5:793-802). Heparanases, are enzymes that can degrade heparan sulfate as well as heparin and heparan sulfate proteoglycans.

The carbohydrate fragments generated by glycosidase action also promote the cancer phenotype since many are growth-stimulatory. For example, heparanase activity can release heparan sulfate fragments, which can increase the potency of a variety of growth factors, and can also elicit cell growth stimulation once bound by an appropriate cell surface receptor (e.g. Folkman and Shing (1992) Adv. Exp. Med. Biol., 313:355-64).

Inhibitors of ECM carbohydrate degradation are potent anticancer agents. For example, sulfated oligosaccharide heparanase inhibitors block tumour metastasis in some animal models (Nlodavsky et al., (1994) Invasion Metastasis, 14:290-302; Parish et al., (1999) Cancer Res., 59:3433-41). Furthermore, heparanase activity results in the release of growth factors that can stimulate angiogenesis and promote tumour growth (Bashkin et al., (1989) Biochemistry, 28:1737-43).

Heparanase activity correlates with the ability of activated cells of the immune system to leave the circulation and elicit both inflammatory and autoimmune responses. Interaction of platelets, granulocytes, T and B lymphocytes, macrophage and mast cells with the subendothelial ECM is associated with degradation of heparan sulfate by heparanase activity (Nlodavsky et al., (1992) Invasion Metastasis, 12, 112-127). Heparanase inhibitors may be able to prevent or inhibit the progression of autoimmime and inflammatory diseases.

Heparinomimetic compounds are currently being developed as anticoagulant and antiproliferative agents for the control of thrombotic and proliferative disorders (Demir et al., Clin. Appl. Thromb. Hemost., 2001 Apr; 7(2): 131-40). Thus, a secondary function of heparanase inhibitors may have a role in cardiovascular diseases including blood-clotting conditions, for example thromboembolic disease, arterial thrombosis and restenosis.

WO01/35967 discloses the use of heparanase inhibitors for the treatment or prevention of congestive heart failure e.g. primary cardiomyopathy. Associated conditions treated or prevented with the inhibitor are especially peripheral oedemas, pulmonary and hepatic congestion, dyspnoea, hydrothorax and ascites. Renal problems, e.g. nocturia can also be treated.

WO02/060374 discloses benzimidazole, benzoxazole and benzothiaziole derivatives as heparanase inhibitors.

The present invention provides a novel class of compounds, which can be used as inhibitors of heparanase. These compounds provide the opportunity for establishing new treatments for cancer, angiogenesis, inflammatory and autoimmune conditions and cardiovascular diseases.

The invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

(I) wherein

R¹, R² and R³ are independently, hydrogen, halogen, CF₃, OR⁶, NR⁷R⁸, NR⁸COR¹⁰, NR⁸SO₂R¹⁰ or Cι_₆ alkyl optionally substituted by hydroxy, C .₆ alkoxy or NR⁷R⁸; R⁴ is NR⁸CONR⁸R⁹;

R⁵ is

wherein one of X and Y is R¹¹ and the other is hydrogen or halogen; or X and Y together with the carbon atoms to which they are attached form a fused six-membered aromatic ring; Z is NR⁸, O or S;

R⁶ is hydrogen or Cι_₆ alkyl, C₃.₆ alkenyl or C₃.₆ alkynyl any of which can optionally be substituted by hydroxy, C .₆ alkoxy or NR⁷R⁸;

R⁷ is hydrogen or Cι_₆ alkyl or C₃.₆ alkenyl either of which is optionally substituted by d-β alkoxy or a 5- or 6-membered heterocyclic ring containing up to three heteroatoms selected from NR⁸, S and O;

R⁸ is hydrogen or Cι_₆ alkyl; or the groups R⁷ and R⁸ may together with the nitrogen to which they are attached form a 5- or 6- membered ring which optionally contains up to two further heteroatom selected from NR⁸, S and O;

R⁹ is Ci-io alkyl or C₃-ι₀ alkenyl wherein a -CH₂- group other than that adjacent to the N may be replaced by -O- and wherein the alkyl or alkenyl is substituted by one or more carboxylic acid or tetrazole groups; or in R⁴ the groups R⁸ and R⁹ may together with the nitrogen to which they are attached form a 5- or 6-membered ring, which is substituted with one or more carboxylic acid or tetrazole groups;

R¹⁰ is Cι.₆ alkyl; and

R¹¹ is hydrogen, halogen, Cι_₆ alkyl, OR⁶ or phenyl optionally substituted by one or more substituents selected from halogen, .₆ alkyl, CF₃, OCF₃, OR⁶, CN and methylenedioxo; or a 5- to 10- membered heteroaryl group containing up to three heteroatoms selected from O, N and S, which heteroaryl group may optionally be substituted by one or more substituents selected from Cι-₆ alkyl, -β alkoxy and halogen.

Preferably R¹, R² and R³ are independently, hydrogen, halogen, CF₃, OR⁶, NR⁷R⁸, NR⁸COR¹⁰, NR⁸SO₂R¹⁰ or -β alkyl optionally substituted by hydroxy or Cι-₆ alkoxy.

More preferably R¹, R² and R³ are independently, hydrogen, halogen, OR⁶, NR⁷R⁸, or Cι_₆ alkyl optionally substituted by hydroxy or Cι-₆ alkoxy.

Preferably Z is O.

Preferably R⁶ is hydrogen or Cχ.₆ alkyl or C₃.₆ alkenyl either of which can optionally be substituted by hydroxy or Cι.₆ alkoxy.

R^s is preferably:

Preferably at least one of X and Y is other than hydrogen.

X is preferably R¹¹.

Preferably R¹¹ is phenyl optionally substituted by one or more substituents selected from halogen, Cι-₆ alkyl, CF₃, OCF₃, OR⁶, CN and methylenedioxo; or a 5- to 10-membered heteroaryl group containing up to three heteroatoms selected from O, N and S which heteroaryl group may optionally be substituted by one or more substituents selected from C .₆ alkyl, .₆ alkoxy and halogen.

More preferably R¹ is hydrogen, OR⁶ or NR⁷R⁸.

More preferably R² is hydrogen.

More preferably R³ is hydrogen, halogen or OR⁶.

In the group NR⁷R⁸, when the R⁷ and R⁸ substituents, together with the nitrogen to which they are attached form a 5- or 6-membered ring, the ring may be, for example, morpholine, piperazine or N- methyl piperazine.

When R^π is a 5- to 10-membered heteroaryl group containing up to three heteroatoms selected from O, N and S, the group may be, for example, benzofuran or benzothiophene.

The configuration of the R groups is preferably,

The term "alkyl" and "alkylene" as used herein whether on its own or as part of a larger group e.g. "alkoxy" includes both straight and branched chain radicals. The term alkyl also includes those radicals wherein one or more hydrogen atoms are replaced by fluorine. The terms "alkenyl", "alkenylene", "alkynyl" and "alkynylene" should be interpreted accordingly.

The term "heteroaryl" as used herein means a 5- to 10-membered, substituted or unsubstituted, mono- or bicyclic aromatic ring containing up to three heteroatoms selected from oxygen, nitrogen and sulfur. Examples include benzofuran e.g. 2-benzofuran, benzothiophene e.g. 2-benzothiophene, benzoxazole e.g. 2-benzoxazole, benzothiazole e.g. 2-benzothiazole, quinoline, isoquinoline, pyridine, pyrimidine, pyrazine, oxadiazole, imidazole, tetrazole, furan and thiophene.

Specific compounds of the invention that may be mentioned include those provided in the examples. A preferred list of specific compounds of the invention include those compounds provided in Examples 2, 9, 14, 26, 27, 28, 29, 30, 31, 34, 35 and 36. For clarity, example compounds a) are esters of example compounds b).

The compounds of the invention preferably have a molecular weight of less than 800, more preferably less than 600.

Suitable pharmaceutically acceptable salts of the compounds include those derived from inorganic and organic bases. Examples of suitable inorganic bases include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases. Such organic bases are well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; meglumine; and the like.

Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of formula (I) with a solution of the base, for example, potassium or sodium hydroxide, or potassium or sodium hydrogen carbonate.

The invention also includes prodrugs of the aforementioned compounds. A prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug, which is converted to the active ingredient or drug in the body. Examples of prodrugs include pharmaceutically acceptable esters, including Cι-C₆ alkyl esters and pharmaceutically acceptable amides, including secondary - alkylamides.

Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. Where a compound contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof. When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1% w/w of the other isomers.

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably at least 10% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.

The compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.

The invention also provides a process for preparing a compound of formula (I), from a compound of formula (II):

dD wherein R^x is NO₂, NHR⁸, or NCO and R¹, R², R³, R⁵ _.and R⁸ are as defined for formula (I), by the processes described below.

A compound of formula (II) where R^x is NH₂ may be prepared from a corresponding compound where R^x is NO₂ by methods well known to those skilled in the art, for example, hydrogenation with palladium on a charcoal catalyst or treatment with Zn and acetic acid. A compound of formula (II) wherein R^x is NH₂ may be converted to a compound of formula (H) wherein R^x is NCO by reaction with, for example, triphosgene. A compound of formula (II) wherein R^x is NH₂ may be converted to another compound of formula (II) wherein R^x is NHR⁸ and R⁸ is -e alkyl, by an alkylation or reductive amination reaction using methods well known to those skilled in the art.

The invention provides a process for preparing a compound of formula (I), comprising: treating a compound of formula (II) wherein R^xis NHR⁸, with a compound of formula (-TJ):

R^— N⁼⁼¹=0 (HI) wherein R^A is C_Wo alkyl or C₃_ι₀ alkenyl wherein a -CH₂- group other than that adjacent to the N may be replaced by -O- and wherein the alkyl or alkenyl is substituted with one or more carboxylate ester or CN groups, e.g. by stirring at room temperature or with heating in a suitable solvent, for example THF. When R^Ais substituted by CN a further reaction with for example, sodium azide and ammonium chloride in a suitable solvent, e.g. DMF, converts the CN group to a tetrazole group.

An ester compound of formula (I) can be converted to a free acid compound of formula (I) by hydrolysis, a method well known to those skilled in the art.

Alternatively, a compound of formula (II) wherein R^xis NCO, is treated with a compound of formula (IV):

R— NH₂

(IN) wherein R^A is as defined for formula (IH), e.g. by stirring at room temperature or with heating in a suitable solvent. Compounds of formula (111) and (TV) may be available through the usual commercial sources. They and derivatives thereof miay also be prepared by methods well known to those skilled in the art.

The compounds of formula (II) wherein R^x is ΝO₂, R¹, R², R³ and R⁵ are as defined for formula (I) and Z is O or S, may be prepared by treatment of a compound of formula (V):

(V) wherein RR¹¹,, RR²² aanndd RR³³ aarree aass ddeefifinneedd ffoorr ffcormula (I) and R^B is CO₂H or CHO, with a compound of formula (VI):

(VI) wherein X and Y are as defined for formula (I) and Z is S or O, by e.g. either (i) heating in a condensation/cyclisation reaction, using for example polyphosphoric acid, or (ii) by firstly coupling a compound of formula (V) to a compound of formula (VI) via either an ester/ thioester or amide formation reaction using methods well known to those of skill in the art followed by direct heating or heating with an acidic media with a suitable solvent to effect cyclisation, for example, p-toluenesulfonic acid in toluene. Alternatively, this may be achieved via oxidative cyclisation of a Schiff base, derived from the condensation of the 2-aminophenol or 2-aminothiophenol and aldehydes, using various oxidants such as PhI(OAc)₂, Pb(OAc)₄ or DDQ..

Compounds of formulae (V) and (VI) may be available through the usual commercial sources. They and derivatives thereof may also be prepared by methods well known to those skilled in the art.

The compounds of formula (II) wherein R^x is NO₂, R¹, R², R³ and R⁵ are as defined for formula (I) and Z is NR⁸, may be prepared by treatment of a compound of formula (V) with a compound of formula (NH):

(NIT) wherein X, Y and R⁸ are as defined for formula (I), in e.g. the following reactions:

(i) if R^B in compound (V) is CO₂H, heating in a condensation/cyclisation reaction using for example polyphosphoric acid; or

(ii) if R^B in compound (V) is CHO, heating in acetonitrile followed by oxidation using for example O₂/FeCl₃ (cat.) in acetonitrile.

Compounds of formula (NIT) may be prepared by reduction of compounds, of formula (NDI):

(vm) wherein X, Y and R⁸ are as defined for formula (I) by methods well known to those skilled in the art, for example, hydrogenation with palladium on a charcoal catalyst or treatment with Zn and acetic acid.

Compounds of formula (NDI) may be prepared by nitration of compounds of formula (IX):

(IX) wherein X, Y and R⁸ are as defined for formula (I), by methods well known to those skilled in the art, for example using fuming nitric acid and sulfuric acid or fuming nitric acid and tin (IN) chloride. Compounds of formula (IX) may be available through the usual commercial sources. They and derivatives thereof may also be prepared by methods well known to those skilled in the art.

The compounds of formula (II), wherein X or Y is halogen, can be modified to give a corresponding set of compounds of formula (H) wherein X or Y is phenyl or a 5- to 10-membered heteroaryl group optionally substituted by one or more substituents as defined in formula (I). The modification may be achieved by a coupling reaction with compounds of formula (X):

_Rc B(OH)₂

(X) where R^c is phenyl or a 5- to 10-membered heteroaryl group optionally substituted by one or more substituents as defined for formula (I), using an appropriate catalyst for example tetrakis (triphenylphosphine) palladium.

Additionally, compounds of formula (II) where R^x is NO₂, R³ is halogen at a position ortho or para to the R^x group and R¹, R² and R⁵ are as defined for formula (I) may be converted to a corresponding subset of compounds of formula (II) where R³ is OR⁶ or NR⁷R⁸, by reaction with an alcohol or amine via a nucleophilic aromatic substitution.

Compounds of formula (IT) where R³ is NR⁸COR¹⁰ or NR⁸SO₂R¹⁰ may be prepared from corresponding compounds of formula (II) where R³ is NHR⁸ by reaction with the appropriate carboxylic acid/chloride or sulfonyl chloride, i.e. R¹⁰CO₂H/(R¹⁰CO₂C1) or R¹⁰SO₂C1 wherein R¹⁰ is as defined for formula (I).

During the synthesis of the compounds of formula (I), labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. The protecting groups may be removed at any stage in the synthesis of the compounds of formula (I) or may be present on the final compound of formula (I). A comprehensive discussion of the ways in which various labile functional groups groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (Wiley- Interscience, New York, 2nd edition, 1991).

Further details for the preparation of compounds of formula (I) are found in the examples.

The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I). Libraries of compounds of formula (I) may be prepared by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.

Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I) or pharmaceutically acceptable salts, esters and prodrugs thereof.

Any novel intermediate compounds as described herein also fall within the scope of the present invention, e.g. the compounds of fomula (H). In particular, the invention provides a compound of formula

(Ha) wherein R^x is NO₂, NHR⁸, or NCO; R⁵ is

wherein one of X and Y is R¹¹ and the other is hydrogen or halogen; or X and Y together with the carbon atoms to which they are attached form a fused six-membered aromatic ring;

R¹¹ is phenyl optionally, and preferably, substituted by one or more substituents selected from halogen, Cι-₆ alkyl, CF₃, OCF₃, OR⁶, CN and methylenedioxo; or a 5- to 10-membered heteroaryl group containing up to three heteroatoms selected from O, N and S, which heteroaryl group may optionally be substituted by one or more substituents selected from Cι_₆ alkyl, .₆ alkoxy and halogen; and

Z, R¹, R², R³ and R⁸ are as defined for formula (I).

Preferred intermediate compounds of the invention include Intermediate compounds 1 to 31 described in the Examples, in particular Intermediate compounds 2, 9, 14b), 14c), 26a), 26b), 27a), 27b), 28a)-31a) and 28b)-31b).

The invention also provides a compound of formula (I) when prepared by any of the above mentioned methods.

The pharmaceutically effective compounds of formula (I) and pharmaceutically acceptable salts, esters and prodrugs thereof, may be administered in conventional dosage forms prepared by combining a compound of formula (I) ("active ingredient") with standard pharmaceutical carriers or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester or prodrύg thereof, together with one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or mtradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318, (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

The pharmaceutical formulations according to the invention are preferably adapted for oral administration.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sμlphate. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the active ingredient and a sterile vehicle, water being preferred. The active ingredient, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The active ingredient can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active ingredient, depending on the method of administration.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per dose. Such a unit may contain for example lOOmg/kg to lmg/kg depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a formula (I) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the compound of formula (I) given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

The compounds of the present invention are useful in that they are capable of inhibiting heparanase. Thus, the compounds can be used in the treatment of cancer.

The compounds of the present invention can also be used in combination with one or more additional treatments or therapeutic compounds for cancer. Examples of such treatments include, surgery and radiation therapy. Examples of therapeutic compounds include but are not limited to cisplatin, cyclophosphamide, methotrexate, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody, capecitabine and raloxifene hydrochloride.

The compounds of the present invention can also be used in the treatment of angiogenesis and angiogenesis dependent diseases, which include angiogenesis associated with the growth of solid tumours and retinopathy. The compounds of the present invention can also be used in combination with one or more additional treatments or therapeutic compounds for angiogenesis. Examples of such other therapeutic compounds include, but are not limited to, recombinant platelet-derived growth factor-BB (Regranex™).

The compounds of the present invention can also be used in the treatment of inflammatory conditions, including, but not limited to, rheumatoid arthritis, inflammatory bowel disease, and wound healing.

The compounds of the present invention can also be used in the treatment of autoimmune diseases, such as, but not limited to, multiple sclerosis.

The compounds of the present invention can also be used in the treatment of cardiovascular diseases, such as, but not limited to, blood clotting conditions, for example thromboembolic disease, arterial thrombosis and restenosis.

By the term "treating" is meant either prophylactic or therapeutic therapy.

The term cancer or 'carcinoma' is a malignant new growth that arises from epithelium, found in skin or, more commonly, the lining of body organs. Carcinomas tend to infiltrate into adjacent tissues and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain. Herein, cancer includes both metastatic tumour cells and tissue and examples include, but are not limited to, melanoma, mesothelioma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, mastocytoma and the following tissue carcinomas: colorectal, colon, prostate, lung, breast, pancreatic, intestinal, renal, gastric, bladder, ovarian, uterine, cervical, hepatic and stomach.

In additional aspects, therefore, the present invention provides:

(i) the use of a compound of formula (I) as an inhibitor of the enzyme heparanase.

(ii) the use of a compound of formula (I) in the manufacture of a medicament for the treatment of cancer.

(iii) the use of a compound of formula (I) in the manufacture of a medicament for the treatment of angiogenesis and angiogenesis dependent diseases which include angiogenesis associated with the growth of solid tumours and retinopathy.

(iv) the use of a compound of formula (I) in the manufacture of a medicament for the treatment of inflammatory conditions such as but not limited to rheumatoid arthritis, inflammatory bowel disease, and wound healing.

(v) the use of a compound of formula (I) in the manufacture of a medicament for the treatment of autoimmune diseases such as but not limited to multiple sclerosis.

(vi) the use of a compound of formula (I) in the manufacture of a medicament for the treatment of cardiovascular diseases such as but not limited to blood clotting conditions, for example thromboembolic disease, arterial thrombosis and restenosis.

(vii) a method for the treatment of cancer, which comprises the step of administering to a patient an effective amount of a compound of formula (I).

(viii) a method for the treatment of angiogenesis and angiogenesis dependent diseases, which include angiogenesis associated with the growth of solid tumours and retinopathy, which comprises the step of administering to a patient an effective amount of a compound of formula (I).

(ix) a method for the treatment of inflammatory diseases, such as but not limited to rheumatoid arthritis, inflammatory bowel disease, and wound healing which comprises the step of administering to a patient an effective amount of a compound of formula (I).

(x) a method for the treatment of autoimmune diseases, such as but not limited to multiple sclerosis, which comprises the step of administering to a patient an effective amount of a compound of formula (I). (xi) a method for the treatment of cardiovascular diseases, such as but not limited to blood clotting conditions, for example thromboembolic disease, arterial thrombosis and restenosis which comprises the step of administering to a patient an effective amount of a compound of formula (I).

All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

The invention will now be described by reference to the following examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

Examples Examples la)-31a)

The following compounds were prepared by adding ethyl 6-isocyanatohexanoate (36μL, 0.2mmol) to a solution of the corresponding aminobenzoxazole, Intermediates 1-9, 10c)-14c), 15b)-26b), 27e) and 28b)-31b) (0.2mmol) in THF (2ml). After stirring overnight at 40°C the reaction was concentrated under reduced pressure to give the product.

Examples lb)-31b)

The following compounds were prepared by addition of a solution of LiOH (24mg l.Ommol) in water (0.5ml) to a solution of the corresponding ethyl ester, Examples la)-31a), (0.2mmol) in THF/MeOH (1:1, 1.5ml). After stirring for 6 h the reaction was acidified with 2M HCl and the resulting precipitate filtered and dried under vacuum.

Example 32: 4-[[2-Methoxy-5-[(5-phenyl)-benzoxazol-2-yl]phenylamino]carbonylamino]butanoic acid a) 4-[[2-Methoxy-5-[(5-phenyl)-benzoxazol-2-yl]phenylamino]carbonylamino]butanoic acid ethyl ester

Ethyl-4-isocyanatobutyrate (46μL, 0.16mmol) was added to a solution of 2-(3-amino-4- methoxyphenyl)-5-phenylbenzoxazole, Intermediate 9, (50mg, O.lόmmol) in THF at 40°C. After stirring overnight the reaction was concentrated to give the subtitle compound. MS (APCI-)«z/z: 472.1. b) 4-[[2-Methoxy-5-[(5-phenyl)-benzoxazol-2-yl]phenylamino]carbonylamino]butanoic acid

Prepared by the addition of a solution of LiOH (19mg, 0.8mmol) in water to a solution of 4-[[2- methoxy-5-[(5-phenyl)-benzoxazol-2-yl]phenylamino]carbonylamino]butanoic acid ethyl ester, Example 32a), (73mg, 0.16mmol) in THF/MeOH (1:1, 1.5ml). After stirring for 6 h the reaction was acidified with 2M HCl and the resulting title product precipitate filtered and dried under vacuum (44mg, 62%). H NMR (DMSO) δ 1.68 (2H, m), 2.29 (2H, t), 3.14 (2H, q), 3.96 (3H, s), 7.02 (IH, bt), 7.20 (IH, d), 7.38 (IH, t), 7.50 (2H, m), 7.65-7.85 (5H, m), 8.01 (IH, d), 8.13 (IH, s), 9.08 (IH, d). MS (APCl-)m/z: 444.0. Example 33: 4-[[4-N-n-propyIamino-5-[(5-phenyl)-benzoxazol-2-yl]phenylamino]carbonylamino] butanoic acid a) 4-[[4-N-n-propylamino-5-[(5-phenyl)-benzoxazol-2-yl]phenylaniino]carbonylamino] butanoic acid ethyl ester

Ethyl-4-isocyanatobutyrate (15μl, O.lmmol) was added to a solution of 2-(3-amino-6-N-«- propylaminophenyl)-5-phenylbenzoxazole, Intermediate 14c), (35mg, O.lmmol) in THF (2ml). After stirring overnight at 40°C the reaction was concentrated under reduced pressure to give the subtitle compound (49mg, 99%). ^!H NMR (DMSO) δ 1.04 (3H, t), 1.19 (3H, t), 1.65-1.75 (4H, m), 2.33 (2H, t), 3.11 (2H, q), 3.27 (2H, q), 4.07 (2H, q), 6.11 (IH, bt), 6.83 (IH, d), 7.32 (IH, dd), 7.40 (IH, d), 7.49 (2H, m), 7.68-7.78 (4H, m), 7.86 (IH, d), 7.99-8.03 (2H, m), 8.25-8.28 (2H, m). b) 4-[[4-N-ra-propylamino-5-[(5-phenyl)-benzoxazol-2-yl]phenylamino]carbonylamino] butanoic acid

Prepared by the method of Examples lb)-31b) from 4-[[4-N-n-propylamino-5-[(5-phenyl)- benzoxazol-2-yl]phenylamino]carbonylamino] butanoic acid ethyl ester, Example 33a), (47mg, O.lmmol) the title compound was obtained. W NMR (DMSO) δ 1.04 (3H, t), 1.70 (4H, m), 2.25 (2H, t), 3.10 (2H, q), 3.27 (2H, q), 6.11 (IH, bt), 6.82 (IH, d), 7.29-7.41 (2H, m), 7.49 (2H, t), 7.68-7.77 (3H, m), 7.86 (IH, d), 7.99-8.03 (2H, m), 8.25-8.28 (2H, m). MS (APCI- n/z: 471.2. Examples 34a)-36a)

Triphosgene (89mg, 0.3mmol) was added to a solution of 2-(3-amino-4-methoxyphenyl)-5- (benzofuran-2-yl)benzoxazole, Intermediate 27b), (250mg, 0.7mmol) in DCM (2ml). After 30 min the aminoester (0.7mmol) and DIPEA (122μL, 0.7mmol) were added and the reaction vessel sealed and heated (Microwave) to 110°C for 10 min. The reaction mixture was diluted with DCM (20ml) and washed with 2M HCl (20ml) and then water (20ml). The organic layer was dried over sodium sulfate and concentrated to give the product.

Examples 34b)-36b)

The following compounds were prepared by addition of a solution of LiOH (24mg l.Ommol) in water (0.5ml) to a solution of the corresponding ethyl ester, Examples 34a)-36a), (0.2mmol) in THF MeOH (1:1, 1.5ml). After stirring for 6 h the reaction was acidified with 2M HCl and the resulting precipitate filtered and dried under vacuum.

Preparation of Intermediates Intermediates 1-9

The following intermediates were prepared by mixing the corresponding aminobenzoic acid (3.0mmol) and corresponding aminophenol (3.0mmol) in polyphosphoric acid (5ml) and heating the mixture to 200°C for 4 h. The reaction mixture was slowly poured into ice water (100ml) and the resulting mixture basified with solid sodium hydroxide. At pH5-6 the precipitate was filtered, washed with water and dried under vacuum.

Intermediates 10a)-14a)

The following compounds were prepared by adding a solution of 2-fluoro-5-nitrobenzoyl chloride (lg, 5.0mmol) in THF (5ml) to a solution of the corresponding 2-aminophenol (5.0mmol). After stirring overnight the reactions were filtered and the solid dried under vacuum. The crude product (2.5mmol) was added to a solution of p-toluenesulfonic acid (1.04g, 5.5mmol) in toluene (10ml) and the mixture heated to reflux for 6 h. The cooled reaction mixture was neutralized with saturated NaHCO₃, the slurry filtered and the solid dried under vacuum.

Intermediates 10b)-14b)

The following intermediates were prepared by adding propylamine (492μL, ό.Ommol) to a solution of the corresponding fluorobenzoxazole, Intermediates 10a)-14a), (2.0mmol) in THF (10ml). After stirring overnight the reaction was concentrated and the solid triturated with methanol. The resulting product was filtered and dried under vacuum.

Intermediate 37 : 2-(2-Fluoro-5-nitrophenyl)-5-bromobenzoxazole

A solution of 2-fluoro-5-nitrobenzoyl chloride (4.42g, 21.7mmol) in THF (75ml) was slowly added to a solution of 4-bromo-2-aminophenol (4.08g, 21.7mmol) in THF (75ml). After stirring overnight the reaction was filtered and the solid dried under vacuum. The crude product was added to a solution of p-toluenesulfonic acid (8.66g, (45.6mmol) in toluene (200ml) and the mixture heated to reflux with a Dean-Stark trap fitted for 6 h. The cooled reaction mixture was neutralized with saturated NaHCO₃, the slurry filtered and the solid dried under vacuum. Η NMR (DMSO) δ 7.72 (IH, dd), 7.87 (IH, t), 7.93 (IH, d), 8.23 (IH, d), 8.57-8.63 (IH, m), 8.97-9.00 (IH, m). Intermediate 38 : 2-(2-Methoxy-5-nitrophenyl)-5-bromobenzoxazole

Sodium methoxide (80mg, 1.5mmol) in MeOH was added to a suspension of 2-(2-fluoro-5- nitrophenyl)-5 -bromobenzoxazole (Intermediate 37) (500mg, 1.5mmol) in MeOH (2ml). The mixture was heated to 85°C for 4 h. The reaction was quenched with ice water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound, 360mg (78%). *H NMR (DMSO) δ 4.09 (3H, s), 7.52 (IH, d), 7.63 (IH, dd), 7.83 (IH, d),

8.12 (IH, d), 8.48 (IH, dd), 8.84 (IH, d).

Intermediate 39: 2-(2-N-Propylamine-5-nitrophenyl)-5-bromobenzoxazoIe

Propylamine (1.95ml, 23.7mmol) was added to a solution of 2-(2-fluoro-5-nitrophenyl)-5- bromobenzoxazole (Intermediate 37) (2.0g, 5.9mmol) in THF (50ml). After stirring for 4 h the reaction was concentrated and the residue triturated with methanol. The precipitate was filtered and dried under vacuum to give the title compound. ^!H NMR (DMSO) δ 1.04 (3H, t), 1.74 (2H, m), 3.44 (2H, m), 7.05 (IH, d), 7.63 (IH, dd), 7.84 (IH, d), 8.03 (IH, d), 8.21 (IH, dd), 8.77 (IH, d), 9.08 (IH, t). Intermediate 40: 2-(3-Nitro-4-methoxyphenyl)-5-bromobenzoxazole

a) 4-Methoxy-3-nitro-benzoyl chloride

Oxalyl chloride (15.8ml, 180mmol) was added dropwise with stirring to a solution of 4-methoxy- 3-nitrobenzoic acid (7.00g, 36.00mmol) in THF containing lOμL DMF. After 1 h the solvent was removed under reduced pressure. The product was used directly in the next step. b) 2-(4-Methoxy-3-nitrophenyl)-carbonylamino-4-bromophenol

A solution of 4-methoxy-3-nitro-benzoyl chloride (7.12g, 33.0mmol) in THF (50 ml) was added dropwise with stirring to a solution of 4-bromo-2-aminophenol (6.20g, 33.0mmol) in THF (50ml) containing triethylamine (6.82ml, 66.0mmol). After addition was complete the reaction was stirred at room temperature overnight. The reaction mixture was concentrated to approximately half the original volume and the precipitate collected by filtration. The solid was washed with methanol and ether and dried under vacuum to give the subtitle compound as a brown solid (5.24g, 42%). H NMR (DMSO) δ 4.05 (3H, s), 6.68 (IH, dd), 6.68 (IH, dd), 6.96 (2H, m), 7.55 (IH, d), 8.36 (IH, dd), 8.58 (IH, d). c) 2-(3-Nitro-4-methoxyphenyl)-5-bromobenzoxazole

A suspension of 2-(4-methoxy-3-nitrophenyl)-carbonylamino-4-bromophenol (5.24g, 14.2mmol) and toluenesulfonic acid (5.36g, 31.2mmol) in toluene (100ml) was heated to reflux overnight. The cooled reaction mixture was washed with saturated sodium hydrogen carbonate solution (care foaming) and the organic layer separated. The aqueous layer was extracted with ethyl acetate (2x50ml) and the combined organic layers dried over sodium sulfate and the solvent removed under reduced pressure. The residue was triturated with ether, filtered and dried under vacuum to give the title compound as a pale pink solid (4.5 lg, 93%). ^XH NMR (DMSO) δ 4.05 (3H, s), 7.61 (2H, m), 7.79 (IH, d), 8.05 (IH, d), 8.42 (IH, dd), 8.61 (IH, d). MS m/z 349.0 (M+H)⁺. Intermediates 15a)-26a) and 28a)-31a)

The following intermediates were prepared by adding tetrakis(triphenylphosphine)palladium(0) (0.06 mmol) to a degassed solution of the corresponding bromobenzoxazole, Intermediates 38, 39 and 40c), (1.1 mmol) in 1,4-dioxane (18 ml) at room temperature under argon. The solution was further degassed and 2M aqueous sodium carbonate (1.0 ml, 2.3 mmol) and the boronic acid (1.7 mmol) were added. The resulting suspension was heated at reflux for 16 h. On cooling to room temperature the mixture was diluted with DCM (10 ml), washed with water (10 ml), brine (10 ml) and dried (Na₂SO ). The solvent was removed under reduced pressure and the residue triturated with methanol. The solid was collected by filtration and dried under vacuum to give the product.

Intermediates 10c)-14c), 15b)-26b) and 28b)-31b)

The following intermediates were prepared by adding zinc dust (523mg, 8.0mmol) to a stirred solution of the corresponding nitrobenzoxazole, Intermediates 10b)-26b) and 28b)-31b), (0.8mmol) in acetic acid/ethanol (1:1, 10ml). After stirring overnight the reactions were concentrated, the residue dissolved in EtOAc (50ml) and washed with saturated NaHCO₃. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the product.

Intermediate 27: 2-(3-Amino-4-methoxyphenyI)-5-(benzofuran-2-yl)benzoxazole

a) 2-(3-Nitro-4-methoxyphenyl)-5-(benzofuran-2-yl)benzoxazole

2-(3-Nitro-4-methoxyphenyl)-5-bromobenzoxazole, Intermediate 40c), (200mg, 0.57mmol) was suspended in degassed ethylene glycol dimethyl ether (DME, 10ml). Tetrakis

(triphenylphosphine)palladium (0) (33mg, 0.03mmol), 2M sodium carbonate (0.5ml) and benzofuran-2- boronic acid (137mg (0.85mmol) were added and the reaction was further degassed. The reaction was heated to reflux for 16 h. The cooled reaction mixture was diluted with water (10ml) and extracted with dichloromethane (2xl0ml). The combined organic extracts were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was triturated with methanol (5ml) and filtered. The solid was dried under vacuum to give the subtitle compound (50mg, 15%). *H NMR (DMSO) δ 4.04 (3H, s), 7.25-7.36 (2H, m), 7.54 (IH, s), 7.59-7.69 (3H, m), 7.92 (IH, d), 8.01 (IH, dd), 8.29 (IH, d), 8.44 (IH, dd), 8.63 (IH, d). b) 2-(3-Amino-4-methoxyphenyl)-5-(benzofuran-2-yl)benzoxazole

A suspension of 2-(3-nitro-4-methoxyphenyl)-5-(benzofuran-2-yl)benzoxazole (50mg, 0.13mmol) in dioxane (10ml) was placed under an atmosphere of argon. Palladium on carbon (10%) (lOmg) was added and the reaction purged with hydrogen and stirred at room temperature for 36 h. The reaction was filtered through a bed of celite and the filtrate concentrated to give the title compound (40mg, 86%). MS m/z 357.1 (M+H)⁺.

Biological Data

Heparanase assay: The assay is based upon the use of the specific binding of basic fibroblast growth factor (bFGF) to heparan sulfate. Heparan sulfate can be detected via binding of bFGF using a horse radish peroxidase-conjugated bFGF antibody. Following cleavage of high molecular weight heparan sulfate by heparanase, the smaller material generated will no longer adhere to the surface of a 96 well plate and hence heparanase activity can be followed as a reduction in bFGF binding.

Nunc Maxisorp 96-well plates are coated for 16h at RT with 100μ]/well 0.04mg/ml heparan sulfate in PBS. The wells are then aspirated and blocked for lh with 200μlΛvell 1% BSA-PBS. Following five washes with 0.01% BSA, 0.05% Tween20 PBS (wash buffer), 100μl of recombinant human basic FGF (90ng/ml in 0.1% BSA/PBS) is added per well and the plate is incubated at room temperature for lh.

After a further five washes with the wash buffer, 10μl of test compound (in 10% DMSO) and 90μl of human heparanase in lOOmM Sodium acetate, 5mM CaCl₂, pH 5.5 are added to each well and the plate incubated for 2h at 37°C. The wells are washed again with wash buffer and lOOμl of bFGF antibody-horse radish peroxidase conjugate added. The plate is incubated at room temperature for lh and washed again five times with wash buffer. lOOμl of TMB peroxidase substrate is added and the colour allowed to develop for 10 min. The reaction is stopped with 50μl 1M H₂SO₄and the colour read at 450nm on a plate reader.

The following table gives the heparanase inhibitory activity of represenatative compounds of the invention.

Claims

CLAIMS:

1. A compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

(I) wherein

R¹, R² and R³ are independently, hydrogen, halogen, CF₃, OR⁶, NR⁷R⁸, NR⁸COR¹⁰, NR⁸SO₂R¹⁰ or Q.₆ alkyl optionally substituted by hydroxy, Q.₆ alkoxy or NR⁷R⁸;

R⁴ is NR⁸CONR⁸R⁹; R⁵ is

wherein one of X and Y is R¹¹ and the other is hydrogen or halogen; or X and Y together with the carbon atoms to which they are attached form a fused six-membered aromatic ring; Z is NR⁸, O or S;

R⁶ is hydrogen or Q.₆ alkyl, C₃.₆ alkenyl or C₃.₆ alkynyl any of which can optionally be substituted by hydroxy, Cι.₆ alkoxy or NR⁷R⁸;

R⁷ is hydrogen or Q.₆ alkyl or C₃.₆ alkenyl either of which is optionally substituted by Q.₆ alkoxy or a 5- or 6-membered heterocyclic ring containing up to three heteroatoms selected from NR⁸, S and O;

R⁸ is hydrogen or Q.₆ alkyl; or the groups R⁷ and R⁸ may together with the nitrogen to which they are attached form a 5- or 6- membered ring which optionally contains up to two further heteroatom selected from NR⁸, S and O;

R⁹ is Cι_ιo alkyl or C₃.ι₀ alkenyl wherein a -CH₂- group other than that adjacent to the N may be replaced by -O- and wherein the alkyl or alkenyl is substituted by one or more carboxylic acid or tetrazole groups; or in R⁴ the groups R⁸ and R⁹ may together with the nitrogen to which they are attached form a 5- or 6-membered ring, which is substituted with one or more carboxylic acid or tetrazole groups;

R¹⁰ is .₆ alkyl; and

R¹¹ is hydrogen, halogen, Q-₆ alkyl, OR⁶ or phenyl optionally substituted by one or more substituents selected from halogen, Q.₆ alkyl, CF₃, OCF₃, OR⁶, CN and methylenedioxo; or a 5- to 10- membered heteroaryl group containing up to three heteroatoms selected from O, N and S, which heteroaryl group may optionally be substituted by one or more substituents selected from Q.β alkyl, -₆ alkoxy and halogen.

2. A compound according to claim 1 where R¹, R² and R³ are independently, hydrogen, halogen, OR⁶, NR⁷R⁸, or Q.6 alkyl optionally substituted by hydroxy or Q_₆ alkoxy.

3. A compound according to any one of the preceding claims where Z is O.

4. A compound according to any one of the preceding claims where R⁶ is hydrogen or Q.₆ alkyl, C₃.₆ alkenyl or .6 alkynyl any of which can optionally be substituted by hydroxy or Q.β alkoxy.

5. A compound according to any one of the preceding claims where R^u is phenyl optionally substituted by one or more substituents selected from halogen, Q.₆ alkyl, CF₃, OCF₃, OR⁶, CN and methylenedioxo; or a 5- to 10-membered heteroaryl group containing up to three heteroatoms selected from O, N and S, which heteroaryl group may optionally be substituted by one or more substituents selected from Q.₆ alkyl, Q.₆ alkoxy and halogen.

6. A compound according to any one of the preceding claims where R¹ is hydrogen, OR⁶ or NR⁷R⁸.

7. A compound according to any one of the preceding claims where R² is hydrogen.

8. A compound according to any one of the preceding claims where R³ is hydrogen, halogen or OR⁶

9. A compound according to any one of the preceding claims where the configuration of the R groups is:

10. A compound of formula (I) as described in any one of Examples 1 to 36 or a pharmaceutically acceptable salt, ester or prodrug thereof.

11. A compound as defined in any one of claims 1 to 10 for use in medicine.

12. A process for the preparation of a compound as defined in any one of claims 1 to 10 which comprises: a) treating a compound of formula (H):

R²

_R fc R 3^:

(II) wherein R^xis NHR⁸, with a compound of formula (HI):

_R^L__Nχχ__₀

(HI) wherein R^A is C_wo alkyl or Q_₁₀ alkenyl wherein a -CH₂- group other than that adjacent to the N may be replaced by -O- and wherein the alkyl or alkenyl is substituted with one or more carboxylate ester or CN groups; and when R^A is substituted by CN, conversion of the CN to a tetrazole group; or b) treating a compound of formula (II) wherein R^x is NCO, with a compound of formula (IV):

R — NH_a (IV) wherein R^A is as defined for formula (HI).

13. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 10 together with a pharmaceutically acceptable carrier or excipient.

14. The use of a compound as defined in any one of claims 1 to 10 in the manufacture of a medicament for the inhibition of heparanase.

15. The use of a compound as defined in any one of claims 1 to 10 in the manufacture of a medicament for the treatment of a subject with cancer.

16. The use of a compound as defined in any one of claims 1 to 10, in the manufacture of a medicament for the treatment of a disease selected from angiogenesis or an angiogenesis dependent disease, an inflammatory disease, an autoimmune disease and a cardiovascular disease.

17. A compound of formula (II).

(Ha) wherein R^x is NO₂, NHR⁸, or NCO;

R⁵ is

wherein one of X and Y is R¹¹ and the other is hydrogen or halogen; or X and Y together with the carbon atoms to which they are attached form a fused six-membered aromatic ring;

R^π is phenyl optionally substituted by one or more substituents selected from halogen, Q_₆ alkyl, CF₃, OCF₃, OR⁶, CN and methylenedioxo; or a 5- to 10-membered heteroaryl group containing up to three heteroatoms selected from O, N and S, which heteroaryl group may optionally be substituted by one or more substituents selected from Q_₆ alkyl, Q.₆ alkoxy and halogen; and

Z, R¹, R², R³ and R⁸ are as defined in claim 1.