WO2004046123A1 - Derives de benzoxazole, benzthiazole et benzimidazole utiles en tant qu'inhibiteurs d'heparanase - Google Patents

Derives de benzoxazole, benzthiazole et benzimidazole utiles en tant qu'inhibiteurs d'heparanase Download PDF

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Publication number
WO2004046123A1
WO2004046123A1 PCT/GB2003/004980 GB0304980W WO2004046123A1 WO 2004046123 A1 WO2004046123 A1 WO 2004046123A1 GB 0304980 W GB0304980 W GB 0304980W WO 2004046123 A1 WO2004046123 A1 WO 2004046123A1
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alkyl
compound
formula
hydrogen
halogen
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PCT/GB2003/004980
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Stephen Martin Courtney
Philip Andrew Hay
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Oxford Glycosciences (Uk) Ltd
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Priority to AU2003285498A priority Critical patent/AU2003285498A1/en
Publication of WO2004046123A1 publication Critical patent/WO2004046123A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • 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 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.
  • 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.
  • angiogenesis new blood vessel formation
  • 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.
  • 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.
  • 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).
  • 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).
  • 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:
  • R 1 , R 2 and R 3 are independently, hydrogen, halogen, CF 3 , OR 6 , NR 7 R 8 , NR 8 COR 10 , NR 8 SO 2 R 10 or C ⁇ _ 6 alkyl optionally substituted by hydroxy, C . 6 alkoxy or NR 7 R 8 ;
  • R 4 is NR 8 CONR 8 R 9 ;
  • X and Y are R 11 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 NR 8 , O or S;
  • R 6 is hydrogen or C ⁇ _ 6 alkyl, C 3 . 6 alkenyl or C 3 . 6 alkynyl any of which can optionally be substituted by hydroxy, C . 6 alkoxy or NR 7 R 8 ;
  • R 7 is hydrogen or C ⁇ _ 6 alkyl or C 3 . 6 alkenyl either of which is optionally substituted by d- ⁇ alkoxy or a 5- or 6-membered heterocyclic ring containing up to three heteroatoms selected from NR 8 , S and O;
  • R 8 is hydrogen or C ⁇ _ 6 alkyl; or the groups R 7 and R 8 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 NR 8 , S and O;
  • R 9 is Ci-io alkyl or C 3 - ⁇ 0 alkenyl wherein a -CH 2 - 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 R 4 the groups R 8 and R 9 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;
  • R 10 is C ⁇ . 6 alkyl
  • R 11 is hydrogen, halogen, C ⁇ _ 6 alkyl, OR 6 or phenyl optionally substituted by one or more substituents selected from halogen, . 6 alkyl, CF 3 , OCF 3 , OR 6 , 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, - ⁇ alkoxy and halogen.
  • R 1 , R 2 and R 3 are independently, hydrogen, halogen, CF 3 , OR 6 , NR 7 R 8 , NR 8 COR 10 , NR 8 SO 2 R 10 or - ⁇ alkyl optionally substituted by hydroxy or C ⁇ - 6 alkoxy.
  • R 1 , R 2 and R 3 are independently, hydrogen, halogen, OR 6 , NR 7 R 8 , or C ⁇ _ 6 alkyl optionally substituted by hydroxy or C ⁇ - 6 alkoxy.
  • Z is O.
  • R 6 is hydrogen or C ⁇ . 6 alkyl or C 3 . 6 alkenyl either of which can optionally be substituted by hydroxy or C ⁇ . 6 alkoxy.
  • R s is preferably:
  • At least one of X and Y is other than hydrogen.
  • X is preferably R 11 .
  • R 11 is phenyl optionally substituted by one or more substituents selected from halogen, C ⁇ - 6 alkyl, CF 3 , OCF 3 , OR 6 , 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.
  • R 1 is hydrogen, OR 6 or NR 7 R 8 .
  • R 2 is hydrogen
  • R 3 is hydrogen, halogen or OR 6 .
  • the ring may be, for example, morpholine, piperazine or N- methyl piperazine.
  • R ⁇ 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,
  • 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.
  • alkyl also includes those radicals wherein one or more hydrogen atoms are replaced by fluorine.
  • alkenyl alkenylene
  • alkynyl alkynylene
  • 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.
  • heterofuran 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 e.g. 2-benzothiophene
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 C ⁇ -C 6 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.
  • the alkene can be presented as a cis or trans isomer or a mixture thereof.
  • an isomeric form of a compound of the invention 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.
  • 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 NO 2 , NHR 8 , or NCO and R 1 , R 2 , R 3 , R 5 . and R 8 are as defined for formula (I), by the processes described below.
  • a compound of formula (II) where R x is NH 2 may be prepared from a corresponding compound where R x is NO 2 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 NH 2 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 NH 2 may be converted to another compound of formula (II) wherein R x is NHR 8 and R 8 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 x is NHR 8 , with a compound of formula (-TJ):
  • a suitable solvent for example THF.
  • 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.
  • 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.
  • 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..
  • R B in compound (V) is CHO, heating in acetonitrile followed by oxidation using for example O 2 /FeCl 3 (cat.) in acetonitrile.
  • 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):
  • 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.
  • compounds of formula (II) where R x is NO 2 , R 3 is halogen at a position ortho or para to the R x group and R 1 , R 2 and R 5 are as defined for formula (I) may be converted to a corresponding subset of compounds of formula (II) where R 3 is OR 6 or NR 7 R 8 , by reaction with an alcohol or amine via a nucleophilic aromatic substitution.
  • R 3 is NR 8 COR 10 or NR 8 SO 2 R 10
  • R 3 is NHR 8 by reaction with the appropriate carboxylic acid/chloride or sulfonyl chloride, i.e. R 10 CO 2 H/(R 10 CO 2 C1) or R 10 SO 2 C1 wherein R 10 is as defined for formula (I).
  • labile functional groups in the intermediate compounds e.g. hydroxy, carboxy and amino groups
  • 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).
  • 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.
  • 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).
  • the invention provides a compound of formula
  • R x is NO 2 , NHR 8 , or NCO
  • R 5 is wherein one of X and Y is R 11 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 11 is phenyl optionally, and preferably, substituted by one or more substituents selected from halogen, C ⁇ - 6 alkyl, CF 3 , OCF 3 , OR 6 , 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; and
  • R 1 , R 2 , R 3 and R 8 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.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester or prodr ⁇ g thereof, together with one or more pharmaceutically acceptable carriers or excipients.
  • 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.
  • compositions 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).
  • compositions 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.
  • compositions 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.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318, (1986).
  • compositions 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.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions 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.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or enemas.
  • compositions 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.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions 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.
  • 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.
  • suitable 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 s ⁇ lphate.
  • 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.
  • 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
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • 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.
  • the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • 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.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active ingredient, depending on the method of administration.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per dose.
  • 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.
  • 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.
  • 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.
  • treatments include, surgery and radiation therapy.
  • 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.
  • additional treatments or therapeutic compounds for angiogenesis include, but are not limited to, recombinant platelet-derived growth factor-BB (RegranexTM).
  • 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.
  • cardiovascular diseases such as, but not limited to, blood clotting conditions, for example thromboembolic disease, arterial thrombosis and restenosis.
  • treating is meant either prophylactic or therapeutic therapy.
  • 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.
  • 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.
  • tissue carcinomas colorectal, colon, prostate, lung, breast, pancreatic, intestinal, renal, gastric, bladder, ovarian, uterine, cervical, hepatic and stomach.
  • the present invention provides:
  • (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).
  • inflammatory diseases such as but not limited to rheumatoid arthritis, inflammatory bowel disease, and wound healing
  • autoimmune diseases such as but not limited to multiple sclerosis
  • 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).
  • 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
  • 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
  • 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 (122 ⁇ L, 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.
  • 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 NaHCO 3 , the slurry filtered and the solid dried under vacuum.
  • 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.
  • bFGF basic fibroblast growth factor
  • Nunc Maxisorp 96-well plates are coated for 16h at RT with 100 ⁇ ]/well 0.04mg/ml heparan sulfate in PBS. The wells are then aspirated and blocked for lh with 200 ⁇ l ⁇ vell 1% BSA-PBS. Following five washes with 0.01% BSA, 0.05% Tween20 PBS (wash buffer), 100 ⁇ l 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.
  • test compound in 10% DMSO
  • human heparanase in lOOmM Sodium acetate, 5mM CaCl 2 , 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 lOO ⁇ l 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.
  • lOO ⁇ l of TMB peroxidase substrate is added and the colour allowed to develop for 10 min.
  • the reaction is stopped with 50 ⁇ l 1M H 2 SO 4 and the colour read at 450nm on a plate reader.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à des composés de formule (I), dans laquelle : R1, R2 et R3 sont indépendamment hydrogène, halogène, CF3, OR6, NR7 R8, NR8COR10, NR8SO2R10 ou alkyle en C1-C6 éventuellement substitué par hydroxy, alcoxy en C1-C8 ou NR7R8; R4 est NR8CONR8R9, et R5 correspond à la formule (Ia). L'invention a également trait à leurs procédés de synthèse, des compositions pharmaceutiques en contenant et leur utilisation médicale, notamment pour le traitement du cancer.
PCT/GB2003/004980 2002-11-16 2003-11-17 Derives de benzoxazole, benzthiazole et benzimidazole utiles en tant qu'inhibiteurs d'heparanase WO2004046123A1 (fr)

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US7214696B2 (en) 2002-12-19 2007-05-08 The Scripps Research Institute Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US7868033B2 (en) 2004-05-20 2011-01-11 Foldrx Pharmaceuticals, Inc. Compounds, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US9249112B2 (en) 2011-09-16 2016-02-02 Pfizer Inc. Solid forms of a transthyretin dissociation inhibitor
CN106536478A (zh) * 2014-05-22 2017-03-22 悉尼大学 ω‑3类似物
CN108299413A (zh) * 2018-01-22 2018-07-20 复旦大学 一种无金属催化制备2-(胺基苯基)苯并噁唑及其衍生物的方法
EP3381907A1 (fr) 2017-03-27 2018-10-03 Leadiant Biosciences SA Composés de 2-aminophényl-benzazolyl-5-acétate symétriques et leur utilisation comme anti-héparanase
EP3381906A1 (fr) 2017-03-27 2018-10-03 Leadiant Biosciences SA Composes utiles comme inhibiteurs d'heparanase

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8653119B2 (en) 2002-12-19 2014-02-18 The Scripps Research Institute Methods for treating transthyretin amyloid diseases
US7214695B2 (en) 2002-12-19 2007-05-08 The Scripps Research Institute Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US7560488B2 (en) 2002-12-19 2009-07-14 The Scripps Research Institute Methods for treating transthyretin amyloid diseases
US7214696B2 (en) 2002-12-19 2007-05-08 The Scripps Research Institute Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US8168663B2 (en) 2002-12-19 2012-05-01 The Scripps Research Institute Pharmaceutically acceptable salt of 6-carboxy-2-(3,5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof
US7868033B2 (en) 2004-05-20 2011-01-11 Foldrx Pharmaceuticals, Inc. Compounds, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US8338459B2 (en) 2004-05-20 2012-12-25 Foldrx Pharmaceuticals, Inc. Compounds, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US9249112B2 (en) 2011-09-16 2016-02-02 Pfizer Inc. Solid forms of a transthyretin dissociation inhibitor
CN106536478A (zh) * 2014-05-22 2017-03-22 悉尼大学 ω‑3类似物
EP3381907A1 (fr) 2017-03-27 2018-10-03 Leadiant Biosciences SA Composés de 2-aminophényl-benzazolyl-5-acétate symétriques et leur utilisation comme anti-héparanase
EP3381906A1 (fr) 2017-03-27 2018-10-03 Leadiant Biosciences SA Composes utiles comme inhibiteurs d'heparanase
WO2018177857A1 (fr) 2017-03-27 2018-10-04 Leadiant Biosciences Sa In Liquidazione Composés symétriques de 2-aminophényl-benzazolyl-5-acétate et leur utilisation comme anti-héparanase
WO2018177865A1 (fr) 2017-03-27 2018-10-04 Leadiant Biosciences Sa In Liquidazione Composés destinés à être utilisés comme inhibiteurs d'héparanase
CN108299413A (zh) * 2018-01-22 2018-07-20 复旦大学 一种无金属催化制备2-(胺基苯基)苯并噁唑及其衍生物的方法

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