WO2005042496A1 - (benzimidazol-2-yl)-phenyl-benzyl-amine derivatives and methods for inhibiting heparanase activity - Google Patents

Abstract

The present invention encompasses heparanase inhibitors, particularly to certain (benzimidazol-2-yl)-phenyl-benzyl-amine derivatives that inhibit heparanase, pharmaceutical compositions that contain the compounds, methods for making the compounds, and methods of treating heparanase-dependent diseases and conditions in mammals by administering a therapeutically effective amount of the compounds to the mammals.

Description

(BENZIMιDAZOL-2-YL)-PHENYL-BENZYL-AMINE DERINATINES AND METHODS FOR INHLBITING HEPARANASE ACTIVITY

Related Applications This application claims the benefit of U.S. Provisional Application No.

60/512,787, filed October 21, 2003. Field of the Invention The present invention encompasses (benzimidazol-2-yl)-phenyl-benzyl-amine derivative compounds, compositions thereof, and methods for inhibiting heparanase activity. More particularly, the present mvention encompasses methods for treatment of conditions associated with heparanase activity using (benzimidazol-2-yl)-phenyl-benzyl- amine derivatives.

Background of the Invention Heparan sulfate proteoglycans (HSPGs) are widely distributed in mammalian tissues. They are composed of a core protein to which chains of the glycosaminoglycan heparan sulfate ("HS") are attached. The polysaccharide HS chains are typically composed of repeating hexuronic and D-glucosamine disaccharide units that are modified at various positions by sulfonation, epimerization, and N-acetylation, yielding clusters of sulfonated disaccharides separated by low or non-sulfonated regions. The existence of various classes of core protein, in addition to highly polymorphic HS chains, creates a superfamily of macromolecules with considerable diversity of structure and function. HSPGs interact with many proteins, including growth factors, chemokines and structural proteins of the extracellular matrix ("ECM") to influence cell growth, differentiation, and the cellular response to the environment. Specifically, interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial ECM is associated with degradation of HS by a specific, endo-β-D- glucuronidase (heparanase) activity. See Nakajima et al., Science, 220: 611-613 (1983). The heparanase enzyme that degrades HS is released from intracellular compartments, for example, from lysosomes and specific granules, in response to various activation signals, such as thrombin, calcium ionophore, immune complexes, antigens and mitogens, suggesting its regulated involvement in inflammation and cellular immunity. Heparanase expressed by intact cells, platelets, mast cells, neutrophils and lymphoma cells was found to release active HS-bound basic fibroblast growth factor (bFGF) from ECM and basement membranes. Heparanase can thus elicit an indirect neovascular response in processes such as wound repair (resulting from injury) and inflammation. See generally Nlodavsky et al., Invasion & Metastasis, 14: 290-302 (1994); Νakajima et al., J. Cell Biochem., 36(2): 157-67 (1988). HSPGs are involved in a number of processes related to malignancy. See generally Blackball et al, Br. J. Cancer, 85(8): 1094-8 (Oct. 2001). Elevated levels of heparanase have been detected in sera from metastatic tumor-bearing animals and this malignant melanoma patients, and a correlation exists between serum heparanase activity and the extent of tumor metastases. Cleavage of HSPGs by heparanase leads to disassembly of the ECM and release of bioactive agents such as pro-angiogenic factors. The successful penetration of endothelial basement membranes is an important process in the formation of hematogenous tumormetastas.es. Heparanase-inhibiting, non- anticoagulant species of heparin, as well as laminarin sulfate and mannopentaose phosphate sulfate (PI-88), markedly reduced the incidence of lung metastasis in experimental animals, Nlodavsky et al., 1994, supra; Miao et al., Int. J. Cancer, 83: 424- 31 (1999); Νakajima, 1988, supra; Parish et al., Int. J. Cancer, 40: 511-7 (1987), as well as tumor growth and angiogenesis, Parish et al., Cancer Res., 59: 3433-41 (1999), suggesting that heparanase is potentially a useful marker for tumor development. These non-anticoagulant species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Nlodavsky et al.,1992, supra. Furthermore, treatment with heparanase inhibitors markedly reduced the incidence of experimental autoimmune encephalomyelitis, adjuvant arthritis and graft rejection, see Nlodavsky et al., 1992, supra; Lider et al., J. 5 Clin. Invest., 83: 752-6 (1989); Willenborg & Parish, J. Immunol., 140: 3401-5 (1988), indicating that immunotherapeutic treatments targeting heparanase activity may be potentially useful for these conditions. Thus, immunotherapy targeting heparanase activity may be a potentially useful treatment for both tumor growth and angiogenesis, for which there is great need. Summary of the Invention The mvention encompasses compounds of Formula I:

Formula I wherein m is 0-4; n is 1-4; each Ri independently is a) F, Br, CI, I, NO₂, NH₂, CN, or OH; b) Ci-Ce alkyl; c) C₆-Cιo aryl; or d) C₃-Cιo heteroaryl; and each R₂ independently is a) Cι-C₆ alkoxy; b) C₆-Cιo aryl; c) C₅-C₁₀ heteroaryl; d) -NH-(Cι-C₆)alkyl; e) -NHCO-(C₆-Cιo)aryl; f) -NHCO-(C₃-Ci₀)heteroaryl; g) -CONH-(C₆-Cι₀)aryl; or h) -CONH-(C₃-Cιo)heteroaryl. Ri may optionally be substituted with at least one R , wherein each R₃ independently is F, CI, Br, I, CN, NH₂, NO₂, or OH. R₂ may optionally be substituted with at least one R₄, wherein each j independently is F, CI, Br, I, CN, NH₂, NO₂, OH, Cι-C₆ alkyl, Cι-C₆ alkoxy, C₆-Cιo aryl, C₅-Cι₀ heteroaryl, CO₂H, CO₂(Cι-C₆ alkyl), CONH(C₆-Ci₀ aryl), or CONH(C₅-Cι₀ heteroaryl). The invention also encompasses pharmaceutical compositions comprising the compound of Formula I and a pharmaceutical carrier. The pharmaceutical composition may be in the form and the dosage form may be at least one of a tablet, capsule, troche, lozenge, or soft gelatin capsule. The invention also encompasses methods of inhibiting heparanase activity comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of such therapy. In the method, the inhibition of heparanase activity may inhibit the release of bioactive agents from heparan sulfate proteoglycans.

Detailed Description of the Invention The present invention encompasses compounds of capable of inhibiting, modulating, or regulating the activity of heparanase. The present invention is directed to (benzimidazol-2-yl)-phenyl-benzyl-amine derivatives and to methods of inhibiting heparanase activity using (benzimidazol-2-yl)-phenyl-benzyl-amine derivatives. The invention also encompasses pharmaceutical compositions of (benzimidazol-2-yl)-phenyl- benzyl-amine derivatives. In particular, the invention encompasses compounds of Formula I:

Formula I wherein Ri, R , m, and n are as defined herein. Not to be limited by theory, it is believed that the compounds of the invention inhibit the degradation of HSPGs by inhibiting heparanase activity. In a similar manner, the compounds of the invention may block the degradation of the extracellular matrix to inhibit the penetration of endothelial basement membranes by extravasating cells and the release of bioactive agents such as pro-angiogenic factors. Definitions As used herein, the term "alkyl" refers to a saturated hydrocarbon radical having 1 to 8 carbon atoms. The alkyl group may be straight, branched, substituted or unsubstituted. Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, or pentyl. As used herein, the term "alkoxy" refers to a substituted or unsubstituted an -O-alkyl, -O-cycloalkyl, or -O-heterocyclyl, wherein alkyl is as defined above and cycloalkyl and heterocyclyl are as defined below. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy, or vinyloxy. As used herein, the term "cycloalkyl" refers to a cyclic hydrocarbon radical having 3 to 8 carbon atoms, which may be substituted or unsubstituted. Optionally, the cycloalkyl group may have at least one carbon to carbon double bond. Cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, or cyclohexyl. As used herein, the term "heterocyclyl" or "heterocycle" refers to cycloalkyl rings that include within the ring at least one nitrogen, oxygen, or sulfur atom. Optionally, the heterocyclyl may include one or two double bonds. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. The term "heterocyclyl" also refers to dihydro and tetrahydro analogs of heteroaryls. The heterocyclyl ring may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure. The heterocycle ring may be substituted or unsubstituted including, but not limited to, aziridinyl, homopiperazinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholino, oxadiazolyl, oxazolidinyl, oxazolinyl, 4-piperidonyl, piperazinyl, pyranyl, pyradazinyl, pyrazolidinyl, pyrrolidirxyl, quinuclidinyl, tertrahydrofuranyl, tetrahydrothienyl, tetrahydrothiophenyl, thiazolidinyl, thiazolinyl, thiomorpholino, thiomαrpholinyl sulfoxide, thiomorpholinyl sulfone, or thiophenyl. As used herein, the term "aryl" refers to carbocyclic aromatic groups including, but not limited to, phenyl, biphenyl, naphthyl, or anthracyl. The term "aryl" also refers to any bicyclic group in which a cycloalkyl or heterocyclyl ring is fused to a benzene ring, examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, benzopyranyl, benzothiazolyl, benzothienyl, benzotriazole, benzoxazolyl, indolinyl, indolizinyl, isoindolyl, isoquinolinyl, or quinolinyl. An aryl ring may be unsubstituted or substituted with at least one suitable substituent. As used herein the term "heteroaryl" refers to a monocyclic or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and at least one heteroatom, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. The term "heteroaryl" includes, but is not limited to, azepinyl, benzimidazoyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, isoimidazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiadiazoyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, or 1,2,4-triazolyl. A heteroaryl group can be unsubstituted or substituted. As used herein, a "suitable substituent" means a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the mvention or the intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: Cι-C₈ alkyl; C -C₈ alkenyl; C₂-C₈ alkynyl; C₆ aryl; C₃-C₅ heteroaryl; C₃-C cycloalkyl; Ci-Cβ alkoxy; C₆ aryloxy; -CN; -OH; oxo; halo; -CO₂H; -NH₂; -NH(Cι-C₈ alkyl); -N(Cι-C₈ alkyl)₂; -NH(C₆ aryl); -N(C₆ aryl)₂; -CHO; -CO(C₁-C₈ alkyl); -CO(C₆ aryl); -CO₂(Cι-C₈ alkyl); and -CO₂(C₆ aryl). One of skill in art can readily choose a suitable substituent based on the stability and pharmacological and synthetic activity of the compound of the invention. As used herein, the term "halo" or "halogen" includes fluorine, chlorine, bromine, or iodine, including fluoro, chloro, bromo, or iodo. When one or more chiral centers are present in the compounds of the present invention, the individual isomers, i.e., enantiomers, diastereomers, etc. and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. Also included are individual polymorphs of each compound of the present invention. As used herein the terms "pharmaceutically acceptable salts" and "hydrates" refer to those salts and hydrated forms of the compound that would be apparent to those in the art, i. e. , those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism, and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity, and flowability of the resulting bulk drug. Pharmaceutically acceptable salts may be prepared by the addition of an appropriate acid. Thus, the compound can be used in the form of salts derived from inorganic or organic acids. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, succinate, tartrate, or undecanoate. As used herein, the term "subject" refers to a mammal, preferably a human, but can also be an animal in need of veterinary treatment. The term "mammal" as used herein is intended to include, but is not limited to, humans, laboratory animals, domestic pets, and farm animalέ. As used herein, the term "modulation" or "modulating" refers to a reduction in the level and/or activity of target gene product relative to the level and/or activity of the target gene product in the absence of the modulatory treatment. Alternatively, the term, as used herein, refers to a reduction in the number and or proliferation rate of the transformed cancer cells as compared to the proliferation rate of the transformed cancer cells in the absence of the modulatory treatment. As used herein, the term "treating" refers to an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. For example, within the context of treating subjects in need of an heparanase inhibitor, successful treatment may include a reduction in the proliferation of cancer cells or diseased tissue, a halting in capillary proliferation, or a halting in the progression of a disease such as cancer or in the growth of cancerous cells. The term "treating" includes, but is not limited to, preventing the disease from occurring in a subject which may be predisposed to the disease but does not yet experience or display symptoms of the disease, inhibiting the disease, i.e., arresting the development of the disease, or relieving symptoms of the disease, i.e., causing regression of the disease. As used herein, the term "therapeutically effective amount" refers to the amount of heparanase inhibitor, or a pharmaceutically acceptable salt thereof, which, alone or in combination with other drugs, provides a therapeutic benefit in the prevention, treatment, or management of conditions or diseases in which the disassemble of the ECM and the release of bioactive agents are implicated, cancer, tumor formation, primary tumors, tumor progression, tumor metastasis, neoangiogenesis, neovascularization, inflammatory diseases, age related macular degeneration, retinal vascularization, inflammatory diseases, amelioration, neoplasia, cell proliferative disorders, or one or more symptoms associated with such disorders. The amount of the compound will depend upon on the subject being treated. The subject's weight, severity of illness, manner of administration, and judgment of the prescribing physician should be taken into account in deciding the proper amount. Different therapeutically effective amounts may be applicable for each disorder, as will be readily known by those of ordinary skill in the art. The mvention encompasses compounds of Formula I:

Formula I wherein m is 0-4; nis 1-5; each Ri independently is a) halogen, NO₂, NH₂, CN, or OH; b) alkyl, optionally substituted with at least one R₃; c) aryl, optionally substituted with at least one R₃; or d) heteroaryl, optionally substituted with at least one R , wherein each R₃ independently is, halogen, CN, NH₂, NO₂, or OH; and each R₂ independently is a) alkoxy, optionally substituted with at least one R₄; b) aryl, optionally substituted with at least one P^; c) heteroaryl, optionally substituted with at least one R₄; d) -NH-alkyl, optionally substituted with at least one R₄; e) -NHCO-aryl, optionally substituted with at least one R ; f) -NHCO-heteroaryl, optionally substituted with at least one R ; g) -CONH-aryl, optionally substituted with at least one R ; or h) -CONH-heteroaryl, optionally substituted with at least one P , wherein each R independently is halogen, CN, H₂, NO , or OH, alkyl, alkoxy, aryl, heteroaryl, CO₂H, CO₂(alkyl), CONH(aryl), or CONH(heteroaryl). Preferably, the invention encompasses compounds of Formula I:

Formula I wherein m is 0-4; n is 1-4; each Ri independently is a) F, Br, CI, I, NO₂, NH₂, CN, or OH; b) Cι-C₆ alkyl, optionally substituted with at least one R₃; c) C₆-Cιo aryl, optionally substituted with at least one R ; or d) C₃-Cιo heteroaryl, optionally substituted with at least one R , wherein each R₃ independently is F, CI, Br, I, CN, NH₂, N0₂, or OH; and each R₂ independently is a) Cι-C₆ alkoxy, optionally substituted with at least one R4; b) C₆-Cιo aryl, optionally substituted with at least one R4; c) C₄-Cιo heteroaryl, optionally substituted with at least one P^; d) -NH-(Cι-C₆)alkyl, optionally substituted with at least one R^ e) -NHCO-(C₆-Cιo)aryl, optionally substituted with at least one R₄; f) -NHCO-(C₃-Cι₀)heteroaryl, optionally substituted with at least one R₄; g) -CONH-(C₆-Cιo)aryl, optionally substituted with at least one Ri; or h) -CONH-(C₃-Cιo)heteroaryl, optionally substituted with at least one R₄, wherein each independently is F, CI, Br, I, CN, NH₂, NO₂, OH, Cι-C₆ alkyl, d-C₆ alkoxy, C₆-Cιo aryl, C5-C10 heteroaryl, C0₂H, CO₂(Cι-C₆ alkyl), CONH(C₆-Cιo aryl), or CONH(C₅-Cι₀ heteroaryl). More preferably, the invention encompasses compounds of Formula I:

Formula I wherein m is 0-2; n is 1-2; each Ri independently is a) F, Br, CI, I, NO₂, NH₂, CN, or OH; b) Cι-C₄ alkyl, optionally substituted with at least one R₃; c) C₆-Cιo aryl, optionally substituted with at least one R₃; or d) C₃-Cιo heteroaryl, optionally substituted with at least one R₃, wherein each R₃ independently is F, CI, Br, I, CN, NH₂, NO₂, or OH; and each R₂ independently is a) Cι-C₆ alkoxy, optionally substituted with at least one R₄; b) C₆-Cιo aryl, optionally substituted with at least one R₄; c) C₄-Cιo heteroaryl, optionally substituted with at least one P^; d) -NH-(Cι-C₆)alkyl, optionally substituted with at least one R₄; e) -NHCO-(C₆-Cιo)aryl, optionally substituted with at least one R₄; f) -NHCO-(C₃-Cιo)heteroaryl, optionally substituted with at least one R₄; g) -CONH-(C₆-Cιo)aryl, optionally substituted with at least one R₄; or h) -CONH-(C₃-Ci₀)heteroaryl, optionally substituted with at least one R4, wherein each R4 independently is F, CI, Br, I, CN, NH₂, NO₂, OH, Cι-C₆ alkyl, Cι-C₆ alkoxy, C₆-Cι₀ aryl, C₅-C10 heteroaryl, CO₂H, CO₂(Cι-C₆ alkyl), CONH(C₆-Cι₀ aryl), or CONH(C₅-Cι₀ heteroaryl). The following table exemplifies compounds of the invention and their heparanase inhibition. In particular, Table 1 illustrates compounds of Formula I with particular groups for Ri, R , R₃, and R₄. The percent inhibition ranged from 29 to 109 at 33 μM.

^a Measure as a percent n t on at 33 μM. Preferred embodiments of the invention include: N-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-^ methoxy-benzamide; 2,3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid (4-{[4-(lH-benzoimidazol-2- yl)-phenylamino]-methyl}-phenyl)-amide; 3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid (4-{[4-(5,6-dimethyl-lH- benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-amide; 3-Bromo-N-(4-{[4-(5,6-dimethyl-lH-benzoimidazol-2-yl)-phenylamino]- methyl}-phenyl)-4-methoxy-benzamide; Thiazole-4-carboxylic acid (4- {[4-(lH-benzoimidazol-2-yl)-ρhenylamino]- methyl} -phenyl)-amide; N-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-nicotinamide; N-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-furan-2-yl-

4-methoxy-benzamide; 2-(4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-isoindole-l,3- dione; N-(3-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4- methoxy-benzamide; N-(4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-benzamide; N-(4- { [4-( 1 H-benzoimidazol-2-yl)-phenylamino] -methyl} -phenyl)-4-methyl- benzamide; N-(4-{[4-(5-pyridin-3-yl-lH-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)- benzamide; [4-(lH-benzoimidazol-2-yl)-benzyl]-[4-(lH-benzoimidazol-2-yl)-phenyl]-amine; 4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}-N-p-tolyl-benzamide; 2-(3-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-l,3-dioxo-2,3- dihydro- 1 H-isoindole-5-carboxylic acid; N-(lH-Benzoimidazol-2-yl)-4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]- methyl} -benzamide; (4- {[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl} -phenoxy)-acetic acid; [4-(lH-benzoimidazol-2-yl)-phenyl]-(4-(N-methyl)-benzyl)-amine; 2-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenoxy)-N-p-tolyl- acetamide; and N-(lH-Benzoimidazol-2-yl)-2-(4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]- methyl} -phenoxy)-acetamide. More preferred compounds of the invention include: N-(4- { [4-( 1 H-Benzoimidazol-2-yl)-phenylamino] -methyl} -phenyl)-3 -bromo-4- methoxy-benzamide; 2,3-Dihydro-benzo[l ,4]dioxine-6-carboxylic acid (4- {[4-(lH-benzoimidazol-2- yl)-phenylamino]-methyl}-phenyl)-amide; 3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid (4-{[4-(5,6-dimethyl-lH- benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-amide; 3-Bromo-N-(4-{[4-(5,6-dimethyl-lH-benzoimidazol-2-yl)-phenylamino]- methyl}-phenyl)-4-methoxy-benzamide; Thiazole-4-carboxylic acid (4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]- methyl} -phenyl)-amide; N-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-nicotinamide; N-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-furan-2-yl- 4-methoxy-benzamide; N-(3-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4- methoxy-benzamide; N-(4- { [4-( 1 H-benzoimidazol-2-yl)-phenylamino] -methyl} -phenyl)-benzamide; N-(4- { [4-( 1 H-benzoimidazol-2-yl)-phenylamino] -methyl} -phenyl)-4-methyl- benzamide; N-(4- { [4-(5-pyridin-3 -yl- 1 H-benzoimidazol-2-yl)-phenylamino] -methyl} -phenyl)- benzamide; [4-(lH-benzoimidazol-2-yl)-benzyl]-[4-(lH-benzoimidazol-2-yl)-phenyl]-amine; 4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}-N-p-tolyl-benzamide; 2-(3-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-l,3-dioxo-2,3- dihydro- 1 H-isoindole-5-carboxylic acid; N-( 1 H-B enzoimidazol-2-yl)-4- { [4-( 1 H-benzoimidazol-2-yl) -phenylamino] - methyl} -benzamide; 2-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenoxy)-N-p-tolyl- acetamide; and N-(lH-Benzoimidazol-2-yl)-2-(4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]- methyl} -phenoxy)-acetamide. The compounds of the invention are synthesized using a variety of schemes, such as those illustrated below and exemplified in the Example section. One of ordinary skill in the art readily understands that reaction conditions may vary slightly due to specific reactants, when necessary the compounds may use protecting groups, or that more than one substituent may be included in the reaction. Although, the following schemes exemplify compounds having one Ri and R₂, with little or no experimentation one of ordinary skill in the art can easily alter the reagents and reaction conditions to include any combination of substituents as defined above. Also, the skilled artisan can easily use interchangeable steps for each synthetic process and incorporate isolation and/or purification steps as deemed necessary. Although the schemes illustrate six membered rings with one substitution, i.e., Ri, methodologies to introduce a second, third, or fourth substitution are well within the abilities of the ordinarily skilled artisan. For example, one method comprises selecting a starting material with more than one substituent, e.g., the aromatic ring may contain two or more Ri. Alternatively, additional substituents may be added by the functionalization of existing groups. Functionalization of the substituent groups may be carried out using a variety of methods including, but not limited to, reduction, oxidation, alkylation, amination, etherification, esterification, or halogenation. As commonly known to the ordinary skilled artisan, functionalization may necessitate the protection of functional groups within the compound such as those described by Theodora W. Greene, "Protective Groups in Organic Synthesis," John Wiley & Sons, New York (1981). During the synthesis, the reactions may be carried out with intervening isolation and/or purification steps or the products may be carried forth in the reaction sequence without isolation and/or purification. Starting materials useful for the preparing the compounds of the invention and intermediates therefor, are commercially available or can be prepared by well known synthetic methods. One method of making the compounds of the invention is illustrated in Scheme 1. In the first step of Scheme 1, a benzoimidazole is synthesized by reacting an ortho diamine phenyl with an amine substituted benzoic acid. As an example of possible interchangeability, one of ordinary skill in the art can use an aldehyde or a halo acid instead of the carboxylic acid. See, Tett. Lett., 39(25), 4481 (1998); J. Med. Chem., 43, 4084 (2000). Although the ortho diamine phenyl is mono-substituted with one Ri, one of ordinary skill in the art can easily multiply substitute the ortho diamine phenyl as desired. Examples of optionally substituted ortho phenyl diamines include, but are not limited to, 4-methoxybenzene- 1 ,2-diamine, 4-fluorobenzene- 1 ,2-diamine, 4-bromobenzene-l ,2- diamine, 4-pyridin-4-ylbenzene-l,2-diamine, 4,5-dimethylbenzene-l,2-diamine, 3- methylbenzene-l,2-diamine, or 3,4-dimethylbenzene-l,2-diamine. The reaction is carried out in the presence of an acid, such as polyphosphoric acid, at a suitable temperature, such as 220°C, to form a benzoimidazol-2-yl-phenylamine, Compound A. See, Asian J. Chem., 15(2), 987 (2003). Alternative acids suitable for the reaction include, but are not limited to, sulfuric acid, or toluene-4-sulfonic acid. See, Khim. Geterotsiklicheskikh Soedinenii, 7, 975 (1983); Tett. Lett., 40, 4119 (1999). hi the second step, a substituted benzoic acid is allowed to react with oxalyl chloride to form the acid chloride and subsequently, allowed to react with 4-aminobenzyl alcohol to form 3-bromo-N-(4- hydroxymethyl-phenyl)-4-methoxy-benzamide, Compound B. Other acid halides may be used in the reaction including, but not limited to, acid fluoride or an acid bromide. See, J.A. C.S., 117, 5401 (1995). The third step in Scheme 1 is a Dess Martin oxidation to yield a 3-bromo-N-(4-formyl-phenyl)-4-methoxy-benzamide, Compound C. See,

Organic Synthesis Vol. 77, p. 141. Alternative oxidations maybe used, such as Swern oxidation and the Parikh-Doering Oxidation. See, J.O.C., 62, 8276 (1997); J.A.C.S., 89, 5505 (1967). The fourth step of Scheme 1 is the condensation and reduction reaction of Compound A with Compound C in the presence of a reducing agent to form N-(4-{[4- (lH-benzoimidazol-2-yl)-phenylamino-methyl} -phenyl)-3-bromo-4-methoxy-benzamide, compound D. See, Organic Reactions, 1, 59 (New York, 2002). Reducing agents include, but are not limited to, borohydrides or diisobutlyaluminum hydrides. J.O.C., 52, 671 (1987); J.O.C, 50, 2443 (1985). Although Scheme 1 is exemplified with a bromo and methoxy substituted benzoic acid as the R₂ groups, the skilled artisan with little or no experimentation can easily modify the reaction conditions to further substitute the phenyl rings. H0₂C- -NH₂ H NH_? N ^Rι O _NH Acid N ^ // -NH₂ Compound A

Reduction Compound A + Compound C »-

Scheme 1 In Scheme 2, the synthetic scheme is illustrated with a heteroaryl; substituents may be added depending upon the desired substitution pattern. The first step in Scheme 2 comprises the formation of an acid chloride using the methods described above to form N-(4-hydroxymethyl-phenyl)-nicotinamide, Compound E. Thereafter, in the second step of Scheme 2, Compound E undergoes a Dess-Martin oxidation to yield an N-(4-formyl- phenyl)-nicotinamide, Compound F. Finally, Compound A and Compound F are allowed to undergo a condensation followed by a reduction to yield an N-(4-{[lH-benxoimidaolz- 2-yl)-phenylamino]-methyl}-phenyl)-nicotinamide, Compound G. ^{Dess Martin}

Compound F

-N /=\ -NH₂ ^ /> Reduction ~ N Compound A

Scheme 2 Yet another method for synthesizing the compounds of the invention is illustrated in Scheme 3. Scheme 3 illustrates an alternative for the synthesis of the compounds, in particular for 4- { [4-( 1 H-benzoimidazol-2-yl)-phenylamino] -methyl} -N-p-tolyl- benzamides. In Scheme 3, a benzoimidazol-2-yl-phenylamine, Compound A, made as described above, is allowed to react with 4-carbaldehydebenzoic acid to yield a 4-{[4- (lH-benzoimidazol-2-yl)-phenylamino]-methyl} -benzoic acid, Compound H. Compound H, is allowed to react with a 4-methylaniline in the presence of carbonyldiimidazole (GDI) to yield a 4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}-N-p-tolyl- benzamide, Compound I. See, JO. C, 57, 3454 (1992). Although Scheme 3 is exemplified with a methyl substituted aniline, the skilled artisan with little or no experimentation can easily modify the reaction conditions to further substitute the phenyl rings to obtain the desired substitution pattern. H OHC— ^~J^~{ H /==\ OH _" XtPP - * _"r£cK N c M Compound H Compound A

Compound I Scheme 3 The products of the above-described synthesis may be purified using techniques commonly known to one skilled in the art such as preparatory chromatography, thin-layer chromatography, HPLC, or crystallization. Another embodiment of the invention encompasses pharmaceutical compositions of at least one compound of Formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof, in combination with a pharmaceutically acceptable carrier. When the compound is negatively charged, it is balanced by a counterion, such as, an alkali metal cation such as sodium or potassium. Other suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations, such as tetramethylammonium, tetrabutylammonium, choline, triethymydroammonium, meglumine, triethanol-hydroammonium, and the like. An appropriate number of counterions are associated with the molecule to maintain overall charge neutrality. Likewise, when the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions are present to maintain overall charge neutrality. These pharmaceutically acceptable salts are within the scope of the present invention. Pharmaceutically acceptable salts may be prepared by the addition of an ' appropriate acid. Thus, the compound can be used in the form of salts derived from inorganic or organic acids. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, succinate, tartrate or undecanoate. If the compound has an acidic proton, a salt may be formed by the addition of base to form a pharmaceutically acceptable base addition salt. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. The basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. The presence of pharmaceutically acceptable salts within the scope of the present compounds is not intended to limit the compounds of the present invention to those that are synthetically prepared. The compounds of the present invention also include compounds that are converted within the body and prodrugs. "Pro-drug" means a form of a compound of the present invention suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use. A pro-drug can be transformed to yield the parent compound of the formula (I) herein, for example by hydrolysis in blood (Higuchi et al., 1987). When a compound of the present invention is present as a salt or hydrate that is nonpharmaceutically acceptable, that compound can be converted in certain circumstances to a salt or hydrate form that is pharmaceutically acceptable in accordance with the present invention. The invention also encompasses methods of inhibiting heparanase and methods of treating heparanase-dependent diseases and conditions in mammals using the heparanase inhibitors of Formula I. The diseases and conditions that may be treated or prevented by the present methods include cancer, an inflammatory disorder, or an autoimmune disease. The method includes administering to a mammal in need of such treatment a therapeutically effective amount of one or more compounds of the present invention. The inhibitory effect of the compounds of the present invention on heparanase activity can be evaluated by several methods carried out in vitro, ex vitro, or in vivo. Some of the in vitro assays used according to the present invention were described in U.S. 6,190,875, which is incorporated by reference in particular for its teaching of how to conduct in vitro assays of heparanase activity. In these assays, heparanase is incubated with a heparanase substrate in the presence and in the absence of a compound of the present invention, and the inhibitory effect of the compound on the catalytic activity of the heparanase on its substrate is evaluated. The heparanase may be natural mammalian heparanase, such as human heparanase purified as described in U.S. Patent 5,362,641 or, recombinant mammalian, e.g., human or mouse recombinant heparanase as described in U.S. 5,968,822, U.S.6,190,875, and WO 99/57244, in purified or non-purified form. A source of non- purified recombinant heparanase is, for example, an extract of cells in which mammalian heparanase cDNA is expressed. U.S. Patents Nos. 5,362,641, 5,968,822, 6,190,875, and International Publication No. WO 99/57244 are incorporated by reference in their entirety and in particular for their teaching of how to recover heparanase from biological sources. The heparanase substrate may be a natural heparan sulfate substrate, or an alternative substrate of the enzyme as described in U.S. 6,190,875 (which is herein incorporated by reference in its entirety), for example, heparin (e.g., heparin immobilized on a gel such as Sepharose), heparin fragments (e.g., several species of low molecular weight heparin), modified non-anticoagulant species of heparin, other sulfated polysaccharides (e.g., pentosan polysulfate), soluble HSPG or ECM. Evaluation of the inhibitory effect can be carried out, for example, as described in

U.S. Patent 6,190,875, by a size separation assay adapted for detection of degradation products of the heparanase substrate. Examples of such assays include gel electrophoresis and column chromatography. Qualitative and quantitative evaluation of the catalytic activity of heparanase on its substrate and the inhibitory effect of a candidate inhibitor can be effected, for example, by radioactive assays, in which the substrate used is radiolabeled, either in vitro, or metabolically. Another possibility, although less preferred, consists in evaluating the catalytic activity of heparanase on the substrate by colorimetric assays. Quantitative colorimetric assays include the dimethylmethylene blue (DMB) assay, or the carbazole assay. The ex vivo assays for evaluating the inhibitory effect of the compounds on heparanase activity include angiogenic sprout formation and transmigration assays, the angiogenic sprout formation assay is carried out in the rat aorta model (Nicosia et al., Am. J. Path., 151(5), 1379-1386 (1997)), whereby rat aorta rings are in embedded in a basement membrane like matrix composed of ECM-derived proteins such as laminin and collagen type IN, and HSPG, thus constituting a relevant heparanase substrate. The rings then develop angiogenic sprouts and angiogenesis can be quantified. The compounds to be tested are added to the embedded aortic rings and their effect on angiogenic sprout formation is then evaluated. In the ex vivo transwell migration assay, immune cell migration is evaluated, optionally in the presence of a chemoattractant factor such as stromal cell-derived factor (SDF-1), a process which mimics in vivo extravasation of immune cells from the vasculature to the sites of inflammation, h this assay, immune cells such as lymphocytes are let to migrate from the upper to the lower chamber through a transwell filter coated with a basement membrane like matrix composed of ECM-derived proteins. The migration rate of the cells through the filter is then evaluated by counting the number of cells added on top of the upper chamber. Over expression of heparanase in the immune cells results in an increase in the transmigration rate of the cells while addition of a heparanase inhibitor reduces the transmigration rate of the cells. The inhibitory effect of the compounds on heparanase activity may be also assayed in vivo, for example, using the primary tumor growth or metastasis animal models or the sponge inflammation assay. The heparanase inhibitors of the present invention can be used for the treatment of diseases and disorders caused by or associated with heparanase catalytic activity such as, but not limited to, cancer, inflammatory disorders and autoimmune diseases. One embodiment of the invention encompasses compounds of Formula I used for inhibition of angiogenesis, and are thus useful for the treatment of diseases and disorders associated with angiogenesis and neovasculation such as, but not limited to, tumor angiogenesis, ophthalmologic disorders such as diabetic retinopathy and macular degeneration, particularly age-related macular degeneration, reperfusion of gastric ulcer, and also for contraception or for inducing abortion at early stages of pregnancy. Another embodiment of the invention encompasses the compounds of Formula I useful for treatment or inhibition of a malignant cell proliferative disease or disorder. According to this embodiment and due to the angiogenesis inhibitory activity of the compounds, they can be used for the treatment or inhibition of non-solid cancers, e.g., hematopoietic malignancies such as all types of leukemia, e.g., acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), mast cell leukemia, hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, Burkitt's lymphoma and multiple myeloma, as well as for the treatment or inhibition of solid tumors such as tumors in lip and oral cavity, pharynx., larynx, paranasal sinuses, major salivary glands, thyroid gland, esophagus, stomach, small intestine, colon, colorectum, anal canal, liver, gallbladder, extrahepatic bile ducts, ampulla of vater, exocrine pancreas, lung, pleural mesothehoma, bone, soft tissue sarcoma, carcinoma, and malignant melanoma of the skin, breast, vulva, vagina, cervix uteri, corpus uteri, ovary, fallopin tube, gestational trophoblastic tumors, penis, prostate, testis, kidney, renal pelvis, ureter, urinary bladder, urethra, carcinoma of the eyelid, carcinoma of the conjunctiva, malignant melanoma of the conjunctiva, malignant melanoma of the uvea, retinoblastoma, carcinoma of the lacrimal gland, sarcoma of the orbit, brain, spinal cord, vascular system, hemangiosarcoma and Kaposi's sarcoma. It is to be understood that the compounds of the Formula I are useful for treating or inhibiting tumors at all stages, namely tumor formation, primary tumors, tumor progression, or tumor metastasis. The compounds of Formula I are also useful for inhibiting or treating cell proliferative diseases or disorders such as psoriasis, hypertrophic scars, acne and sclerosis/scleroderma, and for inhibiting or treatment of other diseases or disorders such as polyps, multiple exostosis hereditary exostosis, retrolental fibroplasia, hemangioma, and arteriovenous malformation. In one embodiment, the compounds of Formula I are useful for treatment of or amelioration of inflammatory symptoms in any diseases, condition or disorder where immune and/or inflammation suppression is beneficial such as, but not limited to, treatment of or amelioration of inflammatory symptoms associated with hypersensitivity, allergic reactions, asthma, atherosclerosis, otitis and other otorhinolaryngological diseases, dermatitis and other skin diseases, posterior and anterior uveitis, conjunctivitis, optic neuritis, scleritis and other immune and/or inflammatory ophthalmic diseases. In another preferred embodiment, the compounds of Formula I are useful for treatment of or amelioration of an autoimmune disease such as, but not limited to, Eaton- Lambert syndrome, Goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, autoimmune hemolytic anemia (AJHA), hepatitis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis, plexus disorders, e.g., acute brachial neuritis, polyglandular deficiency syndrome, primary biliary cirrhosis, rheumatoid arthritis, scleroderma, thrombocytopenia, thyroiditis, e.g., Hashimoto's disease, Sjogren's syndrome, allergic purpura, psoriasis, mixed connective tissue disease, polymyostitis, dermatomyositis, vasculitis, polyarteritis nodosa, polymyalgia rheumatica, Wegener's granulomatosis, Reiter's syndrome, Behcets's syndrome, ankylosing sondylitis, pemphigus, bullous pemphigoid, dermatitis herpetiformis, Crohn's disease and autism. Moreover, the compounds of Formula I may be used for in vivo and in vitro investigative, diagnostic, or prophylactic methods, which are well known in the art. In the methods of the present invention, a therapeutically effective amount of at least one compound of Formula I is administered to a mammal in need. The term "administering" as used herein means delivering the compounds of the present invention to a mammal by any method that may achieve the result sought. They may be administered, for example, orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation. Another embodiment of the invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of at least one of the compounds of Formula I or pharmaceutically acceptable salts thereof. Compositions of the present invention include at least one compound of the present invention as described herein (that is, a compound of Formula I) or a pharmaceutically acceptable salt, hydrate or pro-dmg thereof, in combination with a pharmaceutically acceptable carrier. The compounds of the present invention may be employed in solid or liquid form including for example, powder or crystalline form, in solution or in suspension. They may be administered in numerous different ways, such as orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation. The choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and the provisions to be observed in pharmaceutical practice. Thus, the carrier employed may be, for example, either a solid or liquid. One method of administering a solid dosage form is to form solid compositions for rectal administration, which include suppositories formulated in accordance with known methods and containing at least one compound of the present invention. Examples of solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. Injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. The aqueous solutions, also including solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation, microfiltration, and/or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Examples of injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation may include vacuum drying and a freeze-dry technique that yields a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof. Examples of injectable solids include powders that are reconstituted, dissolved or suspended in a liquid prior to injection, hi injectable compositions, the carrier typically includes sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included within the compositions of the present invention. For oral administration, the active compound may be administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet, or may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Examples of oral solid dosage forms include tablets, capsules, troches, lozenges and the like. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like. Carriers for oral use (solid or liquid) may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. To prepare a capsule, it may be advantageous to use lactose and liquid carrier, such as high molecular weight polyethylene glycols. Topical administration, in the form of gels (water or alcohol based), creams or ointments, for example, containing compounds of the invention may be used. Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders. Such topical formulations can be used for example, to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like. Compounds of the invention maybe also incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier. For administration by inhalation, compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler. Compositions according to the invention may also be formulated in a manner that resists rapid clearance from the vascular (arterial or venous) wall by convection and/or diffusion, thereby increasing the residence time of the viral particles at the desired site of action. A periadventitial depot comprising a compound according to the invention may be used for sustained release. One such useful depot for administering a compound according to the invention maybe a copolymer matrix, such as ethylene- vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic shell. Alternatively, a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia. An alternative approach for minimizing washout of a compound according to the invention during percutaneous, transvascular delivery comprises the use of nondiffusible, drug-eluting microparticles. The microparticles may be included a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Such microparticles enable strategic manipulation of variables including total dose of drug and kinetics of its release. Microparticles can be injected efficiently into the arterial or venous wall through a porous balloon catheter or a balloon over stent, and are retained in the vascular wall and the periadventitial tissue for at least about two weeks. Formulations and methodologies for local, intravascular site-specific delivery of therapeutic agents are discussed in Reissen et al. (J. Am. Coll. Cardiol. 1994; 23: 1234- 1244). A composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge. Such polymers have been described, for example, in application WO93/08845. Certain of them, such as, in particular, those obtained from ethylene and or propylene oxide are commercially available. Another embodiment of the invention provides for a compound according to the invention to be administered by means of perfusion balloons. These perfusion balloons, which make it possible to maintain a blood flow and thus to decrease the risks of ischaemia of the myocardium, on inflation of the balloon, also enable the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes, which may be necessary for its optimal action. Alternatively, a channeled balloon catheter (such as "channelled balloon angioplasty catheter," Mansfield Medical, Boston Scientific Corp., Watertown, Mass.) may be used. This catheter includes a conventional balloon covered with a layer of 24 perforated channels that are perfused via an independent lumen through an additional infusion orifice. Narious types of balloon catheters, such as double balloon, porous balloon, microporous balloon, channel balloon, balloon over stent and hydrogel catheters, all of which maybe used to practice the invention, are disclosed in Reissen et al. (1994). Another aspect of the present invention relates to a pharmaceutical composition including a compound according to the invention and poloxamer, such as Poloxamer 407, which is a non-toxic, biocompatible polyol, commercially available (e.g., from BASF, Parsippany, N.J.). A poloxamer impregnated with a compound according to the invention may be deposited for example, directly on the surface of the tissue to be treated, for example during a surgical intervention. Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity. The use of a channel balloon catheter with a poloxamer impregnated with a compound according to the invention may be advantageous in that it may keep the balloon inflated for a longer period of time, while retaining the properties of facilitated sliding, and of site-specificity of the poloxamer. The composition may also be administered to a patient via a stent device. In this embodiment, the composition is a polymeric material in which the compound of the invention is incorporated, which composition is applied to at least one surface of the stent device. Polymeric materials suitable for incorporating the compound of the invention include polymers having relatively low processing temperatures such as polycaprolactone, poly(ethylene-co-vinyl acetate) or poly(vinyl acetate or silicone gum rubber and polymers having similar relatively low processing temperatures. Other suitable polymers include non-degradable polymers capable of carrying and delivering therapeutic drugs such as latexes, urethanes, polysiloxanes, styrene-ethylene butylene- styrene block copolymers (SEBS) and biodegradable, bioabsorbable polymers capable of carrying and delivering therapeutic drugs, such as poly-DL-lactic acid (DL-PLA), and poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, and polyphosphazenes. In addition to the active compound and the pharmaceutically acceptable carrier, the compositions of the present mvention optionally contain one or more excipients that are conventional in the art. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, troches, pills, capsules and the like. Narious other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used. In addition, the active compound may be incorporated into sustained-release preparations and formulations. The percentage of active ingredient in the compositions of the invention may be varied. Several unit dosage forms may be administered at about the same time. A suitable dose employed may be determined by a physician or qualified medical professional, and depends upon various factors including the desired therapeutic effect, the nature of the illness being treated, the route of administration, the duration of the treatment, and the condition of the patient, such as age, weight, general state of health and other characteristics, which can influence the efficacy of the compound according to the mvention. In adults, doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation; from about 0.01 to about 100, preferably 0.1 to 70, more preferably 0.5 to 10, mg kg body weight per day by oral administration; from about 0.1 to about 150 mg kg body weight per day when applied externally; and from about 0.001 to about 10, preferably 0.01 to 10, mg/kg body weight per day by intravenous or intramuscular administration. The compounds and compositions according to the invention may be administered as frequently as necessary as determined by a skilled practitioner in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. For other patients, it may be necessary to prescribe not more than one or two doses per day. The compounds of the present invention may also be formulated for use in conjunction with other therapeutically active compounds or in connection with the application of therapeutic techniques to address pharmacological conditions, which may be ameliorated through the application of a compound according to the present invention. The invention is further defined by reference to the following examples, describing in detail the preparation of the compound and the compositions of the present invention, as well as their utility. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.

Examples The ingredients and method steps should be understood as examples that are intended to be illustrative only. In particular, the invention is not intended to be limited to the methods, protocols, conditions and the like specifically recited herein, insofar as those skilled in the art would be able to substitute other conditions, methods, amounts, materials, etc. based on the present disclosure to arrive at compounds within the scope of the invention. While the present invention is described with respect to particular examples and preferred embodiments, the present invention is not limited to these examples and embodiments. In particular, the compounds encompassed by the present invention may involve the use of a different starting material depending on the desired final compound, different amounts of various ingredients, or substitution of different ingredients such as other reactants or catalysts that would be suitable depending on the starting material and result to be achieved. Moreover, the methods of the present invention are not limited to treating only the exemplified diseases and conditions, but rather any disease or condition that may be treated by the inhibition of heparanase. Unless stated otherwise, temperatures are given in degrees Celsius (°C); procedures carried out at room or ambient temperature are carried out at a temperature in the range of about 18°C to about 25 °C; organic solutions were dried over anhydrous sodium sulfate; and evaporation of solvent was performed using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60 °C. The final products were characterized using proton nuclear magnetic resonance (NMR) spectra and mass spectra. Yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if additional material was required. When present, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz with perdeuterio dimethyl sulfoxide (DMSO-d₆) as solvent unless otherwise indicated. Chemical symbols have their usual meanings and SI units and symbols are used. Where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example.

Compound A + Compound B

Scheme 4 Example 1: Preparation of N-(4-{[4-(lH-Benzoimidazol-2-yl -phenylaminol-methyl|- phenyl)-3-bromo-4-methoxy-benzamide (Compound 1)

Compound 1 was made following the synthetic scheme illustrated in Scheme 4. Step 1 : 4-(lH-benzoimidazol-2-yl)-phenylamine (Compound A) 1,2-Phenlendiamine (6.5 g, 60 mmol), 4-aminobenzoic acid (7.0 g, 51 mmol) and polyphosphoric acid (25 g) were placed into a flask and were stirred at 220 °C for 4 hrs. After the mixture was cooled to ambient temperature, to the dark lump was added aq. K₂CO₃ (10%, 400 mL). The lump was neutralized with aq. NaHCO₃ to pH ca. 7, and the formed solid was collected by filtration. The solid was washed with hot water (50 - 70 °C) till the water was colorless, recrystalhzation in ethyl acetate (800 ml, Charcoal 3g) gave a white solid (4.2 g, 33%) as pure product. MS m/z = 210 (M+l).

Step 2: 1, 3-bromo-N-(4-hydroxymethyl-phenyl)-4-methoxy-benzamide (Compound B) To a solution of 3-bromo-4-methoxy-benzoic acid (1.15 g, 5.0 mmol) in methylene chloride (10.0 mL) was added oxalyl chloride solution in methylene chloride (2 M, 3 mL, 6.0 mmol). Four drops of DMF was added with stirring at ambient temperature. Volatile materials were completely removed by evaporation under vacuum after it was stirred at ambient temperature for 1.5 h to give a residue. To the residual was added DMAP (20 mg), 4-aminobenzyl alcohol (0.615 g, 5.0 mmol) and THF (20 mL). Then, Et₃N (1 ml) was added. The mixture was stirred at room temperature for 24 hrs. Then THF was removed under vacuum and water (20 mL) was added. The solid formed was filtered and washed with water (2 5 ml), ether (3 x 15 mL). An off-white solid (1.34 g, 80%) was obtained. MS m/z = 337 (M+2). MS m/z = 337 (M+2).

Step 3: 3-Bromo-N-(4-formyl-phenyl)-4-methoxy-benzamide (Compound C) 3-Bromo-N-(4-hydroxymethyl-phenyl)-4-methoxy-benzamide (1 mmol, 0.335 g) and Dess-Martin periodinance (2 mmol, 0.848 g) were stirred in anhydrous CH₂C1₂ (5 ml) for 1.5 h at room temperature. Then, 1 M NaHCO₃ was added to quench the reaction. Ethyl acetate (50 ml) was added to extract the aqueous layer. The combined organic layer was dried over Na₂SO₄, and concentrated. The residue was separated by silica gel column chromatography (eluent: ether/hexanes = 1/1, v/v). An off white solid (0.133 g, 40%) was obtained as the product. MS m/z = 335 (M+2).

Step 4: N-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4- methoxy-benzamide (Compound 1) To a solution of 4-(lH-benzoimidazol-2-yl)-phenylamine (0.042 mg, 0.2 mmol) in

DMF (3 ml) was added 3-bromo-N-(4-formyl-phenyl)-4-methoxy-benzamide (0.067 g, 0.2 mmol). NaBH(OAc)₃ (0.211 g, 1 mol) was added to the solution. The resulting mixture was stirred for 36 h at room temperature. Then additional NaBH(OAc)₃ (0.211 g, 1 mol) was added and the reaction was continued for another 36 h. Water (10 ml) was added to quench the reaction, followed by aq. K₂CO₃ solution (5%) to neutralize to pH ca. 7. The solid formed was filtered and washed with water (2 x 4 ml). Recrystalhzation from MeOH H₂O (1/1, v/v) afforded the compound as a brown crystalline solid (complex with 1 equivalent of methanol, 0.052 g, 47%). ¹HNMR (DMSO-d6) δ 3.17 (s, 3H), 3.93 (s, 3H), 4.09 (br s, IH), 4.33 (d, J= 6.0 Hz, 2H), 6.69-6.76 (m, 3H), 7.08-7.12 (m, 2H), 7.25 (d, J= 8.0 Hz, IH), 7.34-7.43 (m, 3H), 7.52-7.55 (m, IH), 7.70 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 8.00 (dd, J= 8.7, 2.1 Hz, IH), 8.22 (d, J= 2.1 Hz, IH), 10.17 (s, IH), 12.41 (s, IH). LC-MS m/z = 527 (M+l). Example 2: Preparation of N-(4-{r4-(lH-Benzoimidazol-2-yl -phenylaminol-methyl>- phenylV3-furan-2-yl-4-methoxy-benzamide (Compound 7 :

To a solution of N-(4-{[4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl}- phenyl)-3-bromo-4-methoxy-benzamide (0.052 g, 0.098 mmol) in ethylene glycol dimethyl ether (5 ml) was added tetrakis(triphenylρhosphine)palladium (0.022 g, 0.02 mmol) and sodium carbonate (0.3 ml, 2M). 2-Furanboronic acid (0.033 g, 0.3 mmol) in EtOH (0.3 ml) was then added to the mixture. The resulting mixture was refluxed for over night under argon. The reaction mixture was then cooled to room temperature, filtered through a pad of celite. The filter cake was washed using methanol (3 X 5 ml). The organic solvent was evaporated under reduced pressure to give a residue. The residue was triturated with ether to afford a solid, which was filtered and washed with ether (2 X 3 ml) and dried. Then the solid was dissolved in methanol (2 ml). The none soluble solid in MeOH was filtered away. The filtrate was concentrated to afford the title product as an off-white crystalline. ¹HNMR (DMSO-d6) δ 4.00 (s, 3H), 4.33 (d, J= 6.0 Hz, 2H), 6.62- 6.64 (m, IH), 6.70-6.76 (m, 3H), 7.00 (d, J= 3.0 Hz, IH), 7.07-7.14 (m, 2H), 7.00 (d, J= 3.0 Hz, IH), 7.07-7.14 (m, 2H), 7.26 (d, J= 8.4 Hz, IH), 7.36 (d, J= 8.4 Hz, 2H), 7.40- 7.43 (m, IH), 7.52-7.55 (m, IH), 7.74 (d, J= 8.4 Hz, 2H), 7.81 (d, J= 1.2 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 7.94 (dd, J= 8.7, 2.4 Hz, IH), 8.37 (d, J= 2.1 Hz, IH), 10.23 (s, IH), 12.41 (s, lH). MS m/z = 515 (M+l).

H

Scheme 5 Example 3: Preparation of N-(4-{r4-(lH-Benzoimidazol-2-ylVphenylamino]-methv - phenvD-nicotinamide (Compound 6): Compound 6 was made following the synthetic scheme illustrated in Scheme 5. Step 1 : N-(4-hydroxymethyl-phenyl)-nicotinamide Following the procedure of the second step of Example 1 and using appropriate starting materials, the title compound was obtained as an off-white solid (0.67g, 59%). MS m/z = 228 (M).

Step 2: N-(4-formyl-phenyl)-nicotinamide Following the procedure of the third step of Example 1 and using appropriate starting materials, the title compound was obtained as an brown solid (0.20 g, 40%). MS m/z = 227 (M+l).

Step 3: N-(4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-nicotinamide (Compound 6) Following the procedure described in the fourth step of Example 1 and using N- (4-formyl-phenyl)-nicotinamide (0.068 g, 0.3 mmol) and 4-(lH-benzoimidazol-2-yl)- phenylamine (0.063 g, 0.3 mmol), the title compound was obtained as an brown solid (O.084g, 68%). 'HNMR (DMSO-d6) δ 4.34 (d, J= 6.0 Hz, 2H), 6.69-6.75 (m, 3H), 7.09- 7.12 (m, 2H), 7.36-7.42 (m, 3H), 7.52-7.58 (m, 2H), 7.73 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 8.26-8.29 (m, IH), 8.74-8.76 (m, IH), 9.09 (d, J= 1.8 Hz, IH), 10.42 (s, IH), 12.41 (s, IH). MS m/z = 420 (M+l).

Example 4: Preparation of 3-Bromo-N-(4-{|^"4-(5,6-dimethyl-lH-benzoimidazol-2-yl)- phenylamino1-methy -phenyl)-4-methoxy-benzamide (Compound 4):

Step 1: 4-(5,6-Dimethyl-lH-benzoimidazol-2-yl)-phenylamine Following the procedure of Step 1 for Example 1 and starting with 4,5-dimethyl- benzene- 1,2-diamine (6.80 g, 50 mmol), the title compound was obtained as a brown solid (2.44 g, 21%). MS m/z = 238 (M+l). Step 2: 3-Bromo-N-(4-{[4-(5,6-dimethyl-lH-benzoimidazol-2-yl)-phenylamino]- methyl}-phenyl)-4-methoxy-benzamide (Compound 4): Following the procedure of the fourth Step of example 4 and using appropriate starting materials, the title compound was obtained as a brown solid (0.067 g, 61%). ¹HNMR (DMSO-d6) δ 2.28 (s, 3H), 2.30 (s, 3H), 3.93 (s, 3H), 4.32 (d, J= 6.0 Hz, 2H), 6.63-6.70 (m, 3H), 7.17 (s, IH), 7.23-7.37 (m, 4H), 7.71 (d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 7.99-8.02 (m, IH), 8.22 (d, J= 2.4 Hz, IH), 10.16 (s, IH), 12.13 (s, IH). MS m/z = 555 (M+l).

Example 5: Preparation of 2,3-Dihvdro-benzo[^'L41dioxine-6-carboxylic acid (4-{ 4-(5,6- dimethyl-lH-benzoimidazol-2-yl)-phenylaminol-methyl>-phenyl)-amide (Compound 3):

Step 1: 2,3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid (4-hydroxymethyl-phenyl)- amide Following the procedure of Step 2 of Example 1 and using 2,3-dihydro- benzo[l,4]dioxine-6-carboxylic acid (0.90 g, 5 mmol) the title compound was obtained as a white solid (1.12 g, 79%). MS m/z = 286 (M+l).

Step 2: 2,3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid (4-formyl-phenyl)-amide Following the procedure of Step 3 of Example 1 and starting from 2,3-dihydro- benzo[l,4]dioxine-6-carboxylic acid (4-hydroxymethyl-phenyl)-amide (0.50 g, 1.75 mmol), the title compound was obtained as a brown solid (0.35 g, 71%). MS m/z = 284 (M+l).

Step 3: 2,3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid (4-{[4-(5,6-dimethyl-lH- benzoimidazol-2-yl)-phenylamino]-methyl} -phenyl)-amide (Compound 3) Following the procedure.of Step 4 of Example 4 and using appropriate starting materials, the title compound was obtained as a brown solid (0.064 g, 63%). ¹HNMR (DMSO-d6) δ 2.28 (s, 3H), 2.30 (s, 3H), 4.30 (br s, 6H), 6.66-6.70 (m, 3H), 6.98 (d, J= 8.4 Hz, IH), 7.17 (s, IH), 7.30-7.35 (m, 3H), 7.47-7.51 (m, 2H), 7.71 (d, J= 8.4 Hz, 2H), 7.82 (d, J= 8.4 Hz, 2H), 10.01 (s, IH), 12.13 (s, IH). MS m/z = 505 (M+l).

Example 6: Preparation of 2,3-Dihvdro-benzo[l,4]dioxine-6-carboxylic acid (4-{[4-(lH- benzoimidazol-2-yl)-phenylaminol -methyl) -phenvD-amide (Compound 2):

2,3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid (4-formyl-phenyl)-amide (0.1 mmol, 0.0284 g), 4-(lH-benzoimidazol-2-yl)-phenylamine (0.1 mmol, 0.021 g) and NaBH(OAc)₃ (1.0 mmol, 0.211 g) were stirred in DMF (2 ml) at room temperature for 24 h. Then NaBH(OAc) (0.5 mmol, 0.11 g) was added to the reaction. The resulting mixture was stirred at room temperature for 36 h. Water (10 ml) was added to quench the reaction. Aq. K CO solution (5%) was added to neutralize the pH to ca. 7. The formed solid was filtered and washed with water (2 X 4 ml). The title compound was obtained as brown solid (0.042 g, 88%). 1H NMR δ 4.33-4.30 (m, 6H), 6.72-6.69 (m, 3H), 6.97 (d, J= 8.1 Hz, IH), 7.12-7.08 (m, 2H), 7.35 (d,J= 8.1 Hz, 2H), 7.55-7.40 (m, 4H), 7.71 (d, J= 8.1 Hz, 2H), 7.87 (d, J= 8.1 Hz, 2H), 10.02 (s, IH), 12.41 (br s, IH). MS m/z = 477 (M+l).

Example 7: Preparation of thiazole-4-carboxylic acid (4-{[^"4-(lH-benzoimidazol-2-ylV phenylaminol-methyll-phenvD-amide (Compound 5):

Following the procedure of Step 4 of Example 1 and using appropriate starting materials, the title compound was obtained as a brown solid (0.074 g, 88.1%). 1H NMR δ 4.33 (d, J= 5.1 Hz, 2H), 6.72-6.69 (m, 3H), 7.11 -7.09 (m, 2H), 7.54-7.34 (m, 4H), 7.88- 7.79 (m, 4H), 8.48 (br s, IH), 9.26 (br s, IH), 10.29 (s, IH), 12.40 (br s, IH). MS m z = 426 (M+l).

Example 8: Preparation of 2-(4-(r4-(lH-benzoimidazol-2-ylVphenylamino1-methyl}- phenyl)-isoindole-L3-dione (Compound 8):

Following the procedure of Step 4 of Example 1 and using appropriate starting materials, the title compound was obtained as a brown solid (0.044 g, 50%). 1H NMR δ

4.34 (d, J= 5.1 Hz, 2H), 6.89-6.72 (m, 3H), 7.12-7.08 (m, 2H), 7.54-7.40 (m, 6H), 7.97- 7.87 (m, 6H), 12.42 (br s, IH). MS m/z = 445 (M+l).

Example 9 : Preparation of N-(3-{[4-(lH-Benzoimidazol-2-vD-phenylamino1-methyl>- phenyl -3-bromo-4-methoxy-benzamide (Compound 9):

Following the of Step 4 of Example 1 and using appropriate starting materials, the title compound was obtained as a brown solid (0.050 g, 47.4%). 1H NMR δ 4.36 (d, J= 5.7 Hz, 2H), 6.83-6.69 (m, 3H), 7.35-7.06 (m, 5H), 7.48 (br s, 2H), 7.67-7.65 (m, IH), 8.03-7.80 (m, 4H), 8.22 (br s, IH), 10.20 (s, IH), 12.43 (br s, IH). MS m/z = 527 (M+l).

Example 10: Preparation of N-(4-{|^"4-(lH-benzoimidazol-2-yl)-phenylaminol-methyl|- phenvu-benzamide (Compound 10):

Following the procedure of Step 4 of Example 1 and using appropriate starting materials, the title compound was obtained as a brown solid (0.072 g, 86%). Η NMR δ 4.33 (d, J= 5.7 Hz, 2H), 6.76-6.69 (m, 3H), 7.13-7.07 (m, 2H), 7.61-7.35 (m, 6H), 7.74 (d, J= 5.7 Hz, 2H), 7.88 (d, J= 5.7 Hz, 2H), 7.95-7.93 (m, 3H), 10.24 (s, IH), 12.46 (br s, IH). MS m/z = 419 (M+l).

Example 11 : Preparation of N-(4-{r4-(lH-benzoimidazol-2-yl)-phenylamino]-methyl>- phenyl -4-methyl-benzamide (Compound 11):

Following the procedure of Step 4 of Example 1 and using appropriate starting materials, the title compound was obtained as a brown solid (0.074 g, 85%). 1H NMR δ 2.38 (s, 3H), 4.33 (d, J= 6.0 Hz, 2H), 6.76-6.69 (m, 3H), 7.11-7.09 (m, 2H), 7.43-7.31 (m, 5H), 7.55-7.51 (m, IH), 7.74 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 7.8 Hz, 2H), 10.13 (s, IH), 12.41 (br s, IH). MS m z = 433 (M+l).

Example 12: Preparation of 4-{[4-(lH-benzoimidazol-2-yl -phenylamino]-methyl>-N-p- tolyl-benzamide (Compound 14):

Step 1: 4- {[4-(lH-Benzoimidazol-2-yl)-phenylamino]-methyl} -benzoic acid. Following the procedure of Step 4 of Example 1 and using appropriate starting materials, the title compound was obtained as a brown solid (0.040 g, 58%). MS m/z = 344 (M+l).

Step 2 : 4- { [4-( 1 H-benzoimidazol-2-yl)-phenylamino] -methyl} -N-p-tolyl-benzamide (Compound 14) 4-{[4-(lH-Benzoimidazol-2-yl)-phenylamino}-methyl}-benzoic acid (0.2 mmol,

0.069 g) and 1,1 -carbonyldiimidazole (0.22 mmol, 0.036 g) were stirred in DMF (2 mL) at 60°C for lh. Then p-toluidine (0.22 mmol, 0.024 g) in DMF (1 mL) was added. The resulting mixture was stirred over night at 100 °C. The reaction was cooled to rt. Water (10 mL) was added. The precipitation was filtered and washed with water (3 mL). After recrystalhzation from ethyl acetate, the title compound was obtained as a brown solid (0.040 g, 46%). 1H NMR δ 2.27 (s, 3H), 4.45 (d, J= 6.0 Hz, 2H), 6.70 (d, J= 8.7 Hz, 2H), 6.90-6.86 ( , IH), 7.15-7.09 (m, 4H), 7.43-7.39 (m, IH), 7.55-7.50 (m, 3H), 7.64 (d, J= 8.4 Hz, 2H), 7.92-7.85 (m, 4H), 10.10 (s, IH), 12.42 (s, IH). MS m/z = 433 (M+l).

Example 13: Preparation of N-(4-{[4-(5-pyridin-3-yl-lH-benzoimidazol-2-yl)- phenylamino]-methyl)-phenyl)-benzamide (Compound 12)

(HOJjET ,J

Step 1 : 4-(5 -pyridin-3 -yl- 1 H-benzoimidazol-2-yl)-phenylamine In a sealed tube was placed 4-(5-bromo-lH-benzoimidazol-2-yl)-phenylamine (127 mg, 0.44 mmol), and cat. Pd(PPh )₄ in ethylene glycol dimethyl ether (5 mL). Boronic acid (109 mg, 0.88 mmol) in ethanol (1 mL) was added, followed by aq. K₂CO₃ (2 M, 0.88 mL). The reaction was stirred at 80 °C for over night. The mixture was then cooled to room temperature, quenched with water (3 mL). The heterogeneous mixture was filtered, and the filtrate was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried to afford a deep brown color crude product. Recrystalhzation of the crude product from methyl alcohol afforded the desired product as a yellow solid. MS m/z = 287.11 (M+H).

Step 2 : N-(4- { [4-(5 -pyridin-3-yl- 1 H-benzoimidazol-2-yl)-phenylamino] -methyl} - phenyl)-benzamide (Compound 12) In a 15 L round bottomed flask were placed 4-(5 -pyridin-3 -yl-lH- benzoimidazol-2-yl)-phenylamine (35 mg, 0.12 mmol), N-(4-formyl-phenyl)-benzamide (27 mg, 0.12 mmol) in 10 mL of ethylene glycol dimethyl ether. To this mixture was added NaBH(OAc)₃ (254 mg, 1.2 mmol), and the resulted mixture was stirred for 15 h at room temperature. The reaction was then quenched with water (10 mL), followed by ammonia in methyl alcohol (2M, 2 mL). The solution resulted was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried, concentrated to afford a crude product. Column chromatography (5/95, MeOH/EtOAc) afforded the desired product as a white solid. MS m/z = 496.20 (M+H); 1H NMR δ 12.66 (s, IH), 10.31 (s, IH), 9.00 (s, IH), 8.62 (d, IH, J = 5.2 Hz), 8.18 (d, IH, J = 7.5 Hz), 8.08-7.96 (m, 4H), 7.83 (d, 2H, J = 8.5 Hz), 7.76-7.48 (m, 7H), 7.46 (d, 2H, J = 7.2 Hz), 6.88 (t, IH, J = 5.5 Hz), 6.82 (d, 2H, J = 7.5 Hz), 4.43 (d, 2H, J = 5.6 Hz).

Example 14: Preparation of |^"4-(lH-benzoimidazol-2-yl)-benzyll-r4-(lH-benzoimidazol- 2-yl)-phenyl]-amine (Compound 13):

LiAIH₄

Step 1: N-[4-(lH-benzoimidazol-2-yl)-phenyl]-4-formyl-benzamide In a 100 mL round bottomed flask was placed 4-formyl-benzoic acid (500 mg, 3.33 mmol) in 30 mL of dichloromethane. To this suspension was added oxalyl chloride (2M in dichloromethane, 2.5 mL, 5 mmol), followed by 3 drops of DMF. The reaction was stirred at room temperature for 30 min, and then concentrated to afford the crude 4- formyl-benzoyl chloride as a yellow solid. In a 100 mL round bottomed flask was placed the crude 4-formyl-benzoyl chloride in ethylene glycol dimethyl ether (30 mL). To this solution was added a solution of 4-(lH-benzoimidazol-2-yl)-phenylamine (696 mg, 3.33 mmol) and triethyl amine (672 mg, 6.66 mmol) in ethylene glycol dimethyl ether (20 mL). The mixture was stirred at room temperature for 4 h, then quenched with water (10 mL). The solid formed was filtered to give the crude product as a brown color solid. Recrystalhzation of the crude product from methyl alcohol afforded the N-[4-(lH-benzoimidazol-2-yl)-phenyl]-4- formyl-benzamide as a yellow solid. MS m/z = 342.17 (M+H).

Step 2: 9, 4-(lH-benzoimidazol-2-yl)-N-[4-(lH-benzoimidazol-2-yl)-phenyl]-benzamide In a 15 mL round bottomed flask were placed N-[4-(lH-benzoimidazol-2-yl)- phenyl]-4-formyl-benzamide (100 mg, 0.29 mmol) and benzene- 1,2-diamine (32 mg, 0.29 mmol) in 2 mL of nitrobenzene. The solution was stirred at 150 °C for 12 h, then quenched with hexane (10 mL). The yellow solid formed was filtered, washed with methyl alcohol (2 x 3 mL) to afford the product as a yellow solid. MS m/z = 430.07 (M+H).

Step 3 : Preparation of [4-(lH-benzoimidazol-2-yl)-benzyl]-[4-(lH-benzoimidazol-2-yl)- phenyl]-amine (Compound 13) In a 15 mL round bottomed flask was placed 4-(lH-benzoimidazol-2-yl)-N-[4- (lH-benzoimidazol-2-yl)-phenyl] -benzamide (55 mg, 0.13 mmol) in 1,4-dioxane (10 mL). To this solution was added LiAlH₄ (1M in THF, 0.39 mL), and the reaction was stirred for 12 h at 60 °C. The reaction was then diluted with dichloromethane (10 mL), and aq. saturated sodium sulfate solution (5 mL) was added slowly. The resulted mixture was stirred at rt for 1 h. The heterogeneous mixture was then filtered, and the filtrate was concentrated to give the cmde product. Column chromatography (2/98, MeOH/EtOAc) afforded the desired product as a yellow solid. MS m/z = 416.03 (M+H); 1H NMR δ 12.95 (s, IH), 12.43 (s, IH), 8.22 (d, 2H, J = 7.5 Hz), 7.95 (d, 2H, J = 7.5 Hz), 7.81-7.50 (m, 5H), 7.49-7.44 (m, IH), 7.33-7.08 (m, 4H), 6.92 (t, IH, J = 5.5 Hz), 6.74 (d, 2H, J = 7.8 Hz), 4.55 (d, 2H, J = 5.5 Hz).

Example 15 : Preparation of 2-(3-{r4-(lH-benzoimidazol-2-yl)-phenylaminol-methyl}- phenyl)-l,3-dioxo-2,3-dihvdro-lH-isoindole-5-carboxylic acid (Compound 15):

[4-(lH-Benzoimidazol-2-yl)-phenyl]-(3-amino-benzyl)-amine (0.2 mmol, 0.062 g) and 1,2,4-benzenetricarboxylic anhydride (0.2 mmol, 0.040 g) were refluxed in acetic acid (3 mL) for 4 h. Then the reaction was cooled to rt. The precipitation was filtered out and washed with water (2 x 5 mL) and ethyl acetate (2 x 5 mL). The title compound was obtained as a brown solid (0.049 g, 50%). 1H NMR δ 4.44 (d, J= 5.4 Hz, 2H), 6.72 (d, J = 8.1 Hz, 2H), 6.90-6.86 (m, IH), 7.12-7.09 (m, 2H), 7.36-7.34 (m, IH), 7.52-7.48 (m, 5H), 7.88 (d, J= 8.4 Hz, 2H), 8.04 (d, J= 7.8 Hz, IH), 8.30 (s, IH), 8.40 (d, J= 7.8 Hz, IH), 12.48 (br s, IH), 13.80 (br s, IH). MS m/z = 489 (M+l). Example 16: Preparation of N-(lH-Benzoimidazol-2-yl)-4-{r4-(lH-benzoimidazol-2-yl)- phenylamino]-methyl}-benzamide (Compound 16):

Following the procedure of Step 2 of Example 12 and using appropriate starting materials, the title compound was obtained as a brown solid (0.041 g, 48%). 1H NMR δ 4.47 (d, J= 5.7 Hz, 2H), 6.72 (d, J= 8.7 Hz, 2H), 6.88 (t, J= 5.7 Hz, IH), 7.12-7.08 (m, 4H), 7.54-7.40 (m, 6H), 7.88 (d, J= 8.7 Hz, 2H), 8.12 (d, J= 8.1 Hz, 2H), 12.30 (br s, IH), 12.42 (br s, IH). MS m/z = 459 (M+l).

Example 17: Preparation of (4- (f4-(l H-benzoimidazol-2-yl)-phenylamino1 -methyl) - phenoxy)-acetic acid (Compound 17).

Following the procedure of Step 4 of Example 1 and using 4- formaylphenoxyacetic acid as the starting material, the title compound was obtained as a brown solid (0.061 g, 82%). 1H NMR δ 4.27 (d, J= 5.7 Hz, 2H), 4.63 (s, 2H), 6.71-6.4 (m, 3H), 6.88 (d, J= 8.4 Hz, 2H), 7.13-7.09 (m, 2H), 7.30 (d, J= 8.4 Hz, 2H), 7.48 (br s, 2H), 7.86 (d, J= 8.7 Hz, 2H), 12.43 (br s, IH), 13.00 (br s, IH). MS m/z = 374 (M+l).

Example 18: Preparation of 4-(lH-benzoimidazol-2-yl)-phenyl]-(4-(N-methyl)-benzyl)- amine (Compound 18):

Following the procedure of Step 4 of Example 1 and using appropriate starting materials, the title compound was obtained as brown solid (0.033 g, 50%). 1H NMR δ 2.65 (d, J= 5.1 Hz, 3H), 4.16 (d, J= 5.7 Hz, 2H), 5.52 (q, J= 5.1 Hz, IH), 6.54-6.49 (m, 3H), 6.71-6.68 (m, 2H), 7.12-7.08 (m, 4H), 7.54-7.40 (m, 2H), 7.86 (d, J= 8.4 Hz, 2H), 12.39 (br s, IH). MS m/z = 329 (M+l).

Example 19: Heparanase activity assays: Human heparanase protein was purified from human platelets using a modified protocol (Freeman et al, Biochem. J. 330, 1341-1350 (1998)). Heparan sulfate (HS, Seikagaku), derived from bovine kidney, was labeled with sodium boro[³H]hydride (specific activity: 34 Ci/mmol, Amersham-Pharmacia Biotech). 10 mg of HS was dissolved in 0.5 ml of 0.5 N NaOH and the solution was mixed with 0.2 ml of sodium boro[³H]hydride (5 mCi), and incubated at room temperature with constant rocking for 24 h. The reaction was terminated by adding 2.5 ml of 0.1 M NaHCO . Subsequently, the ³H-HS was purified by size exclusion chromatography using PD10 columns. The specific activity was determined as 98.4 cpm/ng HS. The labeling efficiency was -30%. The purified 3H-HS was then immobilized on CNBr-activated Sepharose beads (Pharmacia) according to manufacturer's instructions. Heparanase activity was determined using 96-well plates."¹ Human platelet heparanase (2.67 nM) was pre-mixed with a compound of the invention (33 μM for single point screening, or various concentrations for IC50 studies) in a total volume of 125 μl. ³H-HS-Sepharose slurry (25 μl, 4 nM) was then added into the mixture, and incubated overnight at 37 °C. The reaction buffer (100 μl) was harvested into single scintillation tubes to detect the released radioactivity in a beta-liquid scintillation counter. In some experiments, the reaction buffer was transferred to 96-well corresponding Luma plates (Perkin Elmer). The plates were air dried for overnight, the radioactivity was directly detected in a TopCounter (Perkin Elmer). The results of example 19 are summarized in Table 1.

Claims

Claims What is claimed is: 1. A compound of Formula I:

Formula I wherein m is 0-4; n is 1-4; each Ri independently is a) F, Br, CI, I, NO₂, NH₂, CN, or OH; b) Cι-C₆ alkyl; c) C₆-Ci₀ aryl; or d) C₄-Cιo heteroaryl; and each R₂ independently is a) Cι-C₆ alkoxy; b) C₆-Cι₀ aryl; c) C₅-C1₀ heteroaryl; d) -NH-(Cι-C₆)alkyl; e) -NHCO-(C₆-Cι₀)aryl; f) -NHCO-(C₃-Cι₀)heteroaryl; g) -CONH-(C₆-Ci₀)aryl; or h) -CONH-(C₃-Cιo)heteroaryl.

2. The compound of Formula I according to claim 1, wherein Ri is substituted with at least one R₃ and each R₃ independently is F, CI, Br, I, CN, NH₂, NO₂, or OH.

3. The compound of Formula I according to claim 1, wherein R₂ is substituted with at least one R₄ and each R₄ independently is F, CI, Br, I, CN, NH₂, NO₂, OH, C C₆ alkyl, Cι-C₆ alkoxy, C₆-C_]0 aryl, C5-C10 heteroaryl, CO₂H, CO₂(Cι-C₆ alkyl), CONH(C₆- C₁₀ aryl), or CONH(C₅-Cι₀ heteroaryl)

4. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutical carrier.

5. The pharmaceutical composition according to claim 4 in the form of a dosage form.

6. The pharmaceutical dosage form according to claim 5, wherein the dosage is in the form of a tablet, capsule, troche, lozenge, or soft gelatin capsule.

7. A method of inhibiting heparanase activity comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need of such therapy.

8. The method according to claim 7, wherein the inhibition of heparanase activity inhibits the release of bioactive agents from heparan sulfate proteoglycans.