WO2005042495A1 - Composes de (benzimidazol-2-yl)-phenyl-phenyl-uree et procedes d'inhibition de l'activite de l'heparanase - Google Patents

Composes de (benzimidazol-2-yl)-phenyl-phenyl-uree et procedes d'inhibition de l'activite de l'heparanase Download PDF

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WO2005042495A1
WO2005042495A1 PCT/US2004/034671 US2004034671W WO2005042495A1 WO 2005042495 A1 WO2005042495 A1 WO 2005042495A1 US 2004034671 W US2004034671 W US 2004034671W WO 2005042495 A1 WO2005042495 A1 WO 2005042495A1
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phenyl
benzoimidazol
compound
urea
heparanase
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PCT/US2004/034671
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English (en)
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Hu Liu
Weitao Pan
Yong-Jiang Xu
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Imclone Systems Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2

Definitions

  • the present invention encompasses (benzimidazol-2-yl)-phenyl-phenyl-urea compounds, compositions thereof, and methods for inhibiting heparanase activity. More particularly, the present invention encompasses methods for treatment of conditions associated with heparanase activity using (benzimidazol-2-yl)-phenyl-phenyl-urea derivatives.
  • HSPGs 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.
  • 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.
  • ECM extracellular matrix
  • heparanase endo- ⁇ -D- glucuronidase
  • 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 Vlodavsky et al, Invasion & Metastasis, 14: 290-302 (1994); Nakajima et al., J Cell Biochem., 36(2): 157-67 (1988). HSPGs are involved in a number of processes related to malignancy. See generally Blackhall et al, Br. J. Cancer, 85(8): 1094-8 (Oct.
  • bFGF basic fibroblast growth factor
  • immunotherapeutic treatments targeting heparanase activity may be potentially useful for these conditions.
  • immunotherapy targeting heparanase activity may be a potentially useful treatment for both tumor growth and angiogenesis, for which there is great need.
  • the invention encompasses compounds having Formula I: Formula I wherein m is from 0 to 2; n is from 1 to 2; each Ri independently is a) F, Br, Cl, I, NO 2 , NH 2 , CN, or OH; b) Ci-C 6 alkyl; or c) C C 6 alkoxy; and each R 2 independently is a) F, Br, Cl, I, NO 2 , NH 2 , CN, or OH; b) C ⁇ -C 6 alkyl; c) Ci-C 6 alkoxy; d) C 6 -C 10 aryl; e) C 3 -C 10 heteroaryl; f) -CO2-(Ci-C 6 )alkyl; g) -CONH-(C 6 -C 10 )aryl; h) -NH-(C 8 -C 10 )araalkyl; i) -NHCO-(C 1 -C 4 )alkyl; j)
  • R t of the compounds of Formula I may be substituted with at least one R 3 , wherein each R 3 independently is F, Br, Cl, I, NO 2 , NH 2 , CN, or OH.
  • R 2 of the compounds of Formula I may be substituted with at least one P ⁇ , wherein each Rj independently is F, Br, Cl, I, NO 2 , NH 2 , (CrC ⁇ alkyl, (C 1 -C 6 )alkoxy, CO 2 H, CO 2 Me, or (Cs-C ⁇ 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 of a dosage 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 at least one compound of Formula I to a patient in need of such therapy.
  • the inhibition of heparanase activity may inhibit the release of bioactive agents from heparan sulfate proteoglycans.
  • the present invention encompasses compounds of capable of inhibiting, modulating, or regulating the activity of heparanase.
  • the present invention is directed to (benzimidazol-yl)-phenyl-phenyl urea derivatives and to methods of inhibiting heparanase activity using (benzimidazol-yl)-phenyl-phenyl urea derivatives.
  • the invention also encompasses pharmaceutical compositions of (benzimidazol-yl)-phenyl- phenyl urea derivatives.
  • the invention encompasses compounds of Formula I:
  • R 1 ⁇ R 2 , m, and n are as defined herein.
  • the compounds of the invention inhibit the degradation of HSPGs by inhibiting heparanase activity.
  • 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.
  • alkyl refers to a monovalent alkane (hydrocarbon) radical having 1 to 10 carbon atoms. The alkyl may be substituted or unsubstituted, straight, branched, or cyclic.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • alkoxy refers to a substituent -O-alkyl wherein alkyl is as defined above.
  • the alkoxy may be substituted with at least one phenyl ring, in which the alkoxy may be for example, a benzyloxy group.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, or vinyloxy.
  • the "alkoxy" radicals maybe further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • halo atoms such as fluoro, chloro or bromo
  • examples of such radicals include, but are not limited to, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, or fluoropropoxy.
  • cycloalkyl refers to a cyclic hydrocarbon radical having 3 to 8 carbon atoms, which may be substituted or unsubstituted.
  • 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.
  • heterocyclyl or “heterocycle” refers to cycloalkyl rings that include within the ring at least one nitrogen, oxygen, or sulfur atom.
  • the heterocyclyl may include one or two double bonds.
  • 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, pyrrolidinyl, quinuclidinyl, tertrahydrofuranyl, tetrahydrothienyl, tetrahydrothiophenyl, thiazolidinyl, thiazolinyl, thiomorpholino, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, or thiophenyl.
  • aryl refers to carbocyclic aromatic groups including, but not limited to, phenyl, biphenyl, naphthyl, or anthracyl.
  • 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.
  • aryl ring may be unsubstituted or substituted with at least one suitable substituent.
  • 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 quaternized.
  • 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, thiadiazoyt, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, or 1,2,4-triazolyl.
  • a heteroaryl group can be unsubstituted or substituted.
  • aralkyl refers to a straight-chain alkyl, alkenyl, or alkynyl group wherein one of the hydrogen atoms bonded to a terminal carbon is replaced with an aryl moiety.
  • Typical aralkyl groups include, but are not limited to, benzyl, benzylidene, benzylidyne, benzenobenzyl, naphthenobenzyl, and the like.
  • carbamoyl refers to a radical -CON(R)- or -(R)NCO-, wherein R is further defined herein.
  • urea or “urealyl” refers to a radical -RNCONR-, wherein R may be the same or different is further defined herein.
  • halo or "halogen” as used herein is intended to include the halogen atoms fluorine, chlorine, bromine, or iodine.
  • suitable optional substituent refers to formyl, C O alkyl, C -6 cycloalkyl, C 2-10 alkenyl, cycloalkenyl, C 2-10 alkynyl, cycloalkynyl, halo, perhaloalkyl such as trifluoromethyl, mercapto, halogen-lower alkylmercapto, thioalkyl, hydroxy, hydroxy etherified by lower alkyl, e.g., methyl, or by halogen-lower alkyl, e.g., trifluoromethyl, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamyl, N-mono- or N, N-disubstituted carbamoyl, amidino, guanidine,
  • the individual isomers and mixtures thereof are intended to be encompassed by the formulae depicted herein.
  • 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.
  • compositions may be prepared by the addition of an appropriate acid.
  • 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.
  • 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 animals.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 invention encompasses compounds of Formula I:
  • each Ri independently is a) halogen, NO 2 , NH 2 , CN, or OH; b) alkyl, optionally substituted with at least one R 3 ; or c) alkoxy, optionally substituted with at least one R 3 , wherein R 3 is halogen, NO 2 , NH 2 , CN, or OH; and each R 2 independently is a) halogen, NO 2 , NH 2 , CN, or OH; b) alkyl, optionally substituted with at least one R 4 ; c) alkoxy, optionally substituted with at least one ; d) aryl, optionally substituted with at least one ⁇ e) heteroaryl, optionally substituted with at least one R 4 ; f) -CO 2 -alkyl, optionally substituted with at least one ; g) -CONH-aryl, optionally substituted with at least one ⁇
  • m is from 0 to 2; n is from 1 to 2; each R independently is a) F, Cl, Br, NO 2 , or NH 2 ; b) C 1 -C 4 alkyl, optionally substituted with at least one R 3 ; or c) -C 4 alkoxy, optionally substituted with at least one R 3 , wherein R 3 is F, Br, Cl, I, NO 2 , NH 2 , CN, or OH; and each R 2 independently is a) F, Br, Cl, NO 2 , NH 2 , CN, or OH; b) -C 4 alkyl, optionally substituted with at least one R 4 ; c) C 1 -C 4 alkoxy, optionally substituted with at least one R 4 ; d) C 6 -C 10 aryl, optionally substituted with at least one R 4 ; e) C 3 -C 10 heteroaryl, optionally substituted with at least one R 4 ; f) -CO
  • Preferred embodiments of the invention include: l-[4-(lH-Benzoimidazol-2-yl)-phenyl]-3-(3-bromo-4-ethoxy-phenyl)-urea; 4- ⁇ 3-[4-(lH-Benzoimidazol-2-yl)-phenyl]-ureido ⁇ -benzoic acid methyl ester; 1 - [4-( 1 H-Benzoimidazol-2-yl)-phenyl] -3-(4-bromo-phenyl)-urea; 4- ⁇ 3-[4-(lH-Benzoimidazol-2-yl)-phenyl]-ureido ⁇ -N-(4-methoxy-phenyl)- benzamide; l-[4-(5-Methyl-lH-benzoimidazol-2-yl)-phenyl]-3-(4-nitro-phenyl)-urea; l-[4-(l
  • More preferred compounds of the invention include: 1 - [4-( 1 H-Benzoimidazol-2-yl)-phenyl] -3 -(3 -bromo-4-ethoxy-phenyl)-urea; N-(4- ⁇ 3 - [4-( 1 H-Benzoimidazol-2-yl)-phenyl] -ureido ⁇ -phenyl)-4-ethoxy- benzamide; N-(4- ⁇ 3-[4-(lH-Benzoimidazol-2-yl)-phenyl]-ureido ⁇ -phenyl)-3-bromo-4- methoxy-benzamide; l-[4-(lH-Benzoimidazol-2-yl)-phenyl]-3-(3-bromo-4-methoxy-phenyl)-urea; N-(4- ⁇ 3 - [4-( 1 H-Benzoimidazol-2-yl)-phenyl]
  • the compounds of the invention are synthesized using a variety of schemes, such as those illustrated below and exemplified in the Example section.
  • 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.
  • the following schemes exemplify compounds having Ri and R 2 , 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.
  • the skilled artisan can easily use interchangeable steps for each synthetic process and incorporate isolation and/or purification steps as deemed necessary.
  • one method comprises selecting a starting material with more than one substituent, i.e., the aromatic ring may contain two or more Ri.
  • 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.
  • optionally substituted ortho phenyl diamines include, but are not limited to, 4-methoxybenzene- 1,2-diamine, 4-fluorobenzene-l,2-diamine, 4- bromobenzene-1 ,2-diamine, 4-pyridin-4-ylbenzene-l ,2-diamine, 4,5-dimethylbenzene- 1,2-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,
  • Scheme 1 illustrates the versatility of benzoimidazol-2-yl-phenyl carboxylic acid in the synthesis of the compounds of the invention.
  • a substituted ortho dinitrobenzene is reduced to the substituted benzene 1,2-diamine compound.
  • the substituted benzene 1,2-diamine compound is allowed to react with a 4-carbaldehydebenzoic acid to yield a substituted 4-(lH-benzoimidazol-2- yl)-benzoic acid, Compound B.
  • Scheme 2 illustrates one example of many known to the skilled artisan to modify the reaction sequence to derivatize a compound and obtain various additional compounds within the scope of the invention.
  • Step 1 of Scheme 3 Compound A is allowed to react with l-isocyanato-4-nitrobenzene in DMSO at a temperature of about 60 °C to yield a 1- [4-(lH-benzoimidazol-2-yl)-phenyl]-3-(4-nitro-phenyl)-urea, Compound D.
  • the l-[4-(lH-benzoimidazol-2-yl)-phenyl]-3-(4-nitro-phenyl)-urea, Compound D is reduced to yield a l-(4-amino-phenyl)-3-[4-(lH-benzoimidazol-2-yl)- phenylj-urea, Compound E.
  • the reduction may be carried out using H 2 with a palladium catalyst. See, J.A.C.S., 81, 505 (1959); J.O.C., 58, 2302 (1993).
  • Compound E may be transformed into a variety of derivative compounds.
  • Step 4 Compound E is transformed into an amide by reaction with l-(4-amino-phenyl)-3- [4-(lH-benzoimidazol-2-yl)-phenyl]-urea, Compound E, with benzoyl chloride to yield an TSf-(4- ⁇ 3-[4-(lH-benzoimidazol-2-yl)-phenyl]-ureido ⁇ -phenyl)-benzamide, Compound F.
  • Step 4 l-(4-amino-phenyl)-3-[4-(lH- benzoimidazol-2-yl)-phenyl]-urea, Compound E, may react with 4-methoxybenzaldehyde to yield a l-[4-(lH-benzoimidazol-2-yl)-phenyl]-3-[4-(4-methoxy-benzylamino)- ⁇ henyl]- urea, Compound G.
  • 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.
  • a counterion such as, an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations, such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanol-hydroammomum, and the like.
  • An appropriate number of counterions are associated with the molecule to maintain overall charge neutrality.
  • the compound when the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions are present to maintain overall charge neutrality.
  • Pharmaceutically acceptable salts are within the scope of the present invention.
  • Pharmaceutically acceptable salts may be prepared by the addition of an appropriate acid.
  • 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.
  • 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 quaternized 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.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • 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 Formula I herein, for example by hydrolysis in blood (Higuchi et al, 1987).
  • 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.
  • 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.
  • 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.
  • 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.
  • DMB dimethylmethylene blue
  • 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 IV, 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.
  • 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.
  • SDF-1 stromal cell-derived factor
  • 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.
  • 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 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.
  • 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 general Formula I useful for treatment or inhibition of a malignant cell proliferative disease or disorder.
  • 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
  • ALL acute lymphocytic leukemia
  • AML acute myelogenous leukemia
  • At least one compound of Formula I is useful for treating or inhibiting tumors at all stages, namely tumor formation, primary tumors, tumor progression or tumor metastasis.
  • At least one compound of Formula I is 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.
  • At least one compound of Formula I is 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.
  • At least one compound of Formula I is 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 (AIHA), 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 no
  • least one compound of Formula I may be used for in vivo and in vitro investigative, diagnostic, or prophylactic methods, which are well known in the art.
  • a therapeutically effective amount of at least one compound of Formula I is administered to a mammal in need.
  • administering means delivering the compounds of the present invention to a mammal by any method that may achieve the result sought. They may be admimstered, 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 compound of Formula I.
  • 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-drug 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.
  • 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.
  • solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • injectable solids examples include powders that are reconstituted, dissolved or suspended in a liquid prior to injection.
  • the carrier typically includes sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
  • various buffering agents, preservatives and the like can be included within the compositions of the present invention.
  • 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.
  • oral solid dosage forms include tablets, capsules, troches, lozenges and the like.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • Carriers for oral use may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • time delay materials such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • 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 maybe 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.
  • 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 may be also incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier.
  • compounds of the invention maybe 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 may.be a copolymer matrix, such as ethylene- vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic shell.
  • a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia.
  • 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.
  • 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.
  • a 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.
  • 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.
  • a channeled balloon catheter such as "channelled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Corp., Watertown, Mass.
  • 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.
  • 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.).
  • 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.
  • 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.
  • compositions of the present invention optionally contain one or more excipients that are conventional in the art.
  • 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.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be 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.
  • 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 invention, hi 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.
  • ingredients and method steps should be understood as examples that are intended to be illustrative only.
  • 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.
  • the present invention is described with respect to particular examples and prefened embodiments, the present invention is not limited to these examples and embodiments.
  • 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.
  • 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.
  • 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.
  • NMR proton nuclear magnetic resonance
  • 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-d 6 ) as solvent unless otherwise indicated.
  • TMS tetramethylsilane
  • DMSO-d 6 perdeuterio dimethyl sulfoxide
  • Step 2 3-Methoxy-benzene- 1,2-diamine l-Methoxy-2,3-dinitro-benzene (540 mg, 2.7 mmol), and palladium on carbon (10%, 150 mg) were placed in a flask that was capped with a septum. Methanol (50 mL) was carefully introduced followed by a balloon full of hydrogen through a needle. The reaction mixture was stined at 55 °C for 24 h. The mixture was then cooled to ambient temperature and passed through a short pad of silica gel. The silica gel pad was rinsed with ether. Removal of solvents from the combined organic layer afforded light brown grease (450 mg), which was used directly without further purification.
  • Example 18 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[ 3 H]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[ 3 H]hydride (5 mCi), and incubated at room temperature with constant rocking for 24 h.
  • HS Heparan sulfate
  • 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[ 3 H]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 3 .
  • the 3 H-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. Human platelet heparanase (2.67 nM) was pre-mixed with a compound of the invention (33 ⁇ M for single point screening, or various concentrations for IC50 studies) in a total volume of 125 ⁇ l.

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Abstract

L'invention concerne des inhibiteurs d'héparanase, notamment certains dérivés de (benzimidazol-2-yl)-phényl-phényl-urée qui inhibent l'héparanase, les compositions pharmaceutiques contenant ces composés, les procédés de préparation de ces composés, et des procédés de traitement de maladies et de troubles dépendant de l'héparanase chez des mammifères par administration d'une quantité efficace sur le plan thérapeutique de ces composés auxdits mammifères.
PCT/US2004/034671 2003-10-21 2004-10-21 Composes de (benzimidazol-2-yl)-phenyl-phenyl-uree et procedes d'inhibition de l'activite de l'heparanase WO2005042495A1 (fr)

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1724258A1 (fr) * 2004-02-23 2006-11-22 Chugai Seiyaku Kabushiki Kaisha Derive d'heteroarylphenyluree
EP1724258A4 (fr) * 2004-02-23 2007-10-03 Chugai Pharmaceutical Co Ltd Derive d'heteroarylphenyluree
JPWO2005080330A1 (ja) * 2004-02-23 2007-10-25 中外製薬株式会社 ヘテロアリールフェニルウレア誘導体
JP4866236B2 (ja) * 2004-02-23 2012-02-01 中外製薬株式会社 ヘテロアリールフェニルウレア誘導体
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US8148401B2 (en) 2007-06-29 2012-04-03 Pfizer Inc. Benzimidazole derivatives
US8431597B2 (en) 2007-06-29 2013-04-30 Pfizer Inc. Benzimidazole derivatives
US9856252B2 (en) 2013-02-20 2018-01-02 Cancer Therapeutics Crc Pty Ltd 2-(hetero)aryl-benzimidazole and imidazopyridine derivatives as inhibitors of asparagime emethyl transferase
US10005792B2 (en) 2014-09-03 2018-06-26 Ctxt Pty. Ltd. Aminoindane-, aminotetrahydronaphthalene- and aminobenzocyclobutane-derived PRMT5-inhibitors
US10647708B2 (en) 2014-09-03 2020-05-12 Ctxt Pty. Ltd Tetrahydroisoquinoline derived PRMT5-inhibitors
US10494376B2 (en) 2014-09-03 2019-12-03 Ctxt Pty. Ltd. Tetrahydroisoquinoline derived PRMT5-inhibitors
US10421743B2 (en) 2016-03-09 2019-09-24 Ctxt Pty Ltd Tetrahydroisoquinolines as PRMT5 inhibitors
US10787434B2 (en) 2016-03-09 2020-09-29 Ctxt Pty, Ltd Benzopiperdine derivatives and their use in the treatment of cancer and hemoglobinopathies
US11028101B2 (en) 2016-03-09 2021-06-08 Ctxt Pty Ltd 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies
US10961256B2 (en) 2016-03-09 2021-03-30 Ctxt Pty Ltd PRMT5 inhibitors
US10745380B2 (en) 2016-03-09 2020-08-18 Ctxt Pty Ltd Pyridine derivatives and their use in the treatment of cancer and hemoglobinopathies
US10519167B2 (en) 2016-03-09 2019-12-31 Ctxt Pty Ltd 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies
US10550096B2 (en) 2016-03-09 2020-02-04 Ctxt Pty Ltd Tetrahydroisoquinolines as PRMT5 inhibitors
AU2017230437B2 (en) * 2016-03-11 2020-11-26 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Urea compound, preparation method therefor and medical use thereof
RU2741596C2 (ru) * 2016-03-11 2021-01-27 Энкьюриэлл Фармасьютикал (Шанхай) Ко., Лтд. Соединение мочевины, способ его получения и его медицинское применение
EP3424924A4 (fr) * 2016-03-11 2019-08-07 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Composé d'urée, son procédé de préparation et son utilisation médicale
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
EP3381898A1 (fr) * 2017-03-27 2018-10-03 Leadiant Biosciences SA Derives de tris-aryl-amides symmmetriques et leur utilisation en tant qu'anti-heparanase
WO2018177861A1 (fr) * 2017-03-27 2018-10-04 Leadiant Biosciences Sa In Liquidazione Dérivés symétriques de tris-aryl-amide et leur utilisation comme anti-héparanase
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
US11702421B2 (en) 2018-12-31 2023-07-18 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11845753B2 (en) 2018-12-31 2023-12-19 Biomea Fusion, Inc. Inhibitors of menin-mll interaction
US12018032B2 (en) 2021-08-20 2024-06-25 Biomea Fusion, Inc. Crystalline forms of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(r)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide as an irreversible inhibitor of menin-MLL interaction

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