WO2016164394A1 - Antagonistes de la sélectine contenant du 2-halo-galactose - Google Patents

Antagonistes de la sélectine contenant du 2-halo-galactose Download PDF

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WO2016164394A1
WO2016164394A1 PCT/US2016/026116 US2016026116W WO2016164394A1 WO 2016164394 A1 WO2016164394 A1 WO 2016164394A1 US 2016026116 W US2016026116 W US 2016026116W WO 2016164394 A1 WO2016164394 A1 WO 2016164394A1
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compound
chosen
compound according
groups
subject
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PCT/US2016/026116
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John L. Magnani
John M. Peterson
Arun K. Sarkar
Indranath Ghosh
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Glycomimetics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • leukocytes When a tissue is infected or damaged, the inflammatory process directs leukocytes and other immune system components to the site of infection or injury. Within this process, leukocytes play an important role in the engu!fment and digestion of microorganisms. The recruitment of leukocytes to infected or damaged tissue is critical for mounting an effective immune defense.
  • Selectins are a group of structurally similar cell surface receptors important for mediating leukocyte binding to endothelial ceils. These proteins are type 1 membrane proteins and are composed of an amino terminal lectin domain, an epidermai growth factor (EGF)-like domain, a variable number of complement receptor related repeats, a hydrophobic domain spanning region and a cytoplasmic domain, The binding interactions appear to be mediated by contact of the lectin domain of the selectins and various carbohydrate ligands.
  • EGF epidermai growth factor
  • E-selectin is found on the surface of activated endothelial cells, which line the interior wali of
  • E-seiectin binds to the carbohydrate sialyl-Lewis* (SLe x ), which is presented as a glycoprotein or glycolipid on the surface of certain leukocytes (monocytes and neutrophils) and helps these cells adhere to capillary wails in areas where surrounding tissue is infected or damaged; and E-selectin also binds to sialyl-Lewis 8 (SLe ⁇ ), which is expressed on many tumor ceils. P-selectin is expressed on inflamed endothelium and platelets, and also recognizes SLe and SLe 8 , but also contains a second site that interacts with sulfated tyrosine.
  • SLe x carbohydrate sialyl-Lewis*
  • SLe ⁇ sialyl-Lewis 8
  • E-seiectin and P-selectin are generally increased when the tissue adjacent to a capillary is infected or damaged.
  • L-sefectin is expressed on leukocytes.
  • Se!ectin-rnediated intercellular adhesion is an example of a seiectin-mediated function.
  • Modulators of selectin-medialed function include the PSGL-1 protein (and smaller peptide fragments), fucoidart, glycyrrhizin (and derivatives), anti-seleetin antibodies, sulfated lactose derivatives, heparin and heparin fragments, sulfated hya!uronie acid, eondroitin sulfate, sulfated dextran, sulfatides, and particular glycomimetic compounds (see. e.g., US RE44,778). Ail but the glyc-omirnetics have shown to be unsuitable for drug development due to insufficient activity, toxicity, lack of specificity, poor ADME characteristics, and/or availability of material.
  • selectin-rnediated cell adhesion is required tor fighting infection and destroying foreign material, there are situations in which such cell adhesion is undesirable or excessive, resulting in tissue damage instead of repair.
  • many pathologies such as autoimmune and inflammatory diseases, shock and reperfusiors injuries
  • Such abnormal ceil adhesion may also play a role in transplant and graft rejection, in addition, some circulating cancer cells appear to take advantage of the inflammatory mechanism to bind to activated endothelium, in such circumstances, modulation of selectin-rnediated intercellular adhesion may be desirable.
  • R' is chosen from Ci. f 2 alky I, C ⁇ n alkenyl, C 2 .. j2 alkynyl, C 1 . 12 haloalkyl, C 2 .. 12 haloalkenyl, and C 2- i 2 haloalkynyl groups;
  • R 2 is chosen from H, CM2 alkyl, C2- 12 alkenyl, C 2 -i 2 alkynyl, -C( ::: )0Y', and -C( ::: 0)NY Y" groups, wherein Y and Y , which may be identical or different, are independently chosen from H, C ⁇ . ⁇ 2 alkyl, C 2 - 12 alkenyl, C 2 - 12 alkynyl, Cj. 12 haloalkyl, C2- 12 haloalkenyl, C2-12 haloalkynyl, C fi .n aryi, CMS heteroaryl, and Cj.n heterocyciyl groups, wherein Y ! and Y 2 may join together to form a ring;
  • R is chosen from H, C[.g alkyl, C 2 ,s alkenyl, C 2 -8 alkynyl, haloalkyl, C 2 .g haloalkenyl, C 2 _g haloalkynyl, C[.g aikoxy, C -ia aryl, and C 2 -13 heteroaryl groups: and
  • X is chosen from halogens.
  • 'compound of Formula (IV includes giycomimetics of Formula (1), pharmaceutically acceptable salts of giycomimetics of Formula (1), prodrugs of giycomimetics of Formula (I), and pharmaceutically acceptable salts of prodrugs of giycomimetics of Formula (I),
  • compositions comprising at least one- compound of Formula (1) and optionally at least one additional pharmaceutically acceptable ingredient are presented.
  • a method for treatment and/or prevention of at least one disease, disorder, and/or condition where inhibition of E-selectin mediated functions is useful comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (I) or a pharmaceutical composition comprising at least one compound of Formula (I) and optionally at least once pharmaceutically acceptable ingredient.
  • Figure 1 is a diagram illustrating the synthesis of an embodiment (compound 10) of the compounds disclosed herein,
  • Figure 2 is a diagram illustrating the synthesis of an embodiment (compound 20) of the compounds disclosed herein.
  • Figure 3 is a diagram illustrating the synthesis of an embodiment (compound 22) of the compounds disclosed herein.
  • Figure 4 is a diagram illustrating the synthesis of an embodiment (compound 24) of the compounds disclosed herein.
  • Figure 5 is a diagram illustrating the synthesis of an embodiment (compound 27) of the compounds disclosed herein.
  • Disciosed herein are compounds and compositions for treating and/or preventing at least one disease, disorder, and/or condition in which inhibiting binding of E-selectin to at least one E-selectin ligand may play a role.
  • the compounds may have a variety of uses in vitro arsd in vivo.
  • R 1 is chosen from ⁇ _ ⁇ ) 2 aikyi, C 2 . ;2 aikenyl, C 2 .i 2 aikynyl, CY 2 haloaikyl, C 2 .i 2 haioaikenyl, and C 2- 12 haioalkynyl groups;
  • R" is chosen from H, Ci.3 ⁇ 4 2 alkyl, C 2 -!2 aikenyl, C2.12 aikynyl, -C( ::: 0)OY', and ⁇ €(- ⁇ ) ⁇ ! Y groups, wherein Y 1 and Y", which may be identical or different, are independently chosen from H, CM? aikyi, C2-12 aikenyl, C 2 .j 2 aikynyl, . n haloaikyl, C2-12 haioaikenyl, C 2 -i 2 haioalkynyl, C s* aryl, Cm heteroaryi, and C ⁇ . heterocycfyl groups, wherein Y : and Y 2 may join together to form a ring;
  • R is chosen from H, C s alkyl, C 2 -s aikenyl, C 2 _g aikynyl, CYs haloaikyl, C?-?, haioaikenyl, CYs haioalkynyl, C a a!koxy, Ce-i g ary!, and C 2 .; 3 heteroaryi groups; and
  • X is chosen from halogens.
  • R is chosen from Q-52 alkyl groups, in some embodiments.
  • R is chosen from Q-g alkyl groups, In some embodiments, R 1 is chosen from C1-4 alkyl groups, in some embodiments, R : is chosen from methyl and ethyi. In some embodiments, R : is methyl. In some embodiments, R ! is ethyi.
  • R is H.
  • R J is chosen from
  • R. 4 is chosen from C ⁇ .. « alkyl and Ci .g haioaikyi groups.
  • R" is chosen from -(CH 2 )nCH 2 Z, ⁇ (03 ⁇ 4) ⁇ -1 ⁇ 2 , and ⁇ (CH 2 ), 1 CZ 3 , wherein n is chosen from integers ranging from 0 to 7 and Z is chosen from F, CI, Br, and ⁇ .
  • n is chosen from integers ranging from 0 to 4, such as 0, I, 2, 3. or 4.
  • Z is F.
  • R 4 is ethyl, In some embodiments, R 4 is n-propyl. in some embodiments, is n-butyl. In some embodiments, R " is cyclopropylmethyl. in some embodiments, R 4 is cyciohexylmethyl. In some embodiments, R 4 is 3,3,3-trifluoropropyi. In some embodiments, R '1 is 4 ,4,4-trifluorobutyl.
  • X is chosen from F and Ci. In some embodiments, X is F. In some embodiments, X is CL
  • At least one compound is chosen from compounds of the following Formulae;
  • At least one compound is chosen from compounds of the following Formulae:
  • At least one compound is chosen from compounds of the following Formulae:
  • At least one compound is chosen from compounds of the following Formulae:
  • At least one compound is chosen from compounds of the following Formulae:
  • At least one prodrug is chosen from compounds of the following Formulae:
  • compositions comprising at ieast one compound of Formula (I), Such pharmaceutical compositions are described in greater detail herein.
  • the compounds and composinons disclosed herein may be used in die methods described herein.
  • a method for treating and/or preventing at ieast one disease, disorder, and/or condition where inhibition of E-seiectin mediated functions may be useful is disciosed, the method comprising administering at least one compound of Formuia (I) and/or a pharmaceutical composition comprising at ieast one coinpound of Formula (I) and optionally at ieast one additional pharmaceutically acceptable ingredient.
  • a method for treating and/or preventing inflammatory disease or disorder in which the adhesion and/or migration of ceils occurs in the disease or disorder comprising administering at least one compound of Formula (I) and/or a pharmaceutical composition comprising at ieast one compound of Formuia (I) and optionally at ieast one additional pharmaceutically acceptable ingredient.
  • a method for inhibiting adhesion of a cancer cri that expresses a ligand of E-seiectin to an endothelial cri expressing E-seiectin on the cell surface of the endothelial ceil is disciosed, the method comprising contacting the endothelial ceil and at least one compound of Formula (I) and/or a pharmaceutical composition comprising at least one compound of Formula (I) and optionally at least one additional pharmaceutically acceptable ingredient such that the at least one compound of Formula (I) in teracts with E- seleetin on the endothelial ceil, thereby inhibiting binding of the cancer ceil to the endothelial ceil.
  • the endothelial ceil is present in the bone marrow.
  • a method for treating and/or preventing a cancer comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (I) and/or a pharmaceutical composition comprising at least one compound of Formula (1) and optionally at least one additional pharmaceutically acceptable ingredient.
  • the compound and/or pharmaceutical composition comprising the compound may be administered in conjunction with (i.e., as an adjunct therapy, which is also called adjunctive therapy) chemotherapy and/or radiotherapy.
  • the chemotherapy and/or radiotherapy may be referred to as the primary antitumor or anti-cancer therapy that is being administered to the subject to treat the particular cancer.
  • a method for reducing (i.e., inhibiting, diminishing) ehemosensitivity and/or radtosensitivity of hematopoietic stem cells (HSC) to the chemotherapeutic drug(s) and/or radiotherapy, respectively is disclosed, the method comprising administering to a subject in need thereof an effective amount of at least one compound of Formula ( ⁇ ) and/or a pharmaceutical composition comprising at least one compound of Formula (I) and optionally one additional pharmaceutically acceptable ingredient.
  • a method for enhancing (i.e., promoting) survival of hematopoietic stem cells comprising administering to a subject in need thereof at least one compound of Formula (I) or a pharmaceutical composition comprising at least one compound of Formula (I) and optionally at least one additional pharmaceutically acceptable ingredient.
  • a method for decreasing the likelihood of occurrence of metastasis of cancer cells in a subject who is in need thereof is disclosed, the method comprising administering an effective amount of at least one compound of Formula (I) and/or a pharmaceutical composition comprising at least one compound of Formula. (I) and optionally at least one additional pharmaceutically acceptable ingredient.
  • a method for treatment and/or prevention of at least one cancer in which the cancer cells may leave the primary site comprising administering to a subject in need thereof an effective amount of at least one compound of Formula ( ⁇ ) and/or a. pharmaceutical composition comprising at least one compound of Formula ( ⁇ ) and optionally at least one additional pharmaceutically acceptable ingredient.
  • a primary site may be, tor example, solid tissue (e.g., breast or prostate) or the bloodstream.
  • a method for treatment and/or prevention of at least one cancer in which it is desirable to mobilize cancer cells from a site into the bloodstream and/or retain the cancer cells in the bloodstream comprising administering to a subject in need thereof an effective amount of at least one compound of Formul (i) and/or a pharmaceutical composition comprising at least one compound of Formula (I) and optionally at least one additional pharmaceutically acceptable ingredient,
  • a method for decreasing the likelihood of occurrence of infiltration of cancer ceils into bone marrow comprises administering to a subject in need thereof an effective amount of at least one compound of Formula (I) and/or a pharmaceutical composition comprising at. least one compound of Formula (I) and optionally at least one additional pharmaceutically acceptable ingredient.
  • a method for releasing cells into circulating blood and enhancing retention of the ceils in the blood comprising
  • the method further includes collecting the released cel ls.
  • collecting the released ceils utilizes apheresis.
  • the released cel ls are stem cells (e.g., bone marrow progenitor cells).
  • G- CSF is administered to the individual.
  • a method for treating and/or preventing thrombosis comprising administering to a subject in need thereof an effective amount of at least one compound of Formuia (1) and/or a pharmaceutical composition comprising at least one compound of Formula (1) and optionally at least one additional pharmaceutical acceptable ingredient.
  • a method for treating and/or preventing mucositis comprising administering to a subject in need thereof an effective amount of at ieast one compound of Formula (I) and/or a pharmaceutical composition comprising at least one compound of Formula (1) and optionally at least one additional pharmaceutically acceptable ingredient,
  • a compound of Formula (I) and/or a pharmaceutic l composition comprising at ieast one compound of Formuia (I) may be used for die preparation and/or manufacture of a medicament for use in treating and/or preventing at least one of the diseases, disorders, and/or conditions described herein,
  • C alkyf groups includes, independently, Ci aikyl groups, C 2 a!ky! groups, C-> alky! groups, and C aikyl groups.
  • the term "at least one” refers to one or more, such as one, two, etc.
  • the term “at ieast one C aikyl group” refers to one or more C aikyl groups, such as one C M aikyl group, two C aikyl groups, etc.
  • aikyl includes saturated straight, branched, and cyclic (also identified as cycioalkyl), primary, secondary, and tertiary hydrocarbon groups.
  • aikyl groups include methyl ethyl propyl, .vopropyl, eyclopropyi, butyl, secbutyi, isobutyl, tertbut l, eyclobutyl.
  • an aikyl group may be optionally substituted.
  • alkenyl includes straight, branched, and cyclic hydrocarbon groups comprising at least one double bond.
  • the double bond of an alkenyl group can be unconjugated or conjugated with another unsaturated group.
  • alkenyi groups include vinyl, aihyl, huten.yl, pentenyL hexenyl, bu adienyl, pentadienyl, hexadienyl, 2-etbylhexeny ⁇ 5 and cyclopent-l-en-1 -y].
  • an alkenyi group may be optionally substituted,
  • alkynyl includes straight and branched hydrocarbon groups comprising at least one triple bond.
  • the triple bond of an alkynyl group can be unconjugated or conjugated with another unsaturated group.
  • alkynyl groups include ethynyl propynyi, butynyl, pentynyl, and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted.
  • alkylene or "alkylene chain” includes straight and branched divalent hydrocarbon groups, consisting solely of carbon and hydrogen, linking the rest of the molecule to a second group.
  • the alkylene ma be unsaturated or partially or fully saturated.
  • Non-limiting examples of alkylene groups include methylene, ethylene, propylene,
  • alkylene chain is attached to the rest of the molecule through a single or double bond and to the second group through a single or double bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the second group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted.
  • aryl includes hydrocarbon ring system groups comprising at least 6 carbon atoms and at least one aromatic ring.
  • the aryl group may be a monocyclic, bicyciic, tricyclic or tetracyclic ring system, which ma include fused or bridged ring systems.
  • Non- limiting examples of aryl groups include aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, os-indacene, .v-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pfeiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group may be optionally substituted.
  • cycloaikyl includes saturated monocyclic or polycyclic hydrocarbon group, which may include fused or bridged ring systems, Non-limiting examples of cycloaikyl groups include cyclopropyl, cycfobutyl, cyciopentyl, cyelohexyL cycloheptyl, cyclooctyl, adamantyl, and norbornyl. Unless otherwise stated specifically in the
  • E-selectin antagonist includes inhibitors of E-selectin only, as well as inhibitors of E-selectin and either P ⁇ seleetin or L-seleetin, and inhibitors of E-selectin, P- seisctin, and L-selectin,
  • fused includes any ring structure described herein which is fused to an existing ring structure.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes pari of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • glycomimetic includes any naturally occurring or non-natural ly occurring carbohydrate compound in which at least one substituent has been replaced, or at least one ring has been modified (e.g. , substitution of carbon for a ring oxygen), to yield a compound that is not fully carbohydrate.
  • halo or halogen includes fiuoro, chioro. bromo, and iodo.
  • haloalkyl includes aikyi groups, as defined herein, substituted by at least one halogen, as defined herein.
  • Non-limiting examples of haloalkyl groups include trifiuoromethyL difluoromethyl, trichloromethyi, 2,2,2-trifluoroethyi, 1 ,2-diiluoroethyl, 3 ⁇ brorao-2-fluoropropyl, and 1 ,2-dibromoethyi.
  • a "fluoroalkyl” is a haloalkyl wherein at least one halogen is fiuoro. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • haloalkenyl includes aikenyi groups, as defined herein, substituted by at least one halogen, as defined herein.
  • Non-limiting examples of haloalkenyl groups include fiuoroethenyi, 1 ,2-difluoroethenyl, 3-bromo-2-fluoropropenyl, and 1 ,2-dibronioethen I ,
  • a "fiuoroalkenyl” is a haloalkenyl substituted with at least one fiuoro group. Unless stated otherwise specifically in the specification, a haloalkenyl group may be optionally substituted.
  • haloalkynyl includes alkynyl groups, as defined herein, substituted by at least one halogen, as defined herein, Non-limiting examples include fluoroethynyl, i ,2-difluoroethynyl, 3-bromo-2-fluoropropynyl, and 1 ,2-dibromoethynyl.
  • fluoroaikyny! is a haloalkynyl wherein at leas one halogen is fiuoro. Unless stated otherwise specifically in the specification, a haloalkynyl group may be optionally substituted,
  • heterocyclyl or “heterocyclic ring” includes 3- to 2 -membered saturated or partially unsaturated non-aromatic ring groups comprising 2 to 23 ring carbon atoms and 1 to 8 ring heteroatom(s) each independently chosen from N, €), and S. Unless stated otherwise specifically in the specification., the heterocyciyl groups may be
  • heterocyclic ring monocyclic, hicyciic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems, and may be partially or fully saturated; any nitrogen, carbon or sulfur atom(s) in the heterocyciyl group may be optionally oxidized; any nitrogen atom in the heterocyciyl group may be optionally quaternized; and the heterocyciyl group
  • heterocyclic ring include dioxoianyi, thienyi[l ,3]dithiany],
  • heteroaryl includes 5- to 14-niembered ring groups comprising 1 to 13 ring carbon atoms and 1 to 6 ring heteroatom(s) each independently chosen from N, O, and S, and at least one aromatic ring.
  • the heteroaryl group may be a monocyclic, bicyelic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; an nitrogen, carbon or sulfur atom(s) in the heteroaryl radical may be optionally oxidized: and any nitrogen atom may be optionally quaternized.
  • Non-limiting examples of heteroaryl groups include azepinyl, acrid my I, benzimidazolyi.
  • benzothiazoiyl benzindolyl, benzodioxo!yl, benzofuranyl, henzooxazo!yi, benzothiazolyl, benzothiadiazolyl, benzo[&][i,4]dioxepinyl, 1 ,4-benzodioxanyl,
  • benzonaphthofuranyi benzoxazoiyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyi, benzothienyl (benzothiophenyl), benzotriazolyl, henzo[4,0]imidazo[ l,2-a]pyridinyl, carbazoiyl, cinno!inyl, dibenzofuranyl, dibenzothiophenyi. furanyl, furanonyl. isothiazolyl, imidazolyl, indazolyl, indoiyl, indazoly!, isoindolyl.
  • indolinyl isoindolinyi, isoquinolyl, indoiizinyl, isoxazoiyi, naphthyridinyl, oxadiazolyl, 2-oxoaz.eptnyi, oxazolyl, oxiranyi, 1 -oxidopyridinyl, 1 -oxidopyrtraidinyl, 1- oxidopyrazinyi, 1 -oxidopyridazinyl, 1 -phenyl- 1 H-pyrroiyi, phenazinyl, phenothi&zinyl, phenoxazinyi, phthaiazinyl, pteridinyl, purmyi, pyrrolyl, pyrazoiyl, pyridinyi, pyrazinyi, pyrimidirryi, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinu
  • a heteroaryi group may be optionally substituted.
  • pharmaceutically acceptable salts includes both acid and base addition salts
  • pharmaceutically acceptable acid addition salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maieates, citrates, benzoates, salicylates, and ascorbates.
  • pharmaceutically acceptable base addition salts include sodium, potassium, lithium, ammonium (substituted and unsubstituted). calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Pharmaceutically acceptable salts may, for example, be obtained using standard procedures well known in the field of pharmaceuticals.
  • prodrug includes compounds that may be converted, for example, under physiological conditions or by solvolysis, to a biologically active compound described herein,
  • prodrug includes metabolic precursors of compounds described herein thai are pharmaceutically acceptable,
  • a discussion of prodrugs can be found, for example, in Higuchi, T., et al,, "Pro-drugs as Novel Delivery Systems," A.C.S, Symposium Series, Vol, 14. and in Bioreversible Carriers in Drug Design, ed. Edward B, Roche, American Pharmaceutical Association and Pergamon Press. 1 987.
  • prodrug also includes covalently bonded carriers that release the active compound(s) as described herein in vivo when such prodrug is administered to a subject.
  • prodrugs include ester and amide derivatives of hydroxy, carboxy, mercapto and amino functional groups in the compounds described herein,
  • substituted ' ' includes the situation where, in any of the above groups, at least one hydrogen atom is replaced by a non-hydrogen atom such as, for example, a halogen atom such as F, CI, Br, and I: an oxygen atom in groups such as hydroxy!
  • a non-hydrogen atom such as, for example, a halogen atom such as F, CI, Br, and I: an oxygen atom in groups such as hydroxy!
  • a sulfur atom in groups such as thiol groups, thioaikyi groups, sulfone groups, sulfonyi groups, and sulfoxide groups
  • a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamin.es, diaryiamines, N ⁇ oxides, imides, and enamines
  • a silicon atom in groups such as trtalkylsily!
  • Substituted also includes th situation where, in any of the above groups, at least, one hydrogen atom is replaced by a higher-order bond (e.g. , a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyi, carboxyi, and ester groups; and nitrogen in. groups such as imines, oximes, hydrazones, and nitri!es.
  • a higher-order bond e.g. , a double- or triple-bond
  • nitrogen in. groups such as imines, oximes, hydrazones, and nitri!es.
  • the present disclosure includes within its scope all the possible geometric isomers, e.g., Z and E isomers (CM and trans isomers), of the compounds as well as ail the possibie optical isomers, e.g. diastereomers and enantiomers, of the compounds.
  • the present disclosure includes in. its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures.
  • the individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods.
  • optical isomers e.g., enantiomers
  • conventional resolution methods e.g. fractional crystallization
  • the present disclosure includes within its cope all possible tautomers.
  • the present disclosure includes in its scope both the individual tautomers and any mixtures thereof.
  • Synthesis of the compounds of Formula (I) may be performed as described herein, including the Examples, using techniques familiar to a person skilled in the art. Synthetic methods for preparing exemplary compounds described herein are described in Examples 1 - 13. The methods may be used for synthesis of the compounds of Formula (I) by using appropriate reactants for preparation of the specific compound using the techniques and methods described herein, and that are routinely practiced in the art. By way of further example. Figures 1-5 provide schematics of synthesis schemes for exemplary compounds disclosed herein.
  • Suitable protecting groups include hydroxy, amino, mercapto and carboxyiic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyi or diarylaikylsilyl (for example, /-butyldimethylsily!, i-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups tor amino, amidino and guanidino include r-butoxycarbonyl, benzyioxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryi or arylalkyl), j-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxyiic acid include alkyl, aryl or arylalkyi esters.
  • Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley.
  • the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
  • Analogous reactants to those described above may be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially avaiiabie in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses ⁇ e.g., those listed above) provide custom synthesis services.
  • a reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahl & C. G, Wermuth "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.
  • the compounds used in the reactions described herein may be made according to Examples 1 - 1 3, Figures 1-5, and/or organic synthesis techniques known to those of ordinary skill in this art, starting from commercially avaiiabie chemicals and/or from compounds described in the chemicai literature.
  • “Commercially available chemicals” may be obtained from standard commercial sources including Acros Organics (Pittsburgh PA), Aldrieh Chemical (Milwaukee WL including Sigma Chemicai and Fiuka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester PA), Crescent Chemical Co.
  • Bioactivity of a compound described herein may be determined, for example, by performing at least one in vitro and/or in vivo study routinely practiced in the art and described herein or in the art.
  • In vitro assays include without limitation binding assays, immunoassays, competitive binding assays and cell based activity assays,
  • An inhibition assay may be used to screen for antagonists of E-selectin.
  • an assay may be performed to characterize the capability of a compound described herein to inhibit (i.e. , reduce, block, decrease, or prevent in a statistically or biologically .significant manner) interaction of E-selectin with sLe 8 or sLe x .
  • the inhibition assay may be a competitive binding assay, which allows the determination of IC .3 ⁇ 4 values.
  • E-selectin/Ig chimera may be immobilized onto a matrix ⁇ e.g.
  • a multi-well plate which may he made from a polymer, such as polystyrene: a test tube, and the like); a compositio may be added to reduce nonspecific binding (e.g., a composition comprising non-fat dried milk or bovine serum albumin or other blocking buffer routinely used by a person skilled in the art); the immobilized E-selectin may be contacted with the candidate compound in the presence of sLe a comprising a reporter group under conditions and for a time sufficient to permit sLe a to bind to the immobilized E-selectin; the immobilized E- selectin may be washed; and the amount of sLe * bound to immobilized E-selectin may be detected. Variations of such steps can be readily and routinely accomplished by a person of ordinary skill in the art.
  • Conditions for a particular assay include temperature, buffers (including salts, cations, media), and other components that maintain the integrity of any cell used in the assay and the compound, which a person of ordinary skill in the art will be familiar and/or which can be readily determined. A person of ordinary skill in the ait also readily appreciates that appropriate controls can be designed and included when performing the in vitro methods and in vivo methods described herein,
  • the source of a compound that is characterized by at least one assay and techniques described herein and in the art may be a biological sample that is obtained from a subject who has been treated with the compound.
  • the cells that may be used in the assay may also be provided in a biological sample.
  • a "biological sample” may include a sampie from a subject, and may be a blood sample (from which serum or plasma may be prepared), a biopsy specimen, one or more body fluids (e.g.
  • a biological sampie may further include a tissue or cell preparation in which the morphological integrity or physical state has been disrupted, for example, by dissection, dissociation, solubilization,
  • the subject or biological source may be a human or non-human animal, a primary cell culture (e.g., immune ceils), or culture adapted cel l line, including but not limited to, genetically engineered cell lines that may contain
  • chromosomaiiy integrated or episoma! recombinant nucleic acid sequences, immortalized or immortalizable ceil lines, somatic ceil hybrid cell lines, differentiated or differentiatable cell lines, transformed ceil lines, and the like.
  • methods for characterizing E-seiectin antagonists include animal model studies.
  • animal models for liquid cancers used in the art include multiple myeloma (see, e.g., DeWeerdt. Mature 480:S38-S39 (1 5 December 201 1) doi: 10.1038/480S38a; Published online 14 December 201 1 ; Mitsiades et ah, Clin. Cancer Res. 2009 15: 1210021 (2009)); acute myeloid leukemia (AMI,) (Zuber et al. s Genes Dev. 2009 April 1 ; 23(7): 877-889).
  • Animal models for acute lymphoblastic leukemia (ALL) have been used by persons of ordinary skill in the art for more than two decades. Numerous exemplary animal models for solid tumor cancers are routinely used and are well known to persons of ordinary skill in the art.
  • therapeutic and/or prophylactic benefit includes, for example, an improved clinical outcome, wherein the object is to prevent or slow or retard (lessen) an undesired physiological change or disorder, or to prevent or slow or retard (lessen) the expansion or severity of such disorder.
  • beneficial or desired clinical results from treating a subject include, but are not limited to, abatement, lessening, or alleviation of symptoms that result from or are associated with the disease, condition, or disorder to be treated; decreased occurrence of symptoms; improved quaiity of life; longer disease-tree status (i.e., decreasing the likelihood or the propensity that a subject will present symptoms on the basis of which a diagnosis of a disease is made); diminishment of extent of disease; stabilized ( . ⁇ ?., not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission (whether partial or total), whether detectable or undetectable: and/or overall survival, "Treatment" can include prolonging survival when compared to expected survival if a subject were not receiving treatmen
  • the subject in some embodiments of the methods described herein, is a human, in some embodiments of the methods described herein, the subject is a non-human animal
  • Non-human animals that may be treated include mammals, for example, non-human primates (e.g., monkey, chimpanzee, goril la, and the like), rodents (e.g., rats, mice, gerbiis, hamsters, ferrets, rabbits), iagomorphs, swine (e.g. , pig, miniature pig), equine, canine, feline, bovine, and other domestic, farm, and zoo a imals.
  • non-human primates e.g., monkey, chimpanzee, goril la, and the like
  • rodents e.g., rats, mice, gerbiis, hamsters, ferrets, rabbits
  • iagomorphs e.g. , pig, miniature pig
  • the effectiveness of the compounds of the present disclosure in treating and/or preventing diseases, disorders, or conditions treatable by inhibiting an activity of E-se!ectin can readily be determined by a person of ordinary skill in the relevant art. Determining and adjusting an appropriate dosing regimen (e.g., adjusting the amount of compound per dose and/or number of doses and frequency of dosing) can also readily be performed b a person of ordinary skill in the relevant art. One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and performance of analytical tests and methods described herein, may be used tor monitoring the health status of the subject.
  • compositions comprising at least one compound of Formula (I).
  • the pharmaceutical composition further comprises at least one additional pharmaceutically acceptable ingredient.
  • any one or more of the compounds of the present disclosure may be administered in the form of a pharmaceutically acceptable derivative, such as a salt, and/or it/they may also be used alone and/or in appropriate association, as web as in combination, with other pharmaceutically active compounds.
  • An effective amount or therapeutically effective amount refers to an amount of at least one compound of the present disclosure or a pharmaceutical composition comprising at least one such compound that when administered to a subject, either as a single dose or as part of a series of doses, is effective to produce at least one therapeutic effect.
  • Optimal doses may generally be determined using experimental models and/or clinical trials. Design and execution of pre-clineai and clinical studies for each of the therapeutics (including when administered for prophylactic benefit) described herein are well within the skill of a person of ordinary skill in the relevant art, The optima!
  • dose of a therapeutic may depend upon the body mass, weight, and/or blood volume of the subject, in general, the amount of at least one compound of Formula (I) as described herein, that is present irs a dose, may range from about 0.01 ,ug to about 1000 ,ug per kg weight of the subject. The minimum dose that is sufficient to provide effective therapy may be used in some embodiments. Subjects may generally be monitored for therapeutic effectiveness using assays suitable for the disease or condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • the level of a compound that is administered to a subject may be monitored by determining the level of the compound (or a metabolite of the compound) in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound, or metabolite thereof, may be used to measure the level of the compound during the course of a therapeutic regimen.
  • the dose of a compound described herein may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease ; general health status, as well as age, gender, and weight, and other factors apparent to a person of ordinary skill in the medical art Similarly, the dose of the therapeutic for treating a disease or disorder may be determined according to parameters understood by a person of ordinary skill in the medical art. [0091] Pharmaceutical compositions may be administered in any manner appropriate to the disease or disorder to be treated as determined by persons of ordinary skill in the medical arts.
  • an appropriate dose and a suitable duration and frequency of administration will be determined by such factors as discussed herein, including the condition of the patient, the type and severity of the patient's disease, the particuiar form of the active ingredient, and the method of administration.
  • an appropriate dose (or effective dose) and treatfnent regimen provides the composition ⁇ ) as described herein in an amount sufficient to provide therapeutic and/or prophylactic benefit (for example, an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity or other benefit as described in detai l above).
  • compositions described herein may be administered to a subject in need thereof by any one of several routes that effectively delivers an effective amount of the compound.
  • suitable administrative routes include topical, oral, nasal, intrathecal, enteral, buccal, sublingual, transdermal, rectal, vaginal, intraocular, subconjunctival, sublingual, and parenteral administration, including
  • compositions described herein may, for example, be sterile aqueous or sterile non-aqueous solutions, suspensions, or emulsions, and may additionally comprise at least one pharmaceutically acceptable excipient (i.e., a non-toxic material that does not interfere with the activity of the active ingredient), Such compositions may, for example, be in the form of a solid, liquid, or gas (aerosol). Alternatively, the compositions described herein may, for example, be formulated as a Syophiiizate, or compounds described herein may be encapsulated within liposomes using technology known in the art. The pharmaceutical compositions may further comprise at least one additional pharmaceutically acceptable ingredient, which may be biologically active or inactive.
  • Non-limiting examples of such ingredients include buffers (e.g. , neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitoi, proteins, polypeptides, amino acids (e.g. , glycine), antioxidants, chelating agents (e.g., EDTA and glutathione), stabilizers, dyes, flavoring agents, suspending agents, and preservatives.
  • buffers e.g. , neutral buffered saline or phosphate buffered saline
  • carbohydrates e.g., glucose, mannose, sucrose or dextrans
  • mannitoi proteins
  • proteins e.g., glycine
  • antioxidants e.g., EDTA and glutathione
  • compositions may be formulated tor the particular mode of administration.
  • pharmaceutical compositions may further comprise water, saline, alcohols, fats, waxes, and buffers.
  • compositions may further comprise at least one component chosen, for example, from any of the aforementioned ingredients, excipients and carriers, such as mannitoi, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, kaolin, glycerin, starch dextrins, sodium alginate, carhoxymethyleellulose, ethyl cellulose, glucose, sucrose, and magnesium carbonate.
  • excipients and carriers such as mannitoi, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, kaolin, glycerin, starch dextrins, sodium alginate, carhoxymethyleellulose, ethyl cellulose, glucose, sucrose, and magnesium carbonate.
  • the pharmaceutical compositions may be in the form of a liquid.
  • a liquid composition may include, for example, at least one the following: a sterile diluent such as water for injection, saline solution, preferably physiological saline. Ringer's solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants: chelating agents; buffers and agents tor the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, preferably physiological saline. Ringer's solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents
  • antibacterial agents such as sodium chloride or dextrose.
  • antioxidants chelating agents
  • a parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic, in some embodiments, the pharmaceutical composition comprises physiological saline.
  • the pharmaceutical composition is an injectable composition, and in some embodiments, the injectable composition is sterile,
  • At least one of the compounds of the present disclosure can be used alone or in combination with at least one additive appropriate to make tablets, powders, granules and/or capsules, for example, those chosen from conventional additives, disintegrators, lubricants, dil ents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical compositions may be formulated to include at least one buffering agent, which may provide for protection of the active ingredient from low pH of the gastric environment and/or an enteric coating,
  • a pharmaceutical composition may be formulated for oral delivery with at least one flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating,
  • Oral formulations may be provided as gelatin capsules, which may contain the active compound or biological along with powdered carriers. Similar carriers and diluents may be used to make compressed tablets. Tablets and capsules can be manufactured as sustained release products to provide for continuous release of active ingredients over a period of time. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract,
  • a pharmaceutical composition may be formulated for sustained or slow release.
  • Such compositions may generally be prepared using well known technology and
  • Sustained-release formulations may contain the active therapeutic dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of active therapeutic contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition to be treated or prevented..
  • the pharmaceutical compositions described herein can be formulated as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • the pharmaceutical compositions may be prepared as aerosol formulations to be administered via inhalation.
  • the pharmaceutical compositions may be formulated into pressurized acceptable propellants such as dichlorodiiluoromethane, propane, nitrogen and the like.
  • Topical formulations may be in the form of a transdermal patch, ointment, paste, lotion, cream, gel, and the like. Topical formulations may include one or more of a penetrating agent or enhancer (also call permeation enhancer), thickener, diluent, emulsifier. dispersing aid. or binder.
  • Physical penetration enhancers include, for example, electrophoretic techniques such as iontophoresis, use of ultrasound (or "phonophoresis”), and the like.
  • Chemical penetration enhancers are agents administered either prior to, with, or immediately following administration of the therapeutic, which increase the permeability of the skin, particularly the stratum corneum, to provide for enhanced penetration of the drug through the skin. Additional chemical and physical penetration enhancers are described in, for example, Transdermal Delivery of Drags, A. F. Kydonieus (ED) 1987 CRL Press;
  • Kits comprising unit doses of at least one compound of the present disclosure, for example in oral or injectable doses, are provided.
  • Such kits may include a container comprising the unit dose, an informational package insert describing the use and attendant benefits of the therapeutic in treating the pathological condition of interest, and/or optionally an appliance or device for delivery of the at least one compound of Formula (I) and/or pharmaceutical composition comprising the same.
  • BU2S11O (0.36 g, 1.43 mmoi) were combined In anhydrous MeOH (20 mL) and refluxed for 2,5 h at 90 "C. The solution was concentrated and the residue was co-evaporated with toluene (20 mL*3) then dried under high vacuum for 3 h. A mixture of this Sn-co nplex and CsF (0.5 g, 3,29 mmoi) were dispersed in acetonitrile (15 mL) and stirred for 5 m.in at room temperature under an argon atmosphere. A solution of 7 (1.0 g, 3,08 mmoi) in anhydrous acetonitrile (5 mL) was added dropwise over 2 h. The resulting solution was stirred overnight. The solution was filtered through a celite pad and the cake was washed with EtOAc (30 mL). The combined filtrate was washed with water, brine, dried over then concentrated. The residue was purified by silica gel column chromatography
  • the heterogeneous light bine solution was filtered through atitie pad and the cake was washed with EtOAc (1.0 mL). The combined filtrate washed with water, brine, dried over Na?S04, then concentrated. The product was purified by silica gel column
  • E- selectin/Ig chimera was immobilized in 96 well microliter plates by incubation at 37 °C for 2 hours. To reduce nonspecific binding, bovine serum albumin was added to each well and incubated at room temperature for 2 hours. The plate was washed and serial dilutions of the test compounds were added to the wells in the presence of conjugates of biotinylated, sLe 8 pofyacrylamide with streptavidtn horseradish peroxidase and incubated for 2 hours at room temperature.

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Abstract

L'invention concerne des composés, des compositions et des méthodes de traitement et/ou de prévention d'au moins une maladie, une affection ou une pathologie par inhibition de la liaison d'une sélectine E à un ligand de la sélectine E. L'invention concerne, par exemple, des agents thérapeutiques constituant des antagonistes de la sélectine E et des compositions comprenant au moins un tel agent : RX étant choisi parmi les halogènes.
PCT/US2016/026116 2015-04-08 2016-04-06 Antagonistes de la sélectine contenant du 2-halo-galactose WO2016164394A1 (fr)

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US11291678B2 (en) 2016-03-02 2022-04-05 Glycomimetics, Inc Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin
US11433086B2 (en) 2016-08-08 2022-09-06 Glycomimetics, Inc. Combination of T-cell checkpoint inhibitors with inhibitors of e-selectin or CXCR4, or with heterobifunctional inhibitors of both E-selectin and CXCR4
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US11712446B2 (en) 2017-11-30 2023-08-01 Glycomimetics, Inc. Methods of mobilizing marrow infiltrating lymphocytes and uses thereof
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US10519181B2 (en) 2014-12-03 2019-12-31 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
US11291678B2 (en) 2016-03-02 2022-04-05 Glycomimetics, Inc Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin
US11433086B2 (en) 2016-08-08 2022-09-06 Glycomimetics, Inc. Combination of T-cell checkpoint inhibitors with inhibitors of e-selectin or CXCR4, or with heterobifunctional inhibitors of both E-selectin and CXCR4
US11072625B2 (en) 2016-10-07 2021-07-27 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11780873B2 (en) 2016-10-07 2023-10-10 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11197877B2 (en) 2017-03-15 2021-12-14 Glycomimetics. Inc. Galactopyranosyl-cyclohexyl derivauves as E-selectin antagonists
US11878026B2 (en) 2017-03-15 2024-01-23 Glycomimetics, Inc. Galactopyranosyl-cyclohexyl derivatives as e-selectin antagonists
US11712446B2 (en) 2017-11-30 2023-08-01 Glycomimetics, Inc. Methods of mobilizing marrow infiltrating lymphocytes and uses thereof
WO2019133878A1 (fr) 2017-12-29 2019-07-04 Glycomimetics, Inc. Inhibiteurs hétérobifonctionnels de e-sélectine et de galectine -3
US11548908B2 (en) 2017-12-29 2023-01-10 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11707474B2 (en) 2018-03-05 2023-07-25 Glycomimetics, Inc. Methods for treating acute myeloid leukemia and related conditions
US11845771B2 (en) 2018-12-27 2023-12-19 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3

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