WO2008060378A2 - Glycomimetic replacements for hexoses and n-acetyl hexosamines - Google Patents

Glycomimetic replacements for hexoses and n-acetyl hexosamines Download PDF

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Publication number
WO2008060378A2
WO2008060378A2 PCT/US2007/021541 US2007021541W WO2008060378A2 WO 2008060378 A2 WO2008060378 A2 WO 2008060378A2 US 2007021541 W US2007021541 W US 2007021541W WO 2008060378 A2 WO2008060378 A2 WO 2008060378A2
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Prior art keywords
alkanyl
crc
aryl
heteroaryl
alkynyl
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English (en)
French (fr)
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WO2008060378A3 (en
Inventor
Beat Ernst
Daniel Schwizer
Arun K. Sarkar
John L. Magnani
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Crescent Biopharma Inc
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Glycomimetics Inc
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Priority to EP07867214.4A priority Critical patent/EP2074132B1/en
Priority to JP2009532370A priority patent/JP5298020B2/ja
Priority to CA2666103A priority patent/CA2666103C/en
Publication of WO2008060378A2 publication Critical patent/WO2008060378A2/en
Publication of WO2008060378A3 publication Critical patent/WO2008060378A3/en
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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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to compounds and methods for obtaining oligosaccharide mimics, and more particularly for obtaining oligosaccharide mimics by incorporating or substituting in a cyclohexane derivative.
  • Naturally occurring monosaccharides and oligosaccharides play a role, or are capable of playing a role, in a variety of biological processes.
  • non-naturally occurring monosaccharides and oligosaccharides may serve to replace or even improve upon their naturally occurring counterparts.
  • Monosaccharides and particularly oligosaccharides may be difficult, and thus costly, to produce. Even where the degree of difficulty to produce is not particularly elevated, the production of monosaccharides and oligosaccharides may still nevertheless be costly. This problem is multiplied where a costly monosaccharide or oligosaccharide needs to be mass produced.
  • the invention provides compounds and methods for obtaining oligosaccharide mimics.
  • a method for preparing an oligosaccharide mimic comprising incorporating at least one cyclohexane derivative into an oligosaccharide or glycomimetic compound, wherein the cyclohexane derivative has the formula:
  • R 1 H, C-i-Cs alkanyl, C r C 8 alkenyl, C 1 -C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • the cyclohexane derivative is at least attached to the oligosaccharide or glycomimetic compound at an OH, R 1 or R 2 . Also included are products prepared by the method.
  • a method for substituting a monosaccharide mimic for at least one hexose or hexosamine in an oligosaccharide compound or glycomimetic compound or in an oligosaccharide or glycomimetic of an oligosaccharide-containing or glycomimetic-containing compound comprising replacing at least one hexose or hexosamine in an oligosaccharide or glycomimetic compound with a cyclohexane derivative, wherein the cyclohexane derivative has the formula:
  • R 1 H, CrC 8 alkanyl, C r C 8 alkenyl, Ci-C 8 alkynyl, halogenated C r C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • R 2 H 1 CrC 8 alkanyl, C r C 8 alkenyl, C r C 8 alkynyl, halogenated CrC 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH 1 or NHX
  • the cyclohexane derivative is at least attached to the oligosaccharide or glycomimetic compound at an OH, R 1 or R 2 . Also included are products prepared by the method.
  • the present invention provides an oligosaccharide or glycomimetic compound that contains at least one cyclohexane derivative, wherein the cyclohexane derivative has the formula:
  • R 1 H, CrC 8 alkanyl, C 1 -C 8 alkenyl, d-C 8 alkynyl, halogenated C 1 -C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • R 2 H, CrC 8 alkanyl, C r C 8 alkenyl, C r C 8 alkynyl, halogenated C r C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • the cyclohexane derivative is at least attached to the oligosaccharide or glycomimetic compound at an OH, R 1 or R 2 .
  • the present invention provides a compound comprising:
  • R 1 H, CrC 8 alkanyl, d-C 8 alkenyl, d-Cs alkynyl, halogenated C r C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • R 2 H, C 1 -C 8 alkanyl, C r C 8 alkenyl, CrC 8 alkynyl, halogenated C r C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • n 0-2 and X is independently selected from C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl,
  • R 10 is one of
  • R >5 _ H, D-mannose, L-galactose, D-arabinose, L-fucose, polyols,
  • X CF 3 , cyclopropyl or C r C 8 alkanyl, CrC 8 alkenyl, CrC 8 alkynyl, aryl, heteroaryl, (CH 2 ) m -aryl or (CH 2 ) m -heteroaryl where m is 1-10,
  • Q is H or a physiologically acceptable salt, CrC 8 alkanyl, CrC 8 alkenyl, CrC 8 alkynyl, aryl, heteroaryl,
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • “another of the compound” refers to either a second compound identical to the first compound, or a second compound that is encompassed by the disclosure herein but not identical to the first compound.
  • the present invention provides a compound consisting of:
  • R 1 H, CrC 8 alkanyl, C r C 8 alkenyl, C r C 8 alkynyl, halogenated Ci-C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • R 2 H, CrC 8 alkanyl, d-C 8 alkenyl, CrC 8 alkynyl, halogenated C r C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • n 0-2 and X is independently selected from C 1 -C 8 alkanyl, C 1 -C 8 alkenyl, CrC 8 alkynyl,
  • R 10 is one of
  • R >5 _ H, D-mannose, L-galactose, D-arabinose, L-fucose, polyols,
  • X CF 3 , cyclopropyl or C r C ⁇ alkanyl, d-C 8 alkenyl, C r C ⁇ alkynyl, aryl, heteroaryl, (CH 2 )m-aryl
  • Q is H or a physiologically acceptable salt, CrC 8 alkanyl, CrC 8 alkenyl, CrCe alkynyl, aryl, heteroaryl,
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • Me is methyl and Bz is benzoyl.
  • the compound may include a polyethylene glycol attached thereto. Alternatively, multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula: where Q is H or a physiologically acceptable salt, Me is methyl and Bz is benzoyl.
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • Me is methyl and Bz is benzoyl.
  • the compound may include a polyethylene glycol attached thereto. Alternatively, multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • Me is methyl and Bz is benzoyl.
  • the compound may include a polyethylene glycol attached thereto. Alternatively, multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • Me is methyl and Bz is benzoyl.
  • the compound may include a polyethylene glycol attached thereto. Alternatively, multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula: where Me is methyl, Et is ethyl and Bz is benzoyl.
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • Figure 1 is a diagram illustrating the synthesis of GIcNAc mimics from tetrahydrophthalic anhydride.
  • Figure 2 is a diagram illustrating the synthesis of GIcNAc mimics from cyclohexenon.
  • Figure 3 is a diagram illustrating the synthesis of mimics.
  • Figure 4 is a diagram illustrating the synthesis of mimics.
  • Figure 5 is a diagram illustrating the synthesis of mimics.
  • Figure 6 is a diagram illustrating the synthesis of mimics.
  • Figure 7 is a diagram illustrating the synthesis of mimics.
  • Figure 8 is a diagram illustrating the synthesis of mimics.
  • Figure 9 is a diagram illustrating the synthesis of mimics.
  • Figure 10 is a diagram illustrating the synthesis of a pegylated mimic.
  • Figure 11 is a diagram illustrating the synthesis of a pegylated tetramer of a mimic.
  • Figure 12 is a diagram illustrating the synthesis of mimics.
  • Figure 13 is a diagram illustrating the synthesis of mimics.
  • the present invention provides compounds and methods for obtaining monosaccharide and oligosaccharide mimics. Such mimics have a variety of uses in vitro and in vivo, including as antagonists of E-selectin.
  • an oligosaccharide mimic may be prepared by incorporating one or more cyclohexane derivatives into an oligosaccharide or glycomimetic compound.
  • An oligosaccharide refers to two or more monosaccharides covalently joined. Oligosaccharides are polymers containing monosaccharide units, typically with 2 to about 100 monosaccharides and any integer in-between. Each monosaccharide of an oligosaccharide is independently selected; although two or more monosaccharides may be identical.
  • the cyclohexane derivative of the methods of the present invention has the formula:
  • R 1 may be H, CrC 8 alkanyl, CrC 8 alkenyl, CrC 8 alkynyl, halogenated CrC 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • the cyclohexane derivative is attached to the oligosaccharide or glycomimetic compound at least at one of the OH, the R 1 or the R 2 . In embodiments, attachment is at least at one of the OH or the R 2 .
  • Other options for attachment include at both of the OH, e.g., one monosaccharide or monosaccharide mimic attached at one of the OH and another monosaccharide or monosaccharide mimic attached at the other OH.
  • Such a cyclohexane derivative may also be used in a method for substituting a monosaccharide mimic (a cyclohexane derivative) for at least one hexose or hexosamine.
  • the hexose or hexosamine may be in an oligosaccharide or glycomimetic compound or in an oligosaccharide or glycomimetic possessed by an oligosaccharide-containing or glycpmimetic- containing compound. Such a substitution is accomplished by replacing one or more hexose or hexosamine in an oligosaccharide or glycomimetic compound with a cyclohexane derivative. If it is more than one, then each is independently selected.
  • oligosaccharide-containing compounds include glycoproteins, glycopeptides, glycolipids and glyconucleic, acids.
  • a "Ci-Ce alkanyl” refers to an alkane substituent with one to eight carbon atoms and may be straight chain, branched or cyclic (cycloalkanyl). Examples are methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
  • a "halogenated CrCe alkanyl” refers to a "CrC 8 alkanyl” possessing at least one halogen. Where there is more than one halogen present, the halogens present may be the same or different or both (if at least three present).
  • a “CrC 8 alkenyl” refers to an alkene substituent with one to eight carbon atoms, at least one carbon-carbon double bond, and may be straight chain, branched or cyclic (cycloalkenyl). Examples are similar to “CrC 8 alkanyl” examples except possessing at least one carbon-carbon double bond.
  • a “CrC 8 alkynyl” refers to an alkyne substituent with one to eight carbon atoms, at least one carbon-carbon triple bond, and may be straight chain, branched or cyclic (cycloalkynyl). Examples are similar to "CrCs alkanyl” examples except possessing at least one carbon-carbon triple bond.
  • alkoxy refers to an oxygen substituent possessing a "CrC 8 alkanyl,” “CrC 8 alkenyl” or “C r C 8 alkynyl.” This is -O-alkyl; for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and the like; and alkenyl or alkynyl variations thereof (except for methoxy). It further refers to the group O-alkyl-W-alkyl where W is O or N; for example -O-(CH2) n -W-(CH 2 )m where n and m are independently 1-10.
  • aryl refers to an aromatic substituent with one to fourteen carbon atoms in one or multiple rings which may be separated by a bond or fused.
  • a “heteroaryl” is similar to an “aryl” except the aromatic substituent possesses at least one heteroatom (such as N, O or S) in place of a ring carbon.
  • heteroaryls and heteroaryls include phenyl, naphthyl, pyridinyl, pyrimidinyl, triazolo, furanyl, oxazolyl, thiophenyl, quinolinyl and diphenyl.
  • the term “independently selected” refers to the selection of identical or different substituents.
  • Me and Et represent methyl and ethyl, respectively.
  • Bz represents benzoyl.
  • Ar represents aryl.
  • physiologically acceptable salts include Na, K, Li, Mg and Ca.
  • Monosaccharide substituents recited herein e.g., D-mannose, L-galactose, D-arabinose and L-fucose may be in the furanose, pyranose or open form.
  • a linker arm may be desirable for attachment, for example, to a monosaccharide, a monosaccharide mimic or something else such as an amino acid, nucleic acid or lipid.
  • a linker may include a spacer group, such as — (CH 2 )n — or — O(CH 2 )n — where n is generally about 1-20 (all number ranges disclosed herein include any whole integer range therein).
  • An example of a linker is — NH 2 , e.g., — CH 2 — NH 2 when it includes a short spacer group.
  • Embodiments of linkers include the following:
  • linkers with or without a spacer group e.g., CONH(CH 2 ⁇ NH 2 , COOMe, or polyethylene glycol or derivative
  • linker arm e.g., a linker arm, a cyclohexane derivative may be attached at one or both OH.
  • an oligosaccharide or glycomimetic compound that contains at least one cyclohexane derivative, wherein the cyclohexane derivative has the formula:
  • R 1 is defined as above;
  • R 2 is defined as above; and the cyclohexane derivative is at least attached to the oligosaccharide or glycomimetic compound at an OH, R 1 or R 2 .
  • R 1 of the formula may be H 1 CrC 8 alkanyl, C 1 -Ce alkenyl, CrC 8 alkynyl, halogenated CrC 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • R 3 of the formula may be -OH
  • R 5 of the formula may be H, D-mannose, L-galactose, D-arabinose,
  • R 1 is H, CrC 8 alkanyl, C r C 8 alkenyl, Ci-Ce alkynyl, halogenated C r C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me, OMe, halide, OH, or NHX
  • R 2 is H, CrC 8 alkanyl, C r C 8 alkenyl, d-C 8 alkynyl, halogenated C r C 8 alkanyl, aryl or heteroaryl either of which may be substituted with one or more of Me 1 OMe, halide, OH, or NHX
  • n 0-2 and X is independently selected from CrC 8 alkanyl, CrC 8 alkenyl, C r C 8 alkynyl,
  • R 10 is one of
  • R is H, D u--mmaan ⁇ n ⁇ oussee,, L ⁇ _--galactose, D-arabinose, L-fucose, polyols,
  • the present invention provides a compound having the formula:
  • the present invention provides a compound having the formula:
  • the present invention provides a compound having the formula:
  • the present invention provides a compound having the formula:
  • the present invention provides a compound having the formula:
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • the present invention provides a compound having the formula:
  • the compound may include a polyethylene glycol attached thereto.
  • multimers may be formed whereby the compound is attached to another of the compound by polyethylene glycol.
  • a sodium salt of the acid is merely representative and any physiologically acceptable acid salt (e.g., Li, K, Mg and Ca) is encompassed.
  • a free acid substituent (or salt thereof) may be modified as an ester (e.g., alkanyl ester) or as an amide or amide-like (e.g., CONHOH).
  • a polyethylene glycol (PEG), including derivatives thereof, may be attached to a compound.
  • PEG polyethylene glycol
  • multimers of the same compound or different compounds of the compounds described herein i.e., two or more compounds joined to one another
  • PEG polyethylene glycol
  • Examples of particular compounds amenable to the attachment of a PEG or to the formation of a multimer including PEG, are disclosed above as embodiments of the present invention.
  • Procedures for preparing a pegylated compound or pegylated multimers will be familiar to those in the art or in possession of the present disclosure. Examples are depicted in Figure 10 (a pegylated compound) and Figure 11 (a pegylated tetramer).
  • Iodolactone V (15.73 g, 62.2 mmol) was dissolved in dry THF (340 ml). Then DBU (14 ml, 93.3 mmol) was added and the mixture was refluxed for 20 h (TLC-control: petroleum ether/Et 2 O, 1 :1 ). The reaction mixture was cooled down to r.t., transferred with Et 2 O (200 ml) into a separation funnel and extracted with aqueous HCI (400 ml, 0.5 M) and brine (400 ml). The aqueous layers were extracted three times with Et 2 O (3x 200 ml). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo (350 mbar).
  • the reaction mixture was diluted with CH 2 CI 2 (50 ml) and washed twice with HCI 3% (2 x 50 ml).
  • the aqueous layers were extracted with CH 2 CI 2 (2 x 25 ml) and the combined organic layers were washed with a mixture of brine (80 ml) and water (100 ml).
  • the layers were separated and the aqueous layer was extracted with CH 2 CI 2 (2 x 50 ml).
  • the combined organic layers were concentrated in vacuo to afford a brown residue still dissolved in a few ml of CH 2 CI 2 , and was then treated with activated charcoal and filtered through celite. The clear green mixture was concentrated to dryness.
  • Tritylether XVII (948 mg, 2.79 mmol) was dissolved under argon atmosphere in CH 2 CI 2 (30 ml) and NaHCO 3 (281 mg, 3.34 mmol) was added. The mixture was cooled to 0 0 C and under stirring m-chloroperbenzoic acid (70 %, 960 mg, 5.56 mmol) was added. After stirring for 1.5 h the reaction temperature was gradually raised to room temperature and the mixture was stirred for another 3.5 h. The reaction was diluted with CH 2 CI 2 (50 ml) and transferred to a separation funnel. The excess of m-chloroperbenzoic acid was destroyed by washing with satd.
  • the reaction was diluted with te/ ⁇ -butyl methyl ether (10 ml) and quenched at 0 0 C with satd. solution of NaHCO 3 (10 ml).
  • the reaction mixture was further diluted and extracted with te/t-butyl methyl ether and satd. solution of NaHCO 3 (each 20 ml).
  • the aqueous layer was extracted twice with terf-butyl methyl ether (2 x 50 ml).
  • the combined organic layers were dried with Na 2 SO 4 and concentrated.
  • the residue was purified by flash chromatography (petroleum ether/EtOAc/Et 3 N, 13:1 :0.07) to yield XIX (206 mg, 64 %) as yellowish resin.
  • CH 2 CI 2 was prepared in a second flask. Both suspensions were stirred at room temperature for 4 h, before adding the DMTST suspension via syringe to the other suspension. The reaction was stopped after 43 h and filtered through celite, washing with CH 2 CI 2 . The filtrate was successively washed with satd. solution of NaHC ⁇ 3 (20 ml) and water (60 ml). The aqueous layers were each time extracted with DCM (3 x 30 ml). The combined organic layers were dried with Na 2 SO 4 and concentrated in vacuo.
  • a vinyl lithium solution was generated in situ by treating a solution of tetravinyl tin (409 ⁇ L, 2.25 mmol) in THF (3 ml_) with nBuLi (2.5 M in hexane, 3.35 ml_, 8.38 mmol) during 30 min at O 0 C.
  • CuCN (373 mg, 4.16 mmol) in THF (8 ml.) was treated with the vinyl lithium solution and BF 3 etherate (209 ⁇ L, 1.66 mmol) in THF (1.5 mL) according to general procedure A.
  • a solution of A-IV (90.0 mg, 0.161 mmol) in THF (4 ml_) was added to Pd/C (45.2 mg, 10% Pd) under argon.
  • the mixture was hydrogenated under atmospheric pressure at r.t. After 30 min the reaction was filtered through celite, concentrated under reduced pressure and purified by column chromatography (toluene/petroleum ether/ethyl acetate, 7:7:1 to 5:5:1 ) to yield A-V (69.8 mg, 77%) as a colorless solid.
  • thioglycoside A-Vl (112 mg, 0.144 mmol) and glycosyl acceptor A-V (61.6 mg, 0.110 mmol) in dry CH 2 CI 2 (4 mL) were added via syringe to activated 3A molecular sieves (1 g).
  • a suspension of DMTST (87.0 mg, 0.337 mmol) and activated 3A molecular sieves (500 mg) in CH 2 CI 2 (2 mL) was prepared in a second flask. Both suspensions were stirred at r.t. for 4 h, then the DMTST suspension was added via syringe to the other suspension with some additional CH2CI2 (1 ml_).
  • A-VII (38.2 mg, 29.9 ⁇ mol) was hydrogenated with Pd(OH) 2 /C (50 mg, 10% Pd) in dioxane/H 2 O (4:1 , 3.75 ml_) according to general procedure D. After 24 h the reaction mixture was filtered through celite and evaporated to dryness. The residue was redissolved in methanol (5 ml_) and sodium methoxide (74.6 ⁇ mol in 73 ⁇ l MeOH) was added. After stirring at r.t. for 16 h the reaction was quenched by addition of acetic acid (8.5 ⁇ l_). The mixture was concentrated in vacuo and purified by preparative, reversed-phase HPLC to afford A-VIII (16.3 mg, 77%) as a colorless solid.
  • a cPrLi solution was generated in situ by treating a solution of bromocyclopropane (370 ⁇ l_, 4.63 mmol) in THF (4 ml_) with fBuLi (1.7 M in pentane, 5.45 mL, 9.27 mmol) during 80 min at -78°C.
  • CuCN 210 mg, 2.34 mmol
  • THF 5 mL
  • BF 3 etherate 115 ⁇ L, 0.914 mmol
  • thioglycoside A-Vl (228 mg, 0.292 mmol) and glycosyl acceptor B-Il (129 mg, 0.225 mmol) in dry CH 2 CI 2 (8 ml_) were added via syringe to activated 3A molecular sieves (2 g).
  • a suspension of DMTST (177 mg, 0.685 mmol) and activated 3A molecular sieves (1 g) in CH 2 CI 2 (4 ml_) was prepared in a second flask. Both suspensions were stirred at r.t. for 4 h, then the DMTST suspension was added via syringe to the other suspension with some additional CH 2 CI 2 (2 ml_).
  • B-III (100 mg, 77.7 ⁇ mol) was hydrogenated with Pd(OH) 2 /C (52 mg, 10% Pd) in dioxane/H 2 O (4:1 , 3.75 ml.) according to general procedure D. After 24 h the mixture was filtered through celite and hydrogenated with fresh Pd(OH) 2 /C (50 mg) for another 48 h. The reaction mixture was filtered through celite and evaporated to dryness. The residue was redissolved in methanol (5 ml.) and sodium methoxide (194 ⁇ mol in 190 ⁇ l MeOH) was added. After stirring at r.t. for 16 h the reaction was quenched by addition of acetic acid (22 ⁇ L). The mixture was concentrated in vacuo and purified by preparative, reversed-phase HPLC to afford B-IV (40.5 mg, 72%) as a colorless solid.
  • thioglycoside A-Vl (218 mg, 0.279 mmol) and glycosyl acceptor C-Il (126 mg, 0.215 mmol) in dry CH 2 CI 2 (8 ml_) were added via syringe to activated 3A molecular sieves (2 g).
  • a suspension of DMTST (166 mg, 0.644 mmol) and activated 3A molecular sieves (1 g) in CH 2 CI 2 (4 ml_) was prepared in a second flask. Both suspensions were stirred at r.t. for 4.5 h, then the DMTST suspension was added via syringe to the other suspension with some additional CH 2 CI 2 (2 ml_). The reaction was stopped after 65.5 h and work-up and purification according to general procedure C afforded C-III (224 mg, 80%) as a colorless foam.
  • A-IV (106 mg, 0.189 mmol) was dissolved in CH 2 CI 2 (5 mL) and Grubbs cat. 2 nd gen. (16.0 mg 18.8 ⁇ mol) and methyl acrylate (171 ⁇ l_, 1.90 mmol) were added. The reaction was heated under reflux for 9 d. After 1 d, 2 d and 7 d additional Grubbs cat. 2 nd gen. (each 16.0 mg, 18.8 ⁇ mol) and methyl acrylate (each 171 ⁇ l_, 1.90 mmol) were added.
  • thioglycoside A-Vl 47.9 mg, 61.3 ⁇ mol
  • glycosyl acceptor D-I 29.1 mg, 47.0 ⁇ mol
  • a suspension of DMTST 37.6 mg, 146 ⁇ mol
  • activated 3A molecular sieves 250 mg
  • CH 2 CI 2 (2 ml_) was prepared in a second flask. Both suspensions were stirred at r.t. for 4 h, then the DMTST suspension was added via syringe to the other suspension with some additional CH 2 CI 2 (1 mL).
  • D-III (46.0 mg, 34.4 ⁇ mol) was hydrogenated with Pd(OH) 2 /C (25 mg, 10% Pd) in dioxane/H 2 O (4:1 , 3.75 ml_) according to general procedure D. After 42 h the mixture was filtered through celite and hydrogenated with fresh Pd(OH) 2 /C (27 mg) for additional 24 h. The reaction mixture was filtered through celite and evaporated to dryness. The residue was redissolved in methanol (3 ml_) and sodium methoxide (51.6 ⁇ mol in 55 ⁇ l MeOH) was added. After stirring at r.t. for 16 h the reaction was quenched by addition of acetic acid (6 ⁇ l_). The mixture was concentrated in vacuo and purified by preparative, reversed-phase HPLC to afford D-III (19.2 mg, 73%) as a colorless solid.
  • rac-l 1 R2R5ff)-5-terf-Butyl-2-hvdiOxycvclohexyl benzoate (rac-E-VII).
  • rac-E-VI (135 mg, 0.287 mmol) was suspended in MeOH (5 ml_).
  • the solvents were evaporated in vacuo and the residue was purified by MPLC on silica (toluene/ethyl acetate, 6:0 to 6:1 ) affording rac-E-VII (63.2 mg, 80%) as a white solid.
  • Second compound (5 mg) was mixed with mPEG- nitrophenylcarbonate (5K) 75 mg , triethylamine 5 ul in DMF (2 ml_). The resulting mixture was stirred at rt for 3 h. The solvent was removed at reduced pressure. The residue was purified on C-18 to afford 40 mg product.
  • Second compound (20 mg) from Example 11 was mixed with 200 mg 4-arm PEG glutamidylsuccinate , triethylamine 5 ul and DMF 2 mL The resulting mixture was stirred at rt for 2 hr. After removing the solvent, the residue was purified on HPLC to afford the product.
  • E-selectin Protocol The inhibition assay to screen glycomimetic antagonists of E-selectin is a competitive binding assay, which allows the determination of IC50 values. Briefly, E-selectin/lg chimera is immobilized by incubation at 37 0 C in 96 well microtiter plates for 2 hours. To reduce nonspecific binding, bovine serum albumin is added to each well and incubated at room temperature for 2 hours. The plate is washed and serial dilutions of the test compounds are added to the wells in the presence of conjugates of biotinylated, sLe a polyacrylamide with streptavidin/horseradishperoxidase and incubated for 2 hours at room temperature.
  • the peroxidase substrate 3,3 ⁇ 5,5 1 tetramethylbenzidin (TMB) is added. After 3 minutes, the enzyme reaction is stopped by the addition of H 3 PO 4 and the absorbance of light at a wavelength of 450 nm is determined. The concentration of test compound required to inhibit binding by 50% is determined and reported as the IC50 value for each glycomimetic E-selectin antagonist. In addition to reporting the absolute IC5 0 value as measured above, relative IC 50 values are determined by a ratio of the IC 50 measured for the test compound to that of a glycomimetic internal control (reference) for each assay. The results from the testing in this assay of several of the compounds disclosed herein are shown below.

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CA2666103A1 (en) 2008-05-22
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US20080161546A1 (en) 2008-07-03
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