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WO2008011588A2 - Glycoconjugués d'alkylateurs de phosphoramidate pour le traitement du cancer - Google Patents

Glycoconjugués d'alkylateurs de phosphoramidate pour le traitement du cancer Download PDF

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Publication number
WO2008011588A2
WO2008011588A2 PCT/US2007/074012 US2007074012W WO2008011588A2 WO 2008011588 A2 WO2008011588 A2 WO 2008011588A2 US 2007074012 W US2007074012 W US 2007074012W WO 2008011588 A2 WO2008011588 A2 WO 2008011588A2
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Prior art keywords
glufosfamide
group
tetraacetyl
compound
formula
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PCT/US2007/074012
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English (en)
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WO2008011588A3 (fr
Inventor
Jian-Xin Duan
Jason Lewis
Hailong Jiao
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Threshold Pharmaceuticals, Inc.
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Publication of WO2008011588A2 publication Critical patent/WO2008011588A2/fr
Publication of WO2008011588A3 publication Critical patent/WO2008011588A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C07H11/04—Phosphates; Phosphites; Polyphosphates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention provides novel anti-cancer compounds, methods of making them, and methods for treating cancer and other hyperproliferative disease conditions with them, and so relates to the fields of medicine, pharmacology, chemistry, and biology.
  • Glufosfamide also known as ⁇ -D-glucosyl-ifosfamide mustard and glc- IPM, is a glycoconjugated prodrug of the phosphoramidate alkylator ifosfamide mustard and is useful in the treatment of cancer (US Pat. No. 5,662,936; PCT App. Pub. No. WO 05/76888; Niculescu-Duvaz, 2002, Curr. Opin. Investig. Drugs, 3:1527-32; Briasoulis et al., 2000, J. CHn.
  • glufosfamide ifosfamide mustard is covalently bonded to the 1 -position of a glucose molecule via a glycoside linkage. Glufosfamide is hydrolyzed in vivo to ifosfamide mustard and glucose. In contrast to ifosfamide, glufosfamide metabolism does not produce the neurotoxin acrolein and so promises to have fewer side effects than ifosfamide.
  • Glufosfamide can be synthesized starting with 2, 3, 4, 6-tetrabenzyl glucose (tetrabenzyl glucose), via tetrabenzyl glufosfamide and hydrogenolyzing the tetrabenzyl glufosfamide with palladized charcoal (Pd/C) and hydrogen (US Patent No. 5,622,936, supra). Because the hydrogenolysis involves a heterogenous reaction mixture, it is problematic for large scale manufacturing, and requires careful monitoring of temperature and hydrogen pressure to avoid decomposition of glufosfamide.
  • the present invention provides bromoglufosfamide having the structure shown below
  • the present invention provides bromoglufosfamide in substantially pure form and pharmaceutically acceptable formulations comprising bromoglufosfamide and pharmaceutically acceptable diluents or excipients.
  • the present invention provides a method of treating cancer and other hyperproliferative diseases comprising administering a therapeutically effective amount of bromoglufosfamide or pharmaceutically acceptable formulations thereof to a patient in need of such treatment.
  • the present invention provides methods of making bromoglufosfamide and glufosfamide.
  • the present invention provides a method of synthesizing glufosfamide, said method comprising the steps of: (i) reacting 1-hydroxytetraacyl glucose (tetraacyl glucose) having a structure of formula:
  • R 6 is selected from CrC 6 alkyl, CrC 6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; with trichloroacetonitrile and a base to obtain a tetraacyl trichloroacetamidate intermediate; (ii) reacting said tetraacyl trichloroacetamidate intermediate with ifosfamide mustard and optionally an acid to obtain a tetraacyl-1- ⁇ -glufosfamide intermediate having structure of formula:
  • step (iii) reacting said tetraacyl-1- ⁇ -glufosfamide obtained in step (ii) with M(OR 8 ) n wherein n is 1-3, M is a metal selected from the group consisting of alkali metals, alkaline earth metals, and lanthanide metals, and Re is CrC 6 alkyl, provided that, if M is an alkali metal, then n is 1 , and if M is an alkaline earth metal, then n is 2, and if M is a lanthanide metal, then n is 3; to synthesize said glufosfamide.
  • M is a metal selected from the group consisting of alkali metals, alkaline earth metals, and lanthanide metals
  • Re is CrC 6 alkyl
  • Section I provides useful definitions
  • Section Il in parts A and B describes in part A bromoglufosfamide and methods for its synthesis, and in part B a preferred method for making glufosfamide the method also being useful to make bromoglufosfamide upon appropriate substitution of starting material
  • Section III describes various methods of treatment employing bromoglufosfamide and the novel compounds of the present invention
  • Section IV provides illustrative examples of the compounds and methods of the invention. This detailed description is organized into sections only for the convenience of the reader, and disclosure found in any section is applicable to disclosure elsewhere in the specification. I. Definitions
  • a or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • Acid refers to either a Lewis acid or a Br ⁇ nsted acid.
  • a Lewis acid is a molecule or a moiety that can accept a pair of lone electrons from electron pair donors such as nitrogen, oxygen, and sulfur atoms.
  • Lewis acids include, metal halides and triflates such as aluminum, zinc, iron, hafnium, and lanthanum halides and triflates, trialkylsilyl triflates, and BF 3 (gaseous and etherate).
  • a Br ⁇ nsted acid is a molecule or a moiety that can donate a proton. Examples of Br ⁇ nsted acids include hydrogen halides, sulfuric acid, phosphoric acid, carboxylic acids, sulfonic acids, and salts of weak bases and strong acids like pyridinium triflates.
  • Acidifying or acidification refers to neutralizing bases present in a reaction mixture or a solution by adding an acid. Acids suitable for neutralizing a reaction mixture are chosen according to the base and a product present in a reaction mixture. Aqueous acids are used for acidifying unless the product is susceptible to aqueous hydrolysis. "Resin bound acids” such as resin bound sulfonic acids are acids useful in acidifying. Water can be used for acidifying depending on the pKa of the base neutralized.
  • Alkali metals refer to Li, Na, K, Rb, and Cs.
  • Alkaline earth metals refer to Mg, Ca, Sr, and Ba.
  • administering or “administration of a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self- administration, and/or indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self- administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • Alkoxide refers to a deprotonated alcohol moiety.
  • an alkoxide is a moiety having structure of formula RO(-), wherein ROH is the corresponding alcohol.
  • An alkoxide can be prepared by reacting the alcohol with a base such as alkali metal hydrides, alkali metals, and alkali metal amides.
  • CrC ⁇ alkoxy refers to a substituted or unsubstituted alkyl group of 1 - 6 carbon atoms covalently bonded to an oxygen atom.
  • a CrC 6 alkoxy group has the general structure -O-(CrC 6 )alkyl.
  • CrC ⁇ alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec- butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • CrC ⁇ alkyl refers to a substituted or unsusbstituted straight or branched chain alkyl groups having 1-6 carbon atoms.
  • CrC 6 alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3- methylpentyl.
  • a CrC 6 alkyl substituent may be covalently bonded to an atom within a molecule of interest via any chemically suitable portion of the CrC 6 alkyl group.
  • Aryl refers to a substituted or unsusbstituted moiety that includes one or more monocyclic or fused ring aromatic systems. Such moieties include any moiety that has one or more monocyclic or bicyclic fused ring aromatic systems, including but not limited to phenyl and naphthyl.
  • Base refers to either a Lewis base or a Br ⁇ nsted base.
  • a Lewis base is a molecule or a moiety that can donate a pair of lone electrons.
  • a Br ⁇ nsted base is a molecule or moiety that can accept a proton.
  • bases include metal hydrides, metal carbonates, metal amides, metal alkoxides, various trialkyl amines including hindered tertiary amines, amidines, and pyridines.
  • Compound refers not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active derivatives, including, but not limited to, salts, hydrates, solvates and the like.
  • Catalytic amount of a reactant or a reagent refers to an amount of reactant or reagent that is less than its stoichiometric amount calculated based on the balanced chemical equation for the reaction. For example, if 1 mmol of a reagent A is required, according to a balanced chemical equation, for a reaction with B, and 0.05 mmol of A is actually used in the reaction, then a catalytic amount of, 5 mole% of A, is used in the reaction.
  • Deprotection refers to a chemical reaction wherein a protecting group is removed (see “Protecting group” infra).
  • dialkyl azodicarboxylate include, but are not limited to, diethyl azodicarboxylate and diisopropyl azodicarboxylate (DIAD).
  • Disaccharide refers to a covalent dimer of monosaccharides formed upon the removal of one molecule of water from two monosaccharides.
  • Halogen or halo refers to fluorine, chlorine, bromine, and iodine.
  • Heteroaryl refers to a substituted or unsusbstituted monocyclic aromatic system having 5 or 6 ring atoms, or a fused ring bicyclic aromatic system having 8 - 20 atoms, in which the ring atoms are C, O, S, SO, SO 2 , or N and at least one of the ring atoms is a heteroatom, i.e., O, S, SO, SO 2 , or N.
  • Heteroaryl groups include, for example, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl
  • Heterocyclyl refers to a monocyclic or fused ring multicyclic cycloalkyl group at least a portion of which is not aromatic and in which one or more of the carbon atoms in the ring system is replaced by a heteroatom selected from O, S, SO, SO 2 , P, or N.
  • heterocyclyl groups include but are not limited to imidazolinyl, morpholinyl, piperidinyl, piperidin-2-only, piperazinyl, pyrrolidinyl, pyrrolidine-2-onyl, tetrahydrofuranyl, and tetrahydroimidazo [4,5-c] pyridinyl.
  • Hydrates refers to a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.
  • Lanthanide metals refer to rare earth metals or lanthanides such as La and Hf.
  • “Monosaccharide” refers to a monomeric carbohydrate having structure of formula [C(H 2 O)] m wherein m is 3-7 or their biologically relevant derivatives.
  • Metal carbonates refer to metal salts of carbonic acid. Examples of metal carbonates include, Li 2 CO 3 , Na 2 COs, K 2 CO 3 , Cs 2 CO 3 , and Ag 2 CO 3 .
  • Metal hydrides refer to salts consisting of metal cations and one or more hydride anions depending on the valency of the metal cations. Examples of metal hydrides include, NaH, KH, and CaH 2 .
  • Overall yield of a compound refers to the yield of the compound obtained after a sequence of reactions. For example, if A reacts to yield B in 50% yield and then B reacts to yield C in 50% yield, then the overall yield of C from A, in the sequence of reactions described, is 25%.
  • “Pharmaceutically acceptable carrier, excipient, or diluent” refers to a carrier, excipient, or diluent that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier, excipient, or diluent that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier, excipient, or diluent” as used in the specification and claims includes both one and more than one such carrier, excipient, or diluent.
  • Prodrug refers to a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property.
  • a pharmaceutically active compound can be modified chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes.
  • a prodrug may have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor, for example (see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
  • Protecting groups refer to groups or moieties covalently bonded to functional groups wherein the groups or moieties can be removed to yield the functional groups.
  • Protecting groups can be used in a reaction to avoid reaction at one or more functional groups while certain other functional group or groups react. Examples of protecting groups are provided for example in the reference Greene et al., Wiley-lnterscience, 3rd Ed. ,1999 (supra).
  • “Reduction” of a symptom or symptoms refers to decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • Solvate as used herein means a compound of the invention or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces in an amount of greater than about 0.3% when prepared according to the invention.
  • Substituent refers to an atom or group, including, for example, amino, C- 1 -C 6 alkylamino or di(Ci-C 6 )alkylamino, C 1 -C 6 alkoxy, CrC 6 alkylthio, aryl, - COOH, -CONH 2 , cyano, ethenyl, ethynyl, halo, heteroaryl, hydroxy, mono- or di(Ci-C 6 )alkylcarboxamido, mono or di(Ci-C 6 )alkylsulfonamido, nitro, -OSO 2 - (CrC 6 )alkyl, and -SO 2 NH 2 .
  • “Therapeutically effective amount" of a drug refers to an amount of a drug that, when administered to a subject with cancer or another hyperproliferative disease, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cancer or another hyperproliferative disease in the subject.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.
  • Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer or another hyperproliferative disease, diminishment of extent of disease, delay or slowing of disease progression, amelioration, palliation or stabilization of the disease state, and other beneficial results described below.
  • Trisubstituted phosphine refers to a compound having structure of formula P(R X ) 3 wherein each R x independently is selected from the group consisting of CrC 6 alkyl, CrC 6 heteroalkyl, C 3 -Cs cycloalkyl, heterocyclyl, aryl, heteroaryl, and CrC 6 alkoxy.
  • R x include, but are not limited to, PPh 3 , P((CH 2 ) 3 CH 3 )3, and PMe 3 .
  • HA Compounds
  • the present invention provides bromoglufosfamide having the structure shown below:
  • Bromoglufosfamide can be synthesized by reacting a suitably protected glucose derivative containing a 1-OH group with
  • Bromoglufosfamide can also be synthesized by reacting a suitably protected glucose derivative containing a 1-trichloroacetamidate group with
  • Glufosfamide is an anticancer drug and consists of a 1- ⁇ -D-glucosyl moiety covalently bonded to ifosfamide mustard and contains four other hydroxy groups.
  • ifosfamide mustard is covalently bonded to the 1 -position of glucose, the protected hydroxy groups are deprotected to yield glufosfamide.
  • Glufosfamide has been synthesized by starting with tetrabenzyl glucose via the tetrabenzyl-1- ⁇ -glufosfamide intermediate (US Patent No. 5,622,936, supra).
  • the benzyl groups are removed by hydrogenolysis using Pd/C. Because each molecule of protected glufosfamide contains four benzyl groups, up to 40 mole% Pd/C is used in the deprotection. It is expensive to perform the hydrogenolysis and produce glufosfamide due to the high costs of palladium.
  • the hydrogenolysis occurs under heterogenous reaction conditions, and because of the presence of the substantial amount of the insoluble catalyst, controlling the reaction conditions and filtering the reaction mixture after the reaction becomes problematic.
  • Employing diatomaceous earth (CELITE ® ) can result in the glufosfamide being absorbed in the CELITE ® and thus reducing reaction yield.
  • Acetyl and pivaloyl protected glucose ifosfamide mustard conjugates and methods of their synthesis are reported in US Patent No. 5,622,936, supra.
  • a 1-bromo group is used as a leaving group and is substituted by the ifosfamide mustard.
  • tetraacetyl- 1- ⁇ - glufosfamide is obtained in only about 5% yield and tetrapivaloyl-1- ⁇ - glufosfamide in about 13% yield from the corresponding 1 -bromotetraacyl glucose derivatives (columns 9 and 10, US Patent No. 5,622,936, supra).
  • Bromotetraacyl glucose derivatives are synthesized from, for example, the corresponding tetraacyl glucose derivatives.
  • the yield of synthesizing 1- bromotetrapivaloyl glucose from tetrapivaloyl glucose is reported to be about 55% (column 10, US Patent No. 5,622,936, supra). Therefore, while the yield of synthesizing tetrapivaloyl-1- ⁇ -glufosfamide from 1-bromotetrapivaloyl glucose is already low at about 13%, the overall yield of synthesizing tetrapivaloyl-1- ⁇ -glufosfamide from tetrapivaloyl glucose is even lower at about 8%. As a result, these methods are not efficient for production of tetraacyl-1 - ⁇ -glufosfamides.
  • the present invention provides methods in which a 1- trichloroacetamidate group is employed as a leaving group (instead of a 1- bromo group), and using the present methods, one can prepare tetraacetyl- 1- ⁇ -glufosfamide in an overall yields of at least about 70% (starting from the tetraacetyl glucose).
  • the yield of tetraacetyl-1- ⁇ -glufosfamide synthesized by employing a tetraacetyl trichloroacetamidate intermediate according to the present methods therefore is much higher, 70%, than that reported previously using the 1-bromo leaving group (at best about 5% overall yield from tetraacetyl glucose). Accordingly, the present methods offer significant advantage over prior methods used for preparing glufosfamide and its hydroxy protected intermediates.
  • the acetyl group present in the 2- position of the tetraacetyl trichloroacetamidate intermediate provides neighboring group assistance for the ifosfamide mustard to be covalently attached to the 1- position of the glucose moiety with the desired ⁇ - stereochemistry.
  • the trichloroacetamidate moiety is removed and the 1- position carbocation is stabilized by an acetyl (or another acyl group) as shown below in Scheme 1 :
  • the mustard reacts from the ⁇ -face and yields the product with the desired ⁇ - stereochemistry.
  • the present invention also provides methods for deprotecting tetraacetyl-1- ⁇ -glufosfamide that employ catalytic amounts of NaOMe in MeOH to provide glufosfamide in yields approaching or greater than 90%.
  • excess alkoxide is neutralized employing an acidic resin. Because the Na salts produced as a result of the neutralization remain resin bound, a filtration of the neutralized reaction mixture yields a solution of glufosfamide essentially free of inorganic impurities and avoids an aqueous work-up that can decompose glufosfamide.
  • the present invention also provides methods in which the reaction between the tetraacetyl trichloroacetamidate intermediate and ifosfamide mustard to form a tetraacetyl-1- ⁇ -glufosfamide is performed in the presence of acids and/or in a polar solvent. These methods are superior relative to other methods not employing an acid and/or a polar solvent because of cleaner reactions that produce lesser amounts of byproducts if at all.
  • acetyl groups are more electron withdrawing compared to benzyl groups, and a tetraacetyl trichloroacetamidate intermediate can react more slowly with ifosfamide mustard than does the corresponding tetrabenzyl trichloroacetamidate intermediate.
  • ifosfamide mustard can not replace the trichloroacetamidate group, the ifosfamide mustard can attack the ifosfamide mustard can attack the ifosfamide mustard.
  • the reaction rate of tetraacetyl trichloroacetamidate with ifosfamide mustard is enhanced by employing an acid catalyst that accelerates the removal of the trichloroacetamidate group relative to a reaction not employing an acid.
  • an acid catalyst that accelerates the removal of the trichloroacetamidate group relative to a reaction not employing an acid.
  • the Br ⁇ nsted acid can bind to the mustard and increase the acidity of the mustard compared to the unbound mustard.
  • the acidic proton of the bound mustard can protonate the trichloroacetamidate group and facilitate its removal.
  • the unbound mustard can attack the 1 -position and form the desired product (Schemes 1 and 2).
  • the use of a polar solvent like THF increases the solubility of ifosfamide mustard in the reacting solvent and accelerates the reaction between the mustard and the tetraacetyl trichloroacetamidate intermediate.
  • the present invention provides a method of synthesizing glufosfamide, said method comprising the steps of: (i) reacting 1- hydroxytetraacyl glucose (tetraacyl glucose) having a structure of formula: wherein R 6 is selected from CrC 6 alkyl, CrC 6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; with trichloroacetonitrile and a base to obtain a tetraacyl trichloroacetamidate intermediate; (ii) reacting said tetraacyl thchloroacetamidate intermediate with ifosfamide mustard and optionally an acid to obtain a tetraacyl-1- ⁇ -glufosfamide intermediate having structure of formula:
  • step (iii) reacting said tetraacyl-1- ⁇ -glufosfamide obtained in step (ii) with M(OR 8 ) n wherein n is 1-3, M is a metal selected from the group consisting of alkali metals, alkaline earth metals, and lanthanide metals, R 8 is CrC 6 alkyl, provided that, if M is an alkali metal, then n is 1 , and if M is an alkaline earth metal, then n is 2, and if M is a lanthanide metal, then n is 3, to synthesize said glufosfamide.
  • M is a metal selected from the group consisting of alkali metals, alkaline earth metals, and lanthanide metals
  • R 8 is CrC 6 alkyl, provided that, if M is an alkali metal, then n is 1 , and if M is an alkaline earth metal, then n is 2, and if M is a lanthanide
  • R 6 is selected from the group consisting of methyl, tert-butyl, ethyl, phenyl, and 4-methylphenyl. In another embodiment, R 6 is methyl, phenyl, and 4-methyl phenyl. In another embodiment, R 6 is methyl.
  • the base employed in step (i) is a non- nucleophilic base that can deprotonate the tetraacyl glucose faster than reacting with trichloroacetonitrile.
  • the base is selected from the group consisting of metal hydrides, metal carbonates, hindered tertiary amines, pyridines, and amidines.
  • the base is selected from metal hydrides, and metal carbonates.
  • the hindered tertiary amine is selected from the group consisting of triisopropyl amine, diisopropylethylamine, triethyl amine, and 2,2,6,6- tetraalkylpiperidine.
  • the amidine is DBU.
  • the acid used in step (ii) is a Lewis acid or a Bronsted acid whose conjugate base is non-nucleophilic. In another embodiment, a catalytic amount of the acid is employed.
  • Other reagents that can be used according to the present methods in place of M(ORs) n in step (iii) include amines in R 8 OH solvents. Examples of useful amines include NH 3 , amines, alkylamines, dialkylamines, and trialkylamines.
  • the reacting in the step (iii) is performed in a solvent and the glufosfamide synthesized is in solution in the solvent.
  • the solution of glufosfamide is alkaline due to the presence of M(ORs) and is neutralized by acidifying. Volatiles are removed from the neutralized glufosfamide solution to obtain solid glufosfamide.
  • the glufosfamide obtained can be purified by column chromatography and/or recrystallization.
  • the acidifying is performed with a resin bound acid.
  • the acidifying is performed with a resin bound sulfonic acid or a resin bound carboxylic acid.
  • the present invention provides a method of synthesizing glufosfamide, said method comprising the steps of: (i) reacting 1-hydroxytetraacetyl glucose (tetraacetyl glucose) having structure of formula:
  • trichloroacetonitrile and a base to obtain a tetraacetyl trichloroacetamidate intermediate, wherein said base is selected from metal hydrides and metal carbonates;
  • step (iii) reacting said tetraacetyl-1- ⁇ -glufosfamide obtained in step (ii) with M(ORs) n wherein n, M, and R 8 are defined as above; to synthesize said glufosfamide.
  • the metal hydride used in step (i) is selected from the group consisting of NaH, KH, and CaH 2 .
  • the reacting in step (ii) is performed employing tetrahydrofuran as a solvent.
  • the acid used in step (ii) is selected from the group consisting of trimethylsilyl thflate, triethylsilyl triflate, and silver triflate.
  • the acid used in step (ii) is trimethylsilyl triflate.
  • a catalytic amount of the acid is used in step (ii).
  • molecular sieves are employed in step (ii) to keep the reacting moisture free.
  • the molecular sieve employed is AW 300.
  • the tetraacetyl-1- ⁇ -glufosfamide obtained in step (ii) is purified before the reacting in step (iii).
  • the purification is performed by column chromatography.
  • the column chromatography is performed using silica gel.
  • the purification is performed by crystallization.
  • the purified tetraacetyl-1- ⁇ -glufosfamide is obtained in an overall yield of at least 10% starting from the tetraacetyl glucose.
  • the overall yield of the purified tetraacetyl -1- ⁇ -glufosfamide is 20% - 80%.
  • M is selected from the group consisting of Na, K, and Mg
  • R 8 is selected from the group consisting of CH 3 , C 2 H 5 , (CH 3 ) 2 CH, and C(Me) 3
  • the M(ORs) n reacted in step (iii) is a catalytic amount of M(ORs) n and the reacting in step (iii) is performed in a solvent having a structure of formula R 8 OH wherein Re is CrC ⁇ alkyl.
  • the catalytic amount is 5-30 mole% of the M(ORs) n -
  • Rs is Me.
  • reagents that can be used according to the present methods in place of M(ORs) n in step (iii) include amines in R 8 OH solvents.
  • useful amines include NH 3 , amines, alkylamines, dialkylamines, and trialkylamines.
  • the reacting in the step (iii) is performed in a solvent and the glufosfamide synthesized is in solution in the solvent.
  • the solution of glufosfamide is alkaline due to the presence of M(OR 8 ) and is neutralized by acidifying.
  • the acidifying is performed with a resin bound acid.
  • the acidifying is performed with a resin bound sulfonic acid or a resin bound carboxylic acid.
  • the resin bound sulfonic acid is Dowex. Volatiles are removed from the glufosfamide solution (pre- or post-acidifying) to obtain glufosfamide in the solid form.
  • the glufosfamide, in solution and in the solid form can be purified by column chromatography and/or recrystallization.
  • the glufosfamide is synthesized in an overall yield of at least 10% starting from the tetraacetyl glucose. In another embodiment, the glufosfamide is synthesized from the tetraacetyl-1- ⁇ - glufosfamide in at least 40% yield.
  • the glufosfamide synthesized is up to 95% or more pure. In certain related embodiments, the glufosfamide contains up to 2%, up to 5%, and up to 10% of the undesired ⁇ -isomer of glufosfamide. In another embodiment, the glufosfamide obtained is purified by chromatography and/or recrystallization.
  • the present invention provides a method of treating cancer and other hyperproliferative diseases comprising administering a therapeutically effective amount of bromoglufosfamide or another novel compound of the present invention to a patient in need of such treatment.
  • Novel compounds of the present invention other than bromoglufosfamide are described in Example 1 in the EXAMPLES section below.
  • the daily dose is administered as a pharmaceutically acceptable formulation.
  • the present invention provides a pharmaceutical formulation comprising bromoglufosfamide or another novel compound of the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the pharmaceutically acceptable diluent is water, saline, or aqueous dextran.
  • Suitable methods for formulation of drugs generally are known in the art and can be used for formulating the novel compounds of the present invention upon appropriate substitution of the drug. See, e.g., Ansel et al., 1999, Pharmaceutical Dosage Forms and Drug Delivery Systems 7th ed. Lippincott Williams & Wilkins, Philadelphia: pp. 1-562; Marshall, 1979.”SoNd Oral Dosage Forms," MODERN PHARMACEUTICS, Vol. 7, (Banker and Rhodes, editors), pp. 359-427.
  • the therapeutically effective amount is administered in a daily dose. In another embodiment, the therapeutically effective amount of the compound is administered in daily doses of about 2.5 g/m 2 - about 8 g/m 2 ; about 3 g/m 2 - about 7 g/m 2 ; about 4 g/m 2 - about 6 g/m 2 ; and about 4.5 g/m 2 .
  • the therapeutically effective daily dose can be administered by employing suitable unit dose forms of the novel compounds of the present invention.
  • the compound is administered in unit dose forms of about 0.5 g - about 5 g and about 1 g - 2 g.
  • the daily dose is administered from once every day, once every two weeks, up to, once every month. In another embodiment, the treatment is continued for a week, a month, a year, or until there is reduction of symptoms, stabilization of the disease state, or slowing of disease progression. In another embodiment, the daily dose is administered parenterally. In another embodiment, the daily dose is administered orally.
  • the novel compound of the present invention is administered in combination with one or more anti-cancer agent or anti-cancer therapy.
  • anti-cancer agents useful for use in accordance with the present invention and their therapeutically effective administration are provided for example and without limitation, in the product descriptions found in the Physicians' Desk Reference, 2003, 57th Ed., Medical Economics Company, Inc., Oradell, N.J; Goodman & Gilman's The Pharmacological Basis of Therapeutics" 2001 , 10 th Edition, McGraw-Hill, New York; and/or are available from the Federal Drug Administration and/or are discussed in the medical literature.
  • various cancers can be treated by administering bromoglufosfamide and other novel compounds of the present invention.
  • the cancer treated is selected from the group consisting of cancer of the adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid.
  • the cancer treated is selected from the group consisting of acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and in situ carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell tumor, glioblastoma multiforma, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid, malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic and other sarcoma, ovarian tumor, pheochromocytoma, polycythemia ver
  • bromoglufosfamide and other novel compounds of the present invention are administered for the treatment of cancer in combination with other anti-cancer agents or other anti-cancer therapies. Suitable other anti-cancer agents, and their administration, useful according to the present methods to treat cancer is described for example in Physicians' Desk Reference, 2003, 57th Ed. (supra).
  • bromoglufosfamide and other novel compounds of the present invention are administered to treat pancreatic cancer as described in US patent application nos. 60/910,403 and 60/915,882 (each of which is incorporated herein by reference), upon appropriate substitution of glufosfamide with bromoglufosfamide or another novel compound of the present invention.
  • the present invention provides a method of treatment of non-cancer hyperproliferative diseases characterized by cellular hyperproliferation (e.g., an abnormally increased rate or amount of cellular proliferation).
  • the hyperproliferative disease is selected from the group consisting of allergic angiitis and granulomatosis (Churg- Strauss disease), asbestosis, asthma, atrophic gastritis, benign prostatic hyperplasia, bullous pemphigoid, coeliac disease, chronic bronchitis and chronic obstructive airway disease, chronic sinusitis, Crohn's disease, demyelinating neuropathies, dermatomyositis, eczema including atopic dermatitis, eustachean tube diseases, giant cell arteritis, graft rejection, hypersensitivity pneumonitis, hypersensitivity vasculitis (Henoch-Schonlein purpura), irritant dermatitis, inflammatory hemolytic anemia, inflammatory neutropen
  • the hyperproliferative disease treated is psoriasis, a disease characterized by the cellular hyperproliferation of keratinocytes which builds up on the skin to form elevated, scaly lesions.
  • the hyperproliferative disease treated is multiple sclerosis, a disease characterized by progressive demyelination in the brain.
  • the hyperproliferative diseases treated is rheumatoid arthritis, a multisystem chronic, relapsing, inflammatory disease that can lead to destruction and ankylosis of joints affected.
  • the compounds of the present invention are administered to prevent a hyperproliferative disease resulting from cellular proliferation on a prosthesis implanted in a subject by coating the prosthesis with a composition containing a compound of the present invention.
  • the present invention provides methods for treating cancer in a cancer patient comprising a preliminary assessment of the cancer patient to determine the degree of susceptibility of the patient's cancer to drug therapy mediated by bromoglufosfamide and other novel compounds of the present invention.
  • the degree of susceptibility of a cancer to drug therapy mediated by a novel compound of the present invention can be measured by determining the uptake of the compound in cancer cells and comparing the uptake with a predetermined value. Methods for determining cellular uptake of other glycoconjugates are described in PCT Pat. Pub. No. WO 04/081181 (incorporated herein by reference) and can be used in the present methods upon appropriate substitution of the glycoconjugate by the compounds of the present invention.
  • Example 1 provides novel compounds of the invention having structure of formula selected from the group consisting of Formulas (I), (II), and (III):
  • X is halo; and each Ri independently is selected from H and methyl.
  • R 4 is selected from the group consisting of:
  • R 4 is selected from the group consisting of:
  • R 4 is selected from the group consisting of 1- glucosyl, 1-mannosyl, 1 -galactosyl, 1-fucosyl, and 1-rhamnosyl.
  • the novel compounds have structures of formula:
  • Example 1 The compounds provided in Example 1 can be synthesized as described below.
  • the present invention provides a method of synthesizing the compound of Formula (I) comprising the steps of:
  • R 3 is selected from the group consisting of CH 2 Rs, CH(Rs) 2 , C(Rs) 3 , and COR 6 ;
  • R 7 is selected from the group consisting of CH 2 R 5 , CH(R 5 ) 2 , and
  • R 6 is selected from the group consisting of C r C 6 alkyl, C r C 6 heteroalkyl, C 3 -Cs cycloalkyl, hetreocyclyl, aryl, and heteroaryl; a trisubstituted phosphine; and a dialkyl azodicarboxylate;
  • step (ii) contacting the product obtained in step (i) and an alkylator having structure of formula:
  • step (iii) converting each of the OR 3 group in the intermediate obtained in step (ii), to an OH group, to yield the compound of Formula (I).
  • the converting in step (iii) involves a deprotection reaction.
  • the present present invention provides a method wherein R 3 is benzyl; the trisubstituted phosphine is PPh 3 ; the dialkyl azodicarboxylate is selected from diisopropyl and diethyl azodicarboxylate; the alkylator has the structure of formula: and the converting in step (iii) to yield the compound is carried out by reacting the intermediate obtained in step (ii) with palladized charcoal, and hydrogen.
  • the present invention provides a method of synthesizing the compound of Formula (II) comprising:
  • each R 3 is independently selected from the group consisting of CH 2 R 5 , CH(R 5 ) 2 , C(R 5 ) 3 , and COR 6 ;
  • R 7 is selected from the group consisting of CH 2 Rs, CH(R 5 ) 2 , C(Rs) 3 ; each R 5 independently is aryl; and each R 6 is independently selected from the group consisting of CrC 6 alkyl, CrC 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl; with a trisubstituted phosphine; and a dialkyl azodicarboxylate;
  • step (ii) contacting the product obtained in step (i) and an alkylator having the formula:
  • the present present invention provides a method wherein R 3 is benzyl; the trisubstituted phosphine is PPh 3 ; the dialkyl azodicarboxylate is selected from diisopropyl and diethyl azodicarboxylate; and the converting in step (iii) to yield the compound is carried out by reacting the intermediate obtained in step (ii) with palladized charcoal, and hydrogen.
  • the present invention provides a method of synthesizing a compound having the formula of Formula (III) comprising:
  • each R 3 is independently selected from the group consisting Of CH 2 Rs, CH(R 5 ) 2 , C(R 5 ) 3 , and COR 6 ;
  • R 7 is selected from the group consisting of CH 2 R 5 , CH(R 5 ) 2 , C(R 5 ) 3 ; each R 5 independently is aryl; and each R 6 is independently selected from the group consisting of CrC 6 alkyl, CrC- 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl; with a trisubstituted phosphine; and a dialkyl azodicarboxylate;
  • step (ii) contacting the product obtained in step (i) and an alkylator having the formula:
  • the present present invention provides a method wherein R 3 is benzyl; the trisubstituted phosphine is PPh 3 ; the dialkyl azodicarboxylate is selected from diisopropyl and diethyl azodicarboxylate; and the converting in step (iii) to yield the compound is carried out by reacting the intermediate obtained in step (ii) with palladized charcoal, and hydrogen.
  • Example 1 The methods described in Example 1 can be used for synthesizing glufosfamide upon appropriate substitution of starting material.
  • the protected monosaccharide or disaccharide is selected from the group consisting of: wherein R 3 is selected from the group consisting of CH 2 Rs, CH(R 5 ) 2 , C(R 5 ) 3 , and COR 6 ; and R 7 is selected from the group consisting of CH 2 Rs, CH(Rs) 2 , C(Rs) 3 - In another embodiment, each R 3 and R 7 is benzyl. In another embodiment, R 3 is acetyl.
  • a novel compound of the present invention can be synthesized comprising the steps of, reacting a compound having structure of formula selected from the group consisting of Formulas (IV), (V), and (Vl) and a compound having structure of formula selected from the group consisting of:
  • R 3 is selected from the group consisting of CH 2 R 5 , CH(Rs) 2 , C(R 5 ) 3 , and COR 6 ;
  • R 7 is selected from the group consisting of CH 2 R 5 , CH(R 5 ) 2 , C(R 5 ) 3 wherein R 5 and R 6 are defined as above to yield an intermediate and converting the intermediate to a novel compound of the present invention.
  • each R 3 and R 7 is benzyl.
  • R 3 is acetyl.
  • the reaction further comprises an acid.
  • the acid is CF 3 SO 3 H or CF 3 CO 2 H.
  • Novel compounds of the invention Compounds iv and v, and bromoglufosfamide was synthesized starting from 2,3,4,6-tetra-O-benzyl-D- glucose (or tetrabenzyl glucose) as described below.
  • Phenyldichlorophosphate (1.66 ml, 11.15 mmol) was added to a suspension of R-2-chloro-1-methyl-ethylamine hydrobromide (2.9 g, 22.3 mmol) in dichloromethane (DCM, 60 ml) at O 0 C, followed by the drop wise addition of triethylamine (TEA, 7.8 ml, 55.8 mmol), and the reaction mixture was stirred vigorously. The reaction mixture was warmed up to room temperature (rt), stirred for 2 hour (h), poured into brine, and the DCM layer separated. The aqueous layer was extracted with DCM and the combined DCM layers were dried over anhydrous MgSO 4 and concentrated to yield a residue.
  • DCM dichloromethane
  • TEA triethylamine
  • Bromoglufosfamide having a structure of formula: was synthesized and separated according to the method described above, by reacting 2,3,4,6-tetra-O-benzyl-D-glucose (349 mg) PPh 3 (169 mg), DIAD (125 ⁇ L) and bromoifosfamide mustard (100 mg) to yield tetrabenzylbromoglufosfamide having a structure of formula:
  • Bromoglufosfamide was also synthesized starting from 2,3,4,6- tetraacetyl glucose as described below.
  • DIAD 2,3,4,6-tetraacetyl glucose (200 mg), bromoifosfamide mustard (178 mg), and PPh 3 (300 mg) maintained at rt and the mixture stirred for 16 h. Then, the volatiles were evaporated and the residue separated by column chromatography in silica gel using acetone/ toluene (0-80%) to yield ⁇ -tetraacetylbromoglufosfamide (86 mg) containing trace amounts of the ⁇ -isomer that was used for deprotection without further separation.
  • the ⁇ -tetraacetylbromoglufosfamide thus obtained was dissolved in anhydrous methanol and a catalytic amount of NaOMe added to it.
  • the pH of the reaction mixture was measured to be about 10.
  • the reaction mixture was filtered though a bed of Amberlite resin (acidic form). The filtrate was concentrated, and the residue separated by column chromatography in silica gel using methanol/ DCM (10-20%) to yield bromoglufosfamide.
  • reaction mixture was stirred at rt for 30 min and poured into a saturated NaHCO 3 solution and extracted with ethyl acetate (EtAc).
  • EtAc ethyl acetate
  • the EtAc portion was concentrated in vacuo and the residue separated by column chromatography in silica gel using acetone/ toluene (0- 90%) to yield bromoglufosfamide.
  • This example describes the synthesis of tetraacetyl glucose, a tetraacyl glucose intermediate employed in the present invention, starting from pentaacetyl glucose which can be readily synthesized by reacting glucose with acetic anhydride and pyridine.
  • benzyl amine BnNH 2
  • method B NaOMe/MeOH
  • Tetraacetyl-1- ⁇ -glufosfamide, a tetraacyl-1- ⁇ -glufosfamide intermediate employed in the present methods is synthesized in high yields by reacting tetraacetyl glucose with trichloroacetonitrile and NaH to yield the tetraacetyl trichloroacetamidate intermediate, and reacting without further purification the trichloroacetamidate intermediate with ifosfamide mustard and trimethylsilyl triflate in anhydrous THF as described in Method A below to obtain tetraacetyl-1 - ⁇ -glufosfamide.
  • Method A
  • Trichloroacetonitrile (0.6 ml_, 5.7 mmol) was added to a solution of tetraacetyl glucose (Compound vi, 0.53 g, 1.5 mmol) in anhydrous THF (4 ml_) maintained at -1O 0 C followed by the addition of NaH (21.3 mg).
  • the temperature of the reaction mixture was raised to rt and stirred for 30 min.
  • the temperature of the reaction mixture was reduced to O 0 C, alumina (0.8 g) added to the reaction mixture, the temperature of the reaction mixture raised to rt and stirred for 30 min.
  • the reaction mixture was filtered, and the residue washed with anhydrous THF (2mL).
  • Tetraacetyl-1- ⁇ - glufosfamide was also synthesized by reacting glufosfamide (1 g) with acetic anhydride (3 ml_) and pyridine (6 ml_) at rt for 1 h. After removing the volatiles and coevaporating the residue with toluene, the residue was separated by flash column chromatography in silica gel employing acetone/toluene (0-80%) as eluent to obtain 1.2 of the tetraacetyl- 1- ⁇ -glufosfamide.
  • This example demonstrates an efficient method of deprotecting acetyl groups in particular and acyl groups in general by employing a catalytic amount of MeO(-)/MeOH for the synthesis of glufosfamide.
  • Glufosfamide adsorbed on the silica was separated by flash column chromatography in silica gel employing water/MeCN (0-15%) as eluent to obtain 560 mg of glufosfamide in 89% yield starting from tetraacetyl-1- ⁇ -glufosfamide.
  • H460 cells ATCC HTB-177 (NCI-H460), 20,000 cells/well/500 ⁇ l
  • RPMI medium Invitrogen Corporation, Carlsbad, CA.
  • these plates were divided into 2 groups - a "control group” and a 2 h "treatment group” where the cells were kept in contact with the test compound for 2 h.
  • the cells were rinsed to remove the test compound and incubated for 3 days and stained with AlamarBlue.

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Abstract

L'invention concerne le bromoglufosfamide et des composés apparentés qui utiles dans le traitement du cancer et autres maladies hyperprolifératives. Le glufosfamide et le bromoglufosfamide sont synthétisés par la réaction des dérivés tétraacétylés correspondants avec MeOH et une quantité catalytique de MeO(-). Le tétraacétyl glufosfamide est obtenu par la réaction d'un intermédiaire tétraacétyl trichloroacétamidate de glucose, l'ifosfamide moutarde, et d'un acide dans un solvant polaire anhydre.
PCT/US2007/074012 2006-07-20 2007-07-20 Glycoconjugués d'alkylateurs de phosphoramidate pour le traitement du cancer WO2008011588A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009086720A1 (fr) * 2008-01-09 2009-07-16 Suzhou Harmony Biotechnology Co., Ltd Diamide de l'acide 2,3,4,6-tétra-o-acétyl-d-glucopyranosyl-[n,n'-di-(2-chloroéthyl)] phosphorique, ses méthodes de préparation, et ses utilisations
WO2011079494A1 (fr) * 2009-12-30 2011-07-07 苏州天人合生物技术有限公司 Dérivés de saccharides didésoxy halogénés, procédé de préparation et utilisation de ceux-ci
US8003625B2 (en) 2005-06-29 2011-08-23 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US8552048B2 (en) 2006-12-26 2013-10-08 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs for the treatment of cancer
WO2019118486A1 (fr) * 2017-12-11 2019-06-20 Cerecor Inc. Promédicaments à base de phosphoramidate de monosaccharide
WO2025026214A1 (fr) * 2023-07-28 2025-02-06 深圳艾欣达伟医药科技有限公司 Traitement de la mutation du gène p53 ou de patients atteints d'un cancer négatif et d'une tumeur

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5306727A (en) * 1993-04-30 1994-04-26 Research Corporation Technologies, Inc. Phosphoramidates useful as antitumor agents
US5622936A (en) * 1988-10-20 1997-04-22 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Tumor inhibiting saccharide conjugates
US6506739B1 (en) * 2001-05-01 2003-01-14 Telik, Inc. Bis-(N,N'-bis-(2-haloethyl)amino)phosphoramidates as antitumor agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622936A (en) * 1988-10-20 1997-04-22 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Tumor inhibiting saccharide conjugates
US5306727A (en) * 1993-04-30 1994-04-26 Research Corporation Technologies, Inc. Phosphoramidates useful as antitumor agents
US6506739B1 (en) * 2001-05-01 2003-01-14 Telik, Inc. Bis-(N,N'-bis-(2-haloethyl)amino)phosphoramidates as antitumor agents

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US9226932B2 (en) 2005-06-29 2016-01-05 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8003625B2 (en) 2005-06-29 2011-08-23 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8507464B2 (en) 2005-06-29 2013-08-13 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8664204B2 (en) 2005-06-29 2014-03-04 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8552048B2 (en) 2006-12-26 2013-10-08 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs for the treatment of cancer
WO2009086720A1 (fr) * 2008-01-09 2009-07-16 Suzhou Harmony Biotechnology Co., Ltd Diamide de l'acide 2,3,4,6-tétra-o-acétyl-d-glucopyranosyl-[n,n'-di-(2-chloroéthyl)] phosphorique, ses méthodes de préparation, et ses utilisations
WO2011079494A1 (fr) * 2009-12-30 2011-07-07 苏州天人合生物技术有限公司 Dérivés de saccharides didésoxy halogénés, procédé de préparation et utilisation de ceux-ci
JP2013515750A (ja) * 2009-12-30 2013-05-09 蘇州天人合生物技術有限公司 ハロゲン化ジデオキシ糖誘導体ならびにその調製方法および応用
KR101478758B1 (ko) 2009-12-30 2015-01-02 수저우 하모니 바이오테크놀로지 컴퍼니 리미티드 할로겐화 다이디옥시글루코오스 유도체 및 그 제조방법과 그 용도
US9296774B2 (en) 2009-12-30 2016-03-29 Suzhou Harmony Biotechnology Co., Ltd. Halogenated dideoxy sugar derivates, preparation method and application thereof
WO2019118486A1 (fr) * 2017-12-11 2019-06-20 Cerecor Inc. Promédicaments à base de phosphoramidate de monosaccharide
WO2025026214A1 (fr) * 2023-07-28 2025-02-06 深圳艾欣达伟医药科技有限公司 Traitement de la mutation du gène p53 ou de patients atteints d'un cancer négatif et d'une tumeur

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