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EP1699806A1 - Composes mimetiques du glycosaminoglycane (gag) - Google Patents

Composes mimetiques du glycosaminoglycane (gag)

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Publication number
EP1699806A1
EP1699806A1 EP04802102A EP04802102A EP1699806A1 EP 1699806 A1 EP1699806 A1 EP 1699806A1 EP 04802102 A EP04802102 A EP 04802102A EP 04802102 A EP04802102 A EP 04802102A EP 1699806 A1 EP1699806 A1 EP 1699806A1
Authority
EP
European Patent Office
Prior art keywords
compound
ome
mhz
compounds
deoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04802102A
Other languages
German (de)
English (en)
Inventor
Robert Hugh Don
Vito Ferro
Ian Bytheway
Siska Cochran
Jon Krueger Fairweather
Edward Timothy Hammond
Tomislav Karoli
Cai Ping Li
Ligong Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Progen Industries Ltd
Original Assignee
Progen Industries Ltd
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Filing date
Publication date
Priority claimed from AU2003907107A external-priority patent/AU2003907107A0/en
Application filed by Progen Industries Ltd filed Critical Progen Industries Ltd
Publication of EP1699806A1 publication Critical patent/EP1699806A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/08—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium
    • C07H5/10—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium to sulfur
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
    • 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
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • 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
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms

Definitions

  • the invention that is the subject of this application lies in the area of compounds that mimic the structure of certain carbohydrates. More particularly, the invention lies in the area of glycosaminoglycan (GAG) mimetics. Specifically, the invention relates to compounds comprising at least one charged group that are designed to mimic the structure of GAGs. The invention also relates to methods for the preparation of the compounds, compositions comprising the compounds, and use of the compounds and compositions thereof for the antiangiogenic, antimetastatic, anti-inflammatory, anticoagulant, antithiOmbotic, and/or antimicrobial treatment of a mammalian subject.
  • GAG glycosaminoglycan
  • the invention further relates to the use ofthe compounds and compositions thereof in the treatment of a mammalian subject having a condition amenable to treatment with such agents.
  • GAGs Glycosaminoglycans
  • ECM extracellular matrix
  • GAG mimetics molecules that mimic the structure of certain GAGs — which molecules are referred to as “GAG mimetics” — can bind to GAG-binding proteins and modulate their biological activity: e.g., the activation of AT-III by various pentasaccharides [7,8], or the activation of fibroblast growth factors (FGFs) by sucrose octasulfate [9].
  • FGFs fibroblast growth factors
  • anticancer agents that have been developed to target HS-binding angiogenic growth factors include polysulfonated compounds [10], suramin and the related suradistas [11], and sulfated oligosaccharides [12,13].
  • the present invention relates to novel, small molecule GAG mimetics that bind to GAG-binding proteins and modulate their functions.
  • the compounds incorporate at least one negatively charged group (preferably a sulfo group) to interact with the positively charged residues in the GAG-binding site of the target proteins, and also contain one or more substituents to form interactions with other protein residues in and around the above-mentioned binding site.
  • a pharmaceutical or veterinary composition for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection, which composition comprises at least one compound according to the first embodiment together with a pharmaceutically or veterinarially acceptable carrier or diluent for said at least one compound.
  • a pharmaceutically or veterinarially acceptable carrier or diluent for said at least one compound.
  • a compound according to the first embodiment in the manufacture of a medicament for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection.
  • two ofthe groups Ri to R 5 may be connected to each other to form a bicyclic strucure; or the cyclic structure of formula I may contain a double bond, i.e., two contiguous XRi to XR 5 groups may be bonds.
  • Preferred compounds ofthe invention have the general structures of formulae III— VI, as defined in Tables 1-4 below. In order that the invention may be more readily understood and put into practice, one or more preferred embodiments thereof will now be described, by way of example only.
  • GAG glycosaminoglycan HS heparan sulfate FGF fibroblast growth factor aFGF acidic fibroblast growth factor (or FGF-1) bFGF basic fibroblast growth factor (or FGF-2) NEGF vascular endothelial growth factor SPR surface plasmon resonance HSN herpes simplex virus
  • FGF-1 FGF acidic fibroblast growth factor
  • FGF-2 FGF basic fibroblast growth factor
  • NEGF vascular endothelial growth factor SPR surface plasmon resonance HSN herpes simplex virus
  • GAG mimetics of the invention can be synthesised using a number of different routes, including the Ugi reaction, and generally incorporating sulfonation in the process.
  • Preferred compounds according to the first embodiment of the invention as defined above include those embraced by generic structures I and II and those included in Tables 1-4 below.
  • the compounds according to the invention have utility in the prevention or treatment in mammalian subjects of a disorder resulting from angiogenesis, metastasis, inflammation, microbial infection, coagulation or thrombosis.
  • the compounds have particular utility in the treatment of the foregoing disorders in humans.
  • the compounds are typically administered as a component of a pharmaceutical composition as described in the following paragraphs.
  • Pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form.
  • a tablet can include a solid carrier such as gelatine or an adjuvant or an inert diluent.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, a mineral oil or a synthetic oil.
  • compositions according to the invention can further include a pharmaceutically or veterinarially acceptable excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant or any other material known to those of skill in the art.
  • compositions typically include such substances so as to maintain the composition at a close to physiological pH or at least within a range of about pH 5.0 to about pH 8.0.
  • compositions according to the invention can also include active ingredients in addition to the at least one compound. Such ingredients will be principally chosen for their efficacy as antiangiogenic, antimetastatic, anti-inflammatory, anticoagulant, antithrombotic, antimicrobial agents but can be chosen for their efficacy against any associated condition.
  • derivatives of the compounds includes salts, coordination complexes with metal irons such as Mn 2+ and Zn 2+ , esters such as in vivo hydrolysable esters, free acids or bases, hydrates, or prodrugs.
  • Compounds having acidic groups such as phosphates or sulfates can form salts with alkaline or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl) amine.
  • Salts can also be formed between compounds with basic groups, such as amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid.
  • inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid
  • organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid.
  • Compounds having both acidic and basic groups can form internal salts.
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques that will be well known to those of skill in the art.
  • Prodrug derivatives ofthe compounds ofthe invention can be transformed in vivo or in vitro into the parent compounds.
  • prodrugs are glycolipid derivatives in which one or more lipid moieties are provided as substituents on the moieties, leading to the release of the free form of the compound by cleavage with an enzyme having phospholipase activity.
  • Prodrugs of compounds of the invention include the use of protecting groups which may be removed in vivo to release the active compound or serve to inhibit clearance of the drug. Suitable protecting groups will be known to those of skill in the art and include an acetate group.
  • the uses of the compounds include the treatment of angiogenesis-dependent diseases such as angiogenesis associated with the growth of solid tumours, and proliferative retinopathies, as well as the treatment of inflammatory diseases and conditions such as rheumatoid arthritis.
  • the compounds may also activate the growth factors and could thus be used in cardiovascular treatments.
  • the compounds of the invention additionally have utility as anticoagulant or antithrombotic agents.
  • the compounds can therefore be used for both the prophylaxis and treatment of many thrombotic and cardiovascular diseases, the most notable of these being deep venous thrombosis, pulmonary embolism, thrombotic stroke, peripheral arterial thrombosis, unstable angina and myocardial infarction.
  • the compounds ofthe invention are also suited for the treatment or prevention of infection resulting from non-viral microbial pathogens which utilise HS as an attachment/entry, for example, Plasmodium (malaria). Most notable is the inhibition by the compounds ofthe invention ofthe cell-to-cell spread of HSN-1 and HSN-2. Having broadly described the invention, non-limiting examples ofthe compounds, their synthesis, and their biological activities, will now be given with reference to the accompanying Tables which will be briefly described in the following section of this specification.
  • the pure fractions were evaporated and co-evaporated (H 2 O) and then lyophilised (H 2 O) to yield the sulfated product.
  • H 2 O lyophilised
  • the product was passed through an ion- exchange resin column (AG ® -50W-X8, Na + form, 1x4 cm, deionized H O, 15 mL) in order to transfer the product uniformly into the sodium salt form.
  • the solution collected was evaporated and lyophilised to give the final product as a colourless glass or white power.
  • Size exclusion chromatography Size exclusion chromatography (SEC) was performed over Bio-Gel P-2 in a 5 x 100 cm column with a flow rate of 2.8 mL/min of 0.1 M NH 4 HCO 3 , collecting 2.8 min (7.8 mL) fractions. Fractions were analysed for carbohydrate content by TLC (charring) and/or for poly- charged species by the dimethyl methylene blue test, and then for purity by capillary electrophoresis (CE) and those deemed to be free of salt were pooled and lyophilised.
  • TLC charring
  • CE capillary electrophoresis
  • Dimethyl methylene blue Test Dimethyl methylene blue (DMB) reagent was prepared by dissolving 16 mg of DMB in 1 L of deionized water containing 3.04 g of glycine, 2.37 g of NaCI. 0.1 M HC1 (95 ml) was added to adjust the pH to 3.0. The stock solution was stored in a brown coloured bottle at r.t. (the solution was stable for at least 3 months under such conditions).
  • a 96-well microtitre plate was loaded with 10 ⁇ L of fraction solution per well. 55 ⁇ L of DMB stock solution was added into each used well. An instant colour change from blue to pink indicated the presence of polycharged species, i.e., sulfated product fractions.
  • General procedure for NIS glycosylations Glycosyl acceptor (1 eq), thioglycoside donor (1.1 eq), 500 mg of freshly activated powdered 3 A molecular sieves and 10 mL of dry DCM were stirred at -20° for 20 min before 1.3 eq of NIS and 1 drop of TfOH were added.
  • the mixture was loaded in a miniclave (B ⁇ chi AG, Uster/Switzerland) and stirred under hydrogen atmosphere (50 psi) for 2-10 h. Alternatively, the mixture was bubbled with hydrogen gas for 1 h then stirred at r.t. under 1 atmosphere of hydrogen for 1-5 days. The reaction was monitored by TLC (EtOAc or MeCN-water 10:1). The mixture was filtered and rinsed with MeOH, or EtOH. The filtrate was evaporated and dried under high vacuum, checked by 1H NMR, freeze- dried and used directly for sulfonation.
  • Step a Methyl 3,4,6-tri- -acetyl-2-0-benzyl- -O-galactopyranosyl-(l- ⁇ 4)-2,3,6- tri-O-benzyl- ⁇ -O-glucopyranoside.
  • Step c Methyl 2-0-sulfo- -O-galactopyranosyl-(l ⁇ 4)-2,3,6-tri-0-sulfo ⁇ -O-glucopyranoside, tetrasodium salt (PG2038)
  • the above disaccharide (32.2 mg, 0.667 mmol), was subjected to the standard sulfonation and deacetylation procedures to give the title compound as a white foam (4.0 mg, 7.8%, 96% purity, CE: 7.18 min).
  • Example 2 PG2046 and PG2047 Step a: 2-Azido-3, 4, 6-tri-0-benzoyl-2-deoxy-a-D-glucopyranosyl-(l ⁇ 4)-l, 6-anhydro-2-azido- 2-deoxy-3-0-benzyl- -D-glucopyranose
  • Step b 2-Deoxy-2-sulfamido-a-O-glucopyranosyl-(l ⁇ 4)-l, 6-anhydro-2-deoxy-2-sulfamido-3- 0-benzyl- -O-glucopyranose, disodium salt (PG2046)
  • Pearlman's catalyst 11 mg
  • ammonium formate 300 mg
  • Step c 2-Deoxy-2-sulfamido-a-O-glucopyranosyl-(l ⁇ 4)-l, 6-anhydro-2-deoxy-2-sulfamido- - O-glucopyranoside, disodium salt
  • PG2047 A mixture of 2-deoxy-2-sulfamido-a-O-glucopyranosyl-(l ⁇ 4)-l, 6-anhydro-2-deoxy-2- sulfamido-3-O-benzyl- ⁇ -O-glucopyranoside, disodium salt (12.9 mg, 20.8 ⁇ mol) and Pearlman's catalyst (5 mg) in purified water (2 mL) was subjected to 50 psi H 2 overnight.
  • Example 3 PG2039 and PG2037 Step a: Methyl 3,4-di-0-acetyl-2,6-di-0-benzyl-a-O-galactopyranosyl-(l ⁇ 4)-2,3,6- tri-0-benzyl- -O-glucopyranoside Methyl 2,3,6-tri-O-benzyl- ⁇ -O-glucopyranoside (287 mg; 618 ⁇ mol), 302 mg (618 ⁇ mol) of ethyl 3,4-di-0-acetyl-2,6-0-dibenzyl-l-thio-fi-D-galactopyranoside [21] and 700 mg of 3 A molecular sieves were subjected to the general NIS glycosylation procedure using 181 mg (803 ⁇ mol
  • Step b Methyl 3,4-di-0-acetyl-a-O-galactopyranosyl-(l ⁇ 4)- -D-glucopyranoside.
  • methyl 3,4-di-0-acetyl-2,6-di- 0-benzyl-a-O-galactopyranosyl-(l ⁇ 4)-2,3,6-tri-0-benzyl-fi-O-glucopyranoside 88 mg, 98.8 ⁇ mol
  • Step c Methyl 2,6-di-0-sulfo-a-O-galactopyranosyl-(l ⁇ 4)-2,3,6-tri-0-sulfo- -O- glucopyranoside, pentasodium salt (PG2039)
  • PG2039 pentasodium salt
  • 42 mg (95.4 ⁇ mol) of methyl 3,4-di-0-acetyl-a-O-galactopyranosyl-(l ⁇ 4)- -O-glucopyranoside was converted to the title compound as a white powder (14.8 mg, 18%, CE: 6.12 min).
  • Step d Methyl 2,6-di-0-benzyl-3,4-di-0-methyl ⁇ -O-galactopyranosyl-(l ⁇ 4)-2,3,6-tri-0- benzyl- -O-glucopyranoside
  • methyl 3,4-di-O- acetyl-2, 6-di-0-benzyl-a-O-galactopyranosyl-(l ⁇ 4)-2, 3, 6-tri-O-benzyl- ⁇ -O-glucopyranoside 72 mg, 80.8 ⁇ mol
  • Step e Methyl 3,4-di-0-methyl-a-O-galactopyranosyl-(l ⁇ 4)-fi-O-glucopyranoside
  • methyl 2,6-di-0-benzyl-3,4-di-0- methyl-a-O-galactopyranosyl-(l ⁇ 4)-2,3,6-tri-0-benzyl- -O-glucopyranoside (62.1 mg, 75.1 ⁇ mol) was deprotected to give the title compound as colourless gum (28 mg, 97%).
  • Stepf Methyl 3, 4-di-0-methyl-2, 6-di-0-sulfo-a-O-galactopyranosyl-(l ⁇ 4)-2, 3, 6-tri-O- sulfo-fi-O-glucopyranoside, pentasodium salt (PG2037) Following the standard sulfonation procedure, methyl 3,4-di-O-methyl-a-O- galactopyranosyl-(l ⁇ 4)- -O-glucopyranoside (28 mg, 72.8 ⁇ mol) gave the title compound (3.2 mg, 4.9%).
  • R D CH 2 OS0 3 Na
  • R G H 2038 77.9 ⁇ M 2.10 mM 368 ⁇ M
  • R A OMe
  • R F ,R H OH
  • R B ,Rc,R E ,R OS0 3 Na 2039 21.8 ⁇ M 3.50 mM 1.27 mM
  • R ⁇ NHCOCH 2 ⁇ Ph(2,4-di-Cl);
  • R Mj R N ,R Q OS ⁇ 3 Na; 2096 35.7 ⁇ M 141 ⁇ M 20.4 ⁇ M
  • R s * CH 2 OS0 3 Na;
  • R P ,RR H
  • Rj/R K H/OMe (anomeric mixture);
  • RS-RN -CH 2 0-; 2165 1.13 mM ⁇ 25.5 mM 1.70 mM
  • R M OBn;
  • R Q OS0 3 Na;
  • RJ,R K ,RL,RO,RP,RR H 2166 3.60 mM 1.90 mM 2.70 mM
  • R ⁇ l,2,3,4-tetra-0-sodi ⁇ un sulfonato-D-glucuronoyl
  • R x COCH 2 C(CH 3 ) 2 CH 2 CO; 2015 2.94 ⁇ M 7.56 ⁇ M 267 nM sulfo- ⁇ -D-mannopyranos- 1 -0-yl)-propyl

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Abstract

L'invention concerne des composés qui sont mis au point pour imiter la structure des GAG; des procédés de préparation de ces composés; des compositions renfermant ces composés; ainsi que l'utilisation de ces composés et compositions dans le traitement anti-angiogénique, antimétastatique, anti-inflammatoire, anticoagulant, antithrombotique, et/ou antimicrobien d'un sujet mammifère.
EP04802102A 2003-12-23 2004-12-21 Composes mimetiques du glycosaminoglycane (gag) Withdrawn EP1699806A1 (fr)

Applications Claiming Priority (2)

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AU2003907107A AU2003907107A0 (en) 2003-12-23 Glycosaminoglycan (GAG) Mimetics
PCT/AU2004/001800 WO2005061523A1 (fr) 2003-12-23 2004-12-21 Composes mimetiques du glycosaminoglycane (gag)

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CA (1) CA2551181A1 (fr)
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CA2723197C (fr) 2008-05-02 2017-09-19 Seattle Genetics, Inc. Procede et compositions pour preparer des anticorps et des derives d'anticorps avec une fucosylation centrale reduite
US8791245B2 (en) 2008-10-03 2014-07-29 Glycan Bioscience LLC Anionic conjugates of glycosylated bacterial metabolite
JO2870B1 (en) 2008-11-13 2015-03-15 ميرك شارب اند دوهم كورب Amino Tetra Hydro Pirans as Inhibitors of Peptide Dipeptide IV for the Treatment or Prevention of Diabetes
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JP5777200B2 (ja) * 2010-11-05 2015-09-09 学校法人常翔学園 抗デングウイルス剤
CN102775450B (zh) * 2012-07-03 2015-04-08 华东师范大学 一种1,6-脱水-2-叠氮-2-脱氧-β-D-吡喃葡萄糖的制备方法
EP2887947B1 (fr) 2012-08-23 2019-06-05 Seattle Genetics, Inc. Analogues de la fucose destinées au traitement de la drépanocytose
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WO2005061523A1 (fr) 2005-07-07
RU2006126718A (ru) 2008-01-27
MXPA06007194A (es) 2007-01-19
CN1906203A (zh) 2007-01-31
KR20060129296A (ko) 2006-12-15
BRPI0417750A (pt) 2007-04-10
NO20063366L (no) 2006-07-20
CA2551181A1 (fr) 2005-07-07
JP2007515434A (ja) 2007-06-14
IL176474A0 (en) 2006-10-05

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